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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 97 %P 1407-1419 %8 2024 Jan 30 %G eng %N 3 %R 10.3233/JAD-230880 %0 Journal Article %J J Alzheimers Dis %D 2024 %T A Continuous Extension of Gene Set Enrichment Analysis Using the Likelihood Ratio Test Statistics Identifies Vascular Endothelial Growth Factor as a Candidate Pathway for Alzheimer's Disease via ITGA5. %A Mahzarnia, Ali %A Lutz, Michael W %A Badea, Alexandra %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Biomarkers %K Cognitive Dysfunction %K Humans %K Likelihood Functions %K tau Proteins %K Vascular Endothelial Growth Factor A %X

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 97 %P 1841-1850 %8 2024 Feb 13 %G eng %N 4 %R 10.3233/JAD-230718 %0 Journal Article %J J Alzheimers Dis %D 2024 %T Improving Healthcare Quality and Clinical Outcomes for Persons with Dementia in the Sub-Acute Hospital Through Person-Centered Care Practice. %A Chenoweth, Lynn %A Burley, Claire %A Cook, Jacquelene %A Cheah, Seong-Leang %A Reyes, Patricia %A Maiden, Genevieve %A McGuire, Jane %A McCade, Donna %A Brodaty, Henry %A Sukhapure, Mayouri %A Harrison, Fleur %A Williams, Anna %X

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

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

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 97 %P 953-961 %8 2024 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/38217596?dopt=Abstract %R 10.3233/JAD-230604 %0 Journal Article %J J Alzheimers Dis %D 2024 %T Mendelian Randomization of Blood Metabolites Suggests Circulating Glutamine Protects Against Late-Onset Alzheimer's Disease. %A Ramadan, Ferris A %A Arani, Gayatri %A Jafri, Ayan %A Thompson, Tingting %A Bland, Victoria L %A Renquist, Benjamin %A Raichlen, David A %A Alexander, Gene E %A Klimentidis, Yann C %X

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

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

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

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

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

%B J Alzheimers Dis %8 2024 Mar 13 %G eng %R 10.3233/JAD-231063 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Alzheimer's Disease and Neurosyphilis: Meaningful Commonalities and Differences of Clinical Phenotype and Pathophysiological Biomarkers. %A Milano, Chiara %A Hoxhaj, Domeniko %A Del Chicca, Marta %A Pascazio, Alessia %A Paoli, Davide %A Tommasini, Luca %A Vergallo, Andrea %A Pizzanelli, Chiara %A Tognoni, Gloria %A Nuti, Angelo %A Ceravolo, Roberto %A Siciliano, Gabriele %A Hampel, Harald %A Baldacci, Filippo %X

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

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

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

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

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

%B J Alzheimers Dis %V 94 %P 611-625 %8 2023 Jul 18 %G eng %N 2 %R 10.3233/JAD-230170 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Alzheimer's Disease Pathology Outside of the Cerebrum Is Related to a Higher Odds of Dementia. %A Buchman, Aron S %A Leurgans, Sue E %A Kim, Namhee %A Agrawal, Sonal %A Oveisgharan, Shahram %A Zammit, Andrea R %A VanderHorst, Veronique %A Nag, Sukrit %A Bennett, David A %X

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 94 %P 497-507 %8 2023 %G eng %N 2 %R 10.3233/JAD-230099 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Associations Between Ambient Air Pollution and Cognitive Abilities from Midlife to Early Old Age: Modification by APOE Genotype. %A Franz, Carol E %A Gustavson, Daniel E %A Elman, Jeremy A %A Fennema-Notestine, Christine %A Hagler, Donald J %A Baraff, Aaron %A Tu, Xin M %A Wu, Tsung-Chin %A De Anda, Jaden %A Beck, Asad %A Kaufman, Joel D %A Whitsel, Nathan %A Finch, Caleb E %A Chen, Jiu-Chiuan %A Lyons, Michael J %A Kremen, William S %X

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

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

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

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

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

%B J Alzheimers Dis %V 93 %P 193-209 %8 2023 May 02 %G eng %N 1 %R 10.3233/JAD-221054 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Associations of the Harvard Automated Phone Task and Alzheimer's Disease Pathology in Cognitively Normal Older Adults: Preliminary Findings. %A Gonzalez, Christopher %A Mimmack, Kayden J %A Amariglio, Rebecca E %A Becker, J Alex %A Chhatwal, Jasmeer P %A Fitzpatrick, Colleen D %A Gatchel, Jennifer R %A Johnson, Keith A %A Katz, Zoe S %A Kuppe, Madeline K %A Locascio, Joseph J %A Udeogu, Onyinye J %A Papp, Kathryn V %A Premnath, Pranitha %A Properzi, Michael J %A Rentz, Dorene M %A Schultz, Aaron P %A Sperling, Reisa A %A Vannini, Patrizia %A Wang, Sharon %A Marshall, Gad A %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Amyloid %K Amyloid beta-Peptides %K Amyloidogenic Proteins %K Cognitive Dysfunction %K Entorhinal Cortex %K Humans %K Positron-Emission Tomography %K tau Proteins %X

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

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

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

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

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

%B J Alzheimers Dis %V 94 %P 217-226 %8 2023 %G eng %N 1 %R 10.3233/JAD-220885 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Cardiorespiratory Fitness Attenuates the Deleterious Effects of Sleep Apnea on Cerebral Structure and Perfusion in the Wisconsin Sleep Cohort Study. %A Edmunds, Kyle J %A Driscoll, Ira %A Hagen, Erika W %A Barnet, Jodi H %A Ravelo, Laurel A %A Plante, David T %A Gaitán, Julian M %A Lose, Sarah R %A Motovylyak, Alice %A Bendlin, Barbara B %A Okonkwo, Ozioma C %A Peppard, Paul E %X

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

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

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

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

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

%B J Alzheimers Dis %V 95 %P 427-435 %8 2023 Sep 12 %G eng %N 2 %R 10.3233/JAD-220910 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Cerebral Gray and White Matter Monogalactosyl Diglyceride Levels Rise with the Progression of Alzheimer's Disease. %A Blusztajn, Jan Krzysztof %A Aytan, Nurgul %A Rajendiran, Thekkelnaycke %A Mellott, Tiffany J %A Soni, Tanu %A Burant, Charles F %A Serrano, Geidy E %A Beach, Thomas G %A Lin, Honghuang %A Stein, Thor D %X

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 96 %P 113-124 %8 2023 %G eng %N 1 %R 10.3233/JAD-230238 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Cleveland Clinic Cognitive Battery (C3B): Normative, Reliability, and Validation Studies of a Self-Administered Computerized Tool for Screening Cognitive Dysfunction in Primary Care. %A Rao, Stephen M %A Galioto, Rachel %A Sokolowski, Megan %A Pierce, Madelyn %A Penn, Lisa %A Sturtevant, Anna %A Skugor, Blazenka %A Anstead, Brent %A Leverenz, James B %A Schindler, David %A Blum, David %A Alberts, Jay L %A Posk, Lori %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Cognition %K Cognitive Dysfunction %K Humans %K Middle Aged %K Neuropsychological Tests %K Primary Health Care %K Reproducibility of Results %K Young Adult %X

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

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

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

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

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

%B J Alzheimers Dis %V 92 %P 1051-1066 %8 2023 %G eng %N 3 %R 10.3233/JAD-220929 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Cognition and Cognitive Changes in a Low-Income Sub-Saharan African Aging Population. %A Kohler, Iliana V %A Kämpfen, Fabrice %A Bandawe, Chiwoza %A Kohler, Hans-Peter %X

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

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

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

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

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

%B J Alzheimers Dis %V 95 %P 195-212 %8 2023 Aug 29 %G eng %N 1 %R 10.3233/JAD-230271 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The Complexity of Nutritional Problems in Persons with Dementia: Expanding a Theoretical Model. %A van Buuren, Cornelia Pieternella %A van der Steen, Jenny Theodora %A Olthof-Nefkens, Maria %A Bakker, Christian %A Koopmans, Raymond Theodorus Catherina Maria %A Perry, Marieke %A Kalf, Johanna Gezina %K Attitude of Health Personnel %K Dementia %K Focus Groups %K Health Personnel %K Humans %K Nursing Homes %X

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

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

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 94 %P S67-S85 %8 2023 %G eng %N s1 %R 10.3233/JAD-221020 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Is Dementia Associated with COVID-19 Mortality? A Multicenter Retrospective Cohort Study Conducted in 50 Hospitals in Germany. %A Kostev, Karel %A Gessler, Nele %A Wohlmuth, Peter %A Arnold, Dirk %A Bein, Berthold %A Bohlken, Jens %A Herrlinger, Klaus %A Jacob, Louis %A Koyanagi, Ai %A Nowak, Lorenz %A Smith, Lee %A Wesseler, Claas %A Sheikhzadeh, Sara %A Wollmer, Marc Axel %K COVID-19 %K COVID-19 Testing %K Dementia %K Germany %K Hospitalization %K Hospitals %K Humans %K Mortality %K Retrospective Studies %X

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

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

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

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

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

%B J Alzheimers Dis %V 91 %P 719-726 %8 2023 %G eng %N 2 %R 10.3233/JAD-220918 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Diagnostic Performance of Cerebrospinal Fluid Neurofilament Light Chain and Soluble Amyloid-β Protein Precursor β in the Subcortical Small Vessel Type of Dementia. %A Axelsson Andrén, Elin %A Kettunen, Petronella %A Bjerke, Maria %A Rolstad, Sindre %A Zetterberg, Henrik %A Blennow, Kaj %A Wallin, Anders %A Svensson, Johan %X

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

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

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

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

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 95 %P 415-426 %8 2023 Sep 12 %G eng %N 2 %R 10.3233/JAD-230162 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Early Life Stress Enhances Cognitive Decline and Alters Synapse Function and Interneuron Numbers in Young Male APP/PS1 Mice. %A Brosens, Niek %A Samouil, Dimitris %A Stolker, Sabine %A Katsika, Efthymia Vasilina %A Weggen, Sascha %A Lucassen, Paul J %A Krugers, Harm J %K Adverse Childhood Experiences %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Cognitive Dysfunction %K Disease Models, Animal %K Interneurons %K Male %K Mice %K Mice, Transgenic %K Plaque, Amyloid %K Presenilin-1 %K Synapses %X

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

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

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

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

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

%B J Alzheimers Dis %V 96 %P 1097-1113 %8 2023 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/37980670?dopt=Abstract %R 10.3233/JAD-230727 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Effect of Metabolic Syndrome Risk Factors on Processing Speed and Executive Function in Three Racialized Groups. %A Bouges, Shenikqua %A Fischer, Barbara %A Norton, Derek L %A Wyman, Mary F %A Lambrou, Nickolas %A Zuelsdorff, Megan %A Van Hulle, Carol A %A Ennis, Gilda E %A James, Taryn T %A Johnson, Adrienne L %A Chin, Nathaniel %A Carlsson, Cynthia M %A Gleason, Carey E %X

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 96 %P 245-260 %8 2023 %G eng %N 1 %R 10.3233/JAD-230305 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The Efficacy and Safety of Physiotherapy in People with Dementia: A Systematic Review. %A Saúde, Alexandra %A Bouça-Machado, Raquel %A Leitão, Mariana %A Benedetti, Andrea %A Ferreira, Joaquim J %K Cognitive Dysfunction %K Dementia %K Humans %K Physical Therapy Modalities %K Resistance Training %X

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

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

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

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

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

%B J Alzheimers Dis %V 94 %P 909-917 %8 2023 %G eng %N 3 %R 10.3233/JAD-230463 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Elevated Pure Tone Thresholds Are Associated with Altered Microstructure in Cortical Areas Related to Auditory Processing and Attentional Allocation. %A McEvoy, Linda K %A Bergstrom, Jaclyn %A Hagler, Donald J %A Wing, David %A Reas, Emilie T %X

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

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

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

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

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

%B J Alzheimers Dis %V 96 %P 1163-1172 %8 2023 Nov 21 %G eng %N 3 %R 10.3233/JAD-230767 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Epileptic Prodromal Alzheimer's Disease Treated with Antiseizure Medications: Medium-Term Outcome of Seizures and Cognition. %A Hautecloque-Raysz, Geoffroy %A Sellal, François %A Bousiges, Olivier %A Phillipi, Nathalie %A Blanc, Frédéric %A Cretin, Benjamin %X

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

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

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

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

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

%B J Alzheimers Dis %V 94 %P 1057-1074 %8 2023 Aug 01 %G eng %N 3 %R 10.3233/JAD-221197 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Extracellular Tau Oligomers Damage the Axon Initial Segment. %A Best, Merci N %A Lim, Yunu %A Ferenc, Nina N %A Kim, Nayoung %A Min, Lia %A Wang, Dora Bigler %A Sharifi, Kamyar %A Wasserman, Anna E %A McTavish, Sloane A %A Siller, Karsten H %A Jones, Marieke K %A Jenkins, Paul M %A Mandell, James W %A Bloom, George S %X

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 93 %P 1135-1151 %8 2023 May 30 %G eng %N 3 %R 10.3233/JAD-221113 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Hippocampal Volume and Episodic Associative Memory Identify Memory Risk in Subjective Cognitive Decline Individuals in the CIMA-Q Cohort, Regardless of Cognitive Reserve Level and APOE4 Status. %A Caillaud, Marie %A Maltezos, Samantha %A Hudon, Carol %A Mellah, Samira %A Belleville, Sylvie %X

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

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

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 92 %P 1229-1239 %8 2023 Apr 18 %G eng %N 4 %R 10.3233/JAD-221031 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The Impact of Routine Vaccinations on Alzheimer's Disease Risk in Persons 65 Years and Older: A Claims-Based Cohort Study using Propensity Score Matching. %A Harris, Kristofer %A Ling, Yaobin %A Bukhbinder, Avram S %A Chen, Luyao %A Phelps, Kamal N %A Cruz, Gabriela %A Thomas, Jenna %A Kim, Yejin %A Jiang, Xiaoqian %A Schulz, Paul E %X

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

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

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

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

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

%B J Alzheimers Dis %V 95 %P 703-718 %8 2023 Sep 12 %G eng %N 2 %R 10.3233/JAD-221231 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Implication of Circulating Extracellular Vesicles-Bound Amyloid-β42 Oligomers in the Progression of Alzheimer's Disease. %A M.R. BenKhedher %A Haddad, Mohamed %A Fülöp, Tamás %A Laurin, Danielle %A Ramassamy, Charles %X

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

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

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

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

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

%B J Alzheimers Dis %V 96 %P 813-825 %8 2023 Nov 07 %G eng %N 2 %R 10.3233/JAD-230823 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Linking Air Pollution Exposure to Blood-Based Metabolic Features in a Community-Based Aging Cohort with and without Dementia. %A Kalia, Vrinda %A Kulick, Erin R %A Vardarajan, Badri %A Gu, Yian %A Manly, Jennifer J %A Elkind, Mitchell S V %A Kaufman, Joel D %A Jones, Dean P %A Baccarelli, Andrea A %A Mayeux, Richard %A Kioumourtzoglou, Marianthi-Anna %A Miller, Gary W %K Aged %K Aging %K Air Pollutants %K Air Pollution %K Dementia %K Environmental Exposure %K Humans %K Nitrogen Dioxide %K Particulate Matter %X

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

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

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

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

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

%B J Alzheimers Dis %V 96 %P 1025-1040 %8 2023 Nov 21 %G eng %N 3 %R 10.3233/JAD-230122 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Lithium Provides Broad Therapeutic Benefits in an Alzheimer's Disease Mouse Model. %A Wiseman, Alyssa L %A Briggs, Clark A %A Peritt, Ariel %A Kapecki, Nicolas %A Peterson, Daniel A %A Shim, Seong S %A Stutzmann, Grace E %K Alzheimer Disease %K Animals %K Calcium %K Disease Models, Animal %K Hippocampus %K Lithium %K Mice %K Mice, Transgenic %K Nitric Oxide Synthase Type I %K tau Proteins %X

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

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

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

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

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

%B J Alzheimers Dis %V 91 %P 273-290 %8 2023 %G eng %N 1 %R 10.3233/JAD-220758 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Longitudinal White and Gray Matter Response to Precision Medicine-Guided Intervention for Alzheimer's Disease. %A Chwa, Won Jong %A Raji, Cyrus A %A Toups, Kat %A Hathaway, Ann %A Gordon, Deborah %A Chung, Henrianna %A Boyd, Alan %A Hill, Benjamin D %A Hausman-Cohen, Sharon %A Attarha, Mouna %A Jarrett, Michael %A Bredesen, Dale E %K Alzheimer Disease %K Atrophy %K Brain %K Cognitive Dysfunction %K Gray Matter %K Humans %K Magnetic Resonance Imaging %K Precision Medicine %K White Matter %X

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

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

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

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

%B J Alzheimers Dis %V 96 %P 1051-1058 %8 2023 %G eng %N 3 %R 10.3233/JAD-230481 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Medial Temporal Lobe Atrophy in Predementia Alzheimer's Disease: A Longitudinal Multi-Site Study Comparing Staging and A/T/N in a Clinical Research Cohort. %A Jarholm, Jonas Alexander %A Bjørnerud, Atle %A Dalaker, Turi Olene %A Akhavi, Mehdi Sadat %A Kirsebom, Bjørn Eivind %A Pålhaugen, Lene %A Nordengen, Kaja %A Grøntvedt, Gøril Rolfseng %A Nakling, Arne %A Kalheim, Lisa F %A Almdahl, Ina S %A Tecelao, Sandra %A Fladby, Tormod %A Selnes, Per %K Alzheimer Disease %K Atrophy %K Cognitive Dysfunction %K Entorhinal Cortex %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Temporal Lobe %X

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

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

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

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

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

%B J Alzheimers Dis %V 94 %P 259-279 %8 2023 %G eng %N 1 %R 10.3233/JAD-221274 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Microglial Imaging in Alzheimer's Disease and Its Relationship to Brain Amyloid: A Human 18F-GE180 PET Study. %A Yang, Zhengshi %A Banks, Sarah J %A Ritter, Aaron R %A Cummings, Jeffrey L %A Sreenivasan, Karthik %A Kinney, Jefferson W %A Caldwell, Jessica K %A Wong, Christina G %A Miller, Justin B %A Cordes, Dietmar %X

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

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

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

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

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

%B J Alzheimers Dis %V 96 %P 1505-1514 %8 2023 Dec 05 %G eng %N 4 %R 10.3233/JAD-230631 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Midlife Neuropsychological Profiles and Associated Vascular Risk: The Bogalusa Heart Study. %A De Anda-Duran, Ileana %A Kolachalama, Vijaya B %A Carmichael, Owen T %A Hwang, Phillip H %A Fernandez, Camilo %A Au, Rhoda %A Bazzano, Lydia A %A Libon, David J %X

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 91 %P 471-481 %8 2023 %G eng %N 1 %R 10.3233/JAD-220889 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Mitochondria Profoundly Influence Apolipoprotein E Biology. %A Gabrielli, Alexander P %A Weidling, Ian %A Ranjan, Amol %A Wang, Xiaowan %A Novikova, Lesya %A Chowdhury, Subir Roy %A Menta, Blaise %A Berkowicz, Alexandra %A Wilkins, Heather M %A Peterson, Kenneth R %A Swerdlow, Russell H %K Alzheimer Disease %K Apolipoproteins E %K Biology %K Cell Line, Tumor %K DNA, Mitochondrial %K Humans %K Mitochondria %K Neuroblastoma %K RNA, Messenger %K Transcription Factors %X

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 92 %P 153-169 %8 2023 %G eng %N 1 %R 10.3233/JAD-221131 %0 Journal Article %J J Alzheimers Dis %D 2023 %T MRI Visible Perivascular Spaces and the Risk of Incident Mild Cognitive Impairment in a Community Sample. %A Pase, Matthew P %A Pinheiro, Adlin %A Rowsthorn, Ella %A Demissie, Serkalem %A Hurmez, Saoresho %A Aparicio, Hugo %A Rodriguez-Lara, Frances %A Gonzales, Mitzi M %A Beiser, Alexa %A DeCarli, Charles %A Seshadri, Sudha %A Romero, Jose Rafael %X

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

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

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 96 %P 683-693 %8 2023 Nov 07 %G eng %N 2 %R 10.3233/JAD-230629 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Neural Stem Cells in the Treatment of Alzheimer's Disease: Current Status, Challenges, and Future Prospects. %A Chen, Xiaokun %A Jiang, Shenzhong %A Wang, Renzhi %A Bao, Xinjie %A Li, Yongning %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Cholinergic Neurons %K Disease Models, Animal %K Humans %K Neural Stem Cells %X

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

%B J Alzheimers Dis %V 94 %P S173-S186 %8 2023 %G eng %N s1 %R 10.3233/JAD-220721 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Neuroprotective Properties of Eudesmin on a Cellular Model of Amyloid-β Peptide Toxicity. %A Castillo, Carolina %A Bravo-Arrepol, Gastón %A Wendt, Aline %A Saez-Orellana, Francisco %A Millar, Camila %A Burgos, Carlos F %A Gavilán, Javiera %A Pacheco, Carla %A Ahumada-Rudolph, Ramón %A Napiórkowska, Mariola %A Pérez, Claudia %A Becerra, José %A Fuentealba, Jorge %A Cabrera-Pardo, Jaime R %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Lignans %K Mice %K Neuroprotective Agents %K PC12 Cells %K Rats %X

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

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

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

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

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

%B J Alzheimers Dis %V 94 %P S97-S108 %8 2023 %G eng %N s1 %R 10.3233/JAD-220935 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Observed Improvement in Cognition During a Personalized Lifestyle Intervention in People with Cognitive Decline. %A Sandison, Heather %A Callan, Nini G L %A Rao, Rammohan V %A Phipps, John %A Bradley, Ryan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K California %K Cognition %K Cognitive Dysfunction %K Diet, Healthy %K Dietary Supplements %K Disease Progression %K Exercise %K Feasibility Studies %K Female %K Healthy Lifestyle %K Humans %K Infections %K Male %K Memory %K Middle Aged %K Nutritional Status %K Pragmatic Clinical Trials as Topic %K Reproducibility of Results %K Stress, Psychological %K Time Factors %K Treatment Outcome %K Verbal Behavior %X

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

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

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

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

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

%B J Alzheimers Dis %V 94 %P 993-1004 %8 2023 %G eng %N 3 %R 10.3233/JAD-230004 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Patterns of Aging Changes in Bodyweight May Predict Alzheimer's Disease. %A Ukraintseva, Svetlana %A Duan, Hongzhe %A Holmes, Rachel %A Bagley, Olivia %A Wu, Deqing %A Yashkin, Arseniy %A Kulminski, Alexander %A Akushevich, Igor %A Whitson, Heather %A Stallard, Eric %A Yashin, Anatoliy %A Arbeev, Konstantin %X

Relationships between patterns of aging-changes in bodyweight and AD are not fully understood. We compared mean age-trajectories of weight between those who did and did not develop late-onset-AD, and evaluated impact of age at maximum weight (AgeMax), and slope of decline in weight, on AD risk. Women with late-onset-AD had lower weight three or more decades before AD onset, and ∼10 years younger AgeMax, compared to AD-free women. APOE4 carriers had younger AgeMax and steeper slope. Older AgeMax and flatter slope predicted lower AD risk. Premature decline in weight could be a sign of accelerated physical aging contributing to AD.

%B J Alzheimers Dis %V 97 %P 163-170 %8 2024 Jan 02 %G eng %N 1 %R 10.3233/JAD-220998 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Plasma Amyloid-β Homeostasis Is Associated with Body Mass Index and Weight Loss in People with Overweight and Obesity. %A Brook, Emily S %A D'Alonzo, Zachary J %A Lam, Virginie %A Chan, Dick %A Dhaliwal, Satvinder Singh %A Watts, Geraldb F %A Mamo, John C L %A Takechi, Ryusuke %X

BACKGROUND: Obesity is linked to a higher incidence of Alzheimer's disease (AD). Studies show that plasma amyloid-β (Aβ) dyshomeostasis, particularly low 42/40 ratio indicates a heightened risk for developing AD. However, the relationship between body mass index (BMI) and circulating plasma Aβ has not been extensively studied.

OBJECTIVE: We hypothesized that people with a high BMI have altered plasma Aβ homeostasis compared with people with a lower BMI. We also tested whether reducing BMI by calorie-restriction could normalize plasma concentrations of Aβ.

METHODS: Plasma concentrations of Aβ 40, Aβ 42, and Aβ 42/40 ratio were measured in 106 participants with BMIs classified as lean, overweight, or obese. From this cohort, twelve participants with overweight or obese BMIs entered a 12-week calorie-restriction weight loss program. We then tested whether decreasing BMI affected plasma Aβ concentrations.

RESULTS: Plasma Aβ 42/40 ratio was 17.54% lower in participants with an obese BMI compared to lean participants (p <  0.0001), and 11.76% lower compared to participants with an overweight BMI (p <  0.0001). The weight loss regimen decreased BMI by an average of 4.02% (p = 0.0005) and was associated with a 6.5% decrease in plasma Aβ 40 (p = 0.0425). However, weight loss showed negligible correlations with plasma Aβ 40, Aβ 42, and Aβ 42/40 ratio.

CONCLUSION: Obesity is associated with aberrant plasma Aβ homeostasis which may be associated with an increased risk for AD. Weight loss appears to lower Aβ 40, but large-scale longitudinal studies in addition to molecular studies are required to elucidate the underlying mechanisms of how obesity and weight loss influence plasma Aβ homeostasis.

%B J Alzheimers Dis %V 93 %P 653-664 %8 2023 May 16 %G eng %N 2 %R 10.3233/JAD-220529 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Plasma Glial Fibrillary Acidic Protein Is Associated with 18F-SMBT-1 PET: Two Putative Astrocyte Reactivity Biomarkers for Alzheimer's Disease. %A Chatterjee, Pratishtha %A Doré, Vincent %A Pedrini, Steve %A Krishnadas, Natasha %A Thota, Rohith %A Bourgeat, Pierrick %A Ikonomovic, Milos D %A Rainey-Smith, Stephanie R %A Burnham, Samantha C %A Fowler, Christopher %A Taddei, Kevin %A Mulligan, Rachel %A Ames, David %A Masters, Colin L %A Fripp, Jurgen %A Rowe, Christopher C %A Martins, Ralph N %A Villemagne, Victor L %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Astrocytes %K Biomarkers %K Brain %K Cognitive Dysfunction %K Glial Fibrillary Acidic Protein %K Humans %K Positron-Emission Tomography %K tau Proteins %X

BACKGROUND: Astrocyte reactivity is an early event along the Alzheimer's disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD.

OBJECTIVE: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers.

METHODS: Plasma GFAP and Aβ were measured using the Simoa® platform in participants who underwent brain 18F-SMBT-1 and Aβ-PET imaging, comprising 54 healthy control (13 Aβ-PET+ and 41 Aβ-PET-), 11 mild cognitively impaired (3 Aβ-PET+ and 8 Aβ-PET-) and 6 probable AD (5 Aβ-PET+ and 1 Aβ-PET-) individuals. Linear regressions were used to assess associations of interest.

RESULTS: Plasma GFAP was associated with 18F-SMBT-1 signal in brain regions prone to early Aβ deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, and soluble Aβ (plasma Aβ42/40 ratio), plasma GFAP was associated with 18F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ɛ4 genotype and insoluble Aβ (Aβ-PET), plasma GFAP was associated with 18F-SMBT-1 signal in the SG.

CONCLUSION: There is an association between plasma GFAP and regional 18F-SMBT-1 PET, and this association appears to be dependent on brain Aβ load.

%B J Alzheimers Dis %V 92 %P 615-628 %8 2023 %G eng %N 2 %R 10.3233/JAD-220908 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Posttraumatic Stress and Traumatic Brain Injury: Cognition, Behavior, and Neuroimaging Markers in Vietnam Veterans. %A Marcolini, Sofia %A Rojczyk, Philine %A Seitz-Holland, Johanna %A Koerte, Inga K %A Alosco, Michael L %A Bouix, Sylvain %X

BACKGROUND: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are common in Veterans and linked to behavioral disturbances, increased risk of cognitive decline, and Alzheimer's disease.

OBJECTIVE: We studied the synergistic effects of PTSD and TBI on behavioral, cognitive, and neuroimaging measures in Vietnam war Veterans.

METHODS: Data were acquired at baseline and after about one-year from male Veterans categorized into: PTSD, TBI, PTSD+TBI, and Veteran controls without PTSD or TBI. We applied manual tractography to examine white matter microstructure of three fiber tracts: uncinate fasciculus (N = 91), cingulum (N = 87), and inferior longitudinal fasciculus (N = 95). ANCOVAs were used to compare Veterans' baseline behavioral and cognitive functioning (N = 285), white matter microstructure, amyloid-β (N = 230), and tau PET (N = 120). Additional ANCOVAs examined scores' differences from baseline to follow-up.

RESULTS: Veterans with PTSD and PTSD+TBI, but not Veterans with TBI only, exhibited poorer behavioral and cognitive functioning at baseline than controls. The groups did not differ in baseline white matter, amyloid-β, or tau, nor in behavioral and cognitive functioning, and tau accumulation change. Progression of white matter abnormalities of the uncinate fasciculus in Veterans with PTSD compared to controls was observed; analyses in TBI and PTSD+TBI were not run due to insufficient sample size.

CONCLUSIONS: PTSD and PTSD+TBI negatively affect behavioral and cognitive functioning, while TBI does not contribute independently. Whether progressive decline in uncinate fasciculus microstructure in Veterans with PTSD might account for cognitive decline should be further studied. Findings did not support an association between PTSD, TBI, and Alzheimer's disease pathology based on amyloid and tau PET.

%B J Alzheimers Dis %V 95 %P 1427-1448 %8 2023 Oct 10 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/37694363?dopt=Abstract %R 10.3233/JAD-221304 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Precision Medicine Approach to Alzheimer's Disease: Rationale and Implications. %A Bredesen, Dale E %A Toups, Kat %A Hathaway, Ann %A Gordon, Deborah %A Chung, Henrianna %A Raji, Cyrus %A Boyd, Alan %A Hill, Benjamin D %A Hausman-Cohen, Sharon %A Attarha, Mouna %A Chwa, Won Jong %A Kurakin, Alexei %A Jarrett, Michael %K Alzheimer Disease %K Cognitive Dysfunction %K Humans %K Neurodegenerative Diseases %K Precision Medicine %X

The neurodegenerative disease field has enjoyed extremely limited success in the development of effective therapeutics. One potential reason is the lack of disease models that yield accurate predictions and optimal therapeutic targets. Standard clinical trials have pre-determined a single treatment modality, which may be unrelated to the primary drivers of neurodegeneration. Recent proof-of-concept clinical trials using a precision medicine approach suggest a new model of Alzheimer's disease (AD) as a chronic innate encephalitis that creates a network insufficiency. Identifying and addressing the multiple potential contributors to cognitive decline for each patient may represent a more effective strategy. Here we review the rationale for a precision medicine approach in prevention and treatment of cognitive decline associated with AD. Results and implications from recent proof-of-concept clinical trials are presented. Randomized controlled trials, with much larger patient numbers, are likely to be significant to establishing precision medicine protocols as a standard of care for prevention and treatment of cognitive decline. Furthermore, combining this approach with the pharmaceutical approach offers the potential for enhanced outcomes. However, incorporating precision medicine approaches into everyday evaluation and care, as well as future clinical trials, would require fundamental changes in trial design, IRB considerations, funding considerations, laboratory evaluation, personalized treatment plans, treatment teams, and ultimately in reimbursement guidelines. Nonetheless, precision medicine approaches to AD, based on a novel model of AD pathophysiology, offer promise that has not been realized to date with monotherapeutic approaches.

%B J Alzheimers Dis %V 96 %P 429-437 %8 2023 %G eng %N 2 %R 10.3233/JAD-230467 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Proteome Network Analysis Identifies Potential Biomarkers for Brain Aging. %A Short, Meghan I %A Fohner, Alison E %A Skjellegrind, Håvard K %A Beiser, Alexa %A Gonzales, Mitzi M %A Satizabal, Claudia L %A Austin, Thomas R %A Longstreth, W T %A Bis, Joshua C %A Lopez, Oscar %A Hveem, Kristian %A Selbæk, Geir %A Larson, Martin G %A Yang, Qiong %A Aparicio, Hugo J %A McGrath, Emer R %A Gerszten, Robert E %A DeCarli, Charles S %A Psaty, Bruce M %A Vasan, Ramachandran S %A Zare, Habil %A Seshadri, Sudha %X

BACKGROUND: Alzheimer's disease and related dementias (ADRD) involve biological processes that begin years to decades before onset of clinical symptoms. The plasma proteome can offer insight into brain aging and risk of incident dementia among cognitively healthy adults.

OBJECTIVE: To identify biomarkers and biological pathways associated with neuroimaging measures and incident dementia in two large community-based cohorts by applying a correlation-based network analysis to the plasma proteome.

METHODS: Weighted co-expression network analysis of 1,305 plasma proteins identified four modules of co-expressed proteins, which were related to MRI brain volumes and risk of incident dementia over a median 20-year follow-up in Framingham Heart Study (FHS) Offspring cohort participants (n = 1,861). Analyses were replicated in the Cardiovascular Health Study (CHS) (n = 2,117, mean 6-year follow-up).

RESULTS: Two proteomic modules, one related to protein clearance and synaptic maintenance (M2) and a second to inflammation (M4), were associated with total brain volume in FHS (M2: p = 0.014; M4: p = 4.2×10-5). These modules were not significantly associated with hippocampal volume, white matter hyperintensities, or incident all-cause or AD dementia. Associations with TCBV did not replicate in CHS, an older cohort with a greater burden of comorbidities.

CONCLUSIONS: Proteome networks implicate an early role for biological pathways involving inflammation and synaptic function in preclinical brain atrophy, with implications for clinical dementia.

%B J Alzheimers Dis %V 96 %P 1767-1780 %8 2023 Dec 05 %G eng %N 4 %R 10.3233/JAD-230145 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Reliability and Validity of Self-Reported Vascular Risk Factors: Hypertension, Diabetes, and Heart Disease, in a Multi-Ethnic Community Based Study of Aging and Dementia. %A Lee, Annie J %A Sanchez, Didi %A Reyes-Dumeyer, Dolly %A Brickman, Adam M %A Lantigua, Rafael A %A Vardarajan, Badri N %A Mayeux, Richard %X

BACKGROUND: Queries for the presence of cardiovascular and cerebrovascular risk factors are typically assessed through self-report. However, the reliability and validity of self-reported cardiovascular and cerebrovascular risk factors remains inconsistent in aging research.

OBJECTIVE: To determine the reliability and validity of the most frequently self-reported vascular risk factors: hypertension, diabetes, and heart disease.

METHODS: 1,870 individuals aged 65 years or older among African Americans, Caribbean Hispanics, and white non-Hispanic individuals were recruited as part of a community study of aging and dementia. We assessed the reliability, validity, sensitivity, specificity, and percent agreement of self-reported hypertension, diabetes, and heart disease, in comparison with direct measures of blood pressure, hemoglobin A1c (HbA1c), and medication use. The analyses were subsequently stratified by age, sex, education, and ethnic group.

RESULTS: Reliability of self-reported for hypertension, diabetes, and heart disease was excellent. Agreement between self-reports and clinical measures was moderate for hypertension (kappa: 0.58), good for diabetes (kappa: 0.76-0.79), and moderate for heart disease (kappa: 0.45) differing slightly by age, sex, education, and ethnic group. Sensitivity and specificity for hypertension was 88.6% -78.1%, for diabetes was 87.7% -92.0% (HbA1c ≥6.5%) or 92.7% -92.8% (HbA1c ≥7%), and for heart disease was 85.8% -75.5%. Percent agreement of self-reported was 87.0% for hypertension, 91.6% -92.6% for diabetes, and 77.4% for heart disease.

CONCLUSION: Ascertainment of self-reported histories of hypertension, diabetes, and heart disease are reliable and valid compared to direct measurements or medication use.

%B J Alzheimers Dis %V 95 %P 275-285 %8 2023 Aug 29 %G eng %N 1 %R 10.3233/JAD-230374 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Retinal Functional and Structural Neural Indices: Potential Biomarkers for the Monitoring of Cerebral Neurodegeneration: The Maastricht Study. %A van der Heide, Frank C T %A Mokhtar, Sara %A Khanna, Anjani %A Said, Mozhda %A Henry, Ronald M A %A Kroon, Abraham A %A Dagnelie, Pieter C %A Eussen, Simone J P M %A Berendschot, Tos T J M %A Schouten, Jan S A G %A Schram, Miranda T %A van der Kallen, Carla J H %A van Greevenbroek, Marleen M J %A Wesselius, Anke %A Savelberg, Hans H C M %A Schaper, Nicolaas C %A Webers, Carroll A B %A Stehouwer, Coen D A %X

BACKGROUND: If retinal indices of neurodegeneration are to be biomarkers for the monitoring of cerebral neurodegeneration, it is important to establish whether potentially modifiable risk factors for dementia are associated with retinal neurodegenerative changes.

OBJECTIVE: To study associations of dementia risk factors with retinal sensitivity, an index of retinal neural function, and retinal nerve fiber layer (RNFL) thickness, an index of retinal neural structure.

METHODS: We used cross-sectional data from The Maastricht Study (up to 5,666 participants, 50.5% men, mean age 59.7), and investigated associations with regression analyses (adjusted for potential confounders).

RESULTS: Most risk factors under study (i.e., hyperglycemia, unhealthy diet, lower cardiorespiratory fitness, smoking, alcohol consumption, and hypertension) were significantly associated with lower retinal sensitivity and lower RNFL thickness.

CONCLUSION: Findings of this population-based study support the concept that retinal neural indices may be biomarkers for the monitoring of therapeutic strategies that aim to prevent early-stage cerebral neurodegeneration and, ultimately, dementia.

%B J Alzheimers Dis %V 93 %P 1471-1483 %8 2023 Jun 13 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/37182886?dopt=Abstract %R 10.3233/JAD-230104 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Safety, Feasibility, and Potential Clinical Efficacy of 40 Hz Invisible Spectral Flicker versus Placebo in Patients with Mild-to-Moderate Alzheimer's Disease: A Randomized, Placebo-Controlled, Double-Blinded, Pilot Study. %A Agger, Mikkel Pejstrup %A Danielsen, Else Rubæk %A Carstensen, Marcus Schultz %A Nguyen, N Mai %A Horning, Maibritt %A Henney, Mark Alexander %A Jensen, Christopher Boe Ravn %A Baandrup, Anders Ohlhues %A Kjær, Troels Wesenberg %A Madsen, Kristoffer Hougaard %A Miskowiak, Kamilla %A Petersen, Paul Michael %A Høgh, Peter %K Alzheimer Disease %K Cognition %K Double-Blind Method %K Feasibility Studies %K Humans %K Pilot Projects %K Treatment Outcome %X

BACKGROUND: Recent studies suggested induction of 40 Hz neural activity as a potential treatment for Alzheimer's disease (AD). However, prolonged exposure to flickering light raises adherence and safety concerns, encouraging investigation of tolerable light stimulation protocols.

OBJECTIVE: To investigate the safety, feasibility, and exploratory measures of efficacy.

METHODS: This two-stage randomized placebo-controlled double-blinded clinical trial, recruited first cognitive healthy participants (n = 3/2 active/placebo), and subsequently patients with mild-to-moderate AD (n = 5/6, active/placebo). Participants were randomized 1:1 to receive either active intervention with 40 Hz Invisible Spectral Flicker (ISF) or placebo intervention with color and intensity matched non-flickering white light.

RESULTS: Few and mild adverse events were observed. Adherence was above 86.1% of intended treatment days, with participants remaining in front of the device for >51.3 min (60 max) and directed gaze >34.9 min. Secondary outcomes of cognition indicate a tendency towards improvement in the active group compared to placebo (mean: -2.6/1.5, SD: 6.58/6.53, active/placebo) at week 6. Changes in hippocampal and ventricular volume also showed no tendency of improvement in the active group at week 6 compared to placebo. At week 12, a potential delayed effect of the intervention was seen on the volume of the hippocampus in the active group compared to placebo (mean: 0.34/-2.03, SD: 3.26/1.18, active/placebo), and the ventricular volume active group (mean: -0.36/2.50, SD: 1.89/2.05, active/placebo), compared to placebo.

CONCLUSION: Treatment with 40 Hz ISF offers no significant safety or adherence concerns. Potential impact on secondary outcomes must be tested in larger scale clinical trials.

%B J Alzheimers Dis %V 92 %P 653-665 %8 2023 %G eng %N 2 %R 10.3233/JAD-221238 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Senescent Microglia Represent a Subset of Disease-Associated Microglia in P301S Mice. %A Ng, Pei Y %A Zhang, Cheng %A Li, Hu %A Baker, Darren J %X

BACKGROUND: The existence and contribution of microglia with senescent-like alterations in the pathogenesis of age-related neurodegenerative diseases like Alzheimer's disease (AD) have been suggested in recent years. However, the identification of this distinct microglial population in vivo has proven challenging, largely due to overlaps in the inflammatory phenotype of activated and senescent microglia. Furthermore, attempts at recapitulating senescence in microglia in vitro are limited.

OBJECTIVE: To identify and characterize senescent microglia that occur in vivo in an animal model of neurodegeneration driven by pathologic tau.

METHODS: We analyzed the RNA expression patterns of individual microglia from normal mice and the pathogenic tau P301 S PS19 mouse model. We have previously demonstrated that p16-expressing senescent microglia occur in these mice when neurodegeneration has occurred.

RESULTS: Here we identify a subset of disease-associated microglia with senescent features, notably characterized by the expression of Ccl4. This signature overlaps with established markers of senescence from other cell types.

CONCLUSION: Our characterization of senescent microglia can be used to better understand the role of senescent microglia in various age-related contexts, including whether clearance of senescent microglia represents a viable therapeutic option.

%B J Alzheimers Dis %V 95 %P 493-507 %8 2023 Sep 12 %G eng %N 2 %R 10.3233/JAD-230109 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Superior Global Cognition in Oldest-Old Is Associated with Resistance to Neurodegenerative Pathologies: Results from The 90+ Study. %A Biswas, Roshni %A Kawas, Claudia %A Montine, Thomas J %A Bukhari, Syed A %A Jiang, Luohua %A Corrada, Maria M %X

BACKGROUND: Some oldest-old individuals can maintain superior cognition despite advanced age. Little is known about the neuropathological changes in the brains of oldest-old superior cognitive performers.

OBJECTIVE: Our objective was to examine the associations between Alzheimer's disease (AD) and non-AD neuropathologic features in relation to superior cognitive performance in oldest-old individuals.

METHODS: We analyzed brain autopsy data from 102 participants with normal cognition from The 90+ Study. Superior global cognitive performers (SGCP) were defined as having Mini-Mental State Examination (MMSE) score ≥28 in the last visit 12 to 2 months before death. To examine the associations between individual and multiple comorbid neuropathologic features with SGCP status we used multiple logistic regression models adjusting for age, sex, and education.

RESULTS: Alzheimer's disease neuropathological change (ADNC) and low levels of vascular pathologic change were not associated with superior cognition. In contrast, participants with limbic (OR = 8.37; 95% CI: 1.48-47.44) and neocortical (OR = 10.80;95% CI: 1.03-113.82) Lewy body disease (LBD), or with hippocampal sclerosis (HS) (OR = 5.28; 95% CI: 1.10-25.47) were more likely to be non-SGCP. High total burden of multiple comorbid neuropathologic features was associated with a lower likelihood of being SGCP.

CONCLUSION: Oldest-old superior cognitive performers were resilient to ADNC and low levels of vascular pathologic change and were resistant to non-AD neurodegenerative changes and multiple comorbid neuropathologic features. Understanding the factors underlying the ability of superior cognitive performers to resist these changes might provide useful insights on maintenance of superior cognition despite advanced age.

%B J Alzheimers Dis %V 93 %P 561-575. %8 2023 May 16 %G eng %N 2 %R 10.3233/JAD-221062 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Two-Year Changes in Physical Activity and Concurrent Changes in Cognitive Function in a Cohort of Adults with Metabolic Syndrome. %A Rognoni, Teresa %A Fernández-Matarrubia, Marta %A Martínez-González, Miguel Ángel %A Salas-Salvadó, Jordi %A Corella, Dolores %A Castañer, Olga %A Martínez, J Alfredo %A Alonso-Gómez, Ángel M %A Gómez-Gracia, Enrique %A Vioque, Jesús %A Romaguera, Dora %A López-Miranda, José %A Estruch, Ramón %A Tinahones, Francisco J %A Santos-Lozano, José Manuel %A Serra-Majem, Lluis %A Cano Ibañez, Naomi %A Tur, Josep A %A Micó Pérez, Rafael %A Pintó, Xavier %A Delgado-Rodríguez, Miguel %A Ortiz Ramos, María %A Vidal Martín, Josep %A Vázquez, Clotilde %A Daimiel, Lidia %A Ros, Emili %A Goñi-Ruiz, Nuria %A Babio, Nancy %A Sorlí, José V %A Schröder, Helmut %A García-Rios, Antonio %A Compañ-Gabucio, Laura %A Warnberg, Julia %A Zulet, M Ángeles %A Chaplin, Alice %A Sacanella, Emilio %A Bouzalmate-Hajjaj, Amira %A Tojal-Sierra, Lucas %A Damas-Fuentes, Miguel %A Vázquez, Zenaida %A Gómez-Martínez, Carlos %A Saiz, Carmen %A Malcampo, Mireia %A Ortiz-Morales, Ana M %A Martínez-Avilés, Vanessa %A García-Gavilan, Jesús %A Abete, Itziar %A Fitó, Montserrat %A Toledo, Estefanía %X

BACKGROUND: It has been proposed that physical activity (PA) could prevent cognitive decline.

OBJECTIVE: To evaluate the association between changes in PA and changes in cognitive function in a cohort of adults with metabolic syndrome.

METHODS: Longitudinal observational study including 5,500 adults (mean age 65 years, SD = 5; women = 49.3%) with metabolic syndrome. Participants underwent physical activity measurements and cognitive evaluation at baseline and at two-years of follow-up. PA was quantified using the Minnesota questionnaire-shortened version. Cognitive function was evaluated using a battery of tests: Mini-Mental Test Examination, Clock Drawing Test, Trail Making Test A and B, Verbal Fluency Test, and Digit Span. The primary outcome was change in cognition at two-year follow-up, as measured through the Global Composite Score (GCS) of all neuropsychological tests. Multivariable-adjusted linear regression models were fitted with baseline PA and their changes as the main exposures and changes in cognitive function as the outcome.

RESULTS: No significant association was found between PA levels (or their changes) and changes in cognitive function, as measured by the GCS. A greater increase in PA levels was associated with a more favorable two-year change in performance on the Trail Making Test A (Q4 versus Q1: b = -2.15, 95% CI -4.25 to -0.05; p-trend = 0.024). No significant association was found for other neuropsychological test.

CONCLUSION: Our results do not support an association between increases in PA and the evolution of the global cognitive function at two-year follow-up, but they suggested a possible beneficial effect of PA on attentional function in older adults.

%B J Alzheimers Dis %V 95 %P 887-899 %8 2023 Sep 26 %G eng %N 3 %R 10.3233/JAD-230105 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Untangling the Role of TREM2 in Conjugation with Microglia in Neuronal Dysfunction: A Hypothesis on a Novel Pathway in the Pathophysiology of Alzheimer's Disease. %A Basha, Sk Chand %A Ramaiah, Mekala Janaki %A Kosagisharaf, Jagannatha Rao %K Alzheimer Disease %K Amyloid beta-Peptides %K Humans %K Membrane Glycoproteins %K Microglia %K Neurons %K Receptors, Immunologic %X

Alzheimer's disease (AD) is a complex neurodegenerative disorder involving heterogenous pathophysiological characteristics, which has become a challenge to therapeutics. The major pathophysiology of AD comprises amyloid-β (Aβ), tau, oxidative stress, and apoptosis. Recent studies indicate the significance of Triggering receptor expressed on myeloid cells 2 (TREM2) and its mutant variants in AD. TREM2 are the transmembrane receptors of microglial cells that performs a broad range of physiological cell processes. Phagocytosis of Aβ is one of the physiological roles of TREM2, which plays a pivotal role in AD progression. R47H, a mutant variant of TREM2, increases the risk of AD by impairing TREM2-Aβ binding. Inconclusive evidence regarding the TREM2 signaling cascade mechanism of Aβ phagocytosis motivates the current review to propose a new hypothesis. The review systematically assesses the cross talk between TREM2 and other AD pathological domains and the influence of TREM2 on amyloid and tau seeding. Disease associated microglia (DAM), a novel state of microglia with unique transcriptional and functional signatures reported in neurodegenerative conditions, also depend on the TREM2 pathway for its differentiation. DAM is suggested to have a neuroprotective role. We hypothesize that TREM2, along with its signaling adaptors and endogenous proteins, play a key role in ameliorating Aβ clearance. We indicate that TREM2 has the potential to ameliorate the Aβ burden, though with differential clearance ability and may act as a potential therapeutic target.

%B J Alzheimers Dis %V 94 %P S319-S333 %8 2023 %G eng %N s1 %R 10.3233/JAD-221070 %0 Journal Article %J J Alzheimers Dis %D 2022 %T 3-Hydroxyacyl-CoA and Alcohol Dehydrogenase Activities of Mitochondrial Type 10 17β-Hydroxysteroid Dehydrogenase in Neurodegeneration Study. %A He, Xue-Ying %A Dobkin, Carl %A Brown, W Ted %A Yang, Song-Yu %X

BACKGROUND: Mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is necessary for brain cognitive function, but its studies were confounded by reports of Aβ-peptide binding alcohol dehydrogenase (ABAD), formerly endoplasmic reticulum-associated Aβ-peptide binding protein (ERAB), for two decades so long as ABAD serves as the alternative term of 17β-HSD10.

OBJECTIVE: To determine whether those ABAD reports are true or false, even if they were published in prestigious journals.

METHODS: 6xHis-tagged 17β-HSD10 was prepared and characterized by well-established experimental procedures.

RESULTS: The N-terminal 6xHis tag did not significantly interfere with the dehydrogenase activities of 17β-HSD10, but the kinetic constants of its 3-hydroxyacyl-CoA dehydrogenase activity are drastically distinct from those of ABAD, and it was not involved in ketone body metabolism as previously reported for ABAD. Furthermore, it was impossible to measure its generalized alcohol dehydrogenase activities underlying the concept of ABAD because the experimental procedures described in ABAD reports violated basic chemical and/or biochemical principles. More incredibly, both authors and journals had not yet agreed to make any corrigenda of ABAD reports.

CONCLUSION: Brain 17β-HSD10 plays a key role in neurosteroid metabolism and further studies in this area may lead to potential treatments of neurodegeneration including AD.

%B J Alzheimers Dis %V 88 %P 1487-1497 %8 2022 Aug 16 %G eng %N 4 %R 10.3233/JAD-220481 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Age-Related Oxidative Redox and Metabolic Changes Precede Intraneuronal Amyloid-β Accumulation and Plaque Deposition in a Transgenic Alzheimer's Disease Mouse Model. %A Pontrello, Crystal G %A McWhirt, Joshua M %A Glabe, Charles G %A Brewer, Gregory J %X

BACKGROUND: Many identified mechanisms could be upstream of the prominent amyloid-β (Aβ) plaques in Alzheimer's disease (AD).

OBJECTIVE: To profile the progression of pathology in AD.

METHODS: We monitored metabolic signaling, redox stress, intraneuronal amyloid-β (iAβ) accumulation, and extracellular plaque deposition in the brains of 3xTg-AD mice across the lifespan.

RESULTS: Intracellular accumulation of aggregated Aβ in the CA1 pyramidal cells at 9 months preceded extracellular plaques that first presented in the CA1 at 16 months of age. In biochemical assays, brain glutathione (GSH) declined with age in both 3xTg-AD and non-transgenic controls, but the decline was accelerated in 3xTg-AD brains from 2 to 4 months. The decline in GSH correlated exponentially with the rise in iAβ. Integrated metabolic signaling as the ratio of phospho-Akt (pAkt) to total Akt (tAkt) in the PI3kinase and mTOR pathway declined at 6, 9, and 12 months, before rising at 16 and 20 months. These pAkt/tAkt ratios correlated with both iAβ and GSH levels in a U-shaped relationship. Selective vulnerability of age-related AD-genotype-specific pAkt changes was greatest in the CA1 pyramidal cell layer. To demonstrate redox causation, iAβ accumulation was lowered in cultured middle-age adult 3xTg-AD neurons by treatment of the oxidized redox state in the neurons with exogenous cysteine.

CONCLUSION: The order of pathologic progression in the 3xTg-AD mouse was loss of GSH (oxidative redox shift) followed by an pAkt/tAkt metabolic shift in CA1, iAβ accumulation in CA1, and extracellular Aβ deposition. Upstream targets may prove strategically more effective for therapy before irreversible changes.

%B J Alzheimers Dis %V 90 %P 1501-1521 %8 2022 Dec 06 %G eng %N 4 %R 10.3233/JAD-220824 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Alzheimer's Disease with Epileptiform EEG Activity: Abnormal Cortical Sources of Resting State Delta Rhythms in Patients with Amnesic Mild Cognitive Impairment. %A Babiloni, Claudio %A Noce, Giuseppe %A Di Bonaventura, Carlo %A Lizio, Roberta %A Eldellaa, Ali %A Tucci, Federico %A Salamone, Enrico M %A Ferri, Raffaele %A Soricelli, Andrea %A Nobili, Flavio %A Famá, Francesco %A Arnaldi, Dario %A Palma, Eleonora %A Cifelli, Pierangelo %A Marizzoni, Moira %A Stocchi, Fabrizio %A Bruno, Giuseppe %A Di Gennaro, Giancarlo %A Frisoni, Giovanni B %A Del Percio, Claudio %X

BACKGROUND: Patients with amnesic mild cognitive impairment due to Alzheimer's disease (ADMCI) typically show a "slowing" of cortical resting-state eyes-closed electroencephalographic (rsEEG) rhythms. Some of them also show subclinical, non-convulsive, and epileptiform EEG activity (EEA) with an unclear relationship with that "slowing."

OBJECTIVE: Here we tested the hypothesis that the "slowing" of rsEEG rhythms is related to EEA in ADMCI patients.

METHODS: Clinical and instrumental datasets in 62 ADMCI patients and 38 normal elderly (Nold) subjects were available in a national archive. No participant had received a clinical diagnosis of epilepsy. The eLORETA freeware estimated rsEEG cortical sources. The area under the receiver operating characteristic curve (AUROCC) indexed the accuracy of eLORETA solutions in the classification between ADMCI-EEA and ADMCI-noEEA individuals.

RESULTS: EEA was observed in 15% (N = 8) of the ADMCI patients. The ADMCI-EEA group showed: 1) more abnormal Aβ 42 levels in the cerebrospinal fluid as compared to the ADMCI-noEEA group and 2) higher temporal and occipital delta (

CONCLUSION: It can be speculated that in ADMCI-EEA patients, AD-related amyloid neuropathology may be related to an over-excitation in neurophysiological low-frequency (delta) oscillatory mechanisms underpinning cortical arousal and quiet vigilance.

%B J Alzheimers Dis %V 88 %P 903-931 %8 2022 Aug 02 %G eng %N 3 %R 10.3233/JAD-220442 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association Between Plasma Biomarkers of Amyloid, Tau, and Neurodegeneration with Cerebral Microbleeds. %A McCarter, Stuart J %A Lesnick, Timothy G %A Lowe, Val J %A Rabinstein, Alejandro A %A Przybelski, Scott A %A Algeciras-Schimnich, Alicia %A Ramanan, Vijay K %A Jack, Clifford R %A Petersen, Ronald C %A Knopman, David S %A Boeve, Bradley F %A Kantarci, Kejal %A Vemuri, Prashanthi %A Mielke, Michelle M %A Graff-Radford, Jonathan %X

BACKGROUND: Cerebral microbleeds (CMBs) are a common vascular pathology associated with future intracerebral hemorrhage. Plasma biomarkers of amyloid, tau, and neurodegeneration may provide a screening avenue to identify those with CMBs, but evidence is conflicting.

OBJECTIVE: To determine the association between plasma biomarkers (Aβ40, Aβ42, t-tau, p-tau181, p-tau217, neurofilament light chain (NfL)) and CMBs in a population-based study of aging and whether these biomarkers predict higher signal on Aβ-PET imaging in patients with multiple CMBs.

METHODS: 712 participants from the Mayo Clinic Study of Aging with T2 * GRE MRI and plasma biomarkers were included. Biomarkers were analyzed utilizing Simoa (Aβ40, Aβ42, t-tau, NfL) or Meso Scale Discovery (p-tau181, p-tau217) platforms. Cross-sectional associations between CMBs, plasma biomarkers and Aβ-PET were evaluated using hurdle models and multivariable regression models.

RESULTS: Among the 188 (26%) individuals with≥1 CMB, a lower plasma Aβ42/Aβ40 ratio was associated with more CMBs after adjusting for covariables (IRR 568.5 95% CI 2.8-116,127). No other biomarkers were associated with risk or number CMBs. In 81 individuals with≥2 CMBs, higher plasma t-tau, p-tau181, and p-tau217 all were associated with higher Aβ-PET signal, with plasma p-tau217 having the strongest predictive value (r2 0.603, AIC -53.0).

CONCLUSION: Lower plasma Aβ42/Aβ40 ratio and higher plasma p-tau217 were associated with brain amyloidosis in individuals with CMBs from the general population. Our results suggest that in individuals with multiple CMBs and/or lobar intracranial hemorrhage that a lower plasma Aβ42/Aβ40 ratio or elevated p-tau217 may indicate underlying cerebral amyloid angiopathy.

%B J Alzheimers Dis %V 87 %P 1537-1547 %8 2022 Jun 14 %G eng %N 4 %R 10.3233/JAD-220158 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association of Brain Volume and Retinal Thickness in the Early Stages of Alzheimer's Disease. %A Mathew, Sunu %A WuDunn, Darrell %A Mackay, Devin D %A Vosmeier, Aaron %A Tallman, Eileen F %A Deardorff, Rachael %A Harris, Alon %A Farlow, Martin R %A Brosch, Jared R %A Gao, Sujuan %A Apostolova, Liana G %A Saykin, Andrew J %A Risacher, Shannon L %X

BACKGROUND: The eye has been considered a 'window to the brain,' and several neurological diseases including neurodegenerative conditions like Alzheimer's disease (AD) also show changes in the retina.

OBJECTIVE: To investigate retinal nerve fiber layer (RNFL) thickness and its association with brain volume via magnetic resonance imaging (MRI) in older adults with subjective or objective cognitive decline.

METHODS: 75 participants underwent ophthalmological and neurological evaluation including optical coherence tomography and MRI (28 cognitively normal subjects, 26 with subjective cognitive decline, 17 patients diagnosed with mild cognitive impairment, and 4 with AD). Differences in demographics, thickness of RNFL, and brain volume were assessed using ANCOVA, while partial Pearson correlations, covaried for age and sex, were used to compare thickness of the peripapillary RNFL with brain volumes, with p < 0.05 considered statistically significant.

RESULTS: Mean RNFL thickness was significantly correlated with brain volumes, including global volume (right eye r = 0.235 p = 0.046, left eye r = 0.244, p = 0.037), temporal lobe (right eye r = 0.242 p = 0.039, left eye r = 0.290, p = 0.013), hippocampal (right eye r = 0.320 p = 0.005, left eye r = 0.306, p = 0.008), amygdala (left eye r = 0.332, p = 0.004), and occipital lobe (right eye r = 0.264 p = 0.024) volumes.

CONCLUSION: RNFL thickness in both eyes was positively associated with brain volumes in subjects with subjective and objective cognitive decline. The RNFL, however, did not correlate with the disease, but the small sample number makes it important to conduct larger studies. RNFL thickness may be a useful non-invasive and inexpensive tool for detection of brain neurodegeneration and may assist with diagnosis and monitoring of progression and treatment in AD.

%B J Alzheimers Dis %V 91 %P 743-752 %8 2023 Jan 17 %G eng %N 2 %R 10.3233/JAD-210533 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association of Carotid Intima Media Thickening with Future Brain Region Specific Amyloid-β Burden. %A Baradaran, Hediyeh %A Peloso, Gina M %A Polak, Joseph F %A Killiany, Ronald J %A Ghosh, Saptaparni %A DeCarli, Charles S %A Thibault, Emma G %A Sperling, Reisa A %A Johnson, Keith A %A Beiser, Alexa %A Romero, Jose R %A Seshadri, Sudha %X

BACKGROUND: Carotid atherosclerosis is associated with cognitive impairment and dementia, though there is limited evidence of a direct link between carotid disease and amyloid-β (Aβ) burden.

OBJECTIVE: We studied the association of baseline and progressive carotid intima media thickness (CIMT) with Aβ on 11C-Pittsburgh Compound B (PiB) to determine if those with carotid atherosclerosis would have higher Aβ burden.

METHODS: We studied 47 participants from the Framingham Offspring cohort with carotid ultrasounds measuring CIMT at their 6th clinic examination (aged 49.5±5.7 years) and an average of 9.6 years later, and PiB imaging measuring Aβ on average 22.1 years post baseline. We used multivariate linear regression analyses to relate baseline, follow-up, mean, and progression of internal carotid artery (ICA) and common carotid artery (CCA) CIMT to Aβ in brain regions associated with Alzheimer's disease (AD) and related dementias (ADRD), adjusting for age, sex, and other vascular risk factors.

RESULTS: Participants with higher mean ICA IMT had more Aβ in the precuneus (beta±standard error [β±SE]: 0.466±0.171 mm, p = 0.01) and the frontal, lateral, and retrosplenial regions (β±SE: 0.392±0.164 mm, p = 0.022) after adjusting for age, sex, vascular risk factors, and medication use. We did not find an association between any CCA IMT measures and Aβ or progression of ICA or CCA IMT and Aβ.

CONCLUSION: Carotid atherosclerosis, as measured by ICA IMT, is associated with increased Aβ burden later in life. These findings support a link between vascular disease and AD/ADRD pathophysiology.

%B J Alzheimers Dis %V 89 %P 223-232 %8 2022 Aug 30 %G eng %N 1 %R 10.3233/JAD-215679 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association of Cholinergic Basal Forebrain Volume and Functional Connectivity with Markers of Inflammatory Response in the Alzheimer's Disease Spectrum. %A Teipel, Stefan J %A Dyrba, Martin %A Ballarini, Tommaso %A Brosseron, Frederic %A Bruno, Davide %A Buerger, Katharina %A Cosma, Nicoleta-Carmen %A Dechent, Peter %A Dobisch, Laura %A Düzel, Emrah %A Ewers, Michael %A Fliessbach, Klaus %A Haynes, John D %A Janowitz, Daniel %A Kilimann, Ingo %A Laske, Christoph %A Maier, Franziska %A Metzger, Coraline D %A Munk, Matthias H %A Peters, Oliver %A Pomara, Nunzio %A Preis, Lukas %A Priller, Josef %A Rámirez, Alfredo %A Roy, Nina %A Scheffler, Klaus %A Schneider, Anja %A Schott, Björn H %A Spottke, Annika %A Spruth, Eike J %A Wagner, Michael %A Wiltfang, Jens %A Jessen, Frank %A Heneka, Michael T %K Aged %K Alzheimer Disease %K Basal Forebrain %K Biomarkers %K Cholinergic Agents %K Cognitive Dysfunction %K Cohort Studies %K Female %K Humans %K Inflammation %K Magnetic Resonance Imaging %K Male %X

BACKGROUND: Inflammation has been described as a key pathogenic event in Alzheimer's disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies.

OBJECTIVE: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum.

METHODS: We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum.

RESULTS: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aβ42/ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small.

CONCLUSION: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aβ42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples.

%B J Alzheimers Dis %V 85 %P 1267-1282 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34924387?dopt=Abstract %R 10.3233/JAD-215196 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association of COVID-19 with New-Onset Alzheimer's Disease. %A Wang, Lindsey %A Davis, Pamela B %A Volkow, Nora D %A Berger, Nathan A %A Kaelber, David C %A Xu, Rong %K Aged %K Aged, 80 and over %K Alzheimer Disease %K COVID-19 %K COVID-19 Testing %K Female %K Humans %K Retrospective Studies %K SARS-CoV-2 %X

An infectious etiology of Alzheimer's disease has been postulated for decades. It remains unknown whether SARS-CoV-2 viral infection is associated with increased risk for Alzheimer's disease. In this retrospective cohort study of 6,245,282 older adults (age ≥65 years) who had medical encounters between 2/2020-5/2021, we show that people with COVID-19 were at significantly increased risk for new diagnosis of Alzheimer's disease within 360 days after the initial COVID-19 diagnosis (hazard ratio or HR:1.69, 95% CI: 1.53-1.72), especially in people age ≥85 years and in women. Our findings call for research to understand the underlying mechanisms and for continuous surveillance of long-term impacts of COVID-19 on Alzheimer's disease.

%B J Alzheimers Dis %V 89 %P 411-414 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35912749?dopt=Abstract %R 10.3233/JAD-220717 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Associations Between Brainstem Volume and Alzheimer's Disease Pathology in Middle-Aged Individuals of the Framingham Heart Study. %A Jacobs, Heidi I L %A O'Donnell, Adrienne %A Satizabal, Claudia L %A Lois, Cristina %A Kojis, Daniel %A Hanseeuw, Bernard J %A Thibault, Emma %A Sanchez, Justin S %A Buckley, Rachel F %A Yang, Qiong %A DeCarli, Charles %A Killiany, Ron %A Sargurupremraj, Muralidharan %A Sperling, Reisa A %A Johnson, Keith A %A Beiser, Alexa S %A Seshadri, Sudha %X

The brainstem is among the first regions to accumulate Alzheimer's disease (AD)-related hyperphosphorylated tau pathology during aging. We aimed to examine associations between brainstem volume and neocortical amyloid-β or tau pathology in 271 middle-aged clinically normal individuals of the Framingham Heart Study who underwent MRI and PET imaging. Lower volume of the medulla, pons, or midbrain was associated with greater neocortical amyloid burden. No associations were detected between brainstem volumes and tau deposition. Our results support the hypothesis that lower brainstem volumes are associated with initial AD-related processes and may signal preclinical AD pathology.

%B J Alzheimers Dis %V 86 %P 1603-1609 %8 2022 Apr 19 %G eng %N 4 %R 10.3233/JAD-215372 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Associations Between Intrathecal Levels of Vitamin D, Cytokines, and Core Biomarkers of Alzheimer's Disease: A Cross-Sectional Study. %A Soares, Jelena Zugic %A Valeur, Jørgen %A Šaltytė Benth, Jūratė %A Knapskog, Anne-Brita %A Selbæk, Geir %A Bogdanovic, Nenad %A Pettersen, Renate %X

BACKGROUND: Several studies have examined association between vitamin D levels in serum and cognition, but little is known of vitamin D levels in cerebrospinal fluid (CSF) and association with Alzheimer's disease (AD).

OBJECTIVE: In this cross-sectional, explorative study we investigated possible associations of vitamin D in CSF with biomarkers for AD, amyloid-β, tau protein/phosphorylated tau protein in CSF, and with the cytokines IL-6, IL-8, and TNF-α in CSF in patients with cognitive impairment and cognitively healthy controls.

METHODS: We included 100 outpatients ≥65 years referred for assessment of cognitive impairment and 76 age- and sex-matched cognitively healthy controls. Levels of 25-hydroxyvitamin D (25(OH)D), amyloid-β, tau protein and phosphorylated tau protein, as well as IL-6, IL-8, and TNF-α, were analyzed in CSF in both groups.

RESULTS: Higher levels of 25(OH)D in CSF in all groups together were associated with lower levels of tau protein (p = 0.01) and phosphorylated tau protein (p = 0.005). We found no association between 25(OH)D levels in CSF and pathological levels of amyloid-β in CSF nor levels of IL-6 or TNF-α in CSF. Higher levels of 25(OH)D in CSF were associated with higher levels of IL-8 in CSF (p = 0.002). However, vitamin D explained only 6% of variance in IL-8. There was no significant difference between the patient groups and the control group regarding the association between 25(OH)D in CSF and any of the three cytokines in CSF.

CONCLUSION: Participants with higher CSF levels of 25(OH)D exhibited reduced CSF levels of tau protein and phosphorylated tau protein.

%B J Alzheimers Dis %V 89 %P 825-834 %8 2022 Sep 27 %G eng %N 3 %R 10.3233/JAD-220407 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis. %A Frenzel, Stefan %A Bis, Josh C %A Gudmundsson, Elias F %A O'Donnell, Adrienne %A Simino, Jeannette %A Yaqub, Amber %A Bartz, Traci M %A Brusselle, Guy G O %A Bülow, Robin %A DeCarli, Charles S %A Ewert, Ralf %A Gharib, Sina A %A Ghosh, Saptaparni %A Gireud-Goss, Monica %A Gottesman, Rebecca F %A Ikram, M Arfan %A Knopman, David S %A Launer, Lenore J %A London, Stephanie J %A Longstreth, W T %A Lopez, Oscar L %A Melo van Lent, Debora %A O'Connor, George %A Satizabal, Claudia L %A Shrestha, Srishti %A Sigurdsson, Sigurdur %A Stubbe, Beate %A Talluri, Rajesh %A Vasan, Ramachandran S %A Vernooij, Meike W %A Völzke, Henry %A Wiggins, Kerri L %A Yu, Bing %A Beiser, Alexa S %A Gudnason, Vilmundur %A Mosley, Thomas %A Psaty, Bruce M %A Wolters, Frank J %A Grabe, Hans J %A Seshadri, Sudha %X

BACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent.

OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables.

METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses.

RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume.

CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

%B J Alzheimers Dis %V 90 %P 1073-1083 %8 2022 Nov 22 %G eng %N 3 %R 10.3233/JAD-220667 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Better Subjective Sleep Quality Partly Explains the Association Between Self-Reported Physical Activity and Better Cognitive Function. %A Cheval, Boris %A Maltagliati, Silvio %A Sieber, Stefan %A Cullati, Stéphane %A Zou, Liye %A Ihle, Andreas %A Kramer, Arthur F %A Yu, Qian %A Sander, David %A Boisgontier, Matthieu P %K Cognition %K Exercise %K Humans %K Self Report %K Sleep %K Sleep Quality %X

BACKGROUND: Physical activity has been associated with better cognitive function and better sleep quality. Yet, whether the beneficial effect of physical activity on cognitive function can be explained by an indirect pathway involving better sleep quality is unclear.

OBJECTIVE: To investigate whether sleep quality mediates the association between physical activity and cognitive function in adults 50 years of age or older.

METHODS: 86,541 community-dwelling European adults were included in the study. Physical activity and sleep quality were self-reported. Indicators of cognitive function (immediate recall, delayed recall, verbal fluency) were assessed using objective tests. All measures were collected six times between 2004 and 2017. The mediation was tested using multilevel mediation analyses.

RESULTS: Results showed that self-reported physical activity was associated with better self-reported sleep quality, which was associated with better performance in all three indicators of cognitive function, demonstrating an indirect effect of physical activity on cognitive function through sleep quality. The mediating effect of sleep quality accounted for 0.41%, 1.46%, and 8.88% of the total association of physical activity with verbal fluency, immediate recall, and delayed recall, respectively.

CONCLUSION: These findings suggest that self-reported sleep quality partly mediates the association between self-reported physical activity and cognitive function. These results need to be confirmed by device-based data of physical activity and sleep quality.

%B J Alzheimers Dis %V 87 %P 919-931 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35404276?dopt=Abstract %R 10.3233/JAD-215484 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Blood Pressure and Later-Life Cognition in Hispanic and White Adults (BP-COG): A Pooled Cohort Analysis of ARIC, CARDIA, CHS, FOS, MESA, and NOMAS. %A Levine, Deborah A %A Gross, Alden L %A Briceño, Emily M %A Tilton, Nicholas %A Whitney, Rachael %A Han, Dehua %A Giordani, Bruno J %A Sussman, Jeremy B %A Hayward, Rodney A %A Burke, James F %A Elkind, Mitchell S V %A Moran, Andrew E %A Tom, Sarah %A Gottesman, Rebecca F %A Gaskin, Darrell J %A Sidney, Stephen %A Yaffe, Kristine %A Sacco, Ralph L %A Heckbert, Susan R %A Hughes, Timothy M %A Lopez, Oscar L %A Allen, Norrina Bai %A Galecki, Andrzej T %X

BACKGROUND: Ethnic differences in cognitive decline have been reported. Whether they can be explained by differences in systolic blood pressure (SBP) is uncertain.

OBJECTIVE: Determine whether cumulative mean SBP levels explain differences in cognitive decline between Hispanic and White individuals.

METHODS: Pooled cohort study of individual participant data from six cohorts (1971-2017). The present study reports results on SBP and cognition among Hispanic and White individuals. Outcomes were changes in global cognition (GC) (primary), executive function (EF) (secondary), and memory standardized as t-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1 SD difference in cognition. Median follow-up was 7.7 (Q1-Q3, 5.2-20.1) years.

RESULTS: We included 24,570 participants free of stroke and dementia: 2,475 Hispanic individuals (median age, cumulative mean SBP at first cognitive assessment, 67 years, 132.5 mmHg; 40.8% men) and 22,095 White individuals (60 years,134 mmHg; 47.3% men). Hispanic individuals had slower declines in GC, EF, and memory than White individuals when all six cohorts were examined. Two cohorts recruited Hispanic individuals by design. In a sensitivity analysis, Hispanic individuals in these cohorts had faster decline in GC, similar decline in EF, and slower decline in memory than White individuals. Higher time-varying cumulative mean SBP was associated with faster declines in GC, EF, and memory in all analyses. After adjusting for time-varying cumulative mean SBP, differences in cognitive slopes between Hispanic and White individuals did not change.

CONCLUSION: We found no evidence that cumulative mean SBP differences explained differences in cognitive decline between Hispanic and White individuals.

%B J Alzheimers Dis %V 89 %P 1103-1117 %8 2022 Sep 27 %G eng %N 3 %R 10.3233/JAD-220366 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Burden of Insomnia and Sleep Disturbances and the Impact of Sleep Treatments in Patients with Probable or Possible Alzheimer's Disease: A Structured Literature Review. %A Benca, Ruth %A Herring, W Joseph %A Khandker, Rezaul %A Qureshi, Zaina P %K Alzheimer Disease %K Caregivers %K Humans %K Prospective Studies %K Quality of Life %K Sleep %K Sleep Initiation and Maintenance Disorders %K Sleep Wake Disorders %X

BACKGROUND: Sleep disturbances are frequent in Alzheimer's disease (AD).

OBJECTIVE: To summarize the impact of sleep disturbances on AD patients and their caregivers and the effects of currently available sleep therapies.

METHODS: Published studies (January 1985-March 2020) assessing the burden associated with insomnia/sleep disturbances in the AD population and insomnia treatment effects were identified by searching PubMed, Embase, and Cochrane Library and screened against inclusion criteria.

RESULTS: 58 studies assessing patient and caregiver burden, institutionalization, and insomnia treatments in AD patients with sleep disturbances were identified. Sleep disturbances were associated with worse cognition, functional ability, and behavioral and neuropsychological functioning. Health status and quality of life of both patients and caregivers were reduced in the presence of sleep disturbances. Sleep disturbances were also associated with institutionalization. Although significant associations between sleep problems and clinical outcomes were apparent, there was generally no control for other influencing factors (e.g., cognitive status). Bright light and behavioral therapies as well as drugs showed some promise in AD patients, but studies were primarily small and limited data were available, particularly in regard to the effect on associated clinical burden.

CONCLUSION: Sleep disturbances are a significant problem for AD patients and caregivers, associated with behavioral and psychological problems and cognitive decline. However, they remain poorly characterized and under-researched. As the global population is aging and AD is on thes rise, data from larger, prospective trials are required to fully understand the clinical correlates of sleep disturbances and the impact insomnia treatments can have.

%B J Alzheimers Dis %V 86 %P 83-109 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35001893?dopt=Abstract %R 10.3233/JAD-215324 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Can Diet Supplements of Macular Pigment of Lutein, Zeaxanthin, and Meso-zeaxanthin Affect Cognition? %A Wang, Hongwei %A Wang, Ge %A Billings, Rebecca %A Li, Daniel %A Haase, Shakaye R %A Wheeler, Pariya F %A Vance, David E %A Li, Wei %X

BACKGROUND: Lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ) are collectively called macular pigment. MZ can be converted from L in the macula. In the recent decade, many studies have been performed to investigate the effects for taking carotenoids, especially L and Z or L, Z, and MZ, as diet supplements on human health.

OBJECTIVE: We examined if diet supplements of L + Z or L + Z + MZ have effects on cognitive function in adults.

METHODS: A systemic literature search was performed in March 2021 with the following keywords: lutein, zeaxanthin, meso-zeaxanthin, cognition, cognitive, and macular pigment. The searched databases included Medline EBSCOhost, Scopus, Elsevier, Cochrane Library, ProQuest, and ClinicalTrials.gov. Findings from eight clinical trials were presented as the strongest evidence on the studied topic.

RESULTS: Most studies have found that macular pigments (L + Z) in blood or macula are positively correlated with cognitive performance. As an index of the amount of macular pigments in the brain, macular pigment optical density is related to cognitive performance in adults. In addition, there is an inverse relationship between a higher amount of macular pigment in the blood and lower risk of mild cognitive impairments or Alzheimer's disease. Based on the findings from the clinical trials, diet supplements of L + Z or L + Z + MZ are associated with improved cognition in adults.

CONCLUSION: The diet supplements of L + Z or L + Z+MZ are associated with better cognitive functioning, which may be via their beneficial effects on the vision.

%B J Alzheimers Dis %V 87 %P 1079-1087 %8 2022 May 31 %G eng %N 3 %R 10.3233/JAD-215736 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Cancer and Vascular Comorbidity Effects on Dementia Risk and Neuropathology in the Oldest-Old. %A Lachner, Christian %A Day, Gregory S %A Camsari, Gamze Balci %A Kouri, Naomi %A Ertekin-Taner, Nilufer %A Boeve, Bradley F %A Labuzan, Sydney A %A Lucas, John A %A Thompson, E Aubrey %A Siddiqui, Habeeba %A Crook, Julia E %A Cabrera-Rodriguez, Janisse N %A Josephs, Keith A %A Petersen, Ronald C %A Dickson, Dennis W %A Reichard, R Ross %A Mielke, Michelle M %A Knopman, David S %A Graff-Radford, Neill R %A Murray, Melissa E %X

BACKGROUND: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes.

OBJECTIVE: Investigate vascular and cancer contributions to dementia and neuropathology in oldest-old.

METHODS: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology.

RESULTS: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95-106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19-0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39-163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17-0.78]; p <  0.01) and lower Braak stage (p = 0.01).

CONCLUSION: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-β plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old.

%B J Alzheimers Dis %V 90 %P 405-417 %8 2022 Oct 25 %G eng %N 1 %R 10.3233/JAD-220440 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Caregiver Tele-Assistance for Reduction of Emotional Distress During the COVID-19 Pandemic. Psychological Support to Caregivers of People with Dementia: The Italian Experience. %A Rotondo, Emanuela %A Galimberti, Daniela %A Mercurio, Matteo %A Giardinieri, Giulia %A Forti, Sara %A Vimercati, Roberto %A Borracci, Vittoria %A Fumagalli, Giorgio G %A Pietroboni, Anna M %A Carandini, Tiziana %A Nobili, Alessandro %A Scarpini, Elio %A Arighi, Andrea %K Aged %K Aged, 80 and over %K Caregiver Burden %K Caregivers %K COVID-19 %K Dementia %K Female %K Humans %K Italy %K Male %K Middle Aged %K Psychological Distress %K Psychosocial Support Systems %K Quality of Life %K Surveys and Questionnaires %K Telephone %X

BACKGROUND: COVID-19 pandemic worsened vulnerability of patients with dementia (PWD). This new reality associated with government restriction and isolation worsened stress burden and psychological frailties in PWD caregivers.

OBJECTIVE: To give tele-psychological support to caregivers and evaluate the effect of this intervention by quantifying stress burden and quality of life during the first COVID-19 lockdown.

METHODS: 50 caregivers were divided into two groups: "Caregiver-focused group" (Cg) and "Patient-focused group" (Pg). Both groups received telephone contact every 2 weeks over a 28-week period, but the content of the call was different: in Cg, caregivers answered questions about the state of the PWD but also explored their own emotional state, stress burden, and quality of life. In Pg instead, telephone contacts were focused only on the PWD, and no evaluation regarding the caregiver mood or state of stress was made. Psychometric scales were administered to evaluate COVID-19 impact, stress burden, and quality of life.

RESULTS: Considering the time of intervention, from baseline (W0) to W28, Zarit Burden Interview and Quality of Life-caregiver questionnaires remained unchanged in Cg as compared with baseline (p > 0.05), whereas they worsened significantly in Pg (p < 0.01), showing increased stress over time and decreased quality of life in this group. Moreover, Impact on Event Scale values improved over the weeks in Cg (p = 0.015), while they remained unchanged in Pg (p = 0.483).

CONCLUSION: Caregivers who received telephone support about their mood and stress burden did not worsen their psychological state during the time of intervention, as did instead those who did not get such support.

%B J Alzheimers Dis %V 85 %P 1045-1052 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34806608?dopt=Abstract %R 10.3233/JAD-215185 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Cerebrospinal Fluid Sphingomyelins in Alzheimer's Disease, Neurodegeneration, and Neuroinflammation. %A Morrow, Autumn %A Panyard, Daniel J %A Deming, Yuetiva K %A Jonaitis, Erin %A Dong, Ruocheng %A Vasiljevic, Eva %A Betthauser, Tobey J %A Kollmorgen, Gwendlyn %A Suridjan, Ivonne %A Bayfield, Anna %A Van Hulle, Carol A %A Zetterberg, Henrik %A Blennow, Kaj %A Carlsson, Cynthia M %A Asthana, Sanjay %A Johnson, Sterling C %A Engelman, Corinne D %X

BACKGROUND: Sphingomyelin (SM) levels have been associated with Alzheimer's disease (AD), but the association direction has been inconsistent and research on cerebrospinal fluid (CSF) SMs has been limited by sample size, breadth of SMs examined, and diversity of biomarkers available.

OBJECTIVE: Here, we seek to build on our understanding of the role of SM metabolites in AD by studying a broad range of CSF SMs and biomarkers of AD, neurodegeneration, and neuroinflammation.

METHODS: Leveraging two longitudinal AD cohorts with metabolome-wide CSF metabolomics data (n = 502), we analyzed the relationship between the levels of 12 CSF SMs, and AD diagnosis and biomarkers of pathology, neurodegeneration, and neuroinflammation using logistic, linear, and linear mixed effects models.

RESULTS: No SMs were significantly associated with AD diagnosis, mild cognitive impairment, or amyloid biomarkers. Phosphorylated tau, neurofilament light, α-synuclein, neurogranin, soluble triggering receptor expressed on myeloid cells 2, and chitinase-3-like-protein 1 were each significantly, positively associated with at least 5 of the SMs.

CONCLUSION: The associations between SMs and biomarkers of neurodegeneration and neuroinflammation, but not biomarkers of amyloid or diagnosis of AD, point to SMs as potential biomarkers for neurodegeneration and neuroinflammation that may not be AD-specific.

%B J Alzheimers Dis %V 90 %P 667-680 %8 2022 Nov 08 %G eng %N 2 %R 10.3233/JAD-220349 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Characterization of Mild Cognitive Impairment and Dementia among Community-Dwelling Mexican Americans and Non-Hispanic Whites. %A O'Bryant, Sid E %A Petersen, Melissa %A Hall, James %A Johnson, Leigh A %A Barber, Robert %A Phillips, Nicole %A Braskie, Meredith N %A Yaffe, Kristine %A Rissman, Robert %A Toga, Arthur %X

BACKGROUND: Despite tremendous advancements in the field, our understanding of mild cognitive impairment (MCI) and Alzheimer's disease (AD) among Mexican Americans remains limited.

OBJECTIVE: The aim of this study was to characterize MCI and dementia among Mexican Americans and non-Hispanic whites.

METHODS: Baseline data were analyzed from n = 1,705 (n = 890 Mexican American; n = 815 non-Hispanic white) participants enrolled in the Health and Aging Brain Study-Health Disparities (HABS-HD).

RESULTS: Among Mexican Americans, age (OR = 1.07), depression (OR = 1.09), and MRI-based neurodegeneration (OR = 0.01) were associated with dementia, but none of these factors were associated with MCI. Among non-Hispanic whites, male gender (OR = 0.33), neighborhood deprivation (OR = 1.34), depression (OR = 1.09), and MRI-based neurodegeneration (OR = 0.03) were associated with MCI, while depression (OR = 1.09) and APOEɛ4 genotype (OR = 4.38) were associated with dementia.

CONCLUSION: Findings from this study revealed that the demographic, clinical, sociocultural and biomarker characteristics of MCI and dementia are different among Mexican Americans as compared to non-Hispanic whites.

%B J Alzheimers Dis %V 90 %P 905-915 %8 2022 Nov 08 %G eng %N 2 %R 10.3233/JAD-220300 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Circulating Cell-Free Genomic DNA Is Associated with an Increased Risk of Dementia and with Change in Cognitive and Physical Function. %A Nidadavolu, Lolita S %A Feger, Danielle %A Wu, Yuqiong %A Grodstein, Francine %A Gross, Alden L %A Bennett, David A %A Walston, Jeremy D %A Oh, Esther S %A Abadir, Peter M %X

BACKGROUND: Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death and turnover, releasing circulating cell-free DNA (ccf-DNA).

OBJECTIVE: The goal of this study is to determine if serum genomic cell-free DNA (ccf-gDNA) is associated with physical and cognitive decline in older adults.

METHODS: We used serum from 631 community-dwelling individuals from the Religious Orders Study or Rush Memory and Aging Project who were without cognitive impairment at baseline. ccf-gDNA fragments in serum were quantified using digital PCR. An array of cognitive and physical traits, risk of dementia, global cognition, and frailty at or nearest the time of blood draw were regressed on ccf-DNA, with adjustment for age, sex, race, and education.

RESULTS: Cross-sectionally, higher ccf-gDNA levels were associated with lower global cognition score and slower gait speed at the evaluation nearest to blood draw. Higher ccf-gDNA levels were associated with increased odds of incident dementia (OR 1.27, 95% CI 1.05, 1.54). Longitudinally, higher levels of ccf-gDNA were associated with steeper general cognitive decline and worsening frailty over eight years of follow up.

CONCLUSION: This study demonstrates that ccf-gDNA fragments have utility for identifying persons at higher risk of developing dementia and worsening cognition and frailty.

%B J Alzheimers Dis %V 89 %P 1233-1240 %8 2022 Oct 11 %G eng %N 4 %R 10.3233/JAD-220301 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Clinical and Imaging Determinants of Neurocognitive Disorders in Post-Acute COVID-19 Patients with Cognitive Complaints. %A Andriuta, Daniela %A Si-Ahmed, Cherifa %A Roussel, Martine %A Constans, Jean-Marc %A Makki, Malek %A Aarabi, Ardalan %A Basille, Damien %A Andrejak, Claire %A Godefroy, Olivier %K Cognition %K COVID-19 %K Humans %K Leukoaraiosis %K Magnetic Resonance Imaging %K Neurocognitive Disorders %K Neuropsychological Tests %K Oxygen %K White Matter %X

BACKGROUND: Neurocognitive disorders (NCDs) are a part of the post-acute coronavirus disease (COVID-19) syndrome. No study has specifically evaluated NCDs in post-acute COVID-19 patients with cognitive complaints or their MRI determinants.

OBJECTIVE: To characterize NCDs in post-acute COVID-19 patients with cognitive complaints. The secondary objectives were to assess their clinical and MRI determinants.

METHODS: We included 46 patients with a post-acute COVID-19 cognitive complaint referred to the Amiens University Hospital Memory Center. They underwent a neuropsychological assessment and 36 had cerebral MRI. The G3 overall summary score was the sum of the mean z scores for the executive function, language, and action speed domains. Neuropsychological profiles were compared in a general linear model. Clinical determinants were analyzed by stepwise linear regression. White matter hyperintensities (WMH) masks were analyzed using parcel-based WMH symptom mapping to identify the locations of WMHs associated with cognitive performance.

RESULTS: Repeated ANOVA showed a group effect (p = 0.0001) due to overall lower performance for patients and a domain effect (p = 0.0001) due to a lower (p = 0.007) action speed score. The G3 overall summary score was significantly associated with solely the requirement for oxygen (R2 = 0.319, p = 0.031). WHMs were associated with the G3 overall summary score in the following structures, all right-sided (p < 0.01): superior frontal region, postcentral region, cingulum, cortico-spinal tract, inferior longitudinal fasciculus, internal capsule, and posterior segment of the arcuate fasciculus.

CONCLUSION: Post-acute COVID-19 patients with cognitive complaints had NCD, with prominent action slowing, significantly associated with the acute phase oxygen requirement and a right-sided WMH structure pattern.

%B J Alzheimers Dis %V 87 %P 1239-1250 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35431242?dopt=Abstract %R 10.3233/JAD-215506 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Clinical Utility of Cerebrospinal Fluid Aβ42 and Tau Measures in Diagnosing Mild Cognitive Impairment in Early Onset Dementia. %A Hosseini, Akram A %A Brown, Thomas %A Mannino, Luca %A Gran, Bruno %A Junaid, Kehinde %A Mukaetova-Ladinska, Elizabeta B %X

BACKGROUND: The differentiation of a preclinical or prodromal Alzheimer's disease (AD) is challenging particularly in patients with early onset Alzheimer's or related dementias (EOARD). We report our experience on diagnostic lumbar puncture to diagnose EOARD at a tertiary neurocognitive referral center in Nottingham, England from March 2018 to October 2020.

OBJECTIVE: To assess amyloid-β42 (Aβ42), total tau, and Thr181-phosphorylated tau (p-tau) measurements in the cerebrospinal fluid (CSF) in patients with mild cognitive impairment (MCI) and in relation to their follow-up cognitive performance.

METHODS: Thirty participants aged 32-68 years old (mean 59 years; 57% female) were included. Clinical diagnosis was based on clinical presentation, neurocognitive profile, neuroradiological features (MRI, FDG-PET CT) and CSF Aβ42, total tau, and p-tau measurements.

RESULTS: Patients with MCI who progressed to AD (prodromal AD) had significantly higher CSF total (797.63 pg/ml) and p-tau (82.31 pg/ml), and lower Aβ42 levels (398.94 pg/ml) in comparison to their counterparts with stable MCI (total tau 303.67 pg/ml, p-tau 43.56 pg/ml, Aβ42 873.44 pg/ml) (p <  0.01 for CSF total and p-tau measures and p <  0.0001 for CSF Aβ42 measures). None of the CSF biomarkers correlated with any of the cognitive performance measures. Principal component analysis confirmed that the clinical diagnosis of MCI secondary to AD, namely prodromal AD (as per NIA-AA criteria) in younger adults, was associated with decreased CSF Aβ42.

CONCLUSION: In early onset AD, low levels of CSF Aβ42 appear to be more sensitive than total and p-tau measures in differentiating AD MCI from other forms of dementia. Further work on larger samples of EOARD in clinical practice will address the cost effectiveness of making an earlier diagnosis.

%B J Alzheimers Dis %V 87 %P 771-780 %8 2022 May 17 %G eng %N 2 %R 10.3233/JAD-215650 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Combinational Drug Repurposing from Genetic Networks Applied to Alzheimer's Disease. %A Nabirotchkin, Serguei %A Bouaziz, Jan %A Glibert, Fabrice %A Mandel, Jonas %A Foucquier, Julie %A Hajj, Rodolphe %A Callizot, Noëlle %A Cholet, Nathalie %A Guedj, Mickaël %A Cohen, Daniel %X

BACKGROUND: Human diseases are multi-factorial biological phenomena resulting from perturbations of numerous functional networks. The complex nature of human diseases explains frequently observed marginal or transitory efficacy of mono-therapeutic interventions. For this reason, combination therapy is being increasingly evaluated as a biologically plausible strategy for reversing disease state, fostering the development of dedicated methodological and experimental approaches. In parallel, genome-wide association studies (GWAS) provide a prominent opportunity for disclosing human-specific therapeutic targets and rational drug repurposing.

OBJECTIVE: In this context, our objective was to elaborate an integrated computational platform to accelerate discovery and experimental validation of synergistic combinations of repurposed drugs for treatment of common human diseases.

METHODS: The proposed approach combines adapted statistical analysis of GWAS data, pathway-based functional annotation of genetic findings using gene set enrichment technique, computational reconstruction of signaling networks enriched in disease-associated genes, selection of candidate repurposed drugs and proof-of-concept combinational experimental screening.

RESULTS: It enables robust identification of signaling pathways enriched in disease susceptibility loci. Therapeutic targeting of the disease-associated signaling networks provides a reliable way for rational drug repurposing and rapid development of synergistic drug combinations for common human diseases.

CONCLUSION: Here we demonstrate the feasibility and efficacy of the proposed approach with an experiment application to Alzheimer's disease.

%B J Alzheimers Dis %V 88 %P 1585-1603 %8 2022 Aug 16 %G eng %N 4 %R 10.3233/JAD-220120 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Comparative Analysis of Alzheimer's Disease Cerebrospinal Fluid Biomarkers Measurement by Multiplex SOMAscan Platform and Immunoassay-Based Approach. %A Timsina, Jigyasha %A Gomez-Fonseca, Duber %A Wang, Lihua %A Do, Anh %A Western, Dan %A Álvarez, Ignacio %A Aguilar, Miquel %A Pastor, Pau %A Henson, Rachel L %A Herries, Elizabeth %A Xiong, Chengjie %A Schindler, Suzanne E %A Fagan, Anne M %A Bateman, Randall J %A Farlow, Martin %A Morris, John C %A Perrin, Richard %A Moulder, Krista %A Hassenstab, Jason %A Chhatwal, Jasmeer %A Mori, Hiroshi %A Sung, Yun Ju %A Cruchaga, Carlos %X

BACKGROUND: The SOMAscan assay has an advantage over immunoassay-based methods because it measures a large number of proteins in a cost-effective manner. However, the performance of this technology compared to the routinely used immunoassay techniques needs to be evaluated.

OBJECTIVE: We performed comparative analyses of SOMAscan and immunoassay-based protein measurements for five cerebrospinal fluid (CSF) proteins associated with Alzheimer's disease (AD) and neurodegeneration: NfL, Neurogranin, sTREM2, VILIP-1, and SNAP-25.

METHODS: We compared biomarkers measured in ADNI (N = 689), Knight-ADRC (N = 870), DIAN (N = 115), and Barcelona-1 (N = 92) cohorts. Raw protein values were transformed using z-score in order to combine measures from the different studies. sTREM2 and VILIP-1 had more than one analyte in SOMAscan; all available analytes were evaluated. Pearson's correlation coefficients between SOMAscan and immunoassays were calculated. Receiver operating characteristic curve and area under the curve were used to compare prediction accuracy of these biomarkers between the two platforms.

RESULTS: Neurogranin, VILIP-1, and NfL showed high correlation between SOMAscan and immunoassay measures (r >  0.9). sTREM2 had a fair correlation (r >  0.6), whereas SNAP-25 showed weak correlation (r = 0.06). Measures in both platforms provided similar predicted performance for all biomarkers except SNAP-25 and one of the sTREM2 analytes. sTREM2 showed higher AUC for SOMAscan based measures.

CONCLUSION: Our data indicate that SOMAscan performs as well as immunoassay approaches for NfL, Neurogranin, VILIP-1, and sTREM2. Our study shows promise for using SOMAscan as an alternative to traditional immunoassay-based measures. Follow-up investigation will be required for SNAP-25 and additional established biomarkers.

%B J Alzheimers Dis %V 89 %P 193-207 %8 2022 Aug 30 %G eng %N 1 %R 10.3233/JAD-220399 %0 Journal Article %J J Alzheimers Dis %D 2022 %T A Comparison of Behavioral and Psychological Symptoms of Dementia (BPSD) and BPSD Sub-Syndromes in Early-Onset and Late-Onset Alzheimer's Disease. %A Altomari, Natalia %A Bruno, Francesco %A Laganà, Valentina %A Smirne, Nicoletta %A Colao, Rosanna %A Curcio, Sabrina %A Di Lorenzo, Raffaele %A Frangipane, Francesca %A Maletta, Raffaele %A Puccio, Gianfranco %A Bruni, Amalia Cecilia %K Affective Symptoms %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apathy %K Behavioral Symptoms %K Dementia %K Female %K Humans %K Italy %K Male %K Middle Aged %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Psychomotor Agitation %K Psychotic Disorders %K Severity of Illness Index %X

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) have a large impact on the quality of life of patients with Alzheimer's disease (AD). Few studies have compared BPSD between early-onset (EOAD) and late-onset (LOAD) patients, finding conflicting results.

OBJECTIVE: The aims of this study were to: 1) characterize the presence, overall prevalence, and time of occurrence of BPSD in EOAD versus LOAD; 2) estimate the prevalence over time and severity of each BPSD in EOAD versus LOAD in three stages: pre-T0 (before the onset of the disease), T0 (from onset to 5 years), and T1 (from 5 years onwards); 3) track the manifestation of BPSD sub-syndromes (i.e., hyperactivity, psychosis, affective, and apathy) in EOAD versus LOAD at T0 and T1.

METHODS: The sample includes 1,538 LOAD and 387 EOAD diagnosed from 1996 to 2018. Comprehensive assessment batteries, including the Neuropsychiatric Inventory (NPI), were administered at the first medical assessment and at different follow-up period.

RESULTS: The overall prevalence for the most of BPSD was significantly higher in EOAD compared to LOAD whereas most BPSD appeared significantly later in EOAD patients. Between the two groups, from pre-T0 to T1 we recorded a different pattern of BPSD prevalence over time as well as for BPSD sub-syndromes at T0 and T1. Results on severity of BPSD did not show significant differences.

CONCLUSION: EOAD and LOAD represent two different forms of a single entity not only from a neuropathological, cognitive, and functional level but also from a psychiatric point of view.

%B J Alzheimers Dis %V 85 %P 691-699 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34864668?dopt=Abstract %R 10.3233/JAD-215061 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Comparison of Steady-State Pharmacokinetics of Donepezil Transdermal Delivery System with Oral Donepezil. %A Tariot, Pierre N %A Braeckman, Rene %A Oh, Charles %K Adolescent %K Adult %K Alzheimer Disease %K Cross-Over Studies %K Donepezil %K Humans %K Middle Aged %K Young Adult %X

BACKGROUND: Donepezil is approved for treatment of dementia of the Alzheimer type and is currently available only in tablet forms in the United States.

OBJECTIVE: To compare steady-state pharmacokinetics of once-weekly 10-mg/d and 5-mg/d Corplex™ donepezil transdermal delivery systems (TDS) with once-daily 10-mg oral donepezil.

METHODS: Open-label, randomized, crossover study (NCT04617782) enrolled healthy participants aged 18-55 years. All participants received 5-mg/d donepezil TDS during the 5-week Period 1, followed by 10-mg/d TDS or 10-mg/d oral donepezil in the 5-week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at steady state on Week 5.

RESULTS: All 60 enrolled participants received 5-mg/d TDS, 55 received 10-mg/d TDS, and 56 received oral donepezil. Adjusted geometric mean ratio (% [90% CI]) for maximum plasma concentration and area under the plasma concentration versus time curve (0-168 h) were 88.7 (81.7-96.2) and 108.6 (100.5-117.4) for 10-mg/d and 86.1 (79.8-92.9) and 105.3 (97.6-113.6) for dose-normalized 5-mg/d TDS and were generally within the 80% -125% range for establishing bioequivalence with oral donepezil. Skin adhesion was similar for both TDSs (>80% of patches remaining ≥75% adhered throughout the wear period). Overall incidence of adverse events (AEs) was similar across treatments. Compared with 10-mg/d TDS, oral donepezil was associated with higher incidence of gastrointestinal and nervous system AEs (14.5% versus 53.6% and 14.5% versus 30.4%, respectively).

CONCLUSION: Donepezil TDSs are bioequivalent to oral donepezil at steady state and have a safety profile that supports their use in treating dementia of the Alzheimer type.

%B J Alzheimers Dis %V 90 %P 161-172 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/36120781?dopt=Abstract %R 10.3233/JAD-220530 %0 Journal Article %J J Alzheimers Dis %D 2022 %T A Comparison of Well-Being of Carers of People with Dementia and Their Ability to Manage Before and During the COVID-19 Pandemic: Findings from the IDEAL Study. %A Gamble, Laura D %A Parker, Sophie %A Quinn, Catherine %A Bennett, Holly Q %A Martyr, Anthony %A Sabatini, Serena %A Pentecost, Claire %A Collins, Rachel %A Dawson, Eleanor %A Hunt, Anna %A Allan, Louise %A Burns, Alistair %A Litherland, Rachael %A Victor, Christina %A Matthews, Fiona E %A Clare, Linda %K Adaptation, Psychological %K Caregivers %K COVID-19 %K Dementia %K Humans %K Pandemics %K Quality of Life %X

BACKGROUND: Social restriction measures imposed to curb the spread of COVID-19 in the United Kingdom impacted on carers of people with dementia, limiting access to support services and increasing perceived burden of caring. Few studies have compared data collected both during and before the pandemic to examine the effect of these changes.

OBJECTIVE: To explore whether the COVID-19 pandemic affected the well-being of carers of people with dementia living in the community, and their ability to cope with their caring responsibilities.

METHODS: Analysis was conducted on two groups of carers who were enrolled in the IDEAL programme; the 'pre-pandemic group' (n = 312), assessed at two time points prior to the pandemic, and the 'pandemic group', assessed prior to and several months into the pandemic (n = 156). For the pre-pandemic group, carers were matched 2:1 to carers in the pandemic group on certain characteristics. Differences in change over time between the two groups on self-reported well-being, quality of life, coping, perceived competence, and role captivity, were investigated using mixed effect modelling.

RESULTS: Compared to the pre-pandemic group, those in the pandemic group appeared to cope better and had more stable self-rated competency and role captivity. They did not differ in terms of well-being or quality of life.

CONCLUSIONS: Despite reports of negative impacts on carers early in the pandemic, the findings suggest the pandemic had little negative longer-term impact on carers of people with dementia, and in fact they appeared to have a more positive attitude towards coping several months into the pandemic.

%B J Alzheimers Dis %V 88 %P 679-692 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35634850?dopt=Abstract %R 10.3233/JAD-220221 %0 Journal Article %J J Alzheimers Dis %D 2022 %T COVID-19 and Neurodegenerative Diseases: Prion-Like Spread and Long-Term Consequences. %A Baazaoui, Narjes %A Iqbal, Khalid %K Aged %K COVID-19 %K Dementia %K Humans %K Neurodegenerative Diseases %K Prions %K SARS-CoV-2 %X

COVID-19 emerged as a global pandemic starting from Wuhan in China and spread at a lightning speed to the rest of the world. One of the potential long-term outcomes that we speculate is the development of neurodegenerative diseases as a long-term consequence of SARS-CoV-2 especially in people that have developed severe neurological symptoms. Severe inflammatory reactions and aging are two very strong common links between neurodegenerative diseases and COVID-19. Thus, patients that have very high viral load may be at high risk of developing long-term adverse neurological consequences such as dementia. We hypothesize that people with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and aged people are at higher risk of getting the COVID-19 than normal adults. The basis of this hypothesis is the fact that SARS-CoV-2 uses as a receptor angiotensin-converting enzyme 2 to enter the host cell and that this interaction is calcium-dependent. This could then suggest a direct relationship between neurodegenerative diseases, ACE-2 expression, and the susceptibility to COVID-19. The analysis of the available literature showed that COVID-19 virus is neurotropic and was found in the brains of patients infected with this virus. Furthermore, that the risk of having the infection increases with dementia and that infected people with severe symptoms could develop dementia as a long-term consequence. Dementia could be developed following the acceleration of the spread of prion-like proteins. In the present review we discuss current reports concerning the prevalence of COVID-19 in dementia patients, the individuals that are at high risk of suffering from dementia and the potential acceleration of prion-like proteins spread following SARS-CoV-2 infection.

%B J Alzheimers Dis %V 88 %P 399-416 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35599487?dopt=Abstract %R 10.3233/JAD-220105 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Demonstration of Clinical Meaningfulness of the Integrated Alzheimer's Disease Rating Scale (iADRS): Association Between Change in iADRS Scores and Patient and Caregiver Health Outcomes. %A Wessels, Alette M %A Belger, Mark %A Johnston, Joseph A %A Yu, Youying %A Rentz, Dorene M %A Dowsett, Sherie A %A Chandler, Julie %K Alzheimer Disease %K Caregivers %K Clinical Trials as Topic %K Cognitive Dysfunction %K Humans %K Observational Studies as Topic %K Outcome Assessment, Health Care %K Quality of Life %X

BACKGROUND: The integrated Alzheimer's Disease Rating Scale (iADRS) is a validated cognitive/functional composite that effectively captures cognitive and functional decline over a broad spectrum of disease. The clinical meaningfulness of change on iADRS can be supported by establishing an association with changes on important health outcome measures.

OBJECTIVE: To evaluate the relationship between change on the iADRS and changes in health outcomes in individuals with mild cognitive impairment (MCI) due to Alzheimer's disease (AD), or mild or moderate AD dementia using placebo data from four AD clinical trials and data from one AD observational study.

METHODS: Analysis of covariate (ANCOVA) models were used to estimate the relationship between 18-month change on the iADRS and changes on health outcome measures (related to cost, quality of life, and caregiver burden). The regression coefficients for the iADRS were used to compute impact of natural disease progression and disease-modifying treatment on health outcomes. Additional ANCOVAs were conducted to understand whether cognition and/or function was the underlying explanation of any association between iADRS and health outcome change.

RESULTS: Across datasets and disease stages, a worsening on the iADRS was significantly associated with increased societal costs, caregiver burden (time and distress) and worsening in measures of patient quality of life.

CONCLUSION: Decline on the iADRS was associated with worsening in health outcome measures. These findings suggest that the iADRS can be used in clinical trials as a proxy measure of clinically meaningful outcomes of AD progression.

%B J Alzheimers Dis %V 88 %P 577-588 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35694928?dopt=Abstract %R 10.3233/JAD-220303 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Diabetic Retinopathy Predicts Risk of Alzheimer's Disease: A Danish Registry-Based Nationwide Cohort Study. %A Pedersen, Frederik Nørregaard %A Stokholm, Lonny %A Pouwer, Frans %A Hass Rubin, Katrine %A Peto, Tunde %A Frydkjær-Olsen, Ulrik %A Thykjær, Anne Suhr %A Andersen, Nis %A Andresen, Jens %A Bek, Toke %A La Cour, Morten %A Heegaard, Steffen %A Højlund, Kurt %A Kawasaki, Ryo %A Hajari, Javad Nouri %A Ohm Kyvik, Kirsten %A Laugesen, Caroline Schmidt %A Schielke, Katja Christina %A Simó, Rafael %A Grauslund, Jakob %K Alzheimer Disease %K Cohort Studies %K Denmark %K Diabetes Mellitus %K Diabetic Retinopathy %K Humans %K Registries %K Risk Factors %X

BACKGROUND: Retinal neurodegeneration is evident in early diabetic retinopathy (DR) which may be associated with other neurodegenerative diseases like Alzheimer's disease (AD).

OBJECTIVE: To investigate diabetes and DR as a risk marker of present and incident AD.

METHODS: A register-based cohort study was performed. We included 134,327 persons with diabetes above 60 years of age, who had attended DR screening, and 651,936 age- and gender-matched persons without diabetes.

RESULTS: At baseline, the prevalence of AD was 0.7% and 1.3% among patients with and without diabetes, respectively. In a multivariable regression model, patients with diabetes were less likely to have AD at baseline (adjusted OR 0.63, 95% CI 0.59-0.68). During follow-up, incident AD was registered for 1473 (0.35%) and 6,899 (0.34%) persons with and without diabetes, respectively. Compared to persons without diabetes, persons with diabetes and no DR had a lower risk to develop AD (adjusted HR 0.87, 95% CI 0.81-0.93), while persons with diabetes and DR had higher risk of AD (adjusted HR 1.24, 95% CI 1.08-1.43). When persons with diabetes and no DR were used as references, a higher risk of incident AD was observed in persons with DR (adjusted HR 1.34, 95% CI 1.18-1.53).

CONCLUSION: Individuals with diabetes without DR were less likely to develop AD compared to persons without diabetes. However, individuals with DR had a 34% higher risk of incident AD, which raise the question whether screening for cognitive impairment should be done among individuals with DR.

%B J Alzheimers Dis %V 86 %P 451-460 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35068460?dopt=Abstract %R 10.3233/JAD-215313 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Does Loss of Integrity of the Cingulum Bundle Link Amyloid-β Accumulation and Neurodegeneration in Alzheimer's Disease? %A Vlegels, Naomi %A Ossenkoppele, Rik %A van der Flier, Wiesje M %A Koek, Huiberdina L %A Reijmer, Yael D %A Wisse, Laura Em %A Biessels, Geert Jan %X

BACKGROUND: Alzheimer's disease is characterized by the accumulation of amyloid-β (Aβ) into plaques, aggregation of tau into neurofibrillary tangles, and neurodegenerative processes including atrophy. However, there is a poorly understood spatial discordance between initial Aβ deposition and local neurodegeneration.

OBJECTIVE: Here, we test the hypothesis that the cingulum bundle links Aβ deposition in the cingulate cortex to medial temporal lobe (MTL) atrophy.

METHODS: 21 participants with mild cognitive impairment (MCI) from the UMC Utrecht memory clinic (UMCU, discovery sample) and 37 participants with MCI from Alzheimer's Disease Neuroimaging Initiative (ADNI, replication sample) with available Aβ-PET scan, T1-weighted and diffusion-weighted MRI were included. Aβ load of the cingulate cortex was measured by the standardized uptake value ratio (SUVR), white matter integrity of the cingulum bundle was assessed by mean diffusivity and atrophy of the MTL by normalized MTL volume. Relationships were tested with linear mixed models, to accommodate multiple measures for each participant.

RESULTS: We found at most a weak association between cingulate Aβ and MTL volume (added R2 <0.06), primarily for the posterior hippocampus. In neither sample, white matter integrity of the cingulum bundle was associated with cingulate Aβ or MTL volume (added R2 <0.01). Various sensitivity analyses (Aβ-positive individuals only, posterior cingulate SUVR, MTL sub region volume) provided similar results.

CONCLUSION: These findings, consistent in two independent cohorts, do not support our hypothesis that loss of white matter integrity of the cingulum is a connecting factor between cingulate gyrus Aβ deposition and MTL atrophy.

%B J Alzheimers Dis %V 89 %P 39-49 %8 2022 Aug 30 %G eng %N 1 %R 10.3233/JAD-220024 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Effect of Probiotic Bifidobacterium breve in Improving Cognitive Function and Preventing Brain Atrophy in Older Patients with Suspected Mild Cognitive Impairment: Results of a 24-Week Randomized, Double-Blind, Placebo-Controlled Trial. %A Asaoka, Daisuke %A Xiao, Jinzhong %A Takeda, Tsutomu %A Yanagisawa, Naotake %A Yamazaki, Takahiro %A Matsubara, Yoichiro %A Sugiyama, Hideki %A Endo, Noemi %A Higa, Motoyuki %A Kasanuki, Koji %A Ichimiya, Yosuke %A Koido, Shigeo %A Ohno, Kazuya %A Bernier, Francois %A Katsumata, Noriko %A Nagahara, Akihito %A Arai, Heii %A Ohkusa, Toshifumi %A Sato, Nobuhiro %K Aged %K Aged, 80 and over %K Atrophy %K Bifidobacterium breve %K Brain %K Cognition %K Cognitive Dysfunction %K Double-Blind Method %K Humans %K Probiotics %X

BACKGROUND: Probiotics have been reported to ameliorate cognitive impairment.

OBJECTIVE: We investigated the effect of the probiotic strain Bifidobacterium breve MCC1274 (A1) in enhancing cognition and preventing brain atrophy of older patients with mild cognitive impairment (MCI).

METHODS: In this RCT, 130 patients aged from 65 to 88 years old with suspected MCI received once daily either probiotic (B. breve MCC1274, 2×1010 CFU) or placebo for 24 weeks. Cognitive functions were assessed by ADAS-Jcog and MMSE tests. Participants underwent MRI to determine brain atrophy changes using Voxel-based Specific Regional Analysis System for Alzheimer's disease (VSRAD). Fecal samples were collected for the analysis of gut microbiota composition.

RESULTS: Analysis was performed on 115 participants as the full analysis set (probiotic 55, placebo 60). ADAS-Jcog subscale "orientation" was significantly improved compared to placebo at 24 weeks. MMSE subscales "orientation in time" and "writing" were significantly improved compared to placebo in the lower baseline MMSE (< 25) subgroup at 24 weeks. VSRAD scores worsened in the placebo group; probiotic supplementation tended to suppress the progression, in particular among those subjects with progressed brain atrophy (VOI Z-score ≥1.0). There were no marked changes in the overall composition of the gut microbiota by the probiotic supplementation.

CONCLUSION: Improvement of cognitive function was observed on some subscales scores only likely due to the lower sensitiveness of these tests for MCI subjects. Probiotics consumption for 24 weeks suppressed brain atrophy progression, suggesting that B. breve MCC1274 helps prevent cognitive impairment of MCI subjects.

%B J Alzheimers Dis %V 88 %P 75-95 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35570493?dopt=Abstract %R 10.3233/JAD-220148 %0 Journal Article %J J Alzheimers Dis %D 2022 %T The Effectiveness of GRADIOR: A Neuropsychological Rehabilitation Program for People with Mild Cognitive Impairment and Mild Dementia. Results of a Randomized Controlled Trial After 4 and 12 Months of Treatment. %A Diaz Baquero, Angie A %A Franco-Martín, Manuel A %A Parra Vidales, Esther %A Toribio-Guzmán, José Miguel %A Bueno-Aguado, Yolanda %A Martínez Abad, Fernando %A Perea Bartolomé, María V %A Asl, Aysan Mahmoudi %A van der Roest, Henriëtte G %X

BACKGROUND: Computer-based cognitive training programs have been developed with promising results on the maintenance/improvement of cognitive performance in people with dementia.

OBJECTIVE: The objective was to evaluate the effectiveness of the cognitive rehabilitation program "GRADIOR" in people with mild cognitive impairment and mild dementia.

METHOD: This study was a single-blind multicenter randomized clinical trial. Participants were recruited from hospitals/day centers. The experimental group (EG) and control group (CG) received computer-based cognitive training (CCT) and routine daily care, respectively. Outcome measures at T0: baseline, T1: at 4 months, T2: at 12 months were compared within and between-groups.

RESULTS: Significant differences or important effect sizes were detected at the intragroup and intergroup level for most variables, observing a trend of improvement and/or maintenance at 4 months by Visual Reasoning of Cambridge Cognitive Examination (CAMCOG), Digit and Arithmetic of WAIS-III, Semantic Verbal Fluency, Mini-Mental State Exam (MMSE), Trail Making Test (TMT)-A-Mistakes and at 12 months by Visual Reasoning of CAMCOG, Digit Symbol of WAIS-III, TMT-B-mistakes, Visual Memory of Rivermead Behavioural Memory Test, Lexical Verbal Fluency-P, Yesavage's Geriatric Depression Scale (GDS), TMT-A-time scales whose objective was to evaluate some executive functions and/or the memory. The CG presented a worsening trend for most of the measures towards 12 months. There was also a significant interaction between "time and group" for MMSE (F = 8.971; p = 0.03; η 2 = 0.019) and the GDS (F = 3.414; p = 0.04; η 2 = 0.041), as well as small effect sizes for TMT-A-time (F = 1.641; p = 0.21; η 2 = 0.021) and TMT-A-mistakes (F = 0.908; p = 0.41; η 2 = 0.019).

CONCLUSION: CCT with GRADIOR has been proved to benefit cognitive functions (ISRCTN:15742788).

%B J Alzheimers Dis %V 86 %P 711-727 %8 2022 Mar 22 %G eng %N 2 %R 10.3233/JAD-215350 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Effects of a 6-Month Multifaceted Diet and Exercise Intervention on Cognition in Older Adults at Risk of Cognitive Decline: The PONDER Double-Blind, Placebo-Controlled Randomized Trial. %A Macpherson, Helen %A Brownell, Sarah %A Harris, Elizabeth %A Duckham, Rachel L %A O'Connell, Stella %A Meyer, Barbara J %A Mirzaee, Sam %A Daly, Robin M %X

BACKGROUND: Multidomain interventions which incorporate exercise and dietary supplementation to target both cognitive and physical health domains may be an important approach to delay cognitive decline.

OBJECTIVE: The Protein Omega-3 aNd vitamin D Exercise Research (PONDER) study investigated the effects of a 6-month multifaceted intervention in community-dwelling older adults with subjective memory impairment on cognition (primary outcome), physical function, and body composition with a further 6-month follow up for cognition (secondary outcomes).

METHODS: Single-center, community-based, parallel-group, randomized, double-blind placebo-controlled trial involving a 6-month multifaceted intervention with a further follow-up at 12 months. A total of 147 participants [mean age 70.2 years (SD 6.1), 70% female] were randomized to a multimodal exercise program consisting of twice-weekly supervised resistance and aerobic training, combined with a daily omega-3 (900 mg EPA, 600 mg DHA), vitamin D (1000 IU) and protein (20 g) supplement (n = 73), or a control condition (n = 74) comprising stretching/flexibility sessions combined with a placebo. The primary outcome was a composite CogState measure and Trail-Making Test B-A.

RESULTS: There were no significant between-group differences in the change of cognition at 6 or 12 months or physical function outcomes at 6 months, but the intervention significantly improved total lean mass compared to controls [0.72 kg (95% CI 0.26-1.19), p = 0.001].

CONCLUSION: A multi-faceted intervention including an omega-3, vitamin D and protein-enriched supplement with twice-weekly exercise training did not provide any benefits to cognitive or physical function in older adults with subjective memory impairment, despite improvements in lean mass.

%B J Alzheimers Dis %V 89 %P 247-263 %8 2022 Aug 30 %G eng %N 1 %R 10.3233/JAD-220234 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Frontal Atrophy and Executive Dysfunction Relate to Complex Numbers Impairment in Progressive Supranuclear Palsy. %A Howard, Erica %A Ballinger, Samantha %A Kinney, Nikolas G %A Balgenorth, Yvonne %A Ehrhardt, Annabess %A Phillips, Jeffrey S %A Irwin, David J %A Grossman, Murray %A Cousins, Katheryn A Q %X

BACKGROUND: Previous research finds a range of numbers impairments in Parkinsonian syndromes (PS), but has largely focused on how visuospatial impairments impact deficits in basic numerical processes (e.g., magnitude judgments, chunking). Differentiation between these basic functions and more complex numerical processes often utilized in everyday tasks may help elucidate neurocognitive and neuroanatomic bases of numbers deficits in PS.

OBJECTIVE: To test neurocognitive and neuroanatomic correlates of complex numerical processing in PS, we assessed number abilities, neuropsychological performance, and cortical thickness in progressive supranuclear palsy (PSP) and Lewy body spectrum disorders (LBSD).

METHODS: Fifty-six patients (LBSD = 35; PSP = 21) completed a Numbers Battery, including basic and complex numerical tasks. The Mini-Mental State Exam (MMSE), letter fluency (LF), and Judgment of Line Orientation (JOLO) assessed global, executive, and visuospatial functioning respectively. Mann-Whitney U tests compared neuropsychological testing and rank-transformed analysis of covariance (ANCOVA) compared numbers performance between groups while adjusting for demographic variables. Spearman's and partial correlations related numbers performance to neuropsychological tasks. Neuroimaging assessed cortical thickness in disease groups and demographically-matched healthy controls.

RESULTS: PSP had worse complex numbers performance than LBSD (F = 6.06, p = 0.02) but similar basic numbers performance (F = 0.38, p >  0.1), covarying for MMSE and sex. Across syndromes, impaired complex numbers performance was linked to poor LF (rho = 0.34, p = 0.01) but not JOLO (rho = 0.23, p >  0.05). Imaging revealed significant frontal atrophy in PSP compared to controls, which was associated with worse LF and complex numbers performance.

CONCLUSION: PSP demonstrated selective impairments in complex numbers processing compared to LBSD. This complex numerical deficit may relate to executive dysfunction and frontal atrophy.

%B J Alzheimers Dis %V 88 %P 1553-1566 %8 2022 Aug 16 %G eng %N 4 %R 10.3233/JAD-215327 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Glucometabolic Changes Are Associated with Structural Gray Matter Alterations in Prodromal Dementia. %A Gentreau, Mélissa %A Reynes, Christelle %A Sabatier, Robert %A Maller, Jerome J %A Meslin, Chantal %A Deverdun, Jeremy %A Le Bars, Emmanuelle %A Raymond, Michel %A Berticat, Claire %A Artero, Sylvaine %X

BACKGROUND: Glucometabolic changes, such as high glycemic load (GL) diet and insulin resistance (IR), are potential risk factor of Alzheimer's disease (AD). Yet, the effect of these factors on brain alterations that contribute to AD pathology has not been clearly demonstrated.

OBJECTIVE: We aimed to assess the relationship of GL and IR with gray matter volumes involved in prodromal dementia.

METHODS: GL and Triglyceride-Glucose (TyG) index, an IR surrogate marker, were calculated in 497 participants who underwent magnetic resonance imaging (MRI). The gray matter volumes most related to prodromal dementia/mild cognitive impairment (diagnosed in 18/158 participants during the 7-year follow-up) were identified using a data-driven machine learning algorithm.

RESULTS: Higher GL diet was associated with reduced amygdala volume. The TyG index was negatively associated with the hippocampus, amygdala, and putamen volumes.

CONCLUSION: These results suggest that GL and IR are associated with lower gray matter volumes in brain regions involved in AD pathology.

%B J Alzheimers Dis %V 89 %P 1293-1302 %8 2022 Oct 11 %G eng %N 4 %R 10.3233/JAD-220490 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Impact of COVID-19 on 'Living Well' with Mild-to-Moderate Dementia in the Community: Findings from the IDEAL Cohort. %A Clare, Linda %A Martyr, Anthony %A Gamble, Laura D %A Pentecost, Claire %A Collins, Rachel %A Dawson, Eleanor %A Hunt, Anna %A Parker, Sophie %A Allan, Louise %A Burns, Alistair %A Hillman, Alexandra %A Litherland, Rachael %A Quinn, Catherine %A Matthews, Fiona E %A Victor, Christina %K Activities of Daily Living %K Adult %K Aged %K Aged, 80 and over %K Caregivers %K COVID-19 %K Dementia %K Female %K Humans %K Male %K Middle Aged %K Neighborhood Characteristics %K Quality of Life %K SARS-CoV-2 %X

BACKGROUND: Negative impacts of the COVID-19 pandemic on people with dementia have been widely-documented, but most studies have relied on carer reports and few have compared responses to information collected before the pandemic.

OBJECTIVE: We aimed to explore the impact of the pandemic on community-dwelling individuals with mild-to-moderate dementia and compare responses with pre-pandemic data.

METHODS: During the second wave of the pandemic, we conducted structured telephone interviews with 173 people with dementia and 242 carers acting as informants, all of whom had previously participated in the IDEAL cohort. Where possible, we benchmarked responses against pre-pandemic data.

RESULTS: Significant perceived negative impacts were identified in cognitive and functional skills and ability to engage in self-care and manage everyday activities, along with increased levels of loneliness and discontinuity in sense of self and a decline in perceived capability to 'live well'. Compared to pre-pandemic data, there were lower levels of pain, depression, and anxiety, higher levels of optimism, and better satisfaction with family support. There was little impact on physical health, mood, social connections and relationships, or perceptions of neighborhood characteristics.

CONCLUSION: Efforts to mitigate negative impacts of pandemic-related restrictions and restore quality of life could focus on reablement to address the effects on participation in everyday activities, creating opportunities for social contact to reduce loneliness, and personalized planning to reconnect people with their pre-COVID selves. Such efforts may build on the resilience demonstrated by people with dementia and carers in coping with the pandemic.

%B J Alzheimers Dis %V 85 %P 925-940 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34776448?dopt=Abstract %R 10.3233/JAD-215095 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Impaired Experience-Dependent Refinement of Place Cells in a Rat Model of Alzheimer's Disease. %A Broussard, John I %A Redell, John B %A Maynard, Mark E %A Zhao, Jing %A Moore, Anthony %A Mills, Rachel W %A Hood, Kimberly N %A Underwood, Erica %A Roysam, Badrinath %A Dash, Pramod K %X

BACKGROUND: Hippocampal place cells play an integral role in generating spatial maps. Impaired spatial memory is a characteristic pathology of Alzheimer's disease (AD), yet it remains unclear how AD influences the properties of hippocampal place cells.

OBJECTIVE: To record electrophysiological activity in hippocampal CA1 neurons in freely-moving 18-month-old male TgF344-AD and age-matched wild-type (WT) littermates to examine place cell properties.

METHODS: We implanted 32-channel electrode arrays into the CA1 subfield of 18-month-old male WT and TgF344-AD (n = 6/group) rats. Ten days after implantation, single unit activity in an open field arena was recorded across days. The spatial information content, in-field firing rate, and stability of each place cell was compared across groups. Pathology was assessed by immunohistochemical staining, and a deep neural network approach was used to count cell profiles.

RESULTS: Aged TgF344-AD rats exhibited hippocampal amyloid-β deposition, and a significant increase in Iba1 immunoreactivity and microglia cell counts. Place cells from WT and TgF344-AD rat showed equivalent spatial information, in-field firing rates, and place field stability when initially exposed to the arena. However, by day 3, the place cells in aged WT rats showed characteristic spatial tuning as evidenced by higher spatial information content, stability, and in-field firing rates, an effect not seen in TgF344-AD rats.

CONCLUSION: These findings support the notion that altered electrophysiological properties of place cells may contribute to the learning and memory deficits observed in AD.

%B J Alzheimers Dis %V 86 %P 1907-1916 %8 2022 Apr 19 %G eng %N 4 %R 10.3233/JAD-215023 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Importance of Accounting for Regional Differences in Modifiable Risk Factors for Alzheimer's Disease and Related Dementias: The Case for Tailored Interventions. %A Hoffmann, Coles M %A Nianogo, Roch A %A Yaffe, Kristine %A Rosenwohl-Mack, Amy %A Carrasco, Anna %A Barnes, Deborah E %X

BACKGROUND: We recently estimated that 36.9% of Alzheimer's disease and related dementias (ADRD) cases in the US may be attributable to modifiable risk factors, but it is not known whether national estimates generalize to specific states or regions.

OBJECTIVE: To compare national estimates of modifiable risk factors of ADRD to California, overall and by sex and race/ethnicity, and to estimate number of cases potentially preventable by reducing the prevalence of key risk factors by 25%.

METHODS: Adults ≥18 years who participated in the Behavioral Risk Factor Surveillance Survey in California (n = 9,836) and the US (n = 378,615). We calculated population attributable risks (PARs) for eight risk factors (physical inactivity, current smoking, depression, low education, diabetes mellitus, midlife obesity, midlife hypertension, and hearing loss) and compared estimates in California and the U.S.

RESULTS: In California, overall, 28.9% of ADRD cases were potentially attributable to the combination of risk factors, compared to 36.9% in the U.S. The top three risk factors were the same in California and the U.S., although their relative importance differed (low education [CA:14.9%; U.S.:11.7% ], midlife obesity [CA:14.9%; U.S.:17.7% ], and physical inactivity [CA:10.3%; U.S.:11.8% ]). The number of ADRD cases attributable to the combined risk factors was 199,246 in California and 2,287,683 in the U.S. If the combined risk factors were reduced by 25%, we could potentially prevent more than 40,000 cases in California and 445,000 cases in the U.S.

CONCLUSION: Our findings highlight the importance of examining risk factors of ADRD regionally, and within sex and race/ethnic groups to tailor dementia risk reduction strategies.

%B J Alzheimers Dis %V 89 %P 563-570 %8 2022 Sep 13 %G eng %N 2 %R 10.3233/JAD-220278 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Improved Alzheimer's Disease versus Frontotemporal Lobar Degeneration Differential Diagnosis Combining EEG and Neurochemical Biomarkers: A Pilot Study. %A Laton, Jorne %A Van Schependom, Jeroen %A Goossens, Joery %A Wiels, Wietse %A Sieben, Anne %A De Deyn, Peter Paul %A Goeman, Johan %A Streffer, Johannes %A van der Zee, Julie %A Martin, Jean-Jacques %A Van Broeckhoven, Christine %A De Vos, Maarten %A Bjerke, Maria %A Nagels, Guy %A Engelborghs, Sebastiaan %X

BACKGROUND: Distinguishing between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) results in poor diagnostic accuracy.

OBJECTIVE: To investigate the utility of electroencephalography (EEG)-based biomarkers in comparison and in addition to established cerebrospinal fluid (CSF) biomarkers in the AD versus FTLD differential diagnosis.

METHODS: The study cohort comprised 37 AD and 30 FTLD patients, of which 17 AD and 9 FTLD patients had definite diagnoses. All participants had CSF neurochemical (NCM) biomarker analyses (Aβ1-42, T-tau, P-tau181, and Nf-L) and underwent 19-channel resting-state EEG. From the EEG spectra, dominant frequency peaks were extracted in four regions resulting in four dominant frequencies. This produced eight features (4 NCM + 4 EEG).

RESULTS: When NCM and EEG markers were combined, the diagnostic accuracy increased significantly. In the whole group, the accuracy went up from 79% (NCM) to almost 82%, while in the definite group only, it went up from around 85% to almost 95% . Two differences in the occurrence of the dominant EEG frequency were discovered: people lacking a clear dominant peak almost all had definite AD, while people with two peaks more often had FTLD.

CONCLUSION: Combining EEG with NCM biomarkers resulted in differential diagnostic accuracies of 82% in clinically diagnosed AD and FTD patients and of 95% in patients having a definite diagnosis, which was significantly better than with EEG or NCM biomarkers alone. This suggests that NCM and EEG markers are complementary, revealing different aspects of the disease and therefore confirms again their relevance in developing additional diagnosis tools.

%B J Alzheimers Dis %V 90 %P 1739-1747 %8 2022 Dec 06 %G eng %N 4 %R 10.3233/JAD-220693 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Incidence and Outcomes of SARS-CoV-2 Infection in Older Adults Living with Dementia: A Population-Based Cohort Study. %A Cascini, Silvia %A Agabiti, Nera %A Marino, Claudia %A Acampora, Anna %A Balducci, Maria %A Calandrini, Enrico %A Davoli, Marina %A Bargagli, Anna Maria %X

BACKGROUND: The identification of risk factors for SARS-CoV-2 infection and mortality in patients with dementia is a key aspect to support clinical decisions and public health interventions.

OBJECTIVE: To assess the incidence of SARS-CoV-2 infection and COVID-19 related death in a cohort of patients with dementia residing in the Lazio region and to investigate predicting factors for both infection and mortality.

METHODS: This population-based study used information from administrative databases and the SARS-CoV-2 infection surveillance system. Patients with dementia (age ≥65) were enrolled as of December 31, 2019 and followed-up until February 28, 2021. Cumulative risk of infection and death within 60 days of infection onset, and age-standardized incidence (SIR) and mortality (SMR) ratios were calculated. Logistic regression models were applied to identify factors associated with infection and mortality.

RESULTS: Among 37,729 dementia patients, 2,548 had a diagnosis of SARS-CoV-2 infection. The crude risk of infection was 6.7% . An increase in risk of infection was observed both in women (SIR 1.72; 95% CI 1.64-1.80) and men (SIR 1.43; 95% CI 1.33-1.54). Pneumonia, cerebrovascular and blood diseases, femur fracture, anxiety, antipsychotic and antithrombotic use were associated with an increased risk of infection. The crude risk of death was 31.0%, the SMRs 2.32 (95% CI 2.05-2.65) for men, and 2.82 (95% CI 2.55-3.11) for women. Factors associated with mortality included: male gender, age ≥85, symptoms at the diagnosis, antipsychotic and systemic antibiotics treatment.

CONCLUSION: These findings emphasize the need of close and tailored monitoring of dementia patients to reduce the impact of COVID-19 on this fragile population.

%B J Alzheimers Dis %V 89 %P 681-693 %8 2022 Sep 13 %G eng %N 2 %R 10.3233/JAD-220369 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Increased Functional Connectivity of the Precuneus in Individuals with a Family History of Alzheimer's Disease. %A Green, Zachary D %A Vidoni, Eric D %A Swerdlow, Russell H %A Burns, Jeffrey M %A Morris, Jill K %A Honea, Robyn A %X

BACKGROUND: First-degree relatives of individuals with late-onset Alzheimer's disease (AD) have increased risk for AD, with children of affected parents at an especially high risk.

OBJECTIVE: We aimed to investigate default mode network connectivity, medial temporal cortex volume, and cognition in cognitively healthy (CH) individuals with (FH+) and without (FH-) a family history of AD, alongside amnestic mild cognitive impairment (aMCI) and AD individuals, to determine the context and directionality of dysfunction in at-risk individuals. Our primary hypothesis was that there would be a linear decline (CH FH- > CH FH+ > aMCI > AD) within the risk groups on all measures of AD risk.

METHODS: We used MRI and fMRI to study cognitively healthy individuals (n = 28) with and without AD family history (FH+ and FH-, respectively), those with aMCI (n = 31) and early-stage AD (n = 25). We tested connectivity within the default mode network, as well as measures of volume and thickness within the medial temporal cortex and selected seed regions.

RESULTS: As expected, we identified decreased medial temporal cortex volumes in the aMCI and AD groups compared to cognitively healthy groups. We also observed patterns of connectivity across risk groups that suggest a nonlinear relationship of change, such that the FH+ group showed increased connectivity compared to the FH- and AD groups (CH FH+ > CH FH- > aMCI > AD). This pattern emerged primarily in connectivity between the precuneus and frontal regions.

CONCLUSION: These results add to a growing literature that suggests compensatory brain function in otherwise cognitively healthy individuals with a family history of AD.

%B J Alzheimers Dis %V 91 %P 559-571 %8 2023 Jan 17 %G eng %N 2 %R 10.3233/JAD-210326 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Insulin-Like Growth Factor, Inflammation, and MRI Markers of Alzheimer's Disease in Predominantly Middle-Aged Adults. %A Wittfeld, Katharina %A Raman, Mekala R %A Conner, Sarah C %A Aslam, Asra %A Teumer, Alexander %A Nauck, Matthias %A Hosten, Norbert %A Habes, Mohamad %A DeCarli, Charles %A Vasan, Ramachandran S %A Beiser, Alexa S %A Himali, Jayandra J %A Seshadri, Sudha %A Grabe, Hans J %A Satizabal, Claudia L %X

BACKGROUND: Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer's disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults.

OBJECTIVE: To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer's disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation.

METHODS: We included participants from the Framingham Heart Study (n = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n = 674, mean age 50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons.

RESULTS: Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI], -0.05 [-0.09, -0.02], p = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes.

CONCLUSION: Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife.

%B J Alzheimers Dis %V 88 %P 311-32 %8 2022 Jun 28 %G eng %N 1 %R 10.3233/JAD-220356 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Isolated Amyloid-β Pathology Is Associated with Preserved Cortical Plasticity in APOE4 Alzheimer's Disease Patients. %A Assogna, Martina %A Motta, Caterina %A Bonní, Sonia %A Borghi, Ilaria %A Casula, Elias P %A Martorana, Alessandro %A Koch, Giacomo %X

BACKGROUND: Long-term potentiation (LTP) like-cortical plasticity impairment and cholinergic neurotransmission deficits have been widely demonstrated in Alzheimer's disease (AD) patients.

OBJECTIVE: In this study we aim to investigate the neurophysiological features underlying cognitive decline in AD patients according to the National Institute on Aging-Alzheimer's Association (NIA-AA) classification and APOE genotype.

METHODS: 65 newly diagnosed AD patients were enrolled. APOE genotype and lumbar puncture for the analysis of cerebrospinal fluid biomarkers were performed for diagnostic purposes. Patients were subdivided upon NIA-AA criteria, according to the presence of biomarkers of Aβ amyloid deposition (A) and fibrillar tau (T), in four groups: A+/T-E4 (n = 9), A+/T-E3 (n = 18), A+/T+ E4 (n = 21), and A+/T+ E3 (n = 17). We applied intermittent theta burst stimulation over the primary motor cortex to assess LTP-like cortical plasticity and short latency afferent inhibition (SAI) protocol to investigate central cholinergic activity. Patients were followed over 24 months. Cognitive decline was evaluated considering changes in Mini-Mental State Examination scores respect to the baseline.

RESULTS: A+/T-E4 patients showed preserved LTP-like cortical plasticity as compared to A+/T-E3 and to A+/T+ patients independently from genotype (p <  0.001). In addition, A+/T-E4 patients showed a slower cognitive decline with respect to A+/T+ E4 (-0.5±2.12 versus -6.05±4.95; post-hoc p = 0.004) and to A+/T+ E3 patients (-4.12±4.14; post-hoc p = 0.028). No differences were found for SAI protocol (p >  0.05).

CONCLUSION: Our results suggest that APOE4 in patients with isolated amyloid pathology could exert positive effects on LTP-like cortical plasticity with a consequent slower cognitive decline.

%B J Alzheimers Dis %V 86 %P 773-778 %8 2022 Mar 22 %G eng %N 2 %R 10.3233/JAD-215218 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Lipid Peroxidation as a Marker of Apathy and Executive Dysfunction in Patients at Risk for Vascular Cognitive Impairment. %A Bawa, Kritleen K %A Ba, Joycelyn %A Kiss, Alex %A Wang, RuoDing %A Feng, Vivian %A Swardfager, Walter %A Andreazza, Ana %A Gallagher, Damien %A Marotta, Giovanni %A Herrmann, Nathan %A Lanctôt, Krista L %X

BACKGROUND: The co-occurrence of apathy and executive dysfunction, a correlate of vascular cognitive impairment (VCI), is highly prevalent, yet facilitating factors are largely unknown.

OBJECTIVE: This study investigates the relationship between lipid peroxidation, apathy, and executive dysfunction in patients at risk for VCI.

METHODS: In participants with coronary artery disease, who are at a high risk of VCI, apathy (Apathy Evaluation Scale), and executive function (composite z-score based on age and education population norms from trails making test B, animal naming, and phonemic fluency tests) were assessed. Serum concentrations of an early (lipid hydroperoxide (LPH)) and late (8-isoprostane (8-ISO)) lipid peroxidation marker, were measured and the 8-ISO/LPH ratio was calculated.

RESULTS: Participants (n = 206, age±SD = 63.0±7.5, 80% men, total years of education = 15.9±3.4, AES score = 28.3±8.8, executive function = 0±1) demonstrated significantly different 8-ISO/LPH ratios between groups (F(3, 202) = 10.915, p <  0.001) with increasing levels in the following order: no apathy or executive dysfunction, only executive dysfunction (executive function composite score≤-1), only apathy (AES≥28), and both apathy and executive dysfunction. A model adjusting for demographics showed that lipid peroxidation was associated with both apathy (B(SE) = 4.63 (0.954), t = 4.852, p <  0.001) and executive function (B(SE) = -0.19 (0.079), t = -2.377, p = 0.018). However, when controlling for both demographics and vascular risk factors, lipid peroxidation was associated with only apathy (B(SE) = 3.11 (0.987), t = 3.149, p = 0.002).

CONCLUSION: The results highlight a potentially important involvement of lipid peroxidation in the co-occurrence of apathy and executive dysfunction in those at risk for VCI.

%B J Alzheimers Dis %V 89 %P 733-743 %8 2022 Sep 13 %G eng %N 2 %R 10.3233/JAD-220274 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Monitoring Alzheimer's Disease Progression in Mild Cognitive Impairment Stage Using Machine Learning-Based FDG-PET Classification Methods. %A Beheshti, Iman %A Geddert, Natasha %A Perron, Jarrad %A Gupta, Vinay %A Albensi, Benedict C %A Ko, Ji Hyun %X

BACKGROUND: We previously introduced a machine learning-based Alzheimer's Disease Designation (MAD) framework for identifying AD-related metabolic patterns among neurodegenerative subjects.

OBJECTIVE: We sought to assess the efficiency of our MAD framework for tracing the longitudinal brain metabolic changes in the prodromal stage of AD.

METHODS: MAD produces subject scores using five different machine-learning algorithms, which include a general linear model (GLM), two different approaches of scaled subprofile modeling, and two different approaches of a support vector machine. We used our pre-trained MAD framework, which was trained based on metabolic brain features of 94 patients with AD and 111 age-matched cognitively healthy (CH) individuals. The MAD framework was applied on longitudinal independent test sets including 54 CHs, 51 stable mild cognitive impairment (sMCI), and 39 prodromal AD (pAD) patients at the time of the clinical diagnosis of AD, and two years prior.

RESULTS: The GLM showed excellent performance with area under curve (AUC) of 0.96 in distinguishing sMCI from pAD patients at two years prior to the time of the clinical diagnosis of AD while other methods showed moderate performance (AUC: 0.7-0.8). Significant annual increment of MAD scores were identified using all five algorithms in pAD especially when it got closer to the time of diagnosis (p <  0.001), but not in sMCI. The increased MAD scores were also significantly associated with cognitive decline measured by Mini-Mental State Examination in pAD (q <  0.01).

CONCLUSION: These results suggest that MAD may be a relevant tool for monitoring disease progression in the prodromal stage of AD.

%B J Alzheimers Dis %V 89 %P 1493-150 %8 2022 Oct 11 %G eng %N 4 %R 10.3233/JAD-220585 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, and Regional Amyloid-β and Tau Pathology in Middle-Aged Adults: The Framingham Study. %A Weinstein, Galit %A O'Donnell, Adrienne %A Davis-Plourde, Kendra %A Zelber-Sagi, Shira %A Ghosh, Saptaparni %A DeCarli, Charles S %A Thibault, Emma G %A Sperling, Reisa A %A Johnson, Keith A %A Beiser, Alexa S %A Seshadri, Sudha %X

BACKGROUND: Liver steatosis and fibrosis are emerging as risk factors for multiple extrahepatic health conditions; however, their relationship with Alzheimer's disease pathology is unclear.

OBJECTIVE: To examine whether non-alcoholic fatty liver disease (NAFLD) and FIB-4, a non-invasive index of advanced fibrosis, are associated with brain amyloid-β (Aβ) and tau pathology.

METHODS: The study sample included Framingham Study participants from the Offspring and Third generation cohorts who attended exams 9 (2011-2014) and 2 (2008-2011), respectively. Participants underwent 11C-Pittsburgh Compound-B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging and abdomen computed tomography, or had information on all components of the FIB-4 index. Linear regression models were used to assess the relationship of NAFLD and FIB-4 with regional tau and Aβ, adjusting for potential confounders and multiple comparisons.

RESULTS: Of the subsample with NAFLD information (N = 169; mean age 52±9 y; 57% males), 57 (34%) had NAFLD. Of the subsample with information on liver fibrosis (N = 177; mean age 50±10 y; 51% males), 34 (19%) had advanced fibrosis (FIB-4 >  1.3). Prevalent NAFLD was not associated with Aβ or tau PET. However, FIB-4 index was significantly associated with increased rhinal tau (β= 1.03±0.33, p = 0.002). Among individuals with prevalent NAFLD, FIB-4 was related to inferior temporal, parahippocampal gyrus, entorhinal and rhinal tau (β= 2.01±0.47, p <  0.001; β= 1.60±0.53, p = 0.007, and β= 1.59±0.47, p = 0.003 and β= 1.60±0.42, p = 0.001, respectively) and to Aβ deposition overall and in the inferior temporal and parahippocampal regions (β= 1.93±0.47, p <  0.001; β= 1.59±0.38, p <  0.001, and β= 1.52±0.54, p = 0.008, respectively).

CONCLUSION: This study suggests a possible association between liver fibrosis and early Alzheimer's disease pathology, independently of cardio-metabolic risk factors.

%B J Alzheimers Dis %V 86 %P 1371-1383 %8 2022 Apr 05 %G eng %N 3 %R 10.3233/JAD-215409 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Novel Invisible Spectral Flicker Induces 40 Hz Neural Entrainment with Similar Spatial Distribution as 40 Hz Stroboscopic Light. %A Agger, Mikkel Pejstrup %A Carstensen, Marcus Schultz %A Henney, Mark Alexander %A Hansen, Luna Skytte %A Baandrup, Anders Ohlhues %A Nguyen, Mai %A Petersen, Paul Michael %A Madsen, Kristoffer Hougaard %A Kjær, Troels Wesenberg %X

BACKGROUND: Exposure to 40 Hz stroboscopic light, for one hour a day, has previously been published as a potential treatment option for Alzheimer's disease in animal models. However, exposure for an hour a day to 40 Hz stroboscopic light can be strenuous and examining other types of 40 Hz inducing stimuli is paramount if chronic treatment is wanted.

OBJECTIVE: A core assumption behind ensuring a therapeutic outcome is that the visual stimuli can induce 40 Hz gamma entrainment. Here, we examine whether a specific visual stimulus, 40 Hz invisible spectral flicker (ISF), can induce gamma entrainment and how it differs from both continuous light (CON) and 40 Hz stroboscopic light (STROBE).

METHODS: The study included non-simultaneous EEG-fMRI neuroimaging of 13 young healthy volunteers during light exposure. Each light condition (i.e., CON, ISF, or STROBE) was active for 30 seconds followed immediately by the next.

RESULTS: Entrainment of 40 Hz neural activity were significantly higher signal-to-noise ratio during exposure to ISF (mean: 3.03, 95% CI 2.07 to 3.99) and STROBE (mean: 12.04, 95% CI 10.18 to 13.87) compared to CON. Additionally STROBE had a higher entrainment than ISF (mean: 9.01, 95% CI 7.16 to 12.14).

CONCLUSION: This study presents a novel method of 40 Hz entrainment using ISF. This enables the possibility of future randomized placebo-controlled clinical trials with acceptable double blinding due to the essentially imperceivable flicker, which is expected to substantially reduce discomfort compared to interventions with stroboscopic flicker.

%B J Alzheimers Dis %V 88 %P 335-344 %8 2022 Jun 28 %G eng %N 1 %R 10.3233/JAD-220081 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Oral Health Status in Subjects with Amnestic Mild Cognitive Impairment and Alzheimer's Disease: Data from the Zabút Aging Project. %A Panzarella, Vera %A Mauceri, Rodolfo %A Baschi, Roberta %A Maniscalco, Laura %A Campisi, Giuseppina %A Monastero, Roberto %K Aging %K Alzheimer Disease %K Case-Control Studies %K Cognitive Dysfunction %K Cohort Studies %K Humans %K Male %K Neuropsychological Tests %K Oral Health %K Quality of Life %X

BACKGROUND: The relationship between Alzheimer's disease (AD) and periodontitis has been recently investigated with heterogenous results.

OBJECTIVE: This study aims to evaluate the oral health status and its relationship with cognitive impairment of participants, enrolled in the Zabút Aging Project, a community-based cohort study performed in a rural community in Sicily, Italy.

METHODS: A case-control study (20 subjects with AD, 20 with amnestic mild cognitive impairment [aMCI], and 20 controls) was conducted. The protocol included a comprehensive medical and cognitive-behavioral examination. Full-mouth evaluation, microbial analysis of subgingival plaque samples (by RT-PCR analysis), and oral health-related quality of life (OHR-QoL) were evaluated.

RESULTS: The decayed, missing, and filled teeth (DMFT) total score of AD subjects was significantly higher than aMCI (p = 0.009) and controls (p = 0.001). Furthermore, the "M" component of DMFT (i.e., the number of missing teeth) was significantly higher in AD than in aMCI (p < 0.001) and controls (p < 0.001). A Poisson regression model revealed that age (p < 0.001), male gender (p = 0.001), and AD (p = 0.001) were positively correlated with DMFT. Concerning oral microbial load, the presence of Fusobacterium nucleatum was significantly higher in AD than in controls (p = 0.02), and a higher load of Treponema denticola was found in aMCI than with AD (p = 0.004). OHR-QoL scores did not differ among the groups.

CONCLUSION: The current research suggests that AD is associated with chronic periodontitis, which is capable of determining tooth loss due to the pathogenicity of Fusobacterium nucleatum. These data remain to be confirmed in larger population-based cohorts.

%B J Alzheimers Dis %V 87 %P 173-183 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32508326?dopt=Abstract %R 10.3233/JAD-200385 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Passive Immunotherapy Targeting Tau Oligomeric Strains Reverses Tauopathy Phenotypes in Aged Human-Tau Mice in a Mouse Model-Specific Manner. %A Bittar, Alice %A Al-Lahham, Rabab %A Bhatt, Nemil %A Moore, Kenya %A Montalbano, Mauro %A Jerez, Cynthia %A Fung, Leiana %A McAllen, Salome %A Ellsworth, Anna %A Kayed, Rakez %X

BACKGROUND: Tau oligomers are one of the most toxic species, displaying prion-like strains which have different conformations resulting in different tauopathies. Passive immunotherapy targeting different tau species is a promising therapeutic approach. Age is one of the greatest risk factors; however, most immunotherapy studies are done in young to middle-aged mice tauopathy models, which is not representative of the many clinical trials done with older humans with established tauopathies.

OBJECTIVE: We utilized two different clones of tau oligomer monoclonal antibodies (TOMAs) in aged Htau and JNPL3 mouse models to investigate the potential of passive immunotherapy.

METHODS: Aged mice received a single intravenous injection of 120 μg/animal of either TOMA1, TOMA3 clones or a non-specific IgG. Their cognitive functions were assessed one-week post-injection using Y-maze and novel object recognition tests. Brain tissues were analyzed using biochemical and immunological assays.

RESULTS: TOMA 1 and 3 rescues cognitive phenotypes in aged animals in a mouse model-specific manner, indicative by a reduction in tau oligomers levels. The TOMAs were shown to have strong reactivity with different tau oligomeric species in the different mouse models in vitro and ex vivo.

CONCLUSION: This is the first study testing tau passive immunotherapy in aged animals and supports our previous reports on of the role of oligomeric tau in disease progression further validating the potential of TOMAs to rescue the late-stage disease pathology and phenotype. Moreover, this study suggests that multiple tau oligomeric strains exist in aged animals; therefore, it is of great importance to further characterize these strains.

%B J Alzheimers Dis %V 90 %P 1103-1122 %8 2022 Nov 22 %G eng %N 3 %R 10.3233/JAD-220518 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Pelargonidin and Berry Intake Association with Alzheimer's Disease Neuropathology: A Community-Based Study. %A Agarwal, Puja %A Holland, Thomas M %A James, Bryan D %A Cherian, Laurel J %A Aggarwal, Neelum T %A Leurgans, Sue E %A Bennett, David A %A Schneider, Julie A %X

BACKGROUND: An anthocyanidin, pelargonidin, primarily found in berries, has antioxidant and anti-inflammatory properties, and is associated with better cognition and reduced Alzheimer's dementia risk.

OBJECTIVE: This study investigated if pelargonidin or berry intake is associated with Alzheimer's disease (AD) neuropathology in human brains.

METHODS: The study was conducted among 575 deceased participants (age at death = 91.3±6.1 years; 70% females) of the Rush Memory and Aging Project, with dietary data (assessed using a food frequency questionnaire) and neuropathological evaluations. Calorie-adjusted pelargonidin intake was modeled in quartiles and berry intake as continuous (servings/week). Mean amyloid-beta load and phosphorylated tau neuronal neurofibrillary tangle density across multiple cortical regions were assessed using immunohistochemistry. Global AD pathology burden, a quantitative summary score of neurofibrillary tangles, and diffuse and neuritic plaques using Bielschowsky silver stains in multiple brain regions, was also assessed.

RESULTS: In a linear regression model adjusted for age at death, sex, education, APOE ɛ4 status, vitamin E, and vitamin C, participants in the highest quartile of pelargonidin intake when compared to those in the lowest quartile, had less amyloid-β load (β (SE) = -0.293 (0.14), p = 0.038), and fewer phosphorylated tau tangles (β (SE) = -0.310, p = 0.051). Among APOE ɛ4 non-carriers, higher strawberry (β (SE) = -0.227 (0.11), p = 0.037) and pelargonidin (Q4 versus Q1: β (SE) = -0.401 (0.16), p = 0.011; p trend = 0.010) intake was associated with less phosphorylated tau tangles, no association was observed in APOE ɛ4 carriers. Berry intake was not associated with AD pathology. However, excluding participants with dementia or mild cognitive impairment at baseline, strawberry (p = 0.004) and pelargonidin (ptrend = 0.007) intake were associated with fewer phosphorylated tau tangles.

CONCLUSION: Higher intake of pelargonidin, a bioactive present in strawberries, is associated with less AD neuropathology, primarily phosphorylated tau tangles.

%B J Alzheimers Dis %V 88 %P 653-661 %8 2022 Jul 19 %G eng %N 2 %R 10.3233/JAD-215600 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Plasma Amyloid and in vivo Brain Amyloid in Late Middle-Aged Hispanics. %A Rippon, Brady %A Palta, Priya %A Tahmi, Mouna %A Sherwood, Greysi %A Soto, Luisa %A Cespedes, Sandino %A Mesen, Yanette %A He, Hengda %A Laing, Krystal %A Moreno, Herman %A Teresi, Jeanne %A Razlighi, Qolamreza %A Brickman, Adam M %A Zetterberg, Henrik %A Luchsinger, Jose A %X

BACKGROUND: Determining amyloid positivity is possible with cerebrospinal fluid and brain imaging of amyloid, but these methods are invasive and expensive.

OBJECTIVE: To relate plasma amyloid-β (Aβ), measured using Single-molecule array (Simoatrademark) assays, to in vivo brain Aβ, measured using positron emission tomography (PET), examine the accuracy of plasma Aβ to predict brain Aβ positivity, and the relation of APOE ɛ4 with plasma Aβ.

METHODS: We performed a cross-sectional analysis in a cohort of 345 late middle-aged Hispanic men and women (age 64 years, 72% women). Our primary plasma variable was Aβ 42/Aβ 40 ratio measured with Simoa. Brain Aβ burden was measured as global SUVR with 18F-Florbetaben PET examined continuously and categorically.

RESULTS: Plasma Aβ 42/Aβ 40 ratio was inversely associated with global Aβ SUVR (β= -0.13, 95% Confidence Interval (CI): -0.23, -0.03; p = 0.013) and Aβ positivity (Odds Ratio: 0.59, 95% CI: 0.38, 0.91; p = 0.016), independent of demographics and APOE ɛ4. ROC curves (AUC = 0.73, 95% CI: 0.64, 0.82; p <  0.0001) showed that the optimal threshold for plasma Aβ 42/Aβ 40 ratio in relation to brain Aβ positivity was 0.060 with a sensitivity of 82.4% and specificity of 62.8% . APOE ɛ4 carriers had lower Aβ 42/Aβ 40 ratio and a higher Aβ positivity determined with the Aβ 42/Aβ 40 ratio threshold of 0.060.

CONCLUSION: Plasma Aβ 42/Aβ 40 ratio assayed using Simoa is weakly correlated with in vivo brain amyloid and has limited accuracy in screening for amyloid positivity and for studying risk factors of brain amyloid burden when in vivo imaging is not feasible.

%B J Alzheimers Dis %V 87 %P 1229-1238 %8 2022 May 31 %G eng %N 3 %R 10.3233/JAD-210391 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Precision Medicine Approach to Alzheimer's Disease: Successful Pilot Project. %A Toups, Kat %A Hathaway, Ann %A Gordon, Deborah %A Chung, Henrianna %A Raji, Cyrus %A Boyd, Alan %A Hill, Benjamin D %A Hausman-Cohen, Sharon %A Attarha, Mouna %A Chwa, Won Jong %A Jarrett, Michael %A Bredesen, Dale E %X

BACKGROUND: Effective therapeutics for Alzheimer's disease are needed. However, previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective strategy.

OBJECTIVE: To determine whether a precision medicine approach to Alzheimer's disease and mild cognitive impairment is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial.

METHODS: Twenty-five patients with dementia or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol, and cognition was assessed at t = 0, 3, 6, and 9 months.

RESULTS: All outcome measures revealed improvement: statistically significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and Alzheimer's Questionnaire Change score were documented. No serious adverse events were recorded. MRI volumetrics also improved.

CONCLUSION: Based on the cognitive improvements observed in this study, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted.

%B J Alzheimers Dis %V 88 %P 1411-1421 %8 2022 Aug 16 %G eng %N 4 %R 10.3233/JAD-215707 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Pre-Diagnostic Symptoms of Young-Onset Dementia in the General Practice up to Five Years Before Diagnosis. %A Hendriks, Stevie %A Peetoom, Kirsten %A Tange, Huibert %A van Bokhoven, Marloes A %A van der Flier, Wiesje M %A Bakker, Christian %A Papma, Janne M %A Koopmans, Raymond %A Verhey, Frans %A Köhler, Sebastian %A de Vugt, Marjolein %X

BACKGROUND: Young-onset dementia (YOD) has many underlying etiologies, leading to a large heterogeneity in first symptoms. This makes it difficult for general practitioners (GPs) to recognize YOD.

OBJECTIVE: Identify early symptoms that are more common in the pre-diagnostic phase of YOD.

METHODS: We performed a case-control study nested in a primary-care registry on 89 cases and 162 matched controls, where we compared symptoms of people with YOD up to 5 years before diagnosis to their matched control group without YOD. The variables included in this study were International Classification of Primary Care codes and symptoms extracted from written GP notes and categorized in groups. We used Generalized Equation Estimation to analyze symptom's time-trajectories and logistic regression and ROC-curves to analyze differences in number of symptom categories reported.

RESULTS: Cognitive symptoms were more common in people with YOD 5 years before diagnosis, affective symptoms 4 years before diagnosis, social symptoms 3 years, behavioral symptoms 2 years, and daily functioning disturbances 1 year before diagnosis. The ROC-curve suggested that reporting two or more symptom categories at the GP gave the best trade-off between sensitivity (85%) and specificity (77% ), for the highest percentage of correctly diagnosed persons.

CONCLUSION: This study showed people with YOD present differently than people without YOD. However, it may still be difficult for GPs to use these symptom categories to distinguish people with YOD, since the symptoms also occur in people with other diseases. A combination of reported symptom categories increases the probability of an underlying cause of YOD.

%B J Alzheimers Dis %V 88 %P 229-239 %8 2022 Jun 28 %G eng %N 1 %R 10.3233/JAD-220215 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Proteomic Profiles of Neurodegeneration Among Mexican Americans and Non-Hispanic Whites in the HABS-HD Study. %A O'Bryant, Sid E %A Zhang, Fan %A Petersen, Melissa %A Hall, James R %A Johnson, Leigh A %A Yaffe, Kristine %A Braskie, Meredith %A Vig, Rocky %A Toga, Arthur W %A Rissman, Robert A %X

BACKGROUND: Hispanics are expected to experience the largest increase in Alzheimer's disease (AD) and AD related dementias over the next several decades. However, few studies have examined biomarkers of AD among Mexican Americans, the largest segment of the U.S. Hispanic population.

OBJECTIVE: We sought to examine proteomic profiles of an MRI-based marker of neurodegeneration from the AT(N) framework among a multi-ethnic, community-dwelling cohort.

METHODS: Community-dwelling Mexican Americans and non-Hispanic white adults and elders were recruited. All participants underwent comprehensive assessments including an interview, functional exam, clinical labs, informant interview, neuropsychological testing, and 3T MRI of the brain. A neurodegeneration MRI meta-ROI biomarker for the AT(N) framework was calculated.

RESULTS: Data was examined from n = 1,291 participants. Proteomic profiles were highly accurate for detecting neurodegeneration (i.e., N+) among both Mexican Americans (AUC = 1.0) and non-Hispanic whites (AUC = 0.98). The proteomic profile of N + was different between ethnic groups. Further analyses revealed that the proteomic profiles of N + varied by diagnostic status (control, MCI, dementia) and ethnicity (Mexican American versus non-Hispanic whites) though diagnostic accuracy was high for all classifications.

CONCLUSION: A proteomic profile of neurodegeneration has tremendous value and point towards novel diagnostic and intervention opportunities. The current findings demonstrate that the underlying biological factors associated with neurodegeneration are different between Mexican Americans versus non-Hispanic whites as well as at different levels of disease progression.

%B J Alzheimers Dis %V 86 %P 1243-1254 %8 2022 Apr 05 %G eng %N 3 %R 10.3233/JAD-210543 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Psychosis as a Treatment Target in Dementia: A Roadmap for Designing Interventions. %A Agüera-Ortiz, Luis %A Babulal, Ganesh M %A Bruneau, Marie-Andrée %A Creese, Byron %A D'Antonio, Fabrizia %A Fischer, Corinne E %A Gatchel, Jennifer R %A Ismail, Zahinoor %A Kumar, Sanjeev %A McGeown, William J %A Mortby, Moyra E %A Nuñez, Nicolas A %A de Oliveira, Fabricio F %A Pereiro, Arturo X %A Ravona-Springer, Ramit %A Rouse, Hillary J %A Wang, Huali %A Lanctôt, Krista L %K Caregivers %K Dementia %K Hallucinations %K Humans %K Psychotic Disorders %K Schizophrenia %X

Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials.

%B J Alzheimers Dis %V 88 %P 1203-1228 %8 2022 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/35786651?dopt=Abstract %R 10.3233/JAD-215483 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Risk of Alzheimer's Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching. %A Bukhbinder, Avram S %A Ling, Yaobin %A Hasan, Omar %A Jiang, Xiaoqian %A Kim, Yejin %A Phelps, Kamal N %A Schmandt, Rosemarie E %A Amran, Albert %A Coburn, Ryan %A Ramesh, Srivathsan %A Xiao, Qian %A Schulz, Paul E %K Adult %K Aged %K Alzheimer Disease %K Chronic Disease %K Cohort Studies %K Female %K Humans %K Influenza, Human %K Male %K Middle Aged %K Propensity Score %K Vaccination %X

BACKGROUND: Prior studies have found a reduced risk of dementia of any etiology following influenza vaccination in selected populations, including veterans and patients with serious chronic health conditions. However, the effect of influenza vaccination on Alzheimer's disease (AD) risk in a general cohort of older US adults has not been characterized.

OBJECTIVE: To compare the risk of incident AD between patients with and without prior influenza vaccination in a large US claims database.

METHODS: Deidentified claims data spanning September 1, 2009 through August 31, 2019 were used. Eligible patients were free of dementia during the 6-year look-back period and≥65 years old by the start of follow-up. Propensity-score matching (PSM) was used to create flu-vaccinated and flu-unvaccinated cohorts with similar baseline demographics, medication usage, and comorbidities. Relative risk (RR) and absolute risk reduction (ARR) were estimated to assess the effect of influenza vaccination on AD risk during the 4-year follow-up.

RESULTS: From the unmatched sample of eligible patients (n = 2,356,479), PSM produced a sample of 935,887 flu-vaccinated-unvaccinated matched pairs. The matched sample was 73.7 (SD, 8.7) years of age and 56.9% female, with median follow-up of 46 (IQR, 29-48) months; 5.1% (n = 47,889) of the flu-vaccinated patients and 8.5% (n = 79,630) of the flu-unvaccinated patients developed AD during follow-up. The RR was 0.60 (95% CI, 0.59-0.61) and ARR was 0.034 (95% CI, 0.033-0.035), corresponding to a number needed to treat of 29.4.

CONCLUSION: This study demonstrates that influenza vaccination is associated with reduced AD risk in a nationwide sample of US adults aged 65 and older.

%B J Alzheimers Dis %V 88 %P 1061-1074 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35723106?dopt=Abstract %R 10.3233/JAD-220361 %0 Journal Article %J J Alzheimers Dis %D 2022 %T The Role of Amyloid-β, Tau, and α-Synuclein Proteins as Putative Blood Biomarkers in Patients with Cerebral Amyloid Angiopathy. %A Piccarducci, Rebecca %A Caselli, Maria Chiara %A Zappelli, Elisa %A Ulivi, Leonardo %A Daniele, Simona %A Siciliano, Gabriele %A Ceravolo, Roberto %A Mancuso, Michelangelo %A Baldacci, Filippo %A Martini, Claudia %X

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β protein (Aβ) within brain blood vessels that develops in elderly people and Alzheimer's disease (AD) patients. Therefore, the investigation of biomarkers able to differentiate CAA patients from AD patients and healthy controls (HC) is of great interest, in particular in peripheral fluids.

OBJECTIVE: The current study aimed to detect the neurodegenerative disease (ND)-related protein (i.e., Aβ 1 - 40, Aβ 1 - 42, tau, and α-synuclein) levels in both red blood cells (RBCs) and plasma of CAA patients and HC, evaluating their role as putative peripheral biomarkers for CAA.

METHODS: For this purpose, the proteins' concentration was quantified in RBCs and plasma by homemade immunoenzymatic assays in an exploratory cohort of 20 CAA patients and 20 HC.

RESULTS: The results highlighted a significant increase of Aβ 1 - 40 and α-synuclein concentrations in both RBCs and plasma of CAA patients, while higher Aβ 1 - 42 and t-tau levels were detected only in RBCs of CAA individuals compared to HC. Moreover, Aβ 1 - 42/Aβ 1 - 40 ratio increased in RBCs and decreased in plasma of CAA patients. The role of these proteins as candidate peripheral biomarkers easily measurable with a blood sample in CAA needs to be confirmed in larger studies.

CONCLUSION: In conclusion, we provide evidence concerning the possible use of blood biomarkers for contributing to CAA diagnosis and differentiation from other NDs.

%B J Alzheimers Dis %V 89 %P 1039-1049 %8 2022 Sep 27 %G eng %N 3 %R 10.3233/JAD-220216 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Safety and Efficacy of Monoclonal Antibodies for Alzheimer's Disease: A Systematic Review and Meta-Analysis of Published and Unpublished Clinical Trials. %A Lacorte, Eleonora %A Ancidoni, Antonio %A Zaccaria, Valerio %A Remoli, Giulia %A Tariciotti, Leonardo %A Bellomo, Guido %A Sciancalepore, Francesco %A Corbo, Massimo %A Lombardo, Flavia L %A Bacigalupo, Ilaria %A Canevelli, Marco %A Piscopo, Paola %A Vanacore, Nicola %K Alzheimer Disease %K Amyloid %K Amyloidogenic Proteins %K Amyloidosis %K Antibodies, Monoclonal %K Cognitive Dysfunction %K Humans %X

BACKGROUND: Monoclonal antibodies (mAbs) are currently among the most investigated targets for potential disease-modifying therapies in Alzheimer's disease (AD).

OBJECTIVE: Our objectives were to identify all registered trials investigating mAbs in MCI due to AD or AD at any stage, retrieve available published and unpublished data from all registered trials, and analyze data on safety and efficacy outcomes.

METHODS: A systematic search of all registered trials on ClinicalTrials.gov and EUCT was performed. Available results were searched on both platforms and on PubMed, ISI Web of Knowledge, and The Cochrane Library.

RESULTS: Overall, 101 studies were identified on 27 mAbs. Results were available for 50 trials investigating 12 mAbs. For 18 trials, data were available from both published and unpublished sources, for 21 trials only from published sources, and for 11 trials only from unpublished sources. Meta-analyses of amyloid-related imaging abnormalities (ARIA) events showed overall risk ratios of 10.65 for ARIA-E and of 1.75 for ARIA-H. The meta-analysis of PET-SUVR showed an overall significant effect of mAbs in reducing amyloid (SMD -0.88), but when considering clinical efficacy, data on CDR-SB showed that treated patients had a statistically significant but clinically non-relevant lower worsening (MD -0.15).

CONCLUSION: Our results suggest that the risk-benefit profile of mAbs remains unclear. Research should focus on clarifying the effect of amyloid on cognitive decline, providing data on treatment response rate, and accounting for minimal clinically important difference. Research on mAbs should also investigate the possible long-term impact of ARIA events, including potential factors predicting their onset.

%B J Alzheimers Dis %V 87 %P 101-129 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35275549?dopt=Abstract %R 10.3233/JAD-220046 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Salivary Proteomics Reveals Significant Changes in Relation to Alzheimer's Disease and Aging. %A Contini, Cristina %A Serrao, Simone %A Manconi, Barbara %A Olianas, Alessandra %A Iavarone, Federica %A Bizzarro, Alessandra %A Masullo, Carlo %A Castagnola, Massimo %A Messana, Irene %A Diaz, Giacomo %A Cabras, Tiziana %X

BACKGROUND: Aging is a risk factor for several pathologies as Alzheimer's disease (AD). Great interest exists, therefore, in discovering diagnostic biomarkers and indicators discriminating biological aging and health status. To this aim, omic investigations of biological matrices, as saliva, whose sampling is easy and non-invasive, offer great potential.

OBJECTIVE: Investigate the salivary proteome through a statistical comparison of the proteomic data by several approaches to highlight quali-/quantitative variations associated specifically either to aging or to AD occurrence, and, thus, able to classify the subjects.

METHODS: Salivary proteomic data of healthy controls under-70 (adults) and over-70 (elderly) years old, and over-70 AD patients, obtained by liquid chromatography/mass spectrometry, were analyzed by multiple Mann-Whitney test, Kendall correlation, and Random-Forest (RF) analysis.

RESULTS: Almost all the investigated proteins/peptides significantly decreased in relation to aging in elderly subjects, with or without AD, in comparison with adults. AD subjects exhibited the highest levels of α-defensins, thymosin β4, cystatin B, S100A8 and A9. Correlation tests also highlighted age/disease associated differences. RF analysis individuated quali-/quantitative variations in 20 components, as oxidized S100A8 and S100A9, α-defensin 3, P-B peptide, able to classify with great accuracy the subjects into the three groups.

CONCLUSION: The findings demonstrated a strong change of the salivary protein profile in relation to the aging. Potential biomarkers candidates of AD were individuated in peptides/proteins involved in antimicrobial defense, innate immune system, inflammation, and in oxidative stress. RF analysis revealed the feasibility of the salivary proteome to discriminate groups of subjects based on age and health status.

%B J Alzheimers Dis %V 89 %P 605-622 %8 2022 Sep 13 %G eng %N 2 %R 10.3233/JAD-220246 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Sex-Specific Patterns of Body Mass Index Relationship with White Matter Connectivity. %A Rahmani, Farzaneh %A Wang, Qing %A McKay, Nicole S %A Keefe, Sarah %A Hantler, Nancy %A Hornbeck, Russ %A Wang, Yong %A Hassenstab, Jason %A Schindler, Suzanne %A Xiong, Chengjie %A Morris, John C %A Benzinger, Tammie L S %A Raji, Cyrus A %X

BACKGROUND: Obesity is an increasingly recognized modifiable risk factor for Alzheimer's disease (AD). Increased body mass index (BMI) is related to distinct changes in white matter (WM) fiber density and connectivity.

OBJECTIVE: We investigated whether sex differentially affects the relationship between BMI and WM structural connectivity.

METHODS: A cross-sectional sample of 231 cognitively normal participants were enrolled from the Knight Alzheimer Disease Research Center. Connectome analyses were done with diffusion data reconstructed using q-space diffeomorphic reconstruction to obtain the spin distribution function and tracts were selected using a deterministic fiber tracking algorithm.

RESULTS: We identified an inverse relationship between higher BMI and lower connectivity in the associational fibers of the temporal lobe in overweight and obese men. Normal to overweight women showed a significant positive association between BMI and connectivity in a wide array of WM fibers, an association that reversed in obese and morbidly obese women. Interaction analyses revealed that with increasing BMI, women showed higher WM connectivity in the bilateral frontoparietal and parahippocampal parts of the cingulum, while men showed lower connectivity in right sided corticostriatal and corticopontine tracts. Subgroup analyses demonstrated comparable results in participants with and without positron emission tomography or cerebrospinal fluid evidence of brain amyloidosis, indicating that the relationship between BMI and structural connectivity in men and women is independent of AD biomarker status.

CONCLUSION: BMI influences structural connectivity of WM differently in men and women across BMI categories and this relationship does not vary as a function of preclinical AD.

%B J Alzheimers Dis %V 86 %P 1831-1848 %8 2022 Apr 19 %G eng %N 4 %R 10.3233/JAD-215329 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Shortening of Saccades as a Possible Easy-to-Use Biomarker to Detect Risk of Alzheimer's Disease. %A Hannonen, Sanna %A Andberg, Sami %A Kärkkäinen, Virve %A Rusanen, Minna %A Lehtola, Juha-Matti %A Saari, Toni %A Korhonen, Ville %A Hokkanen, Laura %A Hallikainen, Merja %A Hänninen, Tuomo %A Leinonen, Ville %A Kaarniranta, Kai %A Bednarik, Roman %A Koivisto, Anne M %K Alzheimer Disease %K Biomarkers %K Cognitive Dysfunction %K Humans %K Neuropsychological Tests %K Saccades %X

BACKGROUND: Wide-ranging functional defects in eye movements have been reported in Alzheimer's disease (AD) dementia. The detection of abnormal eye movements and reading problems may identify persons at risk of AD when clear clinical symptoms are lacking.

OBJECTIVE: To examine whether computer-based eye-tracking (ET) analysis of King-Devick (KD) test results differentiates cognitively healthy persons from persons with minor problems in cognitive testing or diagnosed mild AD.

METHODS: We recruited 78 participants (57 non-demented, 21 with mild AD) who underwent neurological examination, the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological test battery (CERAD-NB), and a Clinical Dementia Rating (CDR) interview. The non-demented participants were further divided into control (normal CERAD subtests, mean MMSE = 28) and objective mild cognitive impairment (MCI; decline in at least one CERAD memory score, mean MMSE = 27) groups. The KD reading test was performed using computer-based ET. The total time used for the reading test, errors made, fixation and saccade durations, and saccade amplitudes were analyzed.

RESULTS: We found significant differences between the control, objective MCI, and AD groups in regard to the mean saccade amplitude (3.58, 3.33, and 3.21 ms, respectively, p < 0.03) and duration (27.1, 25.3, and 24.8 ms, respectively, p < 0.05). The KD error scores in the AD group differed significantly (p < 0.01) from the other groups.

CONCLUSION: Computed ET analysis of the KD test may help detect persons with objective MCI early when clear clinical symptoms are lacking. The portable device for ET is easy to use in primary health care memory clinics.

%B J Alzheimers Dis %V 88 %P 609-618 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35662117?dopt=Abstract %R 10.3233/JAD-215551 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Single Nucleus Transcriptome Data from Alzheimer's Disease Mouse Models Yield New Insight into Pathophysiology. %A Weller, Andrew E %A Ferraro, Thomas N %A Doyle, Glenn A %A Reiner, Benjamin C %A Crist, Richard C %A Berrettini, Wade H %X

BACKGROUND: 5XFAD humanized mutant mice and Trem2 knockout (T2KO) mice are two mouse models relevant to the study of Alzheimer's disease (AD)-related pathology.

OBJECTIVE: To determine hippocampal transcriptomic and polyadenylation site usage alterations caused by genetic mutations engineered in 5XFAD and T2KO mice.

METHODS: Employing a publicly available single-nucleus RNA sequencing dataset, we used Seurat and Sierra analytic programs to identify differentially expressed genes (DEGs) and differential transcript usage (DTU), respectively, in hippocampal cell types from each of the two mouse models. We analyzed cell type-specific DEGs further using Ingenuity Pathway Analysis (IPA).

RESULTS: We identified several DEGs in both neuronal and glial cell subtypes in comparisons of wild type (WT) versus 5XFAD and WT versus T2KO mice, including Ttr, Fth1, Pcsk1n, Malat1, Rpl37, Rtn1, Sepw1, Uba52, Mbp, Arl6ip5, Gm26917, Vwa1, and Pgrmc1. We also observed DTU in common between the two comparisons in neuronal and glial subtypes, specifically in the genes Prnp, Rbm4b, Pnisr, Opcml, Cpne7, Adgrb1, Gabarapl2, Ubb, Ndfip1, Car11, and Stmn4. IPA identified 3 statistically significant canonical pathways that appeared in multiple cell types and that overlapped between 5XFAD and T2KO comparisons to WT, including 'FXR/RXR Activation', 'LXR/RXR Activation', and 'Acute Phase Response Signaling'.

CONCLUSION: DEG, DTU, and IPA findings, derived from two different mouse models of AD, highlight the importance of energy imbalance and inflammatory processes in specific hippocampal cell types, including subtypes of neurons and glial cells, in the development of AD-related pathology. Additional studies are needed to further characterize these findings.

%B J Alzheimers Dis %V 90 %P 1233-1247 %8 2022 Nov 22 %G eng %N 3 %R 10.3233/JAD-220391 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Small RNA Sequencing in the Tg4-42 Mouse Model Suggests the Involvement of snoRNAs in the Etiology of Alzheimer's Disease. %A Lio, Chit Tong %A Kacprowski, Tim %A Klaedtke, Maik %A Jensen, Lars R %A Bouter, Yvonne %A Bayer, Thomas A %A Kuss, Andreas W %X

BACKGROUND: The Tg4-42 mouse model for sporadic Alzheimer's disease (AD) has unique features, as the neuronal expression of wild type N-truncated Aβ4-42 induces an AD-typical neurological phenotype in the absence of plaques. It is one of the few models developing neuron death in the CA1 region of the hippocampus. As such, it could serve as a powerful tool for preclinical drug testing and identification of the underlying molecular pathways that drive the pathology of AD.

OBJECTIVE: The aim of this study was to use a differential co-expression analysis approach for analyzing a small RNA sequencing dataset from a well-established murine model in order to identify potentially new players in the etiology of AD.

METHODS: To investigate small nucleolar RNAs in the hippocampus of Tg4-42 mice, we used RNA-Seq data from this particular tissue and, instead of analyzing the data at single gene level, employed differential co-expression analysis, which takes the comparison to gene pair level and thus affords a new angle to the interpretation of these data.

RESULTS: We identified two clusters of differentially correlated small RNAs, including Snord55, Snord57, Snord49a, Snord12, Snord38a, Snord99, Snord87, Mir1981, Mir106b, Mir30d, Mir598, and Mir99b. Interestingly, some of them have been reported to be functionally relevant in AD pathogenesis, as AD biomarkers, regulating tau phosphorylation, TGF-β receptor function or Aβ metabolism.

CONCLUSION: The majority of snoRNAs for which our results suggest a potential role in the etiology of AD were so far not conspicuously implicated in the context of AD pathogenesis and could thus point towards interesting new avenues of research in this field.

%B J Alzheimers Dis %V 87 %P 1671-1681 %8 2022 Jun 14 %G eng %N 4 %R 10.3233/JAD-220110 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Supplementation With Carotenoids, Omega-3 Fatty Acids, and Vitamin E Has a Positive Effect on the Symptoms and Progression of Alzheimer's Disease. %A Nolan, John M %A Power, Rebecca %A Howard, Alan N %A Bergin, Paula %A Roche, Warren %A Prado-Cabrero, Alfonso %A Pope, George %A Cooke, John %A Power, Tommy %A Mulcahy, Riona %X

BACKGROUND: Preliminary work by our center has reported behavior and functional benefits in patients with Alzheimer's disease (AD) following targeted micronutritional supplementation.

OBJECTIVE: To build on the existing exploratory research and investigate the impact of these micronutrients on the natural progression of AD in a randomized controlled trial.

METHODS: Patients with mild-moderate AD consumed daily 1 g fish oil (of which 500 mg DHA, 150 mg EPA), 22 mg carotenoids (10 mg lutein, 10 mg meso-zeaxanthin, 2 mg zeaxanthin), and 15 mg vitamin E or placebo for 12 months in a double-blind, placebo-controlled, randomized clinical trial. Carotenoids, ω-3FAs, and vitamin E were quantified in blood. Carotenoids were also measured in skin. AD severity was measured using the mini-mental state examination and dementia severity rating scale tools. Behavior, mood, and memory were measured using an informant-based questionnaire.

RESULTS: Following 12 months of supplementation, the active group (n = 50) compared to the placebo group (n = 27), demonstrated statistically significant improvements in skin carotenoid measurements, blood carotenoids, ω-3FAs, and vitamin E concentrations (p <  0.05, for all). The active group also performed better in objective measures of AD severity (i.e., memory and mood), with a statistically significant difference reported in the clinical collateral for memory (p <  0.001).

CONCLUSION: Exponential increases in the prevalence of AD and its relentless progressive nature is driving the need for interventions that help to ameliorate symptoms and improve quality of life in AD patients. Given the positive outcomes demonstrated in this trial, this combined micronutrient dietary supplement should be considered in the overall management of AD.

%B J Alzheimers Dis %V 90 %P 233-249 %8 2022 Oct 25 %G eng %N 1 %R 10.3233/JAD-220556 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Transcriptome and Translatome Regulation of Pathogenesis in Alzheimer's Disease Model Mice. %A Eastman, Guillermo %A Sharlow, Elizabeth R %A Lazo, John S %A Bloom, George S %A Sotelo-Silveira, José R %X

BACKGROUND: Defining cellular mechanisms that drive Alzheimer's disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre-symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD.

OBJECTIVE: To identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI;NOS2 -/- ) and Tg2576 (APPSw), and their companion wild type (WT) strains at 6 months of age by tandem RNA-Seq and Ribo-Seq (ribosome profiling).

METHODS: Identical starting pools of bulk RNA were used for RNA-Seq and Ribo-Seq. Differential gene expression analysis was performed at the transcriptome, translatome, and translational efficiency levels. Regulated genes were functionally evaluated by gene ontology tools.

RESULTS: Compared to WT mice, AD model mice had similar levels of transcriptome regulation, but differences in translatome regulation. A microglial signature associated with early stages of Aβ accumulation was upregulated at both levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to AβPP metabolism associated with neurotoxicity and neuroprotection.

CONCLUSION: This work represents the first genome-wide study of brain translatome regulation in animal models of AD and provides evidence of a tight and early translatome regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain.

%B J Alzheimers Dis %V 86 %P 365-386 %8 2022 Mar 08 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35034904?dopt=Abstract %R 10.3233/JAD-215357 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Traumatic Brain Injury and Risk of Alzheimer's Disease and Related Dementias in the Population. %A Mielke, Michelle M %A Ransom, Jeanine E %A Mandrekar, Jay %A Turcano, Pierpaolo %A Savica, Rodolfo %A Brown, Allen W %X

BACKGROUND: Epidemiological studies examining associations between traumatic brain injury (TBI) and Alzheimer's disease and related dementias (ADRD) have yielded conflicting results, which may be due methodological differences.

OBJECTIVE: To examine the relationship between the presence and severity of TBI and risk of ADRD using a population-based cohort with medical record abstraction for confirmation of TBI and ADRD.

METHODS: All TBI events among Olmsted County, Minnesota residents aged >  40 years from 1985-1999 were confirmed by manual review and classified by severity. Each TBI case was randomly matched to two age-, sex-, and non-head injury population-based referents without TBI. For TBI events with non-head trauma, the Trauma Mortality Prediction Model was applied to assign an overall measure of non-head injury severity and corresponding referents were matched on this variable. Medical records were manually abstracted to confirm ADRD diagnosis. Cox proportional hazards models examined the relationship between TBI and severity with risk of ADRD.

RESULTS: A total of 1,418 residents had a confirmed TBI (865 Possible, 450 Probable, and 103 Definite) and were matched to 2,836 referents. When combining all TBI severities, the risk of any ADRD was significantly higher for those with a confirmed TBI compared to referents (HR = 1.32, 95% CI: 1.11, 1.58). Stratifying by TBI severity, Probable (HR = 1.42, 95% CI: 1.05, 1.92) and Possible (HR = 1.29, 95% CI: 1.02-1.62) TBI was associated with an increased risk of ADRD, but not Definite TBI (HR = 1.22, 95% CI: 0.68, 2.18).

CONCLUSION: Our analyses support including TBI as a potential risk factor for developing ADRD.

%B J Alzheimers Dis %V 88 %P 1049-1059 %8 2022 Aug 02 %G eng %N 3 %R 10.3233/JAD-220159 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Visually Identified Tau 18F-MK6240 PET Patterns in Symptomatic Alzheimer's Disease. %A Krishnadas, Natasha %A Huang, Kun %A Schultz, Stephanie A %A Doré, Vincent %A Bourgeat, Pierrick %A Goh, Anita M Y %A Lamb, Fiona %A Bozinovski, Svetlana %A Burnham, Samantha C %A Robertson, Joanne S %A Laws, Simon M %A Maruff, Paul %A Masters, Colin L %A Villemagne, Victor L %A Rowe, Christopher C %X

BACKGROUND: In Alzheimer's disease, heterogeneity has been observed in the postmortem distribution of tau neurofibrillary tangles. Visualizing the topography of tau in vivo may facilitate clinical trials and clinical practice.

OBJECTIVE: This study aimed to investigate whether tau distribution patterns that are limited to mesial temporal lobe (MTL)/limbic regions, and those that spare MTL regions, can be visually identified using 18F-MK6240, and whether these patterns are associated with different demographic and cognitive profiles.

METHODS: Tau 18F-MK6240 PET images of 151 amyloid-β positive participants with mild cognitive impairment (MCI) and dementia were visually rated as: tau negative, limbic predominant (LP), MTL-sparing, and Typical by two readers. Groups were evaluated for differences in age, APOE ɛ4 carriage, hippocampal volumes, and cognition (MMSE, composite memory and non-memory scores). Voxel-wise contrasts were also performed.

RESULTS: Visual rating resulted in 59.6% classified as Typical, 17.9% as MTL-sparing, 9.9% LP, and 12.6% as tau negative. Intra-rater and inter-rater reliability was strong (Cohen's kappa values of 0.89 and 0.86 respectively). Tracer retention in a "hook"-like distribution on sagittal sequences was observed in the LP and Typical groups. The visually classified MTL-sparing group had lower APOE ɛ4 carriage and relatively preserved hippocampal volumes. Higher MTL tau was associated with greater amnestic cognitive impairment. High cortical tau was associated with greater impairments on non-memory domains of cognition, and individuals with high cortical tau were more likely to have dementia than MCI.

CONCLUSION: Tau distribution patterns can be visually identified using 18F-MK6240 PET and are associated with differences in APOE ɛ4 carriage, hippocampal volumes, and cognition.

%B J Alzheimers Dis %V 88 %P 1627-1637 %8 2022 Aug 16 %G eng %N 4 %R 10.3233/JAD-215558 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Accelerometer-Measured, Habitual Physical Activity and Circulating Brain-Derived Neurotrophic Factor: A Cross-Sectional Study. %A Spartano, Nicole L %A Himali, Jayandra J %A Trinquart, Ludovic %A Yang, Qiong %A Weinstein, Galit %A Satizabal, Claudia L %A Dukes, Kimberly A %A Beiser, Alexa S %A Murabito, Joanne M %A Vasan, Ramachandran S %A Seshadri, Sudha %X

BACKGROUND: One of the mechanisms suggested to link physical activity (PA) to favorable brain health is through stimulation of neural growth factors such as brain-derived neurotrophic factor (BDNF). Acute bouts of PA stimulate circulating BDNF levels.

OBJECTIVE: In this investigation, we assessed whether habitual, accelerometer-measured PA levels were related to circulating BDNF levels in a middle-aged cohort.

METHODS: In the Framingham Heart Study Third Generation cohort, 1,769 participants provided reliable accelerometry data and were not missing BDNF measurement and platelet counts. In a cross-sectional analysis, using multivariable regression, we related PA measures to serum BDNF levels, adjusting for age, sex, smoking status, platelet count, depression status, and accelerometer wear time.

RESULTS: Our study participants (mean age 47±9 years, 50.8% women) spent an average of 22.3 mins/day moderate-to-vigorous (MV)PA. Most PA variables (steps, MVPA, light activity, and sedentary time) were not related to BDNF levels (p > 0.05). We observed a non-linear trend, where 15-50 mins/week vigorous activity was associated with lower BDNF compared to those with 0 min vigorous activity (β= -0.049±0.024, p = 0.05), but with no significant associations at lower or higher vigorous activity levels. In smokers, MVPA was also associated with lower BDNF levels (β= -0.216±0.079, p = 0.01).

CONCLUSION: Our study reveals that circulating BDNF is not chronically elevated in individuals with higher levels of habitual PA in middle-aged adults from the community and may even be chronically suppressed with higher PA in subgroups, including current smokers. These results do not contradict previous studies demonstrating that circulating BDNF rises acutely after PA.

%B J Alzheimers Dis %V 85 %P 805-814 %8 2022 Jan 18 %G eng %N 2 %R 10.3233/JAD-215109 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Acute Exercise and Cognitive Function in Alzheimer's Disease. %A Ben Ayed, Ines %A Castor-Guyonvarch, Naomie %A Amimour, Souad %A Naija, Salma %A Aouichaoui, Chirine %A Ben Omor, Sana %A Tabka, Zouhair %A El Massioui, Farid %X

BACKGROUND: Many studies have shown the impact of acute aerobic exercises (AAE) on cognition in healthy adults or at a pre-dementia stage. Few studies, however, have explored the positive effects of AAE in moderate Alzheimer's disease (ADM) patients.

OBJECTIVE: Evaluating the effect of AAE on cognitive functions in ADM patients.

METHODS: Overall, 79 (age: 69.62±0.99) ADM patients were recruited. Participants were divided into three groups according to the task: aerobic exercises done alone or combined with cognitive games presented on a screen, and a control group who performed a reading task. The aerobic exercise protocol consisted of a 20-min cycling exercise of moderate intensity, corresponding to 60%of the individual target maximal heart rate recorded in a 6-minute walking test. The participants' cognition was monitored before and after the intervention using the Tower of Hanoi, Digit Span, and Stroop tasks.

RESULTS: After the exercise, the participants' attention in both the physical and combined groups improved for the Stroop, the forward and backward Digit Span tasks, as well as the time taken to solve the Tower of Hanoi, although no significant differences were found in the number of moves taken in the latter. By contrast, the control group did not show any significant improvement for most of the cognitive tasks after the reading session.

CONCLUSION: Current evidence suggests that AAE may help to improve cognitive functions in ADM patients. This improvement is enhanced when the exercise is combined with cognitive games. Safe and progressive types of exercises should be promoted among ADM patients.

%B J Alzheimers Dis %V 82 %P 749-760 %8 2021 Jul 20 %G eng %N 2 %R 10.3233/JAD-201317 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Alzheimer's Disease-Related Neuropathology Among Patients with Medication Treated Type 2 Diabetes in a Community-Based Autopsy Cohort. %A Barthold, Douglas %A Gibbons, Laura E %A Marcum, Zachary A %A Gray, Shelly L %A Dirk Keene, C %A Grabowski, Thomas J %A Postupna, Nadia %A Larson, Eric B %A Crane, Paul K %X

BACKGROUND: Diabetes is a risk factor for Alzheimer's disease and related dementias (ADRD). Epidemiologic evidence shows an association between diabetes medications and ADRD risk; cell and mouse models show diabetes medication association with AD-related neuropathologic change (ADNC).

OBJECTIVE: This hypothesis-generating analysis aimed to describe autopsy-measured ADNC for individuals who used diabetes medications.

METHODS: Descriptive analysis of ADNC for Adult Changes in Thought (ACT) Study autopsy cohort who used diabetes medications, including sulfonylureas, insulin, and biguanides; total N = 118. ADNC included amyloid plaque distribution (Thal phasing), neurofibrillary tangle (NFT) distribution (Braak stage), and cortical neuritic plaque density (CERAD score). We also examined quantitative measures of ADNC using the means of standardized Histelide measures of cortical PHF-tau and Aβ 1-42. Adjusted analyses control for age at death, sex, education, APOE genotype, and diabetes complication severity index.

RESULTS: Adjusted analyses showed no significant association between any drug class and traditional neuropathologic measures compared to nonusers of that class. In adjusted Histelide analyses, any insulin use was associated with lower mean levels of Aβ 1-42 (-0.57 (CI: -1.12, -0.02)) compared to nonusers. Five years of sulfonylureas and of biguanides use was associated with lower levels of Aβ 1-42 compared to nonusers (-0.15 (CI: -0.28, -0.02), -0.31 (CI: -0.54, -0.07), respectively).

CONCLUSION: Some evidence exists that diabetes medications are associated with lower levels of Aβ 1-42, but not traditional measures of neuropathology. Future studies are needed in larger samples to build understanding of the mechanisms between diabetes, its medications, and ADRD, and to potentially repurpose existing medications for prevention or delay of ADRD.

%B J Alzheimers Dis %V 83 %P 1303-1312 %8 2021 Sep 28 %G eng %N 3 %R 10.3233/JAD-210059 %0 Journal Article %J J Alzheimers Dis %D 2021 %T ANMerge: A Comprehensive and Accessible Alzheimer's Disease Patient-Level Dataset. %A Birkenbihl, Colin %A Westwood, Sarah %A Shi, Liu %A Nevado-Holgado, Alejo %A Westman, Eric %A Lovestone, Simon %A Hofmann-Apitius, Martin %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cohort Studies %K Datasets as Topic %K Female %K Gene Expression Profiling %K Genotype %K Humans %K Magnetic Resonance Imaging %K Male %K Proteomics %X

BACKGROUND: Accessible datasets are of fundamental importance to the advancement of Alzheimer's disease (AD) research. The AddNeuroMed consortium conducted a longitudinal observational cohort study with the aim to discover AD biomarkers. During this study, a broad selection of data modalities was measured including clinical assessments, magnetic resonance imaging, genotyping, transcriptomic profiling, and blood plasma proteomics. Some of the collected data were shared with third-party researchers. However, this data was incomplete, erroneous, and lacking in interoperability.

OBJECTIVE: To provide the research community with an accessible, multimodal, patient-level AD cohort dataset.

METHODS: We systematically addressed several limitations of the originally shared resources and provided additional unreleased data to enhance the dataset.

RESULTS: In this work, we publish and describe ANMerge, a new version of the AddNeuroMed dataset. ANMerge includes multimodal data from 1,702 study participants and is accessible to the research community via a centralized portal.

CONCLUSION: ANMerge is an information rich patient-level data resource that can serve as a discovery and validation cohort for data-driven AD research, such as, for example, machine learning and artificial intelligence approaches.

%B J Alzheimers Dis %V 79 %P 423-431 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33285634?dopt=Abstract %R 10.3233/JAD-200948 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Anti-Aβ Antibody Aducanumab Regulates the Proteome of Senile Plaques and Closely Surrounding Tissue in a Transgenic Mouse Model of Alzheimer's Disease. %A Bastrup, Joakim %A Hansen, Kathrine H %A Poulsen, Thomas B G %A Kastaniegaard, Kenneth %A Asuni, Ayodeji A %A Christensen, Søren %A Belling, Dorthe %A Helboe, Lone %A Stensballe, Allan %A Volbracht, Christiane %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Antibodies, Monoclonal, Humanized %K Brain %K Chromatography, Liquid %K Cytoskeletal Proteins %K Disease Models, Animal %K Humans %K Mice %K Mice, Transgenic %K Mitochondrial Proteins %K Plaque, Amyloid %K Presenilin-1 %K Protein Transport %K Proteome %K Proteomics %K Stress, Physiological %K Tandem Mass Spectrometry %X

BACKGROUND: Alzheimer's disease (AD) is characterized by accumulation of amyloid-β (Aβ) species and deposition of senile plaques (SPs). Clinical trials with the anti-Aβ antibody aducanumab have been completed recently.

OBJECTIVE: To characterize the proteomic profile of SPs and surrounding tissue in a mouse model of AD in 10-month-old tgAPPPS1-21 mice after chronic treatment with aducanumab for four months with weekly dosing (10 mg/kg).

METHODS: After observing significant reduction of SP numbers in hippocampi of aducanumab-treated mice, we applied a localized proteomic analysis by combining laser microdissection and liquid chromatography-tandem mass spectrometry (LC-MS/MS) of the remaining SPs in hippocampi. We microdissected three subregions, containing SPs, SP penumbra level 1, and an additional penumbra level 2 to follow the proteomic profile as gradient.

RESULTS: In the aducanumab-treated mice, we identified 17 significantly regulated proteins that were associated with 1) mitochondria and metabolism (ACAT2, ATP5J, ETFA, EXOG, HK1, NDUFA4, NDUFS7, PLCB1, PPP2R4), 2) cytoskeleton and axons (ADD1, CAPZB, DPYSL3, MAG), 3) stress response (HIST1H1C/HIST1H1D, HSPA12A), and 4) AβPP trafficking/processing (CD81, GDI2). These pathways and some of the identified proteins are implicated in AD pathogenesis. Proteins associated with mitochondria and metabolism were mainly upregulated while proteins associated with AβPP trafficking/processing and stress response pathways were mainly downregulated, suggesting that aducanumab could lead to a beneficial proteomic profile around SPs in tgAPPPS1-21 mice.

CONCLUSION: We identified novel proteomic patterns of SPs and surrounding tissue indicating that chronic treatment with aducanumab could inhibit Aβ toxicity and increase phagocytosis and cell viability.

%B J Alzheimers Dis %V 79 %P 249-265 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33252074?dopt=Abstract %R 10.3233/JAD-200715 %0 Journal Article %J J Alzheimers Dis %D 2021 %T APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid. %A Berger, Miles %A Cooter, Mary %A Roesler, Alexander S %A Chung, Stacey %A Park, John %A Modliszewski, Jennifer L %A VanDusen, Keith W %A Thompson, J Will %A Moseley, Arthur %A Devinney, Michael J %A Smani, Shayan %A Hall, Ashley %A Cai, Victor %A Browndyke, Jeffrey N %A Lutz, Michael W %A Corcoran, David L %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Biomarkers %K Chitinase-3-Like Protein 1 %K DNA Copy Number Variations %K Female %K Fructose-Bisphosphate Aldolase %K Humans %K Male %K Proteomics %K Receptors, Immunologic %X

BACKGROUND: APOE4 has been hypothesized to increase Alzheimer's disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear.

OBJECTIVE: Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number.

METHODS: We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction.

RESULTS: Increasing APOE4 copy number was associated with a significant decrease in a CRP peptide level across all five models (q < 0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q < 0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million.

CONCLUSION: Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

%B J Alzheimers Dis %V 79 %P 511-530 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33337362?dopt=Abstract %R 10.3233/JAD-200747 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Apolipoprotein E ɛ4 (APOE ɛ4) Allele is Associated with Long Sleep Duration Among Elderly with Cognitive Impairment. %A Basta, Maria %A Zaganas, Ioannis %A Simos, Panagiotis %A Koutentaki, Eirini %A Dimovasili, Christina %A Mathioudakis, Lambros %A Bourbouli, Mara %A Panagiotakis, Symeon %A Kapetanaki, Stefania %A Vgontzas, Alexandros %X

BACKGROUND: Apolipoprotein E gene (APOE) ɛ4 allele increases the risk for Alzheimer's disease (AD). Furthermore, among patients with cognitive impairment, longer sleep duration is associated with worse cognitive performance. To date, literature examining the associations between APOE ɛ4 allele and objective sleep duration is limited.

OBJECTIVE: Our aim was to assess the association between APOE ɛ4 and objective sleep duration, among patients with mild cognitive impairment (MCI) and AD. A sub-sample of 89 patients with AD (n = 49) and MCI (n = 40) were recruited from a large, population-based cohort of 3,140 elders (>60 years) residing on Crete, Greece.

METHODS: All participants underwent medical history/physical examination, extensive neuropsychiatric and neuropsychological evaluation, 3-day 24 h actigraphy and APOE ɛ4 allele genotyping. Comparisons of sleep duration variables between APOE ɛ4 allele carriers and non-carriers were assessed using ANCOVA, controlling for confounders.

RESULTS: The sample included 18 APOE ɛ4 carriers and 71 non-carriers, aged 78.6±6.6 and 78.2±6.5 years, respectively. Comparisons between the APOE ɛ4 carriers and non-carriers revealed no significant differences in terms of demographic and clinical variables. In terms of objective sleep duration across the two groups, APOE ɛ4 carriers compared to non-carriers had significantly longer nighttime Total Sleep Time (nTST) (7.7±1.4 versus 7.2±1.3  h, respectively, p = 0.011), as well as 24 h TST (8.5±1.6 versus 7.8±1.5  h, respectively, p = 0.012).

CONCLUSION: Among patients with MCI and AD, APOE ɛ4 carriers have longer objective nighttime and 24 h sleep duration compared to non-carriers. These findings further support that objective long sleep duration is a genetically-driven pre-clinical marker associated with worse prognosis in elderly with cognitive impairment.

%B J Alzheimers Dis %V 79 %P 763-771 %8 2021 Jan 19 %G eng %N 2 %R 10.3233/JAD-200958 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Assessing the Progression of Alzheimer's Disease in Real-World Settings in Three European Countries. %A Lladó, Albert %A Froelich, Lutz %A Khandker, Rezaul K %A Roset, Montserrat %A Black, Christopher M %A Lara, Nuria %A Chekani, Farid %A Ambegaonkar, Baishali M %K Alzheimer Disease %K Cholinesterase Inhibitors %K Cognition Disorders %K Disease Progression %K Europe %K Germany %K Humans %K Institutionalization %K Neuropsychological Tests %K Spain %X

BACKGROUND: There exists considerable variation in disease progression rates among patients with Alzheimer's disease (AD).

OBJECTIVE: The primary objective of this observational study is to assess the progression of AD by characterizing cognitive, functional, and behavioral changes during the follow-up period between 6 and 24 months.

METHODS: A longitudinal prospective study with community-dwelling patients with an established clinical diagnosis of AD of mild to moderate severity was conducted in Germany, Spain and the UK. A sample of 616 patients from 69 sites was included.

RESULTS: Patients had a mean of 1.9 years (SD = 1.9) since AD diagnosis at study inclusion. Cognitive symptoms were reported to have first occurred a mean of 1.1 years (SD = 1.7) prior to AD diagnosis and 1.4 (SD = 1.8) years prior to AD treatment. Patients initially diagnosed with mild and moderate AD spent a median (95%CI) of 3.7 (2.8; 4.4) and 11.1 (6.1, 'not reached') years until progression to moderate and severe AD, respectively, according to the Mini-Mental State Examination (MMSE) scores. A mixed model developed for cognitive, functional, and neuropsychiatric scores, obtained from study patients at baseline and during follow-up period, showed progressive deterioration of AD patients over time.

CONCLUSION: The study showed a deterioration of cognitive, functional, and neuropsychiatric functions during the follow-up period. Cognitive deterioration was slightly faster in patients with moderate AD compared to mild AD. The duration of moderate AD can be overestimated due to the use of retrospective data, lack of availability of MMSE scores in clinical charts and exclusion of patients at time of institutionalization.

%B J Alzheimers Dis %V 80 %P 749-759 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33579841?dopt=Abstract %R 10.3233/JAD-201172 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Association of Amyloid-β Pathology with Decision Making and Scam Susceptibility. %A Kapasi, Alifiya %A Yu, Lei %A Stewart, Christopher %A Schneider, Julie A %A Bennett, David A %A Boyle, Patricia A %X

BACKGROUND: Recent findings suggest that poor decision making and increased scam susceptibility are harbingers of Alzheimer's disease (AD) dementia and may be among the earliest behavioral manifestations of pathologic cognitive aging. However, the degree to which poor decision making and scam susceptibility reflect accumulating Alzheimer's disease (AD) pathology remains unclear.

OBJECTIVE: To investigate the associations of AD pathology with decision making and scam susceptibility in older adults without dementia.

METHODS: Data came from 198 deceased participants without clinical dementia (mean age at death = 90 years; 69%women) from two ongoing studies of aging. All underwent annual clinical evaluations, completed assessments of healthcare and financial decision making and scam susceptibility, and brain donation. Neuropathologic evaluations quantified pathologic hallmarks of AD, amyloid-β and tau-tangles, Lewy body pathology, and TDP-43 proteinopathy.

RESULTS: In linear regression models adjusted for demographics, amyloid-β pathology was associated with lower decision making (estimate = -0.35; SE = 0.16, p = 0.03), particularly healthcare decision making (estimate = -0.20; SE = 0.09, p = 0.03), as well as greater scam susceptibility (estimate = 0.12; SE = 0.04, p = 0.003); tau-tangle pathology was not related. Further, TDP-43 pathology was associated with greater scam susceptibility (estimate = 0.10; SE = 0.04; p = 0.02).

CONCLUSION: Accumulating AD pathology, particularly amyloid-β, is associated with poor decision making and increased scam susceptibility among older persons without overt cognitive impairment. These findings provide compelling evidence that decision making and scam susceptibility are sensitive to the earliest pathological changes of AD.

%B J Alzheimers Dis %V 83 %P 879-887 %8 2021 Sep 21 %G eng %N 2 %R 10.3233/JAD-210356 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Association of Essential Metals with APOE Genotype in Alzheimer's Disease. %A Babić Leko, Mirjana %A Jurasović, Jasna %A Nikolac Perković, Matea %A Španić, Ena %A Sekovanić, Ankica %A Orct, Tatjana %A Lukinović Škudar, Vesna %A Bačić Baronica, Koraljka %A Kiđemet-Piskač, Spomenka %A Vogrinc, Željka %A Pivac, Nela %A Borovečki, Fran %A Hof, Patrick R %A Šimić, Goran %X

BACKGROUND: The major confirmed genetic risk factor for late-onset, sporadic Alzheimer's disease (AD) is variant ɛ4 of apolipoprotein E gene (APOE). It is proposed that ApoE, a protein involved in transport of cholesterol to neurons can cause neurodegeneration in AD through interaction with metals. Previous studies mostly associated copper, iron, zinc, and calcium with ApoE4-mediated toxicity.

OBJECTIVE: To test the association of essential metals with APOE genotype.

METHODS: We compared plasma and cerebrospinal fluid (CSF) levels of copper, zinc, iron, sodium, magnesium, calcium, cobalt, molybdenum, manganese, boron, and chromium, and CSF ferritin levels among AD, mild cognitive impairment (MCI) patients, and healthy controls (HC) with different APOE genotype.

RESULTS: Sodium, copper, and magnesium levels were increased in carriers of ɛ4 allele. Additionally, the increase in sodium, calcium and cobalt plasma levels was observed in carriers of ɛ4/ɛx genotype. The decrease in boron plasma levels was observed in carriers of ɛ4 allele and ɛ4/ɛ4 genotype. Additionally, CSF zinc levels as well as plasma sodium levels were increased in AD patients compared to HC.

CONCLUSION: These results indicate that the molecular underpinnings of association of essential metals and metalloids with APOE should be further tested and clarified in vivo and in vitro.

%B J Alzheimers Dis %V 82 %P 661-672 %8 2021 Jul 20 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34057084?dopt=Abstract %R 10.3233/JAD-210158 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Association of Malnutrition with Functional and Cognitive Trajectories in People Living with Dementia: A Five-Year Follow-Up Study. %A Borda, Miguel Germán %A Ayala Copete, Ana María %A Tovar-Rios, Diego Alejandro %A Jaramillo-Jimenez, Alberto %A Giil, Lasse Melvær %A Soennesyn, Hogne %A Gómez-Arteaga, Camilo %A Venegas-Sanabria, Luis Carlos %A Kristiansen, Ida %A Chavarro-Carvajal, Diego Andrés %A Caicedo, Sandra %A Cano-Gutierrez, Carlos Alberto %A Vik-Mo, Audun %A Aarsland, Dag %X

BACKGROUND: In dementia, functional status depends on multiple factors in addition to cognition. Nutritional status is a potentially modifiable factor related to homeostasis and proper functioning of body systems and may contribute to cognitive and functional decline.

OBJECTIVE: This paper aims to analyze the association of malnutrition with the course of cognitive and functional decline in people living with dementia.

METHODS: This is an analysis of a longitudinal cohort study, the Dementia Study of Western Norway. Data of 202 patients diagnosed with mild dementia were analyzed; Alzheimer's disease (AD) (n = 103), Lewy body dementia (LBD) (n = 74), and other dementias (OD) (n = 25). Cognition was assessed with the Mini-Mental State Examination and functional decline through the activities of daily living included in the Rapid Disability Rating Scale. The Global Leadership Initiative on Malnutrition Index was used to determine nutritional status. Associations of nutritional status with cognitive and functional decline were evaluated through adjusted linear mixed models.

RESULTS: At baseline, the prevalence of general malnutrition was 28.7%; 17.32% were classified as moderate malnutrition and 11.38% as severe malnutrition (there were no significant differences between AD and LBD). Malnutrition at diagnosis and over follow-up was a significant predictor of functional-decline, but not of cognitive decline.

CONCLUSION: According to our results malnutrition was associated with faster functional loss but, not cognitive decline in older adults with dementia. A more comprehensive dementia approach including nutritional assessments could improve prognosis.

%B J Alzheimers Dis %V 79 %P 1713-1722 %8 2021 Feb 16 %G eng %N 4 %R 10.3233/JAD-200961 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Association of Midlife Depressive Symptoms with Regional Amyloid-β and Tau in the Framingham Heart Study. %A Gonzales, Mitzi M %A Samra, Jasmeet %A O'Donnell, Adrienne %A Mackin, R Scott %A Salinas, Joel %A Jacob, Mini %A Satizabal, Claudia L %A Aparicio, Hugo J %A Thibault, Emma G %A Sanchez, Justin S %A Finney, Rebecca %A Rubinstein, Zoe B %A Mayblyum, Danielle V %A Killiany, Ron J %A Decarli, Charlie S %A Johnson, Keith A %A Beiser, Alexa S %A Seshadri, Sudha %X

BACKGROUND: Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-β (Aβ) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective.

OBJECTIVE: The study aim was to evaluate the association between depressive symptoms and cerebral Aβ and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ɛ4 allele as a moderator.

METHODS: Participants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aβ and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored.

RESULTS: Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (β= 0.446, SE = 0.155, p = 0.006) and amygdala (β= 0.350, SE = 0.133, p = 0.012).

CONCLUSION: Although longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.

%B J Alzheimers Dis %V 82 %P 249-260 %8 2021 Jun 29 %G eng %N 1 %R 10.3233/JAD-210232 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Behavioral and Psychological Symptoms of Dementia in Down Syndrome Scale (BPSD-DS II): Optimization and Further Validation. %A Dekker, Alain D %A Ulgiati, Aurora M %A Groen, Henk %A Boxelaar, Vincent A %A Sacco, Silvia %A Falquero, Ségolène %A Carfi, Angelo %A di Paola, Antonella %A Benejam, Bessy %A Valldeneu, Silvia %A Fopma, Roelie %A Oosterik, Marjo %A Hermelink, Marloes %A Beugelsdijk, Gonny %A Schippers, Mieke %A Henstra, Hepie %A Scholten-Kuiper, Martine %A Willink-Vos, Judith %A de Ruiter, Lisa %A Willems, Liesbeth %A Loonstra-de Jong, Anneke %A Coppus, Antonia M W %A Tollenaere, Marleen %A Fortea, Juan %A Onder, Graziano %A Rebillat, Anne-Sophie %A Van Dam, Debby %A De Deyn, Peter P %K Adult %K Aged %K Anxiety %K Dementia %K Down Syndrome %K Female %K Humans %K Irritable Mood %K Male %K Middle Aged %K Reproducibility of Results %K Symptom Assessment %X

BACKGROUND: People with Down syndrome (DS) are at high risk to develop Alzheimer's disease dementia (AD). Behavioral and psychological symptoms of dementia (BPSD) are common and may also serve as early signals for dementia. However, comprehensive evaluation scales for BPSD, adapted to DS, are lacking. Therefore, we previously developed the BPSD-DS scale to identify behavioral changes between the last six months and pre-existing life-long characteristic behavior.

OBJECTIVE: To optimize and further study the scale (discriminative ability and reliability) in a large representative DS study population.

METHODS: Optimization was based on item irrelevance and clinical experiences obtained in the initial study. Using the shortened and refined BPSD-DS II, informant interviews were conducted to evaluate 524 individuals with DS grouped according to dementia status: no dementia (DS, N = 292), questionable dementia (DS + Q, N = 119), and clinically diagnosed dementia (DS + AD, N = 113).

RESULTS: Comparing item change scores between groups revealed prominent changes in frequency and severity for anxious, sleep-related, irritable, restless/stereotypic, apathetic, depressive, and eating/drinking behavior. For most items, the proportion of individuals displaying an increased frequency was highest in DS + AD, intermediate in DS + Q, and lowest in DS. For various items within sections about anxious, sleep-related, irritable, apathetic, and depressive behaviors, the proportion of individuals showing an increased frequency was already substantial in DS + Q, suggesting that these changes may serve as early signals of AD in DS. Reliability data were promising.

CONCLUSION: The optimized scale yields largely similar results as obtained with the initial version. Systematically evaluating BPSD in DS may increase understanding of changes among caregivers and (timely) adaptation of care/treatment.

%B J Alzheimers Dis %V 81 %P 1505-1527 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33967040?dopt=Abstract %R 10.3233/JAD-201427 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Bispecific Tau Antibodies with Additional Binding to C1q or Alpha-Synuclein. %A Quint, Wim Hendricus %A Matečko-Burmann, Irena %A Schilcher, Irene %A Löffler, Tina %A Schöll, Michael %A Burmann, Björn Marcus %A Vogels, Thomas %X

BACKGROUND: Alzheimer's disease (AD) and other tauopathies are neurodegenerative disorders characterized by cellular accumulation of aggregated tau protein. Tau pathology within these disorders is accompanied by chronic neuroinflammation, such as activation of the classical complement pathway by complement initiation factor C1q. Additionally, about half of the AD cases present with inclusions composed of aggregated alpha-synuclein called Lewy bodies. Lewy bodies in disorders such as Parkinson's disease and Lewy body dementia also frequently occur together with tau pathology.

OBJECTIVE: Immunotherapy is currently the most promising treatment strategy for tauopathies. However, the presence of multiple pathological processes within tauopathies makes it desirable to simultaneously target more than one disease pathway.

METHODS: Herein, we have developed three bispecific antibodies based on published antibody binding region sequences. One bispecific antibody binds to tau plus alpha-synuclein and two bispecific antibodies bind to tau plus C1q.

RESULTS: Affinity of the bispecific antibodies to their targets compared to their monospecific counterparts ranged from nearly identical to one order of magnitude lower. All bispecific antibodies retained binding to aggregated protein in patient-derived brain sections. The bispecific antibodies also retained their ability to inhibit aggregation of recombinant tau, regardless of whether the tau binding sites were in IgG or scFv format. Mono- and bispecific antibodies inhibited cellular seeding induced by AD-derived pathological tau with similar efficacy. Finally, both Tau-C1q bispecific antibodies completely inhibited the classical complement pathway.

CONCLUSION: Bispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders.

%B J Alzheimers Dis %V 80 %P 813-829 %8 2021 Mar 23 %G eng %N 2 %R 10.3233/JAD-201334 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Body Mass Index and Mild Cognitive Impairment Among Middle-Aged and Older Adults from Low- and Middle-Income Countries. %A Smith, Lee %A Shin, Jae Il %A Oh, Hans %A Carmichael, Christina %A Jacob, Louis %A Stefanac, Sinisa %A Lindsay, Rosie K %A Soysal, Pinar %A Veronese, Nicola %A Tully, Mark A %A Butler, Laurie %A Barnett, Yvonne %A Koyanagi, Ai %X

BACKGROUND: The effect of weight modification on future dementia risk is currently a subject of debate and may be modified by age.

OBJECTIVE: The aim of the present study was to investigate the association between body mass index (BMI) status with mild cognitive impairment (MCI) (a preclinical stage of dementia) in middle-aged and older adults residing in six low- and middle-income countries using nationally representative data.

METHODS: Cross-sectional data from the Study on Global Ageing and Adult Health (SAGE) were analyzed. MCI was defined using the National Institute on Aging-Alzheimer's Association criteria. BMI (kg/m2) was based on measured weight and height and categorized as: underweight (<18.5), normal (18.5-24.9), overweight (25.0-29.9), and obese (≥30.0). Multivariable logistic regression analysis and meta-analysis were conducted to assess associations.

RESULTS: Data on 32,715 individuals aged ≥50 years with preservation in functional abilities were analyzed [mean (SD) age 62.1 (15.6) years; 51.7% females]. Among those aged 50-64 years, compared to normal weight, underweight (OR = 1.44; 95% CI = 1.14-1.81), overweight (OR = 1.17; 95% CI = 1.002-1.37), and obesity (OR = 1.46; 95% CI = 1.09-1.94) were all significantly associated with higher odds for MCI. In those aged ≥65 years, underweight (OR = 0.71; 95% CI = 0.54-0.95) and overweight (OR = 0.72; 95% CI = 0.55-0.94) were associated with significantly lower odds for MCI, while obesity was not significantly associated with MCI.

CONCLUSION: The results of the study suggest that the association between BMI and MCI is likely moderated by age. Future longitudinal studies are required to confirm or refute the present findings before recommendations for policy and practice can be made.

%B J Alzheimers Dis %V 85 %P 1095-1105 %8 2022 Feb 01 %G eng %N 3 %R 10.3233/JAD-215345 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cannabidiol Ameliorates Cognitive Function via Regulation of IL-33 and TREM2 Upregulation in a Murine Model of Alzheimer's Disease. %A Khodadadi, Hesam %A Salles, Évila Lopes %A Jarrahi, Abbas %A Costigliola, Vincenzo %A Khan, M B %A Yu, Jack C %A Morgan, John C %A Hess, David C %A Vaibhav, Kumar %A Dhandapani, Krishnan M %A Baban, Babak %K Alzheimer Disease %K Animals %K Cannabidiol %K Cognition %K Disease Models, Animal %K Humans %K Interleukin-33 %K Male %K Membrane Glycoproteins %K Mice %K Mice, Transgenic %K Receptors, Immunologic %K Up-Regulation %X

There is a dire need for due innovative therapeutic modalities to improve outcomes of AD patients. In this study, we tested whether cannabidiol (CBD) improves outcomes in a translational model of familial AD and to investigate if CBD regulates interleukin (IL)-33 and triggering receptor expressed on myeloid cells 2 (TREM2), which are associated with improved cognitive function. CBD was administered to 5xFAD mice, which recapitulate early onset, familial AD. Behavioral tests and immunoassays were used to evaluate cognitive and motor outcomes. Our findings suggest that CBD treatment enhanced IL-33 and TREM2 expression, ameliorated the symptoms of AD, and retarded cognitive decline.

%B J Alzheimers Dis %V 80 %P 973-977 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33612548?dopt=Abstract %R 10.3233/JAD-210026 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cerebrospinal Fluid Proteome Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction. %A VanDusen, Keith W %A Li, Yi-Ju %A Cai, Victor %A Hall, Ashley %A Hiles, Sarah %A Thompson, J Will %A Moseley, M Arthur %A Cooter, Mary %A Acker, Leah %A Levy, Jerrold H %A Ghadimi, Kamrouz %A Quiñones, Quintin J %A Devinney, Michael J %A Chung, Stacey %A Terrando, Niccolò %A Moretti, Eugene W %A Browndyke, Jeffrey N %A Mathew, Joseph P %A Berger, Miles %X

BACKGROUND: Postoperative cognitive dysfunction (POCD), a syndrome of cognitive deficits occurring 1-12 months after surgery primarily in older patients, is associated with poor postoperative outcomes. POCD is hypothesized to result from neuroinflammation; however, the pathways involved remain unclear. Unbiased proteomic analyses have been used to identify neuroinflammatory pathways in multiple neurologic diseases and syndromes but have not yet been applied to POCD.

OBJECTIVE: To utilize unbiased mass spectrometry-based proteomics to identify potential neuroinflammatory pathways underlying POCD.

METHODS: Unbiased LC-MS/MS proteomics was performed on immunodepleted cerebrospinal fluid (CSF) samples obtained before, 24 hours after, and 6 weeks after major non-cardiac surgery in older adults who did (n = 8) or did not develop POCD (n = 6). Linear mixed models were used to select peptides and proteins with intensity differences for pathway analysis.

RESULTS: Mass spectrometry quantified 8,258 peptides from 1,222 proteins in > 50%of patient samples at all three time points. Twelve peptides from 11 proteins showed differences in expression over time between patients with versus withoutPOCD (q < 0.05), including proteins previously implicated in neurodegenerative disease pathophysiology. Additionally, 283 peptides from 182 proteins were identified with trend-level differences (q < 0.25) in expression over time between these groups. Among these, pathway analysis revealed that 50 were from 17 proteins mapping to complement and coagulation pathways (q = 2.44*10-13).

CONCLUSION: These data demonstrate the feasibility of performing unbiased mass spectrometry on perioperative CSF samples to identify pathways associated with POCD. Additionally, they provide hypothesis-generating evidence for CSF complement and coagulation pathway changes in patients with POCD.

%B J Alzheimers Dis %V 80 %P 1281-1297 %8 2021 Apr 06 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33682719?dopt=Abstract %R 10.3233/JAD-201544 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cerebrospinal Fluid Sulfatide Levels Lack Diagnostic Utility in the Subcortical Small Vessel Type of Dementia. %A Svensson, Johan %A Blomqvist, Maria %A Kettunen, Petronella %A Eckerström, Carl %A Henricsson, Marcus %A Jonsson, Michael %A Bjerke, Maria %A Månsson, Jan-Eric %A Wallin, Anders %X

BACKGROUND: Sulfatides (STs) in cerebrospinal fluid (CSF), as well as magnetic resonance imaging (MRI)-detected white matter hyperintensities (WMHs), may reflect demyelination. Here, we investigated the diagnostic utility of CSF ST levels in the subcortical small vessel type of dementia (SSVD), which is characterized by the presence of brain WMHs.

OBJECTIVE: To study the diagnostic utility of CSF ST levels in SSVD.

METHODS: This was a mono-center, cross-sectional study of SSVD (n = 16), Alzheimer's disease (n = 40), mixed dementia (n = 27), and healthy controls (n = 33). Totally, 20 ST species were measured in CSF by liquid chromatography-mass spectrometry (LC-MS/MS).

RESULTS: CSF total ST levels, as well as CSF levels of hydroxylated and nonhydroxylated ST species, did not differ across the study groups. In contrast, CSF neurofilament light chain (NFL) levels separated the patient groups from the controls. CSF total ST level correlated with CSF/serum albumin ratio in the total study population (r = 0.64, p <  0.001) and in all individual study groups. Furthermore, CSF total ST level correlated positively with MRI-estimated WMH volume in the total study population (r = 0.30, p <  0.05), but it did not correlate with CSF NFL level.

CONCLUSION: Although there was some relation between CSF total ST level and WMH volume, CSF ST levels were unaltered in all dementia groups compared to the controls. This suggests that CSF total ST level is a poor biomarker of demyelination in SSVD. Further studies are needed to investigate the mechanisms underlying the marked correlation between CSF total ST level and CSF/serum albumin ratio.

%B J Alzheimers Dis %V 82 %P 781-790 %8 2021 Jul 20 %G eng %N 2 %R 10.3233/JAD-201552 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cerebrovascular microRNA Expression Profile During Early Development of Alzheimer's Disease in a Mouse Model. %A Chum, Phoebe P %A Hakim, Md A %A Behringer, Erik J %X

BACKGROUND: Emerging evidence demonstrates association of Alzheimer's disease (AD) with impaired delivery of blood oxygen and nutrients to and throughout the brain. The cerebral circulation plays multiple roles underscoring optimal brain perfusion and cognition entailing moment-to-moment blood flow control, vascular permeability, and angiogenesis. With currently no effective treatment to prevent or delay the progression of AD, cerebrovascular microRNA (miRNA) markers corresponding to post-transcriptional regulation may distinguish phases of AD.

OBJECTIVE: We tested the hypothesis that cerebrovascular miRNA expression profiles indicate developmental stages of AD pathology.

METHODS: Total RNA was isolated from total brain vessel segments of male and female 3xTg-AD mice [young, 1-2 mo; cognitive impairment (CI), 4-5 mo; extracellular amyloid-β plaques (Aβ), 6-8 mo; plaques+neurofibrillary tangles (AβT), 12-15 mo]. NanoString technology nCounter miRNA Expression panel for mouse was used to screen for 599 miRNAs.

RESULTS: Significant (p < 0.05) downregulation of various miRNAs indicated transitions from young to CI (e.g., let-7g & miR-1944, males; miR-133a & miR-2140, females) and CI to Aβ (e.g., miR-99a, males) but not from Aβ to AβT. In addition, altered expression of select miRNAs from overall Pre-AD (young + CI) versus AD (Aβ+ AβT) were detected in both males (let-7d, let-7i, miR-23a, miR-34b-3p, miR-99a, miR-126-3p, miR-132, miR-150, miR-151-5p, miR-181a) and females (miR-150, miR-539). Altogether, at least 20 cerebrovascular miRNAs effectively delineate AD versus Pre-AD pathology.

CONCLUSION: Using the 3xTg-AD mouse model, these data demonstrate that cerebrovascular miRNAs pertaining to endothelial function, vascular permeability, angiogenesis, inflammation, and Aβ/tau metabolism can track early development of AD.

%B J Alzheimers Dis %V 85 %P 91-113 %8 2022 Jan 04 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34776451?dopt=Abstract %R 10.3233/JAD-215223 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Cognition and Flow Study: A Feasibility Randomized Controlled Trial of the Effects of Cognitive Training on Cerebral Blood Flow. %A Beishon, Lucy C %A Panerai, Ronney B %A Budgeon, Charley %A Subramaniam, Hari %A Mukaetova-Ladinska, Elizabeta %A Robinson, Thompson G %A Haunton, Victoria J %X

BACKGROUND: Cognitive training (CT) has demonstrated benefits for healthy older adults (HG) and mild cognitive impairment (MCI), but the effects on vascular function are unknown.

OBJECTIVE: This is a feasibility trial investigating the effects of CT on cerebral blood flow velocity (CBFv).

METHODS: Twenty HG, 24 with Alzheimer's disease (AD), and 12 with MCI were randomized to 12 weeks of multi-domain CT or control. Outcomes included: cognition (Addenbrooke's Cognitive Examination III), mood, quality of life (QoL), physical, and neurovascular function (transcranial Doppler ultrasonography measured task activation of CBFv responses). Data are presented as mean difference (MD) and 95% confidence interval (CI).

RESULTS: 47 participants completed the trial. There were three dropouts from the training arm in the AD group, and one in the HG group. The intervention was acceptable and feasible to the majority of participants with a high completion rate (89%). The dropout rate was higher among participants with dementia. Few changes were identified on secondary analyses, but QoL was significantly improved in HG post-training (MD: 4.83 [95% CI: 1.13, 8.54]). CBFv response rate was not significantly different in HG (MD: 1.84 [95% CI: -4.81, 1.12]), but a significant increase was seen in the patient group (MD: 1.79 [95% CI: 0.005, 3.58]), requiring sample sizes of 56 and 84 participants respectively for a fully-powered trial.

CONCLUSION: A 12-week CT program was acceptable and feasible in HG, AD, and MCI. CT may be associated with alterations in vascular physiology which require further investigation in an appropriately powered randomized controlled trial.

%B J Alzheimers Dis %V 80 %P 1567-1581 %8 2021 Apr 20 %G eng %N 4 %R 10.3233/JAD-201444 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cognitive Effects of Aerobic Exercise in Alzheimer's Disease: A Pilot Randomized Controlled Trial. %A Yu, Fang %A Vock, David M %A Zhang, Lin %A Salisbury, Dereck %A Nelson, Nathaniel W %A Chow, Lisa S %A Smith, Glenn %A Barclay, Terry R %A Dysken, Maurice %A Wyman, Jean F %X

BACKGROUND: Aerobic exercise has shown inconsistent cognitive effects in older adults with Alzheimer's disease (AD) dementia.

OBJECTIVE: To examine the immediate and longitudinal effects of 6-month cycling on cognition in older adults with AD dementia.

METHODS: This randomized controlled trial randomized 96 participants (64 to cycling and 32 to stretching for six months) and followed them for another six months. The intervention was supervised, moderate-intensity cycling for 20-50 minutes, 3 times a week for six months. The control was light-intensity stretching. Cognition was assessed at baseline, 3, 6, 9, and 12 months using the AD Assessment Scale-Cognition (ADAS-Cog). Discrete cognitive domains were measured using the AD Uniform Data Set battery.

RESULTS: The participants were 77.4±6.8 years old with 15.6±2.9 years of education, and 55%were male. The 6-month change in ADAS-Cog was 1.0±4.6 (cycling) and 0.1±4.1 (stretching), which were both significantly less than the natural 3.2±6.3-point increase observed naturally with disease progression. The 12-month change was 2.4±5.2 (cycling) and 2.2±5.7 (control). ADAS-Cog did not differ between groups at 6 (p = 0.386) and 12 months (p = 0.856). There were no differences in the 12-month rate of change in ADAS-Cog (0.192 versus 0.197, p = 0.967), memory (-0.012 versus -0.019, p = 0.373), executive function (-0.020 versus -0.012, p = 0.383), attention (-0.035 versus -0.033, p = 0.908), or language (-0.028 versus -0.026, p = 0.756).

CONCLUSION: Exercise may reduce decline in global cognition in older adults with mild-to-moderate AD dementia. Aerobic exercise did not show superior cognitive effects to stretching in our pilot trial, possibly due to the lack of power.

%B J Alzheimers Dis %V 80 %P 233-244 %8 2021 Mar 9 %G eng %N 1 %R 10.3233/JAD-201100 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cortical Thickness and Its Association with Clinical Cognitive and Neuroimaging Markers in Cerebral Amyloid Angiopathy. %A Subotic, Arsenije %A McCreary, Cheryl R %A Saad, Feryal %A Nguyen, Amanda %A Alvarez-Veronesi, Ana %A Zwiers, Angela M %A Charlton, Anna %A Beaudin, Andrew E %A Ismail, Zahinoor %A Bruce Pike, G %A Smith, Eric E %X

BACKGROUND: Cerebral amyloid angiopathy (CAA) contributes to brain neurodegeneration and cognitive decline, but the relationship between these two processes is incompletely understood.

OBJECTIVE: The purpose of this study is to examine cortical thickness and its association with cognition and neurodegenerative biomarkers in CAA.

METHODS: Data were collected from the Functional Assessment of Vascular Reactivity study and the Calgary Normative Study. In total, 48 participants with probable CAA, 72 cognitively normal healthy controls, and 24 participants with mild dementia due to AD were included. Participants underwent an MRI scan, after which global and regional cortical thickness measurements were obtained using FreeSurfer. General linear models, adjusted for age and sex, were used to compare cortical thickness globally and in an AD signature region.

RESULTS: Global cortical thickness was lower in CAA compared to healthy controls (mean difference (MD) -0.047 mm, 95% confidence interval (CI) -0.088, -0.005, p = 0.03), and lower in AD compared to CAA (MD -0.104 mm, 95% CI -0.165, -0.043, p = 0.001). In the AD signature region, cortical thickness was lower in CAA compared to healthy controls (MD -0.07 mm, 95% CI -0.13 to -0.01, p = 0.02). Within the CAA group, lower cortical thickness was associated with lower memory scores (R2 = 0.10; p = 0.05) and higher white matter hyperintensity volume (R2 = 0.09, p = 0.04).

CONCLUSION: CAA contributes to neurodegeneration in the form of lower cortical thickness, and this could contribute to cognitive decline. Regional overlap with an AD cortical atrophy signature region suggests that co-existing AD pathology may contribute to lower cortical thickness observed in CAA.

%B J Alzheimers Dis %V 81 %P 1663-1671 %8 2021 Jun 15 %G eng %N 4 %R 10.3233/JAD-210138 %0 Journal Article %J J Alzheimers Dis %D 2021 %T A Cost-Consequence Analysis of Different Screening Procedures in Alzheimer's Disease: Results from the MOPEAD Project. %A Wimo, Anders %A Belger, Mark %A Bon, Jaka %A Jessen, Frank %A Dumas, Annette %A Kramberger, Milica G %A Jamilis, Laura %A Johansson, Gunilla %A Rodrigo Salas, Adrián %A Rodríguez Gómez, Octavio %A Sannemann, Lena %A Stoekenbroek, Malou %A Gurruchaga Telleria, Miren %A Valero, Sergi %A Vermunt, Lisa %A Waterink, Lisa %A Winblad, Bengt %A Visser, Peter Jelle %A Zwan, Marissa %A Boada, Merce %X

BACKGROUND: For care planning and support, under-detection and late diagnosis of Alzheimer's disease (AD) is a great challenge. Models of Patient-Engagement for Alzheimer's Disease (MOPEAD) is an EU-funded project aiming at testing different strategies to improve this situation.

OBJECTIVE: To make a cost-consequence analysis of MOPEAD.

METHODS: Four screening strategies were tested in five countries (Germany, the Netherlands, Slovenia, Spain, and Sweden): 1) a web-approach; 2) Open-House initiative; 3) in primary care; and 4) by diabetes specialists. Persons-at-risk of AD in all strategies were offered referral to a hospital-based specialist. The primary health-economic outcome was the cost per true-positive case (TP) of AD from the screened population.

RESULTS: Of 2,847 screened persons, 1,121 screened positive (39%), 402 were evaluated at memory clinics (14%), and 236 got an AD diagnosis (8%). The cost per TP of those screened was 3,115€ with the web-approach, 2,722€ with the Open-House, 1,530€ in primary care, and 1,190€ by diabetes specialists. Sensitivity analyses that more likely reflect the real-world situation confirmed the results. The number-needed-to-screen was 30 with the web-approach, 8 with the Open-House and primary care, and 6 with the diabetes specialists.There were country differences in terms of screening rates, referrals to memory clinics, staff-types involved, and costs per TP.

CONCLUSION: In primary care and by the diabetes specialist, the costs per TP/screened population were lowest, but the capacity of such settings to identify cases with AD-risk must be discussed. Hence new diagnostic strategies such as web-solutions and Open-House initiatives may be valuable after modifications.

%B J Alzheimers Dis %V 83 %P 1149-1159 %8 2021 Sep 28 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34420954?dopt=Abstract %R 10.3233/JAD-210303 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Could Altered Evoked Pain Responsiveness Be a Phenotypic Biomarker for Alzheimer's Disease Risk? A Cross-Sectional Analysis of Cognitively Healthy Individuals. %A Romano, Raymond R %A Carter, Michael A %A Dietrich, Mary S %A Cowan, Ronald L %A Bruehl, Stephen P %A Monroe, Todd B %K Adult %K Aged %K Aged, 80 and over %K Alleles %K Alzheimer Disease %K Apolipoprotein E4 %K Biomarkers %K Cross-Sectional Studies %K Female %K Genetic Association Studies %K Hot Temperature %K Humans %K Male %K Middle Aged %K Pain Perception %K Phenotype %K Risk Factors %X

BACKGROUND: This study evaluated whether the apolipoprotein ɛ4 (APOE4) allele, a genetic marker associated with increased risk of developing late-onset Alzheimer's disease (AD), was associated with differences in evoked pain responsiveness in cognitively healthy subjects.

OBJECTIVE: The aim was to determine whether individuals at increased risk of late-onset AD based on APOE allele genotype differ phenotypically in their response to experimentally-induced painful stimuli compared to those who do not have at least one copy of the ɛ4 allele.

METHODS: Forty-nine cognitively healthy subjects aged 30-89 years old with the APOE4 allele (n = 12) and without (n = 37) were assessed for group differences in pain thresholds and affective (unpleasantness) responses to experimentally-induced thermal pain stimuli.

RESULTS: Statistically significant main effects of APOE4 status were observed for both the temperature at which three different pain intensity percepts were reached (p = 0.040) and the level of unpleasantness associated with each (p = 0.014). APOE4 positive participants displayed lower overall pain sensitivity than those who were APOE4 negative and also greater overall levels of pain unpleasantness regardless of intensity level.

CONCLUSION: Cognitively healthy APOE4 carriers at increased risk of late-onset AD demonstrated reduced thermal pain sensitivity but greater unpleasantness to thermal pain stimuli relative to individuals at lower risk of late-onset AD. These results suggest that altered evoked pain perception could potentially be used as a phenotypic biomarker of late-onset AD risk prior to disease onset. Additional studies of this issue may be warranted.

%B J Alzheimers Dis %V 79 %P 1227-1233 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33337380?dopt=Abstract %R 10.3233/JAD-201293 %0 Journal Article %J J Alzheimers Dis %D 2021 %T COVID-19: Association Between Increase of Behavioral and Psychological Symptoms of Dementia During Lockdown and Caregivers' Poor Mental Health. %A Pongan, Elodie %A Dorey, Jean-Michel %A Borg, Céline %A Getenet, Jean Claude %A Bachelet, Romain %A Lourioux, Charles %A Laurent, Bernard %A Rey, Romain %A Rouch, Isabelle %K Aged %K Aged, 80 and over %K Caregivers %K Communicable Disease Control %K COVID-19 %K Cross-Sectional Studies %K Dementia %K Female %K France %K Humans %K Male %K Mental Disorders %K Mental Health %K Middle Aged %K Surveys and Questionnaires %X

BACKGROUND: From March 2020, the support and care systems for caregivers and people with dementia (PWD) were suspended or dramatically changed due to the lockdown during the world pandemic of COVID-19. Thus, these changes in living conditions have had deleterious consequences on the behavior of PWD and subsequently on their caregivers' mental health, the two being linked.

OBJECTIVE: Our study aimed to examine changes in behavior among PWD and to look for associations between the evolution of behavioral and psychological symptoms of dementia (BPSD) and caregivers' mental health in the context of COVID-19.

METHODS: The study was conducted among caregivers of PWD living at home in France. Caregivers were interviewed via an anonymous cross-sectional online survey during the first lockdown between April 15 and June 15, 2020.

RESULTS: Three hundred and eighty-nine caregivers accompanying a relative living at home participated in the study; 43.3%of the PWD presented a worsening of BPSD during the lockdown. With multivariate logistic regressions, a significant association was observed between "more BPSD" and burden, anxiety and depression, between "BPSD equivalent" and anxiety and depression, and between "emerging BPSD" and only depression.

CONCLUSION: The lockdown seems to have an impact on behavioral disorders in PWD and these disorders are associated with poorer mental health of caregivers. Our findings suggest attention should be given to caregivers of PWD who have BPSD before lockdown and the need for continued consultations and professional help in case of new lockdowns.

%B J Alzheimers Dis %V 80 %P 1713-1721 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646163?dopt=Abstract %R 10.3233/JAD-201396 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Current and Future Prevalence Estimates of Mild Cognitive Impairment, Dementia, and Its Subtypes in a Population-Based Sample of People 70 Years and Older in Norway: The HUNT Study. %A GjØra, Linda %A Strand, Bjørn Heine %A Bergh, Sverre %A Borza, Tom %A Brækhus, Anne %A Engedal, Knut %A Johannessen, Aud %A Kvello-Alme, Marte %A Krokstad, Steinar %A Livingston, Gill %A Matthews, Fiona E %A Myrstad, Christian %A Skjellegrind, Håvard %A Thingstad, Pernille %A Aakhus, Eivind %A Aam, Stina %A Selbæk, Geir %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Dementia %K Female %K Forecasting %K Humans %K Male %K Mental Status and Dementia Tests %K Neuropsychological Tests %K Norway %K Prevalence %K Sex Factors %K Surveys and Questionnaires %X

BACKGROUND: Having accurate, up-to-date information on the epidemiology of mild cognitive impairment (MCI) and dementia is imperative.

OBJECTIVE: To determine the prevalence of MCI and dementia in Norway using data from a large population-based study.

METHODS: All people 70 + years of age, n = 19,403, in the fourth wave of the Trøndelag Health Study (HUNT4) were invited to participate in the study HUNT4 70 + . Trained health personnel assessed participants using cognitive tests at a field station, at homes, or at their nursing home. Interviewers also completed a structured carer questionnaire in regard to participants suspected of having dementia. Clinical experts made diagnoses according to DSM-5 criteria. We calculated prevalence weighing the data to ensure population representativeness.

RESULTS: A total of 9,930 (51.2%) of the possible 19,403 people participated, and 9,663 of these had sufficient information for analysis. Standardized prevalence of dementia and MCI was 14.6% (95% confidence interval (CI) 13.9-15.4) and 35.3% (95% CI 34.3-36.4), respectively. Dementia was more prevalent in women and MCI more prevalent in men. The most prevalent dementia subtype was Alzheimer's disease (57%). By adding data collected from a study of persons < 70 years in the same region, we estimate that there are 101,118 persons with dementia in Norway in 2020, and this is projected to increase to 236,789 and 380,134 in 2050 and 2100, respectively.

CONCLUSION: We found a higher prevalence of dementia and MCI than most previous studies. The present prevalence and future projections are vital for preparing for future challenges to the healthcare system and the entire society.

%B J Alzheimers Dis %V 79 %P 1213-1226 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33427745?dopt=Abstract %R 10.3233/JAD-201275 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Deaths with Dementia in Indigenous and Non-Indigenous Australians: A Nationwide Study. %A Waller, Michael %A Buckley, Rachel F %A Masters, Colin L %A Nona, Francis R %A Eades, Sandra %A Dobson, Annette J %X

BACKGROUND: The prevalence of dementia is generally reported to be higher among Indigenous peoples.

OBJECTIVE: The rates and coding of dementia mortality were compared between Indigenous and non-Indigenous Australians.

METHODS: De-identified individual records on causes of death for all people aged 40 years or more who died in Australia between 2006 and 2014 (n = 1,233,084) were used. There were 185,237 records with International Classification of Diseases, Tenth Revision, codes for dementia (Alzheimer's Disease, vascular dementia, or unspecified dementia) as the underlying cause of death or mentioned elsewhere on the death certificate. Death rates were compared using Poisson regression. Logistic regression was used to assess whether dementia was more likely to be classified as 'unspecified' type in Indigenous Australians.

RESULTS: The rates of death with dementia were 57% higher in Indigenous Australians, compared to non-Indigenous, relative rate (RR) 1.57, 95% confidence interval (CI) (1.48, 1.66), p <  0.0001. This excess of deaths was highest at ages below 75 (RRs >  2, test for interaction p <  0.0001), and among men (test for interaction p <  0.0001). When the underreporting of Indigenous status on the death certificate was taken into account the relative rate increased to 2.17, 95% CI (2.07, 2.29). Indigenous Australians were also more likely to have their dementia coded as 'unspecified' on their death certificate (Odds Ratio 1.92, 95% CI (1.66, 2.21), p <  0.0001), compared to the non-Indigenous group.

CONCLUSION: This epidemiological analysis based on population level mortality data demonstrates the higher dementia-related mortality rate for Indigenous Australians especially at younger ages.

%B J Alzheimers Dis %V 81 %P 1589-1599 %8 2021 Jun 15 %G eng %N 4 %R 10.3233/JAD-201175 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Depressive Symptoms Imputed Across the Life Course Are Associated with Cognitive Impairment and Cognitive Decline. %A Brenowitz, Willa D %A Zeki Al Hazzouri, Adina %A Vittinghoff, Eric %A Golden, Sherita H %A Fitzpatrick, Annette L %A Yaffe, Kristine %X

BACKGROUND: Depressive symptoms may increase risk for dementia, but findings are controversial because late-life depression may be a prodromal dementia symptom. Life course data on depression and dementia risk may clarify this association; however, data is limited.

OBJECTIVE: To impute adult depressive symptoms trajectories across adult life stages and estimate the association with cognitive impairment and decline.

METHODS: Using a pooled study of 4 prospective cohorts (ages 20-89), we imputed adult life course depressive symptoms trajectories based on Center for Epidemiologic Studies Depression Scale-10 (CESD-10) and calculated time-weighted averages for early adulthood (ages 20-49), mid-life (ages 50-69), and late-life (ages 70-89) for 6,122 older participants. Adjusted pooled logistic and mixed-effects models estimated associations of imputed depressive symptoms with two cognitive outcomes: cognitive impairment defined by established criteria and a composite cognitive score.

RESULTS: In separate models, elevated depressive symptoms in each life stage were associated with cognitive outcomes: early adulthood OR for cognitive impairment = 1.59 (95%CI: 1.35,1.87); mid-life OR = 1.94 (95%CI:1.16, 3.26); and late-life OR = 1.77 (95%CI:1.42, 2.21). When adjusted for depressive symptoms in the other life-stages, elevated depressive symptoms in early adulthood (OR = 1.73; 95%CI: 1.42,2.11) and late-life (OR = 1.43; 95%CI: 1.08,1.89) remained associated with cognitive impairment and were also associated with faster rates of cognitive decline (p <  0.05).

CONCLUSION: Imputing depressive symptom trajectories from pooled cohorts may help expand data across the life course. Our findings suggest early adulthood depressive symptoms may be a risk factor for cognitive impairment independent of mid- or late-life depressive symptoms.

%B J Alzheimers Dis %V 83 %P 1379-1389 %8 2021 Sep 28 %G eng %N 3 %R 10.3233/JAD-210588 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Diagnosing Mild Cognitive Impairment Among Racially Diverse Older Adults: Comparison of Consensus, Actuarial, and Statistical Methods. %A Devlin, Kathryn N %A Brennan, Laura %A Saad, Laura %A Giovannetti, Tania %A Hamilton, Roy H %A Wolk, David A %A Xie, Sharon X %A Mechanic-Hamilton, Dawn %X

BACKGROUND: Actuarial and statistical methods have been proposed as alternatives to conventional methods of diagnosing mild cognitive impairment (MCI), with the aim of enhancing diagnostic and prognostic validity, but have not been compared in racially diverse samples.

OBJECTIVE: We compared the agreement of consensus, actuarial, and statistical MCI diagnostic methods, and their relationship to race and prognostic indicators among diverse older adults.

METHODS: Participants (N = 354; M age = 71; 68% White, 29% Black) were diagnosed with MCI or normal cognition (NC) according to clinical consensus, actuarial neuropsychological criteria (Jak/Bondi), and latent class analysis (LCA). We examined associations with race/ethnicity, longitudinal cognitive and functional change, and incident dementia.

RESULTS: MCI rates by consensus, actuarial criteria, and LCA were 44%, 53%, and 41%, respectively. LCA identified three MCI subtypes (memory; memory/language; memory/executive) and two NC classes (low normal; high normal). Diagnostic agreement was substantial, but agreement of the actuarial method with consensus and LCA was weaker than the agreement between consensus and LCA. Among cases classified as MCI by actuarial criteria only, Black participants were over-represented, and outcomes were generally similar to those of NC participants. Consensus diagnoses best predicted longitudinal outcomes overall, whereas actuarial diagnoses best predicted longitudinal functional change among Black participants.

CONCLUSION: Consensus diagnoses optimize specificity in predicting dementia, but among Black older adults, actuarial diagnoses may be more sensitive to early signs of decline. Results highlight the need for cross-cultural validity in MCI diagnosis and should be explored in community- and population-based samples.

%B J Alzheimers Dis %V 85 %P 627-644 %8 2022 Jan 18 %G eng %N 2 %R 10.3233/JAD-210455 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Different Inflammatory Signatures in Alzheimer's Disease and Frontotemporal Dementia Cerebrospinal Fluid. %A Boström, Gustaf %A Freyhult, Eva %A Virhammar, Johan %A Alcolea, Daniel %A Tumani, Hayrettin %A Otto, Markus %A Brundin, Rose-Marie %A Kilander, Lena %A Löwenmark, Malin %A Giedraitis, Vilmantas %A Lleo, Alberto %A von Arnim, Christine A F %A Kultima, Kim %A Ingelsson, Martin %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognitive Dysfunction %K Cross-Sectional Studies %K Female %K Frontotemporal Dementia %K Humans %K Inflammation %K Male %K Middle Aged %K Peptide Fragments %K tau Proteins %X

BACKGROUND: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases.

OBJECTIVE: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD.

METHODS: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing.

RESULTS: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14-1.53, q = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20-1.94, q = 0.045; and FTD: FC = 1.42, 95% CI 1.10-1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05).

CONCLUSION: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.

%B J Alzheimers Dis %V 81 %P 629-640 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33814444?dopt=Abstract %R 10.3233/JAD-201565 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Droplet Degeneration of Hippocampal and Cortical Neurons Signifies the Beginning of Neuritic Plaque Formation. %A Streit, Wolfgang J %A Rotter, Jonas %A Winter, Karsten %A Müller, Wolf %A Khoshbouei, Habibeh %A Bechmann, Ingo %X

BACKGROUND: Neuritic plaques contain neural and microglial elements, and amyloid-β protein (Aβ), but their pathogenesis remains unknown.

OBJECTIVE: Elucidate neuritic plaque pathogenesis.

METHODS: Histochemical visualization of hyperphosphorylated-tau positive (p-tau+) structures, microglia, Aβ, and iron.

RESULTS: Disintegration of large projection neurons in human hippocampus and neocortex presents as droplet degeneration: pretangle neurons break up into spheres of numerous p-tau+ droplets of various sizes, which marks the beginning of neuritic plaques. These droplet spheres develop in the absence of colocalized Aβ deposits but once formed become encased in diffuse Aβ with great specificity. In contrast, neurofibrillary tangles often do not colocalize with Aβ. Double-labelling for p-tau and microglia showed a lack of microglial activation or phagocytosis of p-tau+ degeneration droplets but revealed massive upregulation of ferritin in microglia suggesting presence of high levels of free iron. Perl's Prussian blue produced positive staining of microglia, droplet spheres, and Aβ plaque cores supporting the suggestion that droplet degeneration of pretangle neurons in the hippocampus and cortex represents ferroptosis, which is accompanied by the release of neuronal iron extracellularly.

CONCLUSION: Age-related iron accumulation and ferroptosis in the CNS likely trigger at least two endogenous mechanisms of neuroprotective iron sequestration and chelation, microglial ferritin expression and Aβ deposition, respectively, both contributing to the formation of neuritic plaques. Since neurofibrillary tangles and Aβ deposits colocalize infrequently, tangle formation likely does not involve release of neuronal iron extracellularly. In human brain, targeted deposition of Aβ occurs specifically in response to ongoing ferroptotic droplet degeneration thereby producing neuritic plaques.

%B J Alzheimers Dis %V 85 %P 1701-1720 %8 2022 Feb 15 %G eng %N 4 %R 10.3233/JAD-215334 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Effects of COVID-19 Home Confinement on Mental Health in Individuals with Increased Risk of Alzheimer's Disease. %A Soldevila-Domenech, Natalia %A Forcano, Laura %A Boronat, Anna %A Lorenzo, Thais %A Piera, Iris %A Puig-Pijoan, Albert %A Mateus, Julian %A González de Echevarri Gómez, José María %A Knezevic, Iva %A Soteras, Anna %A Fauria, Karine %A Pizarro, Nieves %A Molinuevo, José Luis %A de la Torre, Rafael %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Anxiety Disorders %K Apolipoprotein E3 %K Apolipoprotein E4 %K Cognition Disorders %K Cognitive Dysfunction %K COVID-19 %K Depressive Disorder %K Female %K Humans %K Male %K Mental Health %K Middle Aged %K Psychological Distress %K Quarantine %K Risk %K Spain %X

We explored the impact of the Spanish COVID-19 strict home confinement on mental health and cognition in non-infected subjects (N = 16, 60-80 years) diagnosed with subjective cognitive decline and APOEɛ3/ɛ4 carriers. Mental health was monitored for 2 months on a daily, weekly, or monthly basis, and compared to pre-confinement values. Emotional distress, anxiety, and depression scores increased to pathological threshold values during and after confinement. Those with lower mood during confinement experienced a decline in their mood after confinement. Cognition did not change. These preliminary results suggest that mental health consequences of corona measures in preclinical stages of Alzheimer's disease should be further evaluated.

%B J Alzheimers Dis %V 79 %P 1015-1021 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33386809?dopt=Abstract %R 10.3233/JAD-201408 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Effects of Peroral Omega-3 Fatty Acid Supplementation on Cerebrospinal Fluid Biomarkers in Patients with Alzheimer's Disease: A Randomized Controlled Trial-The OmegAD Study. %A Tofiq, Avin %A Zetterberg, Henrik %A Blennow, Kaj %A Basun, Hans %A Cederholm, Tommy %A Eriksdotter, Maria %A Faxen-Irving, Gerd %A Hjorth, Erik %A Jernerén, Fredrik %A Schultzberg, Marianne %A Wahlund, Lars-Olof %A Palmblad, Jan %A Freund-Levi, Yvonne %X

BACKGROUND: Studies have suggested a connection between a decrease in the levels of polyunsaturated fatty acids (PUFAs) and Alzheimer's disease (AD). We aimed to assess the effect of supplementation with omega-3 fatty acids (n-3 FAs) on biomarkers analyzed in the cerebrospinal fluid (CSF) of patients diagnosed with AD.

OBJECTIVE: To investigate the effects of daily supplementation with 2.3 g of PUFAs in AD patients on the biomarkers in CSF described below. We also explored the possible correlation between these biomarkers and the performance in the cognitive test Mini-Mental State Examination (MMSE).

METHODS: Thirty-three patients diagnosed with AD were randomized to either treatment with a daily intake of 2.3 g of n-3 FAs (n  =  18) or placebo (n  =  15). CSF samples were collected at baseline and after six months of treatment, and the following biomarkers were analyzed: Aβ 38, Aβ 40, Aβ 42, t-tau, p-tau, neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), soluble IL-1 receptor type II (sIL-1RII), and IL-6.

RESULTS: There were no significant differences between the groups concerning the level of the different biomarkers in the CSF at baseline. Within the treatment group, there was a small but significant increase in both YKL-40 (p = 0.04) and NfL (p = 0.03), while the other CSF biomarkers remained stable.

CONCLUSION: Supplementation with n-3 FAs had a statistically significant effect on NfL and YKL-40, resulting in an increase of both biomarkers, indicating a possible increase of inflammatory response and axonal damage. This increase in biomarkers did not correlate with MMSE score.

%B J Alzheimers Dis %V 83 %P 1291-1301 %8 2021 Sep 28 %G eng %N 3 %R 10.3233/JAD-210007 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Enhancing the Sensitivity of Memory Tests: Reference Data for the Free and Cued Selective Reminding Test and the Logical Memory Task from Cognitively Healthy Subjects with Normal Alzheimer's Disease Cerebrospinal Fluid Biomarker Levels. %A Brugulat-Serrat, Anna %A Cañas, Alba %A Canals, Lidia %A Marne, Paula %A Gramunt, Nina %A Milà-Alomà, Marta %A Suárez-Calvet, Marc %A Arenaza-Urquijo, Eider M %A Grau-Rivera, Oriol %A González-de-Echávarri, José María %A Minguillon, Carolina %A Fauria, Karine %A Kollmorgen, Gwendlyn %A Suridjan, Ivonne %A Zetterberg, Henrik %A Blennow, Kaj %A Gispert, Juan Domingo %A Molinuevo, José Luis %A Sánchez-Benavides, Gonzalo %X

BACKGROUND: Cognitive performance of a given individual should be interpreted in the context of reference standards obtained in cognitively healthy populations. Recent evidence has shown that removing asymptomatic individuals with biomarker evidence of Alzheimer's disease (AD) pathology from normative samples increases the sensitivity of norms to detect memory impairments. These kind of norms may be useful for defining subtle cognitive decline, the transitional cognitive decline between normal cognition and mild cognitive impairment.

OBJECTIVE: The present study aims to provide norms for the Free and Cued Selective Reminding Test (FCSRT) and the Logical Memory subtest of the Wechsler Memory Scale-IV in a sample of individuals aged 50-70 years with normal levels of amyloid (A) and tau (T) cerebrospinal fluid (CSF) biomarkers.

METHODS: The sample was composed of 248 individuals from the ALFA+ study with negative amyloid-β and tau CSF biomarker levels. Regression-based norms were developed, including adjustments for age, education, and sex when applicable.

RESULTS: We found that education was associated with the performance in all the variables of both tests while age had a marginal effect only in the delayed free recall of the FCSRT. Sex was also related to the performance in the FCSRT, with women outperforming men. Equations to calculate z-scores and normative percentile tables were created. As compared with previously published norms the reference data presented were more sensitive but less specific, as expected.

CONCLUSION: The use of the norms provided in this work, in combination with the already published conventional norms, may contribute to detecting subtle memory impairment.

%B J Alzheimers Dis %V 84 %P 119-128 %8 2021 Oct 26 %G eng %N 1 %R 10.3233/JAD-210640 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Entorhinal Perfusion Predicts Future Memory Decline, Neurodegeneration, and White Matter Hyperintensity Progression in Older Adults. %A Bangen, Katherine J %A Thomas, Kelsey R %A Sanchez, Danielle L %A Edmonds, Emily C %A Weigand, Alexandra J %A Delano-Wood, Lisa %A Bondi, Mark W %X

BACKGROUND: Altered cerebral blood flow (CBF) has been linked to increased risk for Alzheimer's disease (AD). However, whether altered CBF contributes to AD risk by accelerating cognitive decline remains unclear. It also remains unclear whether reductions in CBF accelerate neurodegeneration and development of small vessel cerebrovascular disease.

OBJECTIVE: To examine associations between CBF and trajectories of memory performance, regional brain atrophy, and global white matter hyperintensity (WMH) volume.

METHOD: 147 Alzheimer's Disease Neuroimaging Initiative participants free of dementia underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) to measure CBF and serial neuropsychological and structural MRI examinations. Linear mixed effects models examined 5-year rate of change in memory and 4-year rate of change in regional brain atrophy and global WMH volumes as a function of baseline regional CBF. Entorhinal and hippocampal CBF were examined in separate models.

RESULTS: Adjusting for demographic characteristics, pulse pressure, apolipoprotein E ɛ4 positivity, cerebrospinal fluid p-tau/Aβ ratio, and neuronal metabolism (i.e., fluorodeoxyglucose standardized uptake value ratio), lower baseline entorhinal CBF predicted faster rates of decline in memory as well as faster entorhinal thinning and WMH progression. Hippocampal CBF did not predict cognitive or brain structure trajectories.

CONCLUSION: Findings highlight the importance of early cerebrovascular dysfunction in AD risk and suggest that entorhinal CBF as measured by noninvasive ASL MRI is a useful biomarker predictive of future cognitive decline and of risk of both.

%B J Alzheimers Dis %V 81 %P 1711-1725 %8 2021 Jun 15 %G eng %N 4 %R 10.3233/JAD-201474 %0 Journal Article %J J Alzheimers Dis %D 2021 %T High Fat Diet Mediates Amyloid-β Cleaving Enzyme 1 Phosphorylation and SUMOylation, Enhancing Cognitive Impairment in APP/PS1 Mice. %A Bao, Jian %A Liang, Zheng %A Gong, Xiaokang %A Yu, Jing %A Xiao, Yifan %A Liu, Wei %A Wang, Xiaochuan %A Wang, Jian-Zhi %A Shu, Xiji %X

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in older adults and extracellular accumulation of amyloid-β (Aβ) is one of the two characterized pathologies of AD. Obesity is significantly associated with AD developing factors. Several studies have reported that high fat diet (HFD) influenced Aβ accumulation and cognitive performance during AD pathology. However, the underlying neurobiological mechanisms have not yet been elucidated.

OBJECTIVE: The objective of this study was to explore the underlying neurobiological mechanisms of HFD influenced Aβ accumulation and cognitive performance during AD pathology.

METHODS: 2.5-month-old male APP/PS1 mice were randomly separated into two groups: 1) the normal diet (ND) group, fed a standard diet (10 kcal%fat); and 2) the HFD group, fed a high fat diet (40 kcal%fat, D12492; Research Diets). After 4 months of HFD or ND feeding, mice in the two groups were subjected for further ethological, morphological, and biochemical analyses.

RESULTS: A long-term HFD diet significantly increased perirenal fat and impaired dendritic integrity and aggravated neurodegeneration, and augmented learning and memory deficits in APP/PS1 mice. Furthermore, the HFD increased beta amyloid cleaving enzyme 1 (BACE1) dephosphorylation and SUMOylation, resulting in enhanced enzyme activity and stability, which exacerbated the deposition of amyloid plaques.

CONCLUSION: Our study demonstrates that long-term HFD consumption aggravates amyloid-β accumulation and cognitive impairments, and that modifiable lifestyle factors, such as obesity, can induce BACE1 post-modifications which may contribute to AD pathogenesis.

%B J Alzheimers Dis %V 85 %P 863-876 %8 2022 Jan 18 %G eng %N 2 %R 10.3233/JAD-215299 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Hypertension and Hypercholesterolemia Modify Dementia Risk in Relation to APOEɛ4 Status. %A Pillai, Jagan A %A Lei, Kou %A Bena, James %A Penn, Lisa %A Leverenz, James B %X

BACKGROUND: There is significant interest in understanding the role of modifiable vascular risk factors contributing to dementia risk across age groups.

OBJECTIVE: Risk of dementia onset was assessed in relation to vascular risk factors of hypertension and hypercholesterolemia among cognitively normal APOEɛ4 carriers and non-carriers.

METHODS: In a sample of prospectively characterized longitudinal cohort from the National Alzheimer's Coordinating Center database, 9,349 participants met criteria for normal cognition at baseline, had a CDR-Global (CDR-G) score of zero, and had concomitant data on APOEɛ4 status and medical co-morbidities including histories of hypertension and hypercholesterolemia. Multivariable Cox proportional hazards models adjusted for well-known potential confounders were used to compare dementia onset among APOEɛ4 carriers and non-carriers by young (≤65 years) and old (>  65 year) age groups.

RESULTS: 519 participants converted to dementia within an average follow up of 5.97 years. Among older APOEɛ4 carriers, hypercholesterolemia was related to lower risk of dementia (HR (95% CI), 0.68 (0.49-0.94), p = 0.02). Among older APOEɛ4 non-carriers, hypertension was related to higher risk of dementia (HR (95% CI), 1.44 (1.13-1.82), p = 0.003). These results were corroborated among a subset with autopsy data characterizing underlying neuropathology. Among younger participants, vascular risk factors did not impact dementia risk, likely from a lower frequency of vascular and Alzheimer's as etiologies of dementia among this cohort.

CONCLUSION: A history of hypercholesterolemia related to a lower risk of dementia among older APOEɛ4 carriers, while hypertension related to a higher risk of dementia among older APOEɛ4 non-carriers.

%B J Alzheimers Dis %V 81 %P 1493-1504 %8 2021 Jun 15 %G eng %N 4 %R 10.3233/JAD-201609 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Impact of Social Isolation on People with Dementia and Their Family Caregivers. %A Azevedo, Lílian Viana Dos Santos %A Calandri, Ismael Luis %A Slachevsky, Andrea %A Graviotto, Héctor Gastón %A Vieira, Maria Carolina Santos %A Andrade, Caíssa Bezerra de %A Rossetti, Adriana Peredo %A Generoso, Alana Barroso %A Carmona, Karoline Carvalho %A Pinto, Ludmilla Aparecida Cardoso %A Sorbara, Marcos %A Pinto, Alejandra %A Guajardo, Tania %A Olavarria, Loreto %A Thumala, Daniela %A Crivelli, Lucía %A Vivas, Ludmila %A Allegri, Ricardo Francisco %A Barbosa, Maira Tonidandel %A Serrano, Cecilia M %A Miranda-Castillo, Claudia %A Caramelli, Paulo %K Activities of Daily Living %K Adult %K Aged %K Aged, 80 and over %K Argentina %K Brazil %K Caregivers %K Chile %K COVID-19 %K Dementia %K Female %K Humans %K Male %K Middle Aged %K Pandemics %K Physical Distancing %K Social Isolation %K Surveys and Questionnaires %X

BACKGROUND: People with dementia and their family caregivers may face a great burden through social isolation due to the COVID-19 pandemic, which can be manifested as various behavioral and clinical symptoms.

OBJECTIVE: To investigate the impacts of social isolation due to the COVID-19 pandemic on individuals with dementia and their family caregivers.

METHODS: Two semi-structured questionnaires were applied via telephone to family caregivers of people diagnosed with dementia in three cities in Argentina, Brazil, and Chile, in order to assess clinical and behavioral changes in people with dementia and in their caregivers.

RESULTS: In general, 321 interviews were conducted. A significant decline in memory function has been reported among 53.0%of people with dementia. In addition, 31.2%of individuals with dementia felt sadder and 37.4%had increased anxiety symptoms. These symptoms of anxiety were greater in individuals with mild to moderate dementia, while symptoms of agitation were greater in individuals with severe dementia. Moreover, compulsive-obsessive behavior, hallucinations, increased forgetfulness, altered appetite, and increased difficulty in activities of daily living were reported more frequently among individuals with moderate to severe dementia. Caregivers reported feeling more tired and overwhelmed during this period and these symptoms were also influenced by the severity of dementia.

CONCLUSION: Social isolation during the COVID-19 pandemic triggered a series of negative behavioral repercussions, both for people with dementia and for their family caregivers in these three South American countries.

%B J Alzheimers Dis %V 81 %P 607-617 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33814446?dopt=Abstract %R 10.3233/JAD-201580 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Impacts of Iron Metabolism Dysregulation on Alzheimer's Disease. %A Jouini, Najla %A Saied, Zakaria %A Ben Sassi, Samia %A Nebli, Fatma %A Messaoud, Taieb %A Hentati, Faycel %A Belal, Samir %X

BACKGROUND: Iron plays an important role in maintaining cell survival, with normal iron trafficking known to be regulated by the ceruloplasmin-transferrin (Cp-Tf) antioxidant system. Disruption to this system is thought to be detrimental to normal brain function.

OBJECTIVE: To determine whether an imbalance of iron and the proteins involved in its metabolism (ceruloplasmin and transferrin) are linked to Alzheimer's disease (AD) and to the expression of amyloid-beta (Aβ) peptide 1-42 (Aβ 1-42), which is a major species of Aβ, and the most toxic.

METHODS: We evaluated the concentrations of iron, calcium, magnesium, and Aβ 1-42 in the cerebrospinal fluid (CSF) of patients with AD and cognitively normal controls. Correlations between the components of the Cp-Tf antioxidant system in plasma were studied to determine the role of peripheral blood in the onset and/or development of AD. We used commercial ELISA immunoassays to measure Aβ 1-42, immunoturbidimetry to quantify ceruloplasmin and transferrin, and colorimetry to quantify iron, calcium, and magnesium.

RESULTS: We found that the AD group had lower CSF concentrations of Aβ 1-42 (p <  0.001) and calcium (p <  0.001), but a higher CSF concentration of iron (p <  0.001). Significantly lower plasma concentrations of ceruloplasmin (p = 0.003), transferrin (mean, p <  0.001), and iron (p <  0.001) were observed in the AD group than in cognitively normal adults. Moreover, we found a strong interdependence between most of these components.

CONCLUSION: Iron dyshomeostasis has a crucial role in the onset of AD and/or its development. Correcting metal misdistribution is an appealing therapeutic strategy for AD.

%B J Alzheimers Dis %V 80 %P 1439-1450 %8 2021 Apr 20 %G eng %N 4 %R 10.3233/JAD-201250 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Improving the Diagnosis of the Frontal Variant of Alzheimer's Disease with the DAPHNE Scale. %A Lehingue, Elsa %A Gueniat, Julien %A Jourdaa, Sandra %A Hardouin, Jean BenoÎt %A Pallardy, Amandine %A Courtemanche, Hélène %A Rocher, Laetitia %A Etcharry-Bouyx, Frédérique %A Auriacombe, Sophie %A Mollion, Hélène %A Formaglio, Maıté %A Rouaud, Olivier %A Bretonnière, Cédric %A Thomas-Antérion, Catherine %A Boutoleau-Bretonnière, Claire %K Aged %K Alzheimer Disease %K Cohort Studies %K Diagnosis, Differential %K Female %K Frontal Lobe %K Frontotemporal Dementia %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %X

BACKGROUND: The frontal variant of Alzheimer's disease (fAD) is poorly understood and poorly defined. The diagnosis remains challenging. The main differential diagnosis is the behavioral variant of frontotemporal degeneration (bvFTD). For fAD, there is some dissociation between the clinical frontal presentation and imaging and neuropathological studies, which do not always find a specific involvement of the frontal lobes. DAPHNE is a behavioral scale, which demonstrated excellent performance to distinguish between bvFTD and AD.

OBJECTIVE: The aim of the present study was to assess the reliability of this new tool to improve the clinical diagnosis of fAD.

METHODS: Twenty fAD patients and their caregivers were prospectively included and were compared with 36 bvFTD and 22 AD patients.

RESULTS: The three main behavioral disorders in the fAD patients were apathy, loss of empathy, and disinhibition. Three disorders were discriminant because they were less frequent and less severe in the fAD patients than in the bvFTD patients, namely hyperorality, neglect, and perseverations. This specific pattern of behavioral disorders was corroborated by SPECT or 18FDG PET-CT scan that showed that patients with fAD could have a medial frontal hypoperfusion, whereas in bvFTD patients the orbitofrontal cortex was the main involved region, with more diffuse hypoperfusion.

CONCLUSION: We demonstrated that DAPHNE had good sensitivity and good specificity to discriminate between the three groups and in particular between fAD and bvFTD patients. DAPHNE is a quick tool that could help clinicians in memory clinics not only to differentiate bvFTD from typical AD but also from fAD.

%B J Alzheimers Dis %V 79 %P 1735-1745 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33459637?dopt=Abstract %R 10.3233/JAD-201088 %0 Journal Article %J J Alzheimers Dis %D 2021 %T In Vivo Amyloid, Neurodegeneration, and Verbal Learning in Late Middle-Aged Hispanics. %A Tahmi, Mouna %A Rippon, Brady %A Palta, Priya %A Sherwood, Greysi %A Hernandez, Gabriela %A Soto, Luisa %A Ceballos, Fernando %A Pardo, Michelle %A Laing, Krystal %A Igwe, Kay %A He, Hengda %A Teresi, Jeanne A %A Moreno, Herman %A Razlighi, Qolamreza %A Brickman, Adam M %A Luchsinger, JosA %X

BACKGROUND: The National Institute on Aging (NIA)/Alzheimer's Association (AA) 2018 framework conceptualizes Alzheimer's disease (AD) biologically. Evidence of brain amyloid by biomarkers defines AD pathologic change and the Alzheimer's continuum. The presence of tau or neurodegeneration in the absence of amyloid defines non-AD pathologic change.

OBJECTIVE: To examine the relation of in vivo amyloid and neurodegeneration with verbal learning, one of the cognitive abilities affected early in AD, in late middle age.

METHODS: This was a cross-sectional study of amyloid and neurodegeneration biomarkers in a community-based cohort of 350 late-middle aged Hispanics without dementia (mean age: 64.15±3.34; 72.0%women). Amyloid (A) was measured as global standardized uptake value ratio (SUVR) with 18F-Florbetaben positron emission tomography (PET). Neurodegeneration (N) was ascertained as cortical thickness (CT) in AD signature areas using brain magnetic resonance imaging. We examined A/N continuously, categorically, by A/N profiles, and profile categories. The amyloid threshold for positivity was defined using the K means method. The CT threshold was defined as 2 standard deviations below the mean CT. Verbal learning was ascertained using total recall and delayed recall in the Buschke Selective Reminding test (SRT).

RESULTS: Higher cortical thickness was associated with higher performance in SRT delayed recall. Amyloid SUVR was not related to SRT performance. The low CT category was associated with lower performance in SRT delayed recall, while Amyloid categories were not related to any SRT score. The non-AD pathologic change group (A-N+) performed worse in SRT delayed recall compared to the Normal A/N profile group (A-N-).

CONCLUSION: In late middle-aged Hispanics without dementia, non-AD pathologic change, but not the Alzheimer's continuum, was related to verbal learning.

%B J Alzheimers Dis %V 82 %P 317-325 %8 2021 Jun 29 %G eng %N 1 %R 10.3233/JAD-201304 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Infectious Disease Burden and the Risk of Alzheimer's Disease: A Population-Based Study. %A Douros, Antonios %A Santella, Christina %A Dell'Aniello, Sophie %A Azoulay, Laurent %A Renoux, Christel %A Suissa, Samy %A Brassard, Paul %X

BACKGROUND: Previous studies suggested a link between various infectious pathogens and the development of Alzheimer's disease (AD), posing the question whether infectious disease could present a novel modifiable risk factor.

OBJECTIVE: To assess whether infectious disease burden due to clinically apparent infections is associated with an increased risk of AD.

METHODS: We conducted a population-based nested case-control study using the United Kingdom Clinical Practice Research Datalink. We included all dementia-free subjects ≥50 years of age enrolling in the database between January 1988 and December 2017. Each case of AD identified during follow-up was matched with up to 40 controls. Conditional logistic regression estimated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of AD associated with ≥1 infection diagnosed >  2 years before the index date compared with no infection during the study period. We further stratified by time since first infection and cumulative number of infections.

RESULTS: The cohort included overall 4,262,092 individuals (mean age at cohort entry 60.4 years; 52% female). During a median follow-up of 10.5 years, 40,455 cases of AD were matched to 1,610,502 controls. Compared with having no burden of infectious disease, having a burden of infectious disease was associated with an increase in the risk of AD (OR, 1.05; 95% CI, 1.02 to 1.08). The risk increased with longer time since first infection, peaking after 12-30 years (OR, 1.11; 95% CI, 1.05-1.17). The risk did not increase with cumulative number of infections.

CONCLUSION: The overall risk of AD associated with infectious disease burden was small but increased gradually with longer time since first infection.

%B J Alzheimers Dis %V 81 %P 329-338 %8 2021 May 04 %G eng %N 1 %R 10.3233/JAD-201534 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Inhibitory Fcγ Receptor and Paired Immunoglobulin Type 2 Receptor Alpha Genotypes in Alzheimer's Disease. %A Pandey, Janardan P %A Namboodiri, Aryan M %A Nietert, Paul J %A Barnes, Lisa L %A Bennett, David A %X

We investigated whether FCGRIIB (rs1050501 C/T) and PILRA (rs1859788 A/G) genotypes contributed to the development of Alzheimer's disease (AD). We genotyped 209 African American (AA) and 638 European American participants for the FCGRIIB and PILRA alleles. In the AA cohort, subjects homozygous for the C allele of FCGRIIB were more than 4 times as likely to develop AD as those homozygous for the alternative T allele. This SNP also interacted with PILRA: participants who were the carriers of the FCGRIIB C allele and PILRA A allele were 3 times as likely to develop AD as those who lacked these alleles.

%B J Alzheimers Dis %V 84 %P 965-968 %8 2021 Nov 23 %G eng %N 3 %R 10.3233/JAD-215174 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Latent Cognitive Class at Enrollment Predicts Future Cognitive Trajectories of Decline in a Community Sample of Older Adults. %A Zammit, Andrea R %A Yang, Jingyun %A Buchman, Aron S %A Leurgans, Sue E %A Muniz-Terrera, Graciela %A Lipton, Richard B %A Hall, Charles B %A Boyle, Patricia %A Bennett, David A %X

BACKGROUND: Methods that can identify subgroups with different trajectories of cognitive decline are crucial for isolating the biologic mechanisms which underlie these groupings.

OBJECTIVE: This study grouped older adults based on their baseline cognitive profiles using a latent variable approach and tested the hypothesis that these groups would differ in their subsequent trajectories of cognitive change.

METHODS: In this study we applied time-varying effects models (TVEMs) to examine the longitudinal trajectories of cognitive decline across different subgroups of older adults in the Rush Memory and Aging Project.

RESULTS: A total of 1,662 individuals (mean age = 79.6 years, SD = 7.4, 75.4%female) participated in the study; these were categorized into five previously identified classes of older adults differing in their baseline cognitive profiles: Superior Cognition (n = 328, 19.7%), Average Cognition (n = 767, 46.1%), Mixed-Domains Impairment (n = 71, 4.3%), Memory-Specific Impairment (n = 274, 16.5%), and Frontal Impairment (n = 222, 13.4%). Differences in the trajectories of cognition for these five classes persisted during 8 years of follow-up. Compared with the Average Cognition class, The Mixed-Domains and Memory-Specific Impairment classes showed steeper rates of decline, while other classes showed moderate declines.

CONCLUSION: Baseline cognitive classes of older adults derived through the use of latent variable methods were associated with distinct longitudinal trajectories of cognitive decline that did not converge during an average of 8 years of follow-up.

%B J Alzheimers Dis %V 83 %P 641-652 %8 2021 Sep 21 %G eng %N 2 %R 10.3233/JAD-210484 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Life Course Air Pollution Exposure and Cognitive Decline: Modelled Historical Air Pollution Data and the Lothian Birth Cohort 1936. %A Russ, Tom C %A Cherrie, Mark P C %A Dibben, Chris %A Tomlinson, Sam %A Reis, Stefan %A Dragosits, Ulrike %A Vieno, Massimo %A Beck, Rachel %A Carnell, Ed %A Shortt, Niamh K %A Muniz-Terrera, Graciela %A Redmond, Paul %A Taylor, Adele M %A Clemens, Tom %A van Tongeren, Martie %A Agius, Raymond M %A Starr, John M %A Deary, Ian J %A Pearce, Jamie R %K Adolescent %K Adult %K Aged %K Air Pollution %K Child %K Cognitive Dysfunction %K Environmental Exposure %K Female %K History, 20th Century %K Humans %K Linear Models %K Male %K Middle Aged %K Particulate Matter %K Scotland %K Young Adult %X

BACKGROUND: Air pollution has been consistently linked with dementia and cognitive decline. However, it is unclear whether risk is accumulated through long-term exposure or whether there are sensitive/critical periods. A key barrier to clarifying this relationship is the dearth of historical air pollution data.

OBJECTIVE: To demonstrate the feasibility of modelling historical air pollution data and using them in epidemiologicalmodels.

METHODS: Using the EMEP4UK atmospheric chemistry transport model, we modelled historical fine particulate matter (PM2.5) concentrations for the years 1935, 1950, 1970, 1980, and 1990 and combined these with contemporary modelled data from 2001 to estimate life course exposure in 572 participants in the Lothian Birth Cohort 1936 with lifetime residential history recorded. Linear regression and latent growth models were constructed using cognitive ability (IQ) measured by the Moray House Test at the ages of 11, 70, 76, and 79 years to explore the effects of historical air pollution exposure. Covariates included sex, IQ at age 11 years, social class, and smoking.

RESULTS: Higher air pollution modelled for 1935 (when participants would have been in utero) was associated with worse change in IQ from age 11-70 years (β = -0.006, SE = 0.002, p = 0.03) but not cognitive trajectories from age 70-79 years (p > 0.05). There was no support for other critical/sensitive periods of exposure or an accumulation of risk (all p > 0.05).

CONCLUSION: The life course paradigm is essential in understanding cognitive decline and this is the first study to examine life course air pollution exposure in relation to cognitive health.

%B J Alzheimers Dis %V 79 %P 1063-1074 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33427734?dopt=Abstract %R 10.3233/JAD-200910 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Lipidomic Network of Mild Cognitive Impairment from the Mayo Clinic Study of Aging. %A Wang, Xuewei %A Bui, Hai %A Vemuri, Prashanthi %A Graff-Radford, Jonathan %A Jack, Clifford R %A Petersen, Ronald C %A Mielke, Michelle M %X

BACKGROUND: Lipid alterations contribute to Alzheimer's disease (AD) pathogenesis. Lipidomics studies could help systematically characterize such alterations and identify potential biomarkers.

OBJECTIVE: To identify lipids associated with mild cognitive impairment and amyloid-β deposition, and to examine lipid correlation patterns within phenotype groupsMethods:Eighty plasma lipids were measured using mass spectrometry for 1,255 non-demented participants enrolled in the Mayo Clinic Study of Aging. Individual lipids associated with mild cognitive impairment (MCI) were first identified. Correlation network analysis was then performed to identify lipid species with stable correlations across conditions. Finally, differential correlation network analysis was used to determine lipids with altered correlations between phenotype groups, specifically cognitively unimpaired versus MCI, and with elevated brain amyloid versus without.

RESULTS: Seven lipids were associated with MCI after adjustment for age, sex, and APOE4. Lipid correlation network analysis revealed that lipids from a few species correlated well with each other, demonstrated by subnetworks of these lipids. 177 lipid pairs differently correlated between cognitively unimpaired and MCI patients, whereas 337 pairs of lipids exhibited altered correlation between patients with and without elevated brain amyloid. In particular, 51 lipid pairs showed correlation alterations by both cognitive status and brain amyloid. Interestingly, the lipids central to the network of these 51 lipid pairs were not significantly associated with either MCI or amyloid, suggesting network-based approaches could provide biological insights complementary to traditional association analyses.

CONCLUSION: Our attempt to characterize the alterations of lipids at network-level provides additional insights beyond individual lipids, as shown by differential correlations in our study.

%B J Alzheimers Dis %V 81 %P 533-543 %8 2021 May 18 %G eng %N 2 %R 10.3233/JAD-201347 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Locus Coeruleus in Aging and Alzheimer's Disease: A Postmortem and Brain Imaging Review. %A Beardmore, Rebecca %A Hou, Ruihua %A Darekar, Angela %A Holmes, Clive %A Boche, Delphine %K Aging %K Alzheimer Disease %K Animals %K Autopsy %K Brain Stem %K Humans %K Locus Coeruleus %K Magnetic Resonance Imaging %K Melanins %K Mice %K Norepinephrine %K Rats %K tau Proteins %X

The locus coeruleus (LC), a tiny nucleus in the brainstem and the principal site of noradrenaline synthesis, has a major role in regulating autonomic function, arousal, attention, and neuroinflammation. LC dysfunction has been linked to a range of disorders; however particular interest is given to the role it plays in Alzheimer's disease (AD). The LC undergoes significant neuronal loss in AD, thought to occur early in the disease process. While neuronal loss in the LC has also been suggested to occur in aging, this relationship is less clear as the findings have been contradictory. LC density has been suggested to be indicative of cognitive reserve and the evidence for these claims will be discussed. Recent imaging techniques allowing visualization of the LC in vivo using neuromelanin-sensitive MRI are developing our understanding of the role of LC in aging and AD. Tau pathology within the LC is evident at an early age in most individuals; however, the relationship between tau accumulation and neuronal loss and why some individuals then develop AD is not understood. Neuromelanin pigment accumulates within LC cells with age and is proposed to be toxic and inflammatory when released into the extracellular environment. This review will explore our current knowledge of the LC changes in both aging and AD from postmortem, imaging, and experimental studies. We will discuss the reasons behind the susceptibility of the LC to neuronal loss, with a focus on the role of extracellular neuromelanin and neuroinflammation caused by the dysfunction of the LC-noradrenaline pathway.

%B J Alzheimers Dis %V 83 %P 5-22 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34219717?dopt=Abstract %R 10.3233/JAD-210191 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Longitudinal Body Weight Change, Visit-To-Visit Body Weight Fluctuation, and Cognitive Decline Among Older Adults. %A Lan, Yu-Tung %A Blacker, Deborah %A Yuan, Changzheng %A Chibnik, Lori B %A Hofman, Albert %A Ma, Yuan %X

BACKGROUND: The evidence regarding dementia and late-life weight change is inconsistent, and data on body weight fluctuation and dementia are limited.

OBJECTIVE: To test the hypothesis that weight loss and substantial weight fluctuation predict cognitive decline independent of body weight and traditional risk factors of dementia.

METHODS: This study utilized longitudinal data from the National Alzheimer's Coordinating Center for 10,639 stroke- and dementia-free older adults (60.9%female, mean age 71.6 years, median follow-up 5.5 years). Trends in weight change and weight fluctuation were estimated for each individual by regressing repeated body weight measurements on time. Cognitive decline was examined as diagnostic progression from normal to mild cognitive impairment (MCI) or dementia and from MCI to dementia.

RESULTS: Compared to participants with stable weight, those with weight loss had increased odds of diagnostic progression (adjusted OR = 1.35, 95%CI [1.21, 1.51]). Also, large weight fluctuation was associated with increased odds of diagnostic progression (OR comparing the extreme quartiles = 1.20, 95%CI [1.04, 1.39]) after adjusting for traditional risk factors for dementia and body weight change. The magnitude of the association appeared larger among those older than 80 and those with 3 or more cardiometabolic risk factors at baseline (both p for interaction <  0.05).

CONCLUSION: Weight loss and substantial weight fluctuation during late-life were associated with increased odds of cognitive decline independent of body weight and traditional risk factors of dementia. Our results suggested the linkage between late-life body weight instability and cognitive decline especially among those with greater age or higher cardiometabolic risk.

%B J Alzheimers Dis %V 84 %P 777-786 %8 2021 Nov 09 %G eng %N 2 %R 10.3233/JAD-210625 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Longitudinal Trajectories in Cortical Thickness and Volume Atrophy: Superior Cognitive Performance Does Not Protect Against Brain Atrophy in Older Adults. %A Gardener, Samantha L %A Weinborn, Michael %A Sohrabi, Hamid R %A Doecke, James D %A Bourgeat, Pierrick %A Rainey-Smith, Stephanie R %A Shen, Kai-Kai %A Fripp, Jurgen %A Taddei, Kevin %A Maruff, Paul %A Salvado, Olivier %A Savage, Greg %A Ames, David %A Masters, Colin L %A Rowe, Christopher C %A Martins, Ralph N %X

BACKGROUND: Previous research has identified a small subgroup of older adults that maintain a high level of cognitive functioning well into advanced age. Investigation of those with superior cognitive performance (SCP) for their age is important, as age-related decline has previously been thought to be inevitable.

OBJECTIVE: Preservation of cortical thickness and volume was evaluated in 76 older adults with SCP and 100 typical older adults (TOAs) assessed up to five times over six years.

METHODS: Regions of interest (ROIs) found to have been associated with super-aging status (a construct similar to SCP status) in previous literature were investigated, followed by a discovery phase analyses of additional regions. SCPs were aged 70 + at baseline, scoring at/above normative memory (CVLT-II) levels for demographically similar individuals aged 30-44 years old, and in the unimpaired range for all other cognitive domains over the course of the study.

RESULTS: In linear mixed models, following adjustment for multiple comparisons, there were no significant differences between rates of thinning or volume atrophy between SCPs and TOAs in previously identified ROIs, or the discovery phase analyses. With only amyloid-β negative individuals in the analyses, again there were no significant differences between SCPs and TOAs.

CONCLUSION: The increased methodological rigor in classifying groups, together with the influence of cognitive reserve, are discussed as potential factors accounting for our findings as compared to the extant literature on those with superior cognitive performance for their age.

%B J Alzheimers Dis %V 81 %P 1039-1052 %8 2021 Jun 01 %G eng %N 3 %R 10.3233/JAD-201243 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Low Doses of Ionizing Radiation as a Treatment for Alzheimer's Disease: A Pilot Study. %A Cuttler, Jerry M %A Abdellah, Eslam %A Goldberg, Yael %A Al-Shamaa, Sarmad %A Symons, Sean P %A Black, Sandra E %A Freedman, Morris %K Aged, 80 and over %K Alzheimer Disease %K Cranial Irradiation %K Female %K Humans %K Male %K Pilot Projects %K Radiation, Ionizing %X

BACKGROUND: In 2015, a patient in hospice with Alzheimer's disease (AD) was treated with ionizing radiation to her brain using repeated CT scans. Improvement in cognition, speech, movement, and appetite was observed. These improvements were so momentous that she was discharged from the hospice to a long-term care home. Based on this case, we conducted a pilot clinical trial to examine the effect of low-dose ionizing radiation (LDIR) in severe AD.

OBJECTIVE: To determine whether the previously reported benefits of LDIR in a single case with AD could be observed again in other cases with AD when the same treatments are given.

METHODS: In this single-arm study, four patients were treated with three consecutive treatments of LDIR, each spaced two weeks apart. Qualitative changes in communication and behavior with close relatives were observed and recorded. Quantitative measures of cognition and behavior were administered pre and post LDIR treatments.

RESULTS: Minor improvements on quantitative measures were noted in three of the four patients following treatment. However, the qualitative observations of cognition and behavior suggested remarkable improvements within days post-treatment, including greater overall alertness. One patient showed no change.

CONCLUSION: LDIR may be a promising, albeit controversial therapy for AD. Trials of patients with less severe AD, double-blind and placebo-controlled, should be carried out to determine the benefits of LDIR. Quantitative measures are needed that are sensitive to the remarkable changes induced by LDIR, such as biological markers of oxidative stress that are associated with AD.

%B J Alzheimers Dis %V 80 %P 1119-1128 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646146?dopt=Abstract %R 10.3233/JAD-200620 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Lung Function Impairment and the Risk of Incident Dementia: The Rotterdam Study. %A Xiao, Tian %A Wijnant, Sara R A %A Licher, Silvan %A Terzikhan, Natalie %A Lahousse, Lies %A Ikram, M Kamran %A Brusselle, Guy G %A Ikram, M Arfan %X

BACKGROUND: The etiology of dementia may partly be underpinned by impaired lung function via systemic inflammation and hypoxia.

OBJECTIVE: To prospectively examine the association between chronic obstructive pulmonary disease (COPD) and subclinical impairments in lung function and the risk of dementia.

METHODS: In the Rotterdam Study, we assessed the risk of incident dementia in participants with Preserved Ratio Impaired Spirometry (PRISm; FEV1/FVC≥0.7, FEV1 < 80% predicted) and in participants with COPD (FEV1/FVC < 0.7) compared to those with normal spirometry (controls; FEV1/FVC≥0.7, FEV1≥80% predicted). Hazard ratios (HRs) with 95% confidence intervals (CI) for dementia were adjusted for age, sex, education attainment, smoking status, systolic blood pressure, body mass index, triglycerides, comorbidities and Apolipoprotein E (APOE) genotype.

RESULTS: Of 4,765 participants, 110 (2.3%) developed dementia after 3.3 years. Compared to controls, participants with PRISm, but not COPD, had an increased risk for all-type dementia (adjusted HRPRISm 2.70; 95% CI, 1.53-4.75; adjusted HRCOPD 1.03; 95% CI, 0.61-1.74). These findings were primarily driven by men and smokers. Similarly, participants with FVC% predicted values in the lowest quartile compared to those in the highest quartile were at increased risk of all-type dementia (adjusted HR 2.28; 95% CI, 1.31-3.98), as well as Alzheimer's disease (AD; adjusted HR 2.13; 95% CI, 1.13-4.02).

CONCLUSION: Participants with PRISm or a low FVC% predicted lung function were at increased risk of dementia, compared to those with normal spirometry or a higher FVC% predicted, respectively. Further research is needed to elucidate whether this association is causal and how PRISm might contribute to dementia pathogenesis.

%B J Alzheimers Dis %V 82 %P 621-630 %8 2021 Jul 20 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34057085?dopt=Abstract %R 10.3233/JAD-210162 %0 Journal Article %J J Alzheimers Dis %D 2021 %T MIND Diet, Common Brain Pathologies, and Cognition in Community-Dwelling Older Adults. %A Dhana, Klodian %A James, Bryan D %A Agarwal, Puja %A Aggarwal, Neelum T %A Cherian, Laurel J %A Leurgans, Sue E %A Barnes, Lisa L %A Bennett, David A %A Schneider, Julie A %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid %K Autopsy %K Brain %K Chicago %K Cognition %K Diet, Mediterranean %K Female %K Humans %K Independent Living %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Surveys and Questionnaires %X

BACKGROUND: MIND diet, a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension diet, is associated with a slower cognitive decline and lower risk of Alzheimer's disease (AD) dementia in older adults.

OBJECTIVE: We aim to examine whether the association of the MIND diet with cognition is independent of common brain pathologies.

METHODS: Utilizing data from the Rush Memory and Aging Project (MAP), a longitudinal clinical-pathologic study, we studied 569 decedents with valid dietary data, cognitive testing proximate to death, and complete autopsy data at the time of these analyses. A series of regression analyses were used to examine associations of the MIND diet, dementia-related brain pathologies, and global cognition proximate to death adjusting for age, sex, education, APOEɛ4, late-life cognitive activities, and total energy intake.

RESULTS: A higher MIND diet score was associated with better global cognitive functioning proximate to death (β= 0.119, SE = 0.040, p = 0.003), and neither the strength nor the significance of association changed substantially when AD pathology and other brain pathologies were included in the model. The β-estimate after controlling for global AD pathology was 0.111 (SE = 0.037, p = 0.003). The MIND diet-cognition relationship remained significant when we restricted our analysis to individuals without mild cognitive impairment at the baseline (β= 0.121, SE = 0.042, p = 0.005) or in people diagnosed with postmortem diagnosis of AD based on NIA-Reagan consensus recommendations (β= 0.114, SE = 0.050, p = 0.023).

CONCLUSION: MIND diet is associated with better cognitive functioning independently of common brain pathology, suggesting that the MIND diet may contribute to cognitive resilience in the elderly.

%B J Alzheimers Dis %V 83 %P 683-692 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34334393?dopt=Abstract %R 10.3233/JAD-210107 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Modifiable Barriers for Recruitment and Retention of Older Adults Participants from Underrepresented Minorities in Alzheimer's Disease Research. %A Indorewalla, Khushnoo K %A O'Connor, Maureen K %A Budson, Andrew E %A Guess DiTerlizzi, Christina %A Jackson, Jonathan %K Alzheimer Disease %K Clinical Trials as Topic %K Humans %K Minority Groups %K Patient Selection %X

Clinical Alzheimer's disease (AD) trials currently face a critical shortfall of thousands of eligible participants, which inflates the duration and cost of the clinical study as well as threatens the scientific merit of promising clinical interventions. This recruitment crisis is further compounded by the fact that underrepresented and marginalized populations-particularly those identifying as a racial or ethnic minority, those with low socioeconomic status, or living in rural areas-have been historically underrepresented in ongoing AD clinical trials despite overwhelming evidence that such populations are at increased risk for developing dementia. As a result of various recruitment barriers, current AD clinical studies frequently reflect a decreasingly representative segment of the US population, which threatens the overall generalizability of these findings. The current narrative review provides an updated examination and critique of common recruitment barriers and potential solutions, as well as a discussion of theoretical approaches that may address barriers disproportionately experienced by underrepresented communities. AD clinical researchers are encouraged to take purposive action aimed at increasing diversity of enrolled AD clinical trial cohorts by actively identifying and quantifying barriers to research participation-especially recruitment barriers and health disparities that disproportionately prevent underrepresented and marginalized populations from participating in research. Furthermore, researchers are encouraged to closely track which individuals who express interest in AD research ultimately enroll in research studies to examine whether AD research participation is appropriately representative of the intended population for whom these new and novel AD interventions are being designed.

%B J Alzheimers Dis %V 80 %P 927-940 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33612540?dopt=Abstract %R 10.3233/JAD-201081 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Neuropsychiatric Symptoms in Patients with Dementia Associated with Increased Psychological Distress in Caregivers During the COVID-19 Pandemic. %A Borelli, Wyllians Vendramini %A Augustin, Marina Coutinho %A de Oliveira, Paola Bell Felix %A Reggiani, Lorenzo Casagrande %A Bandeira-de-Mello, Renato Gorga %A Schumacher-Schuh, Artur Francisco %A Chaves, Marcia Lorena Fagundes %A Castilhos, Raphael Machado %K Adult %K Aged %K Aged, 80 and over %K Brazil %K Caregivers %K COVID-19 %K Cross-Sectional Studies %K Dementia %K Female %K Humans %K Male %K Mental Disorders %K Middle Aged %K Outpatient Clinics, Hospital %K Pandemics %K Psychological Distress %K Social Isolation %K Young Adult %X

BACKGROUND: The social isolation imposed by COVID-19 pandemic can have a major impact on the mental health of dementia patients and their caregivers.

OBJECTIVE: We aim to evaluate the neurological decline of patients with dementia and the caregivers' burden during the pandemic.

METHODS: We performed a cross-sectional study. Caregivers of dementia patients following in the outpatient clinic were included. A structured telephone interview composed of the Neuropsychiatric Inventory Questionnaire (NPI-Q), Zarit Burden Interview (ZBI), Beck Depression (BDI) and Anxiety (BAI) Inventories to address cognitive, behavioral, and functional changes associated with social distancing during the Sars-Cov-2 outbreak. Patients were divided in two groups according to caregivers' report: with perceived Altered Cognition (AC) and Stable Cognition (SC).

RESULTS: A total of 58 patients (median age: 57 years [21-87], 58.6%females) and caregivers (median age: 76.5 years [55-89], 79.3%females) were included. Cognitive decline was shown by most patients (53.4%), as well as behavioral symptoms (48.3%), especially apathy/depression (24.1%), and functional decline (34.5%). The AC group (n = 31) presented increased behavioral (67.7%versus 25.9%, p = 0.002) and functional (61.3%versus 3.7%, p < 0.001) changes when compared to the SC group. In the AC group, ZBI, BDI, NPI-Q caregiver distress, and NPI-Q patient's severity of symptoms scores were worse than the SC group (p < 0.005 for all).

CONCLUSION: Patients' neuropsychiatric worsening and caregiver burden were frequent during the pandemic. Worsening of cognition was associated with increased caregivers' psychological distress.

%B J Alzheimers Dis %V 80 %P 1705-1712 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646168?dopt=Abstract %R 10.3233/JAD-201513 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Neuropsychiatric Symptoms in Patients with Neurocognitive Disorder and Their Performance Between Mild and Major Stages. %A Botero-Rodríguez, Felipe %A Córdoba Sastoque, Ana Melisa %A Escudero, José Manuel Santacruz %A Santamaría-García, Hernando %X

BACKGROUND: The neuropsychiatric symptoms (NPS) in patients with neurocognitive disorders (NCD) increases the risk of exhibiting significant cognitive and functional decline. However, to the best of our knowledge, few studies have evaluated to what extent the presence of chronic and early NPS impacts cognition and functionality in patients with minor or major stages of NCD.

OBJECTIVE: We aimed to assess the interplay between early and chronic NPS and cognitive and functional presentation of patients with mild and major forms of NCD.

METHODS: We used two NPS tools tracking early and late NPS and assessed to what extent they determine cognitive and functional outcomes in patients with mild and major forms of NCD.

RESULTS: We found an inverse relationship between the presence of NPS, as measured by the Neuropsychiatric Inventory and Mild Behavioral Impairment Checklist (MBI-C), and cognitive and functional variables in major forms of NCD. In contrast, the minor stage of NCD was associated with increased MBI-C scores.

CONCLUSION: Our results revealed that NPS are associated with cognitive and functional outcomes in mild and chronic forms of NCD. Crucially our results suggest that NPS could be considered as a pathological marker of the clinical course of dementia. Additionally, our study calls to study early and late forms of NPS as both impact cognition and functionality of NCD.

%B J Alzheimers Dis %V 85 %P 1735-1744 %8 2022 Feb 15 %G eng %N 4 %R 10.3233/JAD-215283 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Neurotrophic Treatment Initiated During Early Postnatal Development Prevents the Alzheimer-Like Behavior and Synaptic Dysfunction. %A Wei, Wei %A Liu, Yinghua %A Dai, Chunling %A Baazaoui, Narjes %A Tung, Yunn-Chyn %A Liu, Fei %A Iqbal, Khalid %X

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Cognitive dysfunction and loss of neuronal plasticity are known to begin decades before the clinical diagnosis of the disease. The important influence of congenital genetic mutations on the early development of AD provides a novel opportunity to initiate treatment during early development to prevent the Alzheimer-like behavior and synaptic dysfunction.

OBJECTIVE: To explore strategies for early intervention to prevent Alzheimer's disease.

METHODS: In the present study, we investigated the effect of treatment during early development with a ciliary neurotrophic factor (CNTF) derived peptidergic compound, P021 (Ac-DGGLAG-NH2) on cognitive function and synaptic plasticity in 3xTg-AD transgenic mouse model of AD. 3xTg-AD and genetic background-matched wild type female mice were treated from birth to postnatal day 120 with P021 in diet or as a control with vehicle diet, and cognitive function and molecular markers of neuroplasticity were evaluated.

RESULTS: P021 treatment during early development prevented cognitive impairment and increased expressions of pCREB and BDNF that activated downstream various signaling cascades such as PLC/PKC, MEK/ERK and PI3K/Akt, and ameliorated synaptic protein deficit in 4-month-old 3xTg-AD mice.

CONCLUSION: These findings indicate that treatment with the neurotrophic peptide mimetic such as P021 during early development can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial AD and related tauopathies.

%B J Alzheimers Dis %V 82 %P 631-646 %8 2021 Jul 20 %G eng %N 2 %R 10.3233/JAD-201599 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Pharmacological Strategies to Improve Dendritic Spines in Alzheimer's Disease. %A Ettcheto, Miren %A Busquets, Oriol %A Cano, Amanda %A Sánchez-López, Elena %A Manzine, Patricia R %A Espinosa-Jimenez, Triana %A Verdaguer, Ester %A Sureda, Francesc X %A Olloquequi, Jordi %A Castro-Torres, Ruben D %A Auladell, Carme %A Folch, Jaume %A Casadesus, Gemma %A Camins, Antoni %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Dendritic Spines %K Diet, Healthy %K Exercise %K Gastrointestinal Microbiome %K Humans %K Mannose %K Oligosaccharides %K Synapses %X

To deeply understand late onset Alzheimer's disease (LOAD), it may be necessary to change the concept that it is a disease exclusively driven by aging processes. The onset of LOAD could be associated with a previous peripheral stress at the level of the gut (changes in the gut microbiota), obesity (metabolic stress), and infections, among other systemic/environmental stressors. The onset of LOAD, then, may result from the generation of mild peripheral inflammatory processes involving cytokine production associated with peripheral stressors that in a second step enter the brain and spread out the process causing a neuroinflammatory brain disease. This hypothesis could explain the potential efficacy of Sodium Oligomannate (GV-971), a mixture of acidic linear oligosaccharides that have shown to remodel gut microbiota and slowdown LOAD. However, regardless of the origin of the disease, the end goal of LOAD-related preventative or disease modifying therapies is to preserve dendritic spines and synaptic plasticity that underlay and support healthy cognition. Here we discuss how systemic/environmental stressors impact pathways associated with the regulation of spine morphogenesis and synaptic maintenance, including insulin receptor and the brain derived neurotrophic factor signaling. Spine structure remodeling is a plausible mechanism to maintain synapses and provide cognitive resilience in LOAD patients. Importantly, we also propose a combination of drugs targeting such stressors that may be able to modify the course of LOAD by acting on preventing dendritic spines and synapsis loss.

%B J Alzheimers Dis %V 82 %P S91-S107 %8 2021 %G eng %N s1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33325386?dopt=Abstract %R 10.3233/JAD-201106 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Physical Activity and Trajectory of Cognitive Change in Older Persons: Mayo Clinic Study of Aging. %A Krell-Roesch, Janina %A Syrjanen, Jeremy A %A Bezold, Jelena %A Trautwein, Sandra %A Barisch-Fritz, Bettina %A Boes, Klaus %A Woll, Alexander %A Forzani, Erica %A Kremers, Walter K %A Machulda, Mary M %A Mielke, Michelle M %A Knopman, David S %A Petersen, Ronald C %A Vassilaki, Maria %A Geda, Yonas E %X

BACKGROUND: Little is known about the association between physical activity (PA) and cognitive trajectories in older adults.

OBJECTIVE: To examine the association between PA and change in memory, language, attention, visuospatial skills, and global cognition, and a potential impact of sex or Apolipoprotein E (APOE) ɛ4 status.

METHODS: Longitudinal study derived from the population-based Mayo Clinic Study of Aging, including 2,060 cognitively unimpaired males and females aged ≥70 years. Engagement in midlife (ages 50-65) and late-life (last year) PA was assessed using a questionnaire. Neuropsychological testing was done every 15 months (mean follow-up 5.8 years). We ran linear mixed-effect models to examine whether mid- or late-life PA at three intensities (mild, moderate, vigorous) was associated with cognitive z-scores.

RESULTS: Light intensity midlife PA was associated with less decline in memory function compared to the no-PA reference group (time x light PA; estimate [standard error] 0.047 [0.016], p = 0.004). Vigorous late-life PA was associated with less decline in language (0.033 [0.015], p = 0.030), attention (0.032 [0.017], p = 0.050), and global cognition (0.039 [0.016], p = 0.012). Females who were physically inactive in midlife experienced more pronounced cognitive decline than females physically active in midlife and males regardless of PA (p-values for time interaction terms with midlife PA levels and sex were all p <  0.05 for global cognition). APOE ɛ4 carriership did not moderate the association between PA and cognition.

CONCLUSION: Engaging in PA, particularly of vigorous intensity in late-life, was associated with less pronounced decline in global and domain-specific cognition. This association may differ by sex.

%B J Alzheimers Dis %V 79 %P 377-388 %8 2021 Jan 5 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33216032?dopt=Abstract %R 10.3233/JAD-200959 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Plasma EFEMP1 Is Associated with Brain Aging and Dementia: The Framingham Heart Study. %A McGrath, Emer R %A Himali, Jayandra J %A Levy, Daniel %A Yang, Qiong %A DeCarli, Charles S %A Courchesne, Paul %A Satizabal, Claudia L %A Finney, Rebecca %A Vasan, Ramachandran S %A Beiser, Alexa S %A Seshadri, Sudha %X

BACKGROUND: Epidermal growth factor containing fibulin extracellular matrix protein-1 (EFEMP1) has been associated with increased white matter hyperintensities (WMH) burden and disorders of premature aging and may have a shared pathophysiological role in the development of WMH and dementia.

OBJECTIVE: To determine the association between plasma EFEMP1 levels and MRI markers of vascular brain injury and incident all-cause and Alzheimer's disease (AD) dementia.

METHODS: We measured plasma EFEMP1 levels in 1597 [53% women, mean age 68.7 (SD 5.7) years] dementia-free Framingham Offspring cohort participants between 1998-2001 and subsequently followed them for incident dementia. Secondary outcomes included stroke, structural MRI brain measures and neurocognitive test performance.

RESULTS: During a median 11.8 [Q1, Q3 : 7.1, 13.3] year follow-up, 131 participants developed dementia. The highest quintile of plasma EFEMP1, compared to the bottom four quintiles, was associated with an increased risk of time to incident all-cause dementia (HR 1.77, 95% CI 1.18-2.64) and AD dementia (HR 1.76, 95% CI 1.11-2.81) but not with markers of vascular brain injury (WMH, covert brain infarcts or stroke). Higher circulating EFEMP1 concentrations were also cross-sectionally associated with lower total brain (β±SE, -0.28±0.11, p = 0.01) and hippocampal volumes (-0.006±0.003, p = 0.04) and impaired abstract reasoning (Similarities test, -0.18±0.08, p = 0.018 per standard deviation increment in EFEMP1).

CONCLUSION: Elevated circulating EFEMP1 is associated with an increased risk of all-cause and AD dementia, smaller hippocampal and total brain volumes, and poorer cognitive performance. EFEMP1 may play an important biological role in the development of AD dementia. Further studies to validate these findings are warranted.

%B J Alzheimers Dis %V 85 %P 1657-1666 %8 2022 Feb 15 %G eng %N 4 %R 10.3233/JAD-215053 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Plasma Neurofilament Light Chain Predicts Cognitive Progression in Prodromal and Clinical Dementia with Lewy Bodies. %A Pilotto, Andrea %A Imarisio, Alberto %A Carrarini, Claudia %A Russo, Mirella %A Masciocchi, Stefano %A Gipponi, Stefano %A Cottini, Elisabetta %A Aarsland, Dag %A Zetterberg, Henrik %A Ashton, Nicholas J %A Hye, Abdul %A Bonanni, Laura %A Padovani, Alessandro %X

Plasma neurofilament light chain (NfL) is a marker of neuronal damage in different neurological disorders and might predict disease progression in dementia with Lewy bodies (DLB). The study enrolled 45 controls and 44 DLB patients (including 17 prodromal cases) who underwent an extensive assessment at baseline and at 2 years follow-up. At baseline, plasma NfL levels were higher in both probable DLB and prodromal cases compared to controls. Plasma NfL emerged as the best predictor of cognitive decline compared to age, sex, and baseline severity variables. The study supports the role of plasma NfL as a useful prognostic biomarker from the early stages of DLB.

%B J Alzheimers Dis %V 82 %P 913-919 %8 2021 Aug 03 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34151807?dopt=Abstract %R 10.3233/JAD-210342 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Polyphenols as Potential Metal Chelation Compounds Against Alzheimer's Disease. %A Lakey-Beitia, Johant %A Burillo, Andrea M %A La Penna, Giovanni %A Hegde, Muralidhar L %A Rao, K S %K Alzheimer Disease %K Amyloid beta-Peptides %K Antioxidants %K Chelating Agents %K Copper %K Humans %K Oxidative Stress %K Polyphenols %K Zinc %X

Alzheimer's disease (AD) is the most common neurodegenerative disease affecting more than 50 million people worldwide. The pathology of this multifactorial disease is primarily characterized by the formation of amyloid-β (Aβ) aggregates; however, other etiological factors including metal dyshomeostasis, specifically copper (Cu), zinc (Zn), and iron (Fe), play critical role in disease progression. Because these transition metal ions are important for cellular function, their imbalance can cause oxidative stress that leads to cellular death and eventual cognitive decay. Importantly, these transition metal ions can interact with the amyloid-β protein precursor (AβPP) and Aβ42 peptide, affecting Aβ aggregation and increasing its neurotoxicity. Considering how metal dyshomeostasis may substantially contribute to AD, this review discusses polyphenols and the underlying chemical principles that may enable them to act as natural chelators. Furthermore, polyphenols have various therapeutic effects, including antioxidant activity, metal chelation, mitochondrial function, and anti-amyloidogenic activity. These combined therapeutic effects of polyphenols make them strong candidates for a moderate chelation-based therapy for AD.

%B J Alzheimers Dis %V 82 %P S335-S357 %8 2021 Jun 22 %G eng %N s1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32568200?dopt=Abstract %R 10.3233/JAD-200185 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Porphyromonas gingivalis (W83) Infection Induces Alzheimer's Disease-Like Pathophysiology in Obese and Diabetic Mice. %A Bahar, Bojlul %A Kanagasingam, Shalini %A Tambuwala, Murtaza M %A Aljabali, Alaa A A %A Dillon, Stephanie A %A Doaei, Saeid %A Welbury, Richard %A Chukkapalli, Sasanka S %A Singhrao, Sim K %X

BACKGROUND: Periodontal disease(s) and metabolic illnesses negatively impact the quality of life and, eventually mental health.

OBJECTIVE: This study investigated the effect of Porphyromonas gingivalis (W83) oral infection on the development of Alzheimer's disease (AD) pathophysiology in a wild-type obese, diabetic (db/db) mouse model.

METHODS: The db/db mice were either orally infected with P. gingivalis and Fusobacterium nucleatum or sham infected for 16 weeks. The presence of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) were assessed using a silver impregnation technique and subsequently by immunohistochemistry for tau and neuroinflammation. The mRNA abundance of a panel of 184 genes was performed using quantitative real-time PCR, and the differentially expressed genes were analyzed by Ingenuity Pathway Analysis.

RESULTS: While no Aβ plaques and NFTs were evident by silver impregnation, immunohistochemistry (glial cell markers) of the P. gingivalis-infected mice tissue sections exhibited neuroinflammation in the form of reactive microglia and astrocytes. Anti-tau immunopositivity, in addition to cells, was prominent in thickened axons of hippocampal CA neurons. The mRNA abundance of crucial genes in the insulin signaling pathway (INSR, IGF1, IRS, IDE, PIK3R, SGK1, GYS, GSK3B, AKT1) were upregulated, potentially exacerbating insulin resistance in the brain by P. gingivalis oral infection. Increased mRNA abundance of several kinases, membrane receptors, transcription factors, and pro-inflammatory mediators indicated hyperactivation of intracellular cascades with potential for tau phosphorylation and Aβ release in the same infection group.

CONCLUSION: P. gingivalis W83 infection of db/db mice provides a disease co-morbidity model with the potential to reproduce AD pathophysiology with induced periodontal disease.

%B J Alzheimers Dis %V 82 %P 1259-1275 %8 2021 Aug 03 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34151813?dopt=Abstract %R 10.3233/JAD-210465 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Quantifying and Examining Reserve in Symptomatic Former National Football League Players. %A Foley, Éimear M %A Tripodis, Yorghos %A Yhang, Eukyung %A Koerte, Inga K %A Martin, Brett M %A Palmisano, Joseph %A Makris, Nikos %A Schultz, Vivian %A Lepage, Chris %A Muehlmann, Marc %A Wróbel, Paweł P %A Guenette, Jeffrey P %A Cantu, Robert C %A Lin, Alexander P %A Coleman, Michael %A Mez, Jesse %A Bouix, Sylvain %A Shenton, Martha E %A Stern, Robert A %A Alosco, Michael L %X

BACKGROUND: Repetitive head impacts (RHI) from contact sports have been associated with cognitive and neuropsychiatric disorders. However, not all individuals exposed to RHI develop such disorders. This may be explained by the reserve hypothesis. It remains unclear if the reserve hypothesis accounts for the heterogenous symptom presentation in RHI-exposed individuals. Moreover, optimal measurement of reserve in this population is unclear and likely unique from non-athlete populations.

OBJECTIVE: We examined the association between metrics of reserve and cognitive and neuropsychiatric functioning in 89 symptomatic former National Football League players.

METHODS: Individual-level proxies (e.g., education) defined reserve. We additionally quantified reserve as remaining residual variance in 1) episodic memory and 2) executive functioning performance, after accounting for demographics and brain pathology. Associations between reserve metrics and cognitive and neuropsychiatric functioning were examined.

RESULTS: Higher reading ability was associated with better attention/information processing (β=0.25; 95% CI, 0.05-0.46), episodic memory (β=0.27; 95% CI, 0.06-0.48), semantic and phonemic fluency (β=0.24; 95% CI, 0.02-0.46; β=0.38; 95% CI, 0.17-0.59), and behavioral regulation (β=-0.26; 95% CI, -0.48, -0.03) performance. There were no effects for other individual-level proxies. Residual episodic memory variance was associated with better attention/information processing (β=0.45; 95% CI, 0.25, 0.65), executive functioning (β=0.36; 95% CI, 0.15, 0.57), and semantic fluency (β=0.38; 95% CI, 0.17, 0.59) performance. Residual executive functioning variance was associated with better attention/information processing (β=0.44; 95% CI, 0.24, 0.64) and episodic memory (β=0.37; 95% CI, 0.16, 0.58) performance.

CONCLUSION: Traditional reserve proxies (e.g., years of education, occupational attainment) have limitations and may be unsuitable for use in elite athlete samples. Alternative approaches of reserve quantification may prove more suitable for this population.

%B J Alzheimers Dis %V 85 %P 675-689 %8 2022 Jan 18 %G eng %N 2 %R 10.3233/JAD-210379 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Relation of Literacy and Music Literacy to Dementia in Older Black and White Brazilians. %A Capuano, Ana W %A Wilson, Robert S %A Leurgans, Sue E %A Sampaio, Carolina %A Farfel, Jose M %A Barnes, Lisa L %A Bennett, David A %X

BACKGROUND: Literacy is more consistently reported than education as protective against dementia in developing regions.

OBJECTIVE: To study the association of verbal literacy, numeracy, and music literacy with dementia in older Black and White Brazilians with a broad spectrum of education.

METHODS: We studied 1,818 Black, Mixed-race, and White deceased Brazilians 65 years or older at death (mean = 79.64). Data were retrospectively obtained within 36 hours after death in a face-to-face interview with an informant, usually a family member. Dementia was classified using the Clinical Dementia Rating (CDR) scale. Three forms of literacy were ascertained: verbal literacy (10 questions: reading and writing), numeracy (3 questions: multiplication, percentages, and use of a calculator), and music literacy (1 question: reading music). Black (11%) and Mixed-race (23%) older adults were combined in analyses. Models adjusted for age and sex.

RESULTS: Dementia was identified in 531 people. Participants had 0 to 25 years of education (median = 4). More literacy was associated with lower odds of dementia (all p≤0.039). Participants that read music had about half the odds of having dementia. Participants in the highest quartile of numeracy and verbal literacy had respectively 27%and 15%lower odds of having dementia compared to the lowest quartile. Literacy was lower in Blacks (p <  0.001, except music p = 0.894) but the effect of literacy on dementia was similar (interaction p >  0.237). In secondary analyses, playing instruments without reading music was not associated with dementia (p = 0.887).

CONCLUSION: In a large sample of Brazilians, verbal literacy, numeracy, and music literacy were associated with lower odds of dementia. The effect was similar across races.

%B J Alzheimers Dis %V 84 %P 737-744 %8 2021 Nov 09 %G eng %N 2 %R 10.3233/JAD-210601 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Relationship Between Cardiovascular Health and Rate of Cognitive Decline in Young-Old and Old-Old Adults: A Population-Based Study. %A Speh, Andreja %A Wang, Rui %A Winblad, Bengt %A Kramberger, Milica G %A Bäckman, Lars %A Qiu, Chengxuan %A Laukka, Erika J %X

BACKGROUND: Modifiable vascular risk factors have been associated with late-life cognitive impairment. The Life Simple 7 (LS7) score comprises seven cardiovascular health metrics: smoking, diet, physical activity, body mass index, plasma glucose, total serum cholesterol, and blood pressure.

OBJECTIVE: To investigate the association between individual and composite LS7 metrics and rate of cognitive decline, and potential differences in these associations between young-old and old-old individuals.

METHODS: This cohort study included 1,950 participants aged≥60 years (M = 70.7 years) from the Swedish National Study on Aging and Care-Kungsholmen (SNAC-K), who underwent repeated neuropsychological testing (episodic and semantic memory, verbal fluency, processing speed, global cognition) across 12 years. The LS7 score was assessed at baseline and categorized as poor, intermediate, or optimal. Level and change in cognitive performance as a function LS7 categories were estimated using linear mixed-effects models.

RESULTS: Having an optimal LS7 total score was associated with better performance (expressed in standard deviation units) at baseline for perceptual speed (β= 0.21, 95%CI 0.12-0.29), verbal fluency (β= 0.08, 0.00-0.16), and global cognition (β= 0.06, 0.00-0.12) compared to the poor group. Age-stratified analyses revealed associations for cognitive level and change only in the young-old (<  78 years) group. For the specific metrics, diverging patterns were observed for young-old and old-old individuals.

CONCLUSION: Meeting the LS7 criteria for ideal cardiovascular health in younger old age is associated with slower rate of cognitive decline. However, the LS7 criteria may have a different meaning for cognitive function in very old adults.

%B J Alzheimers Dis %V 84 %P 1523-1537 %8 2021 Dec 07 %G eng %N 4 %R 10.3233/JAD-210280 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Relevance of a Truncated PRESENILIN 2 Transcript to Alzheimer's Disease and Neurodegeneration. %A Moussavi Nik, Seyyed Hani %A Porter, Tenielle %A Newman, Morgan %A Bartlett, Benjamin %A Khan, Imran %A Sabale, Miheer %A Eccles, Melissa %A Woodfield, Amy %A Groth, David %A Doré, Vincent %A Villemagne, Victor L %A Masters, Colin L %A Martins, Ralph N %A Laws, Simon M %A Lardelli, Michael %A Verdile, Giuseppe %X

BACKGROUND: The PRESENILIN genes (PSEN1, PSEN2) encoding for their respective proteins have critical roles in many aspects of Alzheimer's disease (AD) pathogenesis. The PS2V transcript of PSEN2 encodes a truncated protein and is upregulated in AD brains; however, its relevance to AD and disease progression remains to be determined.

OBJECTIVE: Assess transcript levels in postmortem AD and non-AD brain tissue and in lymphocytes collected under the Australian Imaging Biomarker and Lifestyle (AIBL) study.

METHODS: Full length PSEN2 and PS2V transcript levels were assessed by quantitative digital PCR in postmortem brain tissue (frontal cortex and hippocampus) from control, AD, frontotemporal dementia (FTD), and Lewy body dementia (LBD). Transcript levels were also assessed in lymphocytes obtained from the Perth subset of the AIBL study (n = 160). Linear regression analysis was used to assess correlations between transcript copy number and brain volume and neocortical amyloid load.

RESULTS: PS2V levels increased in AD postmortem brain but PS2V was also present at significant levels in FTD and LBD brains. PS2V transcript was detected in lymphocytes and PS2V/PSEN2 ratios were increased in mild cognitive impairment (p = 0.024) and AD (p = 0.019) groups compared to control group. Increased ratios were significantly correlated with hippocampal volumes only (n = 62, β= -0.269, p = 0.03).

CONCLUSION: Taken together, these results suggest that PS2V may be a marker of overall neurodegeneration.

%B J Alzheimers Dis %V 80 %P 1479-1489 %8 2021 Apr 20 %G eng %N 4 %R 10.3233/JAD-201133 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Research Attitudes and Interest Among Elderly Latinxs: The Impact of a Collaborative Video and Community Peers. %A Sewell, Margaret C %A Neugroschl, Judith %A Umpierre, Mari %A Chin, Shehan %A Zhu, Carolyn W %A Velasco, Nelly %A Gonzalez, Sabrina %A Acabá-Berrocal, Alexandra %A Bianchetti, Luca %A Silva, Gabriela %A Collazo, Alma %A Sano, Mary %X

BACKGROUND: Latinx elders are underrepresented in dementia research. In a previous study we assessed research attitudes in urban minority elders and found a significant minority expressed neutral to negative attitudes relating to trust, safety, and personal responsibility to help research.

OBJECTIVE: To assess the impact of a composite intervention on attitudes toward research and research participation among elderly Latinx. The intervention was a collaboratively produced research participation video shown during presentations with our elderly community advisory board (CAB) as co-presenters.

METHODS: The video was created by the ADRC and CAB. All senior center attendees were eligible to participate. Afterwards, the Research Attitudes Questionnaire (RAQ) and a brief questionnaire on the impact of the video were administered. Using Wilcoxon Rank Sum Tests, Chi Square, and OLS regressions, RAQ responses were compared to those from a historical cohort from similar centers.

RESULTS: 74 in the "Historical Cohort 1" and 104 in "Intervention Cohort 2" were included. RAQ total score was higher in Cohort 2 than Cohort 1 (28.5 versus 26.1, p <  0.05) after controlling for age, education, and country of origin. In response to the question "Has the video influenced your willingness and interest to participate in research", 88.7%of the participants in Cohort 2 reported being "more" or "much more" interested in research.

CONCLUSION: Tailoring community research recruitment programs to include relatable peers using novel recruitment techniques may have positive implications for improving enrollment of diverse elderly individuals in research.

%B J Alzheimers Dis %V 82 %P 771-779 %8 2021 Jul 20 %G eng %N 2 %R 10.3233/JAD-210027 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Right Temporal Variant of Frontotemporal Dementia Is Not Genetically Sporadic: A Case Series. %A Ulugut Erkoyun, Hulya %A van der Lee, Sven J %A Nijmeijer, Bas %A van Spaendonk, Rosalina %A Nelissen, Anne %A Scarioni, Marta %A Dijkstra, Anke %A Samancı, Bedia %A Gürvit, Hakan %A Yıldırım, Zerrin %A Tepgeç, Fatih %A Bilgic, Basar %A Barkhof, Frederik %A Rozemuller, Annemieke %A van der Flier, Wiesje M %A Scheltens, Philip %A Cohn-Hokke, Petra %A Pijnenburg, Yolande %K Aphasia, Primary Progressive %K DNA-Binding Proteins %K Female %K Frontotemporal Dementia %K Functional Laterality %K Genetic Testing %K Genetic Variation %K Gyrus Cinguli %K Humans %K Male %K Middle Aged %K Progranulins %K tau Proteins %X

BACKGROUND: Right temporal variant frontotemporal dementia (rtvFTD) has been generally considered as a right sided variant of semantic variant primary progressive aphasia (svPPA), which is a genetically sporadic disorder. Recently, we have shown that rtvFTD has a unique clinical syndrome compared to svPPA and behavioral variant frontotemporal dementia.

OBJECTIVE: We challenge the assumption that rtvFTD is a sporadic, non-familial variant of FTD by identifying potential autosomal dominant inheritance and related genes in rtvFTD.

METHODS: We collected all subjects with a diagnosis of FTD or primary progressive aphasia who had undergone genetic screening (n = 284) and subsequently who had a genetic variant (n = 48) with a diagnosis of rtvFTD (n = 6) in 2 specialized memory clinics.

RESULTS: Genetic variants in FTD related genes were found in 33% of genetically screened rtvFTD cases; including MAPT (n = 4), GRN (n = 1), and TARDBP (n = 1) genes, whereas only one svPPA case had a genetic variant in our combined cohorts. Additionally, 4 out of 6 rtvFTD subjects had a strong family history for dementia.

CONCLUSION: Our results demonstrate that rtvFTD, unlike svPPA, is not a pure sporadic, but a heterogeneous potential genetic variant of FTD, and screening for genetic causes for FTD should be performed in patients with rtvFTD.

%B J Alzheimers Dis %V 79 %P 1195-1201 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33427744?dopt=Abstract %R 10.3233/JAD-201191 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Role of Microglia in Sporadic Alzheimer's Disease. %A Streit, Wolfgang J %A Khoshbouei, Habibeh %A Bechmann, Ingo %K Aging %K Alzheimer Disease %K Humans %K Microglia %X

Microglia constitute the brain's immune system and their involvement in Alzheimer's disease has been discussed. Commonly, and in line with the amyloid/neuroinflammation cascade hypothesis, microglia have been portrayed as potentially dangerous immune effector cells thought to be overactivated by amyloid and producing neurotoxic inflammatory mediators that lead to neurofibrillary degeneration. We disagree with this theory and offer as an alternative the microglial dysfunction theory stating that microglia become impaired in their normally neuroprotective roles because of aging, i.e., they become senescent and aging neurons degenerate because they lack the needed microglial support for their survival. Thus, while the amyloid cascade theory relies primarily on genetic data, the dysfunction theory incorporates aging as a critical etiological factor. Aging is the greatest risk factor for the sporadic (late-onset) and most common form of Alzheimer's disease, where fully penetrant genetic mutations are absent. In this review, we lay out and discuss the human evidence that supports senescent microglial dysfunction and conflicts with the amyloid/neuroinflammation idea.

%B J Alzheimers Dis %V 79 %P 961-968 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33361603?dopt=Abstract %R 10.3233/JAD-201248 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Serum Uric Acid May Aggravate Alzheimer's Disease Risk by Affecting Amyloidosis in Cognitively Intact Older Adults: The CABLE Study. %A Li, Lin-Lin %A Ma, Ya-Hui %A Bi, Yan-Lin %A Sun, Fu-Rong %A Hu, Hao %A Hou, Xiao-He %A Xu, Wei %A Shen, Xue-Ning %A Dong, Qiang %A Tan, Lan %A Yang, Jiu-Long %A Yu, Jin-Tai %X

BACKGROUND: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer's disease (AD) pathology remains unclear.

OBJECTIVE: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD.

METHODS: We analyzed cognitively intact participants (n = 839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-β [Aβ], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models.

RESULTS: Levels of SUA in the preclinical AD elevated compared with the healthy controls (p = 0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p = 0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aβ1 - 42 (p = 0.019) and Aβ1 - 42/Aβ1 - 40 (p = 0.027) were decreased and CSF p-Tau/Aβ1 - 42 (p = 0.009) and t-Tau/Aβ1 - 42 (p = 0.043) were increased with the highest (>  75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them.

CONCLUSION: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA.

%B J Alzheimers Dis %V 81 %P 389-401 %8 2021 May 04 %G eng %N 1 %R 10.3233/JAD-201192 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Site-Specific Cerebrospinal Fluid Tau Hyperphosphorylation in Response to Alzheimer's Disease Brain Pathology: Not All Tau Phospho-Sites are Hyperphosphorylated. %A Barthélemy, Nicolas R %A Toth, Balazs %A Manser, Paul T %A Sanabria-Bohórquez, Sandra %A Teng, Edmond %A Keeley, Michael %A Bateman, Randall J %A Weimer, Robby M %A Wildsmith, Kristin R %X

BACKGROUND: Understanding patterns of association between CSF phosphorylated tau (p-tau) species and clinical disease severity will aid Alzheimer's disease (AD) diagnosis and treatment.

OBJECTIVE: To evaluate changes in tau phosphorylation ratios to brain imaging (amyloid PET, [18F]GTP1 PET, and MRI) and cognition across clinical stages of AD in two different cohorts.

METHODS: A mass spectrometry (MS)-based method was used to evaluate the relationship between p-tau/tau phosphorylation ratios on 11 sites in CSF and AD pathology measured by tau PET ([18F]GTP1) and amyloid PET ([18F]florbetapir or [18F]florbetaben). Cohort A included cognitively normal-amyloid negative (n = 6) and positive (n = 5) individuals, and amyloid positive prodromal (n = 13), mild (n = 12), and moderate AD patients (n = 10); and Cohort B included amyloid positive prodromal (n = 24) and mild (n = 40) AD patients.

RESULTS: In this cross-sectional analysis, we identified clusters of phosphosites with different profiles of phosphorylation ratios across stages of disease. Eight of 11 investigated sites were hyperphosphorylated and associated with the SUVR measures from [18F]GTP1 and amyloid PET. Novel sites 111, 153, and 208 may be relevant biomarkers for AD diagnosis to complement tau hyperphosphorylation measures on previously established sites 181, 205, 217, and 231. Hypophosphorylation was detected on residues 175, 199, and 202, and was inversely associated with [18F]GTP1 and amyloid PET.

CONCLUSION: Hyperphosphorylated and hypophosphorylated forms of tau are associated with AD pathologies, and due to their different site-specific profiles, they may be used in combination to assist with staging of disease.

%B J Alzheimers Dis %V 85 %P 415-429 %8 2022 Jan 04 %G eng %N 1 %R 10.3233/JAD-210677 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Social Robot Interventions for People with Dementia: A Systematic Review on Effects and Quality of Reporting. %A Hirt, Julian %A Ballhausen, Nicola %A Hering, Alexandra %A Kliegel, Matthias %A Beer, Thomas %A Meyer, Gabriele %K Dementia %K Humans %K Research %K Robotics %K Social Behavior %X

BACKGROUND: Using non-pharmacological interventions is a current approach in dementia care to manage responsive behaviors, to maintain functional capacity, and to reduce emotional stress. Novel technologies such as social robot interventions might be useful to engage people with dementia in activities and interactions as well as to improve their cognitive, emotional, and physical status.

OBJECTIVE: Assessing the effects and the quality of reporting of social robot interventions for people with dementia.

METHODS: In our systematic review, we included quasi-experimental and experimental studies published in English, French, or German, irrespective of publication year. Searching CINAHL, Cochrane Library, MEDLINE, PsycINFO, and Web of Science Core Collection was supplemented by citation tracking and free web searching. To assess the methodological quality of included studies, we used tools provided by the Joanna Briggs Institute. To assess the reporting of the interventions, we applied CReDECI 2 and TIDieR.

RESULTS: We identified sixteen studies published between 2012 and 2018, including two to 415 participants with mostly non-defined type of dementia. Eight studies had an experimental design. The predominant robot types were pet robots (i.e., PARO). Most studies addressed behavioral, emotion-related, and functional outcomes with beneficial, non-beneficial, and mixed results. Predominantly, cognitive outcomes were not improved. Overall, studies were of moderate methodological quality.

CONCLUSION: Heterogeneous populations, intervention characteristics, and measured outcomes make it difficult to generalize the results with regard to clinical practice. The impact of social robot interventions on behavioral, emotion-related, and functional outcomes should therefore be assessed considering the severity of dementia and intervention characteristics.

%B J Alzheimers Dis %V 79 %P 773-792 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33361589?dopt=Abstract %R 10.3233/JAD-200347 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Synaptic Molecular and Neurophysiological Markers Are Independent Predictors of Progression in Alzheimer's Disease. %A Smailovic, Una %A Kåreholt, Ingemar %A Koenig, Thomas %A Ashton, Nicholas J %A Winblad, Bengt %A Höglund, Kina %A Nilsson, Per %A Zetterberg, Henrik %A Blennow, Kaj %A Jelic, Vesna %X

BACKGROUND: Cerebrospinal fluid (CSF) neurogranin and quantitative electroencephalography (qEEG) are potential molecular and functional markers of synaptic pathology in Alzheimer's disease (AD). Synaptic markers have emerged as candidate prognostic indicators of AD since synaptic degeneration was shown to be an early event and the best correlate of cognitive deficits in patients along the disease continuum.

OBJECTIVE: The present study investigated the association between CSF neurogranin and qEEG measures as well as their potential to predict clinical deterioration in mild cognitive impairment (MCI) patients.

METHODS: Patients diagnosed with MCI (n = 99) underwent CSF conventional AD biomarkers and neurogranin analysis and resting-state EEG recordings. The study population was further stratified into stable (n = 41) and progressive MCI (n = 31), based on the progression to AD dementia during two years follow-up. qEEG analysis included computation of global field power and global field synchronization in four conventional frequency bands.

RESULTS: CSF neurogranin levels were associated with theta power and synchronization in the progressive MCI group. CSF neurogranin and qEEG measures were significant predictors of progression to AD dementia, independent of baseline amyloid status in MCI patients. A combination of CSF neurogranin with global EEG power in theta and global EEG synchronization in beta band exhibited the highest classification accuracy as compared to either of these markers alone.

CONCLUSION: qEEG and CSF neurogranin are independent predictors of progression to AD dementia in MCI patients. Molecular and neurophysiological synaptic markers may have additive value in a multimodal diagnostic and prognostic approach to dementia.

%B J Alzheimers Dis %V 83 %P 355-366 %8 2021 Aug 31 %G eng %N 1 %R 10.3233/JAD-201234 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Taking the A Train? Limited Consistency of Aβ42 and the Aβ42/40 Ratio in the AT(N) Classification. %A Gouilly, Dominique %A Tisserand, Camille %A Nogueira, Leonor %A Saint-Lary, Laura %A Rousseau, Vanessa %A Benaiteau, Marie %A Rafiq, Marie %A Carlier, Jasmine %A Milongo-Rigal, Emilie %A Pagès, Jean-Christophe %A Pariente, Jérémie %X

The consistency of cerebrospinal fluid amyloid-β (Aβ)42/40 ratio and Aβ 42 has not been assessed in the AT(N) classification system. We analyzed the classification changes of the dichotomized amyloid status (A+/A-) in 363 patients tested for Alzheimer's disease biomarkers after Aβ 42 was superseded by the Aβ 42/40 ratio. The consistency of Aβ 42 and the Aβ 42/40 ratio was very low. Notably, the proportions of "false" A+T-patients were considerable (74-91%) and corresponded mostly to patients not clinically diagnosed with Alzheimer's disease. Our results suggest that the interchangeability of Aβ 42/40 ratio and Aβ 42 is limited for classifying patients in clinical setting using the AT(N) scheme.

%B J Alzheimers Dis %V 83 %P 1033-1038 %8 2021 Sep 28 %G eng %N 3 %R 10.3233/JAD-210236 %0 Journal Article %J J Alzheimers Dis %D 2021 %T TAR DNA-Binding Protein 43 Is Associated with Rate of Memory and Functional and Global Cognitive Decline in the Decade Prior to Death. %A Buciuc, Marina %A Tosakulwong, Nirubol %A Machulda, Mary M %A Whitwell, Jennifer L %A Weigand, Stephen D %A Murray, Melissa E %A Ross Reichard, R %A Parisi, Joseph E %A Dickson, Dennis W %A Boeve, Bradley F %A Knopman, David S %A Petersen, Ronald C %A Josephs, Keith A %X

BACKGROUND: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with memory impairment and overall cognitive decline. It is unclear how TDP-43 contributes to the rate of clinical decline.

OBJECTIVE: To determine whether cross-sectional and longitudinal cognitive and functional decline are associated with anatomical distribution of TDP-43 in the brain.

METHODS: Longitudinal clinical-neuropathologic autopsy cohort study of 385 initially cognitively normal/mildly impaired older adults prospectively followed until death. We investigated how TDP-43, amyloid-β (Aβ), tau neurofibrillary tangles (NFT), Lewy body disease (LBD), age, sex, and genetics are associated with clinical scores and rates of their longitudinal decline.

RESULTS: Of 385 participants, 260 (68%) had no TDP-43, 32 (8%) TDP-43 limited to amygdala, and 93 (24%) TDP-43 in the hippocampus and beyond. Higher TDP-43 and Braak NFT stages independently were associated with faster decline in global cognition, functional performance measured by Clinical Dementia Rating scale, and naming and episodic memory, whereas older age was associated with slower rate of cognitive, psychiatric, and functional decline. Cross-sectionally the following associations were found: higher TDP-43 and Braak NFT - worse performance; higher Aβ burden - worse global cognition, more behavioral changes, the latter also with higher LBD; older age - worse naming, lower frequency of behavioral changes; female sex - more impaired naming and better preserved episodic memory. There were no genetic associations.

CONCLUSION: The association of TDP-43 distribution with decline in cognitive and functional performance suggests that TDP-43 is playing a role in the clinical progression to dementia. Further characterization of clinical features associated with TDP-43 can facilitate establishment of antemortem diagnosis.

%B J Alzheimers Dis %V 80 %P 683-693 %8 2021 Mar 23 %G eng %N 2 %R 10.3233/JAD-201166 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Thrombin Signaling Contributes to High Glucose-Induced Injury of Human Brain Microvascular Endothelial Cells. %A Rao, Haripriya V %A Bihaqi, Syed W %A Iannucci, Jaclyn %A Sen, Abhik %A Grammas, Paula %X

BACKGROUND: Diabetes is one of the strongest disease-related risk factors for Alzheimer's disease (AD). In diabetics, hyperglycemia-induced microvascular complications are the major cause of end-organ injury, contributing to morbidity and mortality. Microvascular pathology is also an important and early feature of AD. The cerebral microvasculature may be a point of convergence of both diseases. Several lines of evidence also implicate thrombin in AD as well as in diabetes.

OBJECTIVE: Our objective was to investigate the role of thrombin in glucose-induced brain microvascular endothelial injury.

METHODS: Cultured Human brain microvascular endothelial cells (HBMVECs) were treated with 30 mM glucose±100 nM thrombin and±250 nM Dabigatran or inhibitors of PAR1, p38MAPK, MMP2, or MMP9. Cytotoxicity and thrombin activity assays on supernatants and western blotting for protein expression in lysates were performed.

RESULTS: reatment of HBMVECs with 30 mM glucose increased thrombin activity and expression of inflammatory proteins TNFα, IL-6, and MMPs 2 and 9; this elevation was reduced by the thrombin inhibitor dabigatran. Direct treatment of brain endothelial cells with thrombin upregulated p38MAPK and CREB, and induced TNFα, IL6, MMP2, and MMP9 as well as oxidative stress proteins NOX4 and iNOS. Inhibition of thrombin, thrombin receptor PAR1 or p38MAPK decrease expression of inflammatory and oxidative stress proteins, implying that thrombin may play a central role in glucose-induced endothelial injury.

CONCLUSION: Since preventing brain endothelial injury would preserve blood-brain barrier integrity, prevent neuroinflammation, and retain intact functioning of the neurovascular unit, inhibiting thrombin, or its downstream signaling effectors, could be a therapeutic strategy for mitigating diabetes-induced dementia.

%B J Alzheimers Dis %V 79 %P 211-224 %8 2021 Jan 5 %G eng %N 1 %R 10.3233/JAD-200658 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus. %A Lukkarinen, Heikki %A Tesseur, Ina %A Pemberton, Darrel %A van der Ark, Peter %A Timmers, Maarten %A Slemmon, Randy %A Janssens, Luc %A Streffer, Johannes %A Van Nueten, Luc %A Bottelbergs, Astrid %A Rauramaa, Tuomas %A Koivisto, Anne M %A Herukka, Sanna-Kaisa %A Korhonen, Ville E %A Junkkari, Antti %A Hiltunen, Mikko %A Engelborghs, Sebastiaan %A Blennow, Kaj %A Zetterberg, Henrik %A Kolb, Hartmuth C %A Leinonen, Ville %X

BACKGROUND: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant.

OBJECTIVE: To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared.

METHODS: L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs.

RESULTS: All biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p <  0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4.

CONCLUSION: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.

%B J Alzheimers Dis %V 80 %P 1629-1642 %8 2021 Apr 20 %G eng %N 4 %R 10.3233/JAD-201361 %0 Journal Article %J J Alzheimers Dis %D 2021 %T tRNA-Derived Fragments in Alzheimer's Disease: Implications for New Disease Biomarkers and Neuropathological Mechanisms. %A Wu, Wenzhe %A Lee, Inhan %A Spratt, Heidi %A Fang, Xiang %A Bao, Xiaoyong %K Aged %K Alzheimer Disease %K Biomarkers %K Blotting, Northern %K Case-Control Studies %K Hippocampus %K Humans %K Polymerase Chain Reaction %K RNA, Small Untranslated %K RNA, Transfer %X

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia caused by irreversible neurodegeneration, with the onset mechanisms elusive. tRNA-derived RNA fragments (tRFs), a recently discovered family of small non-coding RNAs (sncRNAs), have been found to associate with many human diseases, including infectious, metabolic, and neurological diseases. However, whether tRFs play a role in human AD development is not known.

OBJECTIVE: This study aimed to explore whether tRFs are involved in human AD.

METHODS: Thirty-four postmortem human hippocampus samples were used. The expression of Drosha, Dicer, and angiogenin (ANG), three ribonucleases responsible for the biogenesis of sncRNAs, was determined by qRT-PCR and western blot. The tRFs in the hippocampus was detected by qRT-PCR or northern blot. We also used qRT-PCR to quantify NOP2/Sun RNA methyltransferase 2 (NSun2) and polyadenylation factor I subunit 1 (CLP1), two tRNA modification enzymes.

RESULTS: tRFs derived from a subset of tRNAs are significantly altered in the hippocampus of AD patients. The expression change of some tRFs showed age- and disease stage-dependent. ANG is significantly enhanced in AD, suggesting its role in inducing tRFs in AD. The expression of NSun2 in AD patients younger than 65 was significantly decreased. According to a previous report supporting NSun2-mediated tRNA methylation modification making tRNA less susceptible to ANG-mediated cleavage, our results suggested that the decrease in NSun2 may make tRNAs less methylated and subsequently enhanced tRF production from ANG-mediated tRNA cleavage.

CONCLUSION: Our studies demonstrated for the first time the involvement of tRFs in human AD.

%B J Alzheimers Dis %V 79 %P 793-806 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33337366?dopt=Abstract %R 10.3233/JAD-200917 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Upregulation of Cortical A2A Adenosine Receptors Is Reflected in Platelets of Patients with Alzheimer's Disease. %A Merighi, Stefania %A Battistello, Enrica %A Casetta, Ilaria %A Gragnaniello, Daniela %A Poloni, Tino Emanuele %A Medici, Valentina %A Cirrincione, Alice %A Varani, Katia %A Vincenzi, Fabrizio %A Borea, Pier Andrea %A Gessi, Stefania %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Blood Platelets %K Cerebral Cortex %K Female %K Humans %K Male %K Receptor, Adenosine A2A %K Up-Regulation %X

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative pathology covering about 70%of all cases of dementia. Adenosine, a ubiquitous nucleoside, plays a key role in neurodegeneration, through interaction with four receptor subtypes. The A2A receptor is upregulated in peripheral blood cells of patients affected by Parkinson's and Huntington's diseases, reflecting the same alteration found in brain tissues. However, whether these changes are also present in AD pathology has not been determined.

OBJECTIVE: In this study we verified any significant difference between AD cases and controls in both brain and platelets and we evaluated whether peripheral A2A receptors may reflect the status of neuronal A2A receptors.

METHODS: We evaluated the expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, in postmortem AD patients and control subjects, through [3H]ZM 241385 binding experiments. The same analysis was performed in peripheral platelets from AD patients versus controls.

RESULTS: The expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, revealed a density (Bmax) of 174±29, 219±33, and 358±84 fmol/mg of proteins, respectively, in postmortem AD patients in comparison to 104±16, 103±19, and 121±20 fmol/mg of proteins in controls (p < 0.01). The same trend was observed in peripheral platelets from AD patients versus controls (Bmax of 214±17 versus 95±4 fmol/mg of proteins, respectively, p < 0.01).

CONCLUSION: AD subjects show significantly higher A2A receptor density than controls. Values on platelets seem to correlate with those in the brain supporting a role for A2A receptor as a possible marker of AD pathology and drug target for novel therapies able to modify the progression of dementia.

%B J Alzheimers Dis %V 80 %P 1105-1117 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646165?dopt=Abstract %R 10.3233/JAD-201437 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Visual Memory Deficits in Middle-Aged APOEɛ4 Homozygotes Detected Using Unsupervised Cognitive Assessments. %A Lim, Yen Ying %A Pase, Matthew P %A Buckley, Rachel F %A Yassi, Nawaf %A Bransby, Lisa %A Fowler, Christopher %A Laws, Simon M %A Masters, Colin L %A Maruff, Paul %X

BACKGROUND: The apolipoprotein E (APOE) ɛ4 allele is associated with dose-response effects on cognitive dysfunction and dementia risk in older adults. However, its effects on cognition in middle-aged adults remains unclear.

OBJECTIVE: We examined effects of ɛ4 heterozygosity and homozygosity on objective and subjective cognition in middle-aged adults enrolled in the Healthy Brain Project (HBP) and in older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.

METHODS: HBP participants (1,000 non-carriers; 450 ɛ4 heterozygotes; 50 ɛ4 homozygotes) completed unsupervised assessments of the Cogstate Brief Battery (CBB), ratings of subjective cognitive function and provided a saliva sample. AIBL cognitively normal participants (650 non-carriers; 204 ɛ4 heterozygotes; 31 ɛ4 homozygotes) completed in-person assessments of the CBB, ratings of subjective cognitive function and provided a blood sample.

RESULTS: Greater memory impairment was observed in middle-aged ɛ4 homozygotes compared with ɛ4 heterozygotes and non-carriers. When data from middle-aged (HBP) and older (AIBL) adults were pooled, the effect of ɛ4 homozygosity and memory impairment increased with age. In both middle-aged and older adults, ɛ4 heterozygotes did not differ from non-carriers on any measure of objective or subjective cognition.

CONCLUSION: Memory impairment in ɛ4 homozygotes is evident in adults aged 50-60 years, and this can be detected through unsupervised cognitive assessments. The effect of ɛ4 homozygosity increases with older age. APOEɛ4 homozygosity has a negative impact on memory as early as midlife, but due to the subtle magnitude of effect, our findings support the necessity of online platforms in large cohorts to assess these complex relationships.

%B J Alzheimers Dis %V 79 %P 1563-1573 %8 2021 Feb 16 %G eng %N 4 %R 10.3233/JAD-201281 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Vitamin D Levels, APOE Allele, and MRI Volumetry Assessed by NeuroQuant in Norwegian Adults with Cognitive Symptoms. %A Soares, Jelena Z %A Pettersen, Renate %A Benth, Jūratė Š %A Persson, Karin %A Strobel, Carsten %A Selbæk, Geir %A Bogdanovic, Nenad %X

BACKGROUND: Allele ɛ4 of the apolipoprotein (APOE∈4) gene is the strongest known genetic risk factor for late-onset sporadic Alzheimer's disease. A possible relationship between vitamin D and APOE is not yet clear.

OBJECTIVE: In this exploratory, cross-sectional study, we examined the association between serum levels of 25-hydroxyvitamin D [25(OH)D] and brain volumes and the associations of both serum levels of 25(OH)D and APOE polymorphism to brain volumes in 127 persons (mean age 66 years) with cognitive symptoms.

METHODS: All subjects were examined with fully automated software for MRI volumetry, NeuroQuant.

RESULTS: After adjustment for relevant covariates, higher serum 25(OH)D levels were associated with greater volumes of cortical gray matter on both left (p = 0.02) and right (p = 0.04) sides. When both 25(OH)D levels and APOE genotype were used as the main covariates, no significant associations were found between vitamin D level and brain volume in any of the 11 brain regions. In adjusted models, only homozygous but not heterozygous APOE∈4 allele carriers had significantly larger inferior lateral ventricles (p = 0.003) and smaller hippocampal volume (p = 0.035) than those without ɛ4. Homozygous APOE∈4 carriers also had significantly higher vitamin D levels (p = 0.009) compared to persons without the APOE∈4 allele.

CONCLUSION: Higher vitamin D levels might have a preserving effect on cortical grey matter volume.

%B J Alzheimers Dis %V 79 %P 311-321 %8 2021 Jan 5 %G eng %N 1 %R 10.3233/JAD-201018 %0 Journal Article %J J Alzheimers Dis %D 2021 %T White Matter Connectivity in Incident Mild Cognitive Impairment: A Diffusion Spectrum Imaging Study of World Trade Center Responders at Midlife. %A Huang, Chuan %A Kritikos, Minos %A Clouston, Sean A P %A Deri, Yael %A Serrano-Sosa, Mario %A Bangiyev, Lev %A Santiago-Michels, Stephanie %A Gandy, Sam %A Sano, Mary %A Bromet, Evelyn J %A Luft, Benjamin J %K Brain %K Cognitive Dysfunction %K Diffusion Tensor Imaging %K Emergency Responders %K Female %K Humans %K Incidence %K Male %K Middle Aged %K September 11 Terrorist Attacks %K White Matter %X

BACKGROUND: Individuals who participated in response efforts at the World Trade Center (WTC) following 9/11/2001 are experiencing elevated incidence of mild cognitive impairment (MCI) at midlife.

OBJECTIVE: We hypothesized that white matter connectivity measured using diffusion spectrum imaging (DSI) would be restructured in WTC responders with MCI versus cognitively unimpaired responders.

METHODS: Twenty responders (mean age 56; 10 MCI/10 unimpaired) recruited from an epidemiological study were characterized using NIA-AA criteria alongside controls matched on demographics (age/sex/occupation/race/education). Axial DSI was acquired on a 3T Siemen's Biograph mMR scanner (12-channel head coil) using a multi-band diffusion sequence. Connectometry examined whole-brain tract-level differences in white matter integrity. Fractional anisotropy (FA), mean diffusivity (MD), and quantified anisotropy were extracted for region of interest (ROI) analyses using the Desikan-Killiany atlas.

RESULTS: Connectometry identified both increased and decreased connectivity within regions of the brains of responders with MCI identified in the corticothalamic pathway and cortico-striatal pathway that survived adjustment for multiple comparisons. MCI was also associated with higher FA values in five ROIs including in the rostral anterior cingulate; lower MD values in four ROIs including the left rostral anterior cingulate; and higher MD values in the right inferior circular insula. Analyses by cognitive domain revealed nominal associations in domains of response speed, verbal learning, verbal retention, and visuospatial learning.

CONCLUSIONS: WTC responders with MCI at midlife showed early signs of neurodegeneration characterized by both increased and decreased white matter diffusivity in regions commonly affected by early-onset Alzheimer's disease.

%B J Alzheimers Dis %V 80 %P 1209-1219 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646156?dopt=Abstract %R 10.3233/JAD-201237 %0 Journal Article %J J Alzheimers Dis %D 2020 %T ABCA7 Genotype Moderates the Effect of Aerobic Exercise Intervention on Generalization of Prior Learning in Healthy Older African Americans. %A Sinha, Neha %A Berg, Chelsie N %A Shaw, Ashlee %A Gluck, Mark A %X

African Americans are at elevated risk for age-related cognitive decline, with double the prevalence of Alzheimer's disease (AD) compared to Caucasians Americans. Various behavioral, biological, and lifestyle factors may underlie this health disparity, but little is known about the relative importance and interactions among these different risk factors in African Americans. While the neuroprotective effects of aerobic exercise on biomarkers are well established, few studies have examined the differential benefits of exercise based on genetic risk for AD. Furthermore, evidence is limited regarding the potential moderating effects of ABCA7, a gene known to confer significantly greater AD risk in African Americans. In a case-control matched sample of 56 healthy older African Americans, we investigated the effect of an aerobic exercise intervention on a hippocampus-related assessment of generalization following rule learning, in individuals who were carriers of the ABCA7 rs3764650 non-risk (TT) or high-risk (GG) genotypes. Following the exercise-intervention, the non-risk group made significantly fewer generalization errors, while there was no improvement in generalization for the high-risk group. For the controls, no changes in generalization scores were observed regardless of genotype status. Our results indicate that the ongoing adverse effects of ABCA7 high-risk genotype may diminish the benefits associated with aerobic exercise. As such, the potential disease-modifying effects of aerobic exercise on AD-related neuropathology may be limited to carriers of the ABCA7 rs3764650 non-risk genotype.

%B J Alzheimers Dis %V 74 %P 309-318 %8 2020 Mar 10 %G eng %N 1 %R 10.3233/JAD-190723 %0 Journal Article %J J Alzheimers Dis %D 2020 %T An Active Lifestyle Is Associated with Better Cognitive Function Over Time in APOE ɛ4 Non-Carriers. %A Fernández-Matarrubia, Marta %A Goni, Leticia %A Rognoni, Teresa %A Razquin, Cristina %A Fernández-Lázaro, César Ignacio %A Bes-Rastrollo, Maira %A Martínez-González, Miguel Ángel %A Toledo, Estefanía %X

BACKGROUND: Available evidence on the association of physical activity (PA) or sedentary behavior with cognitive decline is inconclusive.

OBJECTIVE: To assess the association between an active lifestyle score and leisure-time physical activity (LTPA) and changes in cognitive function in the Seguimiento Universidad de Navarra (SUN) prospective cohort.

METHODS: Cognitive function was evaluated in a subsample of 806 participants of the SUN cohort study using the validated Telephone Interview for Cognitive Status-modified (STICS-m) questionnaire at baseline and after 6 years. LTPA was evaluated with a previously validated 17-item self-administered questionnaire and with information on sedentary lifestyles. We also calculated a multidimensional 8-item PA score. Multivariable linear regression analysis evaluated the association between PA and changes in cognitive function and its interaction by APOE genotype.

RESULTS: Mean age of participants was 66 (SD 5.3) years and 69.7% were male. When stratifying by APOE variants, no significant associations between the active lifestyle score or LTPA and changes in cognitive performance over time were found among APOE ɛ4 carriers. However, we observed that a higher adherence to an active lifestyle (high versus low PA score β= 0.76 95% CI 0.15,1.36; p trend = 0.011) and a high LTPA (Q4 versus Q1 β= 0.63; 95% CI -0.01,1.26; p trend = 0.030) were associated with more favorable changes in cognitive function over time among APOE ɛ4 non-carriers with statistically significant interactions in both cases (p for interaction = 0.042 for PA score, and p = 0.039 for LTPA).

CONCLUSION: The results of the present study suggest that an active lifestyle is associated with a better status of cognitive function over time only among APOE ɛ4 non-carriers.

%B J Alzheimers Dis %V 79 %P 1257-1268 %8 2021 Feb 2 %G eng %N 3 %R 10.3233/JAD-201090 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Age of Migration and Cognitive Function Among Older Latinos in the United States. %A Garcia, Marc A %A Ortiz, Kasim %A Arévalo, Sandra P %A Diminich, Erica D %A Briceño, Emily %A Vega, Irving E %A Tarraf, Wassim %X

BACKGROUND: Age of migration has been shown to have a robust association with Latino immigrant health outcomes; however, the relationship between timing of migration and cognition is less understood.

OBJECTIVE: To examine associations between race/ethnicity, nativity, age of migration, and cognitive aging among US-born (USB) non-Latino Whites (NLW) and USB and foreign-born Latinos 50 years and older.

METHODS: We used longitudinal biennial data from the Health and Retirement Study (HRS; 2006-2014) to fit generalized linear and linear latent growth curve models for: 1) global cognition (Modified Telephone Interview for Cognitive Status; TICS-M); 2) memory and attention subdomains of TICS-M; and 3) cognitive dysfunction. We also tested for sex modifications.

RESULTS: In age and sex adjusted models, all Latino subgroups, independent of nativity and age of migration, had lower global and domain-specific cognitive scores and higher propensity of cognitive impairment classification compared to USB-NLWs. Differences between USB Latinos, but not other Latino subgroups, and USB-NLWs remained after full covariate adjustment. Latinas, independent of nativity or age of migration, had poorer cognitive scores relative to NLW females. Differences between all Latinos and USB-NLWs were principally expressed at baseline. Racial/ethnic, nativity, and age of migration grouping was not associated with slope (nor explained variance) of cognitive decline.

CONCLUSION: Older US-born Latinos, regardless of sex exhibit poorer cognitive function than older USB-NLWs and foreign-born Latinos. Social determinants that differentially affect cognitive function, particularly those that compensate for education and sex differences among US-born Latinos and foreign-born Latinos, require further exploration.

%B J Alzheimers Dis %V 76 %P 1493-1511 %8 2020 Aug 18 %G eng %N 4 %R 10.3233/JAD-191296 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes. %A Brewer, Gregory J %A Herrera, Robert A %A Philipp, Stephan %A Sosna, Justyna %A Reyes-Ruiz, Jorge Mauricio %A Glabe, Charles G %X

 This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iAβ), and the mechanism of an age-related increase in iAβ in adult AD-model mouse neurons. A new end-specific antibody for Aβ45 and another for aggregated forms of Aβ provide new insight into the composition of iAβ and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iAβ levels containing aggregates of Aβ45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iAβ was 8 times more abundant in 3xTg-AD than non-transgenic neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized Alz50 tau colocalized with iAβ and rapidly increased following a brief metabolic stress with glutamate. AβPP-CTF, Aβ45, and aggregated Aβ colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iAβ by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long Aβs by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iAβ processing may lead to application of countermeasures to prolong dementia-free health span.

%B J Alzheimers Dis %V 73 %P 229-246 %8 2020 Jan 07 %G eng %N 1 %R 10.3233/JAD-190835 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Age-Specific Retinal and Cerebral Immunodetection of Amyloid-β Plaques and Oligomers in a Rodent Model of Alzheimer's Disease. %A Habiba, Umma %A Merlin, Sam %A Lim, Jeremiah K H %A Wong, Vickie H Y %A Nguyen, Christine T O %A Morley, John W %A Bui, Bang V %A Tayebi, Mourad %X

BACKGROUND: Amyloid-β soluble oligomers (Aβo) are believed to be the cause of the pathophysiology underlying Alzheimer's disease (AD) and are normally detected some two decades before clinical onset of the disease. Retinal pathology associated with AD pathogenesis has previously been reported, including ganglion cell loss, accumulation of Aβ deposits in the retina, and reduction of nerve fiber layer thickness as well as abnormalities of the microvasculature.

OBJECTIVE: This study's aim is to better understand the relationship between brain and retinal Aβo deposition and in particular to quantify levels of the toxic Aβo as a function of age in the retina of a rodent model of AD.

METHODS: Retinas and brain tissue from 5×FAD mice were stained with Congo red, Thioflavin-T (Th-T), and Aβ plaque-specific and Aβo-specific antibodies.

RESULTS: We show that retinas displayed an age-dependent increase of Th-T-specific amyloid fibrils. Staining with anti-Aβ antibody confirmed the presence of the Aβ plaques in all 5×FAD retinas tested. In contrast, staining with anti-Aβo antibody showed an age-dependent decrease of retinal Aβo. Of note, Aβo was observed mainly in the retinal nuclear layers. Finally, we confirmed the localization of Aβo to neurons, typically accumulating in late endosomes, indicating possible impairment of the endocytic pathway.

CONCLUSION: Our results demonstrate the presence of intraneuronal Aβo in the retina and its accumulation inversely correlated with retinal Aβ plaque deposition, indicating an age-related conversion in this animal model. These results support the development of an early AD diagnostic test targeting Aβo in the eye.

%B J Alzheimers Dis %V 76 %P 1135-1150 %8 2020 Aug 04 %G eng %N 3 %R 10.3233/JAD-191346 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Is Alzheimer's Disease a Liver Disease of the Brain? %A Bassendine, Margaret F %A Taylor-Robinson, Simon D %A Fertleman, Michael %A Khan, Michael %A Neely, Dermot %X

Clinical specialization is not only a force for progress, but it has also led to the fragmentation of medical knowledge. The focus of research in the field of Alzheimer's disease (AD) is neurobiology, while hepatologists focus on liver diseases and lipid specialists on atherosclerosis. This article on AD focuses on the role of the liver and lipid homeostasis in the development of AD. Amyloid-β (Aβ) deposits accumulate as plaques in the brain of an AD patient long before cognitive decline is evident. Aβ generation is a normal physiological process; the steady-state level of Aβ in the brain is determined by balance between Aβ production and its clearance. We present evidence suggesting that the liver is the origin of brain Aβ deposits and that it is involved in peripheral clearance of circulating Aβ in the blood. Hence the liver could be targeted to decrease Aβ production or increase peripheral clearance.

%B J Alzheimers Dis %V 75 %P 1-14 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32250293?dopt=Abstract %R 10.3233/JAD-190848 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Alzheimer's Disease-Like Neurodegeneration in Porphyromonas gingivalis Infected Neurons with Persistent Expression of Active Gingipains. %A Haditsch, Ursula %A Roth, Theresa %A Rodriguez, Leo %A Hancock, Sandy %A Cecere, Thomas %A Nguyen, Mai %A Arastu-Kapur, Shirin %A Broce, Sean %A Raha, Debasish %A Lynch, Casey C %A Holsinger, Leslie J %A Dominy, Stephen S %A Ermini, Florian %X

BACKGROUND: Porphyromonas gingivalis (P. gingivalis) and its gingipain virulence factors have been identified as pathogenic effectors in Alzheimer's disease (AD). In a recent study we demonstrated the presence of gingipains in over 90% of postmortem AD brains, with gingipains localizing to the cytoplasm of neurons. However, infection of neurons by P. gingivalis has not been previously reported.

OBJECTIVE: To demonstrate intraneuronal P. gingivalis and gingipain expression in vitro after infecting neurons derived from human inducible pluripotent stem cells (iPSC) with P. gingivalis for 24, 48, and 72 h.

METHODS: Infection was characterized by transmission electron microscopy, confocal microscopy, and bacterial colony forming unit assays. Gingipain expression was monitored by immunofluorescence and RT-qPCR, and protease activity monitored with activity-based probes. Neurodegenerative endpoints were assessed by immunofluorescence, western blot, and ELISA.

RESULTS: Neurons survived the initial infection and showed time dependent, infection induced cell death. P. gingivalis was found free in the cytoplasm or in lysosomes. Infected neurons displayed an accumulation of autophagic vacuoles and multivesicular bodies. Tau protein was strongly degraded, and phosphorylation increased at T231. Over time, the density of presynaptic boutons was decreased.

CONCLUSION: P. gingivalis can invade and persist in mature neurons. Infected neurons display signs of AD-like neuropathology including the accumulation of autophagic vacuoles and multivesicular bodies, cytoskeleton disruption, an increase in phospho-tau/tau ratio, and synapse loss. Infection of iPSC-derived mature neurons by P. gingivalis provides a novel model system to study the cellular mechanisms leading to AD and to investigate the potential of new therapeutic approaches.

%B J Alzheimers Dis %V 75 %P 1361-1376 %8 2020 Jun 16 %G eng %N 4 %R 10.3233/JAD-200393 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Amyloid Hypothesis: The Emperor's New Clothes? %A Høilund-Carlsen, Poul F %A Barrio, Jorge R %A Werner, Tom J %A Newberg, Andrew %A Alavi, Abass %X

The lengthy debate on the validity of the amyloid hypothesis and the usefulness of amyloid imaging and anti-amyloid therapeutic interventions in dementia continues unabated, even though none of them have been able to convince the medical world of their correctness and clinical value. There are huge financial interests associated with promoting both, but in spite of the large sums of money in their support, no effective anti-amyloid treatments or diagnostic use of amyloid imaging have emerged. There are solid scientific reasons that explain these negative results, and it is time to move forward to other promising options for the benefit of the patients.

%B J Alzheimers Dis %V 78 %P 1363-1366 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33164938?dopt=Abstract %R 10.3233/JAD-200990 %0 Journal Article %J J Alzheimers Dis %D 2020 %T The Amyloid, Tau, and Neurodegeneration (A/T/N) Classification Applied to a Clinical Research Cohort with Long-Term Follow-Up. %A Grøntvedt, Gøril Rolfseng %A Lauridsen, Camilla %A Berge, Guro %A White, Linda R %A Salvesen, Øyvind %A Bråthen, Geir %A Sando, Sigrid Botne %X

BACKGROUND: The unbiased amyloid, tau, and neurodegeneration (A/T/N) classification is designed to characterize individuals in the Alzheimer continuum and is currently little explored in clinical cohorts.

OBJECTIVE: A retrospective comparison of the A/T/N classification system with the results of a two-year clinical study, with extended follow-up up to 10 years after inclusion.

METHODS: Patients (n = 102) clinically diagnosed as Alzheimer's disease (AD) with dementia or amnestic mild cognitive impairment (MCI), and 61 cognitively healthy control individuals were included. Baseline cerebrospinal fluid core biomarkers for AD (Aβ42, phosphorylated tau, and total tau) were applied to the A/T/N classification using the final clinical diagnosis at extended follow-up as the gold standard.

RESULTS: A + T + N+ was a strong predictor for AD dementia, even among cognitively healthy individuals. Amnestic MCI was heterogenous, considering both clinical outcome and distribution within A/T/N. Some individuals with amnestic MCI progressed to clinical AD dementia within all four major A/T/N groups. The highest proportion of progression was among triple positive cases, but progression was also common in individuals with suspected non-Alzheimer pathophysiology (A-T + N+), and those with triple negative status. A-T-N- individuals who were cognitively healthy overwhelmingly remained cognitively intact over time, but in amnestic MCI the clinical outcome was heterogenous, including AD dementia, other dementias, and recovery.

CONCLUSION: The A/T/N framework accentuates biomarkers over clinical status. However, when selecting individuals for research, a combination of the two may be necessary since the prognostic value of the A/T/N framework depends on clinical status.

%B J Alzheimers Dis %V 74 %P 829-837 %8 2020 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/32116257?dopt=Abstract %R 10.3233/JAD-191227 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Amyloid-β Causes Mitochondrial Dysfunction via a Ca2+-Driven Upregulation of Oxidative Phosphorylation and Superoxide Production in Cerebrovascular Endothelial Cells. %A Quintana, Dominic D %A Garcia, Jorge A %A Anantula, Yamini %A Rellick, Stephanie L %A Engler-Chiurazzi, Elizabeth B %A Sarkar, Saumyendra N %A Brown, Candice M %A Simpkins, James W %X

Cerebrovascular pathology is pervasive in Alzheimer's disease (AD), yet it is unknown whether cerebrovascular dysfunction contributes to the progression or etiology of AD. In human subjects and in animal models of AD, cerebral hypoperfusion and hypometabolism are reported to manifest during the early stages of the disease and persist for its duration. Amyloid-β is known to cause cellular injury in both neurons and endothelial cells by inducing the production of reactive oxygen species and disrupting intracellular Ca2+ homeostasis. We present a mechanism for mitochondrial degeneration caused by the production of mitochondrial superoxide, which is driven by increased mitochondrial Ca2+ uptake. We found that persistent superoxide production injures mitochondria and disrupts electron transport in cerebrovascular endothelial cells. These observations provide a mechanism for the mitochondrial deficits that contribute to cerebrovascular dysfunction in patients with AD.

%B J Alzheimers Dis %V 75 %P 119-138 %8 2020 May 05 %G eng %N 1 %R 10.3233/JAD-190964 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Amyloid-β in Alzheimer's Disease: A Study of Citation Practices of the Amyloid Cascade Hypothesis Between 1992 and 2019. %A Daly, Timothy %A Houot, Marion %A Barberousse, Anouk %A Agid, Yves %A Epelbaum, Stéphane %X

The amyloid cascade hypothesis (ACH) has dominated contemporary biomedical research into Alzheimer's disease (AD) since the 1990 s but still lacks definitive confirmation by successful clinical trials of anti-amyloid medicines in human AD. In this uncertain period regarding the centrality of amyloid-β (Aβ) in AD pathophysiology, and with the community apparently divided about the ACH's validity, we used citation practices as a proxy for measuring how researchers have invested their belief in the hypothesis between 1992 and 2019. We sampled 445 articles citing Hardy & Higgins (1992, "HH92") and classified the polarity of their HH92 citation according to Greenberg (2009)'s citation taxonomy of positive, neutral, and negative citations, and then tested four hypotheses. We identified two major attitudes towards HH92: a majority (62%) of neutral attitudes with consistent properties across the time period, and a positive attitude (35%), tending to cite HH92 earlier on within the bibliography as time went by, tending to take HH92 as an established authority. Despite the majority of neutral HH92 citations, there was a positive majority of attitudes toward different versions of the ACH and anti-amyloid therapeutic strategies (65%), suggesting that the ACH has been dominant and has undergone significant refinement since 1992. Finally, of those 110 original articles within the sample also testing the ACH empirically, an overwhelming majority (89%) returned a pro-ACH test result, suggesting that the ACH's central claim is reproducible. Further studies will quantify the extent to which results from different methods within such original studies convergence to provide a robust conclusion vis-à-vis Aβ's pathogenicity in AD.

%B J Alzheimers Dis %V 74 %P 1309-1317 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32250306?dopt=Abstract %R 10.3233/JAD-191321 %0 Journal Article %J J Alzheimers Dis %D 2020 %T APOE4 Status is Related to Differences in Memory-Related Brain Function in Asymptomatic Older Adults with Family History of Alzheimer's Disease: Baseline Analysis of the PREVENT-AD Task Functional MRI Dataset. %A Rabipour, Sheida %A Rajagopal, Sricharana %A Yu, Elsa %A Pasvanis, Stamatoula %A Lafaille-Magnan, Marie-Elyse %A Breitner, John %A Rajah, M Natasha %X

BACKGROUND: Episodic memory decline is one of the earliest symptoms of late-onset Alzheimer's disease (AD). Older adults with the apolipoprotein E ɛ4 (+APOE4) genetic risk factor for AD may exhibit altered patterns of memory-related brain activity years prior to initial symptom onset.

OBJECTIVE: Here we report the baseline episodic memory task functional MRI results from the PRe-symptomatic EValuation of Experimental or Novel Treatments for Alzheimer's Disease cohort in Montreal, Canada, in which 327 healthy older adults were scanned within 15 years of their parent's conversion to AD.

METHODS: Volunteers were scanned as they encoded and retrieved object-location spatial source associations. The task was designed to discriminate between brain activity related to spatial source recollection and object-only (recognition) memory. We used multivariate partial least squares (PLS) to test the hypothesis that +APOE4 adults with family history of AD would exhibit altered patterns of brain activity in the recollection-related memory network, comprised of medial frontal, parietal, and medial temporal cortices, compared to APOE4 non-carriers (-APOE4). We also examined group differences in the correlation between event-related brain activity and memory performance.

RESULTS: We found group similarities in memory performance and in task-related brain activity in the recollection network, but differences in brain activity-behavior correlations in ventral occipito-temporal, medial temporal, and medial prefrontal cortices during episodic encoding.

CONCLUSION: These findings are consistent with previous literature on the influence of APOE4 on brain activity and provide new perspective on potential gene-based differences in brain-behavior relationships in people with first-degree family history of AD.

%B J Alzheimers Dis %V 76 %P 97-119 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32474466?dopt=Abstract %R 10.3233/JAD-191292 %0 Journal Article %J J Alzheimers Dis %D 2020 %T APOEɛ4-TOMM40L Haplotype Increases the Risk of Mild Cognitive Impairment Conversion to Alzheimer's Disease. %A Cardoso, Remy %A Lemos, Carolina %A Oliveiros, Bárbara %A Rosário Almeida, Maria %A Baldeiras, Ines %A Fragão Pereira, Cláudia %A Santos, Ana %A Duro, Diana %A Vieira, Daniela %A Santana, Isabel %A Resende Oliveira, Catarina %X

BACKGROUND: Mild cognitive impairment (MCI) has been considered as a pre-dementia stage, although the factors leading to Alzheimer's disease (AD) conversion remain controversial.

OBJECTIVE: Evaluate whether TOMM40 poly-T (TOMM40' 523) polymorphism is associated with the risk and conversion time from MCI to AD and secondly with AD cerebrospinal fluid (CSF) biomarkers, disentangling the APOE genotype.

METHODS: 147 AD patients, 102 MCI patients, and 105 cognitively normal controls were genotyped for poly-T polymorphism. MCI patients were subdivided into two groups, the group of patients that converted to AD (MCI-AD) and the group of those that remained stable (MCI-S).

RESULTS: TOMM40' 523 L allele was significantly more frequent in the MCI-AD group and having at least one L allele significantly increased the risk of conversion from MCI to AD (OR = 8.346, p <  0.001, 95% CI: 2.830 to 24.617). However, when adjusted for the presence of APOEɛ4 allele, both the L allele and ɛ4 allele lost significance in the model (p >  0.05). We then analyzed the APOEɛ4-TOMM40' 523 haplotype and observed that patients carrying this haplotype had significantly higher risk (OR = 5.83; 95% CI = 2.30-14.83) and mean lower times of conversion to AD (p = 0.003). This haplotype was also significantly associated with a biomarker profile compatible with AD (p = 0.007).

CONCLUSION: This study shows that the APOEɛ4-TOMM40' 523 haplotype is associated with a higher risk and shorter times of conversion from MCI to AD, possibly driven by CSF biomarkers and mitochondrial dysfunction.

%B J Alzheimers Dis %V 78 %P 587-601 %8 2020 Nov 10 %G eng %N 2 %R 10.3233/JAD-200556 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Association of Low Systolic Blood Pressure with Postmortem Amyloid-β and Tau. %A Oveisgharan, Shahram %A Capuano, Ana W %A Kapasi, Alifiya %A Buchman, Aron S %A Schneider, Julie A %A Bennett, David A %A Arvanitakis, Zoe %X

BACKGROUND: Vascular mechanisms may contribute to the accumulation of AD pathology.

OBJECTIVE: We examined whether the burden of vascular risk factors proximate to death is associated with amyloid-β and tau levels or modified their known association.

METHODS: We examined the brains of 1, 585 participants from two longitudinal community-based studies of older adults. Amyloid-β and tau were quantified by postmortem examination. The burden of vascular risk factors was summarized by calculating the Framingham general cardiovascular risk score (FRS) proximate to death. Using linear regressions, we examined the association of the FRS with the amyloid-β and tau levels and examined if the FRS modified the association of the amyloid-β with tau.

RESULTS: On average, participants were nearly 90 years old and two-thirds were women. The FRS was not associated with amyloid-β (Spearman r  = -0.00, p  = 0.918) or tau (r = 0.01, p = 0.701). However, the FRS as a whole (estimate = -0.022, SE = 0.008, p = 0.009), and specifically the systolic blood pressure (SBP) component (estimate = -0.033, SE = 0.012, p = 0.009), modified the association of the amyloid-β with tau. Further analysis showed that the association between amyloid-β and tau was stronger at lower levels of SBP.

CONCLUSION: Late-life vascular risk scores were not related to postmortem levels of amyloid-β or tau. However, lower levels of vascular risk scores and SBP were associated with a stronger association between amyloid-β and tau. These data suggest that vascular risk factors may modify the relation of AD pathology markers to one another.

%B J Alzheimers Dis %V 78 %P 1755-1764 %8 2020 Dec 08 %G eng %N 4 %R 10.3233/JAD-200412 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Brain Volume Predicts Behavioral and Psychological Symptoms in Alzheimer's Disease. %A Boublay, Nawele %A Bouet, Romain %A Dorey, Jean-Michel %A Padovan, Catherine %A Makaroff, Zaza %A Federico, Denis %A Gallice, Isabelle %A Barrellon, Marie-Odile %A Robert, Philippe %A Moreaud, Olivier %A Rouch, Isabelle %A Krolak-Salmon, Pierre %X

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are frequent and troublesome for patients and caregivers. Considering possible preventive approaches, a better understanding of underlying neural correlates of BPSD is crucial.

OBJECTIVE: The aim is to assess whether brain regional volume predicts behavioral changes in mild AD.

METHODS: This work took part from the PACO study, a multicenter and prospective study that included 252 patients with mild AD from 2009 to 2014. Fifty-three patients were retained. Forty healthy matched control subjects from the ADNI cohort were included as controls. Voxel-based morphometry analysis was conducted to assess regional brain volume using baseline MRI scans as a predictor of future behavioral changes over a period of 18 months. Behavior was assessed at baseline and longitudinally at 6-month intervals using the shortened form of the Neuropsychiatric Inventory (NPI).

RESULTS: The volume of 23 brain structures in frontal, temporal, parietal, occipital, subcortical regions and cerebellum predicted the evolution of NPI scores. Frontal volume was the most powerful predictor with frontal gyri, anterior cingulate cortex, and orbital gyri being particularly involved.

CONCLUSION: To our knowledge, this is the first study assessing regional brain volumes as predictors of behavioral changes considered at earlier stages of AD. Up to 23 brain structures were associated with an increased risk of developing BPSD. Frontal lobe volume was the strongest predictor of future evolution of NPI. The involvement of multiple structures in the prediction of behavior suggests a role of the main large-scale networks involved in cognition.

%B J Alzheimers Dis %V 73 %P 1343-1353 %8 2020 Feb 18 %G eng %N 4 %R 10.3233/JAD-190612 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Characterizing Clinical and Neuropathological Traits of APOE Haplotypes in African Americans and Europeans. %A Mezlini, Aziz M %A Magdamo, Colin %A Merrill, Emily %A Chibnik, Lori B %A Blacker, Deborah L %A Hyman, Bradley T %A Das, Sudeshna %X

BACKGROUND: The APOEɛ4 allele is the largest genetic risk factor for late-onset Alzheimer's disease (AD). Recent literature suggested that the contribution of APOEɛ4 to AD risk could be population-specific, with ɛ4 conferring a lower risk to Blacks or African Americans.

OBJECTIVE: To investigate the effect of APOE haplotypes on AD risk in individuals with European ancestry (EU) and Blacks or African Americans (AA).

METHODS: We selected data from 1) the National Alzheimer's Coordinating Center: a total of 3,486 AD cases and 4,511 controls (N = 7,997, 60% female) with genotypes from the Alzheimer's Disease Genetics Consortium (ADGC), and 2) the Rush University Religious Orders Study and Memory and Aging Project (ROSMAP) cohort with 578 AD and 670 controls (N = 1,248, 60% female). Using ɛ3 homozygotes as the reference, we compared the association of various APOE haplotypes with the clinical and neuropathological correlates of dementia in AA and EU.

RESULTS: In both cohorts, we find no difference in the odds or age of onset of AD among the ɛ4-linked haplotypes defined by rs769449 within either AA or EU. Additionally, while APOEɛ4 was associated with a faster rate of decline, no differences were found in rate of decline, clinical or neuropathological features among the ɛ4-linked haplotypes. Further analysis with other variants near the APOE locus failed to identify any effect modification.

CONCLUSION: Our study finds similar effects of the ɛ4-linked haplotypes defined by rs769449 on AD as compared to ɛ3 in both AA and EU. Future studies are required to understand the heterogeneity of APOE conferred risk of AD among various genotypes and populations.

%B J Alzheimers Dis %V 78 %P 467-477 %8 2020 Oct 27 %G eng %N 1 %R 10.3233/JAD-200228 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer's Disease Dementia in a Large National Survey. %A Beydoun, May A %A Beydoun, Hind A %A Hossain, Sharmin %A El-Hajj, Ziad W %A Weiss, Jordan %A Zonderman, Alan B %X

Microbial agents including periodontal pathogens have recently appeared as important actors in Alzheimer's disease (AD) pathology. We examined associations of clinical periodontal and bacterial parameters with incident all-cause and AD dementia as well as AD mortality among US middle-aged and older adults. Clinical [Attachment Loss (AL); probing pocket depth (PPD)] and bacterial [pathogen immunoglobulin G (IgG)] periodontal markers were investigated in relation to AD and all-cause dementia incidence and to AD mortality, using data from the third National Health and Nutrition Examination Surveys (NHANES III, 1988-1994) linked longitudinally with National Death Index and Medicare data through January 1, 2014, with up to 26 years of follow-up. Sex- and age-specific multivariable-adjusted Cox proportional hazards models were conducted. Among those ≥65 years, AD incidence and mortality were consistently associated with PPD, two factors and one cluster comprised of IgG titers against Porphyromonas gingivalis (P. gingivalis), Prevotella melaninogenica (P. melaninogenica) and Campylobacter rectus (C. rectus) among others. Specifically, AD incidence was linked to a composite of C. rectus and P. gingivalis titers (per SD, aHR = 1.22; 95% CI, 1.04-1.43, p = 0.012), while AD mortality risk was increased with another composite (per SD, aHR = 1.46; 95% CI, 1.09-1.96, p = 0.017) loading highly on IgG for P. gingivalis, Prevotella intermedia, Prevotella nigrescens, Fusobacterium nucleatum, C. rectus, Streptococcus intermedius, Capnocylophaga Ochracea, and P. melaninogenica. This study provides evidence for an association between periodontal pathogens and AD, which was stronger for older adults. Effectiveness of periodontal pathogen treatment on reducing sequelae of neurodegeneration should be tested in randomized controlled trials.

%B J Alzheimers Dis %V 75 %P 157-172 %8 2020 May 05 %G eng %N 1 %R 10.3233/JAD-200064 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Cognitive Impairment Is a Common Comorbidity in Deceased COVID-19 Patients: A Hospital-Based Retrospective Cohort Study. %A Martín-Jiménez, Paloma %A Muñoz-García, Mariana I %A Seoane, David %A Roca-Rodríguez, Lucas %A García-Reyne, Ana %A Lalueza, Antonio %A Maestro, Guillermo %A Folgueira, Dolores %A Blanco-Palmero, Víctor A %A Herrero-San Martín, Alejandro %A Llamas-Velasco, Sara %A Pérez-Martínez, David A %A González-Sánchez, Marta %A Villarejo-Galende, Alberto %K Adolescent %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Comorbidity %K COVID-19 %K Female %K Hospital Mortality %K Hospitals %K Humans %K Male %K Middle Aged %K Palliative Care %K Patient Admission %K Retrospective Studies %K Spain %K Young Adult %X

We analyzed the frequency of cognitive impairment (CI) in deceased COVID-19 patients at a tertiary hospital in Spain. Among the 477 adult cases who died after admission from March 1 to March 31, 2020, 281 had confirmed COVID-19. CI (21.1% dementia and 8.9% mild cognitive impairment) was a common comorbidity. Subjects with CI were older, tended to live in nursing homes, had shorter time from symptom onset to death, and were rarely admitted to the ICU, receiving palliative care more often. CI is a frequent comorbidity in deceased COVID-19 subjects and is associated with differences in care.

%B J Alzheimers Dis %V 78 %P 1367-1372 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33074239?dopt=Abstract %R 10.3233/JAD-200937 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Common Bacterial Infections and Risk of Dementia or Cognitive Decline: A Systematic Review. %A Muzambi, Rutendo %A Bhaskaran, Krishnan %A Brayne, Carol %A Davidson, Jennifer A %A Smeeth, Liam %A Warren-Gash, Charlotte %X

BACKGROUND: Bacterial infections may be associated with dementia, but the temporality of any relationship remains unclear.

OBJECTIVES: To summarize existing literature on the association between common bacterial infections and the risk of dementia and cognitive decline in longitudinal studies.

METHODS: We performed a comprehensive search of 10 databases of published and grey literature from inception to 18 March 2019 using search terms for common bacterial infections, dementia, cognitive decline, and longitudinal study designs. Two reviewers independently performed the study selection, data extraction, risk of bias and overall quality assessment. Data were summarized through a narrative synthesis as high heterogeneity precluded a meta-analysis.

RESULTS: We identified 3,488 studies. 9 met the eligibility criteria; 6 were conducted in the United States and 3 in Taiwan. 7 studies reported on dementia and 2 investigated cognitive decline. Multiple infections were assessed in two studies. All studies found sepsis (n = 6), pneumonia (n = 3), urinary tract infection (n = 1), and cellulitis (n = 1) increased dementia risk (HR 1.10; 95% CI 1.02-1.19) to (OR 2.60; 95% CI 1.84-3.66). The range of effect estimates was similar when limited to three studies with no domains at high risk of bias. However, the overall quality of evidence was rated very low. Studies on cognitive decline found no association with infection but had low power.

CONCLUSION: Our review suggests common bacterial infections may be associated with an increased risk of subsequent dementia, after adjustment for multiple confounders, but further high-quality, large-scale longitudinal studies, across different healthcare settings, are recommended to further explore this association.

%B J Alzheimers Dis %V 76 %P 1609-1626 %8 2020 Aug 18 %G eng %N 4 %R 10.3233/JAD-200303 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Comorbidity of Cerebrovascular and Alzheimer's Disease in Aging. %A Xia, Ying %A Yassi, Nawaf %A Raniga, Parnesh %A Bourgeat, Pierrick %A Desmond, Patricia %A Doecke, James %A Ames, David %A Laws, Simon M %A Fowler, Christopher %A Rainey-Smith, Stephanie R %A Martins, Ralph %A Maruff, Paul %A Villemagne, Victor L %A Masters, Colin L %A Rowe, Christopher C %A Fripp, Jurgen %A Salvado, Olivier %X

BACKGROUND: Cerebrovascular disease often coexists with Alzheimer's disease (AD). While both diseases share common risk factors, their interrelationship remains unclear. Increasing the understanding of how cerebrovascular changes interact with AD is essential to develop therapeutic strategies and refine biomarkers for early diagnosis.

OBJECTIVE: We investigate the prevalence and risk factors for the comorbidity of amyloid-β (Aβ) and cerebrovascular disease in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing, and further examine their cross-sectional association.

METHODS: A total of 598 participants (422 cognitively normal, 89 with mild cognitive impairment, 87 with AD) underwent positron emission tomography and structural magnetic resonance imaging for assessment of Aβ deposition and cerebrovascular disease. Individuals were categorized based on the comorbidity status of Aβ and cerebrovascular disease (V) as Aβ-V-, Aβ-V+, Aβ+V-, or Aβ+V+.

RESULTS: Advancing age was associated with greater likelihood of cerebrovascular disease, high Aβ load and their comorbidity. Apolipoprotein E ɛ4 carriage was only associated with Aβ positivity. Greater total and regional WMH burden were observed in participants with AD. However, no association were observed between Aβ and WMH measures after stratification by clinical classification, suggesting that the observed association between AD and cerebrovascular disease was driven by the common risk factor of age.

CONCLUSION: Our observations demonstrate common comorbid condition of Aβ and cerebrovascular disease in later life. While our study did not demonstrate a convincing cross-sectional association between Aβ and WMH burden, future longitudinal studies are required to further confirm this.

%B J Alzheimers Dis %V 78 %P 321-334 %8 2020 Oct 27 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32986666?dopt=Abstract %R 10.3233/JAD-200419 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Comparative Cognitive Effects of Choreographed Exercise and Multimodal Physical Therapy in Older Adults with Amnestic Mild Cognitive Impairment: Randomized Clinical Trial. %A Bisbe, Marta %A Fuente-Vidal, Andrea %A López, Elisabet %A Moreno, Marta %A Naya, Marian %A de Benetti, Claudio %A Milà, Raimon %A Bruna, Olga %A Boada, Merce %A Alegret, Montserrat %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Combined Modality Therapy %K Dance Therapy %K Exercise Therapy %K Female %K Humans %K Linear Models %K Male %K Neuropsychological Tests %K Physical Therapy Modalities %K Single-Blind Method %X

BACKGROUND: Recent research on mild cognitive impairment (MCI) has primarily focused on searching for measures to prevent or delay the progression of MCI to dementia. Physical exercise has shown to be effective in the prevention of age-related cognitive decline in elderly adults with MCI. However, the most effective type and dose of exercise for the improvement of cognition are yet to be determined.

OBJECTIVE: To compare the cognitive effects of choreographed exercise (Choreography group) with a multimodal physical therapy program (Physical Therapy group) in elderly adults with amnestic MCI, a population with an increased risk of developing dementia.

METHODS: We conducted a randomized clinical trial with two parallel groups under allocation concealment and assessor blinding. Participants were allocated into Choreography or Physical Therapy group and performed exercises twice per week in 60-minute sessions during 12 weeks.

RESULTS: Thirty-six participants with amnestic MCI, ages 65 to 85, were assessed at baseline and after 12 weeks of intervention, by comprehensive validated neuropsychological and physical assessments. A Repeated measures General Lineal Model showed statistically significant differences in cognitive and physical outcomes. Both groups significantly improved in visual delayed recall. The Choreography group exhibited significantly more benefits on verbal recognition memory than the Physical Therapy group.

CONCLUSION: Greater cognitive benefits were achieved in the choreographic intervention than in the multimodal physical therapy, mainly in those functions more related to the risk of conversion to dementia. Additional studies are needed to confirm whether the observed effects are related to delayed onset of Alzheimer's disease in elderly adults with amnestic MCI.

%B J Alzheimers Dis %V 73 %P 769-783 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/31868666?dopt=Abstract %R 10.3233/JAD-190552 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Computational Modeling of Catecholamines Dysfunction in Alzheimer's Disease at Pre-Plaque Stage. %A Caligiore, Daniele %A Silvetti, Massimo %A D'Amelio, Marcello %A Puglisi-Allegra, Stefano %A Baldassarre, Gianluca %X

BACKGROUND: Alzheimer's disease (AD) etiopathogenesis remains partially unexplained. The main conceptual framework used to study AD is the Amyloid Cascade Hypothesis, although the failure of recent clinical experimentation seems to reduce its potential in AD research.

OBJECTIVE: A possible explanation for the failure of clinical trials is that they are set too late in AD progression. Recent studies suggest that the ventral tegmental area (VTA) degeneration could be one of the first events occurring in AD progression (pre-plaque stage).

METHODS: Here we investigate this hypothesis through a computational model and computer simulations validated with behavioral and neural data from patients.

RESULTS: We show that VTA degeneration might lead to system-level adjustments of catecholamine release, triggering a sequence of events leading to relevant clinical and pathological signs of AD. These changes consist first in a midfrontal-driven compensatory hyperactivation of both VTA and locus coeruleus (norepinephrine) followed, with the progression of the VTA impairment, by a downregulation of catecholamine release. These processes could then trigger the neural degeneration at the cortical and hippocampal levels, due to the chronic loss of the neuroprotective role of norepinephrine.

CONCLUSION: Our novel hypothesis might contribute to the formulation of a wider system-level view of AD which might help to devise early diagnostic and therapeutic interventions.

%B J Alzheimers Dis %V 77 %P 275-290 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32741822?dopt=Abstract %R 10.3233/JAD-200276 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia. %A Shiells, Helen %A Schelter, Bjoern O %A Bentham, Peter %A Baddeley, Thomas C %A Rubino, Christopher M %A Ganesan, Harish %A Hammel, Jeffrey %A Vuksanovic, Vesna %A Staff, Roger T %A Murray, Alison D %A Bracoud, Luc %A Wischik, Damon J %A Riedel, Gernot %A Gauthier, Serge %A Jia, Jianping %A Moebius, Hans J %A Hardlund, Jiri %A Kipps, Christopher M %A Kook, Karin %A Storey, John M D %A Harrington, Charles R %A Wischik, Claude M %X

BACKGROUND: Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins.

OBJECTIVE: To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD.

METHODS: We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination - Revised (ACE-R), the Functional Activities Questionnaire (FAQ), and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug.

RESULTS: There were no significant differences between the two doses as randomized. There were steep concentration-response relationships for plasma levels in the range 0.3-0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure-dependent differences at 8 mg/day for FAQ, Modified-CGIC, and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day.

CONCLUSIONS: Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20-60 mg/day. A confirmatory placebo-controlled trial is now planned.

%B J Alzheimers Dis %V 75 %P 501-519 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32280089?dopt=Abstract %R 10.3233/JAD-191173 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Costs and Resource Use Associated with Community-Dwelling Patients with Alzheimer's Disease in Japan: Baseline Results from the Prospective Observational GERAS-J Study. %A Nakanishi, Miharu %A Igarashi, Ataru %A Ueda, Kaname %A Brnabic, Alan J M %A Treuer, Tamas %A Sato, Masayo %A Kahle-Wrobleski, Kristin %A Meguro, Kenichi %A Yamada, Masahito %A Mimura, Masaru %A Arai, Heii %X

BACKGROUND: As the Japanese population ages, caring for people with Alzheimer's disease (AD) dementia is becoming a major socioeconomic issue.

OBJECTIVE: To determine the contribution of patient and caregiver costs to total societal costs associated with AD dementia.

METHODS: Baseline data was used from the longitudinal, observational GERAS-J study. Using the Mini-Mental State Examination (MMSE) score, patients routinely visiting memory clinics were stratified into three groups based on AD severity. Health care resource utilizationwas recorded using the Resource Utilization in Dementia questionnaire. Total monthly societal costs were estimated using Japan-specific unit costs of services and products (patient direct health care use, patient social care use, and informal caregiving time). Uncertainty around mean costs was estimated using bootstrapping methods.

RESULTS: Overall, 553 community-dwelling patients withADdementia (28.3% mild[MMSE21-26], 37.8% moderate[MMSE 15-20], and 34.0% moderately severe/severe [MMSE < 14]) and their caregivers were enrolled. Patient characteristics were: mean age 80.3 years, 72.7% female, and 13.6% living alone. Caregiver characteristics were: mean age 62.1 years, 70.7% female, 78.8% living with patient, 49.0% child of patient, and 39.2% sole caregiver. Total monthly societal costs of AD dementia (Japanese yen) were: 158,454 (mild), 211,301 (moderate), and 294,224 (moderately severe/severe). Informal caregiving costs comprised over 50% of total costs.

CONCLUSION: Baseline results of GERAS-J showed that total monthly societal costs associated with AD dementia increased with AD severity. Caregiver-related costs were the largest cost component. Interventions are needed to decrease informal costs and decrease caregiver burden.

%B J Alzheimers Dis %V 74 %P 127-138 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31985460?dopt=Abstract %R 10.3233/JAD-190811 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Costs of Early Stage Alzheimer's Disease in the United States: Cross-Sectional Analysis of a Prospective Cohort Study (GERAS-US)1. %A Robinson, Rebecca L %A Rentz, Dorene M %A Andrews, Jeffrey Scott %A Zagar, Anthony %A Kim, Yongin %A Bruemmer, Valerie %A Schwartz, Ronald L %A Ye, Wenyu %A Fillit, Howard M %X

BACKGROUND: Costs associated with early stages of Alzheimer's disease (AD; mild cognitive impairment [MCI] and mild dementia [MILD]) are understudied.

OBJECTIVE: To compare costs associated with MCI and MILD due to AD in the United States.

METHODS: Data included baseline patient/study partner medical history, healthcare resource utilization, and outcome assessments as part of a prospective cohort study. Direct, indirect, and total societal costs were derived by applying standardized unit costs to resources for the 1-month pre-baseline period (USD2017). Costs/month for MCI and MILD cohorts were compared using analysis of variance models. To strengthen the confidence of diagnosis, amyloid-β (Aβ) tests were included and analyses were replicated stratifying within each cohort by amyloid status [+ /-].

RESULTS: Patients (N = 1327) with MILD versus MCI had higher total societal costs/month ($4243 versus $2816; p < 0.001). These costs were not significantly different within each severity cohort by amyloid status. The largest fraction of overall costs were informal caregiver costs (45.1%) for the MILD cohort, whereas direct medical patient costs were the largest for the MCI cohort (39.0%). Correspondingly, caregiver time spent on basic activities of daily living (ADLs), instrumental ADLs, and supervision time was twice as high for MILD versus MCI (all p < 0.001).

CONCLUSION: Early AD poses a financial burden, and despite higher functioning among those with MCI, caregivers were significantly impacted. The major cost driver was the patient's clinical cognitive-functional status and not amyloid status. Differences were primarily due to rising need for caregiver support.

%B J Alzheimers Dis %V 75 %P 437-450 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32250304?dopt=Abstract %R 10.3233/JAD-191212 %0 Journal Article %J J Alzheimers Dis %D 2020 %T COVID-19: Review of a 21st Century Pandemic from Etiology to Neuro-psychiatric Implications. %A Yamamoto, Vicky %A Bolanos, Joe F %A Fiallos, John %A Strand, Susanne E %A Morris, Kevin %A Shahrokhinia, Sanam %A Cushing, Tim R %A Hopp, Lawrence %A Tiwari, Ambooj %A Hariri, Robert %A Sokolov, Rick %A Wheeler, Christopher %A Kaushik, Ajeet %A Elsayegh, Ashraf %A Eliashiv, Dawn %A Hedrick, Rebecca %A Jafari, Behrouz %A Johnson, J Patrick %A Khorsandi, Mehran %A Gonzalez, Nestor %A Balakhani, Guita %A Lahiri, Shouri %A Ghavidel, Kazem %A Amaya, Marco %A Kloor, Harry %A Hussain, Namath %A Huang, Edmund %A Cormier, Jason %A Wesson Ashford, J %A Wang, Jeffrey C %A Yaghobian, Shadi %A Khorrami, Payman %A Shamloo, Bahman %A Moon, Charles %A Shadi, Payam %A Kateb, Babak %K Coronavirus Infections %K COVID-19 %K Humans %K Immunotherapy %K Mental Health %K Nutritional Support %K Pandemics %K Pneumonia, Viral %X

COVID-19 is a severe infectious disease that has claimed >150,000 lives and infected millions in the United States thus far, especially the elderly population. Emerging evidence has shown the virus to cause hemorrhagic and immunologic responses, which impact all organs, including lungs, kidneys, and the brain, as well as extremities. SARS-CoV-2 also affects patients', families', and society's mental health at large. There is growing evidence of re-infection in some patients. The goal of this paper is to provide a comprehensive review of SARS-CoV-2-induced disease, its mechanism of infection, diagnostics, therapeutics, and treatment strategies, while also focusing on less attended aspects by previous studies, including nutritional support, psychological, and rehabilitation of the pandemic and its management. We performed a systematic review of >1,000 articles and included 425 references from online databases, including, PubMed, Google Scholar, and California Baptist University's library. COVID-19 patients go through acute respiratory distress syndrome, cytokine storm, acute hypercoagulable state, and autonomic dysfunction, which must be managed by a multidisciplinary team including nursing, nutrition, and rehabilitation. The elderly population and those who are suffering from Alzheimer's disease and dementia related illnesses seem to be at the higher risk. There are 28 vaccines under development, and new treatment strategies/protocols are being investigated. The future management for COVID-19 should include B-cell and T-cell immunotherapy in combination with emerging prophylaxis. The mental health and illness aspect of COVID-19 are among the most important side effects of this pandemic which requires a national plan for prevention, diagnosis and treatment.

%B J Alzheimers Dis %V 77 %P 459-504 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32925078?dopt=Abstract %R 10.3233/JAD-200831 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Dementia Care in Times of COVID-19: Experience at Fundació ACE in Barcelona, Spain. %A Benaque, Alba %A Gurruchaga, Miren Jone %A Abdelnour, Carla %A Hernandez, Isabel %A Cañabate, Pilar %A Alegret, Montserrat %A Rodríguez, Isabel %A Rosende-Roca, Maitee %A Tartari, Juan Pablo %A Esteban, Ester %A López, Rogelio %A Gil, Silvia %A Vargas, Liliana %A Mauleón, Ana %A Espinosa, Ana %A Ortega, Gemma %A Sanabria, Ángela %A Pérez, Alba %A Alarcón, Emilio %A González-Pérez, Antonio %A Marquié, Marta %A Valero, Sergi %A Tárraga, Lluís %A Ruiz, Agustin %A Boada, Merce %K Aged %K Aged, 80 and over %K Betacoronavirus %K Coronavirus Infections %K COVID-19 %K Dementia %K Female %K Follow-Up Studies %K Holistic Health %K Humans %K Male %K Pandemics %K Patient-Centered Care %K Pneumonia, Viral %K SARS-CoV-2 %K Spain %K Telemedicine %X

BACKGROUND: Fundació ACE is a non-profit organization providing care based on a holistic model to persons with cognitive disorders and their families for 25 years in Barcelona, Spain. Delivering care to this vulnerable population amidst the COVID-19 pandemic has represented a major challenge to our institution.

OBJECTIVE: To share our experience in adapting our model of care to the new situation to ensure continuity of care.

METHODS: We detail the sequence of events and the actions taken within Fundació ACE to swiftly adapt our face-to-face model of care to one based on telemedicine consultations. We characterize individuals under follow-up by the Memory Unit from 2017 to 2019 and compare the number of weekly visits in 2020 performed before and after the lockdown was imposed.

RESULTS: The total number of individuals being actively followed by Fundació ACE Memory Unit grew from 6,928 in 2017 to 8,147 in 2019. Among those newly diagnosed in 2019, most patients had mild cognitive impairment or mild dementia (42% and 25%, respectively). Weekly visits dropped by 60% following the suspension of face-to-face activity. However, by April 24 we were able to perform 78% of the visits we averaged in the weeks before confinement began.

DISCUSSION: We have shown that Fundació ACE model of care has been able to successfully adapt to a health and social critical situation as COVID-19 pandemic. Overall, we were able to guarantee the continuity of care while preserving the safety of patients, families, and professionals. We also seized the opportunity to improve our model of care.

%B J Alzheimers Dis %V 76 %P 33-40 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32538856?dopt=Abstract %R 10.3233/JAD-200547 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology. %A Shi, Liu %A Winchester, Laura M %A Liu, Benjamine Y %A Killick, Richard %A Ribe, Elena M %A Westwood, Sarah %A Baird, Alison L %A Buckley, Noel J %A Hong, Shengjun %A Dobricic, Valerija %A Kilpert, Fabian %A Franke, Andre %A Kiddle, Steven %A Sattlecker, Martina %A Dobson, Richard %A Cuadrado, Antonio %A Hye, Abdul %A Ashton, Nicholas J %A Morgan, Angharad R %A Bos, Isabelle %A Vos, Stephanie J B %A Ten Kate, Mara %A Scheltens, Philip %A Vandenberghe, Rik %A Gabel, Silvy %A Meersmans, Karen %A Engelborghs, Sebastiaan %A De Roeck, Ellen E %A Sleegers, Kristel %A Frisoni, Giovanni B %A Blin, Olivier %A Richardson, Jill C %A Bordet, Régis %A Molinuevo, José L %A Rami, Lorena %A Wallin, Anders %A Kettunen, Petronella %A Tsolaki, Magda %A Verhey, Frans %A Lleo, Alberto %A Alcolea, Daniel %A Popp, Julius %A Peyratout, Gwendoline %A Martínez-Lage, Pablo %A Tainta, Mikel %A Johannsen, Peter %A Teunissen, Charlotte E %A Freund-Levi, Yvonne %A Frölich, Lutz %A Legido-Quigley, Cristina %A Barkhof, Frederik %A Blennow, Kaj %A Rasmussen, Katrine Laura %A Nordestgaard, Børge Grønne %A Frikke-Schmidt, Ruth %A Nielsen, Sune Fallgaard %A Soininen, Hilkka %A Vellas, Bruno %A Kloszewska, Iwona %A Mecocci, Patrizia %A Zetterberg, Henrik %A Morgan, B Paul %A Streffer, Johannes %A Visser, Pieter Jelle %A Bertram, Lars %A Nevado-Holgado, Alejo J %A Lovestone, Simon %X

BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.

OBJECTIVE: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.

METHODS: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).

RESULTS: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.

CONCLUSIONS: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.

%B J Alzheimers Dis %V 77 %P 1353-1368 %8 2020 Sep 29 %G eng %N 3 %R 10.3233/JAD-200208 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Dyadic Group Exercises for Persons with Memory Deficits and Care Partners: Mixed-Method Findings from the Paired Preventing Loss of Independence through Exercise (PLIÉ) Randomized Trial. %A Mehling, E Wolf %A Scott, M Travis %A Duffy, James %A Whitmer, A Rachel %A Chesney, A Margaret %A Boscardin, W John %A Barnes, E Deborah %X

BACKGROUND: Non-pharmacological therapies for persons with dementia (PWD) are needed.

OBJECTIVE: To develop and test the Paired Preventing Loss of Independence through Exercise (PLIÉ) program, an integrative group movement program for PWD and care partners (CPs).

METHODS: Participants were randomized to immediate or delayed start to Paired PLIÉ in community-based classes (1 hour, 2 days/week, 12 weeks, 3 home visits). Co-primary outcomes included standard measures of cognition, physical function,and quality of life (PWD) and caregiver burden (CPs) assessed by blinded assessors, analyzed using linear mixed models to calculate effect sizes for outcome changes during Paired PLIÉ, controlling for randomization group. Anonymous satisfaction surveys included satisfaction ratings and thematic analysis of open-ended responses.

RESULTS: Thirty dyads enrolled, 24 (80%) completed. PWD (mean age 80; 55% female) experienced significant improvement in self-rated quality of life (Effect Size+0.23; p = 0.016) when participating in Paired PLIÉ, while CPs experienced a non-significant increase in burden (-0.23, p = 0.079). Changes in physical and cognitive function in PWD were not significant. All CPs returning the satisfaction survey (n = 20) reported being moderately-to-highly satisfied with the program. Thematic analyses identified physical (e.g., sit-to-stand, more energy), emotional (enjoyment), and social benefits (peer-to-peer interaction) for PWD and CPs; challenges were primarily related to getting to the in-person classes.

CONCLUSION: Paired PLIÉ is a promising integrative group movement program that warrants further study. It is feasible and may improve self-rated quality of life in PWD. Although CPs may experience increased burden due to logistical challenges, most reported high satisfaction and physical, emotional, and social benefits.

%B J Alzheimers Dis %V 78 %P 1689-1706 %8 2020 Dec 08 %G eng %N 4 %R 10.3233/JAD-200713 %0 Journal Article %J J Alzheimers Dis %D 2020 %T The Effects of Confinement on Neuropsychiatric Symptoms in Alzheimer's Disease During the COVID-19 Crisis. %A Boutoleau-Bretonnière, Claire %A Pouclet-Courtemanche, Hélene %A Gillet, Aurelie %A Bernard, Amelie %A Deruet, Anne Laure %A Gouraud, Ines %A Mazoue, Aurelien %A Lamy, Estelle %A Rocher, Laetitia %A Kapogiannis, Dimitrios %A El Haj, Mohamad %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Betacoronavirus %K Cohort Studies %K Coronavirus Infections %K COVID-19 %K Female %K Humans %K Male %K Mental Disorders %K Mental Status and Dementia Tests %K Middle Aged %K Pandemics %K Pneumonia, Viral %K Quarantine %K SARS-CoV-2 %X

BACKGROUND: Neuropsychiatric symptoms, such as depression, anxiety, apathy, agitation, and hallucinations, are frequent in Alzheimer's disease (AD) and their prevalence tends to increase with external stressors.

OBJECTIVE: We offer the first investigation of the effects of confinement during the COVID-19 crisis on neuropsychiatric symptoms in patients with AD.

METHODS: We contacted caregivers of 38 patients with AD who were confined to their homes for nearly two months and asked them to report whether patients experienced any change in neuropsychiatric symptoms during, compared to before, the confinement and rate its severity and impact on themselves using the Neuropsychiatric Inventory-Questionnaire.

RESULTS: Among the 38 patients, only 10 demonstrated neuropsychiatric changes during the confinement. Cognitive function of these 10 patients, assessed with the Mini-Mental State Examination, was worse than that of patients who did not demonstrate neuropsychiatric changes. Interestingly, among the 10 patients with neuropsychiatric changes, the duration of confinement significantly correlated with the severity of symptoms as well as with their caregivers' distress.

DISCUSSION: The confinement seems to impact neuropsychiatric symptomatology in AD patients with low baseline cognitive function.

%B J Alzheimers Dis %V 76 %P 41-47 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32568211?dopt=Abstract %R 10.3233/JAD-200604 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Environmental Nanoparticles, SARS-CoV-2 Brain Involvement, and Potential Acceleration of Alzheimer's and Parkinson's Diseases in Young Urbanites Exposed to Air Pollution. %A Calderón-Garcidueñas, Lilian %A Torres-Jardón, Ricardo %A Franco-Lira, Maricela %A Kulesza, Randy %A González-Maciel, Angelica %A Reynoso-Robles, Rafael %A Brito-Aguilar, Rafael %A García-Arreola, Berenice %A Revueltas-Ficachi, Paula %A Barrera-Velázquez, Juana Adriana %A García-Alonso, Griselda %A García-Rojas, Edgar %A Mukherjee, Partha S %A Delgado-Chávez, Ricardo %K Adult %K Air Pollution %K Alzheimer Disease %K Brain Diseases %K Coronavirus Infections %K COVID-19 %K Disease Progression %K Environmental Pollutants %K Humans %K Middle Aged %K Nanoparticles %K Pandemics %K Parkinson Disease %K Pneumonia, Viral %K Suicide %K Urban Population %X

Alzheimer's and Parkinson's diseases (AD, PD) have a pediatric and young adult onset in Metropolitan Mexico City (MMC). The SARS-CoV-2 neurotropic RNA virus is triggering neurological complications and deep concern regarding acceleration of neuroinflammatory and neurodegenerative processes already in progress. This review, based on our MMC experience, will discuss two major issues: 1) why residents chronically exposed to air pollution are likely to be more susceptible to SARS-CoV-2 systemic and brain effects and 2) why young people with AD and PD already in progress will accelerate neurodegenerative processes. Secondary mental consequences of social distancing and isolation, fear, financial insecurity, violence, poor health support, and lack of understanding of the complex crisis are expected in MMC residents infected or free of SARS-CoV-2. MMC residents with pre-SARS-CoV-2 accumulation of misfolded proteins diagnostic of AD and PD and metal-rich, magnetic nanoparticles damaging key neural organelles are an ideal host for neurotropic SARS-CoV-2 RNA virus invading the body through the same portals damaged by nanoparticles: nasal olfactory epithelium, the gastrointestinal tract, and the alveolar-capillary portal. We urgently need MMC multicenter retrospective-prospective neurological and psychiatric population follow-up and intervention strategies in place in case of acceleration of neurodegenerative processes, increased risk of suicide, and mental disease worsening. Identification of vulnerable populations and continuous effort to lower air pollution ought to be critical steps.

%B J Alzheimers Dis %V 78 %P 479-503 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32955466?dopt=Abstract %R 10.3233/JAD-200891 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Epilepsy in Neurodegenerative Dementias: A Clinical, Epidemiological, and EEG Study. %A Arnaldi, Dario %A Donniaquio, Andrea %A Mattioli, Pietro %A Massa, Federico %A Grazzini, Matteo %A Meli, Riccardo %A Filippi, Laura %A Grisanti, Stefano %A Famá, Francesco %A Terzaghi, Michele %A Girtler, Nicola %A Brugnolo, Andrea %A Doglione, Elisa %A Pardini, Matteo %A Villani, Flavio %A Nobili, Flavio %X

BACKGROUND: Seizures are common in patients with dementia but precise epidemiologic data of epilepsy in neurodegenerative dementia is lacking.

OBJECTIVE: The first aim of the study was to investigate prevalence and clinical characteristics of epilepsy in a large cohort of patients with neurodegenerative dementias. Subsequently, we explored clinical, neuropsychological, and quantitative electroencephalogram (qEEG) data of Alzheimer's disease (AD) patients with epilepsy (AD-EPI) as compared to AD patients without epilepsy (AD-CTR).

METHODS: We retrospectively evaluated consecutive patients with a diagnosis of a neurodegenerative dementia and a clinically diagnosed epilepsy that required antiepileptic drugs (AED). All patients underwent baseline comprehensive neuropsychological assessment. A follow-up of at least one year was requested to confirm the dementia diagnosis. In AD patients, qEEG power band analysis was performed. AD-CTR and AD-EPI patients were matched for age, Mini-Mental State Examination score, and gender.

RESULTS: Thirty-eight out of 2,054 neurodegenerative dementia patients had epilepsy requiring AED. The prevalence of epilepsy was 1.82% for AD, 1.28% for the behavioral variant of frontotemporal dementia (bvFTD), 2.47% for dementia with Lewy bodies (DLB), and 12% for primary progressive aphasia. Epilepsy were more drug-responsive in AD than in non-AD dementias. Finally, no significant differences were found in neuropsychological and qEEG data between AD-EPI and AD-CTR patients.

CONCLUSION: In our cohort, AD, FTD, and DLB dementias have similar prevalence of epilepsy, even if AD patients were more responsive to AED. Moreover, AD-EPI patients did not have significant clinical, neuropsychological qEEG differences compared with AD-CTR patients.

%B J Alzheimers Dis %V 74 %P 865-874 %8 2020 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/32116260?dopt=Abstract %R 10.3233/JAD-191315 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Examining Cognitive Decline Across Black and White Participants in the Harvard Aging Brain Study. %A Amariglio, Rebecca E %A Buckley, Rachel F %A Rabin, Jennifer S %A Papp, Kathryn V %A Quiroz, Yakeel T %A Mormino, Elizabeth C %A Sparks, Kathryn P %A Johnson, Keith A %A Rentz, Dorene M %A Sperling, Reisa A %X

BACKGROUND: Black Americans are approximately twice as likely to develop dementia as compared to White Americans and the magnitude of this disparity is often attributed to a variety of factors that include psychosocial and vascular risk factors. However, less is known about the potential contribution of Alzheimer's disease pathological differences.

OBJECTIVE: To examine potential differences incross-sectional and longitudinal cognitive performance in black and white participants who were clinically normal at baseline.

METHODS: 296 participants (48 African-American/black participants) underwent MRI and amyloid PET at baseline. Linear mixed models were used to examine the main effects of race, years of education, reading ability, Framingham Heart Study cardiovascular risk score (FHS-CVD), white matter hyperintensities (WMH), and amyloid (Aβ) burden on the Preclinical Alzheimer Cognitive Composite-5 (PACC5).

RESULTS: Lower levels of educationalattainment and reading ability were found for blacks compared to whites. By contrast, no differences in FHS-CVD, WMH, or Aβ were found by racial group. Baseline differences in PACC5 score were attenuated after adjusting for educationalfactors, vascular factors, and Aβ, but remained lower for blacks compared to whites (β= -0.24, p = 0.014). Further, blacks demonstrated a faster rate of PACC5 decline longitudinally compared to whites (β  = -0.055, p = 0.025) after adjusting for covariates.

CONCLUSION: Accounting for educationalfactors, vascular factors, and Aβ burden diminished, but did not eliminate, racial differences in PACC5 performance longitudinally. Understanding potential differences in longitudinal cognitive outcomes by race may be important for upcoming secondary prevention trials.

%B J Alzheimers Dis %V 75 %P 1437-1446 %8 2020 Jun 16 %G eng %N 4 %R 10.3233/JAD-191291 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Exploration of Plasma Lipids in Mild Cognitive Impairment due to Alzheimer's Disease. %A Bergland, Anne Katrine %A Proitsi, Petroula %A Kirsebom, Bjørn-Eivind %A Soennesyn, Hogne %A Hye, Abdul %A Larsen, Alf Inge %A Xu, Jin %A Legido-Quigley, Cristina %A Rajendran, Lawrence %A Fladby, Tormod %A Aarsland, Dag %X

BACKGROUND: Lipids have important structural roles in cell membranes and changes to these membrane lipids may influence β- and γ-secretase activities and thus contribute to Alzheimer's disease (AD) pathology.

OBJECTIVE: To explore baseline plasma lipid profiling in participants with mild cognitive impairment (MCI) with and without AD pathology.

METHODS: We analyzed 261 plasma lipid profiles using reversed phase chromatography mass spectrometry in cerebrospinal fluid amyloid positive (Aβ+) or negative (Aβ-) participants with MCI as compared to controls. Additionally, we analyzed the potential associations of plasma lipid profiles with performance on neuropsychological tests at baseline and after two years.

RESULTS: Sphingomyelin (SM) concentrations, particularly, SM(d43:2), were lower in MCI Aβ+ individuals compared to controls. Further, SM(d43:2) was also nominally reduced in MCI Aβ+ individuals compared to MCI Aβ-. No plasma lipids were associated with performance on neuropsychological tests at baseline or between the two time points after correction for multiple testing.

CONCLUSION: Reduced plasma concentrations of SM were associated with AD.

%B J Alzheimers Dis %V 77 %P 1117-1127 %8 2020 Sep 29 %G eng %N 3 %R 10.3233/JAD-200441 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Falls Associate with Neurodegenerative Changes in ATN Framework of Alzheimer's Disease. %A Keleman, Audrey %A Wisch, Julie K %A Bollinger, Rebecca M %A Grant, Elizabeth A %A Benzinger, Tammie L %A Morris, John C %A Ances, Beau M %A Stark, Susan L %X

BACKGROUND: Behavioral markers for Alzheimer's disease (AD) are not included within the widely used amyloid-tau-neurodegeneration framework.

OBJECTIVE: To determine when falls occur among cognitively normal (CN) individuals with and without preclinical AD.

METHODS: This cross-sectional study recorded falls among CN participants (n = 83) over a 1-year period. Tailored calendar journals recorded falls. Biomarkers including amyloid positron emission tomography (PET) and structural and functional magnetic resonance imaging were acquired within 2 years of fall evaluations. CN participants were dichotomized by amyloid PET (using standard cutoffs). Differences in amyloid accumulation, global resting state functional connectivity (rs-fc) intra-network signature, and hippocampal volume were compared between individuals who did and did not fall using Wilcoxon rank sum tests. Among preclinical AD participants (amyloid-positive), the partial correlation between amyloid accumulation and global rs-fc intra-network signature was compared for those who did and did not fall.

RESULTS: Participants who fell had smaller hippocampal volumes (p = 0.04). Among preclinical AD participants, those who fell had a negative correlation between amyloid uptake and global rs-fc intra-network signature (R = -0.75, p = 0.012). A trend level positive correlation was observed between amyloid uptake and global rs-fc intra-network signature (R = 0.70, p = 0.081) for preclinical AD participants who did not fall.

CONCLUSION: Falls in CN older adults correlate with neurodegeneration biomarkers. Participants without falls had lower amyloid deposition and preserved global rs-fc intra-network signature. Falls most strongly correlated with presence of amyloid and loss of brain connectivity and occurred in later stages of preclinical AD.

%B J Alzheimers Dis %V 77 %P 843-853 %8 2020 Sep 15 %G eng %N 2 %R 10.3233/JAD-200192 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Fascicle- and Glucose-Specific Deterioration in White Matter Energy Supply in Alzheimer's Disease. %A Roy, Maggie %A Rheault, François %A Croteau, Etienne %A Castellano, Christian-Alexandre %A Fortier, Mélanie %A St-Pierre, Valérie %A Houde, Jean-Christophe %A Turcotte, Éric E %A Bocti, Christian %A Fülöp, Tamás %A Cunnane, Stephen C %A Descoteaux, Maxime %X

BACKGROUND: White matter energy supply to oligodendrocytes and the axonal compartment is crucial for normal axonal function. Although gray matter glucose hypometabolism is extensively reported in Alzheimer's disease (AD), glucose and ketones, the brain's two main fuels, are rarely quantified in white matter in AD.

OBJECTIVE: Using adual-tracer PET method combined with a fascicle-specific diffusion MRI approach, robust to white matter hyper intensities and crossing fibers, we aimed to quantify both glucose and ketone metabolismin specific white matter fascicles associated with mild cognitive impairment (MCI; n = 51) and AD (n = 13) compared to cognitively healthy age-matched controls (Controls; n = 14).

METHODS: Eight white matter fascicles of the limbic lobe and corpus callosum were extracted and analyzed into fascicle profiles of five sections. Glucose (18F-fluorodeoxyglucose) and ketone (11C-acetoacetate) uptake rates, corrected for partial volume effect, were calculated along each fascicle.

RESULTS: The only fascicle with significantly lower glucose uptake in AD compared to Controls was the left posterior cingulate segment of the cingulum (-22%; p = 0.016). Non-significantly lower glucose uptake in this fascicle was also observed in MCI. In contrast to glucose, ketone uptake was either unchanged or higher in sections of the fornix and parahippocampal segment of the cingulum in AD.

CONCLUSION: To our knowledge, this is the first report of brain fuel uptake calculated along white matter fascicles in humans. Energetic deterioration in white matter in AD appears to be specific to glucose and occurs first in the posterior cingulum.

%B J Alzheimers Dis %V 76 %P 863-881 %8 2020 Aug 04 %G eng %N 3 %R 10.3233/JAD-200213 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Gait Disturbances are Associated with Increased Cognitive Impairment and Cerebrospinal Fluid Tau Levels in a Memory Clinic Cohort. %A Muurling, Marijn %A Rhodius-Meester, Hanneke F M %A Pärkkä, Juha %A van Gils, Mark %A Frederiksen, Kristian S %A Bruun, Marie %A Hasselbalch, Steen G %A Soininen, Hilkka %A Herukka, Sanna-Kaisa %A Hallikainen, Merja %A Teunissen, Charlotte E %A Visser, Pieter Jelle %A Scheltens, Philip %A van der Flier, Wiesje M %A Mattila, Jussi %A Lötjönen, Jyrki %A de Boer, Casper %X

BACKGROUND: Gait analysis with accelerometers is a relatively inexpensive and easy to use method to potentially support clinical diagnoses of Alzheimer's disease and other dementias. It is not clear, however, which gait features are most informative and how these measures relate to Alzheimer's disease pathology.

OBJECTIVE: In this study, we tested if calculated features of gait 1) differ between cognitively normal subjects (CN), mild cognitive impairment (MCI) patients, and dementia patients, 2) are correlated with cerebrospinal fluid (CSF) biomarkers related to Alzheimer's disease, and 3) predict cognitive decline.

METHODS: Gait was measured using tri-axial accelerometers attached to the fifth lumbar vertebra (L5) in 58 CN, 58 MCI, and 26 dementia participants, while performing a walk and dual task. Ten gait features were calculated from the vertical L5 accelerations, following principal component analysis clustered in four domains, namely pace, rhythm, time variability, and length variability. Cognitive decline over time was measured using MMSE, and CSF biomarkers were available in a sub-group.

RESULTS: Linear mixed models showed that dementia patients had lower pace scores than MCI patients and CN subjects (p < 0.05). In addition, we found associations between the rhythm domain and CSF-tau, especially in the dual task. Gait was not associated with CSF Aβ42 levels and cognitive decline over time as measured with the MMSE.

CONCLUSION: These findings suggest that gait-particularly measures related to pace and rhythm-are altered in dementia and have a direct link with measures of neurodegeneration.

%B J Alzheimers Dis %V 76 %P 1061-1070 %8 2020 Aug 04 %G eng %N 3 %R 10.3233/JAD-200225 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Gene Ontology Curation of Neuroinflammation Biology Improves the Interpretation of Alzheimer's Disease Gene Expression Data. %A Kramarz, Barbara %A Huntley, Rachael P %A Rodríguez-López, Milagros %A Roncaglia, Paola %A Saverimuttu, Shirin C C %A Parkinson, Helen %A Bandopadhyay, Rina %A Martin, Maria-Jesus %A Orchard, Sandra %A Hooper, Nigel M %A Brough, David %A Lovering, Ruth C %X

BACKGROUND: Gene Ontology (GO) is a major bioinformatic resource used for analysis of large biomedical datasets, for example from genome-wide association studies, applied universally across biological fields, including Alzheimer's disease (AD) research.

OBJECTIVE: We aim to demonstrate the applicability of GO for interpretation of AD datasets to improve the understanding of the underlying molecular disease mechanisms, including the involvement of inflammatory pathways and dysregulated microRNAs (miRs).

METHODS: We have undertaken a systematic full article GO annotation approach focused on microglial proteins implicated in AD and the miRs regulating their expression. PANTHER was used for enrichment analysis of previously published AD data. Cytoscape was used for visualizing and analyzing miR-target interactions captured from published experimental evidence.

RESULTS: We contributed 3,084 new annotations for 494 entities, i.e., on average six new annotations per entity. This included a total of 1,352 annotations for 40 prioritized microglial proteins implicated in AD and 66 miRs regulating their expression, yielding an average of twelve annotations per prioritized entity. The updated GO resource was then used to re-analyze previously published data. The re-analysis showed novel processes associated with AD-related genes, not identified in the original study, such as 'gliogenesis', 'regulation of neuron projection development', or 'response to cytokine', demonstrating enhanced applicability of GO for neuroscience research.

CONCLUSIONS: This study highlights ongoing development of the neurobiological aspects of GO and demonstrates the value of biocuration activities in the area, thus helping to delineate the molecular bases of AD to aid the development of diagnostic tools and treatments.

%B J Alzheimers Dis %V 75 %P 1417-1435 %8 2020 %G eng %N 4 %R 10.3233/JAD-200207 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Heavy Metals Exposure and Alzheimer's Disease and Related Dementias. %A Bakulski, Kelly M %A Seo, Young Ah %A Hickman, Ruby C %A Brandt, Daniel %A Vadari, Harita S %A Hu, Howard %A Park, Sung Kyun %X

Alzheimer's disease and related dementias lack effective treatment or cures and are major public health challenges. Risk for Alzheimer's disease and related dementias is partially attributable to environmental factors. The heavy metals lead, cadmium, and manganese are widespread and persistent in our environments. Once persons are exposed to these metals, they are adept at entering cells and reaching the brain. Lead and cadmium are associated with numerous health outcomes even at low levels of exposure. Although manganese is an essential metal, deficiency or environmental exposure or high levels of the metal can be toxic. In cell and animal model systems, lead, cadmium, and manganese are well documented neurotoxicants that contribute to canonical Alzheimer's disease pathologies. Adult human epidemiologic studies have consistently shown lead, cadmium, and manganese are associated with impaired cognitive function and cognitive decline. No longitudinal human epidemiology study has assessed lead or manganese exposure on Alzheimer's disease specifically though two studies have reported a link between cadmium and Alzheimer's disease mortality. More longitudinal epidemiologic studies with high-quality time course exposure data and incident cases of Alzheimer's disease and related dementias are warranted to confirm and estimate the proportion of risk attributable to these exposures. Given the widespread and global exposure to lead, cadmium, and manganese, even small increases in the risks of Alzheimer's disease and related dementias would have a major population impact on the burden on disease. This article reviews the experimental and epidemiologic literature of the associations between lead, cadmium, and manganese on Alzheimer's disease and related dementias and makes recommendations of critical areas of future investment.

%B J Alzheimers Dis %V 76 %P 1215-1242 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32651318?dopt=Abstract %R 10.3233/JAD-200282 %0 Journal Article %J J Alzheimers Dis %D 2020 %T An Immunomodulatory Therapeutic Vaccine Targeting Oligomeric Amyloid-β. %A Song, Ge %A Yang, Haiqiang %A Shen, Ning %A Pham, Phillip %A Brown, Breanna %A Lin, Xiaoyang %A Hong, Yuzhu %A Sinu, Paul %A Cai, Jianfeng %A Li, Xiaopeng %A Leon, Michael %A Gordon, Marcia %A Morgan, David %A Zhang, Sai %A Cao, Chuanhai %X

BACKGROUND: Aging is considered the most important risk factor for Alzheimer's disease (AD). Recent research supports the theory that immunotherapy targeting the "oligomeric" forms of amyloid-β (Aβ) may halt the progression of AD. However, previous clinical trial of the vaccine against Aβ, called AN1792, was suspended due to cases of meningoencephalitis in patients.

OBJECTIVE: To develop a peptide sensitized dendritic cells (DCs) vaccine that would target oligomer Aβ and prevent an autoimmune response.

METHODS: Double transgenic APPswe/PS1ΔE9 (Tg) and C57BL/6J control mice were used in this study. Cytokine expression profile detection, characterization of antisera, brain GSK-3β, LC3 expression, and spatial working memory testing before and post-vaccination were obtained.

RESULTS: Epitope prediction indicated that E22W42 could generate 13 new T cell epitopes which can strengthen immunity in aged subjects and silence several T cell epitopes of the wild type Aβ. The silenced T cell epitope could help avoid the autoimmune response that was seen in some patients of the AN-1792 vaccine. The E22W42 not only helped sensitize bone marrow-derived DCs for the development of an oligomeric Aβ-specific antibody, but also delayed memory impairment in the APP/PS1 mouse model. Most importantly, this E22W42 peptide will not alter the DC's natural immunomodulatory properties.

CONCLUSION: The E22W42 vaccine is possibly safer for patients with impaired immune systems. Since there is increasing evidence that oligomeric form of Aβ are the toxic species to neurons, the E22W42 antibody's specificity for these "oligomeric" Aβ species could provide the opportunity to produce some clinical benefits in AD subjects.

%B J Alzheimers Dis %V 77 %P 1639-1653 %8 2020 Oct 13 %G eng %N 4 %R 10.3233/JAD-200413 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Inflammation in Traumatic Brain Injury. %A Postolache, Teodor T %A Wadhawan, Abhishek %A Can, Adem %A Lowry, Christopher A %A Woodbury, Margaret %A Makkar, Hina %A Hoisington, Andrew J %A Scott, Alison J %A Potocki, Eileen %A Benros, Michael E %A Stiller, John W %X

There is an increasing evidence that inflammation contributes to clinical and functional outcomes in traumatic brain injury (TBI). Many successful target-engaging, lesion-reducing, symptom-alleviating, and function-improving interventions in animal models of TBI have failed to show efficacy in clinical trials. Timing and immunological context are paramount for the direction, quality, and intensity of immune responses to TBI and the resulting neuroanatomical, clinical, and functional course. We present components of the immune system implicated in TBI, potential immune targets, and target-engaging interventions. The main objective of our article is to point toward modifiable molecular and cellular mechanisms that may modify the outcomes in TBI, and contribute to increasing the translational value of interventions that have been identified in animal models of TBI.

%B J Alzheimers Dis %V 74 %P 1-28 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32176646?dopt=Abstract %R 10.3233/JAD-191150 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Levels of Retinal Amyloid-β Correlate with Levels of Retinal IAPP and Hippocampal Amyloid-β in Neuropathologically Evaluated Individuals. %A Schultz, Nina %A Byman, Elin %A Wennström, Malin %X

BACKGROUND: Previous studies have used immunohistology to demonstrate Alzheimer's disease (AD) characteristic accumulation of amyloid-β (Aβ) in the retina of AD patients, a finding indicating retina examination as a potential diagnostic tool for AD pathology.

OBJECTIVE: To further explore this idea by investigating whether levels of Aβ42 and Aβ40 in retina are associated with corresponding levels in hippocampus, neuropathological assessments, apolipoprotein E (APOE) genotype, and levels of islet amyloid polypeptide (IAPP).

METHODS: Levels of high molecular weight (HMW) Aβ42, Aβ40, and IAPP in ultra-centrifuged homogenates of retina and hippocampus from patients with AD, multiple sclerosis, AD with Lewy bodies, and non-demented controls were analyzed using Mesoscale Discovery electrochemiluminescence technology employing immunoassay and enzyme-linked immunosorbent assay.

RESULTS: Higher levels of retinal and hippocampal Aβ42-HMW, Aβ40-HMW, and IAPP-HMW were found in individuals with high neuropathological scores of Aβ plaques and in individuals carrying the APOEɛ4 allele. The retinal levels of Aβ42-HMW and Aβ40-HMW correlated with corresponding levels in hippocampus as well as with neurofibrillary tangles (NFT) and Aβ scores. Retinal IAPP-HMW correlated with retinal levels of Aβ42-HMW and with NFT and Aβ scores.

CONCLUSION: These results show that different isoforms of Aβ can be detected in the human retina and moreover support the growing number of studies indicating that AD-related pathological changes occurring in the brain could be reflected in the retina.

%B J Alzheimers Dis %V 73 %P 1201-1209 %8 2020 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/31884473?dopt=Abstract %R 10.3233/JAD-190868 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Loss of Functional Dentition is Associated with Cognitive Impairment. %A Han, Ji Hyun %A Lee, Hyo-Jung %A Han, Ji Won %A Suh, Seung Wan %A Lee, Ju Ri %A Byun, Seonjeong %A Kim, Keun Suh %A Kim, Sung Yeol %A Lee, Jung-Tae %A Yoo, Eunha %A Chang, Na-Hee %A Kim, Tae Hui %A Kim, Ki Woong %X

BACKGROUND: Although tooth loss is known to increase the risk of cognitive impairment and dementia, few studies have investigated the association between functional teeth including rehabilitated lost teeth and cognitive functionObjective:We investigated the associations of the numbers of functional teeth and functional occlusal units with cognitive impairment and cognitive function in late life.

METHODS: The current study was conducted as a part of the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD), a community-based elderly cohort study. We analyzed 411 participants who have agreed with the additional dental exam. Geriatric psychiatrists and neuropsychologists administered the Consortium to Establish a Registry for Alzheimer's disease Assessment Packet Clinical and Neuropsychological Assessment Battery to all participants, and dentists examined their dental status.

RESULTS: Higher number of functional teeth (OR = 0.955, 95% CI = 0.914-0.997, p = 0.037) and higher number of functional occlusal units (OR = 0.900, 95% CI = 0.813-0.996, p = 0.042) were associated with lower odds of cognitive impairment. When we analyzed these relationships separated by the location of teeth, only the numbers of functional teeth (OR = 0.566, 95% CI = 0.373-0.857, p = 0.007) and functional occlusal units (OR = 0.399, 95% CI = 0.213-0.748, p = 0.004) in the premolar area were associated with lower odds of cognitive impairment.

CONCLUSION: Loss of functional teeth and functional occlusal units (especially in the premolar region) were associated with increased cognitive impairment.

%B J Alzheimers Dis %V 73 %P 1313-1320 %8 2020 Feb 18 %G eng %N 4 %R 10.3233/JAD-190971 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Morphometric Analysis of Hippocampal and Neocortical Pyramidal Neurons in a Mouse Model of Late Onset Alzheimer's Disease. %A Mehder, Rasha H %A Bennett, Brian M %A Andrew, R David %X

The study of late-onset (sporadic) Alzheimer's disease (LOAD) has lacked animal models where impairments develop with aging. Oxidative stress promotes LOAD, so we have developed an oxidative stress-based model of age-related cognitive impairment based on gene deletion of aldehyde dehydrogenase 2 (ALDH2). This enzyme is important for the detoxification of endogenous aldehydes arising from lipid peroxidation. Compared to wildtype (WT) mice, the knockout (KO) mice exhibit a progressive decline in recognition and spatial memory and AD-like pathologies. Here we performed morphometric analyses in the dorsal and ventral hippocampal CA1 regions (dCA1 and vCA1) as well as in overlying primary sensory cortex to determine if altered neuronal structure can help account for the cognitive impairment in 12-month old KO mice. Dendritic morphology was quantitatively analyzed following Golgi-Cox staining using 9 WT mice (108 neurons) and 15 KO mice (180 neurons). Four pyramidal neurons were traced per mouse in each region, followed by branched structured analysis and Sholl analysis. Compared to WT controls, the morphology and complexity of dCA1 pyramidal neurons from KOs showed significant reductions in apical and basal dendritic length, dendrite intersections, ends, and nodes. As well, spine density along dorsal CA1 apical dendrites was significantly lower in KO versus WT. In contrast, pyramidal arborization in the vCA1 and primary sensory cortex were only minimally reduced in KO versus WT mice. These data suggest a region-specific vulnerability to oxidative stress-induced damage and/or a major and specific reduction in synaptic input to the pyramidal neurons of the dorsal hippocampus. This is in keeping with studies showing that lesions to the dorsal hippocampus impair primarily cognitive memory whereas ventral hippocampal lesions cause deficits in stress, emotion, and affect.

%B J Alzheimers Dis %V 74 %P 1069-1083 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32144984?dopt=Abstract %R 10.3233/JAD-191067 %0 Journal Article %J J Alzheimers Dis %D 2020 %T A Narrative Review of Alzheimer's Disease Stigma. %A Rosin, Eric R %A Blasco, Drew %A Pilozzi, Alexander R %A Yang, Lawrence H %A Huang, Xudong %X

As the most common form of senile dementia, Alzheimer's disease (AD) is accompanied by a great deal of uncertainty which can lead to fear and stigma for those identified with this devastating disease. As the AD definition evolves from a syndromal to a biological construct, and early diagnoses becomes more commonplace, more confusion and stigma may result. We conducted a narrative review of the literature on AD stigma to consolidate information on this body of research. From the perspective of several stigma theories, we identified relevant studies to inform our understanding of the way in which implementation of the new framework for a biological based AD diagnosis may have resulted in new and emerging stigma. Herein, we discuss the emergence of new AD stigma as our understanding of the definition of the disease changes. We further propose recommendations for future research to reduce the stigma associated with AD.

%B J Alzheimers Dis %V 78 %P 515-528 %8 2020 Nov 10 %G eng %N 2 %R 10.3233/JAD-200932 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Neuropathologic Correlates of White Matter Hyperintensities in a Community-Based Cohort of Older Adults. %A Arfanakis, Konstantinos %A Evia, Arnold M %A Leurgans, Sue E %A Cardoso, Luis F C %A Kulkarni, Arman %A Alqam, Nabil %A Lopes, Lucas F %A Vieira, Diego %A Bennett, David A %A Schneider, Julie A %X

BACKGROUND: The association of white matter hyperintensities (WMH) with age-related vascular and neurodegenerative pathologies remains incompletely understood.

OBJECTIVE: The objective of this work was to elucidate the neuropathologic correlates of WMH in a large community-based cohort of older adults.

METHODS: Cerebral hemispheres from 603 community-based older adults were imaged with MRI ex vivo. All participants underwent annual clinical evaluation, cognitive assessment, and neuropathologic examination. WMH burden was assessed using a modified Fazekas rating scale. Multiple ordinal logistic regression was used to test the association of WMH burden with an array of age-related neuropathologies, adjusting for demographics. Mixed effects models of cognition controlling for neuropathologies and demographics were used to determine whether WMH burden contributes to cognitive decline beyond measured pathologies.

RESULTS: WMH burden in the whole group was associated with both vascular and Alzheimer's disease (AD) pathologies: arteriolosclerosis (p < 10-4), gross (p < 10-4), and microscopic infarcts (p = 0.04), and amyloid-β plaques (p = 0.028). In non-demented participants (mild or no cognitive impairment) (N = 332), WMH burden was related to gross infarcts (p = 10-4) and arteriolosclerosis (p < 10-4), but not to AD pathology. Similarly, in those with no cognitive impairment (N = 178), WMH burden was related to gross infarcts (p = 8×10-4) and arteriolosclerosis (p = 0.014). WMH burden was associated with faster decline in perceptual speed in both the whole (p = 0.038) and non-demented (p = 0.006) groups.

CONCLUSION: WMH burden has independent associations with vascular pathologies in older adults regardless of clinical status, and with AD pathology later in the progression of AD. Moreover, WMH burden may reflect additional tissue injury not captured with traditional neuropathologic indices.

%B J Alzheimers Dis %V 73 %P 333-345 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31771057?dopt=Abstract %R 10.3233/JAD-190687 %0 Journal Article %J J Alzheimers Dis %D 2020 %T New BACE1 Chimeric Peptide Inhibitors Selectively Prevent AβPPβ Cleavage Decreasing Amyloid-β Production and Accumulation in Alzheimer's Disease Models. %A Resende, Rosa %A Ferreira-Marques, Marisa %A Moreira, Patrícia %A Coimbra, Judite R M %A Baptista, Salete J %A Isidoro, Ciro %A Salvador, Jorge A R %A Dinis, Teresa C P %A Pereira, Cláudia F %A Santos, Armanda E %X

BACKGROUND: A disease-modifying therapy for Alzheimer's disease (AD) is still an unmet clinical need. The formation of amyloid-β (Aβ) requires the initial cleavage of the amyloid-β protein precursor (AβPP) by BACE1 (beta-site AβPP cleaving enzyme 1), which is a prime therapeutic target for AD.

OBJECTIVE: We aimed to design and develop a selective BACE1 inhibitor suitable to AD treatment.

METHODS: The new BACE1 inhibitors consist on a chimeric peptide including a sequence related to the human Swedish mutant form of AβPP (AβPPswe) conjugated with the TAT carrier that facilitates cell membrane permeation and the crossing of the blood-brain barrier. Additionally to the chimeric peptide in the L-form, we developed a D-retro in verso chimeric peptide. The latter strategy, never used with BACE1 inhibitors, is considered to favor a significantly higher half-life and lower immunogenicity.

RESULTS: We found that both chimeric peptides inhibit recombinant BACE1 activity and decrease Aβ40/42 production in Neuro-2a (N2A) cells expressing AβPPswe without inducing cytotoxicity. The intraperitoneal administration of these peptides to 3xTg-AD mice decreased plasma and brain Aβ40/42 levels, as well as brain soluble AβPPβ production. Also, a reduction of insoluble Aβ was observed in the brain after chronic treatment. Noteworthy, the chimeric peptides selectively inhibited the AβPPβ cleavage relatively to the proteolysis of other BACE1 substrates such as close homologue of L1 (CHL1) and seizure-related gene 6 (SEZ6).

CONCLUSIONS: Overall these new BACE1 chimeric peptideshold promising potential as a selective disease-modifying therapy for AD.

%B J Alzheimers Dis %V 76 %P 1317-1337 %8 2020 Aug 18 %G eng %N 4 %R 10.3233/JAD-200381 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Plasma High Density Lipoprotein Small Subclass is Reduced in Alzheimer's Disease Patients and Correlates with Cognitive Performance. %A Pedrini, Steve %A Hone, Eugene %A Gupta, Veer B %A James, Ian %A Teimouri, Elham %A Bush, Ashley I %A Rowe, Christopher C %A Villemagne, Victor L %A Ames, David %A Masters, Colin L %A Rainey-Smith, Stephanie %A Verdile, Giuseppe %A Sohrabi, Hamid R %A Raida, Manfred R %A Wenk, Markus R %A Taddei, Kevin %A Chatterjee, Pratishtha %A Martins, Ian %A Laws, Simon M %A Martins, Ralph N %X

BACKGROUND: The link between cholesterol and Alzheimer's disease (AD) has received much attention, as evidence suggests high levels of cholesterol might be an AD risk factor. The carriage of cholesterol and lipids through the body is mediated via lipoproteins, some of which, particularly apolipoprotein E (ApoE), are intimately linked with AD. In humans, high density lipoprotein (HDL) is regarded as a "good" lipid complex due to its ability to enable clearance of excess cholesterol via 'cholesterol reverse transport', although its activities in the pathogenesis of AD are poorly understood. There are several subclasses of HDL; these range from the newly formed small HDL, to much larger HDL.

OBJECTIVE: We examined the major subclasses of HDL in healthy controls, mild cognitively impaired, and AD patients who were not taking statins to determine whether there were HDL profile differences between the groups, and whether HDL subclass levels correlated with plasma amyloid-β (Aβ) levels or brain Aβ deposition.

METHODS: Samples from AIBL cohort were used in this study. HDL subclass levels were assessed by Lipoprint while Aβ1-42 levels were assessed by ELISA. Brain Aβ deposition was assessed by PET scan. Statistical analysis was performed using parametric and non-parametric tests.

RESULTS: We found that small HDL subclass is reduced in AD patients and it correlates with cognitive performance while plasma Aβ concentrations do not correlate with lipid profile or HDL subfraction levels.

CONCLUSION: Our data indicate that AD patients exhibit altered plasma HDL profile and that HDL subclasses correlate with cognitive performances.

%B J Alzheimers Dis %V 77 %P 733-744 %8 2020 Sep 15 %G eng %N 2 %R 10.3233/JAD-200291 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Potential for Digital Monitoring to Enhance Wellbeing at Home for People with Mild Dementia and Their Family Carers. %A Fowler-Davis, Sally %A Barnett, Deborah %A Kelley, John %A Curtis, David %X

Digital technologies have the potential to assist people with dementia to monitor day to day activities and mitigate the risks of living independently. This purposive pilot study surveyed participants for frailty, wellbeing, and perceived carer burden using the 3Rings™ digital plug. 30 paired participants used the digital device for four months. People with dementia reported a decline in wellbeing and increased frailty. Family carers reported a decline in wellbeing but 18 reported a reduction in burden. The use of digital monitoring by family carers demonstrated a reduction in their perceived burden and the device was acceptable to people with mild dementia living alone.

%B J Alzheimers Dis %V 73 %P 867-872 %8 2020 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/31884471?dopt=Abstract %R 10.3233/JAD-190844 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Reduced Hippocampal Glutamate and Posterior Cingulate N-Acetyl Aspartate in Mild Cognitive Impairment and Alzheimer's Disease Is Associated with Episodic Memory Performance and White Matter Integrity in the Cingulum: A Pilot Study. %A Wong, Dickson %A Atiya, Samir %A Fogarty, Jennifer %A Montero-Odasso, Manuel %A Pasternak, Stephen H %A Brymer, Chris %A Borrie, Michael J %A Bartha, Robert %X

Identification of biological changes underlying the early symptoms of Alzheimer's disease (AD) will help to identify and stage individuals prior to symptom onset. The limbic system, which supports episodic memory and is impaired early in AD, is a primary target. In this study, brain metabolism and microstructure evaluated by high field (7 Tesla) proton magnetic resonance spectroscopy (1H-MRS) and diffusion tensor imaging (DTI) were evaluated in the limbic system of eight individuals with mild cognitive impairment (MCI), nine with AD, and sixteen normal elderly controls (NEC). Left hippocampal glutamate and posterior cingulate N-acetyl aspartate concentrations were reduced in MCI and AD compared to NEC. Differences in DTI metrics indicated volume and white matter loss along the cingulum in AD compared to NEC. Metabolic and microstructural changes were associated with episodic memory performance assessed using Craft Story 21 Recall and Benson Complex Figure Copy. The current study suggests that metabolite concentrations measured using 1H-MRS may provide insight into the underlying metabolic and microstructural processes of episodic memory impairment.

%B J Alzheimers Dis %V 73 %P 1385-1405 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/31958093?dopt=Abstract %R 10.3233/JAD-190773 %0 Journal Article %J J Alzheimers Dis %D 2020 %T A Review of the Brain-Gut-Microbiome Axis and the Potential Role of Microbiota in Alzheimer's Disease. %A Sun, Miao %A Ma, Kai %A Wen, Jie %A Wang, Guangxian %A Zhang, Changliang %A Li, Qi %A Bao, Xiaofeng %A Wang, Hui %X

Alzheimer's disease (AD) is a neurodegenerative process characterized by loss of neurons in the hippocampus and cerebral cortex, leading to progressive cognitive decline. Pathologically, the hallmark of AD is accumulation of "senile" plaques composed of amyloid-β (Aβ) protein surrounding neurons in affected regions. Despite extensive research into AD pathogenesis and therapeutic targets, there remains no breakthroughs in its management. In recent years, there has been a spark of interest in the connection between the brain and gastrointestinal tract, referred to as the brain-gut axis, and its potential implications for both metabolic and neurologic disease. Moreover, the gastrointestinal flora, referred to as the microbiome, appears to exert significant influence over the brain-gut axis. With the need for expanded horizons in understanding and treating AD, many have turned to the brain-gut-microbiome axis for answers. Here we provide a review of the brain-gut-microbiome axis and discuss the evidence supporting alterations of the axis in the pathogenesis of AD. Specifically, we highlight the role for the microbiome in disruption of Aβ metabolism/clearance, increased permeability of the blood-brain barrier and modulation of the neuroinflammatory response, and inhibition of hippocampal neurogenesis. The majority of the above described findings are the result of excellent, albeit basic and pre-clinical studies. Therefore, we conclude with a brief description of documented clinical support for brain-gut-microbiome axis alteration in AD, including potential microbiome-based therapeutics for AD. Collectively, these findings suggest that the brain-gut-microbiome axis may be a "lost link" in understanding and treating AD and call for future work.

%B J Alzheimers Dis %V 73 %P 849-865 %8 2020 %G eng %N 3 %R 10.3233/JAD-190872 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Serum Hepcidin Levels in Cognitively Normal Older Adults with High Neocortical Amyloid-β Load. %A Chatterjee, Pratishtha %A Mohammadi, Maryam %A Goozee, Kathryn %A Shah, Tejal M %A Sohrabi, Hamid R %A Dias, Cintia B %A Shen, Kaikai %A Asih, Prita R %A Dave, Preeti %A Pedrini, Steve %A Ashton, Nicholas J %A Hye, Abdul %A Taddei, Kevin %A Lovejoy, David B %A Zetterberg, Henrik %A Blennow, Kaj %A Martins, Ralph N %X

BACKGROUND/OBJECTIVE: Hepcidin, an iron-regulating hormone, suppresses the release of iron by binding to the iron exporter protein, ferroportin, resulting in intracellular iron accumulation. Given that iron dyshomeostasis has been observed in Alzheimer's disease (AD) together with elevated serum hepcidin levels, the current study examined whether elevated serum hepcidin levels are an early event in AD pathogenesis by measuring the hormone in cognitively normal older adults at risk of AD, based on high neocortical amyloid-β load (NAL).

METHODS: Serum hepcidin levels in cognitively normal participants (n = 100) aged between 65-90 years were measured using ELISA. To evaluate NAL, all participants underwent 18F-florbetaben positron emission tomography. A standard uptake value ratio (SUVR)

RESULTS: Serum hepcidin was significantly higher in participants with high NAL compared to those with low NAL before and after adjusting for covariates: age, gender, and APOEɛ4 carriage (p < 0.05). A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve, AUC = 0.766), but was outperformed when serum hepcidin was added to the base model (AUC = 0.794) and further improved with plasma Aβ42/40 ratio (AUC = 0.829).

CONCLUSION: The present findings indicate that serum hepcidin is increased in individuals at risk for AD and contribute to the body of evidence supporting iron dyshomeostasis as an early event of AD. Further, hepcidin may add value to a panel of markers that contribute toward identifying individuals at risk of AD; however, further validation studies are required.

%B J Alzheimers Dis %V 76 %P 291-301 %8 2020 Jun 30 %G eng %N 1 %R 10.3233/JAD-200162 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Sleep-Wake Cycle in Alzheimer's Disease Is Associated with Tau Pathology and Orexin Dysregulation. %A Liguori, Claudio %A Spanetta, Matteo %A Izzi, Francesca %A Franchini, Flaminia %A Nuccetelli, Marzia %A Sancesario, Giulia Maria %A Di Santo, Simona %A Bernardini, Sergio %A Mercuri, Nicola Biagio %A Placidi, Fabio %X

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. It is mainly characterized by a progressive deterioration of cognition, but sleep-wake cycle disturbances frequently occur. Irregular sleep-wake cycle, insomnia, and daytime napping usually occur in patients with AD in the course of the disease.

OBJECTIVE: The aim of the present study was to verify the sleep-wake cycle in mild to moderate AD patients compared to controls, and to evaluate the relationship between the sleep-wake cycle impairment and the neuropsychological testing, CSF AD biomarkers, and CSF orexin concentrations.

METHODS: Mild to moderate AD patients were enrolled and underwent 14-day actigraphic recording, sleep diary, neuropsychological testing, and CSF biomarkers analysis. All patients were compared to controls.

RESULTS: Eighteen AD patients were compared to ten controls. AD patients showed the alteration of the sleep-wake cycle, featured by sleep dysregulation and daytime wake fragmentation, with respect to controls. Considering the correlation analysis, we documented the correlation between tau proteins and orexin CSF levels and sleep-wake cycle dysregulation.

CONCLUSION: This study confirmed the dysregulation of sleep-wake cycle in AD patients, as reflected by the daytime wake fragmentation, irregular sleep-wake rhythm, and nocturnal sleep impairment. This sleep-wake cycle disorder correlates with AD neuropathological in vivo features and brain orexin activity. Hence, we suppose that a more marked AD pathology coupled with orexinergic system dysregulation may promote sleep-wake cycle impairment in AD patients.

%B J Alzheimers Dis %V 74 %P 501-508 %8 2020 Mar 24 %G eng %N 2 %R 10.3233/JAD-191124 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Specific Neuropsychiatric Symptoms Are Associated with Faster Progression in Alzheimer's Disease: Results of the Prospective Dementia Registry (PRODEM-Austria). %A Defrancesco, Michaela %A Marksteiner, Josef %A Kemmler, Georg %A Dal-Bianco, Peter %A Ransmayr, Gerhard %A Benke, Thomas %A Mosbacher, Jochen %A Höller, Yvonne %A Schmidt, Reinhold %X

BACKGROUND: Neuropsychiatric symptoms (NPS) occur frequently in the course of Alzheimer's disease (AD) and are suspected to be associated with a faster dementia progression. Numerous reports have defined specific subsyndromes, summarized in clusters of items of the Neuropsychiatric Inventory (NPI).

OBJECTIVE: This study investigated the influence of specific NPI subsyndromes and clinical patient characteristics on dementia progression.

METHODS: Data of the prospective registry on dementia in Austria (PRODEM) were retrospectively analyzed. Cognitive functioning was determined at baseline and 2 yearly follow-up visits using the Mini-Mental State Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer's dementia neuropsychological test battery (CERAD). To assess NPS, the NPI was used: NPI items were classified in three subsyndromes (psychotic cluster, behavioral cluster, emotional cluster).

RESULTS: Out of the 662 included patients (mean age 76.4±8.4 years), 43% completed follow-up visits for two years. Significant correlation between higher scores in all three subsyndromes and worse cognitive performance were found for MMSE score, naming, and verbal fluency. Results of linear mixed model analysis revealed lower age and higher scores in the psychotic cluster as significant predictors of changes in MMSE with time.

CONCLUSION: In this study, we report the influence of psychotic subsyndromes and lower age on faster MMSE decline in early AD. These results emphasize the importance of not only assessing but also differentiating neuropsychiatric symptoms in subsyndromes in the early stages of AD as a possible predictor of disease progression.

%B J Alzheimers Dis %V 73 %P 125-133 %8 2020 Jan 07 %G eng %N 1 %R 10.3233/JAD-190662 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Structural Brain Changes in Pre-Clinical FTD MAPT Mutation Carriers. %A Domínguez-Vivero, Clara %A Wu, Liwen %A Lee, Seonjoo %A Manoochehri, Masood %A Cines, Sarah %A Brickman, Adam M %A Rizvi, Batool %A Chesebro, Anthony %A Gazes, Yunglin %A Fallon, Emer %A Lynch, Timothy %A Heidebrink, Judith L %A Paulson, Henry %A Goldman, Jill S %A Huey, Edward %A Cosentino, Stephanie %X

BACKGROUND: Frontotemporal dementia (FTD) is the second most common cause of early-onset neurodegenerative dementia. Several studies have focused on early imaging changes in FTD patients, but once subjects meet full criteria for the FTD diagnosis, structural changes are generally widespread.

OBJECTIVE: This study aims to determine the earliest structural brain changes in asymptomatic MAPT MUTATION carriers.

METHODS: This is a cross-sectional multicenter study comparing global and regional brain volume and white matter integrity in a group of MAPT mutation preclinical carriers and controls. Participants belong to multiple generations of six families with five MAPT mutations. All participants underwent a medical examination, neuropsychological tests, genetic analysis, and a magnetic resonance scan (3T, scout, T1-weighted image followed by EPI (BOLD), MPRAGE, DTI, FLAIR, and ASL sequences).

RESULTS: Volumes of five cortical and subcortical areas were strongly correlated with mutation status: temporal lobe (left amygdala, left temporal pole), cingulate cortex (left rostral anterior cingulate gyrus, right posterior cingulate), and the lingual gyrus in the occipital lobe. We did not find significant differences in whole brain volume, white matter hyperintensities volume, and white matter integrity using DTI analysis.

CONCLUSION: Temporal lobe, cingulate cortex and the lingual gyrus seem to be early targets of the disease and may serve as biomarkers for FTD prior to overt symptom onset.

%B J Alzheimers Dis %V 75 %P 595-606 %8 2020 May 19 %G eng %N 2 %R 10.3233/JAD-190820 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Structural Brain Magnetic Resonance Imaging to Rule Out Comorbid Pathology in the Assessment of Alzheimer's Disease Dementia: Findings from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) Study and Clinical Trials Over the Past 10 Years. %A Kapoor, Arunima %A Bartha, Robert %A Black, Sandra E %A Borrie, Michael %A Freedman, Morris %A Gao, Fuqiang %A Herrmann, Nathan %A Mandzia, Jennifer %A Ozzoude, Miracle %A Ramirez, Joel %A Scott, Christopher J M %A Symons, Sean %A Fischer, Corinne E %A Frank, Andrew %A Seitz, Dallas %A Wolf, Michael Uri %A Verhoeff, Nicolaas Paul L G %A Naglie, Gary %A Reichman, William %A Masellis, Mario %A Mitchell, Sara B %A Tang-Wai, David F %A Tartaglia, Maria Carmela %A Kumar, Sanjeev %A Pollock, Bruce G %A Rajji, Tarek K %A Finger, Elizabeth %A Pasternak, Stephen H %A Swartz, Richard H %X

BACKGROUND/OBJECTIVE: Structural brain magnetic resonance imaging (MRI) is not mandatory in Alzheimer's disease (AD) research or clinical guidelines. We aimed to explore the use of structural brain MRI in AD/mild cognitive impairment (MCI) trials over the past 10 years and determine the frequency with which inclusion of standardized structural MRI acquisitions detects comorbid vascular and non-vascular pathologies.

METHODS: We systematically searched ClinicalTrials.gov for AD clinical trials to determine their neuroimaging criteria and then used data from an AD/MCI cohort who underwent standardized MRI protocols, to determine type and incidence of clinically relevant comorbid pathologies.

RESULTS: Of 210 AD clinical trials, 105 (50%) included structural brain imaging in their eligibility criteria. Only 58 (27.6%) required MRI. 16,479 of 53,755 (30.7%) AD participants were in trials requiring MRI. In the observational AD/MCI cohort, 141 patients met clinical criteria; 22 (15.6%) had relevant MRI findings, of which 15 (10.6%) were exclusionary for the study.

DISCUSSION: In AD clinical trials over the last 10 years, over two-thirds of participants could have been enrolled without brain MRI and half without even a brain CT. In a study sample, relevant comorbid pathology was found in 15% of participants, despite careful screening. Standardized structural MRI should be incorporated into NIA-AA diagnostic guidelines (when available) and research frameworks routinely to reduce diagnostic heterogeneity.

%B J Alzheimers Dis %V 74 %P 747-757 %8 2020 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/32116253?dopt=Abstract %R 10.3233/JAD-191097 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Telemedicine for Delivery of Care in Frontotemporal Lobar Degeneration During COVID-19 Pandemic: Results from Southern Italy. %A Capozzo, Rosa %A Zoccolella, Stefano %A Frisullo, Maria Elisa %A Barone, Roberta %A Dell'Abate, Maria Teresa %A Barulli, Maria Rosaria %A Musio, Marco %A Accogli, Miriam %A Logroscino, Giancarlo %K Aged %K Aged, 80 and over %K Behavior %K Coronavirus Infections %K COVID-19 %K Delivery of Health Care %K Disease Progression %K Female %K Frontotemporal Lobar Degeneration %K Humans %K Italy %K Language %K Male %K Mental Status and Dementia Tests %K Middle Aged %K Pandemics %K Pneumonia, Viral %K Quality of Life %K Quarantine %K Surveys and Questionnaires %K Telemedicine %K Triage %X

BACKGROUND: The COVID-19 pandemic is changing clinical practice in neurology, after the governments decided the introduction of social distancing and interruption of medical non-emergency services in many countries. Teleneurology is an effective tool for the remote evaluation of patients but its adoption for frontotemporal lobar dementia (FTD) is in a preliminary stage.

OBJECTIVE: We evaluated multidisciplinary assessment of patients with FTD using telehealth during the COVID-19 pandemic.

METHODS: All patients received a diagnosis of FTD during 2018-2019 according to international criteria. A structured questionnaire and Clinical Dementia Rating Scale (CDR)-FTD were used by the neurologist with patients and/or caregivers. Index symptoms of COVID-19 infection were searched.

RESULTS: Twenty-eight clinical interviews were completed with caregivers and four with both patients/caregivers. Most patients and caregivers were satisfied with the neurological interview and expressed their willingness to continue to be included in remote evaluation programs (90%). Fifty percent of patients experienced significant worsening of clinical picture and quality of life since the start of social distancing. The CDR-FTD scale revealed a significant worsening of behavior (p = 0.01) and language functions (p = 0.009), compared to the last in-person evaluation at the center. One patient presented index symptoms of COVID-19 infection and was confirmed to be positive for COVID-19 with pharyngeal swab.

CONCLUSION: The study was conducted in Italy, one of the countries hit particularly hard by the COVID-19 pandemic, with interruption of all non-emergency medical services. Our study indicates that telemedicine is a valid tool to triage patients with FTD to increase practice outreach and efficiency.

%B J Alzheimers Dis %V 76 %P 481-489 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32651328?dopt=Abstract %R 10.3233/JAD-200589 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Ultra-High Field MRI in Alzheimer's Disease: Effective Transverse Relaxation Rate and Quantitative Susceptibility Mapping of Human Brain In Vivo and Ex Vivo Compared to Histology. %A Tuzzi, Elisa %A Balla, David Z %A Loureiro, Joana R A %A Neumann, Manuela %A Laske, Christoph %A Pohmann, Rolf %A Preische, Oliver %A Scheffler, Klaus %A Hagberg, Gisela E %X

Alzheimer's disease (AD) is the most common cause of dementia worldwide. So far, diagnosis of AD is only unequivocally defined through postmortem histology. Amyloid plaques are a classical hallmark of AD and amyloid load is currently quantified by Positron Emission tomography (PET) in vivo. Ultra-high field magnetic resonance imaging (UHF-MRI) can potentially provide a non-invasive biomarker for AD by allowing imaging of pathological processes at a very-high spatial resolution. The first aim of this work was to reproduce the characteristic cortical pattern previously observed in vivo in AD patients using weighted-imaging at 7T. We extended these findings using quantitative susceptibility mapping (QSM) and quantification of the effective transverse relaxation rate (R2*) at 9.4T. The second aim was to investigate the origin of the contrast patterns observed in vivo in the cortex of AD patients at 9.4T by comparing quantitative UHF-MRI (9.4T and 14.1T) of postmortem samples with histology. We observed a distinctive cortical pattern in vivo in patients compared to healthy controls (HC), and these findings were confirmed ex vivo. Specifically, we found a close link between the signal changes detected by QSM in the AD sample at 14.1T and the distribution pattern of amyloid plaques in the histological sections of the same specimen. Our findings showed that QSM and R2* maps can distinguish AD from HC at UHF by detecting cortical alterations directly related to amyloid plaques in AD patients. Furthermore, we provided a method to quantify amyloid plaque load in AD patients at UHF non-invasively.

%B J Alzheimers Dis %V 73 %P 1481-1499 %8 2020 Feb 18 %G eng %N 4 %R 10.3233/JAD-190424 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Utility of MemTrax and Machine Learning Modeling in Classification of Mild Cognitive Impairment. %A Bergeron, Michael F %A Landset, Sara %A Zhou, Xianbo %A Ding, Tao %A Khoshgoftaar, Taghi M %A Zhao, Feng %A Du, Bo %A Chen, Xinjie %A Wang, Xuan %A Zhong, Lianmei %A Liu, Xiaolei %A Ashford, J Wesson %X

BACKGROUND: The widespread incidence and prevalence of Alzheimer's disease and mild cognitive impairment (MCI) has prompted an urgent call for research to validate early detection cognitive screening and assessment.

OBJECTIVE: Our primary research aim was to determine if selected MemTrax performance metrics and relevant demographics and health profile characteristics can be effectively utilized in predictive models developed with machine learning to classify cognitive health (normal versus MCI), as would be indicated by the Montreal Cognitive Assessment (MoCA).

METHODS: We conducted a cross-sectional study on 259 neurology, memory clinic, and internal medicine adult patients recruited from two hospitals in China. Each patient was given the Chinese-language MoCA and self-administered the continuous recognition MemTrax online episodic memory test on the same day. Predictive classification models were built using machine learning with 10-fold cross validation, and model performance was measured using Area Under the Receiver Operating Characteristic Curve (AUC). Models were built using two MemTrax performance metrics (percent correct, response time), along with the eight common demographic and personal history features.

RESULTS: Comparing the learners across selected combinations of MoCA scores and thresholds, Naïve Bayes was generally the top-performing learner with an overall classification performance of 0.9093. Further, among the top three learners, MemTrax-based classification performance overall was superior using just the top-ranked four features (0.9119) compared to using all 10 common features (0.8999).

CONCLUSION: MemTrax performance can be effectively utilized in a machine learning classification predictive model screening application for detecting early stage cognitive impairment.

%B J Alzheimers Dis %V 77 %P 1545-1558 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32894241?dopt=Abstract %R 10.3233/JAD-191340 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort. %A Westwood, Sarah %A Baird, Alison L %A Anand, Sneha N %A Nevado-Holgado, Alejo J %A Kormilitzin, Andrey %A Shi, Liu %A Hye, Abdul %A Ashton, Nicholas J %A Morgan, Angharad R %A Bos, Isabelle %A Vos, Stephanie J B %A Baker, Susan %A Buckley, Noel J %A Ten Kate, Mara %A Scheltens, Philip %A Teunissen, Charlotte E %A Vandenberghe, Rik %A Gabel, Silvy %A Meersmans, Karen %A Engelborghs, Sebastiaan %A De Roeck, Ellen E %A Sleegers, Kristel %A Frisoni, Giovanni B %A Blin, Olivier %A Richardson, Jill C %A Bordet, Régis %A Molinuevo, José L %A Rami, Lorena %A Wallin, Anders %A Kettunen, Petronella %A Tsolaki, Magda %A Verhey, Frans %A Lleo, Alberto %A Sala, Isabel %A Popp, Julius %A Peyratout, Gwendoline %A Martínez-Lage, Pablo %A Tainta, Mikel %A Johannsen, Peter %A Freund-Levi, Yvonne %A Frölich, Lutz %A Dobricic, Valerija %A Legido-Quigley, Cristina %A Bertram, Lars %A Barkhof, Frederik %A Zetterberg, Henrik %A Morgan, B Paul %A Streffer, Johannes %A Visser, Pieter Jelle %A Lovestone, Simon %X

We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.

%B J Alzheimers Dis %V 74 %P 213-225 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31985466?dopt=Abstract %R 10.3233/JAD-190434 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Adverse Vascular Risk Relates to Cerebrospinal Fluid Biomarker Evidence of Axonal Injury in the Presence of Alzheimer's Disease Pathology. %A Osborn, Katie E %A Alverio, Jonathan M %A Dumitrescu, Logan %A Pechman, Kimberly R %A Gifford, Katherine A %A Hohman, Timothy J %A Blennow, Kaj %A Zetterberg, Henrik %A Jefferson, Angela L %X

BACKGROUND: Vascular risk factors promote cerebral small vessel disease and neuropathological changes, particularly in white matter where large-caliber axons are located. How Alzheimer's disease pathology influences the brain's vulnerability in this regard is not well understood.

OBJECTIVE: Systemic vascular risk was assessed in relation to cerebrospinal fluid concentrations of neurofilament light, a biomarker of large-caliber axonal injury, evaluating for interactions by clinical and protein markers of Alzheimer's disease.

METHODS: Among Alzheimer's Disease Neuroimaging Initiative participants with normal cognition (n = 117), mild cognitive impairment (n = 190), and Alzheimer's disease (n = 95), linear regression related vascular risk (as measured by the modified Framingham Stroke Risk Profile) to neurofilament light, adjusting for age, sex, education, and cognitive diagnosis. Interactions were assessed by cognitive diagnosis, and by cerebrospinal fluid markers of Aβ42, hyperphosphorylated tau, and total tau.

RESULTS: Vascular risk and neurofilament light were not related in the main effect model (p = 0.08). However, interactions emerged for total tau (p = 0.01) and hyperphosphorylated tau (p = 0.002) reflecting vascular risk becoming more associated with cerebrospinal fluid neurofilament light in the context of greater concentrations of tau biomarkers. An interaction also emerged for the Alzheimer's disease biomarker profiles (p = 0.046) where in comparison to the referent 'normal' biomarker group, individuals with abnormal levels of both Aβ42 and total tau showed stronger associations between vascular risk and neurofilament light.

CONCLUSION: Older adults may be more vulnerable to axonal injury in response to higher vascular risk burdens in the context of concomitant Alzheimer's disease pathology.

%B J Alzheimers Dis %V 71 %P 281-290 %8 2019 Sep 3 %G eng %N 1 %R 10.3233/JAD-190077 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Air Pollution and Dementia: A Systematic Review. %A Peters, Ruth %A Ee, Nicole %A Peters, Jean %A Booth, Andrew %A Mudway, Ian %A Anstey, Kaarin J %X

BACKGROUND: Both air pollution and dementia are current and growing global issues. There are plausible links between exposure to specific air pollutants and dementia.

OBJECTIVE: To systematically review the evidence base with respect to the relationship between air pollution and later cognitive decline and dementia.

METHODS: Medline, Embase, and PsychINFO® were searched from their inception to September 2018, for publications reporting on longitudinal studies of exposure to air pollution and incident dementia or cognitive decline in adults. Studies reporting on exposure to tobacco smoke including passive smoking or on occupational exposure to pollutants were excluded. Using standard Cochrane methodology, two readers identified relevant abstracts, read full text publications, and extracted data into structured tables from relevant papers, as defined by inclusion and exclusion criteria. Papers were also assessed for validity. CRD42018094299Results:From 3,720 records, 13 papers were found to be relevant, with studies from the USA, Canada, Taiwan, Sweden, and the UK. Study follow-up ranged from one to 15 years. Pollutants examined included particulate matter ≤2.5 μ (PM2.5), nitrogen dioxide (NO2), nitrous oxides (NOx), carbon monoxide (CO), and ozone. Studies varied in their methodology, population selection, assessment of exposure to pollution, and method of cognitive testing. Greater exposure to PM2.5, NO2/NOx, and CO were all associated with increased risk of dementia. The evidence for air pollutant exposure and cognitive decline was more equivocal.

CONCLUSION: Evidence is emerging that greater exposure to airborne pollutants is associated with increased risk of dementia.

%B J Alzheimers Dis %V 70 %P S145-S163 %8 2019 %G eng %N s1 %R 10.3233/JAD-180631 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Amyloidogenic Nanoplaques in Blood Serum of Patients with Alzheimer's Disease Revealed by Time-Resolved Thioflavin T Fluorescence Intensity Fluctuation Analysis. %A Tiiman, Ann %A Jelic, Vesna %A Jarvet, Jüri %A Järemo, Petter %A Bogdanovic, Nenad %A Rigler, Rudolf %A Terenius, Lars %A Gräslund, Astrid %A Vukojević, Vladana %X

BACKGROUND: Biomarkers are central to current research on molecular mechanisms underlying Alzheimer's disease (AD). Their further development is of paramount importance for understanding pathophysiological processes that eventually lead to disease onset. Biomarkers are also crucial for early disease detection, before clinical manifestation, and for development of new disease modifying therapies.

OBJECTIVE: The overall aim of this work is to develop a minimally invasive method for fast, ultra-sensitive and cost-effective detection of structurally modified peptide/protein self-assemblies in the peripheral blood and in other biological fluids. Specifically, we focus here on using this method to detect structured amyloidogenic oligomeric aggregates in the blood serum of apparently healthy individuals and patients in early AD stage, and measure their concentration and size.

METHODS: Time-resolved detection of Thioflavin T (ThT) fluorescence intensity fluctuations in a sub-femtoliter observation volume element was used to identify in blood serum ThT-active structured amyloidogenic oligomeric aggregates, hereafter called nanoplaques, and measure with single-particle sensitivity their concentration and size.

RESULTS: The concentration and size of structured amyloidogenic nanoplaques are significantly higher in the blood serum of individuals diagnosed with AD than in control subjects.

CONCLUSION: A new method with the ultimate, single-particle sensitivity was successfully developed. The proposed approach neither relies on the use of immune-based probes, nor on the use of radiotracers, signal-amplification or protein separation techniques, and provides a minimally invasive test for fast and cost-effective early determination of structurally modified peptides/proteins in the peripheral blood, as shown here, but also in other biological fluids.

%B J Alzheimers Dis %V 68 %P 571-582 %8 2019 Mar 29 %G eng %N 2 %R 10.3233/JAD-181144 %0 Journal Article %J J Alzheimers Dis %D 2019 %T APOE Effect on Amyloid-β PET Spatial Distribution, Deposition Rate, and Cut-Points. %A Toledo, Jon B %A Habes, Mohamad %A Sotiras, Aristeidis %A Bjerke, Maria %A Fan, Yong %A Weiner, Michael W %A Shaw, Leslie M %A Davatzikos, Christos %A Trojanowski, John Q %X

There are conflicting results regarding how APOE genotype, the strongest genetic risk factor for Alzheimer's disease (AD), influences spatial and longitudinal amyloid-β (Aβ) deposition and its impact on the selection of biomarker cut-points. In our study, we sought to determine the impact of APOE genotype on cross-sectional and longitudinal florbetapir positron emission tomography (PET) amyloid measures and its impact in classification of patients and interpretation of clinical cohort results. We included 1,019 and 1,072 Alzheimer's Disease Neuroimaging Initiative participants with cerebrospinal fluid Aβ1 - 42 and florbetapir PET values, respectively. 623 of these subjects had a second florbetapir PET scans two years after the baseline visit. We evaluated the effect of APOE genotype on Aβ distribution pattern, pathological biomarker cut-points, cross-sectional clinical associations with Aβ load, and longitudinal Aβ deposition rate measured using florbetapir PET scans. 1) APOEɛ4 genotype influences brain amyloid deposition pattern; 2) APOEɛ4 genotype does not modify Aβ biomarker cut-points estimated using unsupervised mixture modeling methods if white matter and brainstem references are used (but not when cerebellum is used as a reference); 3) findings of large differences in Aβ biomarker value differences based on APOE genotype are due to increased probability of having AD neuropathology and are most significant in mild cognitive impairment subjects; and 4) APOE genotype and age (but not gender) were associated with increased Aβ deposition rate. APOEɛ4 carrier status affects rate and location of brain Aβ deposition but does not affect choice of biomarker cut-points if adequate references are selected for florbetapir PET processing.

%B J Alzheimers Dis %V 69 %P 783-793 %8 2019 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/31127775?dopt=Abstract %R 10.3233/JAD-181282 %0 Journal Article %J J Alzheimers Dis %D 2019 %T APOE ɛ4 Carriers Show Delayed Recovery of Verbal Memory and Smaller Entorhinal Volume in the First Year After Ischemic Stroke. %A Werden, Emilio %A Khlif, Mohamed Salah %A Bird, Laura J %A Cumming, Toby %A Bradshaw, Jennifer %A Khan, Wasim %A Pase, Matthew %A Restrepo, Carolina %A Veldsman, Michele %A Egorova, Natalia %A Patel, Sheila K %A Gottlieb, Elie %A Brodtmann, Amy %X

BACKGROUND: The apolipoprotein E (APOE) gene ɛ4 allele is a risk factor for Alzheimer's disease and cardiovascular disease. However, its relationship with cognition and brain volume after stroke is not clear.

OBJECTIVE: We compared cognition and medial temporal lobe volumes in APOEɛ4 carriers and non-carriers in the first year after ischemic stroke.

METHODS: We sampled 20 APOEɛ4 carriers and 20 non-carriers from a larger cohort of 135 ischemic stroke participants in the longitudinal CANVAS study. Participants were matched on a range of demographic and stroke characteristics. We used linear mixed-effect models to compare cognitive domain z-scores (attention, processing speed, executive function, verbal and visual memory, language, visuospatial function) and regional medial temporal lobe volumes (hippocampal, entorhinal cortex) between groups at each time-point (three, 12-months post-stroke), and within groups across time-points. APOE gene single nucleotide polymorphisms (SNPs; rs7412, rs429358) were genotyped on venous blood.

RESULTS: APOEɛ4 carriers and non-carriers did not differ on any demographic, clinical, or stroke variable. Carriers performed worse than non-carriers in verbal memory at three months post-stroke (p = 0.046), but were better in executive function at 12 months (p = 0.035). Carriers demonstrated a significant improvement in verbal memory (p = 0.012) and executive function (p = 0.015) between time-points. Non-carriers demonstrated a significant improvement in visual memory (p = 0.0005). Carriers had smaller bilateral entorhinal cortex volumes (p <  0.05), and larger-right-sided and contralesional hippocampal volumes, at both time-points (p <  0.05).

CONCLUSION: APOE ɛ4 is associated with delayed recovery of verbal memory function and reduced entorhinal cortex volumes in the first year after ischemic stroke.

%B J Alzheimers Dis %V 71 %P 245-259 %8 2019 Sep 3 %G eng %N 1 %R 10.3233/JAD-190566 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Association between Adipokines and Biomarkers of Alzheimer's Disease: A Cross-Sectional Study. %A Letra, Liliana %A Matafome, Paulo %A Rodrigues, Tiago %A Duro, Diana %A Lemos, Raquel %A Baldeiras, Ines %A Patrício, Miguel %A Castelo-Branco, Miguel %A Caetano, Gina %A Seiça, Raquel %A Santana, Isabel %X

BACKGROUND: Adipose tissue dysfunction has been implicated in the pathophysiology of Alzheimer's disease. However, the involvement of adipokines, particularly adiponectin, remains unclear.

OBJECTIVE: To compare serum and cerebrospinal fluid (CSF) levels of adiponectin, leptin and leptin-to-adiponectin ratio in patients within the spectrum of Alzheimer's disease and evaluate their relationship with classical biomarkers and their value as markers of progression.

METHODS: Amnestic mild cognitive impairment (MCI, n = 71) and Alzheimer's dementia (AD, n = 53) subjects were consecutively recruited for serum and CSF adiponectin and leptin determination using an analytically validated commercial enzyme-linked immunosorbent assay (ELISA). Correlations were explored using adjusted Spearman's correlation coefficients. A logistic regression model and ROC analysis were performed to evaluate the staging predictive value of adipokines.

RESULTS: Serum adiponectin was 33% higher in AD when compared to MCI patients. Adiponectin CSF levels, similar in both groups, were positively correlated with Aβ42 and cognitive function, though only in women. The area under the ROC curve was 0.673 (95% CI:0.57-0.78) for serum adiponectin as predictor of dementia stage and the cut-off 10.85μg/ml maximized the sum of specificity (87%) and sensitivity (44%).

CONCLUSION: Although longitudinal studies are required, we hypothesize that higher serum adiponectin in AD patients constitutes a strategy to compensate possible central signaling defects. In addition, adiponectin might be specifically assigned to neuroprotective functions in women and eventually involved in the female-biased incidence of Alzheimer's disease.

%B J Alzheimers Dis %V 67 %P 725-735 %8 2019 %G eng %N 2 %R 10.3233/JAD-180669 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Cerebrospinal Fluid Level of Aquaporin4: A New Window on Glymphatic System Involvement in Neurodegenerative Disease? %A Arighi, Andrea %A Di Cristofori, Andrea %A Fenoglio, Chiara %A Borsa, Stefano %A D'Anca, Marianna %A Fumagalli, Giorgio Giulio %A Locatelli, Marco %A Carrabba, Giorgio %A Pietroboni, Anna Margherita %A Ghezzi, Laura %A Carandini, Tiziana %A Colombi, Annalisa %A Scarioni, Marta %A De Riz, Milena Alessandra %A Serpente, Maria %A Rampini, Paolo Maria %A Scarpini, Elio %A Galimberti, Daniela %X

 Aquaporin4 (AQP4) is a water channel protein located at astrocyte foot processes that plays a role in glymphatic system, a highly organized fluid transport pathway which seems to be involved in Alzheimer's disease (AD) and normal pressure hydrocephalus (NPH) pathophysiology. Cerebrospinal fluid (CSF) AQP4 levels were determined in 11 patients with AD, 10 patients with NPH, and 9 controls. We found significantly reduced AQP4 in AD patients, a trend in reduction in NPH patients, and a correlation between AQP4 and amyloid-β CSF levels. This study indicates the potential role of AQP4 and glymphatic system in neurodegenerative diseases pathophysiology.

%B J Alzheimers Dis %V 69 %P 663-669 %8 2019 Jun 4 %G eng %N 3 %R 10.3233/JAD-190119 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Choroid Plexus Acts as Gatekeeper for TREM2, Abnormal Accumulation of ApoE, and Fibrillary Tau in Alzheimer's Disease and in Down Syndrome Dementia. %A Raha-Chowdhury, Ruma %A Henderson, James W %A Raha, Animesh Alexander %A Vuono, Romina %A Bickerton, Anastasia %A Jones, Elizabeth %A Fincham, Robert %A Allinson, Kieren %A Holland, Anthony %A Zaman, Shahid H %X

BACKGROUND: Genetic factors that influence Alzheimer's disease (AD) risk include mutations in TREM2 and allelic variants of Apolipoprotein E, influencing AD pathology in the general population and in Down syndrome (DS). Evidence shows that dysfunction of the choroid plexus may compromise the blood-cerebrospinal fluid (CSF) barrier, altering secretary, transport and immune function that can affect AD pathology.

OBJECTIVE: To investigate the genotype and phenotype of DS individuals in relation to choroid plexus damage and blood-CSF barrier leakage to identify markers that could facilitate early diagnosis of AD in DS.

METHODS: To assess allele frequency and haplotype associations ApoE, Tau, TREM2, and HLA-DR were analyzed by SNP analysis in DS participants (n = 47) and controls (n = 50). The corresponding plasma protein levels were measured by ELISA. Postmortem brains from DS, AD, and age-matched controls were analyzed by immunohistochemistry.

RESULTS: Haplotype analysis showed that individuals with Tau H1/H1 and ApoEɛ4 genotypes were more prevalent among DS participants with an earlier diagnosis of dementia (17%) compared to H1/H2 haplotypes (6%). Plasma TREM2 levels decreased whereas phospho-tau levels increased with age in DS. In AD and DS brain, insoluble tau and ApoE were found to accumulate in the choroid plexus.

CONCLUSION: Accumulation of tau and ApoE in the choroid plexus may increase the oligomerization rate of Aβ42 and impair tau trafficking, leading to AD pathology. We have identified a high-risk haplotype: ApoEɛ4, Tau/H1, and TREM2/T, that manifests age-related changes potentially opening a window for treatment many years prior to the manifestation of the AD dementia.

%B J Alzheimers Dis %V 69 %P 91-109 %8 2019 May 7 %G eng %N 1 %R 10.3233/JAD-181179 %0 Journal Article %J J Alzheimers Dis %D 2019 %T The Clinical Phenotype of Vascular Cognitive Impairment in Patients with Type 2 Diabetes Mellitus. %A Groeneveld, Onno N %A Moneti, Costanza %A Heinen, Rutger %A de Bresser, Jeroen %A Kuijf, Hugo J %A Exalto, Lieza G %A Boomsma, Jooske M F %A Kappelle, L Jaap %A Barkhof, Frederik %A Prins, Niels D %A Scheltens, Philip %A van der Flier, Wiesje M %A Biessels, Geert Jan %X

BACKGROUND: Type 2 diabetes mellitus (T2DM) increases the risk of vascular cognitive impairment (VCI). It is unknown which type of vascular lesions and co-morbid etiologies, in particular Alzheimer's disease pathology, are associated with T2DM in patients with VCI, and how this relates to cognition and prognosis.

OBJECTIVE: To compare brain MRI and cerebrospinal fluid (CSF) markers, cognition, and prognosis in patients with possible VCI with and without T2DM.

METHODS: We included 851 memory clinic patients with vascular brain injury on MRI (i.e., possible VCI) from a prospective cohort study (T2DM: n = 147, 68.4±7.9 years, 63% men; no T2DM: n = 704, 67.6±8.5 years, 52% men). At baseline, we assessed between-group differences in brain MRI abnormalities, CSF markers of Alzheimer's disease, and cognitive profile. After two years follow-up, we compared occurrence of cognitive decline, stroke, and death.

RESULTS: The distribution of clinical diagnoses did not differ between patients with and without T2DM. T2DM patients had more pronounced brain atrophy (total and white matter volume), and more lacunar infarcts, whereas microbleeds were less common (all p <  0.05). CSF amyloid-β levels were similar between the groups. T2DM patients performed worse on working memory (effect size: - 0.17, p = 0.03) than those without, whereas performance on other domains was similar. During follow-up, risk of further cognitive decline was not increased in T2DM.∥Conclusion: In patients with possible VCI, presence of T2DM is related to more pronounced brain atrophy and a higher burden of lacunar infarcts, but T2DM does not have a major impact on cognitive profile or prognosis.∥.

%B J Alzheimers Dis %V 68 %P 311-322 %8 2019 Mar 12 %G eng %N 1 %R 10.3233/JAD-180914 %0 Journal Article %J J Alzheimers Dis %D 2019 %T A Clinical Trial of Transcranial Electromagnetic Treatment in Alzheimer's Disease: Cognitive Enhancement and Associated Changes in Cerebrospinal Fluid, Blood, and Brain Imaging. %A Arendash, Gary %A Cao, Chuanhai %A Abulaban, Haitham %A Baranowski, Rob %A Wisniewski, Gary %A Becerra, Lino %A Andel, Ross %A Lin, Xiaoyang %A Zhang, Xiaolin %A Wittwer, David %A Moulton, Jay %A Arrington, John %A Smith, Amanda %X

BACKGROUND: Small aggregates (oligomers) of the toxic proteins amyloid-β (Aβ) and phospho-tau (p-tau) are essential contributors to Alzheimer's disease (AD). In mouse models for AD or human AD brain extracts, Transcranial Electromagnetic Treatment (TEMT) disaggregates both Aβ and p-tau oligomers, and induces brain mitochondrial enhancement. These apparent "disease-modifying" actions of TEMT both prevent and reverse memory impairment in AD transgenic mice.

OBJECTIVE: To evaluate the safety and initial clinical efficacy of TEMT against AD, a comprehensive open-label clinical trial was performed.

METHODS: Eight mild/moderate AD patients were treated with TEMT in-home by their caregivers for 2 months utilizing a unique head device. TEMT was given for two 1-hour periods each day, with subjects primarily evaluated at baseline, end-of-treatment, and 2 weeks following treatment completion.

RESULTS: No deleterious behavioral effects, discomfort, or physiologic changes resulted from 2 months of TEMT, as well as no evidence of tumor or microhemorrhage induction. TEMT induced clinically important and statistically significant improvements in ADAS-cog, as well as in the Rey AVLT. TEMT also produced increases in cerebrospinal fluid (CSF) levels of soluble Aβ1-40 and Aβ1-42, cognition-related changes in CSF oligomeric Aβ, a decreased CSF p-tau/Aβ1-42 ratio, and reduced levels of oligomeric Aβ in plasma. Pre- versus post-treatment FDG-PET brain scans revealed stable cerebral glucose utilization, with several subjects exhibiting enhanced glucose utilization. Evaluation of diffusion tensor imaging (fractional anisotropy) scans in individual subjects provided support for TEMT-induced increases in functional connectivity within the cognitively-important cingulate cortex/cingulum.

CONCLUSION: TEMT administration to AD subjects appears to be safe, while providing cognitive enhancement, changes to CSF/blood AD markers, and evidence of stable/enhanced brain connectivity.

%B J Alzheimers Dis %V 71 %P 57-82 %8 2019 %G eng %N 1 %R 10.3233/JAD-190367 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Clinico-Neuropathological Findings in the Oldest Old from the Georgia Centenarian Study. %A Tanprasertsuk, Jirayu %A Johnson, Elizabeth J %A Johnson, Mary Ann %A Poon, Leonard W %A Nelson, Peter T %A Davey, Adam %A Martin, Peter %A Barbey, Aron K %A Barger, Kathryn %A Wang, Xiang-Dong %A Scott, Tammy M %X

BACKGROUND: Centenarian studies are important sources for understanding of factors that contribute to longevity and healthy aging. Clinico-neuropathological finding is a key in identifying pathology and factors contributing to age-related cognitive decline and dementia in the oldest old.

OBJECTIVE: To characterize the cross-sectional relationship between neuropathologies and measures of premortem cognitive performance in centenarians.

METHODS: Data were acquired from 49 centenarians (≥98 years) from the Georgia Centenarian Study. Cognitive assessment from the time point closest to mortality was used (

RESULTS: Wide ranges of AD-type neuropathological changes were observed in both non-demented and demented subjects. Neocortical NFT and Braak staging were related to clinical dementia rating. Neocortical NFT and NP, Braak and NIARI staging, cerebral and ventricular atrophy, HS, CAA, and TDP-43 proteinopathy were differentially associated with poor performance in multiple cognitive domains and activities of daily living.

CONCLUSION: AD-type pathology was associated with severe dementia and poor cognition but was not the only variable that explained cognitive impairment, indicating the complexity and heterogeneity of pathophysiology of dementia in the oldest old.

%B J Alzheimers Dis %V 70 %P 35-49 %8 2019 Jul 2 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/31177211?dopt=Abstract %R 10.3233/JAD-181110 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Dietary Patterns and Cognitive Health in Older Adults: A Systematic Review. %A Chen, Xi %A Maguire, Brook %A Brodaty, Henry %A O'Leary, Fiona %X

While the role of diet and nutrition in cognitive health and prevention of dementia in older adults has attracted much attention, the efficacy of different dietary patterns remains uncertain. Previous reviews have mainly focused on the Mediterranean diet, but either omitted other dietary patterns, lacked more recent studies, were based on cross-sectional studies, or combined older and younger populations. We followed PRISMA guidelines, and examined the efficacy of current research from randomized controlled trials and cohort studies on the effects of different dietary patterns. We reviewed the Mediterranean diet, Dietary Approach to Stop Hypertension (DASH) diet, the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diet, Anti-inflammatory diet, Healthy diet recommended by guidelines via dietary index, or Prudent healthy diets generated via statistical approaches, and their impact on cognitive health among older adults. Of 38 studies, the Mediterranean diet was the most investigated with evidence supporting protection against cognitive decline among older adults. Evidence from other dietary patterns such as the MIND, DASH, Anti-inflammatory, and Prudent healthy diets was more limited but showed promising results, especially for those at risk of cardiovascular disease. Overall, this review found positive effects of dietary patterns including the Mediterranean, DASH, MIND, and Anti-inflammatory diets on cognitive health outcomes in older adults. These dietary patterns are plant-based, rich in poly- and mono-unsaturated fatty acids with lower consumption of processed foods. Better understanding of the underlying mechanisms and effectiveness is needed to develop comprehensive and practical dietary recommendations against age-related cognitive decline among older adult.

%B J Alzheimers Dis %V 67 %P 583-619 %8 2019 %G eng %N 2 %R 10.3233/JAD-180468 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Education Moderates the Relation Between APOE ɛ4 and Memory in Nondemented Non-Hispanic Black Older Adults. %A Vonk, Jet M J %A Rentería, Miguel Arce %A Medina, Valerie M %A Pericak-Vance, Margaret A %A Byrd, Goldie S %A Haines, Jonathan %A Brickman, Adam M %A Manly, Jennifer J %X

BACKGROUND: The APOEɛ4 allele is a well-known risk factor for Alzheimer's disease (AD). Previous research argues that higher education helps to preserve cognition in older adults with AD pathology because of its key role in cognitive reserve and resilience.

OBJECTIVE: To test if higher educational level buffers the effect of APOEɛ4 on cognition among older non-Hispanic Blacks.

METHODS: Participants were 849 non-demented older non-Hispanic Blacks (38.3% APOEɛ4+), who underwent a comprehensive neuropsychological evaluation. Multiple linear regression models tested the relationship between APOEɛ4 status and twelve cognitive measures with education (up to high school and beyond high school) as a moderator.

RESULTS: Education buffered the effects of the APOEɛ4 allele, such that there was no impact of APOEɛ4 status on word-list memory retention and working memory among participants with more than a high school degree. This pattern was not observed for ten other cognitive measures of verbal and visual episodic memory, semantic memory, executive function, and processing speed-although a similar trend was observed for switching ability in executive functioning. The buffering effect of education was stronger among women than men.

CONCLUSION: Our findings suggest that genetic effects on late-life cognition may be modified by environmental factors such as educational attainment. These results are consistent with the framework of cognitive reserve such that engaging in cognitively enriching activities and acquiring skills and knowledge with more years of education may increase the capacity to maintain cognitive function despite high genetic risk for impairment.

%B J Alzheimers Dis %V 72 %P 495-506 %8 2019 Nov 12 %G eng %N 2 %R 10.3233/JAD-190415 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Genome-Wide Methylation of Mild Cognitive Impairment in Mexican Americans Highlights Genes Involved in Synaptic Transport, Alzheimer's Disease-Precursor Phenotypes, and Metabolic Morbidities. %A Pathak, Gita A %A Silzer, Talisa K %A Sun, Jie %A Zhou, Zhengyang %A Daniel, Ann A %A Johnson, Leigh %A O'Bryant, Sid %A Phillips, Nicole R %A Barber, Robert C %X

The Mexican American population is among the fastest growing aging population and has a younger onset of cognitive decline. This group is also heavily burdened with metabolic conditions such as hypertension, diabetes, and obesity. Unfortunately, limited research has been conducted in this group. Understanding methylation alterations, which are influenced by both genetic and lifestyle factors, is key to identifying and addressing the root cause for mild cognitive impairment, a clinical precursor for dementia. We conducted an epigenome-wide association study on a community-based Mexican American population using the Illumina EPIC array. Following rigorous quality control measures, we identified 10 CpG sites to be differentially methylated between normal controls and individuals with mild cognitive impairment annotated to PKIB, KLHL29, SEPT9, OR2C3, CPLX3, BCL2L2-PABPN1, and CCNY. We found four regions to be differentially methylated in TMEM232, SLC17A8, ALOX12, and SEPT8. Functional gene-set analysis identified four gene-sets, RIN3, SPEG, CTSG, and UBE2L3, as significant. The gene ontology and pathway analyses point to neuronal cell death, metabolic dysfunction, and inflammatory processes. We found 1,450 processes to be enriched using empirical Bayes gene-set enrichment. In conclusion, the functional overlap of differentially methylated genes associated with cognitive impairment in Mexican Americans implies cross-talk between metabolically-instigated systemic inflammation and disruption of synaptic vesicular transport.

%B J Alzheimers Dis %V 72 %P 733-749 %8 2019 Nov 26 %G eng %N 3 %R 10.3233/JAD-190634 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Global Metabolic Shifts in Age and Alzheimer's Disease Mouse Brains Pivot at NAD +/NADH Redox Sites. %A Dong, Yue %A Brewer, Gregory J %X

Age and Alzheimer's disease (AD) share some common features such as cognitive impairments, memory loss, metabolic disturbances, bioenergetic deficits, and inflammation. Yet little is known on how systematic shifts in metabolic networks depend on age and AD. In this work, we investigated the global metabolomic alterations in non-transgenic (NTg) and triple-transgenic (3xTg-AD) mouse brain hippocampus as a function of age by using untargeted Ultrahigh Performance Liquid Chromatography-tandem Mass Spectroscopy (UPLC-MS/MS). We observed common metabolic patterns with aging in both NTg and 3xTg-AD brains involved in energy-generating pathways, fatty acids oxidation, glutamate, and sphingolipid metabolism. We found age-related downregulation of metabolites from reactions in glycolysis that consumed ATP and in the TCA cycle, especially at NAD +/NADH-dependent redox sites, where age- and AD-associated limitations in the free NADH may alter reactions. Conversely, metabolites increased in glycolytic reactions in which ATP is produced. With age, inputs to the TCA cycle were increased including fatty acid β-oxidation and glutamine. Overall age- and AD-related changes were >  2-fold when comparing the declines of upstream metabolites of NAD +/NADH-dependent reactions to the increases of downstream metabolites (p = 10 - 5, n = 8 redox reactions). Inflammatory metabolites such as ceramides and sphingosine-1-phosphate also increased with age. Age-related decreases in glutamate, GABA, and sphingolipid were seen which worsened with AD genetic load in 3xTg-AD brains, possibly contributing to synaptic, learning- and memory-related deficits. The data support the novel hypothesis that age- and AD-associated metabolic shifts respond to NAD(P) +/NAD(P)H redox-dependent reactions, which may contribute to decreased energetic capacity.

%B J Alzheimers Dis %V 71 %P 119-140 %8 2019 Sep 3 %G eng %N 1 %R 10.3233/JAD-190408 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Greater Regional Cortical Thickness is Associated with Selective Vulnerability to Atrophy in Alzheimer's Disease, Independent of Amyloid Load and APOE Genotype. %A Li, Chunfei %A Duara, Ranjan %A Loewenstein, David A %A Izquierdo, Walter %A Cabrerizo, Mercedes %A Barker, Warren %A Adjouadi, Malek %X

BACKGROUND: Regional cortical thickness (rCTh) among cognitively normal (CN) adults (rCThCN) varies greatly between brain regions, as does the vulnerability to neurodegeneration.

OBJECTIVE: The goal of this study was to: 1) rank order rCThCN for various brain regions, and 2) explore their vulnerability to neurodegeneration in Alzheimer's disease (AD) within these brain regions.

METHODS: The relationship between rCTh among the CN group (rCThCN) and the percent difference in CTh (% CThDiff) in each region between the CN group and AD patients was examined. Pearson correlation analysis was performed accounting for amyloid-β (Aβ) protein and APOE genotype using 210 age, gender, and APOE matched CN (n = 105, age range: 56-90) and AD (n = 105, age range: 56-90) ADNI participants.

RESULTS: Strong positive correlations were observed between rCThCN and % CThDiff accounting for Aβ deposition and APOE status. Regions, such as the entorhinal cortex, which had the greatest CTh in the CN state, were also the regions which had the greatest % CThDiff.

CONCLUSIONS: Regions with the greatest CTh at the CN stage are found to aggregate in disease prone regions of AD, namely in the medial temporal lobe, including the temporal pole, ERC, parahippocampal gyrus, fusiform and the middle and inferior temporal gyrus. Although rCTh has been found to vary considerably across the different regions of the brain, our results indicate that regions with the greatest CTh at the CN stage are actually regions which have been found to be most vulnerable to neurodegeneration in AD.

%B J Alzheimers Dis %V 69 %P 145-156 %8 2019 May 7 %G eng %N 1 %R 10.3233/JAD-180231 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Head Position During Sleep: Potential Implications for Patients with Neurodegenerative Disease. %A Levendowski, Daniel J %A Gamaldo, Charlene %A St Louis, Erik K %A Ferini-Strambi, Luigi %A Hamilton, Joanne M %A Salat, David %A Westbrook, Philip R %A Berka, Chris %X

BACKGROUND: The characterization of sleep in those with neurodegenerative disease (NDD) is essential in understanding the potential neurobiological mechanisms that underlie the connection between sleep disruption and NDD manifestations and progression.

OBJECTIVE: Explore the inter-relationships between NDD and age, sex, diagnosis of obstructive sleep apnea, snoring, and duration of sleep time with the head in the supine and non-supine positions.

METHODS: A case-control design was used to evaluate differences in sleep position obtained from multi-night, in-home Sleep Profiler recordings in 45 patients with diagnosed NDD (24 with mild cognitive impairment, 15 with Alzheimer's disease, and 6 with Lewy Body, Parkinson's, or other dementias) and 120 age-sex matched controls with normal cognition (NC).

RESULTS: The frequency of supine sleep >2 h/night was significantly greater in the NDD than in the NC group (p < 0.001, odds ratio = 3.7), and remained significant after controlling for age, sex, snoring, and obstructive sleep apnea diagnosis (p = 0.01). There were no group differences in nocturnal mobility i.e., number of head position changes/h.

CONCLUSION: This study demonstrates the utility of in-home measurements of sleep in defining the association of supine sleep position with neurodegenerative disorders. Our findings warrant further investigation, particularly in light of the recent evidence suggesting that sleep may an active role in the brain's ability to clear CNS neurotoxins and metabolites.

%B J Alzheimers Dis %V 67 %P 631-638 %8 2019 %G eng %N 2 %R 10.3233/JAD-180697 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Higher Body Mass Index Is Associated with Lower Cortical Amyloid-β Burden in Cognitively Normal Individuals in Late-Life. %A Thirunavu, Vineeth %A McCullough, Austin %A Su, Yi %A Flores, Shaney %A Dincer, Aylin %A Morris, John C %A Cruchaga, Carlos %A Benzinger, Tammie L S %A Gordon, Brian A %X

BACKGROUND: Both low and high body mass index (BMI) have been associated with an increased risk of dementia, including that caused by Alzheimer's disease (AD). Specifically, high middle-age BMI or a low late-age BMI has been considered a predictor for the development of AD dementia. Less studied is the relationship between BMI and AD pathology.

OBJECTIVE: We explored the association between BMI and cortical amyloid-β (Aβ) burden in cognitively normal participants that were either in mid-life (45-60 years) or late-life (>60).

METHODS: We analyzed cross-sectional baseline data from the Knight Alzheimer Disease Research Center (ADRC) at Washington University. Aβ pathology was measured in 373 individuals with Aβ PET imaging and was quantified using Centiloid units. We split the cohort into mid- and late-life groups for analyses (n = 96 and n = 277, respectively). We ran general linear regression models to predict Aβ levels from BMI while controlling for age, sex, years of education, and APOE4 status. Analyses were also conducted to test the interaction between BMI and APOE4 genotype and between BMI and sex.

RESULTS: Higher BMI was associated with lower cortical Aβ burden in late-life (β= -0.81, p = 0.0066), but no relationship was found in mid-life (β= 0.04, p > 0.5). The BMI×APOE4+ and BMI×male interaction terms were not significant in the mid-life (β= 0.28, p = 0.41; β= 0.64, p = 0.13) or the late-life (β= 0.17, p > 0.5; β= 0.50, p = 0.43) groups.

CONCLUSION: Higher late-life BMI is associated with lower cortical Aβ burden in cognitively normal individuals.

%B J Alzheimers Dis %V 69 %P 817-827 %8 2019 Jun 4 %G eng %N 3 %R 10.3233/JAD-190154 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Highly Elevated Cerebrospinal Fluid Total Tau Level Reflects Higher Likelihood of Non-Amnestic Subtype of Alzheimer's Disease. %A Pillai, Jagan A %A Bonner-Jackson, Aaron %A Bekris, Lynn M %A Safar, Jiri %A Bena, Jim %A Leverenz, James B %X

BACKGROUND: Cerebrospinal fluid (CSF) levels of total tau (t-tau) protein are thought to reflect the intensity of the neuronal damage in neurodegeneration, including Alzheimer's disease (AD). The recent link of CSF t-tau to rapidly progressive AD raises the question among other AD clinical variants regarding CSF t-tau. We investigated the clinical phenotypes of AD patients with varying CSF t-tau levels.

OBJECTIVE: We tested the hypothesis that highly elevated CSF t-tau level would have a higher likelihood of presenting with atypical non-amnestic variants of AD.

METHODS: Retrospective comparative case study of 97 patients evaluated in a memory clinic with clinical presentation and CSF biomarkers consistent with AD. We compared the age, sex, education, APOEɛ4 status, Montreal Cognitive Assessment (MoCA) score, clinical phenotype, and MRI volumetric measures by CSF t-tau quartile at baseline. Multivariable logistic regression models were used to evaluate if CSF t-tau levels predict non-amnestic presentations controlling for covariates.

RESULTS: Non-amnestic AD had a higher median CSF t-tau level compared to amnestic-AD (p = 0.014). Each 50 pg/ml increase in CSF t-tau was associated with an increase in the odds of having a non-amnestic presentation (7.4%) and aphasia (10.6 %) as the initial presenting symptom even after taking into account; age, sex, education, APOEɛ4, MoCA, and CSF Aβ42. Logopenic AD had higher t-tau and p-tau levels compared to other variants.

CONCLUSIONS: Highly elevated CSF t-tau levels could indicate more cortical involvement presenting with early non-amnestic symptoms in atypical AD subtypes, particularly in the logopenic variant.

%B J Alzheimers Dis %V 70 %P 1051-1058 %8 2019 Aug 20 %G eng %N 4 %R 10.3233/JAD-190519 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Impacts of Overweight and Obesity in Older Age on the Risk of Dementia: A Systematic Literature Review and a Meta-Analysis. %A Danat, Isaac M %A Clifford, Angela %A Partridge, Martin %A Zhou, Weiju %A Bakre, Aishat T %A Chen, Anthony %A McFeeters, Danielle %A Smith, Tina %A Wan, Yuhui %A Copeland, John %A Anstey, Kaarin J %A Chen, Ruoling %X

BACKGROUND: It is unclear whether overweight and obesity in older age reduces or increases the risk of incident dementia.

OBJECTIVE: To assess the impacts of overweight and obesity in older age on incident dementia.

METHODS: We searched cohort studies reporting body weight measured in older age and dementia through PubMed, Embase, Medline, PyschInfo, and Cochrane library until July 2016. Sixteen articles were identified for the review. We pooled data from them and a new unpublished study from China, to calculate relative risk (RR) of incident dementia in relation to body mass index (BMI) and waist circumference (WC).

RESULTS: All 16 cohort studies were undertaken in high income countries, with follow-up periods ranging between 3 to 18 years. Thirteen studies showed an inverse association between BMI and dementia, and three studies demonstrated a positive association. Pooled RR of dementia in relation to continuous BMI from 14 studied populations, including the new Chinese data, was 0.97 (95% CI 0.95-1.00); in those followed up

CONCLUSION: The current evidence did not support a paradox on beneficial impacts of overweight and obesity in older age on incident dementia. More studies with long term follow up are needed to clarify the association of body weight in older age with dementia risk.

%B J Alzheimers Dis %V 70 %P S87-S99 %8 2019 %G eng %N s1 %R 10.3233/JAD-180763 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers. %A Khoonsari, Payam Emami %A Shevchenko, Ganna %A Herman, Stephanie %A Remnestål, Julia %A Giedraitis, Vilmantas %A Brundin, RoseMarie %A Degerman Gunnarsson, Malin %A Kilander, Lena %A Zetterberg, Henrik %A Nilsson, Peter %A Lannfelt, Lars %A Ingelsson, Martin %A Kultima, Kim %X

BACKGROUND: Alzheimer's disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD.

OBJECTIVE: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects.

METHODS: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4-9 years and 21 of these converted to AD, whereas 53 remained stable.

RESULTS: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively.

CONCLUSIONS: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.

%B J Alzheimers Dis %V 67 %P 639-651 %8 Jan 2019 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30614806?dopt=Abstract %R 10.3233/JAD-180855 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Inferring the Molecular Mechanisms of Noncoding Alzheimer's Disease-Associated Genetic Variants. %A Amlie-Wolf, Alexandre %A Tang, Mitchell %A Way, Jessica %A Dombroski, Beth %A Jiang, Ming %A Vrettos, Nicholas %A Chou, Yi-Fan %A Zhao, Yi %A Kuzma, Amanda %A Mlynarski, Elisabeth E %A Leung, Yuk Yee %A Brown, Christopher D %A Wang, Li-San %A Schellenberg, Gerard D %X

Most of the loci identified by genome-wide association studies (GWAS) for late-onset Alzheimer's disease (LOAD) are in strong linkage disequilibrium (LD) with nearby variants all of which could be the actual functional variants, often in non-protein-coding regions and implicating underlying gene regulatory mechanisms. We set out to characterize the causal variants, regulatory mechanisms, tissue contexts, and target genes underlying these associations. We applied our INFERNO algorithm to the top 19 non-APOE loci from the IGAP GWAS study. INFERNO annotated all LD-expanded variants at each locus with tissue-specific regulatory activity. Bayesian co-localization analysis of summary statistics and eQTL data was performed to identify tissue-specific target genes. INFERNO identified enhancer dysregulation in all 19 tag regions analyzed, significant enrichments of enhancer overlaps in the immune-related blood category, and co-localized eQTL signals overlapping enhancers from the matching tissue class in ten regions (ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, EPHA1, FERMT2, ZCWPW1). In several cases, we identified dysregulation of long noncoding RNA (lncRNA) transcripts and applied the lncRNA target identification algorithm from INFERNO to characterize their downstream biological effects. We also validated the allele-specific effects of several variants on enhancer function using luciferase expression assays. By integrating functional genomics with GWAS signals, our analysis yielded insights into the regulatory mechanisms, tissue contexts, genes, and biological processes affected by noncoding genetic variation associated with LOAD risk.

%B J Alzheimers Dis %V 72 %P 301-318 %8 2019 Oct 29 %G eng %N 1 %R 10.3233/JAD-190568 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Intraneuronal Tau Misfolding Induced by Extracellular Amyloid-β Oligomers. %A Rudenko, Lauren K %A Wallrabe, Horst %A Periasamy, Ammasi %A Siller, Karsten H %A Svindrych, Zdenek %A Seward, Matthew E %A Best, Merci N %A Bloom, George S %X

Abnormal folding and aggregation of the microtubule-associated protein, tau, is a hallmark of several neurodegenerative disorders, including Alzheimer's disease (AD). Although normal tau is an intrinsically disordered protein, it does exhibit tertiary structure whereby the N- and C-termini are often in close proximity to each other and to the contiguous microtubule-binding repeat domains that extend C-terminally from the middle of the protein. Unfolding of this paperclip-like conformation might precede formation of toxic tau oligomers and filaments, like those found in AD brain. While there are many ways to monitor tau aggregation, methods to monitor changes in tau folding are not well established. Using full length human 2N4R tau doubly labeled with the Förster resonance energy transfer (FRET) compatible fluorescent proteins, Venus and Teal, on the N- and C-termini, respectively (Venus-Tau-Teal), intensity and lifetime FRET measurements were able to distinguish folded from unfolded tau in living cells independently of tau-tau intermolecular interactions. When expression was restricted to low levels in which tau-tau aggregation was minimized, Venus-Tau-Teal was sensitive to microtubule binding, phosphorylation, and pathogenic oligomers. Of particular interest is our finding that amyloid-β oligomers (AβOs) trigger Venus-Tau-Teal unfolding in cultured mouse neurons. We thus provide direct experimental evidence that AβOs convert normally folded tau into a conformation thought to predominate in toxic tau aggregates. This finding provides further evidence for a mechanistic connection between Aβ and tau at seminal stages of AD pathogenesis.

%B J Alzheimers Dis %V 71 %P 1125-1138 %8 2019 Oct 15 %G eng %N 4 %R 10.3233/JAD-190226 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Lipopolysaccharide Induced Opening of the Blood Brain Barrier on Aging 5XFAD Mouse Model. %A Barton, Shawn M %A Janve, Vaibhav A %A McClure, Richard %A Anderson, Adam %A Matsubara, Joanne A %A Gore, John C %A Pham, Wellington %X

The development of neurotherapeutics for many neurodegenerative diseases has largely been hindered by limited pharmacologic penetration across the blood-brain barrier (BBB). Previous attempts to target and clear amyloid-β (Aβ) plaques, a key mediator of neurodegenerative changes in Alzheimer's disease (AD), have had limited clinical success due to low bioavailability in the brain because of the BBB. Here we test the effects of inducing an inflammatory response to disrupt the BBB in the 5XFAD transgenic mouse model of AD. Lipopolysaccharide (LPS), a bacterial endotoxin recognized by the innate immune system, was injected at varying doses. 24 hours later, mice were injected with either thioflavin S, a fluorescent Aβ-binding small molecule or 30 nm superparamagnetic iron oxide (SPIO) nanoparticles, both of which are unable to penetrate the BBB under normal physiologic conditions. Our results showed that when pretreated with 3.0 mg/kg LPS, thioflavin S can be found in the brain bound to Aβ plaques in aged 5XFAD transgenic mice. Following the same LPS pretreatment, SPIO nanoparticles could also be found in the brain. However, when done on wild type or young 5XFAD mice, limited SPIO was detected. Our results suggest that the BBB in aged 5XFAD mouse model is susceptible to increased permeability mediated by LPS, allowing for improved delivery of the small molecule thioflavin S to target Aβ plaques and SPIO nanoparticles, which are significantly larger than antibodies used in clinical trials for immunotherapy of AD. Although this approach demonstrated efficacy for improved delivery to the brain, LPS treatment resulted in significant weight loss even at low doses, resulting from the induced inflammatory response. These findings suggest inducing inflammation can improve delivery of small and large materials to the brain for improved therapeutic or diagnostic efficacy. However, this approach must be balanced with the risks of systemic inflammation.

%B J Alzheimers Dis %V 67 %P 503-513 %8 2019 %G eng %N 2 %R 10.3233/JAD-180755 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Maintain Your Brain: Protocol of a 3-Year Randomized Controlled Trial of a Personalized Multi-Modal Digital Health Intervention to Prevent Cognitive Decline Among Community Dwelling 55 to 77 Year Olds. %A Heffernan, Megan %A Andrews, Gavin %A Fiatarone Singh, Maria A %A Valenzuela, Michael %A Anstey, Kaarin J %A Maeder, Anthony J %A McNeil, John %A Jorm, Louisa %A Lautenschlager, Nicola T %A Sachdev, Perminder S %A Ginige, Jeewani A %A Hobbs, Megan J %A Boulamatsis, Christos %A Chau, Tiffany %A Cobiac, Lynne %A Cox, Kay L %A Daniel, Kenneth %A Flood, Victoria M %A Guerrero, Yareni %A Gunn, Jane %A Jain, Nidhi %A Kochan, Nicole A %A Lampit, Amit %A Mavros, Yorgi %A Meiklejohn, Jacinda %A Noble, Yian %A O'Leary, Fiona %A Radd-Vagenas, Sue %A Walton, Courtney C %A Brodaty, Henry %X

BACKGROUND: Maintain Your Brain (MYB) is a randomized controlled trial of an online multi-modal lifestyle intervention targeting modifiable dementia risk factors with its primary aim being to reduce cognitive decline in an older age cohort.

METHODS: MYB aims to recruit 8,500 non-demented community dwelling 55 to 77 year olds from the Sax Institute's 45 and Up Study in New South Wales, Australia. Participants will be screened for risk factors related to four modules that comprise the MYB intervention: physical activity, nutrition, mental health, and cognitive training. Targeting risk factors will enable interventions to be personalized so that participants receive the most appropriate modules. MYB will run for three years and up to four modules will be delivered sequentially each quarter during year one. Upon completing a module, participants will continue to receive less frequent booster activities for their eligible modules (except for the mental health module) until the end of the trial.

DISCUSSION: MYB will be the largest internet-based trial to attempt to prevent cognitive decline and potentially dementia. If successful, MYB will provide a model for not just effective intervention among older adults, but an intervention that is scalable for broad use.

%B J Alzheimers Dis %V 70 %P S221-S237 %8 2019 %G eng %N s1 %R 10.3233/JAD-180572 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Methionine Sulfoxide Reductase-B3 Risk Allele Implicated in Alzheimer's Disease Associates with Increased Odds for Brain Infarcts. %A Conner, Sarah C %A Benayoun, Laurent %A Himali, Jayandra J %A Adams, Stephanie L %A Yang, Qiong %A DeCarli, Charles %A Blusztajn, Jan K %A Beiser, Alexa %A Seshadri, Sudha %A Delalle, Ivana %X

Genome-wide association studies identified a single nucleotide polymorphism (SNP) in the MSRB3 gene encoding Methionine Sulfoxide Reductase-B3 (MsrB3) to be associated with the risk for low hippocampal volume and late onset Alzheimer's disease (AD). Subsequently, we identified AD-associated abnormal patterns of neuronal and vascular MsrB3 expression in postmortem hippocampi. The present study investigated the relationship between the MSRB3 SNP rs61921502, G (minor/risk allele) and MRI measures of brain injury including total brain volume, hippocampal volume, and white matter hyperintensities using linear regression models; the presence of brain infarcts using logistic regression models; and the incidence of stroke, dementia, and AD using Cox proportional hazards models in 2,038 Framingham Heart Study Offspring participants with MRI administered close to examination cycle 7 (1998-2001). Participants with neurological conditions that impede evaluation of vascular pathology by MRI, i.e., brain tumors, multiple sclerosis, and major head trauma, were excluded from the study. When adjusted for age and age squared at MRI exam, sex, and presence of Apolipoproteinɛ4 allele (APOE4), individuals with MSRB3 rs61921502 minor allele had increased odds for brain infarcts on MRI compared to those with no minor allele. However, in stratified analyses, MSRB3 rs61921502 minor allele was significantly associated with increased odds for MRI brain infarcts only in the absence of APOE4.

%B J Alzheimers Dis %V 68 %P 357-365 %8 2019 Mar 12 %G eng %N 1 %R 10.3233/JAD-180977 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Neurodegenerative Disease-Related Proteins within the Epidermal Layer of the Human Skin. %A Akerman, S Can %A Hossain, Shireen %A Shobo, Adeola %A Zhong, Yifei %A Jourdain, Roland %A Hancock, Mark A %A George, Kelly %A Breton, Lionel %A Multhaup, Gerhard %X

There is increasing evidence suggesting that amyloidogenic proteins might form deposits in non-neuronal tissues in neurodegenerative disorders such as Alzheimer's or Parkinson's diseases. However, the detection of these aggregation-prone proteins within the human skin has been controversial. Using immunohistochemistry (IHC) and mass spectrometry tissue imaging (MALDI-MSI), fresh frozen human skin samples were analyzed for the expression and localization of neurodegenerative disease-related proteins. While α-synuclein was detected throughout the epidermal layer of the auricular samples (IHC and MALDI-MSI), tau and Aβ34 were also localized to the epidermal layer (IHC). In addition to Aβ peptides of varying length (e.g., Aβ40, Aβ42, Aβ34), we also were able to detect inflammatory markers within the same sample sets (e.g., thymosin β-4, psoriasin). While previous literature has described α-synuclein in the nucleus of neurons (e.g., Parkinson's disease), our current detection of α-synuclein in the nucleus of skin cells is novel. Imaging of α-synuclein or tau revealed that their presence was similar between the young and old samples in our present study. Future work may reveal differences relevant for diagnosis between these proteins at the molecular level (e.g., age-dependent post-translational modifications). Our novel detection of Aβ34 in human skin suggests that, just like in the brain, it may represent a stable intermediate of the Aβ40 and Aβ42 degradation pathway.

%B J Alzheimers Dis %V 69 %P 463-478 %8 2019 May 21 %G eng %N 2 %R 10.3233/JAD-181191 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Neuropsychological Deficit Profiles, Vascular Risk Factors, and Neuropathological Findings in Hispanic Older Adults with Autopsy-Confirmed Alzheimer's Disease. %A Weissberger, Gali H %A Gollan, Tamar H %A Bondi, Mark W %A Nation, Daniel A %A Hansen, Lawrence A %A Galasko, Douglas %A Salmon, David P %X

 This study aimed to determine if patterns of neuropsychological deficits, vascular risk factors, and neuropathology differ in Hispanic and Non-Hispanic patients with autopsy-confirmed Alzheimer's disease (AD). Participants were enrolled in a longitudinal study at the Shiley-Marcos AD Research Center at the University of California, San Diego. Hispanic (n = 14) and Non-Hispanic (n = 20) patients with autopsy-confirmed AD who scored ≥95 on the Dementia Rating Scale (DRS) were included. Patient groups were matched on age, education, global mental status, and severity of functional decline; they were compared to Hispanic (n = 14) or Non-Hispanic (n = 20) cognitively-normal controls of similar age and education. Ethnicity (Hispanic, Non-Hispanic) by disease state (autopsy-confirmed AD or cognitively normal) comparisons were made for cognitive test performance and vascular risk factors. Patient groups were further compared on measures of AD (Braak stage, neuritic plaques, neurofibrillary tangles), vascular neuropathology, and performance across cognitive domains of memory, language, attention, executive functions, and visuospatial abilities after scores were z-transformed based on respective culturally-appropriate control groups. Patient groups had similar overall AD pathology burden, whereas Hispanics with AD had more small parenchymal arteriolar disease and amyloid angiopathy than Non-Hispanics with AD. Despite largely similar pathology, Hispanics with AD were less cognitively impaired (relative to respective NC groups) than Non-Hispanics with AD, and exhibited a different pattern of deficits across cognitive domains. Findings suggest that cognitive deficits that are usually prominent in AD may be less salient in Hispanic patients and this may adversely impact the ability to clinically detect the disease in mild to moderate stages.

%B J Alzheimers Dis %V 67 %P 291-302 %8 2019 %G eng %N 1 %R 10.3233/JAD-180351 %0 Journal Article %J J Alzheimers Dis %D 2019 %T The Pathology of Rapid Cognitive Decline in Clinically Diagnosed Alzheimer's Disease. %A Nance, Christin %A Ritter, Aaron %A Miller, Justin B %A Lapin, Brittany %A Banks, Sarah J %X

BACKGROUND: Variable rate of cognitive decline among individuals with Alzheimer's disease (AD) is an important consideration for disease management, but risk factors for rapid cognitive decline (RCD) are without consensus.

OBJECTIVE: To investigate demographic, clinical, and pathological differences between RCD and normal rates of cognitive decline (NCD) in AD.

METHODS: Neuropsychology test and autopsy data was pulled from the National Alzheimer's Coordinating Center database from individuals with a clinical diagnosis of AD. Individuals with average decline of 3 or more points on the Mini-Mental Status Examination (MMSE) per year over 3 years were labeled RCD; all others were NCD.

RESULTS: Sixty individuals identified as RCD; 230 as NCD. These neuropsychology tests differed at baseline (RCD versus NCD): WMS-LM Immediate Recall (4.35[3.39] versus 6.31[3.97], p < 0.001), Animal Naming (12.1[4.83] versus 13.9[4.83], p = 0.007), TMT Part B (187[86.1] versus 159[79.0], p = 0.02), WAIS-Digit Symbol (29.5[11.3] versus 29.5[11.3], p = 0.04), and the BNT (21.5[7.05] versus 23.6[5.09], p = 0.04). RCD had more thyroid disease (30% versus 16%, p = 0.01) and greater usage of AD medication at baseline (80% versus 62%, p = 0.01). RCD had more severe cerebral amyloid angiopathy (1.62(1.0) versus1.13(1.0), p = 0.002), more neocortical Lewy bodies (20% versus 10%, p = 0.04), and more atrophy (1.54[0.92] versus 1.17[0.83], p = 0.04). A model combining select variables was significant above chance (χ2 = 25.8, p = 0.002), but not to clinical utility (AUC < 0.70; 95% CI).

CONCLUSION: Individuals with RCD have more severe pathology, more comorbidities, and lower baseline neuropsychology test scores of language and executive function.

%B J Alzheimers Dis %V 70 %P 983-993 %8 2019 Aug 20 %G eng %N 4 %R 10.3233/JAD-190302 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Preliminary Report on the Feasibility and Efficacy of the Modified Atkins Diet for Treatment of Mild Cognitive Impairment and Early Alzheimer's Disease. %A Brandt, Jason %A Buchholz, Alison %A Henry-Barron, Bobbie %A Vizthum, Diane %A Avramopoulos, Dimitrios %A Cervenka, Mackenzie C %X

Ketone bodies, the products of fat metabolism, are a source of energy for the brain and are available even when glucose supplies are inadequate (such as with severe carbohydrate deprivation) or its metabolism is faulty (as it is in Alzheimer's disease). This phase I/II randomized clinical trial examined the feasibility of using a modified Atkins diet (MAD) to induce ketogenesis in persons with mild cognitive impairment (MCI) or early AD, and the effect of this diet on memory and other clinical outcomes. In the first 2.5 years of active recruitment, only 27 eligible and willing patients enrolled. After extensive assessment and education, they and their study partners were randomly assigned for 12 weeks to either the MAD or the National Institute on Aging (NIA) recommended diet for seniors. As of April 2018, 9 patients in the MAD arm and 5 in the NIA arm have completed the trial. In spite of extensive teaching, coaching, and monitoring, adherence to both diets was only fair. Among those in the MAD arm who generated at least trace amounts of urinary ketones, there was a large (effect size = 0.53) and statistically significant (p = 0.03) increase in Memory Composite Score between the baseline and week-6 assessment. MAD participants also reported increased energy between baseline and week-6 assessment. Despite challenges to implementing this trial, resulting in a small sample, our preliminary data suggest that the generation of even trace ketones might enhance episodic memory and patient-reported vitality in very early AD.

%B J Alzheimers Dis %V 68 %P 969-981 %8 2019 Apr 8 %G eng %N 3 %R 10.3233/JAD-180995 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Present Algorithms and Future Treatments for Alzheimer's Disease. %A Grossberg, George T %A Tong, Gary %A Burke, Anna D %A Tariot, Pierre N %X

An estimated 47 million people live with Alzheimer's disease (AD) and other forms of dementia worldwide. Although no disease-modifying treatments are currently available for AD, earlier diagnosis and proper management of the disease could have considerable impact on patient and caregiver quality of life and functioning. Drugs currently approved for AD treat the cognitive, behavioral, and functional symptoms of the disease and consist of three cholinesterase inhibitors (ChEIs) and the N-methyl-D-aspartate receptor antagonist memantine. Treatment of patients with mild to moderate AD is generally initiated with a ChEI. Patients who show progression of symptoms while on ChEI monotherapy may be switched to another ChEI and/or memantine can be added to the treatment regimen. In recent years, putative disease-modifying therapies have emerged that aim to slow the progression of AD instead of only addressing its symptoms. However, many therapies have failed in clinical trials in patients with established AD, suggesting that, once developed, disease-modifying agents may need to be deployed earlier in the course of illness. The goal of this narrative literature review is to discuss present treatment algorithms and potential future therapies in AD.

%B J Alzheimers Dis %V 67 %P 1157-1171 %8 2019 %G eng %N 4 %R 10.3233/JAD-180903 %0 Journal Article %J J Alzheimers Dis %D 2019 %T The Prevalence and Subtypes of Young Onset Dementia in Central Norway: A Population-Based Study. %A Kvello-Alme, Marte %A Bråthen, Geir %A White, Linda R %A Sando, Sigrid Botne %X

BACKGROUND: Young onset dementia poses several challenges for the individual, health care, and society that are not normally relevant for late onset dementia, but is little researched.

OBJECTIVE: To determine the prevalence and subtypes of young onset dementia in a defined catchment area in central Norway.

METHODS: The main sources of patient identification were the databases at the Department of Neurology, University Hospital of Trondheim (St. Olav's Hospital), and Department of Psychiatry, Levanger Hospital. Both departments are the main sites for referral of young onset dementia (onset before age 65 years) in the county, covering approximately 90% of the catchment area of the study. Other sources included key persons in the communities, collaborating hospital departments examining dementia, and review of hospital records of all three hospitals in the area. Included patients met the DSM-IV criteria for dementia. The prevalence of dementias was calculated by sex and age.

RESULTS: All patients identified with dementia and onset before 65 years on census date were included in the study (n = 390). Patients younger than 65 on census date were included in the calculation of prevalence, giving a result of 76.3 per 100 000 persons at risk in the age category of 30-65 years, and 163.1 per 100,000 for the category 45-64 years. Etiology was heterogeneous, but the main subtype of dementia was Alzheimer's disease.

CONCLUSIONS: Young onset dementia affects a significant number of people in central Norway. Prevalence figures are higher than previously reported from England and Japan, but are similar to a more recent study from Australia.

%B J Alzheimers Dis %V 69 %P 479-487 %8 2019 %G eng %N 2 %R 10.3233/JAD-181223 %0 Journal Article %J J Alzheimers Dis %D 2019 %T A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Assessing Safety, Tolerability, and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe Alzheimer's Disease. %A Farlow, Martin R %A Thompson, Richard E %A Wei, Lee-Jen %A Tuchman, Alan J %A Grenier, Elaine %A Crockford, David %A Wilke, Susanne %A Benison, Jeffrey %A Alkon, Daniel L %X

BACKGROUND: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-β oligomers, and anti-hyperphosphorylated tau.

OBJECTIVES: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer's disease (AD) patients.

METHODS: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.v. bryostatin for 150 advanced AD patients (55-85) with MMSE-2 of 4-15, randomized 1:1:1 into 20 μg and 40 μg bryostatin, and placebo arms. The Full Analysis Set (FAS) and the Completer Analysis Set (CAS) were pre-specified alternative assessments (1-sided, p < 0.1 for primary efficacy, and 2-sided, p < 0.05 for pre-specified and post hoc exploratory analyses).

RESULTS: The safety profile was similar for 20 μg treatment and placebo patients. The 40 μg patients showed safety and drop-out issues, but no efficacy. Primary improvement of Severe Impairment Battery (SIB) scores at 13 weeks was not significant (p = 0.134) in the FAS, although in the CAS, the SIB comparison favored 20 μg bryostatin compared to placebo patients (p < 0.07). Secondary analyses at weeks 5 and 15 (i.e., 30 days post-final dosing) also favored 20 μg bryostatin compared to placebo patients. A pre-specified ANCOVA for baseline memantine blocking bryostatin and positive post-hoc trend analyses were statistically significant (2-sided, p < 0.05).

CONCLUSION: Although the primary endpoint was not significant in the FAS, primary and secondary analyses in the CAS, and pre-specified and post-hoc exploratory analyses did favor bryostatin 20 μg compared to the placebo cohort. These promising Phase II results support further trials of 20 μg bryostatin- without memantine- to treat AD.

%B J Alzheimers Dis %V 67 %P 555-570 %8 2019 %G eng %N 2 %R 10.3233/JAD-180759 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Self and Informant Memory Reports in FINGER: Associations with Two-Year Cognitive Change. %A Vaskivuo, Laura %A Hokkanen, Laura %A Hänninen, Tuomo %A Antikainen, Riitta %A Bäckman, Lars %A Laatikainen, Tiina %A Paajanen, Teemu %A Stigsdotter-Neely, Anna %A Strandberg, Timo %A Tuomilehto, Jaakko %A Soininen, Hilkka %A Kivipelto, Miia %A Ngandu, Tiia %X

BACKGROUND: Subjective memory complaints (SMCs) may be the first sign of cognitive decline in aging.

OBJECTIVE: To examine whether SMCs reported by oneself and informant predict cognitive change over 2 years among at-risk elderly people, and to determine the relationship of different types of SMCs (prospective and retrospective memory complaints) and change in cognitive function.

METHODS: This investigation is part of the FINGER project, which is a multicenter randomized controlled trial aiming at preventing cognitive decline in cognitively healthy older adults with increased risk of dementia. A subsample of 303 control-group participants (aged 60-80 years) and their informants (n = 261) rated the frequency of SMCs, using the Prospective and Retrospective Memory Questionnaire (PRMQ). Cognitive performance was measured at baseline and at 1- and 2-year follow-up visits using a neuropsychological test battery.

RESULTS: Participants who reported more SMCs improved less in global cognition, executive function, and memory during the subsequent 2 years in the fully-adjusted analyses. Self-reported retrospective memory problems predicted less improvement in all cognitive domains, whereas prospective memory problems did not. Informant-reported memory problems were not linked to subsequent change in cognition.

CONCLUSION: Our results indicate that self-reported SMCs, measured with PRMQ, predict future cognitive change in several cognitive domains. By contrast, reports by informants were not linked to changes in cognition. Among cognitively healthy at-risk elderly individuals, the persons themselves observe more easily problems relevant for their future cognitive trajectories than their informants.

%B J Alzheimers Dis %V 71 %P 785-795 %8 2019 Oct 1 %G eng %N 3 %R 10.3233/JAD-190133 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Sirtuin 3 Mediates Tau Deacetylation. %A Li, Shiping %A Yin, Junxiang %A Nielsen, Megan %A Beach, Thomas G %A Guo, Li %A Shi, Jiong %X

BACKGROUND: Emerging evidence shows tau acetylation has been observed in Alzheimer's disease (AD) brain at early Braak stages and is involved in regulating tau early accumulation. However, the effects of deacetylase Sirtuin 3 (Sirt3) on tau acetylation and its aggregations are unclear.

OBJECTIVE: We studied the effects of Sirt3 on tau acetylation and its aggregations.

METHODS: We investigated the protein levels of Sirt3 and tangle tau in human postmortem brains slices from AD, mild cognitive impairment, and age- and education-matched cognitively normal subjects, and AD model mice. We also measured tau acetylation levels in hippocampal HT22 cells after Sirt3 knockdown or overexpression.

RESULTS: The level of Sirt3 was inversely related with tau protein in brain slices from both human being and AD model mice. Mechanistically, tau acetylation decreased dramatically with Sirt3 overexpression, while tau acetylation increased after Sirt3 knockdown in hippocampal HT22 cells.

CONCLUSIONS: Sirt3 may play a role in tau acetylation and could be a potential target for novel therapy to alleviate tau accumulation.

%B J Alzheimers Dis %V 69 %P 355-362 %8 2019 May 21 %G eng %N 2 %R 10.3233/JAD-190014 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Small Molecule Amyloid-β Protein Precursor Processing Modulators Lower Amyloid-β Peptide Levels via cKit Signaling. %A Chen, Ci-Di %A Zeldich, Ella %A Khodr, Christina %A Camara, Kaddy %A Tung, Tze Yu %A Lauder, Emma C %A Mullen, Patrick %A Polanco, Taryn J %A Liu, Yen-Yu %A Zeldich, Dean %A Xia, Weiming %A Van Nostrand, William E %A Brown, Lauren E %A Porco, John A %A Abraham, Carmela R %X

Alzheimer's disease (AD) is characterized by the accumulation of neurotoxic amyloid-β (Aβ) peptides consisting of 39-43 amino acids, proteolytically derived fragments of the amyloid-β protein precursor (AβPP), and the accumulation of the hyperphosphorylated microtubule-associated protein tau. Inhibiting Aβ production may reduce neurodegeneration and cognitive dysfunction associated with AD. We have previously used an AβPP-firefly luciferase enzyme complementation assay to conduct a high throughput screen of a compound library for inhibitors of AβPP dimerization, and identified a compound that reduces Aβ levels. In the present study, we have identified an analog, compound Y10, which also reduced Aβ. Initial kinase profiling assays identified the receptor tyrosine kinase cKit as a putative Y10 target. To elucidate the precise mechanism involved, AβPP phosphorylation was examined by IP-western blotting. We found that Y10 inhibits cKit phosphorylation and increases AβPP phosphorylation mainly on tyrosine residue Y743, according to AβPP751 numbering. A known cKit inhibitor and siRNA specific to cKit were also found to increase AβPP phosphorylation and lower Aβ levels. We also investigated a cKit downstream signaling molecule, the Shp2 phosphatase, and found that known Shp2 inhibitors and siRNA specific to Shp2 also increase AβPP phosphorylation, suggesting that the cKit signaling pathway is also involved in AβPP phosphorylation and Aβ production. We further found that inhibitors of both cKit and Shp2 enhance AβPP surface localization. Thus, regulation of AβPP phosphorylation by small molecules should be considered as a novel therapeutic intervention for AD.

%B J Alzheimers Dis %V 67 %P 1089-1106 %8 2019 Feb 12 %G eng %N 3 %R 10.3233/JAD-180923 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Social Isolation and Cognitive Function in Later Life: A Systematic Review and Meta-Analysis. %A Evans, Isobel E M %A Martyr, Anthony %A Collins, Rachel %A Brayne, Carol %A Clare, Linda %X

BACKGROUND: There is some evidence to suggest that social isolation may be associated with poor cognitive function in later life. However, findings are inconsistent and there is wide variation in the measures used to assess social isolation.

OBJECTIVE: We conducted a systematic review and meta-analysis to investigate the association between social isolation and cognitive function in later life.

METHODS: A search for longitudinal studies assessing the relationship between aspects of social isolation (including social activity and social networks) and cognitive function (including global measures of cognition, memory, and executive function) was conducted in PsycInfo, CINAHL, PubMed, and AgeLine. A random effects meta-analysis was conducted to assess the overall association between measures of social isolation and cognitive function. Sub-analyses investigated the association between different aspects of social isolation and each of the measures of cognitive function.

RESULTS: Sixty-five articles were identified by the systematic review and 51 articles were included in the meta-analysis. Low levels of social isolation characterized by high engagement in social activity and large social networks were associated with better late-life cognitive function (r = 0.054, 95% CI: 0.043, 0.065). Sub-analyses suggested that the association between social isolation and measures of global cognitive function, memory, and executive function were similar and there was no difference according to gender or number of years follow-up.

CONCLUSIONS: Aspects of social isolation are associated with cognitive function in later life. There is wide variation in approaches to measuring social activity and social networks across studies which may contribute to inconsistencies in reported findings.

%B J Alzheimers Dis %V 70 %P S119-S144 %8 2019 %G eng %N s1 %R 10.3233/JAD-180501 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Spatially Distributed Amyloid-β Reduces Glucose Metabolism in Mild Cognitive Impairment. %A Carbonell, Felix %A Zijdenbos, Alex P %A Bedell, Barry J %X

BACKGROUND: Several positron emission tomography (PET) studies have explored the relationship between amyloid-β (Aβ), glucose metabolism, and the APOEɛ4 genotype. It has been reported that APOEɛ4, and not aggregated Aβ, contributes to glucose hypometabolism in pre-clinical stages of Alzheimer's disease (AD) pathology.

OBJECTIVE: We hypothesize that typical measurements of Aβ taken either from composite regions-of-interest with relatively high burden actually cover significant patterns of the relationship with glucose metabolism. In contrast, spatially weighted measures of Aβ are more related to glucose metabolism in cognitively normal (CN) aging and mild cognitive impairment (MCI).

METHODS: We have generated a score of amyloid burden based on a joint singular value decomposition (SVD) of the cross-correlation structure between glucose metabolism, as measured by [18F]2-fluoro-2-deoxyglucose (FDG) PET, and Aβ, as measured by [18F]florbetapir PET, from the Alzheimer's Disease Neuroimaging Initiative study. This SVD-based score reveals cortical regions where a reduced glucose metabolism is maximally correlated with distributed patterns of Aβ.

RESULTS: From an older population of CN and MCI subjects, we found that the SVD-based Aβ score was significantly correlated with glucose metabolism in several cortical regions. Additionally, the corresponding Aβ network has hubs that contribute to distributed glucose hypometabolism, which, in turn, are not necessarily foci of Aβ deposition.

CONCLUSIONS: Our approach uncovered hidden patterns of the glucose metabolism-Aβ relationship. We showed that the SVD-based Aβ score produces a stronger relationship with decreasing glucose metabolism than either APOEɛ4 genotype or global measures of Aβ burden.

%B J Alzheimers Dis %V 73 %P 543-557 %8 2020 Feb 04 %G eng %N 2 %R 10.3233/JAD-190560 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Stem Cell-Derived Neurons as Cellular Models of Sporadic Alzheimer's Disease. %A Foveau, Bénédicte %A Correia, Ana Sofia %A Hébert, Sébastien S %A Rainone, Sara %A Potvin, Olivier %A Kergoat, Marie-Jeanne %A Belleville, Sylvie %A Duchesne, Simon %A LeBlanc, Andréa C %X

Alzheimer's disease (AD) occurs as either an autosomal dominant inherited disease or sporadically. While familial mutant genes can be expressed in cells or in animal models to assess dysregulated functions, sporadic AD cannot be replicated in models given our lack of understanding of causality. Furthermore, the study of sporadic forms of AD is difficult given the inaccessibility of brain tissues in living individuals and the manifestation of symptoms years after the onset of disease. Here, the objective was to assess if induced pluripotent stem cell-derived neurons from well-ascertained sporadic AD individuals could represent potential cellular models to determine the underlying molecular mechanisms of disease. We used cryopreserved peripheral blood mononuclear cells from three well-ascertained sporadic AD and three non-cognitively impaired (NCI) individuals of the CIMA-Q cohort to obtain iPSC-derived neurons. Microtubule associated protein 2 was decreased in AD neurons, whereas expression of AD-associated amyloid precursor protein, tau, and amyloid-β peptide was similar in AD and NCI individuals. RNA sequencing identified several upregulated and downregulated mRNAs in AD relative to NCI neurons. Of these, complement Factor H (CFH), signal regulatory protein beta1 (SIRPB1), and insulin like growth factor binding protein 5 (IGFBP5) were previously associated with AD. In addition, several transcription factors not previously associated with AD, but involved in neuronal proliferation and differentiation were differentially expressed. The results identify novel avenues for the study of the underlying causes of sporadic AD and support the establishment of additional lines to identify mechanisms of disease in sporadic AD individuals.

%B J Alzheimers Dis %V 67 %P 893-910 %8 2019 %G eng %N 3 %R 10.3233/JAD-180833 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Subjective Cognitive Decline May Be a Stronger Predictor of Incident Dementia in Women than in Men. %A Heser, Kathrin %A Kleineidam, Luca %A Wiese, Birgitt %A Oey, Anke %A Roehr, Susanne %A Pabst, Alexander %A Kaduszkiewicz, Hanna %A van den Bussche, Hendrik %A Brettschneider, Christian %A König, Hans-Helmut %A Weyerer, Siegfried %A Werle, Jochen %A Fuchs, Angela %A Pentzek, Michael %A Mösch, Edelgard %A Bickel, Horst %A Maier, Wolfgang %A Scherer, Martin %A Riedel-Heller, Steffi G %A Wagner, Michael %X

BACKGROUND/OBJECTIVE: Subjective cognitive decline (SCD) has often been associated with an increased risk for subsequent dementia. However, sex-specific associations are understudied until now.

METHODS: Cross-sectional and longitudinal associations over a follow-up period of up to 13 years were investigated in a sample of participants without objective cognitive impairment at baseline (n = 2,422, mean age = 79.63 years). Logistic regression and Cox proportional hazards models were conducted.

RESULTS: Women less frequently reported SCD without worries (p <  0.001), but tended to report more often SCD with worries (p = 0.082) at baseline compared to men. In models adjusted for age, education, cognitive status, and depressive symptoms, SCD at baseline increased the risk for subsequent dementia (p <  0.001), and this effect was less pronounced in males (interaction sex×SCD: p = 0.022). Stratified analyses showed that SCD increased the risk for subsequent dementia in women (HR = 1.77, p <  0.001), but not in men (HR = 1.07, p = 0.682). Similar results were found in analyses with SCD without and with worries, except that SCD with worries also predicted subsequent Alzheimer's disease (AD) in men (p = 0.037).

CONCLUSION: At baseline, men reported more SCD without worries and women tended to report more SCD with worries. SCD in women was more strongly associated with subsequent dementia. SCD without and with worries was related to incident dementia and AD in women, whereas in men only SCD with worries increased the risk for AD, but not for all-cause dementia.

%B J Alzheimers Dis %V 68 %P 1469-1478 %8 2019 Apr 23 %G eng %N 4 %R 10.3233/JAD-180981 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Telomere Length and the Risk of Alzheimer's Disease: The Rotterdam Study. %A Fani, Lana %A Hilal, Saima %A Sedaghat, Sanaz %A Broer, Linda %A Licher, Silvan %A Arp, Pascal P %A van Meurs, Joyce B J %A Ikram, M Kamran %A Ikram, M Arfan %X

There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer's disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of Alzheimer's disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer's disease. We found a U-shaped association between telomere length and risk of Alzheimer's disease: compared to the middle tertile the adjusted hazard ratio was 1.59 (95% confidence interval (CI), 1.13-2.23) for the lowest tertile and 1.47 (1.03-2.10) for the highest tertile. Results were similarly U-shaped but slightly attenuated for all-cause dementia. In conclusion, shorter and longer telomere length are both associated with an increased risk of Alzheimer's disease in the general population.

%B J Alzheimers Dis %V 73 %P 707-714 %8 2020 Jan 21 %G eng %N 2 %R 10.3233/JAD-190759 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Tracking Cognitive Performance in the General Population and in Patients with Mild Cognitive Impairment with a Self-Applied Computerized Test (Brain on Track). %A Ruano, Luis %A Severo, Milton %A Sousa, Andreia %A Ruano, Catarina %A Branco, Mariana %A Barreto, Rui %A Moreira, Sandra %A Araújo, Natália %A Pinto, Paula %A Pais, Joana %A Lunet, Nuno %A Cruz, Vítor Tedim %X

Repeated measurements could be helpful to identify patients with early cognitive decline. We compare the variation of cognitive performance over one year in patients with mild cognitive impairment (MCI) and healthy individuals using the Brain on Track self-applied computerized test (BoT). The study was initiated 30 patients with probable MCI and 377 controls from a population-based cohort, who performed the BoT test from home every three months for one year. The scores were compared using a linear mixed-effects model. All participants increased their scores in the first tests, after 120 days MCI patients started to decline, with a statistically significant higher rate. The area under the curve to detect MCI was 0.94. We identified a significant decline in cognitive performance over one year in patients with MCI using BoT and the test presented a high discriminative ability.

%B J Alzheimers Dis %V 71 %P 541-548 %8 2019 Sep 17 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/31424407?dopt=Abstract %R 10.3233/JAD-190631 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Transcriptome Changes in the Alzheimer's Disease Middle Temporal Gyrus: Importance of RNA Metabolism and Mitochondria-Associated Membrane Genes. %A Piras, Ignazio S %A Krate, Jonida %A Delvaux, Elaine %A Nolz, Jennifer %A Mastroeni, Diego F %A Persico, Antonio M %A Jepsen, Wayne M %A Beach, Thomas G %A Huentelman, Matthew J %A Coleman, Paul D %X

We used Illumina Human HT-12 v4 arrays to compare RNA expression of middle temporal gyrus (MTG; BA21) in Alzheimer's disease (AD = 97) and non-demented controls (ND = 98). A total of 938 transcripts were highly differentially expressed (adj p < 0.01; log2 FC ≥ |0.500|, with 411 overexpressed and 527 underexpressed in AD. Our results correlated with expression profiling in neurons from AD and ND obtained by laser capture microscopy in MTG from an independent dataset (log2 FC correlation: r = 0.504; p = 2.2e-16). Additionally, selected effects were validated by qPCR. ANOVA analysis yielded no difference between genders in response to AD, but some gender specific genes were detected (e.g., IL8 and AGRN in males, and HSPH1 and GRM1 in females). Several transcripts were associated with Braak staging (e.g., AEBP1 and DNALI1), antemortem MMSE (e.g., AEBP1 and GFAP), and tangle density (e.g., RNU1G2, and DNALI1). At the pathway level, we detected enrichment of synaptic vesicle processes and GABAergic transmission genes. Finally, applying the Weighted Correlation Network Analysis, we identified four expression modules enriched for neuronal and synaptic genes, mitochondria-associated membrane, chemical stimulus and olfactory receptor and non-coding RNA metabolism genes. Our results represent an extensive description of MTG mRNA profiling in a large sample of AD and ND. These data provide a list of genes associated with AD, and correlated to neurofibrillary tangles density. In addition, these data emphasize the importance of mitochondrial membranes and transcripts related to olfactory receptors in AD.

%B J Alzheimers Dis %V 70 %P 691-713 %8 2019 Aug 3 %G eng %N 3 %R 10.3233/JAD-181113 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Treatment Combinations for Alzheimer's Disease: Current and Future Pharmacotherapy Options. %A Cummings, Jeffrey L %A Tong, Gary %A Ballard, Clive %X

Although Alzheimer's disease (AD) is the world's leading cause of dementia and the population of patients with AD continues to grow, no new therapies have been approved in more than a decade. Many clinical trials of single-agent therapies have failed to affect disease progression or symptoms compared with placebo. The complex pathophysiology of AD may necessitate combination treatments rather than monotherapy. The goal of this narrative literature review is to describe types of combination therapy, review the current clinical evidence for combination therapy regimens (both symptomatic and disease-modifying) in the treatment of AD, describe innovative clinical trial study designs that may be effective in testing combination therapy, and discuss the regulatory and drug development landscape for combination therapy. Successful combination therapies in other complex disorders, such as human immunodeficiency virus, may provide useful examples of a potential path forward for AD treatment.

%B J Alzheimers Dis %V 67 %P 779-794 %8 2019 %G eng %N 3 %R 10.3233/JAD-180766 %0 Journal Article %J J Alzheimers Dis %D 2019 %T TSPO Ligands Boost Mitochondrial Function and Pregnenolone Synthesis. %A Lejri, Imane %A Grimm, Amandine %A Hallé, François %A Abarghaz, Mustapha %A Klein, Christian %A Maitre, Michel %A Schmitt, Martine %A Bourguignon, Jean-Jacques %A Mensah-Nyagan, Ayikoe Guy %A Bihel, Frederic %A Eckert, Anne %X

 Translocator protein 18 kDa (TSPO) is located in the mitochondrial outer membrane and plays an important role in steroidogenesis and cell survival. In the central nervous system (CNS), its expression is upregulated in neuropathologies such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands based on an imidazoquinazolinone termed 2a and 2b, stimulated pregnenolone synthesis and ATP production in vitro. In the present study, we compared their effects to those of TSPO ligands described in the literature (XBD173, SSR-180,575, and Ro5-4864) by profiling the mitochondrial bioenergetic phenotype before and after treatment and investigating the protective effects of these ligands after oxidative injury in a cellular model of AD overexpressing amyloid-β (Aβ). Of note, ATP levels increased with rising pregnenolone levels suggesting that the energetic performance of mitochondria is linked to an increased production of this neurosteroid via TSPO modulation. Our results further demonstrate that the TSPO ligands 2a and 2b exerted neuroprotective effects by improving mitochondrial respiration, reducing reactive oxygen species and thereby decreasing oxidative stress-induced cell death as well as lowering Aβ levels. The compounds 2a and 2b show similar or even better functional effects than those obtained with the reference TSPO ligands XBD173 and SSR-180.575. These findings indicate that the new TSPO ligands modulate mitochondrial bioenergetic phenotype and protect against oxidative injury probably through the de novo synthesis of neurosteroids, suggesting that these compounds could be potential new therapeutic tools for the treatment of neurodegenerative disease.

%B J Alzheimers Dis %V 72 %P 1045-1058 %8 2019 Dec 12 %G eng %N 4 %R 10.3233/JAD-190127 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Two Year Outcomes, Cognitive and Behavioral Markers of Decline in Healthy, Cognitively Normal Older Persons with Global Deterioration Scale Stage 2 (Subjective Cognitive Decline with Impairment). %A Reisberg, Barry %A Torossian, Carol %A Shulman, Melanie B %A Monteiro, Isabel %A Boksay, Istvan %A Golomb, James %A Guillo Benarous, Francoise %A Ulysse, Anaztasia %A Oo, Thet %A Vedvyas, Alok %A Rao, Julia A %A Marsh, Karyn %A Kluger, Alan %A Sangha, Jaspreet %A Hassan, Mudasar %A Alshalabi, Munther %A Arain, Fauzia %A Shaikh, Naveed %A Buj, Maja %A Kenowsky, Sunnie %A Masurkar, Arjun V %A Rabin, Laura %A Noroozian, Maryam %A Sánchez-Saudinós, Mar A Belén %A Blesa, Rafael %A Auer, Stefanie %A Zhang, Yian %A de Leon, Mony %A Sadowski, Martin %A Wisniewski, Thomas %A Gauthier, Serge %A Shao, Yongzhao %X

BACKGROUND: Little is known with respect to behavioral markers of subjective cognitive decline (SCD), a condition initially described in association with Global Deterioration Scale (GDS) stage 2.

OBJECTIVE: Two-year interval behavioral markers were investigated herein.

METHODS: Subjects from a published 7-year outcome study of GDS stage 2 subjects were selected. This study had demonstrated a hazard ratio of 4.5 for progression of GDS stage 2, in comparison with GDS stage 1 (no subjective or objective cognitive decline) subjects, after controlling for demographic and temporal variables. Because GDS 2 subjects have previously demonstrated impairment in comparison with healthy persons free of complaints, we herein suggest the terminology "SCD(I)" for these persons. 98 SCD(I) persons, 63 women and 35 men, mean baseline age, 67.12±8.75 years, with a mean educational background of 15.55±2.60 years, and mean baseline MMSE scores of 28.9±1.24 were followed for 2.13±0.30 years.

RESULTS: Observed annual decline on the GDS was 6.701% per annum, very close to a 1986 published estimate. At follow up, the MMSE, and 7 of 8 psychometric tests did not decline significantly. Of 21 Hamilton Depression Scale items, 2 improved and the remainder were unchanged. Anxieties declined from multiple perspectives. The Brief Cognitive Rating Scale (BCRS) declined significantly (p < 0.001), with component declines in Remote memory (p < 0.01), and Functioning/self-care (p = 0.01).

CONCLUSION: SCD(I) persons decline at an annual rate of approximately 6.7% /year from several recent studies. The BCRS assessments and the Digit Symbol Substitution Test can be sensitive measures for future studies of progression mitigation.

%B J Alzheimers Dis %V 67 %P 685-705 %8 2019 Jan 22 %G eng %N 2 %R 10.3233/JAD-180341 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Ultrasensitive Detection of Plasma Amyloid-β as a Biomarker for Cognitively Normal Elderly Individuals at Risk of Alzheimer's Disease. %A Chatterjee, Pratishtha %A Elmi, Mitra %A Goozee, Kathryn %A Shah, Tejal %A Sohrabi, Hamid R %A Dias, Cintia B %A Pedrini, Steve %A Shen, Kaikai %A Asih, Prita R %A Dave, Preeti %A Taddei, Kevin %A Vanderstichele, Hugo %A Zetterberg, Henrik %A Blennow, Kaj %A Martins, Ralph N %X

BACKGROUND: Aberrant amyloid-β (Aβ) deposition in the brain occurs two decades prior to the manifestation of Alzheimer's disease (AD) clinical symptoms and therefore brain Aβ load measured using PET serves as a gold standard biomarker for the early diagnosis of AD. However, the uneconomical nature of PET makes blood markers, that reflect brain Aβ deposition, attractive candidates for investigation as surrogate markers.

OBJECTIVE: Investigation of plasma Aβ as a surrogate marker for brain Aβ deposition in cognitively normal elderly individuals.

METHODS: Plasma Aβ40 and Aβ42 concentrations were measured using the ultrasensitive Single Molecule Array (Simoa) assay in 95 cognitively normal elderly individuals, who have all undergone PET to assess brain Aβ deposition. Based on the standard uptake value ratios (SUVR) obtained from PET imaging, using the tracer 18F-Florbetaben, plasma Aβ was compared between 32 participants assessed to have low brain Aβ load (Aβ-, SUVR <1.35) and 63 assessed to have high brain Aβ load (Aβ+, SUVR ≥1.35).

RESULTS: Plasma Aβ42/Aβ40 ratios were lower in the Aβ+ group compared to the Aβ-group. Plasma Aβ40 and Aβ42 levels were not significantly different between Aβ-and Aβ+ groups, although a trend of higher plasma Aβ40 was observed in the Aβ+ group. Additionally, plasma Aβ42/Aβ40 ratios along with the known AD risk factors, age and APOEɛ4 status, resulted in Aβ+ participants being distinguished from Aβ-participants based on an area under the receiver operating characteristic curve shown to be 78%.

CONCLUSION: Plasma Aβ ratios in this study are a potential biomarker for brain Aβ deposition and therefore, for preclinical AD. However, this method to measure plasma Aβ needs further development to increase the accuracy of this promising AD blood biomarker.

%B J Alzheimers Dis %V 71 %P 775-783 %8 2019 Oct 1 %G eng %N 3 %R 10.3233/JAD-190533 %0 Journal Article %J J Alzheimers Dis %D 2019 %T An UNC5C Allele Predicts Cognitive Decline and Hippocampal Atrophy in Clinically Normal Older Adults. %A Yang, Hyun-Sik %A Chhatwal, Jasmeer P %A Xu, Jishu %A White, Charles C %A Hanseeuw, Bernard %A Rabin, Jennifer S %A Papp, Kathryn V %A Buckley, Rachel F %A Schultz, Aaron P %A Properzi, Michael J %A Gatchel, Jennifer R %A Amariglio, Rebecca E %A Donovan, Nancy J %A Mormino, Elizabeth C %A Hedden, Trey %A Marshall, Gad A %A Rentz, Dorene M %A Johnson, Keith A %A De Jager, Philip L %A Sperling, Reisa A %X

BACKGROUND: The UNC5C rs3846455G allele has been linked to poor cognitive resilience against age-related neuropathologies, but this association remains to be replicated, and the allele's effect on hippocampal neurodegeneration needs to be examined.

OBJECTIVE: To further validate the association between rs3846455G and faster cognitive decline, especially among cognitively normal older adults, and to assess whether rs3846455G predicts accelerated hippocampal volume loss in older adults.

METHODS: We assessed participants in the Harvard Aging Brain Study (HABS), a longitudinal cohort study of older adults who were clinically normal at baseline. To avoid bias from population admixture, analyses were limited to participants of European descent with longitudinal neuroimaging data (n = 174). Linear mixed effect models were used to examine the effect of rs3846455G on longitudinal change of the Preclinical Alzheimer Cognitive Composite (PACC) and MRI-measured bilateral hippocampal volume, adjusting for baseline amyloid-β (Aβ) measured by the cortical Pittsburgh Compound B PET distributed volume ratio. We also tested whether hippocampal atrophy mediates the association between rs3846455G and greater PACC decline through a mediation analysis.

RESULTS: rs3846455G was associated with greater PACC decline (β= -0.087/year, 95% CI -0.169 to -0.005, p = 0.039) after controlling for baseline Aβ. Further, rs3846455G predicted accelerated hippocampal atrophy after controlling for baseline Aβ (β= -57.3 mm3/year, 95% CI -102.8 to -11.9, p = 0.014). The association between rs3846455G and greater PACC decline was partially mediated by accelerated hippocampal atrophy (mediated effect (relative scale) = -0.014, 95% CI -0.032 to -6.0×10-4, p = 0.039).

CONCLUSION: UNC5C rs3846455G predicts greater cognitive decline and accelerated hippocampal atrophy in clinically normal older adults.

%B J Alzheimers Dis %V 68 %P 1161-1170 %8 2019 Apr 8 %G eng %N 3 %R 10.3233/JAD-180788 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Understanding the Amyloid Hypothesis in Alzheimer's Disease. %A Paroni, Giulia %A Bisceglia, Paola %A Seripa, Davide %X

The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer's disease (IAD). However, despite the neuropathological overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, we suggested that amyloid-β (Aβ) peptides production and AP formation is a physiological aging process resulting from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. In this pathogenetic model Aβ peptides act as neurotoxic molecules, but only above a critical concentration [Aβ]c. A threshold mechanism triggers IAD/NIAD onset only when [Aβ]≥[Aβ]c. In this process, APOE modifies [Aβ]c threshold in an isoform-specific way. Consequently, all factors influencing Aβ anabolism, such as amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) gene mutations, and/or Aβ catabolism/clearance could contribute to exceed the threshold [Aβ]c, being characteristic of each individual. In this model, AP formation does not depend on [Aβ]c. The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD.

%B J Alzheimers Dis %V 68 %P 493-510 %8 2019 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/30883346?dopt=Abstract %R 10.3233/JAD-180802 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Upregulation of Thioredoxin-Interacting Protein in Brain of Amyloid-β Protein Precursor/Presenilin 1 Transgenic Mice and Amyloid-β Treated Neuronal Cells. %A Wang, Yiran %A Wang, Ying %A Bharti, Veni %A Zhou, Hong %A Hoi, Vanessa %A Tan, Hua %A Wu, Zijian %A Nagakannan, Pandian %A Eftekharpour, Eftekhar %A Wang, Jun-Feng %X

Oxidative stress has been hypothesized to play a role in the pathophysiology of Alzheimer's disease (AD). Previously, we found that total nitrosylated protein levels were increased in the brain of amyloid-β protein precursor (AβPP) and presenilin 1 (PS1) double transgenic mice, an animal model for AD, suggesting that cysteine oxidative protein modification may contribute to this disease. Thioredoxin (Trx) is a major oxidoreductase that can reverse cysteine oxidative modifications such as sulfenylation and nitrosylation, and inhibit oxidative stress. Thioredoxin-interacting protein (Txnip) is an endogenous Trx inhibitor. To understand the involvement of Trx and Txnip in AD development, we investigated Trx and Txnip in the brain of AβPP/PS1 mice. Using immunoblotting analysis, we found that although Trx protein levels were not changed, Txnip protein levels were significantly increased in hippocampus and frontal cortex of 9- and 12-month-old AβPP/PS1 mice when compared to wild-type mice. Txnip protein levels were also increased by amyloid-β treatment in primary cultured mouse cerebral cortical neurons and HT22 mouse hippocampal cells. Using biotin switch and dimedone conjugation methods, we found that amyloid-β treatment increased protein nitrosylation and sulfenylation in HT22 cells. We also found that downregulation of Txnip, using CRISPR/Cas9 method in HT22 cells, attenuated amyloid-β-induced protein nitrosylation and sulfenylation. Our findings suggest that amyloid-β may increase Txnip levels, subsequently inhibiting Trx reducing capability and enhancing protein cysteine oxidative modification. Our findings also indicate that Txnip may be a potential target for the treatment of AD.

%B J Alzheimers Dis %V 72 %P 139-150 %8 2019 Oct 29 %G eng %N 1 %R 10.3233/JAD-190223 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Why Is Amyloid-β PET Requested After Performing Cerebrospinal Fluid Biomarkers? %A Reimand, Juhan %A Groot, Colin %A Teunissen, Charlotte E %A Windhorst, Albert D %A Boellaard, Ronald %A Barkhof, Frederik %A Nazarenko, Sergei %A van der Flier, Wiesje M %A van Berckel, Bart N M %A Scheltens, Philip %A Ossenkoppele, Rik %A Bouwman, Femke %X

BACKGROUND: Amyloid-β PET and cerebrospinal fluid (CSF) Aβ42 are considered interchangeable for clinical diagnosis of Alzheimer's disease.

OBJECTIVE: To explore the clinical reasoning for requesting additional amyloid-β PET after performing CSF biomarkers.

METHODS: We retrospectively identified 72 memory clinic patients who underwent amyloid-β PET after CSF biomarkers analysis for clinical diagnostic evaluation between 2011 and 2019. We performed patient chart reviews to identify factors which led to additional amyloid-β PET. Additionally, we assessed accordance with appropriate-use-criteria (AUC) for amyloid-β PET.

RESULTS: Mean patient age was 62.0 (SD = 8.1) and mean Mini-Mental State Exam score was 23.6 (SD = 3.8). CSF analysis conflicting with the clinical diagnosis was the most frequent reason for requesting an amyloid-β PET scan (n = 53, 74%), followed by incongruent MRI (n = 16, 22%), unusual clinical presentation (n = 11, 15%) and young age (n = 8, 11%). An amyloid-β PET scan was rarely (n = 5, 7%) requested in patients with a CSF Aβ+/tau+ status. Fifteen (47%) patients with a post-PET diagnosis of AD had a predominantly non-amnestic presentation. In n = 11 (15%) cases, the reason that the clinician requested amyloid-β was not covered by AUC. This happened most often (n = 7) when previous CSF analysis did not support current clinical diagnosis, which led to requesting amyloid-β PET.

CONCLUSION: In this single-center study, the main reason for requesting an amyloid-β PET scan after performing CSF biomarkers was the occurrence of a mismatch between the primary clinical diagnosis and CSF Aβ/tau results.

%B J Alzheimers Dis %V 73 %P 559-569 %8 2020 Jan 21 %G eng %N 2 %R 10.3233/JAD-190836 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A 10-Year Follow-Up of Adiposity and Dementia in Swedish Adults Aged 70 Years and Older. %A Arnoldussen, Ilse A C %A Sundh, Valter %A Bäckman, Kristoffer %A Kern, Silke %A Östling, Svante %A Blennow, Kaj %A Zetterberg, Henrik %A Skoog, Ingmar %A Kiliaan, Amanda J %A Gustafson, Deborah R %X

BACKGROUND: Adiposity measured in mid- or late-life and estimated using anthropometric measures such as body mass index (BMI) and waist-to-hip ratio (WHR), or metabolic markers such as blood leptin and adiponectin levels, is associated with late-onset dementia risk. However, during later life, this association may reverse and aging- and dementia-related processes may differentially affect adiposity measures.

OBJECTIVE: We explored associations of concurrent BMI, WHR, and blood leptin and high molecular weight adiponectin levels with dementia occurrence.

METHODS: 924 Swedish community-dwelling elderly without dementia, aged 70 years and older, systematically-sampled by birth day and birth year population-based in the Gothenburg city region of Sweden. The Gothenburg Birth Cohort Studies are designed for evaluating risk and protective factors for dementia. All dementias diagnosed after age 70 for 10 years were identified. Multivariable logistic regression models were used to predict dementia occurrence between 2000-2005, 2005-2010, and 2000-2010 after excluding prevalent baseline (year 2000) dementias. Baseline levels of BMI, WHR, leptin, and adiponectin were used.

RESULTS: Within 5 years of baseline, low BMI (<20 kg/m2) was associated with higher odds of dementia compared to those in the healthy BMI category (≥ 20-24.9 kg/m2). Compared to the lowest quartile, leptin levels in the second quartile were associated with lower odds of dementia in women (p < 0.05).

CONCLUSION: In late-life, anthropometric and metabolic adiposity measures appear to be differentially associated with dementia risk. While BMI and leptin levels are highly positively correlated, our results show that their association with dementia at age ≥70 years, is asynchronous. These data suggest that with aging, the complexity of the adiposity exposure may increase and suggests metabolic dysregulation. Additional studies are needed to better understand this complexity.

%B J Alzheimers Dis %V 63 %P 1325-1335 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758945?dopt=Abstract %R 10.3233/JAD-180099 %0 Journal Article %J J Alzheimers Dis %D 2018 %T 18F-FDG PET for Prediction of Conversion to Alzheimer's Disease Dementia in People with Mild Cognitive Impairment: An Updated Systematic Review of Test Accuracy. %A Smailagic, Nadja %A Lafortune, Louise %A Kelly, Sarah %A Hyde, Chris %A Brayne, Carol %X

BACKGROUND: A previous Cochrane systematic review concluded there is insufficient evidence to support the routine use of 18F-FDG PET in clinical practice in people with mild cognitive impairment (MCI).

OBJECTIVES: To update the evidence and reassess the accuracy of 18F-FDG-PET for detecting people with MCI at baseline who would clinically convert to Alzheimer's disease (AD) dementia at follow-up.

METHODS: A systematic review including comprehensive search of electronic databases from January 2013 to July 2017, to update original searches (1999 to 2013). All key review steps, including quality assessment using QUADAS 2, were performed independently and blindly by two review authors. Meta-analysis could not be conducted due to heterogeneity across studies.

RESULTS: When all included studies were examined across all semi-quantitative and quantitative metrics, exploratory analysis for conversion of MCI to AD dementia (n = 24) showed highly variable accuracy; half the studies failed to meet four or more of the seven sets of QUADAS 2 criteria. Variable accuracy for all metrics was also found across eleven newly included studies published in the last 5 years (range: sensitivity 56-100%, specificity 24-100%). The most consistently high sensitivity and specificity values (approximately ≥80%) were reported for the sc-SPM (single case statistical parametric mapping) metric in 6 out of 8 studies.

CONCLUSION: Systematic and comprehensive assessment of studies of 18FDG-PET for prediction of conversion from MCI to AD dementia reveals many studies have methodological limitations according to Cochrane diagnostic test accuracy gold standards, and shows accuracy remains highly variable, including in the most recent studies. There is some evidence, however, of higher and more consistent accuracy in studies using computer aided metrics, such as sc-SPM, in specialized clinical settings. Robust, methodologically sound prospective longitudinal cohort studies with long (≥5 years) follow-up, larger consecutive samples, and defined baseline threshold(s) are needed to test these promising results. Further evidence of the clinical validity and utility of 18F-FDG PET in people with MCI is needed.

%B J Alzheimers Dis %V 64 %P 1175-1194 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010119?dopt=Abstract %R 10.3233/JAD-171125 %0 Journal Article %J J Alzheimers Dis %D 2018 %T 18F-Flortaucipir Binding in Choroid Plexus: Related to Race and Hippocampus Signal. %A Lee, Christopher M %A Jacobs, Heidi I L %A Marquié, Marta %A Becker, John A %A Andrea, Nicolas V %A Jin, David S %A Schultz, Aaron P %A Frosch, Matthew P %A Gómez-Isla, Teresa %A Sperling, Reisa A %A Johnson, Keith A %X

BACKGROUND: On target 18F-Flortaucipir (FTP) binding of Alzheimer's disease tau aggregates and off-target binding of melanocytes have been demonstrated with autoradiography.

OBJECTIVE: We aimed to investigate the hypothesis that if binding in choroid plexus (CP) is due to melanocytes, the signal would be elevated in Black/African American (B/AA) compared to White (W) participants. In addition, we examined whether CP signal affects measurements in adjacent regions, and whether correcting for spill-in effects has an influence on associations between hippocampus (HC) FTP and amyloid or cognition.

METHODS: FTP race differences in 147 Harvard Aging Brain Study participants (23 B/AA, 124W) were examined in CP, HC, HC covaried for CP, amygdala, inferior temporal gyrus, entorhinal cortex, and fusiform regions. Associations between CP FTP and other regions-of-interest (ROIs) were probed to assess spill-in effects. A statistical regression approach to attenuate CP spill-in was tested by relating adjusted HC SUVR residuals and unadjusted HC SUVR to race, cognition and amyloid. All analyses were covaried for age, sex, education and amyloid deposition, and Bonferroni-corrected for multiple comparisons.

RESULTS: B/AA individuals had elevated CP and HC SUVR (p < 0.007), whereas other ROI SUVR and HC SUVR covaried for CP SUVR did not show race differences (p > 0.05). CP SUVR was associated with HC SUVR (p < 10-14), but with no other ROI SUVR (p > 0.05). When adjusting HC SUVR for CP SUVR, no race differences in residual HC SUVR were detected, and relationships with amyloid and memory became apparent.

CONCLUSION: Melanocyte FTP binding may account partially for high CP signal. This off-target binding affects mainly HC FTP measurements, which should be interpreted with caution.

%B J Alzheimers Dis %V 62 %P 1691-1702 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614677?dopt=Abstract %R 10.3233/JAD-170840 %0 Journal Article %J J Alzheimers Dis %D 2018 %T [18F]-Flutemetamol Uptake in Cortex and White Matter: Comparison with Cerebrospinal Fluid Biomarkers and [18F]-Fludeoxyglucose. %A Kalheim, Lisa Flem %A Fladby, Tormod %A Coello, Christopher %A Bjørnerud, Atle %A Selnes, Per %X

Flutemetamol (18F-Flut) is an [18F]-labelled amyloid PET tracer with increasing availability. The main objectives of this study were to investigate 1) cerebrospinal fluid (CSF) Aβ 1-42 (Aβ42) concentrations associated with regional 18F-Flut uptake, 2) associations between cortical 18F-Flut and [18F]-fludeoxyglucose (18F-FDG)-PET, and 3) the potential use of 18F-Flut in WM pathology. Cognitively impaired, nondemented subjects were recruited (n = 44). CSF was drawn, and 18F-Flut-PET, 18F-FDG-PET, and MRI performed. Our main findings were: 1) Different Alzheimer's disease predilection areas showed increased 18F-Flut retention at different CSF Aβ42 concentrations (posterior regions were involved at higher concentrations). 2) There were strong negative correlations between regional cortical 18F-Flut and 18F-FDG uptake. 3) Increased 18F-Flut uptake were observed in multiple subcortical regions in amyloid positive subjects, including investigated reference regions. However, WM hyperintensity 18F-Flut standardized uptake value ratios (SUVr) were not significantly different, thus we cannot definitely conclude that the higher uptake in 18F-Flut(+) is due to amyloid deposition. In conclusion, our findings support clinical use of CSF Aβ42, putatively relate decreasing CSF Aβ42 concentrations to a sequence of regional amyloid deposition, and associate amyloid pathology to cortical hypometabolism. However, we cannot conclude that 18F-Flut-PET is a suitable marker for WM pathology due to high aberrant WM uptake.

%B J Alzheimers Dis %V 62 %P 1595-1607 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504529?dopt=Abstract %R 10.3233/JAD-170582 %0 Journal Article %J J Alzheimers Dis %D 2018 %T ABCA7 Downregulation Modifies Cellular Cholesterol Homeostasis and Decreases Amyloid-β Peptide Efflux in an in vitro Model of the Blood-Brain Barrier. %A Lamartinière, Yordenca %A Boucau, Marie-Christine %A Dehouck, Lucie %A Krohn, Markus %A Pahnke, Jens %A Candela, Pietra %A Gosselet, Fabien %A Fenart, Laurence %X

The role of ABCA7 in brain homeostasis and Alzheimer's disease (AD) is currently under intense scrutiny, since it has been reported that polymorphisms in the Abca7 gene and a loss of function of the protein are closely linked to excessive accumulation of amyloid peptides and disturbed cholesterol homeostasis. The blood-brain barrier (BBB), which isolates the brain from the blood compartment, is involved in both of these processes. We therefore hypothesized that ABCA7 downregulation might affect cholesterol and amyloid exchanges at the BBB. Using siRNA and primary cultures of mouse endothelial cells purified from brain microvessels and seeded on Transwell ® inserts, we investigated the role of ABCA7 in cholesterol and amyloid exchanges across the BBB. Our results showed that a decrease in ABCA7 expression at the BBB provokes in vitro a reduction in ABCA1 expression and a decrease in APOE secretion. In vitro, these decreases reduce cholesterol exchange across the BBB, particularly for high-density lipoproteins and ApoA-I particles. When ABCA7 was absent, we observed a reduction in Aβ peptide basolateral-to-apical transport in the presence of ApoA-I, with non-significant changes in the expression levels of Rage, Lrp1, Abcb1, Abcc1, and Abcg2. Our study in murine BBB model highlighted a putative new role for ABCA7 in AD via the protein's involvement in cholesterol metabolism and amyloid clearance at the BBB.

%B J Alzheimers Dis %V 64 %P 1195-1211 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010117?dopt=Abstract %R 10.3233/JAD-170883 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Abnormalities of Resting State Cortical EEG Rhythms in Subjects with Mild Cognitive Impairment Due to Alzheimer's and Lewy Body Diseases. %A Babiloni, Claudio %A Del Percio, Claudio %A Lizio, Roberta %A Noce, Giuseppe %A Lopez, Susanna %A Soricelli, Andrea %A Ferri, Raffaele %A Pascarelli, Maria Teresa %A Catania, Valentina %A Nobili, Flavio %A Arnaldi, Dario %A Famá, Francesco %A Aarsland, Dag %A Orzi, Francesco %A Buttinelli, Carla %A Giubilei, Franco %A Onofrj, Marco %A Stocchi, Fabrizio %A Vacca, Laura %A Stirpe, Paola %A Fuhr, Peter %A Gschwandtner, Ute %A Ransmayr, Gerhard %A Garn, Heinrich %A Fraioli, Lucia %A Pievani, Michela %A Frisoni, Giovanni B %A D'Antonio, Fabrizia %A de Lena, Carlo %A Güntekin, Bahar %A Hanoğlu, Lutfu %A Başar, Erol %A Yener, Görsev %A Emek-Savaş, Derya Durusu %A Triggiani, Antonio Ivano %A Franciotti, Raffaella %A Taylor, John Paul %A De Pandis, Maria Francesca %A Bonanni, Laura %X

The present study tested the hypothesis that cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and dementia with Lewy bodies (DLBMCI) as compared to cognitively normal elderly (Nold) subjects. Clinical and rsEEG data in 30 ADMCI, 23 DLBMCI, and 30 Nold subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) score was matched between the ADMCI and DLBMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROCC) classified these sources across individuals. Compared to Nold, IAF showed marked slowing in DLBMCI and moderate in ADMCI. Furthermore, the posterior alpha 2 and alpha 3 source activities were more abnormal in the ADMCI than the DLBMCI group, while widespread delta source activities were more abnormal in the DLBMCI than the ADMCI group. The posterior delta and alpha sources correlated with the MMSE score and correctly classified the Nold and MCI individuals (area under the ROCC >0.85). In conclusion, the ADMCI and DLBMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test the clinical validity of these rsEEG markers.

%B J Alzheimers Dis %V 62 %P 247-268 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439335?dopt=Abstract %R 10.3233/JAD-170703 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Accuracy of Inferred APOE Genotypes for a Range of Genotyping Arrays and Imputation Reference Panels. %A Lupton, Michelle K %A Medland, Sarah E %A Gordon, Scott D %A Goncalves, Tabatha %A MacGregor, Stuart %A Mackey, David A %A Young, Terri L %A Duffy, David L %A Visscher, Peter M %A Wray, Naomi R %A Nyholt, Dale R %A Bain, Lisa %A Ferreira, Manuel A %A Henders, Anjali K %A Wallace, Leanne %A Montgomery, Grant W %A Wright, Margaret J %A Martin, Nicholas G %X

Cohort studies investigating aging and dementia require APOE genotyping. We compared directly measured APOE genotypes to 'hard-call' genotypes derived from imputing genome-wide genotyping data from a range of platforms using several imputation panels. Older GWAS arrays imputed to 1000 Genomes Project (1KGP) phases and the Haplotype Reference Consortium (HRC) reference panels were able to achieve concordance rates of over 98% with stringent quality control (hard-call-threshold 0.8). However, this resulted in high levels of missingness (>12% with 1KGP and 5% with HRC). With recent GWAS arrays, concordance of 99% could be obtained with relatively lenient QC, resulting in no missingness.

%B J Alzheimers Dis %V 64 %P 49-54 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865051?dopt=Abstract %R 10.3233/JAD-171104 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Added Diagnostic Value of Cerebrospinal Fluid Biomarkers for Differential Dementia Diagnosis in an Autopsy-Confirmed Cohort. %A Niemantsverdriet, Ellis %A Feyen, Bart F E %A Le Bastard, Nathalie %A Martin, Jean-Jacques %A Goeman, Johan %A De Deyn, Peter Paul %A Bjerke, Maria %A Engelborghs, Sebastiaan %X

BACKGROUND: Differential dementia diagnosis remains a challenge due to overlap of clinical profiles, which often results in diagnostic doubt.

OBJECTIVE: Determine the added diagnostic value of cerebrospinal fluid (CSF) biomarkers for differential dementia diagnosis as compared to autopsy-confirmed diagnosis.

METHODS: Seventy-one dementia patients with autopsy-confirmed diagnoses were included in this study. All neuropathological diagnoses were established according to standard neuropathological criteria and consisted of Alzheimer's disease (AD) or other dementias (NONAD). CSF levels of Aβ1 - 42, T-tau, and P-tau181 were determined and interpreted based on the IWG-2 and NIA-AA criteria, separately. A panel of three neurologists experienced with dementia made clinical consensus dementia diagnoses. Clinical and CSF biomarker diagnoses were compared to the autopsy-confirmed diagnoses.

RESULTS: Forty-two patients (59%) had autopsy-confirmed AD, whereas 29 patients (41%) had autopsy-confirmed NONAD. Of the 24 patients with an ambiguous clinical dementia diagnosis, a correct diagnosis would have been established in 67% of the cases applying CSF biomarkers in the context of the IWG-2 or the NIA-AA criteria respectively.

CONCLUSION: AD CSF biomarkers have an added diagnostic value in differential dementia diagnosis and can help establishing a correct dementia diagnosis in case of ambiguous clinical dementia diagnoses.

%B J Alzheimers Dis %V 63 %P 373-381 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614653?dopt=Abstract %R 10.3233/JAD-170927 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Age-Related Changes in the Spatial Frequency Threshold of Male and Female 3xTg-AD Mice Using OptoMotry. %A King, Jillian L %A Wong, Aimée A %A Brown, Richard E %K Aging %K Alzheimer Disease %K Animals %K Disease Models, Animal %K Female %K Humans %K Male %K Maze Learning %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Sex Characteristics %K tau Proteins %K Vision, Ocular %X

Visual impairments and retinal abnormalities occur in patients with Alzheimer's disease (AD) and in mouse models of AD. It is important to know the visual ability of mouse models of AD to ensure that age-related cognitive deficits are not confounded by visual impairments. Using OptoMotry, the spatial frequency thresholds of male and female 3xTg-AD mice did not differ from their B6129SF2 wildtype controls between 1-18 months of age, but females had higher spatial frequency thresholds than males. However, the differences were quite small, and the visual ability of all mice was comparable to that of C57BL/6 mice.

%B J Alzheimers Dis %V 62 %P 591-596 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480178?dopt=Abstract %R 10.3233/JAD-170805 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Aging-Related Calcium Dysregulation in Rat Entorhinal Neurons Homologous with the Human Entorhinal Neurons in which Alzheimer's Disease Neurofibrillary Tangles First Appear. %A Gant, John C %A Kadish, Inga %A Chen, Kuey-Chu %A Thibault, Olivier %A Blalock, Eric M %A Porter, Nada M %A Landfield, Philip W %X

Aging is the leading risk factor for idiopathic Alzheimer's disease (AD), indicating that normal aging processes promote AD and likely are present in the neurons in which AD pathogenesis originates. In AD, neurofibrillary tangles (NFTs) appear first in entorhinal cortex, implying that aging processes in entorhinal neurons promote NFT pathogenesis. Using electrophysiology and immunohistochemistry, we find pronounced aging-related Ca2 + dysregulation in rat entorhinal neurons homologous with the human neurons in which NFTs originate. Considering that humans recapitulate many aspects of animal brain aging, these results support the hypothesis that aging-related Ca2 + dysregulation occurs in human entorhinal neurons and promotes NFT pathogenesis.

%B J Alzheimers Dis %V 66 %P 1371-1378 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412490?dopt=Abstract %R 10.3233/JAD-180618 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alterations in the Plasma Levels of Specific Choline Phospholipids in Alzheimer's Disease Mimic Accelerated Aging. %A Dorninger, Fabian %A Moser, Ann B %A Kou, Jianqiu %A Wiesinger, Christoph %A Forss-Petter, Sonja %A Gleiss, Andreas %A Hinterberger, Margareta %A Jungwirth, Susanne %A Fischer, Peter %A Berger, Johannes %X

Alzheimer's disease (AD) is the most common neurodegenerative disease and of continuously rising prevalence. The identification of easy-to-measure biomarkers capable to assist in the prediction and early diagnosis of AD is currently a main research goal. Lipid metabolites in peripheral blood of human patients have recently gained major attention in this respect. Here, we analyzed plasma of 174 participants (not demented at baseline; mean age: 75.70±0.44 years) of the Vienna Transdanube Aging (VITA) study, a longitudinal, population-based birth cohort study, at baseline and after 90 months or at diagnosis of probable AD. We determined the levels of specific choline phospholipids, some of which have been suggested as potential biomarkers for the prediction of AD. Our results show that during normal aging the levels of lysophosphatidylcholine, choline plasmalogen, and lyso-platelet activating factor increase significantly. Notably, we observed similar but more pronounced changes in the group that developed probable AD. Thus, our results imply that, in terms of choline-containing plasma phospholipids, the conversion to AD mimics an accelerated aging process. We conclude that age, even in the comparatively short time frame between 75 and 82.5 years, is a crucial factor in the quest for plasma lipid biomarkers for AD that must be carefully considered in future studies and trials.

%B J Alzheimers Dis %V 62 %P 841-854 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480199?dopt=Abstract %R 10.3233/JAD-171036 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Altered Expression of Circulating Cdc42 in Frontotemporal Lobar Degeneration. %A Saraceno, Claudia %A Catania, Marcella %A Paterlini, Anna %A Fostinelli, Silvia %A Ciani, Miriam %A Zanardini, Roberta %A Binetti, Giuliano %A Di Fede, Giuseppe %A Caroppo, Paola %A Benussi, Luisa %A Ghidoni, Roberta %A Bolognin, Silvia %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Case-Control Studies %K cdc42 GTP-Binding Protein %K Female %K Frontotemporal Lobar Degeneration %K Humans %K Male %K Middle Aged %X

The term frontotemporal lobar degeneration (FTLD) defines a group of heterogeneous conditions histologically characterized by neuronal degeneration, inclusions of various proteins, and synaptic loss. However, the molecular mechanisms contributing to these alterations are still unknown. As the Rho-GTPase family member Cell division cycle 42 (Cdc42) plays a key role in the regulation of actin cytoskeleton dynamics and spine formation, we investigated whether Cdc42 protein levels were altered in the disease. Cdc42 was increased in the frontal cortex of FTLD patients compared to age-matched controls, but also in Alzheimer's disease (AD) patients included in the data-set. On the other hand, the pool of circulating Cdc42 in the plasma was altered in FTLD but not in AD patients. Interestingly, the stratification of the FTLD patients according to the different clinical variants showed a specific decrease of Cdc42 expression in the behavioral subgroup. This data support a role of Cdc42 in FTLD and specifically in the behavioral variant.

%B J Alzheimers Dis %V 61 %P 1477-1483 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376863?dopt=Abstract %R 10.3233/JAD-170722 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Altered microRNA, mRNA, and Protein Expression of Neurodegeneration-Related Biomarkers and Their Transcriptional and Epigenetic Modifiers in a Human Tau Transgenic Mouse Model in Response to Developmental Lead Exposure. %A Masoud, Anwar M %A Bihaqi, Syed W %A Alansi, Bothaina %A Dash, Miriam %A Subaiea, Gehad M %A Renehan, William E %A Zawia, Nasser H %X

Amyloid deposits originating from the amyloid-β protein precursor (AβPP) and aggregates of the microtubule associated protein tau (MAPT) are the hallmarks of Alzheimer's disease (AD). Animal studies have demonstrated a link between early life exposure to lead (Pb) and latent overexpression of the AβPP and MAPT genes and their products via epigenetic reprogramming. The present study monitored APP gene and epigenetic mediators and transcription factors known to regulate it. Western blot analysis and quantitative polymerase chain reaction (qPCR) were used to study the mRNA, miRNA, and proteins levels of AβPP, specificity protein 1 (SP1; a transcriptional regulator of amyloid and tau pathway), and epigenetic intermediates namely: DNA methyltransferase (DNMT) 1, DNMT3a and Methyl- CpG protein binding 2 (MeCP2) in the cerebral cortex of transgenic mice (Knock-in for human MAPT). These transgenic mice were developmentally exposed to Pb and the impact on mRNA, miRNA, and protein levels was scrutinized on postnatal days (PND) 20 and 50. The data revealed a consistent inverse relationship between miRNA and protein levels for SP1 and AβPP both in the basal and exposed conditions, which may influence the levels of their corresponding proteins. On the other hand, the relationship between miRNA and protein levels was not correlative for DNMT1 and DNMT3a. MeCP2 miRNA protein levels corresponded only following environmental exposure. These results suggest that developmental exposure to Pb and subsequent AβPP protein levels may be controlled through transcriptional regulators and epigenetic mechanisms that mainly involve miRNA regulation.

%B J Alzheimers Dis %V 63 %P 273-282 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614648?dopt=Abstract %R 10.3233/JAD-170824 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer-Like Pattern of Hypometabolism Emerges with Elevated Amyloid-β Burden in Down Syndrome. %A Lao, Patrick J %A Handen, Ben L %A Betthauser, Tobey J %A Mihaila, Iulia %A Hartley, Sigan L %A Cohen, Annie D %A Tudorascu, Dana L %A Bulova, Peter D %A Lopresti, Brian J %A Tumuluru, Rameshwari V %A Murali, Dhanabalan %A Mathis, Chester A %A Barnhart, Todd E %A Stone, Charles K %A Price, Julie C %A Devenny, Darlynne A %A Johnson, Sterling C %A Klunk, William E %A Christian, Bradley T %K Adult %K Alzheimer Disease %K Amyloid beta-Peptides %K Down Syndrome %K Female %K Fluorodeoxyglucose F18 %K Gray Matter %K Humans %K Linear Models %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Positron-Emission Tomography %K Radiopharmaceuticals %K United States %X

BACKGROUND: The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimer's disease (AD).

OBJECTIVE: The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD.

METHODS: Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent [11C]PiB, [18F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest.

RESULTS: Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume.

CONCLUSIONS: In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions.

%B J Alzheimers Dis %V 61 %P 631-644 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254096?dopt=Abstract %R 10.3233/JAD-170720 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Amyloid-β is an Antimicrobial Peptide: A Review of the Evidence. %A Gosztyla, Maya L %A Brothers, Holly M %A Robinson, Stephen R %X

The amyloid-β (Aβ) peptide has long been considered to be the driving force behind Alzheimer's disease (AD). However, clinical trials that have successfully reduced Aβ burden in the brain have not slowed the cognitive decline, and in some instances, have resulted in adverse outcomes. While these results can be interpreted in different ways, a more nuanced picture of Aβ is emerging that takes into account the facts that the peptide is evolutionarily conserved and is present throughout life in cognitively normal individuals. Recent evidence indicates a role for Aβ as an antimicrobial peptide (AMP), a class of innate immune defense molecule that utilizes fibrillation to protect the host from a wide range of infectious agents. In humans and in animal models, infection of the brain frequently leads to increased amyloidogenic processing of the amyloid-β protein precursor (AβPP) and resultant fibrillary aggregates of Aβ. Evidence from in vitro and in vivo studies demonstrates that Aβ oligomers have potent, broad-spectrum antimicrobial properties by forming fibrils that entrap pathogens and disrupt cell membranes. Importantly, overexpression of Aβ confers increased resistance to infection from both bacteria and viruses. The antimicrobial role of Aβ may explain why increased rates of infection have been observed in some of the AD clinical trials that depleted Aβ. Perhaps progress toward a cure for AD will accelerate once treatment strategies begin to take into account the likely physiological functions of this enigmatic peptide.

%B J Alzheimers Dis %V 62 %P 1495-1506 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504537?dopt=Abstract %R 10.3233/JAD-171133 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease: A Journey from Amyloid Peptides and Oxidative Stress, to Biomarker Technologies and Disease Prevention Strategies-Gains from AIBL and DIAN Cohort Studies. %A Martins, Ralph N %A Villemagne, Victor %A Sohrabi, Hamid R %A Chatterjee, Pratishtha %A Shah, Tejal M %A Verdile, Giuseppe %A Fraser, Paul %A Taddei, Kevin %A Gupta, Veer B %A Rainey-Smith, Stephanie R %A Hone, Eugene %A Pedrini, Steve %A Lim, Wei Ling %A Martins, Ian %A Frost, Shaun %A Gupta, Sunil %A O'Bryant, Sid %A Rembach, Alan %A Ames, David %A Ellis, Kathryn %A Fuller, Stephanie J %A Brown, Belinda %A Gardener, Samantha L %A Fernando, Binosha %A Bharadwaj, Prashant %A Burnham, Samantha %A Laws, Simon M %A Barron, Anna M %A Goozee, Kathryn %A Wahjoepramono, Eka J %A Asih, Prita R %A Doecke, James D %A Salvado, Olivier %A Bush, Ashley I %A Rowe, Christopher C %A Gandy, Samuel E %A Masters, Colin L %X

Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-β peptide (also known as Aβ or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aβ peptide in Alzheimer's disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E ɛ4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aβ.

%B J Alzheimers Dis %V 62 %P 965-992 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562546?dopt=Abstract %R 10.3233/JAD-171145 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease: Advances in Drug Development. %A Piton, Morgane %A Hirtz, Christophe %A Desmetz, Caroline %A Milhau, Jacqueline %A Lajoix, Anne Dominique %A Bennys, Karim %A Lehmann, Sylvain %A Gabelle, Audrey %X

As of 2018, Alzheimer's disease (AD) is the most common form of neurodegenerative dementia. It contributes to a progressive neuron loss, deterioration of memory, and cognitive impairment. Current therapies may provide a symptomatic benefit, but do not treat the underlying process. Ongoing researches focus on understanding the causal mechanisms and finding neuropathological hallmarks of AD. Therapeutic approaches targeting senile plaques or neurofibrillary tangles have not yet resulted in a significant cognitive improvement. However, recent data according to the analysis of AD clinical trials (clinicaltrials.gov database) show promising results. This literature review aims at summarizing the recent advances and at highlighting the most promising results of the ongoing researches. It compares the merits of small-molecules, antibodies, cell, and gene-based therapies and emphasizes the need for treatment at earlier stages of the disease.

%B J Alzheimers Dis %V 65 %P 3-13 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040716?dopt=Abstract %R 10.3233/JAD-180145 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease in Systemic Sclerosis Patients: A Nationwide Population-Based Cohort Study. %A Watad, Abdulla %A Bragazzi, Nicola L %A Tiosano, Shmuel %A Yavne, Yarden %A Comaneshter, Doron %A Cohen, Arnon D %A Amital, Howard %X

BACKGROUND: Neurological features are often overlooked in systemic sclerosis (SSc) patients and little is known about the link between dementia and SSc.

OBJECTIVES: We sought to investigate whether an association exists between Alzheimer's disease (AD) and SSc, as well as assess the impact of a dual diagnosis on mortality rates, by performing an extensive data analysis on a large subject sample.

METHODS: We utilized the medical database of the Clalit-Health-Services in a case-control study. Patients with SSc were compared with age- and sex-matched controls with regard to the prevalence of AD and its impact on their mortality.

RESULTS: Our study included 2,431 SSc patients and 12,377 age- and sex-matched controls. The mean age of the study population was 63.32±18.06 years and the female to male ratio was 4.5:1. 134 (5.5%) cases had AD as a co-morbidity in comparison with 749 (5.9%) of the controls. The mortality rate was 12.5% among controls and 26.2% among SSc cases. On the Cox multivariate survival analysis, diagnosis of SSc and AD demonstrated significant HRs (2.35 (95% CI 2.05-2.69, p < 0.0001) and 2.19 (95% CI 1.94-2.48, p < 0.0001), respectively). SSc patients with AD had a relative risk of death of 2.35 (95% CI: 1.44-3.83) in comparison with SSc patients without AD.

CONCLUSION: AD is a predictor of death in SSc and therefore preemptive screening may be warranted. Further studies are needed to evaluate whether improvements in the medical regimen for SSc may lead to a reduction in AD development and possibly to increased survival as well.

%B J Alzheimers Dis %V 65 %P 117-124 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040736?dopt=Abstract %R 10.3233/JAD-180516 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease, Oligomers, and Inflammation. %A Forloni, Gianluigi %A Balducci, Claudia %X

The production of soluble amyloid-β oligomers (AβOs) and the activation of inflammation are two important early steps in the pathogenesis of Alzheimer's disease (AD). The central role of oligomers as responsible for the neuronal dysfunction associated with the clinical features has been extended to the other protein misfolding disorders definable, on this basis, as oligomeropathies. In AD, recent evidence indicates that the mechanism of inflammation as a consequence of neurodegeneration must be assessed in favor of a more direct role of glial activation in the alteration of synaptic function. Our own experimental models demonstrate the efficacy of anti-inflammatory treatments in preventing the cognitive deficits induced acutely by AβOs applied directly in the brain. Moreover, some promising clinical tools are based on immunological activation reducing the presence of cerebral Aβ deposits. However, the strategies based on the control of inflammatory factors as well as the amyloid aggregation show poor or non-therapeutic efficacy. Numerous studies have examined inflammatory factors in biological fluids as possible markers of the neuroinflammation in AD. In some cases, altered levels of cytokines or other inflammatory markers in cerebrospinal fluid correlate with the severity of the disease. Here we propose, according to the precision medicine principles, innovative therapeutic approaches to AD based on the patient's inflammatory profile/state. The earlier intervention and a multifactor approach are two other elements considered essential to improve the chances of effective therapy in AD.

%B J Alzheimers Dis %V 62 %P 1261-1276 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562537?dopt=Abstract %R 10.3233/JAD-170819 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease Progression: Factors Influencing Cognitive Decline. %A Ferrari, Camilla %A Lombardi, Gemma %A Polito, Cristina %A Lucidi, Giulia %A Bagnoli, Silvia %A Piaceri, Irene %A Nacmias, Benedetta %A Berti, Valentina %A Rizzuto, Debora %A Fratiglioni, Laura %A Sorbi, Sandro %K Aged %K Aged, 80 and over %K Alleles %K Alzheimer Disease %K Apolipoprotein E4 %K Aspirin %K Cognitive Dysfunction %K Disease Progression %K Female %K Heterozygote %K Humans %K Italy %K Male %K Middle Aged %K Neuropsychological Tests %K Retrospective Studies %K Secondary Prevention %X

BACKGROUND: Alzheimer's disease (AD) patients present high variability in the rate of cognitive decline. Despite the wide knowledge on factors influencing dementia risk, little is known on what accounts for AD progression. Previous studies on this topic have mainly analyzed each factor separately without taking into account the interaction between genetic and non-genetic factors.

OBJECTIVE: The aim of the present study is to evaluate the role of demographic, clinical, therapeutic, and genetic factors and their interaction on cognitive decline among newly diagnosed AD patients.

METHODS: We retrospectively selected 160 AD patients diagnosed at the Neurology Unit of Careggi University Hospital of Florence. We evaluated the occurrence of rapid cognitive changes defined as the worsening of more than four points at the Mini-Mental State Examination after 2-year follow up period.

RESULTS: Among the 160 AD patients, 50% presented rapid disease progression. Extrapyramidal signs at disease onset were predictors of worse outcome (OR 2.2), especially among Apolipoprotein E (APOE) ɛ4 allele carriers, while the presence of family history for dementia decreased the risk of rapid progression by about 50%. Higher educated ɛ4-carriers showed a slower AD progression. We identified the chronic use of aspirin as potential secondary preventative strategy for the non ɛ4-carriers.

CONCLUSION: At dementia onset, some clinical and demographic data can be predictors of future progression. The outcomes of the present study support the already hypothesized interaction between genetic and non-genetic factors during disease course and suggest genetic-based approaches.

%B J Alzheimers Dis %V 61 %P 785-791 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226870?dopt=Abstract %R 10.3233/JAD-170665 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease rs11767557 Variant Regulates EPHA1 Gene Expression Specifically in Human Whole Blood. %A Liu, Guiyou %A Zhang, Yan %A Wang, Longcai %A Xu, Jianyong %A Chen, Xiaoyun %A Bao, Yunjuan %A Hu, Yang %A Jin, Shuilin %A Tian, Rui %A Bai, Weiyang %A Zhou, Wenyang %A Wang, Tao %A Han, Zhifa %A Zong, Jian %A Jiang, Qinghua %K Alzheimer Disease %K Case-Control Studies %K China %K Gene Expression %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Polymorphism, Single Nucleotide %K Receptor, EphA1 %K Risk Assessment %X

Large-scale genome-wide association studies have reported EPHA1 rs11767557 variant to be associated with Alzheimer's disease (AD) risk in the European population. However, it is still unclear how this variant functionally contributes to the underlying disease pathogenesis. The rs11767557 variant is located approximately 3 kb upstream of EPHA1 gene. We think that rs11767557 may modify the expression of nearby genes such as EPHA1 and further cause AD risk. Until now, the potential association between rs11767557 and the expression of nearby genes has not been reported in previous studies. Here, we evaluate the potential expression association between rs11767557 and EPHA1 using multiple large-scale eQTLs datasets in human brain tissues and the whole blood. The results show that rs11767557 variant could significantly regulate EPHA1 gene expression specifically in human whole blood. These findings may further provide important supplementary information about the regulating mechanisms of rs11767557 variant in AD risk.

%B J Alzheimers Dis %V 61 %P 1077-1088 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332039?dopt=Abstract %R 10.3233/JAD-170468 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Amyloid and FDG PET of Successful Cognitive Aging: Global and Cingulate-Specific Differences. %A Baran, Timothy M %A Lin, Feng Vankee %X

BACKGROUND: Some individuals, called Supernormals (SN), maintain excellent memory in old age. While brain structural and functional integrity in SN seem to be aging-resistant, their amyloidosis and neural injury status has not been well studied.

OBJECTIVE: The goal of this study was to compare cortical amyloid deposition and glucose metabolism between SN and older adults with normal cognition (NC), amnestic mild cognitive impairment (MCI), and Alzheimer's disease (AD).

METHODS: Subjects from the ADNI database were included if they received T1-weighted MRI, amyloid PET, FDG-PET, and cognitive testing within a 6-month period, yielding 27 AD, 69 MCI, 172 NC, and 122 SN. PET standardized uptake value ratios (SUVrs) were calculated for the whole cortex and 68 regions of interest, with whole cerebellum serving as reference.

RESULTS: SN had lower whole cortex amyloid than MCI, and higher glucose metabolism than all others. Regional analysis revealed that amyloid burden and glucose metabolism in the right isthmus cingulate cortex differed in SN compared to others, while SN glucose metabolism also differed from others in several frontal and temporal regions.

CONCLUSION: Preserved cortical glucose metabolism, and lower levels of amyloidosis and glucose hypometabolism in the right isthmus cingulate cortex, contributes to the Supernormal phenomenon. These findings may be informative for development of early screening biomarkers and therapeutic targets for modification of cognitive trajectories.

%B J Alzheimers Dis %V 66 %P 307-318 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282358?dopt=Abstract %R 10.3233/JAD-180360 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade. %A Cline, Erika N %A Bicca, Maíra Assunção %A Viola, Kirsten L %A Klein, William L %X

The amyloid-β oligomer (AβO) hypothesis was introduced in 1998. It proposed that the brain damage leading to Alzheimer's disease (AD) was instigated by soluble, ligand-like AβOs. This hypothesis was based on the discovery that fibril-free synthetic preparations of AβOs were potent CNS neurotoxins that rapidly inhibited long-term potentiation and, with time, caused selective nerve cell death (Lambert et al., 1998). The mechanism was attributed to disrupted signaling involving the tyrosine-protein kinase Fyn, mediated by an unknown toxin receptor. Over 4,000 articles concerning AβOs have been published since then, including more than 400 reviews. AβOs have been shown to accumulate in an AD-dependent manner in human and animal model brain tissue and, experimentally, to impair learning and memory and instigate major facets of AD neuropathology, including tau pathology, synapse deterioration and loss, inflammation, and oxidative damage. As reviewed by Hayden and Teplow in 2013, the AβO hypothesis "has all but supplanted the amyloid cascade." Despite the emerging understanding of the role played by AβOs in AD pathogenesis, AβOs have not yet received the clinical attention given to amyloid plaques, which have been at the core of major attempts at therapeutics and diagnostics but are no longer regarded as the most pathogenic form of Aβ. However, if the momentum of AβO research continues, particularly efforts to elucidate key aspects of structure, a clear path to a successful disease modifying therapy can be envisioned. Ensuring that lessons learned from recent, late-stage clinical failures are applied appropriately throughout therapeutic development will further enable the likelihood of a successful therapy in the near-term.

%B J Alzheimers Dis %V 64 %P S567-S610 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843241?dopt=Abstract %R 10.3233/JAD-179941 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Amyloid-β/Drug Interactions from Computer Simulations and Cell-Based Assays. %A Nguyen, Phuong H %A Del Castillo-Frias, Maria P %A Berthoumieux, Olivia %A Faller, Peter %A Doig, Andrew J %A Derreumaux, Philippe %X

Targeting the early oligomers formed by the amyloid-β (Aβ) peptide of 40 and 42 amino acids is considered one promising therapeutic approach for Alzheimer's disease (AD). In vitro experiments and computer simulations are often used in synergy to reveal the modes of interactions of drugs. In this account, we present our contribution to understanding how small molecules bind to Aβ40/Aβ42 peptides, based either on extensive coarse-grained and all-atom simulations, or a variety of experimental techniques. We conclude by offering several perspectives on the future of this field to design more efficient drugs.

%B J Alzheimers Dis %V 64 %P S659-S672 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562512?dopt=Abstract %R 10.3233/JAD-179902 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Antemortem-Postmortem Correlation of Florbetapir (18F) PET Amyloid Imaging with Quantitative Biochemical Measures of Aβ42 but not Aβ40. %A Beach, Thomas G %A Maarouf, Chera L %A Intorcia, Anthony %A Sue, Lucia I %A Serrano, Geidy E %A Lu, Ming %A Joshi, Abhinay %A Pontecorvo, Michael J %A Roher, Alex E %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloidosis %K Aniline Compounds %K Autopsy %K Brain %K Ethylene Glycols %K Humans %K Linear Models %K Peptide Fragments %K Plaque, Amyloid %K Positron-Emission Tomography %X

Amyloid imaging demonstrates the in vivo presence of amyloid-β (Aβ) deposits in the aging human brain but it is still unknown which structural forms and modifications of Aβ are detected. In Alzheimer's disease, most amyloid deposits are predominantly composed of Aβ ending at amino acid residues Val40 or Ala42. It has been reported that Aβ40 is largely restricted to neuritic plaques while Aβ42 may be deposited in amyloid plaques of all types, and is often the sole component of diffuse plaques. The distinction is important as it is mainly the neuritic plaques that correlate with cognitive impairment while diffuse plaques may be the initial type of Aβ deposited. Whether PET amyloid ligands such as florbetapir-18F (Amyvid) are partially or wholly selective for brain deposits of Aβ40 or Aβ42 is currently unknown. We compared antemortem florbetapir PET cortical/cerebellar signal intensity (SUVr) of 55 subjects with postmortem biochemical (ELISA) measurements employing specific antibodies against Aβ40 and Aβ42. Spearman's univariable correlations were significant for both Aβ40 and Aβ42, but were much stronger for Aβ42. Multiple linear regression showed significance only for Aβ42. These results suggest that florbetapir binds only weakly, if at all, to Aβ40. This may be in part due to the higher likelihood for Aβ42 to be present in a β-pleated sheet tertiary structure, or to differences between Aβ40 and Aβ42 in β-pleated sheet tertiary or quaternary structure.

%B J Alzheimers Dis %V 61 %P 1509-1516 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376867?dopt=Abstract %R 10.3233/JAD-170762 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Anti-Tau Monoclonal Antibodies Derived from Soluble and Filamentous Tau Show Diverse Functional Properties in vitro and in vivo. %A Vandermeeren, Marc %A Borgers, Marianne %A Van Kolen, Kristof %A Theunis, Clara %A Vasconcelos, Bruno %A Bottelbergs, Astrid %A Wintmolders, Cindy %A Daneels, Guy %A Willems, Roland %A Dockx, Koen %A Delbroek, Lore %A Marreiro, André %A Ver Donck, Luc %A Sousa, Cristiano %A Nanjunda, Rupesh %A Lacy, Eilyn %A Van De Casteele, Tom %A Van Dam, Debby %A De Deyn, Peter Paul %A Kemp, John A %A Malia, Thomas J %A Mercken, Marc H %X

The tau spreading hypothesis provides rationale for passive immunization with an anti-tau monoclonal antibody to block seeding by extracellular tau aggregates as a disease-modifying strategy for the treatment of Alzheimer's disease (AD) and potentially other tauopathies. As the biochemical and biophysical properties of the tau species responsible for the spatio-temporal sequences of seeding events are poorly defined, it is not yet clear which epitope is preferred for obtaining optimal therapeutic efficacy. Our internal tau antibody collection has been generated by immunizations with different tau species: aggregated- and non-aggregated tau and human postmortem AD brain-derived tau fibrils. In this communication, we describe and characterize a set of these anti-tau antibodies for their biochemical and biophysical properties, including binding, tissue staining by immunohistochemistry, and epitope. The antibodies bound to different domains of the tau protein and some were demonstrated to be isoform-selective (PT18 and hTau56) or phospho-selective (PT84). Evaluation of the antibodies in cellular- and in vivo seeding assays revealed clear differences in maximal efficacy. Limited proteolysis experiments support the hypothesis that some epitopes are more exposed than others in the tau seeds. Moreover, antibody efficacy seems to depend on the structural properties of fibrils purified from tau Tg mice- and postmortem human AD brain.

%B J Alzheimers Dis %V 65 %P 265-281 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040731?dopt=Abstract %R 10.3233/JAD-180404 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Aphasia in Progressive Supranuclear Palsy: As Severe as Progressive Non-Fluent Aphasia. %A Burrell, James R %A Ballard, Kirrie J %A Halliday, Glenda M %A Hodges, John R %K Aged %K Aged, 80 and over %K Case-Control Studies %K Cognition %K Female %K Humans %K Language Tests %K Male %K Middle Aged %K Primary Progressive Nonfluent Aphasia %K Semantics %K Speech %K Supranuclear Palsy, Progressive %X

BACKGROUND: Adynamic speech is characteristic of progressive supranuclear palsy (PSP), but higher language deficits have been reported inconsistently, in the context of clinical and pathological overlaps with progressive non-fluent aphasia (PNFA).

OBJECTIVE: The present study tested two hypotheses: 1) PSP and PNFA display impaired single word repetition, object naming, semantic knowledge, and syntactic comprehension; and 2) PSP have reduced speed on timed cognitive tasks.

METHODS: Structured clinical and neuropsychological assessments of language were performed on patients with clinically defined PSP and PNFA. Language was tested using the Sydney Language Battery (SYDBAT) and the Test of Reception of Grammar (TROG).

RESULTS: In total, 144 participants were studied (PSP 22, PNFA 29, and Control 93). PSP patients had prominent eye movement abnormalities, parkinsonism, and falls. All 4 PSP patients who underwent postmortem examination had 4-Repeat tauopathy, with PSP pathology in 3. The frequency and severity of impairment on the SYDBAT (naming, word comprehension, semantic association), and TROG (syntactic comprehension) did not differ between PSP and PNFA, but PSP were significantly slower on timed non-language cognitive tests.

CONCLUSION: Tested formally, aphasia may be seen in PSP, with a severity similar to that seen in PNFA.

%B J Alzheimers Dis %V 61 %P 705-715 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254097?dopt=Abstract %R 10.3233/JAD-170743 %0 Journal Article %J J Alzheimers Dis %D 2018 %T An Aspartyl Cathepsin Targeted PET Agent: Application in an Alzheimer's Disease Mouse Model. %A Snir, Jonatan A %A Suchy, Mojmir %A Bindseil, Geron A %A Kovacs, Michael %A Chronik, Blaine A %A Hudson, Robert H E %A Pasternak, Stephen H %A Bartha, Robert %K Alzheimer Disease %K Animals %K Brain %K Cathepsin D %K Contrast Media %K Disease Models, Animal %K Female %K Fluorodeoxyglucose F18 %K Glucose %K Mice %K Mice, Transgenic %K Positron-Emission Tomography %X

BACKGROUND: Early detection of Alzheimer's disease (AD) pathology is a serious challenge for both diagnosis and clinical trials. The aspartyl protease, Cathepsin D (CatD), is overexpressed in AD and could be a biomarker of disease. We have previously designed a unique contrast agent (CA) for dual-optical and magnetic resonance imaging of the activity of the CatD class of enzymes.

OBJECTIVE: To compare the uptake and retention of a novel, more sensitive, and clinically-translatable 68Ga PET tracer targeting CatD activity in 5XFAD mice and non-Tg littermates.

METHODS: The targeted CA consisted of an HIV-1 Tat cell penetrating peptide (CPP) conjugated to a specialized cleavage sequence targeting aspartyl cathepsins and a DOTA conjugate chelating 68Ga. PET images were acquired using a Siemens Inveon preclinical microPET in female Tg AD mice and non-Tg age matched female littermates (n = 5-8) following intravenous CA administration at 2, 6, and 9 months of age. Additionally, 18F fluorodeoxyglucose (FDG) PET imaging was performed at 10 months to measure glucose uptake.

RESULTS: The Tg mice showed significantly higher relative uptake rate of the targeting CA in the forebrain relative to hindbrain at all ages compared to controls, consistent with histology. In contrast, no differences were seen in CA uptake in other organs. Additionally, the Tg mice did not show any differences in relative uptake of FDG at 10 months of age in the forebrain relative to the hindbrain compared to age matched non-Tg controls.

CONCLUSIONS: Elevated aspartryl cathepsin activity was detected in vivo in the 5XFAD mouse model of AD using a novel targeted PET contrast agent.

%B J Alzheimers Dis %V 61 %P 1241-1252 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332035?dopt=Abstract %R 10.3233/JAD-170115 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Assessing Working Memory in Mild Cognitive Impairment with Serial Order Recall. %A Emrani, Sheina %A Libon, David J %A Lamar, Melissa %A Price, Catherine C %A Jefferson, Angela L %A Gifford, Katherine A %A Hohman, Timothy J %A Nation, Daniel A %A Delano-Wood, Lisa %A Jak, Amy %A Bangen, Katherine J %A Bondi, Mark W %A Brickman, Adam M %A Manly, Jennifer %A Swenson, Rodney %A Au, Rhoda %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Executive Function %K Female %K Humans %K Male %K Memory Disorders %K Memory, Short-Term %K Mental Recall %K Neuropsychological Tests %K Regression Analysis %K Serial Learning %X

BACKGROUND: Working memory (WM) is often assessed with serial order tests such as repeating digits backward. In prior dementia research using the Backward Digit Span Test (BDT), only aggregate test performance was examined.

OBJECTIVE: The current research tallied primacy/recency effects, out-of-sequence transposition errors, perseverations, and omissions to assess WM deficits in patients with mild cognitive impairment (MCI).

METHODS: Memory clinic patients (n = 66) were classified into three groups: single domain amnestic MCI (aMCI), combined mixed domain/dysexecutive MCI (mixed/dys MCI), and non-MCI where patients did not meet criteria for MCI. Serial order/WM ability was assessed by asking participants to repeat 7 trials of five digits backwards. Serial order position accuracy, transposition errors, perseverations, and omission errors were tallied.

RESULTS: A 3 (group)×5 (serial position) repeated measures ANOVA yielded a significant group×trial interaction. Follow-up analyses found attenuation of the recency effect for mixed/dys MCI patients. Mixed/dys MCI patients scored lower than non-MCI patients for serial position 3 (p < 0.003) serial position 4 (p < 0.002); and lower than both group for serial position 5 (recency; p < 0.002). Mixed/dys MCI patients also produced more transposition errors than both groups (p < 0.010); and more omissions (p < 0.020), and perseverations errors (p < 0.018) than non-MCI patients.

CONCLUSIONS: The attenuation of a recency effect using serial order parameters obtained from the BDT may provide a useful operational definition as well as additional diagnostic information regarding working memory deficits in MCI.

%B J Alzheimers Dis %V 61 %P 917-928 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254087?dopt=Abstract %R 10.3233/JAD-170555 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Assessment of the Genetic Architecture of Alzheimer's Disease Risk in Rate of Memory Decline. %A Del-Aguila, Jorge L %A Fernández, Maria Victoria %A Schindler, Suzanne %A Ibanez, Laura %A Deming, Yuetiva %A Ma, Shengmei %A Saef, Ben %A Black, Kathleen %A Budde, John %A Norton, Joanne %A Chasse, Rachel %A Harari, Oscar %A Goate, Alison %A Xiong, Chengjie %A Morris, John C %A Cruchaga, Carlos %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Dementia %K Disease Progression %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heterozygote %K Humans %K Longitudinal Studies %K Male %K Membrane Glycoproteins %K Memory Disorders %K Middle Aged %K Polymorphism, Single Nucleotide %K Receptors, Immunologic %K Risk Assessment %X

Many genetic studies for Alzheimer's disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (β= 0.146, p = 0.03). In the case of rare variants, TREM2 (β= 0.309, p = 0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.

%B J Alzheimers Dis %V 62 %P 745-756 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480181?dopt=Abstract %R 10.3233/JAD-170834 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association between Hippocampal Shape, Neuroinflammation, and Cognitive Decline in Alzheimer's Disease. %A Cabinio, Monia %A Saresella, Marina %A Piancone, Federica %A LaRosa, Francesca %A Marventano, Ivana %A Guerini, Franca %A Nemni, Raffaello %A Baglio, Francesca %A Clerici, Mario %X

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition characterized by memory impairment and general decrease in cognitive functions and daily living competences, that leads to a complete loss of autonomy. The pathogenesis of AD is characterized by the deposition of amyloid-β plaques (Aβ plaques) and neurofibrillary tangles, initially involving cortical and hippocampal structures, and neuroinflammation. To date, no studies have investigated the topological association between neuroinflammation and hippocampal shape in AD.

OBJECTIVE: The aim of the present study is to assess the association between hippocampal shape, cognitive profile, and neuroinflammation in a group of AD patients in the mild stage of the disease.

METHODS: Thirty-one patients with typical onset AD (mild stage) underwent MRI examination (1.5T scanner); hippocampal structures were segmented using a vertex-wise analysis (FSL-FIRST). Immune parameters were evaluated on peripheral blood mononuclear cells by flow-cytometry. Correlation analyses were performed between hippocampal shape and both cognitive profile (ADAS-Cog and MMSE scores), and neuro-inflammatory variables (i.e., circulating monocytes, cytokines).

RESULTS: Statistically significant correlations (p < 0.05FWE) between right hippocampal shape and cognitive measurements and between left hippocampal shape and inflammatory indices were detected. The hippocampal field mostly involved was the lateral portion of bilateral hippocampi, mainly overlapping with Cornu Ammonis, extending along the entire longitudinal axis.

CONCLUSIONS: A topological relationship between hippocampal atrophy and both cognitive profile and neuroinflammation is found; the association with neuroinflammatory indices is in line with the pattern of AD-associated neuronal death, whereas the association with cognitive test might account for residual cognitive functions.

%B J Alzheimers Dis %V 66 %P 1131-1144 %8 2018 Nov 23 %G eng %N 3 %R 10.3233/JAD-180250 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association between Peripheral Leptin and Adiponectin Levels and Cognitive Decline in Patients with Neurocognitive Disorders ≥65 Years. %A Gilbert, Thomas %A Roche, Sylvain %A Blond, Emilie %A Bar, Jean-Yves %A Drai, Jocelyne %A Cuerq, Charlotte %A Haution-Bitker, Marine %A Ecochard, René %A Bonnefoy, Marc %X

BACKGROUND: There is evidence that adipokines have roles in brain functioning and cognitive decline.

OBJECTIVE: Assess the role of leptin and adiponectin levels in predicting changes in neuro-cognitive disorders (NCD).

METHODS: The study included 205 patients over 65 years of age presenting for a one-day hospitalization for current assessment of cognitive function. Peripheral blood leptin and adiponectin levels were measured at admission. Demographic variables, body mass index (BMI), and history of hypertension were also recorded. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) at admission and at later scheduled visits over a median follow-up period of 14.5 months. Conventional univariate comparisons were made between diagnosis groups (Alzheimer's disease (AD), mild NCD, vascular/mixed dementia). Changes in MMSE scores over time were examined with regard to the above variables using a linear mixed model.

RESULTS: The mean BMI was significantly lower (by 2 kg/m2, p = 0.01) in patients with AD than in patients with either mild-NCD or vascular/mixed dementia. Leptin levels were significantly higher (p = 0.043) and adiponectin levels significantly lower (p = 0.045) in patients with mild-NCD than in patients with major-NCD (AD or vascular/mixed dementia). However, the mixed model suggested no influence of the baseline levels of these two biomarkers on the course of cognitive decline.

CONCLUSION: The present study confirms the associations between leptin and adiponectin and AD or AD-related disorders but did not confirm that these peptides may be used as predictive biomarkers of cognitive decline.

%B J Alzheimers Dis %V 66 %P 1255-1264 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400097?dopt=Abstract %R 10.3233/JAD-180533 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Association between Social Engagement, Loneliness, and Risk of Dementia: A Systematic Review and Meta-Analysis. %A Penninkilampi, Ross %A Casey, Anne-Nicole %A Singh, Maria Fiatarone %A Brodaty, Henry %X

It has been reported that social engagement may be associated with dementia risk. We searched PubMed, EMBASE, PsycINFO, CINAHL, LILACS, Biomed Central, Scopus, and Web of Science from January 2012 - May 2017, supplemented by extraction from previous reviews. We included cohort and case-control studies examining the association between social engagement or loneliness and dementia risk, pooling data using a random-effects model. Registered: PROSPERO (CRD42017067074). We included 31 cohort and 2 case-control studies comprising 2,370,452 participants. Poor social engagement indices were associated with increased dementia risk, including having a poor social network (RR = 1.59, 95% CI 1.31-1.96; I2 = 0.00%) and poor social support (RR = 1.28, 95% CI 1.01-1.62; I2 = 55.51%). In long-term studies (≥10 years), good social engagement was modestly protective (RR = 0.88, 95% CI 0.80-0.96; I2 = 0.00%). Loneliness was non-significantly associated with increased risk (RR = 1.38, 95% CI 0.98-1.94; I2 = 45.32). Our findings encourage interventions targeting social isolation and disengagement for dementia prevention.

%B J Alzheimers Dis %V 66 %P 1619-1633 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30452410?dopt=Abstract %R 10.3233/JAD-180439 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association Between the Use of Antihyperglycemic Drugs and Dementia Risk: A Case-Control Study. %A Bohlken, Jens %A Jacob, Louis %A Kostev, Karel %X

BACKGROUND: There is a conflicting literature on the association between the use of antihyperglycemic drugs and dementia risk.

OBJECTIVE: The goal of this case-control study was to analyze the association between the use of antihyperglycemic drugs and dementia risk in patients followed in general practices in Germany.

METHODS: This study included patients with type 2 diabetes mellitus who had received a first dementia diagnosis in 972 general practices in Germany between January 2013 and December 2017 (index date). Controls without dementia were matched (1:1) to cases by age, gender, index year, and physician. Two multivariate regression models were used to study the association between the use of antihyperglycemic drugs and dementia risk. Model 1 included all antihyperglycemic drugs prescribed to patients regardless of the prescription duration, whereas Model 2 only included the longest therapy prescribed to each patient.

RESULTS: There were 8,276 diabetes patients with dementia and 8,276 diabetes patients without dementia included in this study. In Model 1, glitazones were associated with a decreased dementia risk (odds ratio [OR] = 0.80), whereas insulin was associated with an increased risk of developing the condition (OR = 1.34). In Model 2, metformin, prescribed as monotherapy (OR = 0.71) or as dual therapy with sulfonylureas (OR = 0.90), was associated with a decrease in the likelihood of subsequently being diagnosed with dementia. By contrast, the combination of basal insulin and bolus insulin (OR = 1.47) and premix insulin (OR = 1.33) were risk factors for dementia.

CONCLUSION: Metformin and glitazones were negatively associated with dementia, while insulin was positively associated with dementia.

%B J Alzheimers Dis %V 66 %P 725-732 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320593?dopt=Abstract %R 10.3233/JAD-180808 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease. %A Geijselaers, Stefan L C %A Aalten, Pauline %A Ramakers, Inez H G B %A De Deyn, Peter Paul %A Heijboer, Annemieke C %A Koek, Huiberdina L %A OldeRikkert, Marcel G M %A Papma, Janne M %A Reesink, Fransje E %A Smits, Lieke L %A Stehouwer, Coen D A %A Teunissen, Charlotte E %A Verhey, Frans R J %A van der Flier, Wiesje M %A Biessels, Geert Jan %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Brain %K Cognition Disorders %K Female %K Humans %K Insulin %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Signal Transduction %K tau Proteins %X

BACKGROUND: Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD).

OBJECTIVE: To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype.

METHODS: From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau.

RESULTS: CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029).

CONCLUSION: Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.

%B J Alzheimers Dis %V 61 %P 309-320 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154275?dopt=Abstract %R 10.3233/JAD-170522 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association of Low-Level Ozone with Cognitive Decline in Older Adults. %A Cleary, Ekaterina Galkina %A Cifuentes, Manuel %A Grinstein, Georges %A Brugge, Doug %A Shea, Thomas B %K Age Distribution %K Aged %K Aged, 80 and over %K Aging %K Air Pollutants %K Cognitive Dysfunction %K Female %K Humans %K Male %K Mental Status and Dementia Tests %K Middle Aged %K Ozone %K Regression Analysis %K Retrospective Studies %K United States %X

Increasing evidence points to an association of airborne pollutant exposure with respiratory, cardiovascular, and neurological pathology. We examined whether or not ground-level ozone or fine particulate matter ≤ 2.5 μm in diameter (PM2.5) was associated with accelerated cognitive decline. Using repeated measures mixed regression modeling, we analyzed cognitive performance of a geographically diverse sampling of individuals from the National Alzheimer's Coordinating Center between 2004-2008. Ambient air concentrations of ozone and PM2.5 were established using a space-time Hierarchical Bayesian Model that statistically merged air monitor data and modeled air quality estimates. We then compared the ambient regional concentrations of ozone and PM2.5 with the rate of cognitive decline in residents within those regions. Increased levels of ozone correlated with an increased rate of cognitive decline, following adjustment for key individual and community-level risk factors. Furthermore, individuals harboring one or more APOE4 alleles exhibited a faster rate of cognitive decline. The deleterious association of ozone was confined to individuals with normal cognition who eventually became cognitively impaired as opposed to those who entered the study with baseline impairment. In contrast to ozone, we did not observe any correlation between ambient PM2.5 and cognitive decline at regulatory limits set by the Environmental Protection Agency. Our findings suggest that prolonged exposure to ground-level ozone may accelerate cognitive decline during the initial stages of dementia development.

%B J Alzheimers Dis %V 61 %P 67-78 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103040?dopt=Abstract %R 10.3233/JAD-170658 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Association of Mid- and Late-Life Systemic Inflammation with Brain Amyloid Deposition: The ARIC-PET Study. %A Walker, Keenan A %A Windham, B Gwen %A Brown, Charles H %A Knopman, David S %A Jack, Clifford R %A Mosley, Thomas H %A Selvin, Elizabeth %A Wong, Dean F %A Hughes, Timothy M %A Zhou, Yun %A Gross, Alden L %A Gottesman, Rebecca F %X

BACKGROUND: Although inflammation has been implicated in the pathogenesis of Alzheimer's disease, the effects of systemic inflammation on brain amyloid deposition remain unclear.

OBJECTIVE: We examined the association of midlife and late-life systemic inflammation with late-life brain amyloid levels in a community sample of non-demented older adults from the Atherosclerosis Risk in Communities (ARIC) - PET Study.

METHODS: 339 non-demented participants (age: 75 [SD 5]) were recruited from the ARIC Study to undergo florbetapir PET (amyloid) imaging. Blood levels of high sensitivity C-reactive protein (CRP), a marker of systemic inflammation, were measured 22 years (Visit 2), 16 years (Visit 4), and up to 2 years before PET imaging (Visit 5). Elevated brain amyloid deposition (standardized uptake value ratio >1.2) was the primary outcome.

RESULTS: Our primary analyses found no association of midlife and late-life CRP with late-life brain amyloid levels. However, in secondary stratified analyses, we found that higher midlife (Visit 2) CRP was associated with elevated amyloid among males (OR 1.65, 95% CI: 1.13-2.42), and among white (OR 1.33, 95% CI: 1.02-1.75), but not African American, participants (p-interactions<0.05). Among male participants, those who maintained high CRP levels (≥3 mg/L) throughout mid- and late-life were most likely to have elevated brain amyloid (OR, 8.81; 95% CI: 1.23, 62.91).

CONCLUSIONS: Although our primary analysis does not support an association between systemic inflammation and brain amyloid deposition, we found evidence for sex- and race-dependent associations. However, findings from subgroup analyses should be interpreted with caution.

%B J Alzheimers Dis %V 66 %P 1041-1052 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400093?dopt=Abstract %R 10.3233/JAD-180469 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association of Motoric Cognitive Risk Syndrome with Cardiovascular Disease and Risk Factors: Results from an Original Study and Meta-Analysis. %A Beauchet, Olivier %A Sekhon, Harmehr %A Barden, John %A Liu-Ambrose, Teresa %A Chester, Victoria L %A Szturm, Tony %A Grenier, Sébastien %A Léonard, Guillaume %A Bherer, Louis %A Allali, Gilles %X

BACKGROUND: Motoric cognitive risk (MCR) syndrome, a recently described pre-dementia syndrome, has been associated with cardiovascular disease and their risk factors (CVDRF).

OBJECTIVE: To determine whether MCR syndrome was associated with CVDRF in French community-dwelling older adults, and to quantitatively evaluate, with a systematic review and meta-analysis, the association of MCR syndrome with CVDRF.

METHODS: Based on a cross-sectional design, 238 older adults without dementia were selected from the French GAIT study. An English and French systematic Medline and Embase search (without limiting date of publication) was also conducted in February 2017 using the terms "motoric cognitive risk syndrome" OR "motoric cognitive risk" OR "motoric risk". The systematic review and meta-analysis included 8 studies. CVDRF were defined as cardiovascular diseases, hypertension, diabetes, stroke, obesity and abnormal waist-hip ratio (WHR).

RESULTS: The prevalence of MCR syndrome in the current original study was 16.8%. MCR syndrome was associated with abnormalWHR(Odds ratio [OR] >2.8 with p < 0.020) and high blood pressure (OR >2.5 with p < 0.025). Of the 202 originally identified abstracts, 7 (3.5%) were selected for the systematic review. The meta-analysis showed that all pooled OR were significant with a p-value <0.001 (OR = 1.41 for cardiovascular diseases, 1.21 for hypertension, 1.44 for diabetes, 2.05 for stroke, and 1.34 for obesity). When pooling all CVDRF, the overall OR was 1.38 (95% CI, 1.33-1.45) with p-value <0.001.

CONCLUSION: MCR syndrome is significantly associated with CVDRF. These findings suggest that a vascular mechanism may underlie the pathophysiology of MCR syndrome.

%B J Alzheimers Dis %V 64 %P 875-887 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966199?dopt=Abstract %R 10.3233/JAD-180203 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association of Plasma Neurofilament Light Chain with Neocortical Amyloid-β Load and Cognitive Performance in Cognitively Normal Elderly Participants. %A Chatterjee, Pratishtha %A Goozee, Kathryn %A Sohrabi, Hamid R %A Shen, Kaikai %A Shah, Tejal %A Asih, Prita R %A Dave, Preeti %A ManYan, Candice %A Taddei, Kevin %A Chung, Roger %A Zetterberg, Henrik %A Blennow, Kaj %A Martins, Ralph N %X

BACKGROUND: The disruption of neurofilament, an axonal cytoskeletal protein, in neurodegenerative conditions may result in neuronal damage and its release into the cerebrospinal fluid and blood. In Alzheimer's disease (AD), neurofilament light chain (NFL), a neurofilament subunit, is elevated in the cerebrospinal fluid and blood.

OBJECTIVE: Investigate the association of plasma NFL with preclinical-AD features, such as high neocortical amyloid-β load (NAL) and subjective memory complaints, and cognitive performance in cognitively normal older adults.

METHODS: Plasma NFL concentrations were measured employing the single molecule array platform in participants from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort, aged 65- 90 years. Participants underwent a battery of neuropsychological testing to evaluate cognitive performance and were categorized as low NAL (NAL-, n = 65) and high NAL (NAL+, n = 35) assessed via PET, and further stratified into subjective memory complainers (SMC; nNAL- = 51, nNAL+ = 25) and non-SMC (nNAL- = 14, nNAL+ = 10) based on the Memory Assessment Clinic- Questionnaire.

RESULTS: Plasma NFL inversely correlated with cognitive performance. No significant difference in NFL was observed between NAL+ and NAL- participants; however, within APOEɛ4 non-carriers, higher NAL was observed in individuals with NFL concentrations within quartiles 3 and 4 (versus quartile 1). Additionally, within the NAL+ participants, SMC had a trend of higher NFL compared to non-SMC.

CONCLUSION: Plasma NFL is inversely associated with cognitive performance in elderly individuals. While plasma NFL may not reflect NAL in individuals with normal global cognition, the current observations indicate that onset of axonal injury, reflected by increased plasma NFL, within the preclinical phase of AD may contribute to the pathogenesis of AD.

%B J Alzheimers Dis %V 63 %P 479-487 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29630554?dopt=Abstract %R 10.3233/JAD-180025 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association of the New Variant Tyr424Asp at TBK1 Gene with Amyotrophic Lateral Sclerosis and Cognitive Decline. %A Piaceri, Irene %A Bessi, Valentina %A Matà, Sabrina %A Polito, Cristina %A Tedde, Andrea %A Berti, Valentina %A Bagnoli, Silvia %A Braccia, Arianna %A Del Mastio, Monica %A Pignone, Alberto Moggi %A Pupi, Alberto %A Sorbi, Sandro %A Nacmias, Benedetta %K Aged %K Amyotrophic Lateral Sclerosis %K Aspartic Acid %K C9orf72 Protein %K Cognitive Dysfunction %K DNA Mutational Analysis %K Female %K Fluorodeoxyglucose F18 %K Genetic Association Studies %K Genetic Predisposition to Disease %K Humans %K Italy %K Male %K Mental Status and Dementia Tests %K Middle Aged %K Mutation %K Neuropsychological Tests %K Positron-Emission Tomography %K Protein-Serine-Threonine Kinases %K Tyrosine %X

A new risk gene associated with amyotrophic lateral sclerosis (ALS) has recently been identified: the Tank-binding kinase 1 (TBK1) gene. Up to now, 90 TBK1 variants have been described in ALS patients with or without frontotemporal dementia (FTD), thus making TBK1 the third or fourth most frequent genetic cause of ALS and FTD. A point mutation analysis in a cohort of 69 Italian ALS patients was performed in order to analyze the frequency of TBK1 mutations and the correlation with clinical phenotypes. The analysis identified the novel variant p.Tyr424Asp in a patient with a rapid progression of the disease. Our data supports the implication of TBK1 in ALS pathogenesis in Italy.

%B J Alzheimers Dis %V 61 %P 41-46 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103041?dopt=Abstract %R 10.3233/JAD-170694 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Associations of Dietary Protein and Fiber Intake with Brain and Blood Amyloid-β. %A Fernando, W M A D Binosha %A Rainey-Smith, Stephanie R %A Gardener, Samantha L %A Villemagne, Victor L %A Burnham, Samantha C %A Macaulay, S Lance %A Brown, Belinda M %A Gupta, Veer Bala %A Sohrabi, Hamid R %A Weinborn, Michael %A Taddei, Kevin %A Laws, Simon M %A Goozee, Kathryn %A Ames, David %A Fowler, Christopher %A Maruff, Paul %A Masters, Colin L %A Salvado, Olivier %A Rowe, Christopher C %A Martins, Ralph N %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Australia %K Biomarkers %K Brain %K Cognition %K Cohort Studies %K Cross-Sectional Studies %K Dietary Fiber %K Dietary Proteins %K Female %K Humans %K Logistic Models %K Male %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %X

Accumulating evidence suggests a diet high in protein and fiber may confer some protection against Alzheimer's disease (AD). However, no human studies to-date have assessed the relationship between protein and fiber intake, and plasma and brain amyloid-β (Aβ). Consequently, this cross-sectional study, investigated the association of self-reported dietary intakes of protein and fiber, with plasma and brain Aβ burden (n = 541, and n = 162 respectively), in a well-characterized cohort of cognitively normal older adults, drawn from the larger Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. We observed 12.59 and 8.43 higher odds of 'high' brain Aβ burden (PiB PET SUVR≥1.5) if protein intake fell in the lowest and middle tertile, respectively, compared to the highest tertile (p = 0.008; p = 0.013). Thus, in this cohort, the more protein consumed, the less likelihood of 'high' Aβ burden in the brain. No other significant associations were observed. The results of this study highlight the potentially protective impact of high dietary protein intake on brain Aβ burden in older adults, before objective memory decline is apparent. While longitudinal validation is required, these findings may assist in the development of dietary approaches aimed at preventing or delaying AD onset.

%B J Alzheimers Dis %V 61 %P 1589-1598 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376865?dopt=Abstract %R 10.3233/JAD-170742 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Atrophy in Distributed Networks Predicts Cognition in Alzheimer's Disease and Type 2 Diabetes. %A Buss, Stephanie S %A Padmanabhan, Jaya %A Saxena, Sadhvi %A Pascual-Leone, Alvaro %A Fried, Peter J %X

BACKGROUND: Alzheimer's disease (AD) and type 2 diabetes (T2DM) are common causes of cognitive decline among older adults and share strong epidemiological links. Distinct patterns of cortical atrophy are observed in AD and T2DM, but robust comparisons between structure-function relationships across these two disease states are lacking.

OBJECTIVE: To compare how atrophy within distributed brain networks is related to cognition across the spectrum of cognitive aging.

METHODS: The relationship between structural MRI changes and cognition was studied in 22 mild-to-moderate AD, 28 T2DM, and 27 healthy participants. Cortical thickness measurements were obtained from networks of interest (NOIs) matching the limbic, default, and frontoparietal resting-state networks. Composite cognitive scores capturing domains of global cognition, memory, and executive function were created. Associations between cognitive scores and the NOIs were assessed using linear regression, with age as a covariate. Within-network General Linear Model (GLM) analysis was run in Freesurfer 6.0 to visualize differences in patterns of cortical atrophy related to cognitive function in each group. A secondary analysis examined hemispheric differences in each group.

RESULTS: Across all groups, cortical atrophy within the limbic NOI was significantly correlated with Global Cognition (p = 0.009) and Memory Composite (p = 0.002). Within-network GLM analysis and hemispheric analysis revealed qualitatively different patterns of atrophy contributing to cognitive dysfunction between AD and T2DM.

CONCLUSION: Brain network atrophy is related to cognitive function across AD, T2DM, and healthy participants. Differences in cortical atrophy patterns were seen between AD and T2DM, highlighting neuropathological differences.

%B J Alzheimers Dis %V 65 %P 1301-1312 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149455?dopt=Abstract %R 10.3233/JAD-180570 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Automated Multi-Atlas Segmentation of Hippocampal and Extrahippocampal Subregions in Alzheimer's Disease at 3T and 7T: What Atlas Composition Works Best? %A Xie, Long %A Shinohara, Russell T %A Ittyerah, Ranjit %A Kuijf, Hugo J %A Pluta, John B %A Blom, Kim %A Kooistra, Minke %A Reijmer, Yael D %A Koek, Huiberdina L %A Zwanenburg, Jaco J M %A Wang, Hongzhi %A Luijten, Peter R %A Geerlings, Mirjam I %A Das, Sandhitsu R %A Biessels, Geert Jan %A Wolk, David A %A Yushkevich, Paul A %A Wisse, Laura E M %X

BACKGROUND: Multi-atlas segmentation, a popular technique implemented in the Automated Segmentation of Hippocampal Subfields (ASHS) software, utilizes multiple expert-labelled images ("atlases") to delineate medial temporal lobe substructures. This multi-atlas method is increasingly being employed in early Alzheimer's disease (AD) research, it is therefore becoming important to know how the construction of the atlas set in terms of proportions of controls and patients with mild cognitive impairment (MCI) and/or AD affects segmentation accuracy.

OBJECTIVE: To evaluate whether the proportion of controls in the training sets affects the segmentation accuracy of both controls and patients with MCI and/or early AD at 3T and 7T.

METHODS: We performed cross-validation experiments varying the proportion of control subjects in the training set, ranging from a patient-only to a control-only set. Segmentation accuracy of the test set was evaluated by the Dice similarity coeffiecient (DSC). A two-stage statistical analysis was applied to determine whether atlas composition is linked to segmentation accuracy in control subjects and patients, for 3T and 7T.

RESULTS: The different atlas compositions did not significantly affect segmentation accuracy at 3T and for patients at 7T. For controls at 7T, including more control subjects in the training set significantly improves the segmentation accuracy, but only marginally, with the maximum of 0.0003 DSC improvement per percent increment of control subject in the training set.

CONCLUSION: ASHS is robust in this study, and the results indicate that future studies investigating hippocampal subfields in early AD populations can be flexible in the selection of their atlas compositions.

%B J Alzheimers Dis %V 63 %P 217-225 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614654?dopt=Abstract %R 10.3233/JAD-170932 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Behavioral and Psychological Symptoms of Dementia in Down Syndrome (BPSD-DS) Scale: Comprehensive Assessment of Psychopathology in Down Syndrome. %A Dekker, Alain D %A Sacco, Silvia %A Carfi, Angelo %A Benejam, Bessy %A Vermeiren, Yannick %A Beugelsdijk, Gonny %A Schippers, Mieke %A Hassefras, Lyanne %A Eleveld, José %A Grefelman, Sharina %A Fopma, Roelie %A Bomer-Veenboer, Monique %A Boti, Mariángeles %A Oosterling, G Danielle E %A Scholten, Esther %A Tollenaere, Marleen %A Checkley, Laura %A Strydom, Andre %A Van Goethem, Gert %A Onder, Graziano %A Blesa, Rafael %A Zu Eulenburg, Christine %A Coppus, Antonia M W %A Rebillat, Anne-Sophie %A Fortea, Juan %A De Deyn, Peter P %X

People with Down syndrome (DS) are prone to develop Alzheimer's disease (AD). Behavioral and psychological symptoms of dementia (BPSD) are core features, but have not been comprehensively evaluated in DS. In a European multidisciplinary study, the novel Behavioral and Psychological Symptoms of Dementia in Down Syndrome (BPSD-DS) scale was developed to identify frequency and severity of behavioral changes taking account of life-long characteristic behavior. 83 behavioral items in 12 clinically defined sections were evaluated. The central aim was to identify items that change in relation to the dementia status, and thus may differentiate between diagnostic groups. Structured interviews were conducted with informants of persons with DS without dementia (DS, n = 149), with questionable dementia (DS+Q, n = 65), and with diagnosed dementia (DS+AD, n = 67). First exploratory data suggest promising interrater, test-retest, and internal consistency reliability measures. Concerning item relevance, group comparisons revealed pronounced increases in frequency and severity in items of anxiety, sleep disturbances, agitation & stereotypical behavior, aggression, apathy, depressive symptoms, and eating/drinking behavior. The proportion of individuals presenting an increase was highest in DS+AD, intermediate in DS+Q, and lowest in DS. Interestingly, among DS+Q individuals, a substantial proportion already presented increased anxiety, sleep disturbances, apathy, and depressive symptoms, suggesting that these changes occur early in the course of AD. Future efforts should optimize the scale based on current results and clinical experiences, and further study applicability, reliability, and validity. Future application of the scale in daily care may aid caregivers to understand changes, and contribute to timely interventions and adaptation of caregiving.

%B J Alzheimers Dis %V 63 %P 797-819 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689719?dopt=Abstract %R 10.3233/JAD-170920 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Biallelic Loss of Function of SORL1 in an Early Onset Alzheimer's Disease Patient. %A Le Guennec, Kilan %A Tubeuf, Hélène %A Hannequin, Didier %A Wallon, David %A Quenez, Olivier %A Rousseau, Stéphane %A Richard, Anne-Claire %A Deleuze, Jean-François %A Boland, Anne %A Frebourg, Thierry %A Gaildrat, Pascaline %A Campion, Dominique %A Martins, Alexandra %A Nicolas, Gaël %K Alzheimer Disease %K Case-Control Studies %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genetic Variation %K Humans %K LDL-Receptor Related Proteins %K Male %K Membrane Transport Proteins %K Middle Aged %K Risk Factors %X

Heterozygous SORL1 protein truncating variants (PTV) are a strong risk factor for early-onset Alzheimer's disease (EOAD). In case control studies performed at the genome-wide level, PTV definition is usually straightforward. Regarding splice site variants, only those affecting canonical sites are typically included. Some other variants, not annotated as PTV, could, however, affect splicing and hence result in a loss of SORL1 function. We took advantage of the whole exome sequencing data from the 9/484 patients with a previously reported SORL1 PTV in the French EOAD series and searched for a second variant which may affect splicing and eventually result in more than 50% loss of function overall. We found that one patient, known to carry a variant predicted to disrupt the canonical 5' splice site of exon 8, also carried a second novel intronic variant predicted to affect SORL1 splicing of exon 29. Segregation analysis showed that the second variant was located in trans from the known PTV. We performed ex vivo minigene splicing assays and showed that both variants led to the generation of transcripts containing a premature stop codon. This is therefore the first evidence of a human carrying biallelic SORL1 PTV. This patient had a family history of dementia in both maternal and paternal lineages with later ages of onset than the proband himself. However, his 55 years age at onset was in the same ranges as previously published SORL1 heterozygous PTV carriers. This suggests that biallelic loss of SORL1 function is an extremely rare event that was not associated with a dramatically earlier age at onset than heterozygous SORL1 loss-of-function variant carriers, in this single patient.

%B J Alzheimers Dis %V 62 %P 821-831 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480197?dopt=Abstract %R 10.3233/JAD-170981 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Bi-directional Association of Cerebrospinal Fluid Immune Markers with Stage of Alzheimer's Disease Pathogenesis. %A Meyer, Pierre-François %A Savard, Mélissa %A Poirier, Judes %A Labonte, Anne %A Rosa-Neto, Pedro %A Weitz, Tara M %A Town, Terrence %A Breitner, John %X

Immune mechanisms may be important in the pathogenesis of Alzheimer's disease (AD). Yet, studies comparing cerebrospinal fluid (CSF) and plasma immune marker levels of healthy and demented individuals have yielded conflicting results. We analyzed CSF from 101 members of the parental history-positive PREVENT-AD cohort of healthy aging adults, and 237 participants without dementia from the initial cohort of the Alzheimer's Disease Neuroimaging Initiative (ADNI-1). Following recent practice, we used the biomarkers total-tau and amyloid-β1-42 to allocate participants from each study into four stages of AD pathogenesis: Stage 0 (no abnormality), Stage 1 (reduced amyloid-β1-42), Stage 2 (reduced amyloid-β1-42 and increased total-tau), or "Suspected Non-Alzheimer Pathology" (elevated total-tau only). Investigating the PREVENT-AD participants' CSF assay results for 19 immune/inflammatory markers, we found six that showed a distinct bi-directional relationship with pathogenetic stage. Relative to Stage 0, these were diminished at Stage 1 but strongly increased at Stage 2. Among the ADNI participants (90 healthy controls and 147 with mild cognitive impairment), we found that 23 of 83 available CSF markers also showed this distinct pattern. These results support recent observations that immune activation may become apparent only after the onset of both amyloid and tau pathologies. Unexpectedly, they also suggest that immune marker activity may diminish along with earliest appearance of amyloid-β plaque pathology. These findings may explain discordant results from past studies, and suggest the importance of characterizing the extent of AD pathology when comparing clinical groups.

%B J Alzheimers Dis %V 63 %P 577-590 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29660934?dopt=Abstract %R 10.3233/JAD-170887 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Biological, Neuroimaging, and Neurophysiological Markers in Frontotemporal Dementia: Three Faces of the Same Coin. %A Borroni, Barbara %A Benussi, Alberto %A Premi, Enrico %A Alberici, Antonella %A Marcello, Elena %A Gardoni, Fabrizio %A Di Luca, Monica %A Padovani, Alessandro %X

Frontotemporal dementia (FTD) is a heterogeneous clinical, genetic, and neuropathological disorder. Clinical diagnosis and prediction of neuropathological substrates are hampered by heterogeneous pictures. Diagnostic markers are key in clinical trials to differentiate FTD from other neurodegenerative dementias. In the same view, identifying the neuropathological hallmarks of the disease is key in light of future disease-modifying treatments. The aim of the present review is to unravel the progress in biomarker discovery, discussing the potential applications of available biological, imaging, and neurophysiological markers.

%B J Alzheimers Dis %V 62 %P 1113-1123 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171998?dopt=Abstract %R 10.3233/JAD-170584 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Blood Inflammatory Mediators and Cognitive Decline in Alzheimer's Disease: A Two Years Longitudinal Study. %A Julian, Adrien %A Rioux-Bilan, Agnès %A Ragot, Stéphanie %A Krolak-Salmon, Pierre %A Berrut, Gilles %A Dantoine, Thierry %A Hommet, Caroline %A Hanon, Olivier %A Page, Guylène %A Paccalin, Marc %X

Peripheral inflammatory processes are involved in Alzheimer's disease (AD). We aimed to determine whether plasma inflammatory mediator levels at diagnosis are associated with cognitive decline through a 2-year follow-up in AD patients. Patients (n = 109, mean age 79.44 (6.82) years) were included at diagnosis with MMSE scores between 16 and 25, with C-reactive protein <10 mg/L, and without any acute or chronic inflammation status. Plasma IL-1β, IL-6, TNF-α, and CCL5 were measured using Luminex X-MAP technology at baseline, and after one year and two years of follow-up. The mean values of IL-1β, IL-6, TNF-α, and CCL5 at diagnosis were 0.3, 1.94, 6.57, and 69,615.81 pg/mL, respectively. Mean cognitive decline in MMSE was 3.35 points. No correlation between plasmatic value of IL-1β, IL-6, TNF-α, or CCL5 at diagnosis and cognitive decline during the two years of follow-up was found. Cognitive decline in AD does not appear to be predictable by the tested inflammatory mediators.

%B J Alzheimers Dis %V 63 %P 87-92 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614665?dopt=Abstract %R 10.3233/JAD-171131 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Brain Aging and Late-Onset Alzheimer's Disease: A Matter of Increased Amyloid or Reduced Energy? %A Mecocci, Patrizia %A Baroni, Marta %A Senin, Umberto %A Boccardi, Virginia %X

Alzheimer's disease (AD) represents the most common form of dementia in old age subjects, and despite decades of studies, the underlying etiopathogenetic mechanisms remain unsolved. The definition of AD has changed over the past years, offering an ever more detailed definition of pre-morbid and pre-clinical status, but without a similar strong emphasis on the role of aging as the main risk factor. In fact, while early-onset AD is a clear consequence of gene mutations, late-onset AD is more likely due to a gradual accumulation of age-related damages. The pathogenetic amyloid cascade hypothesis has been recently questioned due to multiple clinical failures. Furthermore, several studies reported that cognitively normal elderly have a high amyloid deposition in the brain comparable to the levels observed in old age subjects with AD. This suggests that amyloid accumulation enters into the normal process of aging and what really triggers neuronal death and clinical manifestation in late-onset AD still needs further explanation. In this context, 'normal brain aging' and AD might represent a different pathway of successful or failed capability to adapt brain structures and cerebral functions. Cellular senescence and age-related changes affecting the brain may be considered as biologic manifestations of increasing entropy. Bioenergetic deficits due to mitochondrial dysfunction may lead to progressive neuronal death and clinical expression of dementia. So, increased amyloid in the brain of old age subjects may represent the downstream event expression of a biological system that is cooling down because of its exhaustion and not the core causative factor of late-onset dementia.

%B J Alzheimers Dis %V 64 %P S397-S404 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562513?dopt=Abstract %R 10.3233/JAD-179903 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Brain Amyloid Contribution to Cognitive Dysfunction in Early-Stage Parkinson's Disease: The PPMI Dataset. %A Fiorenzato, Eleonora %A Biundo, Roberta %A Cecchin, Diego %A Frigo, Anna Chiara %A Kim, Jinhee %A Weis, Luca %A Strafella, Antonio P %A Antonini, Angelo %X

BACKGROUND: The pathological processes underlying cognitive impairment in Parkinson's disease (PD) are heterogeneous and the contribution of cerebral amyloid deposits is poorly defined, particularly in the early stages of the disease.

OBJECTIVE: To investigate regional [18F]florbetaben binding to amyloid-β (Aβ) and its contribution to cognitive dysfunction in early stage PD.

METHODS: A multicenter cohort of 48 PD patients from the Parkinson's Progression Marker Initiative (PPMI) underwent [18F]florbetaben positron emission tomography (PET) scanning. Clinical features, including demographic characteristics, motor severity, cerebrospinal fluid (CSF), and cognitive testing were systematically assessed according to the PPMI study protocol. For the purpose of this study, we analyzed various neuropsychological tests assessing all cognitive functions.

RESULTS: There were 10/48 (21%) amyloid positive PD patients (PDAβ+). Increased [18F]florbetaben uptake in widespread cortical and subcortical regions was associated with poorer performance on global cognition, as assessed by Montreal Cognitive Assessment (MoCA), and impaired performance on Symbol Digit Modality test (SDMT). Further, we found that PDAβ+ patients had higher CSF total-tau/Aβ1 - 42 (p = 0.001) and phosphorylated-tau/Aβ1 - 42 in (p = 0.002) compared to amyloid-negative PD.

CONCLUSION: These findings suggest that multiple disease processes are associated with PD cognitive impairment and amyloid deposits may be observed already in early stages. However, prevalence of amyloid positivity is in the range of literature age-matched control population. Increased cortical and subcortical amyloid is associated with poor performance in attentive-executive domains while cognitive deficits at MoCA and SDMT may identify amyloid-related dysfunction in early PD.

%B J Alzheimers Dis %V 66 %P 229-237 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282359?dopt=Abstract %R 10.3233/JAD-180390 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Can 11C-PiB-PET Relative Delivery R1 or 11C-PiB-PET Perfusion Replace 18F-FDG-PET in the Assessment of Brain Neurodegeneration? %A Oliveira, Francisco P M %A Moreira, Ana Paula %A de Mendonça, Alexandre %A Verdelho, Ana %A Xavier, Carolina %A Barroca, Dalila %A Rio, Joana %A Cardoso, Eva %A Cruz, Ângela %A Abrunhosa, Antero %A Castelo-Branco, Miguel %X

BACKGROUND: Pittsburgh Compound B (PiB) positron emission tomography (PET) is used to visualize in vivo amyloid plaques in the brain. Frequently the PiB examinations are complemented with a fluorodeoxyglucose (FDG) PET scan to further assess neurodegeneration.

OBJECTIVE: Our goal is to identify alternative correlates of FDG images by assessing which kinetic methods originate PiB derived relative delivery ratio (R1) images that can be correlated with the FDG images, and to compare them with PiB perfusion (pPiB) images obtained from the early-phase of PiB acquisition.

METHODS: We selected 52 patients with cognitive impairment who underwent a dynamic PiB and FDG acquisitions. To compute the R1 images, two simplified reference tissue models (SRTM and SRTM2) and two multi-linear reference tissue models (MRTM and MRTM2) were used. The pPiB images were obtained in two different time intervals.

RESULTS: All six types of images were of good quality and highly correlated with the FDG images (mean voxelwise within-subjects r > 0.92). The higher correlation was found for FDG-R1(MRTM). Regarding the voxelwise regional correlation, the higher mean all brain correlations was r = 0.825 for FDG-R1(MRTM) and statistically significant in the whole brain analysis.

CONCLUSION: All R1 and pPiB images here tested have potential to assess the metabolic impact of neurodegeneration almost as reliably as the FDG images. However, this is not enough to validate these images for a single-subject analysis compared with the FDG image, and thus they cannot yet be used clinically to replace the FDG image before such evaluation.

%B J Alzheimers Dis %V 65 %P 89-97 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056421?dopt=Abstract %R 10.3233/JAD-180274 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cannabinoid Receptor 2-Deficiency Ameliorates Disease Symptoms in a Mouse Model with Alzheimer's Disease-Like Pathology. %A Schmöle, Anne-Caroline %A Lundt, Ramona %A Toporowski, Gregor %A Hansen, Jan N %A Beins, Eva %A Halle, Annett %A Zimmer, Andreas %X

It is widely accepted that the endocannabinoid system (ECS) is a modulator of neuroinflammation associated with neurodegenerative disorders, including Alzheimer's disease (AD). Thus, expression of the cannabinoid receptor 2 (CB2) is induced in plaque-associated microglia and astrocytes in brain tissues from AD patients and in genetic mouse models expressing pathogenic variants of the amyloid precursor protein (APP). However, the exact mechanism of CB2 signaling in this mouse model remains elusive, because the genetic deletion of CB2 and the pharmacological activation of CB2 both reduced neuroinflammation. Here, we demonstrate that CB2 deletion also improved cognitive and learning deficits in APP/PS1*CB2-/- mice. This was accompanied by reduced neuronal loss and decreased plaque levels and coincided with increased expression of Aβ degrading enzymes. Interestingly, plaque-associated microglia in APP/PS1*CB2-/- mice showed a less activated morphology, while plaques were smaller and more condensed than in APP/PS1 mice. Taken together, these results indicate a beneficial effect of CB2-deficiency in APP transgenic mice. CB2 appears to be part of a protective system that may be detrimental when engaged continuously.

%B J Alzheimers Dis %V 64 %P 379-392 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865078?dopt=Abstract %R 10.3233/JAD-180230 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Caregiving and Caregiver Burden in Dementia Home Care: Results from the Prospective Dementia Registry (PRODEM) of the Austrian Alzheimer Society. %A Ransmayr, Gerhard %A Hermann, Philipp %A Sallinger, Katharina %A Benke, Thomas %A Seiler, Stephan %A Dal-Bianco, Peter %A Marksteiner, Josef %A Defrancesco, Michaela %A Sanin, Günter %A Struhal, Walter %A Guger, Michael %A Vosko, Milan %A Hagenauer, Karin %A Lehner, Riccarda %A Futschik, Andreas %A Schmidt, Reinhold %X

BACKGROUND: Comprehensive studies on caregiver burden (CB) of persons caring for dementia patients differ methodologically and show variable results.

OBJECTIVE: Analysis of known and hypothesized factors of CB in home care of dementia patients.

METHODS: Multicenter longitudinal study comprising 585 persons caring mostly for Alzheimer's disease patients (age median 77.25 years, Mini-Mental State Examination raw score median 23) using the Zarit Caregiver Burden Interview (CBI). Known patient-related determinants of CB were studied, such as dementia severity (Clinical Dementia Rating, CDR), neuropsychological deficits (CERAD-Plus), neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI), disability (Disability Assessment for Dementia, DAD), dependency (Dependency Scale, DS), and moreover, unclarified potential factors (age, sex, education of patients; age, sex, occupational status of the caregivers; family relationship). Psychological and somatic effects of CB were analyzed (factor analysis).

RESULTS: Caregiver age was median 61. Female caregivers prevailed (67.8%). Median CBI sum score (CBIss) was 16 at baseline. After two years, CBIss was 22 and 37% of the caregivers reported mild to moderate (CBIss 21-40), 16.8% moderate to severe or severe (≥41), and 46.2% absent to little CB (CBIss ≤ 20). CB correlated positively with NPI, CDR, DS scores, disability (DAD), years of education of the patients, and proximity of patient and caregiver sex (female), and negatively with caregiver age. Caregivers reported restrictions of time, health problems, and negative emotions.

CONCLUSION: The findings are applicable to identify persons at risk for substantial CB and its consequences. There is demand for personal, psychological, and medical support of caregivers and increasing male participation.

%B J Alzheimers Dis %V 63 %P 103-114 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614643?dopt=Abstract %R 10.3233/JAD-170657 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebral Amyloid Angiopathy and Cerebral Amyloid Angiopathy-Related Inflammation: Comparison of Hemorrhagic and DWI MRI Features. %A Renard, Dimitri %A Tatu, Lavinia %A Collombier, Laurent %A Wacongne, Anne %A Ayrignac, Xavier %A Charif, Mahmoud %A Boukriche, Yassine %A Chiper, Laura %A Fourcade, Genevieve %A Azakri, Souhayla %A Gaillard, Nicolas %A Mercier, Erick %A Lehmann, Sylvain %A Thouvenot, Eric %X

BACKGROUND: Cerebral amyloid angiopathy (CAA) can be associated with primary vasculitis of small/medium-sized leptomeningeal and cortical arteries, called CAA-related inflammation (CAA-ri).

OBJECTIVE: To compare hemorrhagic and diffusion-weighted imaging (DWI) MRI features in CAA and CAA-ri.

METHODS: We prospectively scored in a consecutive CAA and CAA-ri cohort: presence/number of chronic intracerebral hemorrhage (ICH), cerebral microbleeds (CMB), and cortical superficial siderosis (CSS) on initial T2*-weighted imaging, and DWI lesions on both initial and follow-up imaging. In a subgroup, ApoE, CSF, and 18F-florbetaben-positron emission tomography (FBB-PET) were also analyzed.

RESULTS: In CAA-ri, CMB presence was more frequent (100% versus 40%, p < 0.001) and CMB numbers higher (mean 137 versus 8, p < 0.001). No difference was observed for chronic ICH or CSS. DWI lesions were more frequent in acute compared to chronic CAA-ri (p = 0.025), whereas no such difference was observed between acute and chronic CAA (p = 0.18). Both ApoE4 (genotyping available in 22 CAA-ri and 48 CAA patients) carriers and homozygosity were more frequent in CAA-ri (48% versus 19% [p = 0.014] and 32% versus 2% [p < 0.001] respectively). CSF biomarker analyses (performed in 20 CAA-ri and 45 CAA patients) showed lower Aβ42 levels in CAA-ri compared to CAA (median 312 versus 422 pg/mL, p = 0.0032). FBB-PET (performed in 11 CAA-ri and 20 CAA patients) showed higher standardized uptake value ratios in CAA-ri compared with CAA, only significant when the pons was used as reference (p = 0.037).

CONCLUSION: Compared to CAA, CAA-ri was associated with higher CMB numbers, more frequent ApoE4 carriers and homozygotes, lower CSF Aβ42 levels, and more severe amyloid load on FBB-PET.

%B J Alzheimers Dis %V 64 %P 1113-1121 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010128?dopt=Abstract %R 10.3233/JAD-180269 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid and Plasma Levels of Inflammation Differentially Relate to CNS Markers of Alzheimer's Disease Pathology and Neuronal Damage. %A Bettcher, Brianne M %A Johnson, Sterling C %A Fitch, Ryan %A Casaletto, Kaitlin B %A Heffernan, Kate S %A Asthana, Sanjay %A Zetterberg, Henrik %A Blennow, Kaj %A Carlsson, Cynthia M %A Neuhaus, John %A Bendlin, Barbara B %A Kramer, Joel H %X

Inflammatory markers have been shown to predict neurocognitive outcomes in aging adults; however, the degree to which peripheral markers mirror the central nervous system remains unknown. We investigated the association between plasma and cerebrospinal fluid (CSF) markers of inflammation, and explored whether these markers independently predict CSF indicators of Alzheimer's disease (AD) pathology or neuronal damage. Plasma and CSF samples were analyzed for inflammatory markers in a cohort of asymptomatic older adults (n = 173). CSF samples were analyzed for markers of AD pathology (Aβ42, phosphorylated tau [p-tau], sAβPPβ) or neuronal damage (total tau; neurofilament light chain) (n = 147). Separate linear models for each analyte were conducted with CSF and plasma levels entered simultaneously as predictors and markers of AD pathology or neuronal damage as outcome measures. Strong associations were noted between CSF and plasma MIP-1β levels, and modest associations were observed for remaining analytes. With respect to AD pathology, higher levels of plasma and CSF IL-8, CSF MIP-1β, and CSF IP-10 were associated with higher levels of p-tau. Higher levels of CSF IL-8 were associated with higher levels of CSF Aβ42. Higher CSF sAβPPβ levels were associated with higher plasma markers only (IL-8; MCP-1). In terms of neuronal injury, higher levels of plasma and CSF IL-8, CSF IP-10, and CSF MIP-1β were associated with higher levels of CSF total tau. Exploratory analyses indicated that CSF Aβ42 modifies the relationship between plasma inflammatory levels and CSF tau levels. Results suggest that both plasma and CSF inflammatory markers independently relay integral information about AD pathology and neuronal damage.

%B J Alzheimers Dis %V 62 %P 385-397 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439331?dopt=Abstract %R 10.3233/JAD-170602 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid Biomarkers are Differentially Related to Structural and Functional Changes in Dementia of the Alzheimer's Type. %A Malpas, Charles B %A Saling, Michael M %A Velakoulis, Dennis %A Desmond, Patricia %A Hicks, Rodney J %A Zetterberg, Henrik %A Blennow, Kaj %A O'Brien, Terence J %X

The two cardinal pathologies of Alzheimer's disease (AD) develop according to distinct anatomical trajectories. Cerebral tau-related pathology first accumulates in the mesial temporal region, while amyloid-related pathology first appears in neocortex. The eventual distributions of these pathologies reflect their anatomical origins. An implication is that the cardinal pathologies might exert preferential effects on the structurofunctional brain changes observed in AD. We investigated this hypothesis in 39 patients with dementia of the Alzheimer's type. Interrelationships were analyzed between cerebrospinal fluid biomarkers of the cardinal pathologies, volumetric brain changes using magnetic resonance imaging, and brain metabolism using [18F]-FDG-PET. Amyloid-related pathology was preferentially associated with structurofunctional changes in the precuneus and lateral temporal regions. Tau-related pathology was not associated with changes in these regions. These findings support the hypothesis that tau- and amyloid-pathology exert differential effects on structurofunctional changes in the AD brain. These findings have implications for future therapeutic trials and hint at a more complex relationship between the cardinal pathologies and disruption of brain networks.

%B J Alzheimers Dis %V 62 %P 417-427 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439322?dopt=Abstract %R 10.3233/JAD-170250 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid Biomarkers for Early and Differential Alzheimer's Disease Diagnosis. %A Bjerke, Maria %A Engelborghs, Sebastiaan %X

An accurate and early diagnosis of Alzheimer's disease (AD) is important to select optimal patient care and is critical in current clinical trials targeting core AD neuropathological features. The past decades, much progress has been made in the development and validation of cerebrospinal fluid (CSF) biomarkers for the biochemical diagnosis of AD, including standardization and harmonization of (pre-) analytical procedures. This has resulted in three core CSF biomarkers for AD diagnostics, namely the 42 amino acid long amyloid-beta peptide (Aβ1-42), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181). These biomarkers have been incorporated into research diagnostic criteria for AD and have an added value in the (differential) diagnosis of AD and related disorders, including mixed pathologies, atypical presentations, and in case of ambiguous clinical dementia diagnoses. The implementation of the CSF Aβ1-42/Aβ1-40 ratio in the core biomarker panel will improve the biomarker analytical variability, and will also improve early and differential AD diagnosis through a more accurate reflection of pathology. Numerous biomarkers are being investigated for their added value to the core AD biomarkers, aiming at the AD core pathological features like the amyloid mismetabolism, tau pathology, or synaptic or neuronal degeneration. Others aim at non-AD neurodegenerative, vascular or inflammatory hallmarks. Biomarkers are essential for an accurate identification of preclinical AD in the context of clinical trials with potentially disease-modifying drugs. Therefore, a biomarker-based early diagnosis of AD offers great opportunities for preventive treatment development in the near future.

%B J Alzheimers Dis %V 62 %P 1199-1209 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562530?dopt=Abstract %R 10.3233/JAD-170680 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid Biomarkers in Patients with Frontotemporal Dementia Spectrum: A Single-Center Study. %A Abu-Rumeileh, Samir %A Mometto, Nicola %A Bartoletti-Stella, Anna %A Polischi, Barbara %A Oppi, Federico %A Poda, Roberto %A Stanzani-Maserati, Michelangelo %A Cortelli, Pietro %A Liguori, Rocco %A Capellari, Sabina %A Parchi, Piero %X

Cerebrospinal fluid (CSF) neurofilament light chain protein (NfL) and Alzheimer's disease (AD) core biomarker levels have been evaluated in cohorts of patients with frontotemporal dementia spectrum (FTD), but the distribution of values across the different clinical syndromes and underlying proteinopathies, and the relative diagnostic accuracy appear discordant among studies. We measured CSF NfL, total (t)-tau, phosphorylated (p)-tau, and amyloid-β (Aβ)42 in healthy controls (n = 38) and subjects with a clinical, genetic, CSF biomarker-based, and/or neuropathological diagnosis of FTD (n = 141) or AD (n = 60). Sub-analyses were conducted in a proportion of subjects with definite and/or probable frontotemporal lobar degeneration with tau (FTLD-TAU) (n = 42) or TDP43 pathology (FTLD-TDP) (n = 36). Both FTD and AD groups showed significantly increased CSF NfL levels in comparison to controls (p < 0.001). CSF NfL levels were significantly higher in FTD patients than in AD (p < 0.001), reaching the highest values in amyotrophic lateral sclerosis associated with FTD. Patients with probable and definite FTLD-TDP had significantly higher NfL levels (p < 0.001) and lower p-tau/t-tau values (p < 0.001) in comparison with probable and definite FTLD-TAU cases. NfL showed good diagnostic accuracy in the distinction between FTD and controls (AUC 0.862±0.027) and yielded an accuracy (AUC 0.861±0.045) comparable to that of the p-tau/t-tau ratio (AUC 0.814±0.050), with 80.0% sensitivity and 81.0% specificity, in the discrimination between probable/definite FTLD-TAU and FTLD-TDP. Our data further validate CSF NfL as a surrogate biomarker of neurodegeneration and disease severity in patients with FTD spectrum. Moreover, they demonstrate a good diagnostic value for NfL and p-tau/t-tau ratio in the discrimination between FTLD-TAU and FTLD-TDP.

%B J Alzheimers Dis %V 66 %P 551-563 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320576?dopt=Abstract %R 10.3233/JAD-180409 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid Levels of Angiotensin-Converting Enzyme Are Associated with Amyloid-β42 Burden in Alzheimer's Disease. %A Rocha, Natalia P %A Toledo, Andre %A Corgosinho, Laiane T S %A de Souza, Leonardo C %A Guimarães, Henrique C %A Resende, Elisa P F %A Braz, Nayara F T %A Gomes, Karina B %A Simoes E Silva, Ana C %A Caramelli, Paulo %A Teixeira, Antônio L %X

This study was designed to determine whether the levels of renin-angiotensin system (RAS) components are associated with Alzheimer's disease (AD) pathology. Cerebrospinal fluid levels of Angiotensin (Ang) II, Ang-(1-7), angiotensin-converting enzyme (ACE), ACE2, Amyloid-β (Aβ)40, Aβ42, total tau (hTau), and phospho-tau (pTau) were measured in 18 patients with AD and 10 controls. Patients with AD presented decreased levels of ACE when compared with controls. We found a significant positive correlation between ACE and Aβ42 levels among patients. Our results strengthen the hypothesis that ACE is associated with Aβ pathology in AD.

%B J Alzheimers Dis %V 64 %P 1085-1090 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040721?dopt=Abstract %R 10.3233/JAD-180282 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid, MRI, and Florbetaben-PET in Cerebral Amyloid Angiopathy-Related Inflammation. %A Renard, Dimitri %A Collombier, Laurent %A Demattei, Christophe %A Wacongne, Anne %A Charif, Mahmoud %A Ayrignac, Xavier %A Azakri, Souhayla %A Gaillard, Nicolas %A Boudousq, Vincent %A Lehmann, Sylvain %A Menjot de Champfleur, Nicolas %A Thouvenot, Eric %K Aged %K Aged, 80 and over %K Amyloid beta-Peptides %K Aniline Compounds %K Biomarkers %K Brain %K Cerebral Amyloid Angiopathy %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Multivariate Analysis %K Positron-Emission Tomography %K Prospective Studies %K Stilbenes %K tau Proteins %K Vasculitis, Central Nervous System %X

BACKGROUND: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is associated with a cerebrospinal fluid (CSF) biomarker profile similar to that observed in CAA. Few CAA-ri patients have been studied by fibrillar amyloid-β (Aβ) imaging (using 11C-Pittsburgh compound B and 18F-florbetapir, but not 18F-florbetaben).

OBJECTIVE: To describe CSF biomarkers, magnetic resonance imaging (MRI), and 18F-florbetaben (FBB)-positron emission tomography (PET) changes in CAA-ri patients.

METHODS: CSF levels of total tau, phosphorylated tau, Aβ1-42, and Aβ1-40, MRI (cerebral microbleeds count on susceptibility-weighted imaging and semi-quantitative analysis of fluid-attenuation inversion recovery white matter hyperintensities), and FBB-PET (using both cerebellar cortex and pons to calculate standardized uptake value ratios) were analyzed in nine consecutive CAA-ri patients.

RESULTS: A median number of 769 cerebral microbleeds/patient were counted on MRI. When using the pons as reference region, amyloid load on FBB-PET was very strongly correlated to CSF Aβ1-40 levels (rho = -0.83, p = 0.008) and moderately correlated to cerebral microbleed numbers in the occipital lobes (rho = 0.59, p = 0.001), while comparisons with other CSF biomarkers were not statistically significant (total tau, rho = -0.63, p = 0.076; phosphorylated tau, rho = -0.68, p = 0.05; Aβ1-42, rho = -0.59, p = 0.09). All correlations were weaker, and not statistically significant, when using the cerebellum as reference region. A non-significant correlation (rho = -0.50, p = 0.18) was observed between CSF Aβ1-40 levels and cerebral microbleed numbers.

CONCLUSION: In CAA-ri, CSF Aβ1-40 levels correlated well with amyloid load assessed by FBB-PET when the pons was used as reference, and to a lesser degree with cerebral microbleeds count on MRI. This confirms earlier data on CSF Aβ1-40 as an in vivo marker for CAA and CAA-ri.

%B J Alzheimers Dis %V 61 %P 1107-1117 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254099?dopt=Abstract %R 10.3233/JAD-170843 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid Orexin Levels and Nocturnal Sleep Disruption in Alzheimer's Disease Patients Showing Neuropsychiatric Symptoms. %A Liguori, Claudio %A Mercuri, Nicola Biagio %A Nuccetelli, Marzia %A Izzi, Francesca %A Bernardini, Sergio %A Placidi, Fabio %X

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. It is characterized by a progressive deterioration of cognition, frequently associated with neuropsychiatric symptoms (NPS). Among NPS, sleep disturbances often affect AD patients. Orexinergic system dysregulation has been associated with sleep impairment in AD patients.

OBJECTIVE: The present study investigated CSF orexin levels in AD patients and their relationship with both NPS, measured by the neuropsychiatric inventory (NPI), and sleep, measured via polysomnography.

METHODS: This is a secondary analysis of a previous study investigating CSF biomarkers, sleep impairment and cognitive decline in AD patients. AD patients completing the NPI were included in this analysis and distributed in two groups based on the presence (NPI score ≥4, AD/NPS+) or absence (NPI score <4, AD/NPS-) of NPS.

RESULTS: Twenty-two AD patients constituted the AD/NPS+ group and 20 patients constituted the AD/NPS-group. We observed higher CSF orexin levels in AD/NPS+ than AD/NPS-patients. Moreover, AD/NPS+ showed a more fragmented and the reduction of REM sleep compared to AD/NPS-patients. Notably, higher NPI scores correlated with a more altered sleep structure, higher CSF orexin levels and lower MMSE scores.

CONCLUSION: This study documented that AD patients showing NPS present a more fragmented sleep coupled with higher CSF orexin levels compared to AD patients not affected by NPS. This finding showing the increased orexinergic tone in AD patients affected by NPS suggests the possible influence of the orexinergic system dysregulation not only on sleep impairment but also on neurobehavioral disturbances.

%B J Alzheimers Dis %V 66 %P 993-999 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30372684?dopt=Abstract %R 10.3233/JAD-180769 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrovascular Disease and Neurodegeneration in Alzheimer's Disease with and without a Strong Family History: A Pilot Magnetic Resonance Imaging Study in Dominican Republic. %A Piriz, Angel %A Reyes, Dolly %A Narkhede, Atul %A Guzman, Vanessa A %A Viqar, Fawad %A Meier, Irene B %A Budge, Mariana %A Mena, Pedro %A Dashnaw, Stephen %A Lee, Joseph %A Reitz, Christiane %A Gutierrez, Jose %A Campos, Luis %A Medrano, Martin %A Lantigua, Rafael %A Mayeux, Richard %A Brickman, Adam M %X

The incidence and prevalence of Alzheimer's disease (AD) dementia are higher among Caribbean Hispanics than among non-Hispanic Whites. The causes of this health disparity remain elusive, partially because of the relative limited capacity for biomedical research in the developing countries that comprise Caribbean Latin America. To begin to address this issue, we were awarded a Development Research Award from the US NIH and Fogarty International Center in order to establish the local capacity to integrate magnetic resonance imaging (MRI) into studies of cognitive aging and dementia in Dominican Republic, establish collaborations with Dominican investigators, and conduct a pilot study on the role of cerebrovascular markers in the clinical expression of AD. Ninety older adult participants with and without AD dementia and with and without a strong family history of AD dementia received MRI scans and clinical evaluation. We quantified markers of cerebrovascular disease (white matter hyperintensities [WMH], presence of infarct, and presence of microbleed) and neurodegeneration (entorhinal cortex volume) and compared them across groups. Patients with AD dementia had smaller entorhinal cortex and greater WMH volumes compared with controls, regardless of family history status. This study provides evidence for the capacity to conduct MRI studies of cognitive aging and dementia in Dominican Republic. The results are consistent with the hypothesis that small vessel cerebrovascular disease represents a core feature of AD dementia, as affected participants had elevated WMH volumes irrespective of family history status.

%B J Alzheimers Dis %V 66 %P 1519-1528 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412503?dopt=Abstract %R 10.3233/JAD-180807 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Change in Fitness and the Relation to Change in Cognition and Neuropsychiatric Symptoms After Aerobic Exercise in Patients with Mild Alzheimer's Disease. %A Sobol, Nanna A %A Dall, Christian Have %A Høgh, Peter %A Hoffmann, Kristine %A Frederiksen, Kristian Steen %A Vogel, Asmus %A Siersma, Volkert %A Waldemar, Gunhild %A Hasselbalch, Steen G %A Beyer, Nina %X

BACKGROUND: Physical activity has the potential to improve physical function in patients with Alzheimer's disease (AD) and may contribute to modify disease processes and cognitive function.

OBJECTIVE: The aim of this study was to investigate 1) the effect of moderate-high-intensity aerobic exercise on cardiorespiratory fitness, i.e., peak oxygen uptake (VO2peak) determined by direct breath-by-breath cardiopulmonary exercise test, and 2) the association between changes in VO2peak and changes in cognition and neuropsychiatric symptoms in patients with mild AD.

METHODS: The study is based on secondary outcome analyses from the large single-blinded multi-center study ADEX (Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise). A preselected sub-group of 55 participants (age 52-83 years), 29 from the intervention group (IG) and 26 from the control group (CG), was included. IG performed 16 weeks of supervised moderate-to-high intensity aerobic exercise. Assessments of VO2peak, mental speed and attention (Symbol Digit Modalities Test, SDMT), and neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI) were performed at baseline and at 16 weeks.

RESULT: VO2peak increased 13% in the IG and a between-group difference in mean change (3.92 ml/kg/min, 95% CI 6.34-1.51, p = 0.003) was present in favor of the IG. Combined data from IG and CG showed positive associations between changes in VO2peak and changes in NPI (Rho = - 0.41, p = 0.042) and changes in SDMT (Rho = 0.36, p = 0.010), respectively.

CONCLUSION: Aerobic exercise improves VO2peak in community-dwelling patients with mild AD. Furthermore, changes in VO2peak appear to be associated to changes in cognition and neuropsychiatric symptoms.

%B J Alzheimers Dis %V 65 %P 137-145 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040719?dopt=Abstract %R 10.3233/JAD-180253 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Characterization of Music and Photograph Evoked Autobiographical Memories in People with Alzheimer's Disease. %A Baird, Amee %A Brancatisano, Olivia %A Gelding, Rebecca %A Thompson, William Forde %X

BACKGROUND: Music evoked autobiographical memories (MEAMs) have been documented in people with Alzheimer's disease (AD), but it is unclear whether music is more effective than other familiar stimuli at evoking memories.

OBJECTIVE: To explore the frequency and specificity of memories in response to famous songs compared with photographs of famous events (photograph evoked autobiographical memories, PEAMs), and whether stimuli from the period of the reminiscence bump (10-30 years of age) were more likely to elicit memories.

METHODS: 10 participants with AD and 10 aged-matched healthy elderly people reported memories following exposure to 2 songs (longest time at number one in Australian music charts) and 2 photographs (of prominent famous events) from each decade from 1930 to 2010.

RESULTS: PEAMs were more frequent than MEAMs in healthy elderly (p < 0.05), but no such differences were observed among people with AD. There was no difference in the frequency of MEAMs between groups, but people with AD showed a significant decline in the frequency of PEAMs. In both groups, MEAMs were typically less specific than PEAMs and comprised semantic knowledge or repeated/extended events. Stimuli from when participants were aged 10-30 years triggered more frequent memories compared with stimuli from later decades, but this was only statistically significant for MEAMs.

CONCLUSION: Our findings indicate a preserved mnemonic effect of music relative to pictures in this patient population, corroborating suggestions that MEAMs represent an island of preservation during the progression of AD.

%B J Alzheimers Dis %V 66 %P 693-706 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320586?dopt=Abstract %R 10.3233/JAD-180627 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Chronic Traumatic Encephalopathy and Neurodegeneration in Contact Sports and American Football. %A Zuckerman, Scott L %A Brett, Benjamin L %A Jeckell, Aaron %A Yengo-Kahn, Aaron M %A Solomon, Gary S %X

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by the presence of abnormally phosphorylated tau protein in the depths of one or more cortical sulci. Controversy over the risk of CTE and neurologic disorders later in life among contact sport athletes has taken hold in the public spotlight, most notably in American football. Players, parents, coaches, and legislators have taken action based on the commonly held notion that contact sports invariably lead to neurodegenerative disorders. However, to fully understand the science behind this assumed association, a critical appraisal of the evidence is warranted. With regards to CTE in sports, the objectives of the current report are to: 1) describe the history of CTE, 2) review current CTE definitions, 3) critically evaluate the empiric data, divided into all contact sports and exclusively American football, and 4) summarize notable themes for future research.

%B J Alzheimers Dis %V 66 %P 37-55 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30223396?dopt=Abstract %R 10.3233/JAD-180218 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Circulating miR-127-3p as a Potential Biomarker for Differential Diagnosis in Frontotemporal Dementia. %A Piscopo, Paola %A Grasso, Margherita %A Puopolo, Maria %A D'Acunto, Emanuela %A Talarico, Giuseppina %A Crestini, Alessio %A Gasparini, Marina %A Campopiano, Rosa %A Gambardella, Stefano %A Castellano, Anna Elisa %A Bruno, Giuseppe %A Denti, Michela A %A Confaloni, Annamaria %X

Given the heterogeneous nature of frontotemporal dementia (FTD), sensitive biomarkers are greatly needed for the accurate diagnosis of this neurodegenerative disorder. Circulating miRNAs have been reported as promising biomarkers for neurodegenerative disorders and processes affecting the central nervous system, especially in aging. The objective of the study was to evaluate if some circulating miRNAs linked with apoptosis (miR-29b-3p, miR-34a-5p, miR-16-5p, miR-17-5p, miR-107, miR-19b-3p, let-7b-5p, miR-26b-5p, and 127-3p) were able to distinguish between FTD patients and healthy controls. For this study, we enrolled 127 subjects, including 54 patients with FTD, 20 patients with Alzheimer's disease (AD), and 53 healthy controls. The qRT-PCR analysis showed a downregulation of miR-127-3p in FTD compared to controls, while the levels of other miRNAs remained unchanged. Then, miR-127-3p expression was also analyzed in AD patients, finding a different expression between two patient groups. A receiver operating characteristic curve was then created for miR-127-3p to discriminate FTD versus AD (AUC: 0.8986), and versus healthy controls (AUC: 0.8057). In conclusion, miR-127-3p could help to diagnose FTD and to distinguish it from AD.

%B J Alzheimers Dis %V 65 %P 455-464 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056425?dopt=Abstract %R 10.3233/JAD-180364 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Circulating Progenitor Cells Correlate with Memory, Posterior Cortical Thickness, and Hippocampal Perfusion. %A Nation, Daniel A %A Tan, Alick %A Dutt, Shubir %A McIntosh, Elissa C %A Yew, Belinda %A Ho, Jean K %A Blanken, Anna E %A Jang, Jung Yun %A Rodgers, Kathleen E %A Gaubert, Aimée %K Aged %K Aged, 80 and over %K Antigens, CD %K Apolipoproteins E %K Cerebral Cortex %K Cognitive Dysfunction %K Female %K Flow Cytometry %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Perfusion %K Stem Cells %K White Matter %X

BACKGROUND: Bone marrow-derived progenitor cells survey the vasculature and home to sites of tissue injury where they can promote repair and regeneration. It has been hypothesized that these cells may play a protective role neurodegenerative and vascular cognitive impairment.

OBJECTIVE: To evaluate progenitor cell levels in older adults with and without mild cognitive impairment (MCI), and to relate circulating levels to memory, brain volume, white matter lesion volume, and cerebral perfusion.

METHOD: Thirty-two older adults, free of stroke and cardiovascular disease, were recruited from the community and evaluated for diagnosis of MCI versus cognitively normal (CN). Participants underwent brain MRI and blood samples were taken to quantify progenitor reserve using flow cytometry (CD34+, CD34+CD133+, and CD34+CD133+CD309+ cells).

RESULTS: Participants with MCI (n = 10) exhibited depletion of all CPC markers relative to those who were CN (n = 22), after controlling for age, sex, and education. Post-hoc age, sex, and education matched comparisons (n = 10 MCI, n = 10 CN) also revealed the same pattern of results. Depletion of CD34+ cells correlated with memory performance, left posterior cortical thickness, and bilateral hippocampal perfusion. Participants exhibited low levels of vascular risk and white matter lesion burden that did not correlate with progenitor levels.

CONCLUSIONS: Circulating progenitor cells are associated with cognitive impairment, memory, cortical atrophy, and hippocampal perfusion. We hypothesize that progenitor depletion contributes to, or is triggered by, cognitive decline and cortical atrophy. Further study of progenitor cell depletion in older adults may benefit efforts to prevent or delay dementia.

%B J Alzheimers Dis %V 61 %P 91-101 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103037?dopt=Abstract %R 10.3233/JAD-170587 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Class-Specific Incidence of All-Cause Dementia and Alzheimer's Disease: A Latent Class Approach. %A Zammit, Andrea R %A Hall, Charles B %A Katz, Mindy J %A Muniz-Terrera, Graciela %A Ezzati, Ali %A Bennett, David A %A Lipton, Richard B %X

Identifying preclinical Alzheimer's disease (AD) is an important step toward developing approaches to early treatment and dementia prevention. We applied latent class analysis (LCA) to 10 baseline neuropsychological assessments for 1,345 participants from Einstein Aging Study. Time-to-event models for all-cause dementia and AD were run examining events in 4-year intervals. Five classes were identified: Mixed-Domain Impairment (n = 107), Memory-Specific Impairment (n = 457), Average (n = 539), Frontal Impairment (n = 118), and Superior Cognition (n = 124). Compared to the Average class, the Mixed-Domain Impairment and Memory-Specific Impairment classes were at higher risk of incident all-cause dementia and AD in the first 4 years from baseline, while the Frontal Impairment class was associated with higher risk between 4 and 8 years of follow-up. LCA identified classes which differ in cross-sectional cognitive patterns and in risk of dementia over specific follow-up intervals.

%B J Alzheimers Dis %V 66 %P 347-357 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282367?dopt=Abstract %R 10.3233/JAD-180604 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Clinical Evaluation of Amyloid-Related Imaging Abnormalities in Bapineuzumab Phase III Studies. %A Brashear, H Robert %A Ketter, Nzeera %A Bogert, Jennifer %A Di, Jianing %A Salloway, Stephen P %A Sperling, Reisa %X

BACKGROUND: Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) reported in patients with mild-to-moderate Alzheimer's disease in bapineuzumab phase III studies.

OBJECTIVES: Assess symptoms, clinical severity, and ARIA-E outcomes, and to evaluate effects on cognition and function.

METHODS: A centralized systematic sequential locked procedure and scoring system for assessment of magnetic resonance imaging scans in 1,331 APOE ɛ4 noncarriers and 1,121 carriers was conducted by experienced and trained pairs of neuroradiologists.

RESULTS: Treatment-emergent ARIA-E occurred in 15.8% of bapineuzumab and 0.8% placebo-treated patients. In all treated APOE ɛ4 noncarriers, the percentage of patients with ARIA-E was 5.6%, 13.4%, and 19.9% in the 0.5, 1.0, and 2.0 mg/kg groups respectively, and the incidence of symptomatic ARIA-E was 1.5%, 1.5%, and 7.8%, respectively. In carriers, ARIA-E occurred in 21.2% in the 0.5 mg/kg group, and symptomatic ARIA-E occurred in 2.4%. The clinical severity of ARIA-E in those patients in whom it was detected during the study was mild in 57.1%, 61.3%, and 50.0% of cases in 0.5, 1.0, and 2.0 mg/kg noncarriers respectively, and in 73.8% of cases in 0.5 mg/kg carriers. Vascular risk factors did not appear to increase susceptibility to ARIA-E. Rate of decline in cognition and function measured by changes in ADAS-Cog/11 and DAD total scores did not meaningfully differ in patients with ARIA-E versus those without ARIA-E. Extent of cognitive decline was similar over all visit intervals.

CONCLUSIONS: Overall, ARIA-E was mild and asymptomatic. ARIA-E did not demonstrate clinically meaningful acute or chronic impact on cognition or function.Registration: NCT00574132 (Bapineuzumab-301), NCT00575055 (Bapineuzumab-302).

%B J Alzheimers Dis %V 66 %P 1409-1424 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412493?dopt=Abstract %R 10.3233/JAD-180675 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Clinical Subtypes of Dementia with Lewy Bodies Based on the Initial Clinical Presentation. %A Morenas-Rodriguez, Estrella %A Sala, Isabel %A Subirana, Andrea %A Pascual-Goñi, Elba %A Sánchez-Saudinós, Ma Belén %A Alcolea, Daniel %A Illán-Gala, Ignacio %A Carmona-Iragui, María %A Ribosa-Nogué, Roser %A Camacho, Valle %A Blesa, Rafael %A Fortea, Juan %A Lleo, Alberto %X

BACKGROUND: Dementia with Lewy bodies (DLB) is a heterogeneous disease in which clinical presentation, symptoms, and evolution widely varies between patients.

OBJECTIVE: To investigate the existence of clinical subtypes in DLB based on the initial clinical presentation.

METHODS: 81 patients with a clinical diagnosis of probable DLB were consecutively included. All patients underwent a neurological evaluation including a structured questionnaire about neuropsychiatric symptoms and sleep, an assessment of motor impairment (Unified Parkinson Disease Rating Scale subscale III), and a formal neuropsychological evaluation. Onset of core symptoms (hallucinations, parkinsonism, and fluctuations) and dementia were systematically reviewed from medical records. We applied a K-means clustering method based on the initial clinical presentation.

RESULTS: Cluster analysis yielded three different groups. Patients in cluster I (cognitive-predominant, n = 46) presented more frequently with cognitive symptoms (95.7%, n = 44, p < 0.001), and showed a longer duration from onset to DLB diagnosis (p < 0.001) than the other clusters. Patients in cluster II (neuropsychiatric-predominant, n = 22) were older at disease onset (78.1±5 versus 73.6±6.1 and 73.6±4.2 in clusters I and III, respectively, both p < 0.01), presented more frequently with psychotic symptoms (77.3%, n = 17), and had a shorter duration until the onset of hallucinations (p < 0.001). Patients in cluster III (parkinsonism-predominant, n = 13) showed a shorter time from onset to presence of parkinsonism (p < 0.001) and dementia (0.008).

CONCLUSIONS: Three clinical subtypes of DLB can be defined when considering the differential initial presentations. The proposed subtypes have distinct clinical profiles and progression patterns.

%B J Alzheimers Dis %V 64 %P 505-513 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889064?dopt=Abstract %R 10.3233/JAD-180167 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Clinical-Neuropathological Correlations of Alzheimer's Disease and Related Dementias in Latino Volunteers. %A Soria, Jose A %A Huisa, Branko N %A Edland, Steven D %A Litvan, Irene %A Peavy, Guerry M %A Salmon, David P %A Hansen, Lawrence A %A Galasko, Douglas R %A Brewer, James B %A González, Hector M %A Rissman, Robert A %X

Clinical, neuropsychological, and neurological procedures used to diagnose Alzheimer's disease (AD) and related dementias were largely developed and validated in well-educated, non-Latino, English-speaking populations. Sociocultural and genetic differences in Latinos might influence the accuracy of clinical diagnosis of AD and other dementias. We aim to compare the accuracy of the clinical diagnosis of AD and related dementias in Latinos with the corresponding neuropathological diagnosis. From the UCSD Alzheimer's Disease Research Center longitudinal cohort, we selected all Latino participants who had autopsy neuropathological studies from 1991 to 2017. Participants underwent annual neurological clinical evaluations, standard neuropsychological tests, neuroimaging, and genotyping of Apolipoprotein E. We calculated the sensitivity and specificity of the clinical diagnosis of AD against the primary pathological diagnosis. Of the 34 participants with a primary neuropathological diagnosis of AD, 33 (97.1%) were correctly clinically diagnosed as having AD at the last clinical evaluation, and 1 was incorrectly diagnosed with dementia with Lewy bodies. Of the 19 participants without a primary neuropathological diagnosis of AD, 8 were incorrectly clinically diagnosed with probable AD at the last clinic evaluation. The clinical diagnosis of AD at the last clinical evaluation had 97.1% sensitivity and 57.9% specificity for autopsy-verified AD. In this Latino cohort, clinicians predicted AD pathological findings with high sensitivity but moderate specificity. Tangle-only dementia was the most common misdiagnosis. Our study suggests that current procedures and instruments to clinically determine AD in Latinos have high sensitivity compared with neuropathology, but specificity needs to be improved.

%B J Alzheimers Dis %V 66 %P 1539-1548 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412501?dopt=Abstract %R 10.3233/JAD-180789 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology. %A Alosco, Michael L %A Sugarman, Michael A %A Besser, Lilah M %A Tripodis, Yorghos %A Martin, Brett %A Palmisano, Joseph N %A Kowall, Neil W %A Au, Rhoda %A Mez, Jesse %A DeCarli, Charles %A Stein, Thor D %A McKee, Ann C %A Killiany, Ronald J %A Stern, Robert A %X

BACKGROUND: White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been postulated to be a core feature of Alzheimer's disease. Clinicopathological studies are needed to elucidate and confirm this possibility.

OBJECTIVE: This study examined: 1) the association between antemortem WMH and autopsy-confirmed Alzheimer's disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH, and ADNP.

METHODS: The sample included 82 participants from the National Alzheimer's Coordinating Center's Data Sets who had quantitated volume of WMH from antemortem FLAIR MRI and available neuropathological data. The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy.

RESULTS: 60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p = 0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p = 0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts, and lacunes (ps < 0.04). ADNP+ participants were more likely to have moderate-severe arteriolosclerosis and cerebral amyloid angiopathy compared to ADNP-participants (ps < 0.04).

CONCLUSIONS: This study found a direct association between total volume of WMH and increased odds for having ADNP. In patients with Alzheimer's disease, FLAIR MRI WMH may be able to provide key insight into disease severity and progression. The association between WMH and ADNP may be explained by underlying cerebrovascular disease.

%B J Alzheimers Dis %V 63 %P 1347-1360 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843242?dopt=Abstract %R 10.3233/JAD-180017 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Co-Expression of Glia Maturation Factor and Apolipoprotein E4 in Alzheimer's Disease Brain. %A Thangavel, Ramasamy %A Bhagavan, Sachin M %A Ramaswamy, Swathi Beladakere %A Surpur, Spurthi %A Govindarajan, Raghav %A Kempuraj, Duraisamy %A Zaheer, Smita %A Raikwar, Sudhanshu %A Ahmed, Mohammad E %A Selvakumar, Govindhasamy Pushpavathi %A Iyer, Shankar S %A Zaheer, Asgar %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Brain %K Case-Control Studies %K Fluorescent Antibody Technique %K Glia Maturation Factor %K Humans %K Neurofibrillary Tangles %K Plaque, Amyloid %X

Apolipoprotein E4 (ApoE4) is a major genetic risk factor for Alzheimer's disease (AD). The E4 allele of ApoE plays a crucial role in the inflammatory and neurodegenerative processes associated with AD. This is evident from the multiple effects of the ApoE isoforms in amyloid-β (Aβ) aggregation. Glia maturation factor (GMF) is a brain-specific neuroinflammatory protein that we have previously demonstrated to be significantly upregulated in various regions of AD brains compared to non-AD control brains and that it induces neurodegeneration. We have previously reported that GMF is predominantly expressed in the reactive astrocytes surrounding amyloid plaques (APs) in AD brain. In the present study, using immunohistochemical and dual immunofluorescence staining, we show the expression and colocalization of GMF and ApoE4 in AD brains. Our results show that ApoE4 is present within the APs of AD brain. Further, we found that GMF and ApoE4 were strongly expressed and co-associated in APs and in the reactive astrocytes surrounding APs in AD. An increased expression of GMF in APs and neurofibrillary tangles in the AD brain, and the co-localization of GMF and ApoE4 in APs suggest that GMF and ApoE4 together should be contributing to the neuropathological changes associated with AD.

%B J Alzheimers Dis %V 61 %P 553-560 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29172001?dopt=Abstract %R 10.3233/JAD-170777 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cognitive Impairment is Associated with Mortality in Hemodialysis Patients. %A Angermann, Susanne %A Schier, Johannes %A Baumann, Marcus %A Steubl, Dominik %A Hauser, Christine %A Lorenz, Georg %A Günthner, Roman %A Braunisch, Matthias C %A Kemmner, Stephan %A Satanovskij, Robin %A Haller, Bernhard %A Heemann, Uwe %A Lehnert, Thomas %A Bieber, Richard %A Pachmann, Martin %A Braun, Jürgen %A Scherf, Julia %A Schätzle, Gabriele %A Fischereder, Michael %A Grimmer, Timo %A Schmaderer, Christoph %X

BACKGROUND: The prevalence of cognitive impairment in hemodialysis patients is notably high. In previous studises performed in the general population, cognitive impairment has been associated with increased mortality.

OBJECTIVE: We evaluated the relationship between global cognitive function tested by a short screening instrument and mortality in hemodialysis patients.

METHODS: Cognitive testing was performed in 242 maintenance hemodialysis patients under standardized conditions at baseline using the Montreal Cognitive Assessment (MoCA).Cognitive impairment was defined as a MoCA test score ≤24 points, as published previously. All-cause mortality was monitored during a median follow-up of 3.54 years. Kaplan-Meier plot and Cox regression model adjusted for known risk factors for mortality in hemodialysis patients were used to examine a possible association between global cognitive function and all-cause mortality.

RESULTS: A MoCA test score ≤24 points resulted in a significant almost 3-fold higher hazard for all-cause mortality (unadjusted hazard ratio [HR]: 2.812; 95% confidence interval [95% CI]: 1.683-4.698; p < 0.001). After adjustment, this association was attenuated but remained significant (adjusted HR: 1.749; 95% CI: 1.007-3.038; p = 0.047).

CONCLUSION: Impairment of global cognitive function measured by a short screening instrument was identified for the first time as an independent predictor of all-cause mortality in hemodialysis patients. Thus, implementing the MoCA test in clinical routine could contribute to a better risk stratification of this patient population.

%B J Alzheimers Dis %V 66 %P 1529-1537 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412499?dopt=Abstract %R 10.3233/JAD-180767 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cognitive Training Improves Ratio Processing and Decision Making in Patients with Mild Cognitive Impairment. %A Burgio, Francesca %A Delazer, Margarete %A Meneghello, Francesca %A Pertl, Marie-Theres %A Semenza, Carlo %A Zamarian, Laura %X

BACKGROUND: Patients with mild cognitive impairment (MCI) show lower decision making and ratio processing abilities as compared to healthy peers.

OBJECTIVE: To evaluate whether cognitive training on number processing and/or executive functions improves performance on ratio processing and decision making under risk.

METHODS: In a controlled cross-over study, patients with MCI (n = 23; mean MMSE 26.48, SD 2.43) underwent a week of numerical training followed by a week of executive-functions training (subgroup A), or vice versa (subgroup B). Before training (T1), patients performed experimental tasks of decision making (Game of Dice Task, GDT; Probability-Associated Gambling task, PAG-60 task) and of ratio processing as well as a neuropsychological background assessment. Experimental tasks were also administered after the first (T2) and the second (T3) training week.

RESULTS: The numerical training and the training of executive functions had a differential effect on experimental tasks of ratio processing. Only the numerical training proved to be effective. The effects of the two training types on decision making under risk were less clear-cut. While no changes over time were observed in the GDT, performance on the PAG-60 task improved in both training subgroups. These improvements were apparent in one subgroup after a period of executive-functions training, in the other subgroup after both training weeks. That means, improvements are not attributable to one specific training type.

CONCLUSION: Patients with MCI can profit from a cognitive training on number processing and executive functions. Improvements are reflected in higher ratio processing abilities and more advantageous decisions after training. These results are consistent with assumptions of current cognitive models.

%B J Alzheimers Dis %V 64 %P 1213-1226 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010137?dopt=Abstract %R 10.3233/JAD-180461 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Combining Cognitive, Genetic, and Structural Neuroimaging Markers to Identify Individuals with Increased Dementia Risk. %A Payton, Nicola M %A Kalpouzos, Grégoria %A Rizzuto, Debora %A Fratiglioni, Laura %A Kivipelto, Miia %A Bäckman, Lars %A Laukka, Erika J %X

BACKGROUND: Cognitive and biological markers have shown varying degrees of success in identifying persons who will develop dementia.

OBJECTIVE: To evaluate different combinations of cognitive and biological markers and identify prediction models with the highest accuracy for identifying persons with increased dementia risk.

METHODS: Neuropsychological assessment, genetic testing (apolipoprotein E -APOE), and structural magnetic resonance imaging (MRI) were performed for 418 older individuals without dementia (60-97 years) from a population-based study (SNAC-K). Participants were followed for six years.

RESULTS: Cognitive, genetic, and MRI markers were systematically combined to create prediction models for dementia at six years. The most predictive individual markers were perceptual speed or carrying at least one APOEɛ4 allele (AUC = 0.875). The most predictive model (AUC = 0.924) included variables from all three modalities (category fluency, general knowledge, any ɛ4 allele, hippocampal volume, white matter-hyperintensity volume).

CONCLUSION: This study shows that combining markers within and between modalities leads to increased predictivity for future dementia. However, minor increases in predictive value should be weighed against the cost of additional tests in larger-scale screening.

%B J Alzheimers Dis %V 64 %P 533-542 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889068?dopt=Abstract %R 10.3233/JAD-180199 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Comparing the Electronic and Standard Versions of the Montreal Cognitive Assessment in an Outpatient Memory Disorders Clinic: A Validation Study. %A Berg, Jody-Lynn %A Durant, January %A Léger, Gabriel C %A Cummings, Jeffrey L %A Nasreddine, Ziad %A Miller, Justin B %X

The Montreal Cognitive Assessment (MoCA) has become widely used as a brief test of cognitive function in patients with neurological disease. More convenient application of the MoCA might increase its use and enhance its utility. An electronic version of the MoCA has recently been developed. To establish validity of the electronic version (eMoCA), discrepancy scores, concordance correlation coefficients (CCC), and root mean squared differences (RMSD) were calculated between each administration method in a sample of 43 new adult patients presenting with primary memory complaints. The CCC was 0.84 and the RMSD was 2.27, with 76% of the sample having a difference score within 2 points. Overall, this study establishes adequate convergent validity between the MoCA and eMoCA among an adult population presenting with memory concerns.

%B J Alzheimers Dis %V 62 %P 93-97 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439349?dopt=Abstract %R 10.3233/JAD-170896 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Comparison of Different Hypotheses Regarding the Spread of Alzheimer's Disease Using Markov Random Fields and Multimodal Imaging. %A Dyrba, Martin %A Grothe, Michel J %A Mohammadi, Abdolreza %A Binder, Harald %A Kirste, Thomas %A Teipel, Stefan J %X

Alzheimer's disease (AD) is characterized by a cascade of pathological processes that can be assessed in vivo using different neuroimaging methods. Recent research suggests a systematic sequence of pathogenic events on a global biomarker level, but little is known about the associations and dependencies of distinct lesion patterns on a regional level. Markov random fields are a probabilistic graphical modeling approach that represent the interaction between individual random variables by an undirected graph. We propose the novel application of this approach to study the interregional associations and dependencies between multimodal imaging markers of AD pathology and to compare different hypotheses regarding the spread of the disease. We retrieved multimodal imaging data from 577 subjects enrolled in the Alzheimer's Disease Neuroimaging Initiative. Mean amyloid load (AV45-PET), glucose metabolism (FDG-PET), and gray matter volume (MRI) were calculated for the six principle nodes of the default mode network- a functional network of brain regions that appears to be preferentially targeted by AD. Multimodal Markov random field models were developed for three different hypotheses regarding the spread of the disease: the "intraregional evolution model", the "trans-neuronal spread" hypothesis, and the "wear-and-tear" hypothesis. The model likelihood to reflect the given data was evaluated using tenfold cross-validation with 1,000 repetitions. The most likely graph structure contained the posterior cingulate cortex as main hub region with edges to various other regions, in accordance with the "wear-and-tear" hypothesis of disease vulnerability. Probabilistic graphical models facilitate the analysis of interactions between several variables in a network model and therefore afford great potential to complement traditional multiple regression analyses in multimodal neuroimaging research.

%B J Alzheimers Dis %V 65 %P 731-746 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697557?dopt=Abstract %R 10.3233/JAD-161197 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Complexity and Selectivity of γ-Secretase Cleavage on Multiple Substrates: Consequences in Alzheimer's Disease and Cancer. %A Medoro, Alessandro %A Bartollino, Silvia %A Mignogna, Donatella %A Passarella, Daniela %A Porcile, Carola %A Pagano, Aldo %A Florio, Tullio %A Nizzari, Mario %A Guerra, Germano %A Di Marco, Roberto %A Intrieri, Mariano %A Raimo, Gennaro %A Russo, Claudio %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Humans %K Neoplasms %K Presenilin-1 %X

The processing of the amyloid-β protein precursor (AβPP) by β- and γ-secretases is a pivotal event in the genesis of Alzheimer's disease (AD). Besides familial mutations on the AβPP gene, or upon its overexpression, familial forms of AD are often caused by mutations or deletions in presenilin 1 (PSEN1) and 2 (PSEN2) genes: the catalytic components of the proteolytic enzyme γ-secretase (GS). The "amyloid hypothesis", modified over time, states that the aberrant processing of AβPP by GS induces the formation of specific neurotoxic soluble amyloid-β (Aβ) peptides which, in turn, cause neurodegeneration. This theory, however, has recently evidenced significant limitations and, in particular, the following issues are debated: 1) the concept and significance of presenilin's "gain of function" versus "loss of function"; and 2) the presence of several and various GS substrates, which interact with AβPP and may influence Aβ formation. The latter consideration is suggestive: despite the increasing number of GS substrates so far identified, their reciprocal interaction with AβPP itself, even in the AD field, is significantly unexplored. On the other hand, GS is also an important pharmacological target in the cancer field; inhibitors or GS activity are investigated in clinical trials for treating different tumors. Furthermore, the function of AβPP and PSENs in brain development and in neuronal migration is well known. In this review, we focused on a specific subset of GS substrates that directly interact with AβPP and are involved in its proteolysis and signaling, by evaluating their role in neurodegeneration and in cell motility or proliferation, as a possible connection between AD and cancer.

%B J Alzheimers Dis %V 61 %P 1-15 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103038?dopt=Abstract %R 10.3233/JAD-170628 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Comprehensive Characterization of the Pyroglutamate Amyloid-β Induced Motor Neurodegenerative Phenotype of TBA2.1 Mice. %A Dunkelmann, Tina %A Schemmert, Sarah %A Honold, Dominik %A Teichmann, Kerstin %A Butzküven, Elke %A Demuth, Hans-Ulrich %A Shah, Nadim Joni %A Langen, Karl-Josef %A Kutzsche, Janine %A Willbold, Dieter %A Willuweit, Antje %X

Alzheimer's disease (AD) is the most common neurodegenerative disorder and is being intensively investigated using a broad variety of animal models. Many of these models express mutant versions of human amyloid-β protein precursor (AβPP) that are associated with amyloid-β protein (Aβ)-induced early onset familial AD. Most of these models, however, do not develop bold neurodegenerative pathology and the respective phenotypes. Nevertheless, this may well be essential for their suitability to identify therapeutically active compounds that have the potential for a curative or at least disease-modifying therapy in humans. In this study, the new transgenic mouse model TBA2.1 was explored in detail to increase knowledge about the neurodegenerative process induced by the presence of pyroglutamate modified human Aβ3-42 (pEAβ3-42). Analysis of the sensorimotor phenotype, motor coordination, Aβ pathology, neurodegeneration, and gliosis revealed formation and progression of severe pathology and phenotypes including massive neuronal loss in homozygous TBA2.1 mice within a few months. In contrast, the start of a slight phenotype was observed only after 21 months in heterozygous mice. These data highlight the role of pEAβ3-42 in the disease development and progression of AD. Based on the findings of this study, homozygous TBA2.1 mice can be utilized to gain deeper understanding in the underlying mechanisms of pEAβ3-42 and might be suitable as an animal model for treatment studies targeting toxic Aβ species, complementary to the well described transgenic AβPP mouse models.

%B J Alzheimers Dis %V 63 %P 115-130 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578479?dopt=Abstract %R 10.3233/JAD-170775 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Concordance Between Cerebrospinal Fluid Biomarkers with Alzheimer's Disease Pathology Between Three Independent Assay Platforms. %A Doecke, James D %A Rembach, Alan %A Villemagne, Victor L %A Varghese, Shiji %A Rainey-Smith, Stephanie %A Sarros, Shannon %A Evered, Lisbeth A %A Fowler, Christopher J %A Pertile, Kelly K %A Rumble, Rebecca L %A Trounson, Brett %A Taddei, Kevin %A Laws, Simon M %A Macaulay, S Lance %A Bush, Ashley I %A Ellis, Kathryn A %A Martins, Ralph %A Ames, David %A Silbert, Brendan %A Vanderstichele, Hugo %A Masters, Colin L %A Darby, David G %A Li, Qiao-Xin %A Collins, Steven %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognition Disorders %K Female %K Humans %K Male %K Mental Status Schedule %K Peptide Fragments %K Positron-Emission Tomography %K ROC Curve %K tau Proteins %X

BACKGROUND: To enhance the accuracy of clinical diagnosis for Alzheimer's disease (AD), pre-mortem biomarkers have become increasingly important for diagnosis and for participant recruitment in disease-specific treatment trials. Cerebrospinal fluid (CSF) biomarkers provide a low-cost alternative to positron emission tomography (PET) imaging for in vivo quantification of different AD pathological hallmarks in the brains of affected subjects; however, consensus around the best platform, most informative biomarker and correlations across different methodologies are controversial.

OBJECTIVE: Assessing levels of Aβ-amyloid and tau species determined using three different versions of immunoassays, the current study explored the ability of CSF biomarkers to predict PET Aβ-amyloid (32 Aβ-amyloid-and 45 Aβ-amyloid+), as well as concordance between CSF biomarker levels and PET Aβ-amyloid imaging.

METHODS: Prediction and concordance analyses were performed using a sub-cohort of 77 individuals (48 healthy controls, 15 with mild cognitive impairment, and 14 with AD) from the Australian Imaging Biomarker and Lifestyle study of aging.

RESULTS: Across all three platforms, the T-tau/Aβ42 ratio biomarker had modestly higher correlation with SUVR/BeCKeT (ρ= 0.69-0.8) as compared with Aβ42 alone (ρ= 0.66-0.75). Differences in CSF biomarker levels between the PET Aβ-amyloid-and Aβ-amyloid+ groups were strongest for the Aβ42/Aβ40 and T-tau/Aβ42 ratios (p < 0.0001); however, comparison of predictive models for PET Aβ-amyloid showed no difference between Aβ42 alone and the T-tau/Aβ42 ratio.

CONCLUSION: This study confirms strong concordance between CSF biomarkers and PET Aβ-amyloid status is independent of immunoassay platform, supporting their utility as biomarkers in clinical practice for the diagnosis of AD and for participant enrichment in clinical trials.

%B J Alzheimers Dis %V 61 %P 169-183 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171991?dopt=Abstract %R 10.3233/JAD-170128 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Connected Speech Features from Picture Description in Alzheimer's Disease: A Systematic Review. %A Slegers, Antoine %A Filiou, Renée-Pier %A Montembeault, Maxime %A Brambati, Simona Maria %X

The language changes that occur over the course of Alzheimer's disease (AD) can impact communication abilities and have profound functional consequences. Picture description tasks can be used to approximate everyday communication abilities of AD patients. As various methods and variables have been studied over the years, current knowledge about the most affected features of AD discourse in the context of picture descriptions is difficult to summarize. This systematic review aims to provide researchers with an overview of the most common areas of impairment in AD discourse as they appear in picture description tasks. Based on the 44 articles fulfilling inclusion criteria, our findings reflect a multidimensional pattern of changes in the production (speech rate), syntactic (length of utterance), lexical (word-frequency and use of pronouns), fluency (repetitions and word-finding difficulties), semantic (information units), and discourse (efficiency) domains. We discuss our findings in the light of current research and point to potential scientific and clinical uses of picture description tasks in the context of AD.

%B J Alzheimers Dis %V 65 %P 519-542 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103314?dopt=Abstract %R 10.3233/JAD-170881 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Contribution of Bilingualism to Cognitive Reserve of an Italian Literature Professor at High Risk for Alzheimer's Disease. %A Lombardi, Gemma %A Polito, Cristina %A Berti, Valentina %A Bagnoli, Silvia %A Nacmias, Benedetta %A Pupi, Alberto %A Sorbi, Sandro %X

Bilingualism is an independent component of cognitive reserve that permits to delay dementia onset up to 5 years. We describe a case of a bilingual Italian man affected by mild cognitive impairment with high cognitive reserve that, despite the presence of multiple risk factors (ApoE ɛ4/ɛ4 genotype, older age, untreated Obstructive Sleep Apnea Syndrome, AD-like biomarker alterations) did not convert to Alzheimer's disease up to 5 years follow-up. The present case confirms the role of bilingualism as a strong protective factor for dementia, even in the occurrence of multiple risk factors.

%B J Alzheimers Dis %V 66 %P 1389-1395 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30475769?dopt=Abstract %R 10.3233/JAD-180736 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Conundrum of GSK3 Inhibitors: Is it the Dawn of a New Beginning? %A Bhat, Ratan V %A Andersson, Ulf %A Andersson, Shalini %A Knerr, Laurent %A Bauer, Udo %A Sundgren-Andersson, Anna K %X

Spanning over three decades of extensive drug discovery research, the efforts to develop a potent and selective GSK3 inhibitor as a therapeutic for the treatment of type 2 diabetes, Alzheimer's disease (AD), bipolar disorders and cancer have been futile. Since its initial discovery in 1980 and subsequent decades of research, one cannot underscore the importance of the target and the promise of a game changing disease modifier. Several pharmaceutical companies, biotech companies, and academic institutions raged in a quest to unravel the biology and discover potent and selective GSK3 inhibitors, some of which went through clinical trials. However, the conundrum of what happened to the fate of the AstraZeneca's GSK3 inhibitors and the undertaking to find a therapeutic that could control glycogen metabolism and aberrant tau hyperphosphorylation in the brain, and rescue synaptic dysfunction has largely been untold. AstraZeneca was in the forefront of GSK3 drug discovery research with six GSK3 drug candidates, one of which progressed up to Phase II clinical trials in the quest to untangle the tau hypothesis for AD. Analysis of key toxicity issues, serendipitous findings and efficacy, and biomarker considerations in relation to safety margins have limited the potential of small molecule therapeutics as a way forward. To guide future innovation of this important target, we reveal the roller coaster journey comprising of two decades of preclinical and clinical GSK3 drug discovery at AstraZeneca; the understanding of which could lead to improved GSK3 therapies for disease. These learnings in combination with advances in achieving kinase selectivity, different modes of action as well as the recent discovery of novel conjugated peptide technology targeting specific tissues have potentially provided a venue for scientific innovation and a new beginning for GSK3 drug discovery.

%B J Alzheimers Dis %V 64 %P S547-S554 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758944?dopt=Abstract %R 10.3233/JAD-179934 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Correlates of Subjective Cognitive Decline in Lesbian, Gay, Bisexual, and Transgender Older Adults. %A Flatt, Jason D %A Johnson, Julene K %A Karpiak, Stephen E %A Seidel, Liz %A Larson, Britta %A Brennan-Ing, Mark %X

BACKGROUND: Little is known about subjective cognitive decline (SCD) in lesbian, gay, bisexual, and transgender (LGBT) older adults.

OBJECTIVES: To examine SCD and its association with dementia risk factors, other physical and psychosocial health factors in LGBT older adults.

METHODS: A cross-sectional study of SCD was conducted with LGBT older adults, aged 50 and older (n = 210). SCD was categorized based on endorsement of memory problems and one other cognitive domain. Hierarchical logistic regression examined the associations between demographic factors, dementia risk factors, other health and psychosocial factors, and SCD.

RESULTS: Nearly 25% of LGBT older adults were classified as having SCD. LGBT older adults who were people of color (OR = 2.5; 95% CI = 1.1- 7.8), depressed (OR = 2.9; 95% CI = 1.3- 6.9), or reported having functional impairment (OR = 2.6; 95% CI = 1.1- 6.5) were significantly more likely to be classified as having SCD (Nagelkerke pseudo R2 = 0.27).

CONCLUSION: Depression and functional impairment should be considered when screening LGBT older adults for cognitive impairment and dementia. Future research on the cognitive impairment and dementia risk in LGBT older adults is needed.

%B J Alzheimers Dis %V 64 %P 91-102 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865050?dopt=Abstract %R 10.3233/JAD-171061 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Decade of Blood Biomarkers for Alzheimer's Disease Research: An Evolving Field, Improving Study Designs, and the Challenge of Replication. %A Shi, Liu %A Baird, Alison L %A Westwood, Sarah %A Hye, Abdul %A Dobson, Richard %A Thambisetty, Madhav %A Lovestone, Simon %X

Blood-based biomarkers represent a less invasive and potentially cheaper approach for aiding Alzheimer's disease (AD) detection compared with cerebrospinal fluid and some neuroimaging biomarkers. Acknowledging that many in the field have made great progress, here we review some of the work that our group has pursued to identify and validate blood-based proteomic biomarkers through both case control and AD pathology endophenotype-based approaches. Our focus is primarily to identify a minimally invasive and hopefully cost-effective blood-based biomarker to reduce screen failure in clinical trials where participants have prodromal or even pre-clinical disease. We summarize some of the key findings and approaches taken in these biomarker studies, while addressing the main challenges, including that of limited replication in the field, and discuss opportunities for biomarker development.

%B J Alzheimers Dis %V 62 %P 1181-1198 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562526?dopt=Abstract %R 10.3233/JAD-170531 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Decoupling of Local Metabolic Activity and Functional Connectivity Links to Amyloid in Alzheimer's Disease. %A Scherr, Martin %A Pasquini, Lorenzo %A Benson, Gloria %A Nuttall, Rachel %A Gruber, Martin %A Neitzel, Julia %A Brandl, Felix %A Sorg, Christian %X

BACKGROUND: Both ongoing local metabolic activity (LMA) and corresponding functional connectivity (FC) with remote brain regions are progressively impaired in Alzheimer's disease (AD), particularly in the posterior default mode network (pDMN); however, it is unknown how these impairments interact. It is well known that decreasing mean synaptic activity of a region, i.e., decreasing LMA, reduces the region's sensitivity to afferent input from other regions, i.e., FC.

OBJECTIVE: We hypothesized progressive decoupling between LMA and FC in AD, which is linked to amyloid-β pathology (Aβ).

METHODS: Healthy adults (n=20) and Aβ+patients without memory impairment (n=9), early MCI (n=21), late MCI (n=18) and AD (n=22) were assessed by resting-state fMRI, FDG-PET, and AV-45-PET to measure FC, LMA, and Aβ of the pDMN. Coupling between LMA and FC (rLA/FC) was estimated by voxelwise correlation.

RESULTS: RLMA/FC decreased with disease severity (F=20.09, p<0.001). This decrease was specifically associated with pDMN Aβ (r=-0.273, p=0.029) but not global Aβ (r=-0.112, p=0.378) and with the impact of Aβ on FC (i.e., rAβ/FC,r=-0.339; p=0.006). In multiple regression models rLMA/FC was also associated with memory impairment, reduced cognitive speed and flexibility, outperforming global Aβ, pDMN Aβ, pDMN LMA, and pDMN FC, respectively.

CONCLUSION: Results demonstrate increasing decoupling of LMA from its FC in AD. Data suggest that decoupling is driven by local Aβ and contributes to memory decline.

%B J Alzheimers Dis %V 64 %P 405-415 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843243?dopt=Abstract %R 10.3233/JAD-180022 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation. %A Leoutsakos, Jeannie-Marie S %A Yan, Haijuan %A Anderson, William S %A Asaad, Wael F %A Baltuch, Gordon %A Burke, Anna %A Chakravarty, M Mallar %A Drake, Kristen E %A Foote, Kelly D %A Fosdick, Lisa %A Giacobbe, Peter %A Mari, Zoltan %A McAndrews, Mary Pat %A Munro, Cynthia A %A Oh, Esther S %A Okun, Michael S %A Pendergrass, Jo Cara %A Ponce, Francisco A %A Rosenberg, Paul B %A Sabbagh, Marwan N %A Salloway, Stephen %A Tang-Wai, David F %A Targum, Steven D %A Wolk, David %A Lozano, Andres M %A Smith, Gwenn S %A Lyketsos, Constantine G %X

BACKGROUND: Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years.

OBJECTIVE: To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f treatment of mild AD after two years.

METHODS: 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial.

RESULTS: DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants.

CONCLUSION: DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65.

%B J Alzheimers Dis %V 64 %P 597-606 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914028?dopt=Abstract %R 10.3233/JAD-180121 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Default Mode Network Lateralization and Memory in Healthy Aging and Alzheimer's Disease. %A Banks, Sarah J %A Zhuang, Xiaowei %A Bayram, Ece %A Bird, Chris %A Cordes, Dietmar %A Caldwell, Jessica Z K %A Cummings, Jeffrey L %X

Lateralization of default mode network (DMN) functioning has been shown to change with age. Similarly, lateralization of frontal lobe function has been shown to decline in age. The impact of amyloid pathology and the progression of Alzheimer's disease (AD) on resting state lateralization has not been investigated. Due to the preferential involvement of the left hemisphere in verbal tasks, there may be a benefit to higher levels of left-lateralization in the performance of verbal memory tasks. Here we compared functional lateralization of the anterior and posterior DMN between four groups of participants: amyloid negative (Aβ-) and amyloid positive (Aβ+) groups with normal cognition (NC), and Aβ+ groups with mild cognitive impairment (Aβ+MCI) or dementia (Aβ+AD). Differences were evident between groups in posterior DMN; the Aβ-NC group was more left-lateralized than both cognitively impaired Aβ+ groups. There was no difference in anterior DMN. No differences in overall network connectivity between groups were observed, suggesting that the functional lateralization finding is not secondary to general changes in connectivity. Left-lateralization of both networks was associated with better verbal recall performance. Older subjects, overall, had less left functional lateralization of the anterior DMN.

%B J Alzheimers Dis %V 66 %P 1223-1234 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412488?dopt=Abstract %R 10.3233/JAD-180541 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dementia Research: Populations, Progress, Problems, and Predictions. %A Hunter, Sally %A Smailagic, Nadja %A Brayne, Carol %X

Alzheimer's disease (AD) is a clinicopathologically defined syndrome leading to cognitive impairment. Following the recent failures of amyloid-based randomized controlled trials to change the course of AD, there are growing calls for a re-evaluation of basic AD research. Epidemiology offers one approach to integrating the available evidence. Here we examine relationships between evidence from population-based, clinicopathological studies of brain aging and a range of hypotheses from all areas of AD research. We identify various problems, including a lack of systematic approach to measurement of clinical and neuropathological factors associated with dementia in experimental and clinical settings, poor understanding of the strengths and weaknesses of different observational and experimental designs, a lack of clarity in relation to disease definitions from the clinical, neuropathological, and molecular perspectives, inadequate characterization of brain aging in the human population, difficulties in translation between laboratory-based and population-based evidence bases, and a lack of communication between different sections of the dementia research community. Population studies highlight complexity and predict that therapeutic approaches based on single disease features will not be successful. Better characterization of brain aging in the human population is urgently required to select biomarkers and therapeutic targets that are meaningful to human disease. The generation of detailed and reliable evidence must be addressed before progress toward therapeutic interventions can be made.

%B J Alzheimers Dis %V 64 %P S119-S143 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782317?dopt=Abstract %R 10.3233/JAD-179927 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Depression and Alzheimer's Disease Biomarkers Predict Driving Decline. %A Babulal, Ganesh M %A Chen, Suzie %A Williams, Monique M %A Trani, Jean-Francois %A Bakhshi, Parul %A Chao, Grace L %A Stout, Sarah H %A Fagan, Anne M %A Benzinger, Tammie L S %A Holtzman, David M %A Morris, John C %A Roe, Catherine M %X

BACKGROUND: Symptomatic Alzheimer's disease (AD) and depression independently increase crash risk. Additionally, depression is both a risk factor for and a consequence of AD.

OBJECTIVE: To examine whether a depression diagnosis, antidepressant use, and preclinical AD are associated with driving decline among cognitively normal older adults.

METHODS: Cognitively normal participants, age ≥65, were enrolled. Cox proportional hazards models evaluated whether a depression diagnosis, depressive symptoms (Geriatric Depression Scale), antidepressant use, cerebrospinal fluid (amyloid-β42 [Aβ42], tau, phosphorylated tau181 [ptau181]), and amyloid imaging biomarkers (Pittsburgh Compound B and Florbetapir) were associated with time to receiving a rating of marginal/fail on a road test. Age was adjusted for in all models.

RESULTS: Data were available from 131 participants with age ranging from 65.4 to 88.2 years and mean follow up of 2.4 years (SD = 1.0). A depression diagnosis was associated with a faster time to receiving a marginal/fail rating on a road test and antidepressant use (p = 0.024, HR = 2.62). Depression diagnosis and CSF and amyloid PET imaging biomarkers were associated with driving performance on the road test (p≤0.05, HR = 2.51-3.15). In the CSF ptau181 model, depression diagnosis (p = 0.031, HR = 2.51) and antidepressant use (p = 0.037, HR = 2.50) were statistically significant predictors. There were no interaction effects between depression diagnosis, antidepressant use, and biomarker groups. Depressive symptomology was not a statistically significant predictor of driving performance.

CONCLUSIONS: While, as previously shown, preclinical AD alone predicts a faster time to receiving a marginal/fail rating, these results suggest that also having a diagnosis of depression accelerates the onset of driving problems in cognitively normal older adults.

%B J Alzheimers Dis %V 66 %P 1213-1221 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400098?dopt=Abstract %R 10.3233/JAD-180564 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Depressive Symptoms Are Associated with Cognitive Function in the Elderly with Type 2 Diabetes. %A Guerrero-Berroa, Elizabeth %A Ravona-Springer, Ramit %A Schmeidler, James %A Heymann, Anthony %A Soleimani, Laili %A Sano, Mary %A Leroith, Derek %A Preiss, Rachel %A Zukran, Ruth %A Silverman, Jeremy M %A Beeri, Michal Schnaider %X

BACKGROUND: Type 2 diabetes (T2D) is a metabolic condition associated with poor clinical and cognitive outcomes including vascular disease, depressive symptoms, cognitive impairment, and dementia. In the general elderly population, depression has been consistently identified as a risk factor for cognitive impairment/decline. However, the association between depression and cognitive function in T2D has been understudied.

OBJECTIVE: We investigated the association between depression and cognitive function in a large sample of cognitively normal elderly with T2D.

METHODS: In this cross-sectional study, we examined 738 participants, aged 65-88 years old, enrolled in the Israel Diabetes and Cognitive Decline study. For each cognitive domain (Episodic Memory, Executive Function, Attention/Working Memory, Language/Semantic Categorization) and Overall Cognition, multiple linear regressions assessed its association with depression (score greater than 5 on the 15-item version of the Geriatric Depression Scale [GDS]), adjusting for age, sex, and education.

RESULTS: Depression (n = 66, 8.9%) was associated with worse performance on tasks of Executive Function (p = 0.004), Language/Semantic Categorization (p < 0.001), and Overall Cognition (p < 0.002), but not Episodic Memory (p = 0.643) or Attention/Working Memory (p = 0.488). Secondary analyses using GDS as a continuous variable did not substantially change the results. Adjusting also for a history of antidepressant medication use slightly weakened the findings.

CONCLUSION: Significant associations of depression with several cognitive domains and Overall Cognition even in cognitively normal elderly with T2D, suggest that depression may have a role in impaired cognitive function in T2D, which may be attenuated by antidepressants.

%B J Alzheimers Dis %V 65 %P 683-692 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103313?dopt=Abstract %R 10.3233/JAD-170778 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Designing an Internet-Based Multidomain Intervention for the Prevention of Cardiovascular Disease and Cognitive Impairment in Older Adults: The HATICE Trial. %A Barbera, Mariagnese %A Mangialasche, Francesca %A Jongstra, Susan %A Guillemont, Juliette %A Ngandu, Tiia %A Beishuizen, Cathrien %A Coley, Nicola %A Brayne, Carol %A Andrieu, Sandrine %A Richard, Edo %A Soininen, Hilkka %A Kivipelto, Miia %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cognitive Dysfunction %K Counseling %K Europe %K Exercise %K Female %K Healthy Aging %K Humans %K Internet %K Life Style %K Male %K Practice Guidelines as Topic %K Risk Factors %K Telemedicine %X

BACKGROUND: Many dementia and cardiovascular disease (CVD) cases in older adults are attributable to modifiable vascular and lifestyle-related risk factors, providing opportunities for prevention. In the Healthy Aging Through Internet Counselling in the Elderly (HATICE) randomized controlled trial, an internet-based multidomain intervention is being tested to improve the cardiovascular risk (CVR) profile of older adults.

OBJECTIVE: To design a multidomain intervention to improve CVR, based on the guidelines for CVR management, and administered through a coach-supported, interactive, platform to over 2500 community-dwellers aged 65+ in three European countries.

METHODS: A comparative analysis of national and European guidelines for primary and secondary CVD prevention was performed. Results were used to define the content of the intervention.

RESULTS: The intervention design focused on promoting awareness and self-management of hypertension, dyslipidemia, diabetes mellitus, and overweight, and supporting smoking cessation, physical activity, and healthy diet. Overall, available guidelines lacked specific recommendations for CVR management in older adults. The comparative analysis of the guidelines showed general consistency for lifestyle-related recommendations. Key differences, identified mostly in methods used to assess the overall CVR, did not hamper the intervention design. Minor country-specific adaptations were implemented to maximize the intervention feasibility in each country.

CONCLUSION: Despite differences in CVR management within the countries considered, it was possible to design and implement the HATICE multidomain intervention. The study can help define preventative strategies for dementia and CVD that are applicable internationally.

%B J Alzheimers Dis %V 62 %P 649-663 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480185?dopt=Abstract %R 10.3233/JAD-170858 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Diagnosis of Mild Cognitive Impairment Due to Alzheimer's Disease with Transcranial Magnetic Stimulation. %A Padovani, Alessandro %A Benussi, Alberto %A Cantoni, Valentina %A Dell'Era, Valentina %A Cotelli, Maria Sofia %A Caratozzolo, Salvatore %A Turrone, Rosanna %A Rozzini, Luca %A Alberici, Antonella %A Altomare, Daniele %A Depari, Alessandro %A Flammini, Alessandra %A Frisoni, Giovanni B %A Borroni, Barbara %X

BACKGROUND: Considering the increasing evidence that disease-modifying treatments for Alzheimer's disease (AD) must be administered early in the disease course, the development of diagnostic tools capable of accurately identifying AD at early disease stages has become a crucial target. In this view, transcranial magnetic stimulation (TMS) has become an effective tool to discriminate between different forms of neurodegenerative dementia.

OBJECTIVE: To determine whether a TMS multi-paradigm approach can be used to correctly identify mild cognitive impairment (MCI) due to AD (AD MCI).

METHODS: A sample of 69 subjects with MCI were included and classified as AD MCI or MCI unlikely due to AD (non-AD MCI) based on 1) extensive neurological and neuropsychological evaluation, 2) MRI imaging, and 3) cerebrospinal fluid analysis or/and amyloid PET imaging. A paired-pulse TMS multi-paradigm approach assessing short interval intracortical inhibition-facilitation (SICI-ICF), dependent on GABAergic and glutamatergic intracortical circuits, respectively, and short latency afferent inhibition (SAI), dependent on cholinergic circuits, was performed.

RESULTS: We observed a significant impairment of SAI and unimpaired SICI and ICF in AD MCI as compared to non-AD MCI. According to ROC curve analysis, the SICI-ICF / SAI index differentiated AD MCI from non-AD MCI with a specificity of 87.9% and a sensitivity of 94.4%.

CONCLUSIONS: The assessment of intracortical connectivity with TMS could aid in the characterization of MCI subtypes, correctly identifying AD pathophysiology. TMS can be proposed as an adjunctive, non-invasive, inexpensive, and time-saving screening tool in MCI differential diagnosis.

%B J Alzheimers Dis %V 65 %P 221-230 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010131?dopt=Abstract %R 10.3233/JAD-180293 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Differences Between Women and Men in Incidence Rates of Dementia and Alzheimer's Disease. %A Beam, Christopher R %A Kaneshiro, Cody %A Jang, Jung Yun %A Reynolds, Chandra A %A Pedersen, Nancy L %A Gatz, Margaret %X

In the following brief report, we examined gender differences in incidence rates of any dementia, Alzheimer's disease (AD) alone, and non-Alzheimer's dementia alone in 16,926 women and men in the Swedish Twin Registry aged 65+. Dementia diagnoses were based on clinical workup and national health registry linkage. Incidence rates of any dementia and AD were greater in women than men, with any dementia rates diverging after age 85 and AD rates diverging around 80. This pattern is consistent with women's survival to older ages compared to men. These findings are similar to incidence rates reported in other Swedish samples.

%B J Alzheimers Dis %V 64 %P 1077-1083 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010124?dopt=Abstract %R 10.3233/JAD-180141 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Different Abnormalities of Cortical Neural Synchronization Mechanisms in Patients with Mild Cognitive Impairment due to Alzheimer's and Chronic Kidney Diseases: An EEG Study. %A Lizio, Roberta %A Babiloni, Claudio %A Del Percio, Claudio %A Losurdo, Antonia %A Vernò, Lucia %A De Tommaso, Marina %A Montemurno, Anna %A Dalfino, Giuseppe %A Cirillo, Pietro %A Soricelli, Andrea %A Ferri, Raffaele %A Noce, Giuseppe %A Pascarelli, Maria Teresa %A Catania, Valentina %A Nobili, Flavio %A Famá, Francesco %A Orzi, Francesco %A Giubilei, Franco %A Buttinelli, Carla %A Triggiani, A Ivano %A Frisoni, Giovanni B %A Scisci, Anna Maria %A Mastrofilippo, Nicola %A Procaccini, Deni Aldo %A Gesualdo, Loreto %X

This study tested whether resting state alpha rhythms (8-13 Hz) may characterize mild cognitive impairment due to Alzheimer's disease (ADMCI) compared with MCI due to chronic kidney disease (CKDMCI). Clinical and resting state eyes-closed electroencephalographic (rsEEG) rhythms from 40 ADMCI, 29 CKDMCI, and 45 cognitively normal elderly (Nold) subjects were available in a national archive. Age, gender, and education were matched in the three groups, and Mini-Mental State Evaluation (MMSE) score was paired in the ADMCI and CKDMCI groups. Delta (<4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz), and gamma (30-40 Hz) cortical sources were estimated by eLORETA freeware and classified across individuals by area under the receiver operating characteristic curve (AUROCC). Compared with Nold group, posterior alpha 1 source activities were more reduced in ADMCI than CKDMCI group. In contrast, widespread delta source activities were greater in CKDMCI than ADMCI group. These source activities correlated with the MMSE score and correctly classified between Nold and all MCI individuals (AUROCC = 0.8-0.85) and between ADMCI and CKDMCI subjects (AUROCC = 0.75). These results suggest that early AD affects cortical neural synchronization at alpha frequencies underpinning brain arousal and low vigilance in the quiet wakefulness. In contrast, CKD may principally affect cortical neural synchronization at the delta frequencies. Future prospective cross-validation studies will have to test these candidate rsEEG markers for clinical applications and drug discovery.

%B J Alzheimers Dis %V 65 %P 897-915 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103322?dopt=Abstract %R 10.3233/JAD-180245 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Different Cognitive Frailty Models and Health- and Cognitive-related Outcomes in Older Age: From Epidemiology to Prevention. %A Panza, Francesco %A Lozupone, Madia %A Solfrizzi, Vincenzo %A Sardone, Rodolfo %A Dibello, Vittorio %A Di Lena, Luca %A D'Urso, Francesca %A Stallone, Roberta %A Petruzzi, Massimo %A Giannelli, Gianluigi %A Quaranta, Nicola %A Bellomo, Antonello %A Greco, Antonio %A Daniele, Antonio %A Seripa, Davide %A Logroscino, Giancarlo %X

Frailty, a critical intermediate status of the aging process that is at increased risk for negative health-related events, includes physical, cognitive, and psychosocial domains or phenotypes. Cognitive frailty is a condition recently defined by operationalized criteria describing coexisting physical frailty and mild cognitive impairment (MCI), with two proposed subtypes: potentially reversible cognitive frailty (physical frailty/MCI) and reversible cognitive frailty (physical frailty/pre-MCI subjective cognitive decline). In the present article, we reviewed the framework for the definition, different models, and the current epidemiology of cognitive frailty, also describing neurobiological mechanisms, and exploring the possible prevention of the cognitive frailty progression. Several studies suggested a relevant heterogeneity with prevalence estimates ranging 1.0-22.0% (10.7-22.0% in clinical-based settings and 1.0-4.4% in population-based settings). Cross-sectional and longitudinal population-based studies showed that different cognitive frailty models may be associated with increased risk of functional disability, worsened quality of life, hospitalization, mortality, incidence of dementia, vascular dementia, and neurocognitive disorders. The operationalization of clinical constructs based on cognitive impairment related to physical causes (physical frailty, motor function decline, or other physical factors) appears to be interesting for dementia secondary prevention given the increased risk for progression to dementia of these clinical entities. Multidomain interventions have the potential to be effective in preventing cognitive frailty. In the near future, we need to establish more reliable clinical and research criteria, using different operational definitions for frailty and cognitive impairment, and useful clinical, biological, and imaging markers to implement intervention programs targeted to improve frailty, so preventing also late-life cognitive disorders.

%B J Alzheimers Dis %V 62 %P 993-1012 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562543?dopt=Abstract %R 10.3233/JAD-170963 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Differential Effect of APOE ɛ4 Status and Elevated Pulse Pressure on Functional Decline in Cognitively Normal Older Adults. %A Werhane, Madeleine L %A Thomas, Kelsey R %A Edmonds, Emily C %A Bangen, Katherine J %A Tran, My %A Clark, Alexandra L %A Nation, Daniel A %A Gilbert, Paul E %A Bondi, Mark W %A Delano-Wood, Lisa %X

BACKGROUND/OBJECTIVE: The APOE ɛ4 allele and increased vascular risk have both been independently linked to cognitive impairment and dementia. Since few studies have characterized how these risk factors affect everyday functioning, we investigated the relationship between APOE ɛ4 genotype and elevated pulse pressure (PP) on functional change in cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

METHODS: 738 normally aging participants underwent APOE genotyping, and baseline PP was calculated from blood pressure indices. The Functional Activities Questionnaire (FAQ) was completed by participants' informant at baseline and 6, 12, 24, 36, and 48-month follow-up visits. Multiple linear regression and multilevel modeling were used to examine the effects of PP and APOE ɛ4 genotype on cross-sectional and longitudinal FAQ scores, respectively.

RESULTS: Adjusting for demographic and clinical covariates, results showed that both APOE ɛ4 status and elevated PP predicted greater functional difficulty trajectories across four years of follow-up. Interestingly, however, elevated PP was associated with greater functional decline over time in ɛ4 non-carriers versus carriers.

CONCLUSION: Results show that, although APOE ɛ4 status is the prominent predictor of functional difficulty for ɛ4 carriers, an effect of arterial stiffening on functional difficulty was observed in non-carriers. Future studies are needed in order to clarify the etiology of the association between PP and different brain aging processes, and further explore its utility as a marker of dementia risk. The present study underscores the importance of targeting modifiable risk factors such as elevated PP to prevent or slow functional decline and pathological brain aging.

%B J Alzheimers Dis %V 62 %P 1567-1578 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562507?dopt=Abstract %R 10.3233/JAD-170918 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Differential Pattern of Phospholipid Profile in the Temporal Cortex from E280A-Familiar and Sporadic Alzheimer's Disease Brains. %A Villamil-Ortiz, Javier Gustavo %A Barrera-Ocampo, Alvaro %A Arias-Londoño, Julián David %A Villegas, Andrés %A Lopera, Francisco %A Cardona-Gómez, Gloria Patricia %K Adult %K Aged %K Aged, 80 and over %K Alanine %K Alzheimer Disease %K Analysis of Variance %K Fatty Acids %K Female %K Gene Expression Regulation %K Glutamic Acid %K Humans %K Lysophosphatidylcholines %K Male %K Mass Spectrometry %K Middle Aged %K Mutation %K Phosphatidylethanolamines %K Phospholipids %K Presenilin-1 %K Temporal Lobe %X

Lipids are considered important factors in the pathogenesis of Alzheimer's disease (AD). In this study, we realized a comparative analysis of the phospholipid profile and phospholipid composition of the temporal cortex from E280A-familiar AD (FAD), sporadic AD (SAD), and healthy human brains. Findings showed a significant decrease of lysophosphatidylcholine and phosphatidylethanolamine formed by low levels of polyunsaturated fatty acids (20 : 4, 22 : 6) in AD brains. However, phosphatidylethanolamine-ceramide and phosphoglycerol were significantly increased in SAD, conformed by high levels of (18 : 0/18 : 1) and (30/32/36 : 0/1/2), respectively. Together, the findings suggest a deficiency in lysophosphacholine and phosphatidylethanolamine, and alteration in the balance between poly- and unsaturated fatty acids in both types of AD, and a differential pattern of phospholipid profile and fatty acid composition between E280A FAD and SAD human brains.

%B J Alzheimers Dis %V 61 %P 209-219 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125487?dopt=Abstract %R 10.3233/JAD-170554 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Differentiating between Alzheimer's Disease and Vascular Cognitive Impairment: Is the "Memory Versus Executive Function" Contrast Still Relevant? %A Andriuta, Daniela %A Roussel, Martine %A Barbay, Mélanie %A Despretz-Wannepain, Sandrine %A Godefroy, Olivier %X

BACKGROUND: The contrast between memory versus executive function impairments is commonly used to differentiate between neurocognitive disorders (NCDs) due to Alzheimer's disease (AD) and vascular cognitive impairment (VCI). We reconsidered this question because of the current use of AD biomarkers and the recent revision of the criteria for AD, VCI, and dysexecutive syndrome.

OBJECTIVE: To establish and compare the neuropsychological profiles in AD (i.e., with positive CSF biomarkers) and in VCI.

METHODS: We included 62 patients with mild or major NCDs due to pure AD (with positive CSF biomarker assays), and 174 patients (from the GRECogVASC cohort) with pure VCI. The neuropsychological profiles were compared after stratification for disease severity (mild or major NCD). We defined a memory-executive function index (the mean z score for the third free recall and the delayed free recall in the Free and Cued Selective Reminding Test minus the mean z score for category fluency and the completion time in the Trail Making Test part B) and determined its diagnostic accuracy.

RESULTS: Compared with VCI patients, patients with AD had significantly greater memory impairments (p = 0.001). Executive function was impaired to a similar extent in the two groups (p = 0.11). Behavioral executive disorders were more prominent in the AD group (p = 0.001). Although the two groups differed significant with regard to the memory-executive function index (p < 0.001), the latter's diagnostic accuracy was only moderate (sensitivity: 63%, specificity: 87%).

CONCLUSION: Although the contrast between memory and executive function impairments was supported at the group level it does not reliably discriminate between AD and VCI at the individual level.

%B J Alzheimers Dis %V 63 %P 625-633 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689726?dopt=Abstract %R 10.3233/JAD-171097 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dipeptidyl-Peptidase Activity of Meprin β Links N-truncation of Aβ with Glutaminyl Cyclase-Catalyzed pGlu-Aβ Formation. %A Schlenzig, Dagmar %A Cynis, Holger %A Hartlage-Rübsamen, Maike %A Zeitschel, Ulrike %A Menge, Katja %A Fothe, Anja %A Ramsbeck, Daniel %A Spahn, Claudia %A Wermann, Michael %A Roßner, Steffen %A Buchholz, Mirko %A Schilling, Stephan %A Demuth, Hans-Ulrich %X

The formation of amyloid-β (Aβ) peptides is causally involved in the development of Alzheimer's disease (AD). A significant proportion of deposited Aβ is N-terminally truncated and modified at the N-terminus by a pGlu-residue (pGlu-Aβ). These forms show enhanced neurotoxicity compared to full-length Aβ. Although the truncation may occur by aminopeptidases after formation of Aβ, recently discovered processing pathways of amyloid-β protein precursor (AβPP) by proteases such as meprin β may also be involved. Here, we assessed a role of meprin β in forming Aβ3-40/42, which is the precursor of pGlu-Aβ3-40/42 generated by glutaminyl cyclase (QC). Similar to QC, meprin β mRNA is significantly upregulated in postmortem brain from AD patients. A histochemical analysis supports the presence of meprin β in neurons and astrocytes in the vicinity of pGlu-Aβ containing deposits. Cleavage of AβPP-derived peptides by meprin β in vitro results in peptides Aβ1-x, Aβ2-x, and Aβ3-x. The formation of N-truncated Aβ by meprin β was also corroborated in cell culture. A subset of the generated peptides was converted into pGlu-Aβ3-40 by an addition of glutaminyl cyclase, supporting the preceding formation of Aβ3-40. Further analysis of the meprin β cleavage revealed a yet unknown dipeptidyl-peptidase-like activity specific for the N-terminus of Aβ1-x. Thus, our data suggest that meprin β contributes to the formation of N-truncated Aβ by endopeptidase and exopeptidase activity to generate the substrate for QC-catalyzed pGlu-Aβ formation.

%B J Alzheimers Dis %V 66 %P 359-375 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320570?dopt=Abstract %R 10.3233/JAD-171183 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Disease Course Varies According to Age and Symptom Length in Alzheimer's Disease. %A Barnes, Josephine %A Bartlett, Jonathan W %A Wolk, David A %A van der Flier, Wiesje M %A Frost, Chris %X

Health-care professionals, patients, and families seek as much information as possible about prognosis for patients with Alzheimer's disease (AD); however, we do not yet have a robust understanding of how demographic factors predict prognosis. We evaluated associations between age at presentation, age of onset, and symptom length with cognitive decline as measured using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating sum-of-boxes (CDR-SOB) in a large dataset of AD patients. Age at presentation was associated with post-presentation decline in MMSE (p < 0.001), with younger patients showing faster decline. There was little evidence of an association with change in CDR-SOB. Symptom length, rather than age, was the strongest predictor of MMSE and CDR-SOB at presentation, with increasing symptom length associated with worse outcomes. The evidence that younger AD patients have a more aggressive disease course implies that early diagnosis is essential.

%B J Alzheimers Dis %V 64 %P 631-642 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914016?dopt=Abstract %R 10.3233/JAD-170841 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Distinct Neuroanatomical Correlates of Neuropsychiatric Symptoms in the Three Main Forms of Genetic Frontotemporal Dementia in the GENFI Cohort. %A Sellami, Leila %A Bocchetta, Martina %A Masellis, Mario %A Cash, David M %A Dick, Katrina M %A van Swieten, John %A Borroni, Barbara %A Galimberti, Daniela %A Tartaglia, Maria Carmela %A Rowe, James B %A Graff, Caroline %A Tagliavini, Fabrizio %A Frisoni, Giovanni %A Finger, Elizabeth %A de Mendonça, Alexandre %A Sorbi, Sandro %A Warren, Jason D %A Rohrer, Jonathan D %A Laforce, Robert %X

BACKGROUND: The overlap between frontotemporal dementia (FTD) and primary psychiatric disorders has been brought to light by reports of prominent neuropsychiatric symptoms (NPS) in FTD-related genetic mutations, particularly among C9orf72 and GRN carriers. It has been recently demonstrated that early neuroanatomical changes in genetic FTD may be different across the major disease-causing mutations.

OBJECTIVE: We aimed to identify whether NPS could be driven by distinct structural correlates.

METHODS: One hundred and sixty-seven mutation carriers (75 GRN, 60 C9orf72, and 32 MAPT) were included from the Genetic FTD Initiative (GENFI) study, a large international cohort of genetic FTD. Neuropsychiatric symptoms including delusions, hallucinations (visual, auditory, and tactile), depression, and anxiety were investigated using a structured interview. Voxel-based morphometry was performed to identify neuroanatomical correlates of NPS.

RESULTS: Psychotic symptoms correlated mainly with grey matter (GM) atrophy in the anterior insula, left thalamus, cerebellum, and cortical regions including frontal, parietal, and occipital lobes in GRN mutations carriers. GM atrophy in posterior structures of the default-mode network was associated with anxiety in the GRN group. Delusions in C9orf72 expansion carriers were mainly associated with left frontal cortical atrophy. Cerebellar atrophy was found to be correlated only with anxiety in C9orf72 carriers. NPS in the MAPT group were mainly associated with volume loss in the temporal lobe.

CONCLUSION: Neuroanatomical correlates of NPS appear to be distinct across the main forms of genetic FTD. Overall, our findings support overlapping brain structural changes between FTD and primary psychiatric disorders.

%B J Alzheimers Dis %V 65 %P 147-163 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010122?dopt=Abstract %R 10.3233/JAD-180053 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Distinct White Matter Changes Associated with Cerebrospinal Fluid Amyloid-β1-42 and Hypertension. %A Al-Janabi, Omar M %A Brown, Christopher A %A Bahrani, Ahmed A %A Abner, Erin L %A Barber, Justin M %A Gold, Brian T %A Goldstein, Larry B %A Murphy, Ronan R %A Nelson, Peter T %A Johnson, Nathan F %A Shaw, Leslie M %A Smith, Charles D %A Trojanowski, John Q %A Wilcock, Donna M %A Jicha, Gregory A %X

BACKGROUND: Alzheimer's disease (AD) pathology and hypertension (HTN) are risk factors for development of white matter (WM) alterations and might be independently associated with these alterations in older adults.

OBJECTIVE: To evaluate the independent and synergistic effects of HTN and AD pathology on WM alterations.

METHODS: Clinical measures of cerebrovascular disease risk were collected from 62 participants in University of Kentucky Alzheimer's Disease Center studies who also had cerebrospinal fluid (CSF) sampling and MRI brain scans. CSF Aβ1-42 levels were measured as a marker of AD, and fluid-attenuated inversion recovery imaging and diffusion tensor imaging were obtained to assess WM macro- and microstructural properties. Linear regression analyses were used to assess the relationships among WM alterations, cerebrovascular disease risk, and AD pathology. Voxelwise analyses were performed to examine spatial patterns of WM alteration associated with each pathology.

RESULTS: HTN and CSF Aβ1-42 levels were each associated with white matter hyperintensities (WMH). Also, CSF Aβ1-42 levels were associated with alterations in normal appearing white matter fractional anisotropy (NAWM-FA), whereas HTN was marginally associated with alterations in NAWM-FA. Linear regression analyses demonstrated significant main effects of HTN and CSF Aβ1-42 on WMH volume, but no significant HTN×CSF Aβ1-42 interaction. Furthermore, voxelwise analyses showed unique patterns of WM alteration associated with hypertension and CSF Aβ1-42.

CONCLUSION: Associations of HTN and lower CSF Aβ1-42 with WM alteration were statistically and spatially distinct, suggesting independent rather than synergistic effects. Considering such spatial distributions may improve diagnostic accuracy to address each underlying pathology.

%B J Alzheimers Dis %V 66 %P 1095-1104 %8 2018 Nov 23 %G eng %N 3 %R 10.3233/JAD-180663 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Distribution of Cerebrospinal Fluid Biomarker Profiles in Patients Explored for Cognitive Disorders. %A Paquet, Claire %A Bouaziz-Amar, Elodie %A Cognat, Emmanuel %A Volpe-Gillot, Lisette %A Haddad, Victor %A Mahieux, Florence %A Dekimeche, Siham %A Defontaines, Benedicte %A Chabriat, Hugues %A Belin, Catherine %A Texeira, Antonio %A Goutagny, Stephane %A Questel, Frank %A Azuar, Julien %A Sellier, Pierre-Olivier %A Laplanche, Jean-Louis %A Hugon, Jacques %A Dumurgier, Julien %X

BACKGROUND: CSF Alzheimer's disease (AD) biomarkers allow classifying individuals based on their levels of amyloid and neurodegeneration pathologies.

OBJECTIVE: To investigate the distribution of AD biomarker profiles from patients suffering from cognitive disorders.

METHODS: We analyzed 3001 patients with cognitive disorders and referred by 18 French memory clinics located in and around Paris. Patients were classified as normal, amyloidosis (A+/N-), amyloidosis and neurodegeneration (A+/N+) or suspected non-AD pathophysiology (SNAP), according to their CSF levels of biomarkers. Analysis were performed for the overall population and stratified by gender, age quintiles, and Mini-Mental State Examination (MMSE) score quintiles. Results were compared to previous findings in cohorts of healthy elderly adults.

RESULTS: 37% of the sample were classified as A+/N+, 22% were classified A+/N-, and 15% as SNAP. The A+/N+ profile was associated with female gender, advanced age, and lower MMSE score, while the A+/N-profile was observed more frequently in men and the distribution was stable across age and MMSE. The SNAP profile showed no association with gender or age, was less frequent in patients with lower MMSE, and had a lower repartition than the one previously reported in asymptomatic populations.

CONCLUSIONS: While A+/N+ patients had the clinical characteristics typically observed in AD, A+/N-patients had a different epidemiological pattern (higher frequency in men, no association with advanced age or lower MMSE). The SNAP profile was less frequent than previously reported in the general elderly population, suggesting that this profile is not a frequent cause of memory impairment in this population.

%B J Alzheimers Dis %V 64 %P 889-897 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966201?dopt=Abstract %R 10.3233/JAD-180240 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Does Fatty Acid Composition in Subcutaneous Adipose Tissue Differ between Patients with Alzheimer's Disease and Cohabiting Proxies? %A Faxen-Irving, Gerd %A Falahati, Farshad %A Basun, Hans %A Eriksdotter, Maria %A Vedin, Inger %A Wahlund, Lars-Olof %A Schultzberg, Marianne %A Hjorth, Erik %A Palmblad, Jan %A Cederholm, Tommy %A Freund-Levi, Yvonne %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Dietary Supplements %K Fatty Acids, Omega-3 %K Female %K Humans %K Male %K Regression Analysis %K Subcutaneous Fat %X

Low tissue levels of the major marine ω3 fatty acids (FAs) DHA and EPA are found in Alzheimer's disease (AD). We investigated if healthy proxies to AD patients have higher levels of these ω3 FAs. We observed lower levels of EPA and DHA in subcutaneous adipose tissue biopsies from 64 AD patients compared with 16 cognitively healthy proxies. No significant difference was observed when pairwise comparisons were made between a subset of 16 AD patients and their co-habiting proxies. Larger studies are needed to replicate these findings and to determine if they could depend on FA intake or differences in metabolism.

%B J Alzheimers Dis %V 61 %P 515-519 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154271?dopt=Abstract %R 10.3233/JAD-170359 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Does the Genetic Feature of the Chinese Tree Shrew (Tupaia belangeri chinensis) Support Its Potential as a Viable Model for Alzheimer's Disease Research? %A Fan, Yu %A Luo, Rongcan %A Su, Ling-Yan %A Xiang, Qun %A Yu, Dandan %A Xu, Ling %A Chen, Jia-Qi %A Bi, Rui %A Wu, Dong-Dong %A Zheng, Ping %A Yao, Yong-Gang %K Alzheimer Disease %K Amino Acid Sequence %K Animals %K Biomedical Research %K Disease Models, Animal %K Gene Expression Profiling %K Humans %K Male %K Mice %K Tupaia %X

Alzheimer's disease (AD) is a neurodegenerative disease with increasing incidence across the world and no cure at the present time. An ideal animal model would facilitate the understanding of the pathogenesis of AD and discovery of potential therapeutic targets. The Chinese tree shrew (Tupaia belangeri chinensis) has a closer genetic affinity to primates relative to rodents, and can attain ages of 8 years or older, which represents another advantage for the study of neurodegenerative diseases such as AD compared to primates. Here, we analyzed 131 AD-related genes in the Chinese tree shrew brain tissues based on protein sequence identity, positive selection, mRNA, and protein expression by comparing with those of human, rhesus monkey, and mouse. In particular, we focused on the Aβ and neurofibrillary tangles formation pathways, which are crucial to AD pathogenesis. The Chinese tree shrew had a generally higher sequence identity with human than that of mouse versus human for the AD pathway genes. There was no apparent selection on the tree shrew lineage for the AD-related genes. Moreover, expression pattern of the Aβ and neurofibrillary tangle formation pathway genes in tree shrew brain tissues resembled that of human brain tissues, with a similar aging-dependent effect. Our results provided an essential genetic basis for future AD research using the tree shrew as a viable model.

%B J Alzheimers Dis %V 61 %P 1015-1028 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332044?dopt=Abstract %R 10.3233/JAD-170594 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dual Time-Point [18F]Florbetaben PET Delivers Dual Biomarker Information in Mild Cognitive Impairment and Alzheimer's Disease. %A Florek, Lisa %A Tiepolt, Solveig %A Schroeter, Matthias L %A Berrouschot, Jörg %A Saur, Dorothee %A Hesse, Swen %A Jochimsen, Thies %A Luthardt, Julia %A Sattler, Bernhard %A Patt, Marianne %A Hoffmann, Karl-Titus %A Villringer, Arno %A Classen, Joseph %A Gertz, Hermann-Josef %A Sabri, Osama %A Barthel, Henryk %X

BACKGROUND: Current research diagnostic criteria for Alzheimer's disease (AD) and mild cognitive impairment (MCI) due to AD include biomarkers to supplement clinical testing. Recently, we demonstrated that dual time-point [18F]FBB PET is able to deliver both blood flow and amyloid-β (Aβ) load surrogates.

OBJECTIVE: The aim of this study was to investigate whether these surrogates can be utilized as AD biomarkers.

METHODS: 112 subjects (41 with MCI, 50 with probable/possible AD, 21 with other dementias) underwent dual time-point [18F]FBB PET. Data were visually and relative quantitatively (Herholz scores for the early and composite SUVRs for the late PET data) analyzed.

RESULTS: In the early images AD-typical patterns were present in 42% /27% /33% of probable/possible AD/MCI/other dementia cases. In late [18F]FBB PET, 42% /29% /38% of probable/possible AD/ MCI/other dementia cases were Aβ-positive. 17% of the MCIs were categorized as "MCI due to AD-high likelihood", 44% of the probable ADs as "probable AD with high evidence of AD pathophysiological process" and 28% of the possible ADs as "possible AD with evidence of AD pathophysiological process". 27% of all subjects showed a positive diagnostic and progression biomarker. Herholz scores were lower (0.85±0.05 versus 0.88±0.04, p = 0.015) for probable/possible AD versus MCI. Composite late phase SUVRs were significantly higher (1.65±0.23 versus 1.15±0.17, p < 0.005) in Aβ-positive versus Aβ-negative patients. Herholz and MMSE scores were positively correlated (R = 0.30 p = 0.006).

CONCLUSION: Dual time-point [18F]FBB PET provides dual biomarker information which enables to categorize MCI and AD dementia patients according to established diagnostic criteria. Thus, dual time-point [18F]FBB PET has great potential to supplement diagnostic dementia workups.

%B J Alzheimers Dis %V 66 %P 1105-1116 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400095?dopt=Abstract %R 10.3233/JAD-180522 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dynamic Causal Modeling of Preclinical Autosomal-Dominant Alzheimer's Disease. %A Penny, Will %A Iglesias-Fuster, Jorge %A Quiroz, Yakeel T %A Lopera, Francisco Javier %A Bobes, Maria A %X

Dynamic causal modeling (DCM) is a framework for making inferences about changes in brain connectivity using neuroimaging data. We fitted DCMs to high-density EEG data from subjects performing a semantic picture matching task. The subjects are carriers of the PSEN1 mutation, which leads to early onset Alzheimer's disease, but at the time of EEG acquisition in 1999, these subjects were cognitively unimpaired. We asked 1) what is the optimal model architecture for explaining the event-related potentials in this population, 2) which connections are different between this Presymptomatic Carrier (PreC) group and a Non-Carrier (NonC) group performing the same task, and 3) which network connections are predictive of subsequent Mini-Mental State Exam (MMSE) trajectories. We found 1) a model with hierarchical rather than lateral connections between hemispheres to be optimal, 2) that a pathway from right inferotemporal cortex (IT) to left medial temporal lobe (MTL) was preferentially activated by incongruent items for subjects in the PreC group but not the NonC group, and 3) that increased effective connectivity among left MTL, right IT, and right MTL was predictive of subsequent MMSE scores.

%B J Alzheimers Dis %8 2018 Mar 16 %G eng %R 10.3233/JAD-170405 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early and Persistent O-GlcNAc Protein Modification in the Streptozotocin Model of Alzheimer's Disease. %A Dos Santos, João Paulo Almeida %A Vizuete, Adriana %A Hansen, Fernanda %A Biasibetti, Regina %A Gonçalves, Carlos-Alberto %K Alzheimer Disease %K Analysis of Variance %K Animals %K Antibiotics, Antineoplastic %K Brain %K Disease Models, Animal %K Glial Fibrillary Acidic Protein %K Glucose %K Glutathione %K Insulin Receptor Substrate Proteins %K Lactoylglutathione Lyase %K Male %K Maze Learning %K N-Acetylglucosaminyltransferases %K Rats %K Rats, Wistar %K S100 Calcium Binding Protein beta Subunit %K Streptozocin %K Time Factors %X

 O-GlcNAc transferase (OGT), an enzyme highly expressed in brain tissue, catalyzes the addition of N-acetyl-glucosamine (GlcNAc) to hydroxyl residues of serine and threonine of proteins. Brain protein O-GlcNAcylation is diminished in Alzheimer's disease (AD), and OGT targets include proteins of the insulin-signaling pathway (e.g., insulin receptor susbtrate-1, IRS-1). We hypothesized that ICV streptozotocin (STZ) also affects O-GlcNAc protein modification. We investigated hippocampal metabolic changes in Wistar rats, particularly OGT levels and insulin resistance, as well as related astroglial activities, immediately after ICV STZ administration (first week) and later on (fourth week). We found an early (at one week) and persistent (at fourth week) decrease in OGT in the ICV STZ model of AD, characterized by a spatial cognitive deficit. Consistent with this observation, we observed a decrease in protein O-GlnNAc modification at both times. Increased phosphorylation at serine-307 of IRS-1, which is related to insulin resistance, was observed on the fourth week. The decrease in OGT and consequent protein O-GlnNAc modifications appear to precede the decrease in glucose uptake and increment of the glyoxalase system observed in the hippocampus. Changes in glial fibrillary acidic protein and S100B in the hippocampus, as well as the alterations in cerebrospinal fluid S100B, confirm the astrogliosis. Moreover, decreases in glutamine synthetase and glutathione content suggest astroglial dysfunction, which are likely implicated in the neurodegenerative cascade triggered in this model. Together, these data contribute to the understanding of neurochemical changes in the ICV STZ model of sporadic AD, and may explain the decreases in protein O-GlcNAc levels and insulin resistance observed in AD.

%B J Alzheimers Dis %V 61 %P 237-249 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154269?dopt=Abstract %R 10.3233/JAD-170211 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early and Selective Activation and Subsequent Alterations to the Unfolded Protein Response in Down Syndrome Mouse Models. %A Lanzillotta, Chiara %A Tramutola, Antonella %A Meier, Shelby %A Schmitt, Frederick %A Barone, Eugenio %A Perluigi, Marzia %A Di Domenico, Fabio %A Abisambra, Jose F %X

Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans, which results from the triplication of chromosome 21. DS individuals have an increased risk of developing Alzheimer's disease (AD)-like pathology and dementia by the age of 40 due to the triplication of several genes involved in the formation of amyloid plaques and tau tangles. Further, DS and AD are characterized by the aberrant accumulation of unfolded/misfolded proteins resulting from over-burdened protein quality control systems. The accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR). Long-term activation of the UPR mediates neuronal dysfunction in AD. We hypothesized that the UPR is impacted in a mouse model of DS. To test this, we performed gene and protein expression analysis of ER stress markers in the Ts65Dn mouse model of DS at 3, 9, and 18 months. We identified activation of the PERK pathway in Ts65Dn DS mice at 3 months of age compared to euploid controls. We also determined that the early and overt UPR activation decreased with age, the UPR signal was significantly reduced by 18 months. Our data suggest that UPR activation in DS mouse models occurs early before consistent brain neurodegeneration and might be an essential contributor to dys-proteostasis.

%B J Alzheimers Dis %V 62 %P 347-359 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439332?dopt=Abstract %R 10.3233/JAD-170617 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early Emotional Attention is Impacted in Alzheimer's Disease: An Eye-Tracking Study. %A Bourgin, Jessica %A Guyader, Nathalie %A Chauvin, Alan %A Juphard, Alexandra %A Sauvée, Mathilde %A Moreaud, Olivier %A Silvert, Laetitia %A Hot, Pascal %X

Emotional deficits have been repetitively reported in Alzheimer's disease (AD) without clearly identifying how emotional processing is impaired in this pathology. This paper describes an investigation of early emotional processing, as measured by the effects of emotional visual stimuli on a saccadic task involving both pro (PS) and anti (AS) saccades. Sixteen patients with AD and 25 age-matched healthy controls were eye-tracked while they had to quickly move their gaze toward a positive, negative, or neutral image presented on a computer screen (in the PS condition) or away from the image (in the AS condition). The age-matched controls made more AS mistakes for negative stimuli than for other stimuli, and triggered PSs toward negative stimuli more quickly than toward other stimuli. In contrast, patients with AD showed no difference with regard to the emotional category in any of the tasks. The present study is the first to highlight a lack of early emotional attention in patients with AD. These results should be taken into account in the care provided to patients with AD, since this early impairment might seriously degrade their overall emotional functioning.

%B J Alzheimers Dis %V 63 %P 1445-1458 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782325?dopt=Abstract %R 10.3233/JAD-180170 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early Intervention with a Multi-Ingredient Dietary Supplement Improves Mood and Spatial Memory in a Triple Transgenic Mouse Model of Alzheimer's Disease. %A Hutton, Craig P %A Lemon, Jennifer A %A Sakic, Boris %A Rollo, C David %A Boreham, Douglas R %A Fahnestock, Margaret %A Wojtowicz, J Martin %A Becker, Suzanna %X

The increasing global burden of Alzheimer's disease (AD) and failure of conventional treatments to stop neurodegeneration necessitates an alternative approach. Evidence of inflammation, mitochondrial dysfunction, and oxidative stress prior to the accumulation of amyloid-β in the prodromal stage of AD (mild cognitive impairment; MCI) suggests that early interventions which counteract these features, such as dietary supplements, may ameliorate the onset of MCI-like behavioral symptoms. We administered a polyphenol-containing multiple ingredient dietary supplement (MDS), or vehicle, to both sexes of triple transgenic (3xTg-AD) mice and wildtype mice for 2 months from 2-4 months of age. We hypothesized that the MDS would preserve spatial learning, which is known to be impaired in untreated 3xTg-AD mice by 4 months of age. Behavioral phenotyping of animals was done at 1-2 and 3-4 months of age using a comprehensive battery of tests. As previously reported in males, both sexes of 3xTg-AD mice exhibited increased anxiety-like behavior at 1-2 months of age, prior to deficits in learning and memory, which did not appear until 3-4 months of age. The MDS did not reduce this anxiety or prevent impairments in novel object recognition (both sexes) or on the water maze probe trial (females only). Strikingly, the MDS specifically prevented 3xTg-AD mice (both sexes) from developing impairments (exhibited by untreated 3xTg-AD controls) in working memory and spatial learning. The MDS also increased sucrose preference, an indicator of hedonic tone. These data show that the MDS can prevent some, but not all, psychopathology in an AD model.

%B J Alzheimers Dis %V 64 %P 835-857 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914019?dopt=Abstract %R 10.3233/JAD-170921 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early Stage Alterations in CA1 Extracellular Region Proteins Indicate Dysregulation of IL6 and Iron Homeostasis in the 5XFAD Alzheimer's Disease Mouse Model. %A Gurel, Busra %A Cansev, Mehmet %A Sevinc, Cansu %A Kelestemur, Seda %A Ocalan, Busra %A Cakir, Aysen %A Aydin, Sami %A Kahveci, Nevzat %A Ozansoy, Mehmet %A Taskapilioglu, Ozlem %A Ulus, Ismail Hakki %A Başar, Merve Karayel %A Sahin, Betul %A Tuzuner, Mete Bora %A Baykal, Ahmet Tarik %K Alzheimer Disease %K Animals %K CA1 Region, Hippocampal %K Chromatography, Liquid %K Disease Models, Animal %K Female %K Homeostasis %K Interleukin-6 %K Iron %K Mice %K Mice, Transgenic %K Proteomics %K Tandem Mass Spectrometry %X

In recent years, an increasing number of research papers revealed that the compositional and volumetric alterations in the extracellular matrix are the consequences of aging and may be related to Alzheimer's disease (AD). In this study, we aimed to demonstrate the alterations in hippocampal extracellular fluid proteins in vivo using the 5XFAD mouse model. Samples were obtained from hippocampi of 5XFAD mice (n = 6) and their non-transgenic littermates by intracerebral push-pull perfusion technique at 3 months of age, representing the pre-pathological stage of the AD. Proteins in the hippocampal perfusates were analyzed by Ultra Performance Liquid Chromatography-Electrospray Ionization Quadrupole Time-of-Flight Mass Spectrometry (UPLC-ESI-qTOF-MS/MS). 178 proteins were identified and 19 proteins of them were found to be statistically significantly altered (p≤0.05, fold change ≥40%, unique peptide count ≥3) in the hippocampal CA1 extracellular fluid of the 5XFAD mouse model. Ingenuity pathway analysis of the protein expression results identified IL6 as an upstream regulator. The upregulation of IL6 was validated by immunohistochemical staining of the hippocampus and cortex of the 5XFAD mice prior to Aβ plaque formation. Furthermore, the iron level in the hippocampus was measured by inductively coupled plasma-mass spectrometry as IL6 is mentioned in several studies to take part in iron homeostasis and inflammation and found to be increased in 5XFAD mice hippocampus. Alterations in extracellular matrix proteins in addition to increasing amount of hippocampal IL6 and iron in the early stages of AD may reveal inflammation-mediated iron dyshomeostasis in the early stages of neurodegeneration.

%B J Alzheimers Dis %V 61 %P 1399-1410 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376847?dopt=Abstract %R 10.3233/JAD-170329 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Economic Burden, Mortality, and Institutionalization in Patients Newly Diagnosed with Alzheimer's Disease. %A Black, Christopher M %A Fillit, Howard %A Xie, Lin %A Hu, Xiaohan %A Kariburyo, M Furaha %A Ambegaonkar, Baishali M %A Baser, Onur %A Yuce, Huseyin %A Khandker, Rezaul K %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cohort Studies %K Comorbidity %K Cost of Illness %K Female %K Humans %K Institutionalization %K Male %K Neuropsychological Tests %X

BACKGROUND: Current information is scarce regarding comorbid conditions, treatment, survival, institutionalization, and health care utilization for Alzheimer's disease (AD) patients.

OBJECTIVES: Compare all-cause mortality, rate of institutionalization, and economic burden between treated and untreated newly-diagnosed AD patients.

METHODS: Patients aged 65-100 years with ≥1 primary or ≥2 secondary AD diagnoses (ICD-9-CM:331.0] with continuous medical and pharmacy benefits for ≥12 months pre-index and ≥6 months post-index date (first AD diagnosis date) were identified from Medicare fee-for-service claims 01JAN2011-30JUN2014. Patients with AD treatment claims or AD/AD-related dementia diagnosis during the pre-index period were excluded. Patients were assigned to treated and untreated cohorts based on AD treatment received post-index date. Total 8,995 newly-diagnosed AD patients were identified; 4,037 (44.8%) were assigned to the treated cohort. Time-to-death and institutionalization were assessed using Cox regression. To compare health care costs and utilizations, 1 : 1 propensity score matching (PSM) was used.

RESULTS: Untreated patients were older (83.85 versus 81.44 years; p < 0.0001), with more severe comorbidities (mean Charlson comorbidity index: 3.54 versus 3.22; p < 0.0001). After covariate adjustment, treated patients were less likely to die (hazard ratio[HR] = 0.69; p < 0.0001) and were associated with 20% lower risk of institutionalization (HR = 0.801; p = 0.0003). After PSM, treated AD patients were less likely to have hospice visits (3.25% versus 9.45%; p < 0.0001), and incurred lower annual all-cause costs ($25,828 versus $30,110; p = 0.0162).

CONCLUSION: After controlling for comorbidities, treated AD patients have better survival, lower institutionalization, and sometimes fewer resource utilizations, suggesting that treatment and improved care management could be beneficial for newly-diagnosed AD patients from economic and clinical perspectives.

%B J Alzheimers Dis %V 61 %P 185-193 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103033?dopt=Abstract %R 10.3233/JAD-170518 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effectiveness of a Personalized Brain-Computer Interface System for Cognitive Training in Healthy Elderly: A Randomized Controlled Trial. %A Yeo, Si Ning %A Lee, Tih Shih %A Sng, Wei Theng %A Heo, Min Quan %A Bautista, Dianne %A Cheung, Yin Bun %A Zhang, Hai Hong %A Wang, Chuanchu %A Chin, Zheng Yang %A Feng, Lei %A Zhou, Juan %A Chong, Mei Sian %A Ng, Tze Pin %A Krishnan, K Ranga %A Guan, Cuntai %X

BACKGROUND: Cognitive training has been demonstrated to improve cognitive performance in older adults. To date, no study has explored personalized training that targets the brain activity of each individual.

OBJECTIVE: This is the first large-scale trial that examines the usefulness of personalized neurofeedback cognitive training.

METHODS: We conducted a randomized-controlled trial with participants who were 60-80 years old, with Clinical Dementia Rating (CDR) score of 0-0.5, Mini-Mental State Examination (MMSE) score of 24 and above, and with no neuropsychiatric diagnosis. Participants were randomly assigned to the Intervention or Waitlist-Control group. The training system, BRAINMEM, has attention, working memory, and delayed recall game components. The intervention schedule comprised 24 sessions over eight weeks and three monthly booster sessions. The primary outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score after the 24-session training.

RESULTS: There were no significant between-subjects differences in overall cognitive performance post-intervention. However, a sex moderation effect (p = 0.014) was present. Men in the intervention group performed better than those in the waitlist group (mean difference, +4.03 (95% CI 0.1 to 8.0), p = 0.046. Among females, however, both waitlist-control and intervention participants improved from baseline, although the between-group difference in improvement did not reach significance. BRAINMEM also received positive appraisal and intervention adherence from the participants.

CONCLUSION: A personalized neurofeedback intervention is potentially feasible for use in cognitive training for older males. The sex moderation effect warrants further investigation and highlights the importance of taking sex into account during cognitive training.

%B J Alzheimers Dis %V 66 %P 127-138 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30248056?dopt=Abstract %R 10.3233/JAD-180450 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effects of a 3-Year Multi-Domain Intervention with or without Omega-3 Supplementation on Cognitive Functions in Older Subjects with Increased CAIDE Dementia Scores. %A Chhetri, Jagadish K %A de Souto Barreto, Philipe %A Cantet, Christelle %A Pothier, Kristell %A Cesari, Matteo %A Andrieu, Sandrine %A Coley, Nicola %A Vellas, Bruno %X

Findings from recent Alzheimer's disease prevention trials have shown subjects with increased dementia score based upon mid-life cardiovascular risk factors, to benefit from multi-domain intervention strategies to some extent. The effects of such interventions on cognitive functions remains yet to be well-established. This study is a secondary analysis of the MAPT study, 1,293 older subjects (mean age 75 years) with high CAIDE score (i.e., ≥6) were classified according to the four intervention groups: 1) multi-domain intervention plus placebo, 2) isolated supplementation with Omega-3 polyunsaturated fatty acid (n-3 PUFA), 3) combination of the two interventions, and 4) placebo alone. Linear mixed-model repeated-measures analyses were used to assess the cognitive changes according to various neuropsychological test scores between intervention groups compared to the placebo at 36 months from baseline. Compared to the placebo, group with multi-domain intervention in combination withn-3PUFA was found to show significant improvement in the delayed total recall test of the free and cued selective reminding test (FCSRT) (mean±standard error(SE) = 0.20±0.10) and MMSE orientation test (mean±SE = 0.15±0.06) at 36 months. Isolated multi-domain intervention group showed significant less decline in the MMSE orientation test (mean±SE = 0.12±0.06) compared to the placebo. There was significant less improvement (mean±SE = - 1.01±0.46) in the FCSRT free recall test in the n-3 PUFA intervention group compared to the placebo at 36 months. Our findings show high-risk subjects for dementia screened with CAIDE dementia score might benefit from multi-domain intervention strategies as in the MAPT study, particularly in the orientation and delayed recall domain.

%B J Alzheimers Dis %V 64 %P 71-78 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865075?dopt=Abstract %R 10.3233/JAD-180209 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effects of Meditation and Music-Listening on Blood Biomarkers of Cellular Aging and Alzheimer's Disease in Adults with Subjective Cognitive Decline: An Exploratory Randomized Clinical Trial. %A Innes, Kim E %A Selfe, Terry Kit %A Brundage, Kathleen %A Montgomery, Caitlin %A Wen, Sijin %A Kandati, Sahiti %A Bowles, Hannah %A Khalsa, Dharma Singh %A Huysmans, Zenzi %X

BACKGROUND: Telomere length (TL), telomerase activity (TA), and plasma amyloid-β (Aβ) levels have emerged as possible predictors of cognitive decline and dementia.

OBJECTIVE: To assess the: 1) effects of two 12-week relaxation programs on TL, TA, and Aβ levels in adults with subjective cognitive decline; and 2) relationship of biomarker changes to those in cognitive function, psychosocial status, and quality of life (QOL).

METHODS: Participants were randomized to a 12-week Kirtan Kriya meditation (KK) or music listening (ML) program and asked to practice 12 minutes/day. Plasma Aβ(38/40/42) and peripheral blood mononuclear cell TL and TA were measured at baseline and 3 months. Cognition, stress, sleep, mood, and QOL were assessed at baseline, 3 months, and 6 months.

RESULTS: Baseline blood samples were available for 53 participants (25 KK, 28 ML). The KK group showed significantly greater increases in Aβ40 than the ML group. TA rose in both groups, although increases were significant only among those with higher practice adherence and lower baseline TA. Changes in both TL and TA varied by their baseline values, with greater increases among participants with values ≤50th percentile (ps-interaction <0.006). Both groups improved in cognitive and psychosocial status (ps ≤0.05), with improvements in stress, mood, and QOL greater in the KK group. Rising Aβ levels were correlated with gains in cognitive function, mood, sleep, and QOL at both 3 and 6 months, associations that were particularly pronounced in the KK group. Increases in TL and TA were also correlated with improvements in certain cognitive and psychosocial measures.

CONCLUSION: Practice of simple mind-body therapies may alter plasma Aβ levels, TL, and TA. Biomarker increases were associated with improvements in cognitive function, sleep, mood, and QOL, suggesting potential functional relationships.

%B J Alzheimers Dis %V 66 %P 947-970 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320574?dopt=Abstract %R 10.3233/JAD-180164 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Endogenous Murine Amyloid-β Peptide Assembles into Aggregates in the Aged C57BL/6J Mouse Suggesting These Animals as a Model to Study Pathogenesis of Amyloid-β Plaque Formation. %A Ahlemeyer, Barbara %A Halupczok, Sascha %A Rodenberg-Frank, Elke %A Valerius, Klaus-Peter %A Baumgart-Vogt, Eveline %K Age Factors %K Aged %K Aged, 80 and over %K alpha-Synuclein %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Disease Models, Animal %K Female %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Neurofibrillary Tangles %K Neurons %K Plaque, Amyloid %K tau Proteins %X

Amyloid-β peptide (Aβ), paired helical filament-tau (PHF-tau), and α-synuclein are in the focus of neuroscience research because they aggregate in brains of patients with Alzheimer's and Parkinson's diseases. For this purpose, transgenic mouse models were used containing the human genes for AβPP/presenilin/tau or α-synuclein with the most frequent mutations. This is not ideal because most patients develop sporadic forms of the diseases with no causative single gene defect and furthermore the aggregation of human proteins in man is not necessarily the same in rodents. We hypothesized that for such cases the aged mouse could be an alternative model and analyzed the distribution of endogenous Aβ, PHF-tau, and α-synuclein in mouse brains at different ages. Whereas Aβ was below detectable levels at birth, it was present at high levels in the 15-month-old mouse. Aβ was found in the cytosol and lysosomes of neurons of the temporal cortex, cingulate area, pons, and cerebellum as well as extracellularly in the periventricular zone. Contrary to Aβ, mouse brain was devoid of PHF-tau-positive neurofibrillary tangles. α-Synuclein was detectable in the newborn mouse with highest levels in the marginal zone of the lateral cortex and average levels in the hippocampus, pons, and cerebellum. Brain-area specific differences in the α-synuclein level persisted up to 15 months of age, but increased 3-fold in all areas over time. α-Synuclein resided in the neuropil, but not in intracellular aggregates even in the aged mouse. We suggest the aged mouse as a model to study Aβ plaque formation.

%B J Alzheimers Dis %V 61 %P 1425-1450 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376876?dopt=Abstract %R 10.3233/JAD-170923 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Episodic Memory and Learning Dysfunction Over an 18-Month Period in Preclinical and Prodromal Alzheimer's Disease. %A Baker, Jenalle E %A Lim, Yen Ying %A Jaeger, Judith %A Ames, David %A Lautenschlager, Nicola T %A Robertson, Joanne %A Pietrzak, Robert H %A Snyder, Peter J %A Villemagne, Victor L %A Rowe, Christopher C %A Masters, Colin L %A Maruff, Paul %X

Recent meta-analyses suggest that episodic memory impairment associated with preclinical Alzheimer's disease (AD) equates to 0.15-0.24 standard deviations below that of cognitively healthy older adults. The current study aimed to characterize impairments in verbal acquisition and recall detectable at a single assessment, and investigate how verbal learning and episodic memory deteriorates in preclinical AD. A verbal list-learning task, the International Shopping List Test (ISLT), was administered multiple times over an 18-month period, to three groups of participants: amyloid-beta negative healthy older adults (Aβ- CN; n = 50); Aβ+ positive healthy older adults (preclinical AD; n = 25); and Aβ+ positive individuals diagnosed with mild cognitive impairment (prodromal AD; n = 22). At baseline, there was no significant difference between the preclinical AD and control groups rate of acquisition, or total and delayed recall, however all indices were impaired in prodromal AD. Performance on ISLT total score improved in the control group over the 18-month period, but showed a moderate magnitude decline in the preclinical AD group (Cohen's d = - 0.63, [- 1.12, - 0.14]) and the prodromal AD group (Cohen's d = - 0.36, [- 0.94, 0.22]). No significant impairment in acquisition associated with preclinical AD was seen at baseline. Individuals with preclinical AD showed a significantly different performance on the ISLT total score over an 18-month period, compared to those without abnormal Aβ. Individuals with prodromal AD showed substantial impairment on the ISLT at baseline and declined to a greater extent over time.

%B J Alzheimers Dis %V 65 %P 977-988 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103330?dopt=Abstract %R 10.3233/JAD-180344 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Epitomic Characterization of the Specificity of the Anti-Amyloid Aβ Monoclonal Antibodies 6E10 and 4G8. %A Baghallab, Ibtisam %A Reyes-Ruiz, Jorge Mauricio %A Abulnaja, Khalid %A Huwait, Etimad %A Glabe, Charles %X

The monoclonal antibodies 6E10 and 4G8 are among the first anti-amyloid monoclonal antibodies against Aβ and the most widely used antibodies in Alzheimer's disease research. Although the epitopes for 6E10 and 4G8 have been reported to correspond to residues 1-16 and 17-24, a more recent high-resolution mapping approach indicates that 6E10 maps to residues 4-10 while 4G8 maps to residues 18-23. To characterize the binding specificity of both antibodies in greater detail, we used immunoselection of random sequences from phage display library followed by deep sequencing and analysis of resulting patterns from thousands of immunoselected sequences. We found that the minimum sequence required for 6E10 binding is R-x-D with over half (53%) of the immunoselected sequences conforming to this pattern. The vast majority of these sequences contain an H at position x (R-H-D), corresponding to residues 5-7 of the Aβ target sequences, but Y is also permitted at this position in a minority of sequences. For 4G8 we found that the most frequent pattern is F-x-A contained in approximately 30% of the sequences, followed by F-A, L-x(3)-A, L-x-F, and F-F each accounting for approximately 18% of the sequences. The F-x-A motif also occurs in islet amyloid poly peptide which may explain why 4G8 also recognizes amyloid fibrils of this peptide. Immunoselection of random sequences and deep sequencing may also be a facile and efficient means of determining residues critical for antibody binding and validating the specificity of monoclonal antibodies and polyclonal antisera.

%B J Alzheimers Dis %V 66 %P 1235-1244 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412489?dopt=Abstract %R 10.3233/JAD-180582 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Ethyl Acetate Extract of Leaves of Ugni molinae Turcz. Improves Neuropathological Hallmarks of Alzheimer's Disease in Female APPswe/PS1dE9 Mice Fed with a High Fat Diet. %A Jara-Moreno, Daniela %A Castro-Torres, Rubn D %A Ettcheto, Miren %A Auladell, Carme %A Kogan, Marcelo J %A Folch, Jaume %A Verdaguer, Ester %A Cano, Amanda %A Busquets, Oriol %A Delporte, Carla %A Camins, Antoni %X

The most common type of dementia is Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by impairment in cognitive performance in aged individuals. Currently, there is no effective pharmacological treatment that cures the disease due to the lack of knowledge on the actual mechanisms involved in its pathogenesis. In the last decades, the amyloidogenic hypothesis has been the most studied theory trying to explain the origin of AD, yet it does not address all the concerns relating to its development. In the present study, a possible new preclinical treatment of AD was evaluated using the ethyl acetate extract (EAE) of leaves of Ugni molinae Turcz. (synonym Myrtus ugni Molina Family Myrtacea). The effects were assessed on female transgenic mice from a preclinical model of familial AD (APPswe/PS1dE9) combined with a high fat diet. This preclinical model was selected due to the already available experimental and observational data proving the relationship between obesity, gender, metabolic stress, and cognitive dysfunction; related to characteristics of sporadic AD. According to chemical analyses, EAE would contain polyphenols such as tannins, flavonoid derivatives, and phenolic acids, as well as pentacyclic triterpenoids that exhibit neuroprotective, anti-inflammatory, and antioxidant effects. In addition, the treatment evidenced its capacity to prevent deterioration of memory capacity and reduction of progression speed of AD neuropathology.

%B J Alzheimers Dis %V 66 %P 1175-1191 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400089?dopt=Abstract %R 10.3233/JAD-180174 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Evaluating Peripersonal Space through the Functional Transcranial Doppler: Are We Paving the Way for Early Detecting Mild Cognitive Impairment to Dementia Conversion? %A Marra, Angela %A Naro, Antonino %A Chillura, Antonino %A Bramanti, Alessia %A Maresca, Giuseppa %A De Luca, Rosaria %A Manuli, Alfredo %A Bramanti, Placido %A Calabrò, Rocco Salvatore %X

BACKGROUND: Identifying the patients with mild cognitive impairment (MCI) who may develop dementia (MDC) is challenging. The study of peripersonal space (PPS) by using functional transcranial Doppler (fTCD) could be used for this purpose.

OBJECTIVE: To identify changes in cerebral blood flow (CBF) during motor tasks targeting PPS, which can predict MDC.

METHODS: We evaluated the changes in CBF in 22 patients with MCI and 23 with dementia [Alzheimer's disease (AD) and vascular dementia (VaD)] during a motor task (passive mobilization, motor imagery, and movement observation) in which the hand of the subject moved forward and backward the face.

RESULTS: CBF increased when the hand approached the face and decreased when the hand moved from the face in the healthy controls (HCs). CBF changed were detectable only in patients with MCI but not in those with the AD and those who were MDC after 8-month follow-up. On the other hand, the patients with VaD presented a paradoxical response to the motor task (i.e., a decrease of CBF rather than an increase, as observed in HCs and MCI). Therefore, we found a modulation of PPS-related CBF only in HCs and patients with stable MCI (at the 8-month follow-up).

CONCLUSIONS: fTCD may allow preliminarily differentiating and following-up the patients with MCI and MDC, thus allowing the physician to plan beforehand more individualized cognitive rehabilitative training.

%B J Alzheimers Dis %V 62 %P 133-143 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439353?dopt=Abstract %R 10.3233/JAD-170973 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Exercise Training on Locomotion in Patients with Alzheimer's Disease: A Feasibility Study. %A Pedrinolla, Anna %A Venturelli, Massimo %A Fonte, Cristina %A Munari, Daniele %A Benetti, Maria Vittoria %A Rudi, Doriana %A Tamburin, Stefano %A Muti, Ettore %A Zanolla, Luisa %A Smania, Nicola %A Schena, Federico %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomechanical Phenomena %K Exercise Test %K Exercise Therapy %K Feasibility Studies %K Female %K Gait %K Humans %K Italy %K Male %K Single-Blind Method %X

BACKGROUND: Although current literature has shown that patients with Alzheimer's disease (AD) have worse locomotion compared with healthy counterparts, no studies have focused on the efficacy of exercise training in improving gait abnormalities including biomechanics and metabolic aspects, in this population.

OBJECTIVE: To verify the effectiveness of exercise training (ET) on gait parameters (i.e., speed, step and stride length, single and double support, and energy cost of walking (Cw)) in patients with AD with respect to a standard cognitive treatment (CT).

METHODS: In this study, we included a small portion of data belonging to a larger study (ClinicalTrials.gov number, NCT03034746). Patients with AD (Mini-Mental State Examination 22±5) were included in the study. Gait parameters and Cw were assessed at baseline and after 6 months (72 treatment sessions) of treatment. ET included 90 min of aerobic and strength training. CT included 90 min of cognitive stimuli.

RESULTS: The 16 patients assigned to ET exhibited significant improvement of Cw (-0.9±0.1 J/kg·m-1), while differences in gait parameters were negligible. The effect on gait parameters were undetectable in the 18 patients assigned to CT (-0.2±0.5 J/kg·m-1).

CONCLUSIONS: Data from this study showed that ET program seems effective in improving Cw in patients with AD. Interestingly, the positive effect of ET on Cw was not coupled with ameliorations of patient's gait parameters, suggesting that the gain of metabolic aspects of locomotion were the main factors responsible for this positive result.

%B J Alzheimers Dis %V 61 %P 1599-1609 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376858?dopt=Abstract %R 10.3233/JAD-170625 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Exploring the Profile of Incidental Memory in Patients with Amnestic Mild Cognitive Impairment and Mild Alzheimer's Disease. %A Kontaxopoulou, Dionysia %A Beratis, Ion N %A Fragkiadaki, Stella %A Pavlou, Dimosthenis %A Andronas, Nikos %A Yannis, George %A Economou, Alexandra %A Papanicolaou, Andrew C %A Papageorgiou, Sokratis G %X

Incidental memory can be defined as the ability to acquire information unintentionally. The present study investigated incidental memory performance in amnestic mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD) patients; additionally, hippocampal atrophy between groupswas examined. Twenty-nine aMCI patients (14 with hippocampal atrophy, measured by the Medial Temporal Lobe Atrophy scale), 15 mild AD patients, and 20 cognitively intact individuals underwent a detailed medical and neuropsychological assessment examining intentional memory, using the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test. Participants first took part in a driving simulator experiment, followed by an unexpected incidental memory questionnaire referring to elements related to the driving simulation. The mild AD group performed worse than the aMCI group and the control group both in incidental and intentional memory tasks, whereas the aMCI group differed significantly from the control group only in the intentional memory tasks. The incidental recognition memory task was the only measure that differed between aMCI patients with and without hippocampal atrophy. Moreover, incidental memory tasks were the only measures that correlated significantly with both left and right hippocampal atrophy. The current findings indicate that incidental memory testing may provide potentially useful information for detecting aMCI patients with greater hippocampal atrophy, who may be considered at higher risk of developing dementia due to AD.

%B J Alzheimers Dis %V 65 %P 617-627 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056423?dopt=Abstract %R 10.3233/JAD-180328 %0 Journal Article %J J Alzheimers Dis %D 2018 %T FDDNP-PET Tau Brain Protein Binding Patterns in Military Personnel with Suspected Chronic Traumatic Encephalopathy1. %A Chen, Stephen T %A Siddarth, Prabha %A Merrill, David A %A Martinez, Jacqueline %A D Emerson, Natacha %A Liu, Jie %A Wong, Koon-Pong %A Satyamurthy, Nagichettiar %A Giza, Christopher C %A Huang, Sung-Cheng %A Fitzsimmons, Robert P %A Bailes, Julian %A Omalu, Bennet %A Barrio, Jorge R %A Small, Gary W %X

BACKGROUND: Our group has shown that in vivo tau brain binding patterns from FDDNP-PET scans in retired professional football players with suspected chronic traumatic encephalopathy differ from those of tau and amyloid aggregate binding observed in Alzheimer's disease (AD) patients and cognitively-intact controls.

OBJECTIVE: To compare these findings with those from military personnel with histories of mild traumatic brain injury(mTBI).

METHODS: FDDNP-PET brain scans were compared among 7 military personnel and 15 retired players with mTBI histories and cognitive and/or mood symptoms, 24 AD patients, and 28 cognitively-intact controls. Nonparametric ANCOVAs with Tukey-Kramer adjusted post-hoc comparisons were used to test for significant differences in regional FDDNP binding among subject groups.

RESULTS: FDDNP brain binding was higher in military personnel compared to controls in the amygdala, midbrain, medial thalamus, pons, frontal and anterior and posterior cingulate regions (p < 0.01-0.0001). Binding patterns in the military personnel were similar to those of the players except for the amygdala and striatum (binding higher in players; p = 0.02-0.003). Compared with the AD group, the military personnel showed higher binding in the midbrain (p = 0.0008) and pons (p = 0.002) and lower binding in the medial temporal, lateral temporal, and parietal regions (all p = 0.02).

CONCLUSION: This first study of in vivo tau and amyloid brain signals in military personnel with histories of mTBI shows binding patterns similar to those of retired football players and distinct from the binding patterns in AD and normal aging, suggesting the potential value of FDDNP-PET for early detection and treatment monitoring in varied at-risk populations.

%B J Alzheimers Dis %8 2018 Jul 17 %G eng %R 10.3233/JAD-171152 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The First Historically Reported Italian Family with FTD/ALS Teaches a Lesson on C9orf72 RE: Clinical Heterogeneity and Oligogenic Inheritance. %A Giannoccaro, Maria Pia %A Bartoletti-Stella, Anna %A Piras, Silvia %A Casalena, Alfonsina %A Oppi, Federico %A Ambrosetto, Giovanni %A Montagna, Pasquale %A Liguori, Rocco %A Parchi, Piero %A Capellari, Sabina %K Adult %K Amyotrophic Lateral Sclerosis %K C9orf72 Protein %K Cerebral Cortex %K DNA Repeat Expansion %K Female %K Frontotemporal Dementia %K Genetic Testing %K Humans %K Male %K Membrane Glycoproteins %K Middle Aged %K Multifactorial Inheritance %K Mutation %K Pedigree %X

BACKGROUND: In 1969, Dazzi and Finizio reported the second observation of frontotemporal dementia (FTD) - amyotrophic lateral sclerosis (ALS) association in a large Italian kindred affected by an autosomal dominant form of ALS with high penetrance, frequent bulbar onset, and frequent cognitive decline.

OBJECTIVE: To expand the original characterization of this family and report the link with the C9orf72 repeat expansion (RE).

METHODS: We followed or reviewed the medical records of thirteen patients belonging to the original family and performed genetic analyses in four individuals.

RESULTS: Eight patients presented with ALS, four with FTD, and one with schizophrenia. The C9orf72 RE was found in three patients but not in the healthy survivor. Additionally, we found a novel possible pathogenic variant in the ITM2B gene in one patient with a complex phenotype, associating movement disorders, psychiatric and cognitive features, deafness, and optic atrophy. The neuropathological examination of this patient did not show the classical features of ITM2B mutation related dementias suggesting that the putative pathogenic mechanism does not involve cellular mislocalization of the protein or the formation of amyloid plaques.

CONCLUSION: We showed that the original Italian pedigree described with FTD/ALS carries the C9orf72 RE. Moreover, the finding of an additional mutation in another dementia causing gene in a patient with a more complex phenotype suggests a possible role of genetic modifiers in the disease. Together with other reports showing the coexistence of mutations in multiple ALS/FTD causative genes in the same family, our study supports an oligogenic etiology of ALS/FTD.

%B J Alzheimers Dis %V 62 %P 687-697 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480190?dopt=Abstract %R 10.3233/JAD-170913 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Fragmentation of the Golgi Apparatus in Neuroblastoma Cells Is Associated with Tau-Induced Ring-Shaped Microtubule Bundles. %A Rodríguez-Cruz, Fanny %A Torres-Cruz, Francisco Miguel %A Monroy-Ramírez, Hugo Christian %A Escobar-Herrera, Jaime %A Basurto-Islas, Gustavo %A Avila, Jesús %A Garcia-Sierra, Francisco %X

Abnormal fibrillary aggregation of tau protein is a pathological condition observed in Alzheimer's disease and other tauopathies; however, the presence and pathological significance of early non-fibrillary aggregates of tau remain under investigation. In cell and animal models expressing normal or modified tau, toxic effects altering the structure and function of several membranous organelles have also been reported in the absence of fibrillary structures; however, how these abnormalities are produced is an issue yet to be addressed. In order to obtain more insights into the mechanisms by which tau may disturb intracellular membranous elements, we transiently overexpressed human full-length tau and several truncated tau variants in cultured neuroblastoma cells. After 48 h of transfection, either full-length or truncated tau forms produced significant fragmentation of the Golgi apparatus (GA) with no changes in cell viability. Noteworthy is that in the majority of cells exhibiting dispersion of the GA, a ring-shaped array of cortical or perinuclear microtubule (Mt) bundles was also generated under the expression of either variant of tau. In contrast, Taxol treatment of non-transfected cells increased the amount of Mt bundles but not sufficiently to produce fragmentation of the GA. Tau-induced ring-shaped Mt bundles appeared to be well-organized and stable structures because they were resistant to Nocodazole post-treatment and displayed a high level of tubulin acetylation. These results further indicate that a mechanical force generated by tau-induced Mt-bundling may be responsible for Golgi fragmentation and that the repeated domain region of tau may be the main promoter of this effect.

%B J Alzheimers Dis %8 2018 Aug 14 %G eng %R 10.3233/JAD-180547 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Free Radical-Generating System Regulates Amyloid Oligomers: Involvement of Cathepsin B. %A Llorente, Patricia %A Kristen, Henrike %A Sastre, Isabel %A Toledano-Zaragoza, Ana %A Aldudo, Jesús %A Recuero, María %A Bullido, Maria J %X

Amyloid-β (Aβ), a major component of senile plaques, is generated via the proteolysis of amyloid-β protein precursor (AβPP). This cleavage also produces AβPP fragment-derived oligomers which can be highly neurotoxic. AβPP metabolism/processing is affected by many factors, one of which is oxidative stress (OS). Associated with aging, OS is an important risk factor for Alzheimer's disease. In addition, the protein degradation systems, especially those involving cathepsins, are impaired in aging brains. Moreover, cathepsin B (CTSB) is a cysteine protease with potentially specific roles in AβPP proteolysis (β-secretase activity) and Aβ clearance (Aβ degradative activity). The present work examines the effect of OS and the involvement of CTSB in amyloid oligomer formation. The xanthine/xanthine oxidase (X-XOD) free radical generating system induced the partial inhibition of CTSB activity, which was accompanied by an increase in large amyloid oligomers. These were located throughout the cytosol and in endo-lysosomal vesicles. Cells treated with the CTSB inhibitor CA-074Me also showed increased amyloid oligomer levels, whereas those subjected to OS in the presence of the inhibitor showed no such increase. However, CTSB inhibition clearly modulated the AβPP metabolism/processing induced by X-XOD, as revealed by the increase in intracellular AβPP and secreted α-secretase-cleaved soluble AβPP. The present results suggest that CTSB participates in the changes of amyloid oligomer induced by mild OS.

%B J Alzheimers Dis %V 66 %P 1397-1408 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400084?dopt=Abstract %R 10.3233/JAD-170159 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Frequency and Correlates of Subjective Memory Complaints in Parkinson's Disease with and without Mild Cognitive Impairment: Data from the Parkinson's Disease Cognitive Impairment Study. %A Baschi, Roberta %A Nicoletti, Alessandra %A Restivo, Vincenzo %A Recca, Deborah %A Zappia, Mario %A Monastero, Roberto %X

Subjective memory complaints (SMC) may represent the preclinical phase of mild cognitive impairment (MCI) due to Alzheimer's disease. Dementia/MCI have been described with a high prevalence in Parkinson's disease (PD), but whether SMC may predict the development of cognitive impairment has been barely explored. To evaluate the frequency and clinical correlates of isolated SMC (PD-SMC) or within the construct of MCI in subjects with PD, 147 PD patients from the PArkinson's disease COgnitive impairment Study (PACOS) were consecutively recruited for the study. This is a multicenter study involving two Movement Disorder Centers in south Italy. All subjects underwent comprehensive neuropsychological evaluation and PD-MCI was diagnosed according to Litvan's criteria. The Memory Assessment Clinics Questionnaire was used to assess SMC. Logistic regression analysis, adjusted for demographics and significant covariates, was used to evaluate clinical differences between groups. Forty-two (28.6%) individuals presented with PD without SMC and/or MCI (PDw), 40 (27,2%) with PD-SMC, 48 (32,6%) PD-SMC-MCI, and 17 (11,6%) PD-MCI without SMC (PD-MCI). When compared to PDw, PD-SMC was significantly associated with anxiety (OR = 3.93, 95% CI = 1.18-13.03), while PD-SMC-MCI related to motor progression (OR = 5.29, 95% CI = 1.12-24.86), and instrumental disability (OR = 6.98, 95% CI = 2.08-23.38). About 60% of patients showed SMC, in isolation or within the MCI frame. The role of SMC in PD seems to have a different etiology depending on the presence/absence of MCI. In particular, PD-SMC would represent a subjective reaction to the disease, while PD-SMC-MCI would depict motor progression and disability.

%B J Alzheimers Dis %V 63 %P 1015-1024 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710711?dopt=Abstract %R 10.3233/JAD-171172 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Frequency of Cardiovascular Genetic Risk Factors in a Calabrian Population and Their Effects on Dementia. %A Maletta, Raffaele %A Smirne, Nicoletta %A Bernardi, Livia %A Anfossi, Maria %A Gallo, Maura %A Conidi, Maria Elena %A Colao, Rosanna %A Puccio, Gianfranco %A Curcio, Sabrina A M %A Laganà, Valentina %A Frangipane, Francesca %A Cupidi, Chiara %A Mirabelli, Maria %A Vasso, Franca %A Torchia, Giusi %A Muraca, Maria G %A Di Lorenzo, Raffaele %A Rose, Giuseppina %A Montesanto, Alberto %A Passarino, Giuseppe %A Bruni, Amalia C %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Case-Control Studies %K Cholesterol Ester Transfer Proteins %K Cohort Studies %K Dementia, Vascular %K Female %K Frontotemporal Dementia %K Gene Frequency %K Humans %K Italy %K Male %K Middle Aged %K Polymorphism, Genetic %K Risk Factors %X

BACKGROUND: Several genetic variants playing a key role in cholesterol levels, blood pressure, and vascular dysfunction influence the risk of Alzheimer's disease (AD) and vascular dementia (VaD). The many meta-analysis studies carried out on large numbers of samples in different populations have not provided clear results to date, because a trans-ethnic shift of risk genotypes in different populations is often observed.

OBJECTIVES: To determine genotypes allele frequencies of the polymorphisms most frequently identified to be correlated with cardio-cerebrovascular disease and AD in a Southern Italy population and to investigate their possible association with dementia.

METHODS: The genotype and allele frequencies of 13 cardio-cerebrovascular risk polymorphisms were assessed and their possible association with dementia was investigated in a case-control study, including 221 consecutive unrelated subjects diagnosed with dementia (120 subjects affected by AD, 55 by frontotemporal dementia, and 33 by vascular dementia) and 218 matched controls of Calabrian origin.

RESULTS: Carriers of at least one APOEɛ4 allele resulted to be at higher risk of AD [OR(95% CI) = 2.721(1.477-5.011)] and VaD [OR(95% CI) = 6.205(2.356-16.342)] compared to non-carriers. Individuals with the IV genotype of the CETP polymorphism were more likely to have AD [OR(95% CI) = 2.427(1.364-4.319)] and VaD [OR(95% CI) = 3.649(1.455-9.152)] compared to subjects with the II-VV genotypes.

CONCLUSION: CETP I405V polymorphism is likely a risk factor for AD and VaD in our cohort, independent of APOEɛ4 status. Unmodifiable genetic risk factors should be taken into account to promote a healthy lifestyle to prevent dementia.

%B J Alzheimers Dis %V 61 %P 1179-1187 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332048?dopt=Abstract %R 10.3233/JAD-170687 %0 Journal Article %J J Alzheimers Dis %D 2018 %T From Cerebrospinal Fluid to Blood: The Third Wave of Fluid Biomarkers for Alzheimer's Disease. %A Zetterberg, Henrik %A Blennow, Kaj %X

The past five years have seen an enormous development in the field of fluid biomarkers for Alzheimer's disease (AD) and related disorders. The proteins that constitute the foundation for the cerebrospinal fluid (CSF) tests for the classical AD pathologies are now being explored as potential blood-based biomarkers, thanks to the recent implementation of ultrasensitive measurement technologies in academic and clinical laboratories worldwide. The current blood-derived data are still less clear than those obtained using CSF as the sample type, but independent research suggests that there are biomarker signals in blood that relate to plaque and tangle pathologies in AD, which are relevant to explore further. Additionally, neurofilament light has emerged as the first robust blood-based biomarker for neurodegeneration in a broad range of central nervous system disorders, as well as for acute brain injuries. Here, we briefly recapitulate the first and second waves of fluid biomarker analysis in AD, i.e., the development and validation of established and novel CSF biomarkers for the disorder, followed by a focused discussion on blood-based biomarkers for AD, which we describe as the third wave of fluid biomarker analysis that hopefully will gain further momentum during the coming five years.

%B J Alzheimers Dis %V 64 %P S271-S279 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758941?dopt=Abstract %R 10.3233/JAD-179926 %0 Journal Article %J J Alzheimers Dis %D 2018 %T From Subjective Cognitive Decline to Alzheimer's Disease: The Predictive Role of Neuropsychological Assessment, Personality Traits, and Cognitive Reserve. A 7-Year Follow-Up Study. %A Bessi, Valentina %A Mazzeo, Salvatore %A Padiglioni, Sonia %A Piccini, Carolina %A Nacmias, Benedetta %A Sorbi, Sandro %A Bracco, Laura %X

The aim of this study was to evaluate the accuracy of neuropsychological assessment in predicting conversion from subjective cognitive decline (SCD) and mild cognitive impairment (MCI) to Alzheimer's disease (AD) and the effect of personality traits and cognitive reserve in progression from SCD to MCI. As part of a longitudinal, clinical-neuropsychological-genetic survey on SCD and MCI, 284 patients referred to our hospital between 1990 and 2017 were included. All patients underwent clinical-extensive neuropsychological evaluation and Apolipoprotein E genotyping; personality traits were assessed in a subgroup. Each patient underwent clinical-neuropsychological follow-up. Subjects with a follow-up shorter than two years were excluded. A total of 212 subjects were, after exclusions, considered: 26 out of 109 SCD subjects progressed to MCI (SCD-p), 15 converted to AD (SCD-c), and 68 remained stable (SCD-s). Of 103 MCI subjects, 39 converted to AD (MCI-c) and 64 remained stable (MCI-s). At baseline, SCD-c performed significantly worse than SCD-s in tests assessing long-term verbal memory. MCI-c showed worse performance on neuropsychological tests for short- and long-term verbal memory and for ecological evaluation of memory (RBMT). These tests provided good accuracy in distinguishing MCI-c and MCI-s. Emotional stability was significantly lower in SCD-s than in SCD-p while higher intellectual activities were associated with a lower risk of conversion to MCI. Our results suggest that memory neuropsychological tests may represent a reliable tool to estimate the risk of progression to AD. Personality and lifestyle factors could provide useful information to identify SCD subjects who may develop an objective cognitive impairment.

%B J Alzheimers Dis %V 63 %P 1523-1535 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782316?dopt=Abstract %R 10.3233/JAD-171180 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Frontotemporal Dementia Misdiagnosed for Post-Treatment Lyme Disease Syndrome or vice versa? A Treviso Dementia (TREDEM) Registry Case Report. %A Di Battista, Maria Elena %A Dell'Acqua, Carola %A Baroni, Luciana %A Fenoglio, Chiara %A Galimberti, Daniela %A Gallucci, Maurizio %X

We describe the case of a 61-year-old woman diagnosed with Borreliosis at the age of 57. Subsequently, the patient developed depression, anxiety, and behavioral disturbances. A lumbar puncture excluded the condition of Neuroborreliosis. The diagnostic workup included: an MRI scan, a 18F-FDG PET, a 123I-ioflupane-SPECT, an amyloid-β PET, a specific genetic analysis, and a neuropsychological evaluation. Based on our investigation, the patient was diagnosed with probable behavioral-frontotemporal dementia (bvFTD), whereas in the previous years, the patient had been considered firstly as a case of Post-Treatment-Lyme Disease and, secondly, a psychiatric patient. We believe that, in the present case, such initial symptoms of Borrelia infection may have superimposed on those of bvFTD rather than playing as a contributory cause.

%B J Alzheimers Dis %V 66 %P 445-451 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282363?dopt=Abstract %R 10.3233/JAD-180524 %0 Journal Article %J J Alzheimers Dis %D 2018 %T GDF11 Rejuvenates Cerebrovascular Structure and Function in an Animal Model of Alzheimer's Disease. %A Zhang, Wei %A Guo, Yi %A Li, Bo %A Zhang, Qi %A Liu, Jian-Hui %A Gu, Guo-Jun %A Wang, Jin-Hong %A Bao, Rui-Kang %A Chen, Yu-Jie %A Xu, Jian-Rong %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Behavior, Animal %K Cerebral Amyloid Angiopathy %K Disease Models, Animal %K Growth Differentiation Factors %K Maze Learning %K Mice %K Mice, Transgenic %K Prefrontal Cortex %K Presenilin-1 %X

Cerebral amyloid angiopathy (CAA) is present in up to 90% of patients with Alzheimer's disease (AD), and may interact with classical neuropathology to exacerbate cognitive decline. Since growth differentiation factor 11 (GDF11) can activate vascular remodeling, we tested its effects on cognitive function and neuroinflammatory changes of AD model mice. We intravenously administered GDF11 or vehicle daily to 12-month-old transgenic mice overexpressing the amyloid-β protein precursor (AβPP)/PS1). Cognitive function was monitored using the Morris water maze, and after conclusion of the treatment, we assessed the morphology and presence of inflammatory markers in the cerebral vasculature. Subchronic treatment of adult AβPP/PS1 mice with GDF11 rescued cognitive function and ameliorated cerebrovascular function. In particular, the de novo genesis of small blood vessels and the expression of vascular-related proteins were significantly higher than in the vehicle-treated AβPP/PS1 mice, whereas the expressions of the inflammatory markers Iba-1 and GFAP significantly decreased in proportion to the lower ratio of two forms of amyloid-β (Aβ40/42). Daily intravenous treatment with GDF11-injection can rejuvenate respects of cognition and cerebrovascular changes in AD mice.

%B J Alzheimers Dis %V 62 %P 807-819 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480172?dopt=Abstract %R 10.3233/JAD-170474 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Gene Transfer Induced Hypercholesterolemia in Amyloid Mice. %A Grames, Mychal S %A Dayton, Robert D %A Lu, Xiaohong %A Schilke, Robert M %A Alexander, J Steven %A Orr, A Wayne %A Barmada, Sami J %A Woolard, Matthew D %A Klein, Ronald L %X

A risk factor for cardiovascular disease (CVD), mutant PCSK9, was expressed in APP/PS1 mice to study the CVD-Alzheimer's disease inter-relationship. Cholesterol levels were elevated by 5-6-fold from 3 to 13 weeks after PCSK9 gene transfer. We tested whether hypercholesterolemia would increase amyloid-β plaques at a relatively early stage of plaque deposition. Plaque burden was increased in the hippocampus of PCSK9 treated mice though the increase was modest compared to the large elevation in cholesterol. Elevating cholesterol via gene transfer could be valuable in a variety of disease models compared to making crosses with germ-line transgenic mouse models of CVD.

%B J Alzheimers Dis %V 65 %P 1079-1086 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30124449?dopt=Abstract %R 10.3233/JAD-180494 %0 Journal Article %J J Alzheimers Dis %D 2018 %T General Practice Clinical Data Help Identify Dementia Hotspots: A Novel Geospatial Analysis Approach. %A Bagheri, Nasser %A Wangdi, Kinley %A Cherbuin, Nicolas %A Anstey, Kaarin J %K Age Factors %K Aged %K Aged, 80 and over %K Australia %K Dementia %K Demography %K Epidemiological Monitoring %K Female %K General Practice %K Humans %K Male %K Retrospective Studies %K Sex Factors %K Topography, Medical %X

We have a poor understanding of whether dementia clusters geographically, how this occurs, and how dementia may relate to socio-demographic factors. To shed light on these important questions, this study aimed to compute a dementia risk score for individuals to assess spatial variation of dementia risk, identify significant clusters (hotspots), and explore their association with socioeconomic status. We used clinical records from 16 general practices (468 Statistical Area level 1 s, N = 14,746) from the city of west Adelaide, Australia for the duration of 1 January 2012 to 31 December 2014. Dementia risk was estimated using The Australian National University-Alzheimer's Disease Risk Index. Hotspot analyses were applied to examine potential clusters in dementia risk at small area level. Significant hotspots were observed in eastern and southern areas while coldspots were observed in the western area within the study perimeter. Additionally, significant hotspots were observed in low socio-economic communities. We found dementia risk scores increased with age, sex (female), high cholesterol, no physical activity, living alone (widow, divorced, separated, or never married), and co-morbidities such as diabetes and depression. Similarly, smoking was associated with a lower dementia risk score. The identification of dementia risk clusters may provide insight into possible geographical variations in risk factors for dementia and quantify these risks at the community level. As such, this research may enable policy makers to tailor early prevention strategies to the correct individuals within their precise locations.

%B J Alzheimers Dis %V 61 %P 125-134 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125484?dopt=Abstract %R 10.3233/JAD-170079 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Generation and Partial Characterization of Rabbit Monoclonal Antibody to Pyroglutamate Amyloid-β3-42 (pE3-Aβ). %A Mehta, Pankaj D %A Patrick, Bruce A %A Barshatzky, Marc %A Mehta, Sangita P %A Frackowiak, Janusz %A Mazur-Kolecka, Bozena %A Wegiel, Jerzy %A Wisniewski, Thomas %A Miller, David L %X

N-terminally truncated pyroglutamate amyloid-β (Aβ) peptide starting at position 3 represents a significant fraction of Aβ peptides (pE3-Aβ) in amyloid plaques of postmortem brains from patients with Alzheimer's disease (AD) and older persons with Down syndrome (DS). Studies in transgenic mouse models of AD also showed that pE3-Aβ is a major component of plaques, and mouse monoclonal antibody to pE3-Aβ appears to be a desirable therapeutic agent for AD. Since small peptides do not typically elicit a good immune response in mice, but do so favorably in rabbits, our aims were to generate and partially characterize a rabbit monoclonal antibody (RabmAb) to pE3-Aβ. The generated RabmAb was found to be specific for pE3-Aβ, since it showed no reactivity with Aβ16, Aβ40, Aβ42, Aβ3-11, and pE11-17 Aβ peptides in an enzyme linked immunosorbent assay (ELISA). The isotype of the antibody was found to be IgG class. The antibody possesses high affinity to pE3-Aβ with dissociation constant (KD) for the antibody of 1 nM. The epitope of the antibody lies within the sequence of pE3-FRHD. In dot blotting, the optimal detection of pE3-Aβ was at an antibody concentration of 0.5 μg/ml. The threshold of pE3-Aβ detection was 2 fmol. The antibody was sensitive enough to detect 10 pg/ml of pE3-Aβ in sandwich ELISA. pE3-Aβ was detected in AD and DS brain extracts in ELISA and immunoblotting. Immunohistological studies showed immunolabeling of plaques and blood vessels in brains from patients with AD, and DS showing AD pathology. Thus, the antibody can be widely applied in AD and DS research, and therapeutic applications.

%B J Alzheimers Dis %V 62 %P 1635-1649 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504532?dopt=Abstract %R 10.3233/JAD-170898 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Generation of a New Tau Knockout (tauΔex1) Line Using CRISPR/Cas9 Genome Editing in Mice. %A Tan, Daniel C S %A Yao, Sherilyn %A Ittner, Arne %A Bertz, Josefine %A Ke, Yazi D %A Ittner, Lars M %A Delerue, Fabien %X

Alzheimer's disease and other dementias present with tau pathology. Several mouse lines with knockout of the tau-encoding Mapt gene have been reported, yet findings often differed between lines and sites. Here, we report a new tau knockout strain (tauΔex1), generated by CRISPR/Cas9-mediated genome editing of intron -1/exon 1 of Mapt in C57Bl/6J mice. TauΔex1 mice had no overt phenotype, but, in line with previous models, they showed a significantly reduced susceptibility to excitotoxic seizures, with normal memory formation in young mice. This new in vivo resource will be made freely available to the research community.

%B J Alzheimers Dis %V 62 %P 571-578 %8 2018 %G eng %N 2 %R 10.3233/JAD-171058 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Genetic Heterogeneity of Alzheimer's Disease: Embracing Research Partnerships. %A Nacmias, Benedetta %A Bagnoli, Silvia %A Piaceri, Irene %A Sorbi, Sandro %X

Studies on the genetics of Alzheimer's disease (AD) have revealed the complexity and heterogeneity of the disease. All our studies have supported this evidence and contribute to the current understanding of the genetic architecture of AD. This report reviews the success of our investigations, focusing on the implications and importance of the genetics of AD, and demonstrates the relevance of research strategies embracing partnerships.

%B J Alzheimers Dis %V 62 %P 903-911 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103034?dopt=Abstract %R 10.3233/JAD-170570 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Genetic Interaction with Plasma Lipids on Alzheimer's Disease in the Framingham Heart Study. %A Peloso, Gina M %A Beiser, Alexa S %A DeStefano, Anita L %A Seshadri, Sudha %X

Epidemiological and genetic studies have pointed to the role of cholesterol in Alzheimer's disease (AD). We explored the interaction of a genetic risk score (GRS) of AD risk alleles with mid-life plasma lipid levels (LDL-C, HDL-C, and triglycerides) on risk for AD in the Framingham Heart Study (FHS). Mid-life (between the ages of 40-60 years old) lipid levels were obtained from individuals in the FHS Original and Offspring cohorts (157 cases and 2,882 controls) with genetic data and AD status available. Cox proportional hazards regression was performed to test the interaction between mid-life lipid levels and an AD GRS, as well as the individual contributing SNPs, on risk of incident AD adjusting for age, sex, and cohort. We found a significant interaction between a GRS of AD loci and log triglyceride levels on risk of clinical AD (p = 0.006), but no interaction of the GRS with HDL-C (p = 0.458) or LDL-C (p = 0.366). We then tested the interaction between the individual SNPs contributing to the GRS and log triglycerides. We found two SNPs that had interactions with triglycerides on AD risk that reached a p-value < 0.05 (rs11218343 and APOEɛ4). The association between some AD SNPs and risk of AD may be modified by triglyceride levels. Furthermore, sequential testing of a GRS with a set of traits on disease followed by testing individual SNPs for interaction provides a framework for narrowing the associations that need to be tested for interaction analyses. Replication is needed to confirm these findings.

%B J Alzheimers Dis %V 66 %P 1275-1282 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412497?dopt=Abstract %R 10.3233/JAD-180751 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Genotyping of the Alzheimer's Disease Genome-Wide Association Study Index Single Nucleotide Polymorphisms in the Brains for Dementia Research Cohort. %A Brookes, Keeley J %A McConnell, George %A Williams, Kirsty %A Chaudhury, Sultan %A Madhan, Gaganjit %A Patel, Tulsi %A Turley, Christopher %A Guetta-Baranes, Tamar %A Bras, Jose %A Guerreiro, Rita %A Hardy, John %A Francis, Paul T %A Morgan, Kevin %X

The Brains for Dementia Research project is a recently established longitudinal cohort which aims to provide brain tissue for research purposes from neuropathologically defined samples. Here we present the findings from our analysis on the 19 established GWAS index SNPs for Alzheimer's disease, in order to demonstrate if the BDR sample also displays association to these variants. A highly significant association of the APOEɛ4 allele was identified (p = 3.99×10-12). Association tests for the 19 GWAS SNPs found that although no SNPs survive multiple testing, nominal significant findings were detected and concordance with the Lambert et al. GWAS meta-analysis was observed.

%B J Alzheimers Dis %V 64 %P 355-362 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914034?dopt=Abstract %R 10.3233/JAD-180191 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Growth Hormone-Releasing Hormone Modulation of Neuronal Exosome Biomarkers in Mild Cognitive Impairment. %A Winston, Charisse N %A Goetzl, Edward J %A Baker, Laura D %A Vitiello, Michael V %A Rissman, Robert A %X

Age-related changes in cognition are linked to decreased expression of somatotropins, GHRH and IGF-1. Mild cognitive impairment (MCI) and Alzheimer's disease (AD) are heterogeneous conditions. The loss of GHRH signaling in the brain may be mechanistically involved in AD pathogenesis. The consequent need to identify AD at an early and perhaps more treatable stage has fueled research into blood-based, exosome biomarkers. Plasma exosomes from participants enrolled in a randomized, double-blind, placebo-controlled 20-week trial of GHRH administration, were isolated, precipitated, and enriched by immuno-absorption with anti-L1CAM antibody (neural adhesion protein) from adults with MCI and age-matched, cognitively normal controls (CNC). Extracted protein cargo from neuronally-derived exosomes (NDEs) were assessed by ELISAs for protein levels implicated in AD neuropathology and for synaptic proteins altered by AD. Plasma NDE concentrations of Aβ1-42 were significantly increased while plasma NDE concentrations of NRGN, synaptophysin, synaptotagmin, and synaptopodin were significantly decreased in patients with MCI, independent of GHRH treatment. Plasma NDE concentrations of ptau-S396 and GAP43 were not affected by cognitive status (CNC versus MCI) or by GHRH treatment. Aβ1-42, neurogranin (NRGN), synaptophysin, synaptotagmin, and synaptopodin demonstrated the highest diagnostic accuracy for distinguishing between CNC and MCI patients, while synaptophysin and synaptotagmin demonstrated moderate accuracy in distinguishing between placebo-treated and GHRH-treated, MCI patients.

%B J Alzheimers Dis %V 66 %P 971-981 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30372675?dopt=Abstract %R 10.3233/JAD-180302 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Healthy versus Entorhinal Cortical Atrophy Identification in Asymptomatic APOE4 Carriers at Risk for Alzheimer's Disease. %A Konishi, Kyoko %A Joober, Ridha %A Poirier, Judes %A MacDonald, Kathleen %A Chakravarty, Mallar %A Patel, Raihaan %A Breitner, John %A Bohbot, Véronique D %K Aged %K Alleles %K Alzheimer Disease %K Apolipoprotein E4 %K Atrophy %K Case-Control Studies %K Entorhinal Cortex %K Female %K Heterozygote %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Risk Factors %K Spatial Memory %X

Early detection of Alzheimer's disease (AD) has been challenging as current biomarkers are invasive and costly. Strong predictors of future AD diagnosis include lower volume of the hippocampus and entorhinal cortex, as well as the ɛ4 allele of the Apolipoprotein E gene (APOE) gene. Therefore, studying functions that are critically mediated by the hippocampus and entorhinal cortex, such as spatial memory, in APOE ɛ4 allele carriers, may be key to the identification of individuals at risk of AD, prior to the manifestation of cognitive impairments. Using a virtual navigation task developed in-house, specifically designed to assess spatial versus non-spatial strategies, the current study is the first to differentiate functional and structural differences within APOE ɛ4 allele carriers. APOE ɛ4 allele carriers that predominantly use non-spatial strategies have decreased fMRI activity in the hippocampus and increased atrophy in the hippocampus, entorhinal cortex, and fimbria compared to APOE ɛ4 allele carriers who use spatial strategies. In contrast, APOE ɛ4 allele carriers who use spatial strategies have grey matter levels comparable to non-APOE ɛ4 allele carriers. Furthermore, in a leave-one-out analysis, grey matter in the entorhinal cortex could predict navigational strategy with 92% accuracy.

%B J Alzheimers Dis %V 61 %P 1493-1507 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29278888?dopt=Abstract %R 10.3233/JAD-170540 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Hedonic Assessment of Odors: A Comparison of Two Sensory Scales for Use with Alzheimer's Disease Patients and Elderly Individuals. %A Atanasova, Boriana %A Mondon, Karl %A Dreyfuss, Lise %A Beaufils, Emilie %A Desmidt, Thomas %A Hommet, Caroline %A El-Hage, Wissam %A Belzung, Catherine %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Cognitive Dysfunction %K Female %K Humans %K Linear Models %K Male %K Olfaction Disorders %K Olfactory Perception %K Severity of Illness Index %K Smell %X

BACKGROUND: Several clinical studies concerning the olfactory function of patients with cognitive impairment have used sensory scales to investigate hedonic perception. However, no study has focused on the choice of the most appropriate sensory hedonic scale for the individuals with neurodegenerative disorders or other psychiatric diseases involving cognitive deficits.

OBJECTIVE: The aim of this study was to investigate the ability of patients with Alzheimer's disease (AD) to use two hedonic scales (category scale and linear scale) and compare their discriminatory capacity, repeatability, and ease of use. This should allow us to identify the most appropriate hedonic scale for patients with AD.

METHODS: We recruited 18 patients with mild to moderate AD, and 20 healthy volunteers matched for gender, age, smoking status, and educational level. The participants underwent a clinical assessment and hedonic evaluation of three odorants (pleasant, unpleasant, and neutral), using a five-point category scale and a 10-cm linear scale with a marked mid-point.

RESULTS: AD patients were able to use hedonic scales as well as paired healthy elderly subjects. The linear scale performed slightly better in terms of ease of use for both patients and healthy controls and discriminatory capacity for AD patients. The results for AD patients and controls with both scales were repeatable.

CONCLUSION: The linear scale may be more appropriate for AD patients pending further studies involving a larger population of patients, using several odorants.

%B J Alzheimers Dis %V 61 %P 929-938 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254084?dopt=Abstract %R 10.3233/JAD-170433 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Heritability of Frontotemporal Lobar Degeneration: Validation of Pedigree Classification Criteria in a Northern Italy Cohort. %A Fostinelli, Silvia %A Ciani, Miriam %A Zanardini, Roberta %A Zanetti, Orazio %A Binetti, Giuliano %A Ghidoni, Roberta %A Benussi, Luisa %K Age of Onset %K Aged %K C9orf72 Protein %K Cohort Studies %K Female %K Frontotemporal Lobar Degeneration %K Genetic Counseling %K Genetic Testing %K Humans %K Italy %K Male %K Middle Aged %K Mutation %K Pedigree %K Progranulins %K tau Proteins %X

A large portion of frontotemporal lobar degeneration (FTLD) patients has a family history of disease and the presence of a pathogenic mutation confirms the clinical diagnosis. Recently, standardized criteria to evaluate FTLD pedigree, based on first- and second-degree affected relatives, their age at onset, and clinical phenotype, were proposed and validated in an American cohort. Herein we applied these criteria to 402 Italian FTLD pedigrees and assessed mutation frequencies in GRN, C9orf72, and MAPT genes with the aim of validating these criteria. Moreover, we evaluated whether genetic counseling requests reflect the estimated family risk. 12.4% of pedigrees had high family history, 6.5% medium, 15.4% low; 39% were apparent sporadic cases and 26.6% had family history of unknown significance. Mutations frequencies were in line with the categorization proposed: the highest rate was found in the most at-risk families (74%) and decreased in other categories (medium: 15.4%; low: 9.7%; sporadic: 1.3%). Mutation carriers with unknown family history (5.6%) were mostly early-onset patients. Detected mutation frequency was comparable with the US-cohort (13.7%), but mutations distribution among genes was different, with higher frequency of GRN mutations (9.4%) in our cohort. An elevated proportion of FTLD patients belonging to "high risk" pedigrees asked for genetic counseling (42%); requests decreased according to the estimated family risk (medium: 26.9%; low: 17.7%; sporadic: 5.1%). In conclusion, the proposed pedigree classification criteria, herein further validated, should be incorporated in the FTLD diagnostic work-up. Moreover, our data suggest to extend genetic screening to early-onset patients with unknown family history.

%B J Alzheimers Dis %V 61 %P 753-760 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226869?dopt=Abstract %R 10.3233/JAD-170661 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Hippocampal Stratum Radiatum, Lacunosum, and Moleculare Sparing in Mild Cognitive Impairment. %A Su, Li %A Hayes, Lawrence %A Soteriades, Soteris %A Williams, Guy %A Brain, Susannah A E %A Firbank, Michael J %A Longoni, Giulia %A Arnold, Robert J %A Rowe, James B %A O'Brien, John T %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Atrophy %K Cognitive Dysfunction %K Disease Progression %K Entorhinal Cortex %K Female %K Hippocampus %K Humans %K Imaging, Three-Dimensional %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Reproducibility of Results %X

BACKGROUND: Alzheimer's disease (AD) is associated with atrophy in entorhinal cortex (ERC), the hippocampus, and its subfields Cornu Ammonis 1 (CA1) and subiculum, which predict conversion from mild cognitive impairment (MCI) to clinical AD. The stratum radiatum, lacunosum, and moleculare (SRLM) are also important gateways involving ERC and CA1, which are affected by early AD pathology.

OBJECTIVE: To assess whether the SRLM is affected in MCI and AD.

METHODS: In this proof-of-concept study, 27 controls, 13 subjects with AD, and 22 with MCI underwent 3T MRI. T1 maps were used for whole-hippocampal volumetry, T2 maps were segmented for hippocampal subfield areas, entorhinal cortex and subiculum thickness, and evaluated for SRLM integrity.

RESULTS: Significant CA1 atrophy and subiculum thinning were found in both AD and MCI compared to similarly aged controls. However, SRLM integrity was only significantly reduced in AD but not in MCI compared to controls. There were no significant differences in other hippocampal subfields (CA2, CA3/dentate gyrus) or ERC thickness between the groups. Finally, CA1 and CA3/DG areas and SRLM clarity were correlated with clinical and cognitive measurements of disease severity.

CONCLUSION: Although this study was cross sectional, it suggests a progression of specific subfield changes from MCI to established AD that is associated with the reduced integrity of SRLM, which may reflect more widespread hippocampal involvement as the disease progresses and the relative preservation of SRLM in MCI. These results provide new MRI biomarkers for disease staging and understanding of the neurobiology in AD.

%B J Alzheimers Dis %V 61 %P 415-424 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171994?dopt=Abstract %R 10.3233/JAD-170344 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Hippocampal Subfield Volumetry: Differential Pattern of Atrophy in Different Forms of Genetic Frontotemporal Dementia. %A Bocchetta, Martina %A Iglesias, Juan Eugenio %A Scelsi, Marzia A %A Cash, David M %A Cardoso, M Jorge %A Modat, Marc %A Altmann, Andre %A Ourselin, Sebastien %A Warren, Jason D %A Rohrer, Jonathan D %X

BACKGROUND: Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder, with a strong genetic component. Previous research has shown that medial temporal lobe atrophy is a common feature of FTD. However, no study has so far investigated the differential vulnerability of the hippocampal subfields in FTD.

OBJECTIVES: We aimed to investigate hippocampal subfield volumes in genetic FTD.

METHODS: We in6/2/2018vestigated hippocampal subfield volumes in a cohort of 75 patients with genetic FTD (age: mean (standard deviation) 59.3 (7.7) years; disease duration: 5.1 (3.4) years; 29 with MAPT, 28 with C9orf72, and 18 with GRN mutations) compared with 97 age-matched controls (age: 62.1 (11.1) years). We performed a segmentation of their volumetric T1-weighted MRI scans to extract hippocampal subfields volumes. Left and right volumes were summed and corrected for total intracranial volumes.

RESULTS: All three groups had smaller hippocampi than controls. The MAPT group had the most atrophic hippocampi, with the subfields showing the largest difference from controls being CA1-4 (24-27%, p < 0.0005). For C9orf72, the CA4, CA1, and dentate gyrus regions (8-11%, p < 0.0005), and for GRN the presubiculum and subiculum (10-14%, p < 0.0005) showed the largest differences from controls.

CONCLUSIONS: The hippocampus was affected in all mutation types but a different pattern of subfield involvement was found in the three genetic groups, consistent with differential cortical-subcortical network vulnerability.

%B J Alzheimers Dis %V 64 %P 497-504 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889066?dopt=Abstract %R 10.3233/JAD-180195 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Homocysteine and Dementia: An International Consensus Statement. %A Smith, A David %A Refsum, Helga %A Bottiglieri, Teodoro %A Fenech, Michael %A Hooshmand, Babak %A McCaddon, Andrew %A Miller, Joshua W %A Rosenberg, Irwin H %A Obeid, Rima %K Cognition %K Cognitive Dysfunction %K Consensus %K Dementia %K Dietary Supplements %K Homocysteine %K Humans %K Meta-Analysis as Topic %K Review Literature as Topic %K Risk Factors %K Vitamin B Complex %X

Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer's disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Intervention trials in elderly with cognitive impairment show that homocysteine-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline. The findings are consistent with moderately raised plasma total homocysteine (>11 μmol/L), which is common in the elderly, being one of the causes of age-related cognitive decline and dementia. Thus, the public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins. Further trials are needed to see whether B vitamin treatment will slow, or prevent, conversion to dementia in people at risk of cognitive decline or dementia.

%B J Alzheimers Dis %V 62 %P 561-570 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad171042?id=journal-of-alzheimers-disease%2Fjad171042 %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480200?dopt=Abstract %R 10.3233/JAD-171042 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Hypercapnic and Hypoxic Respiratory Response During Wakefulness and Sleep in a Streptozotocin Model of Alzheimer's Disease in Rats. %A Vicente, Mariane C %A Almeida, Maria C %A Bícego, Kênia C %A Carrettiero, Daniel C %A Gargaglioni, Luciane H %X

Besides the typical cognitive decline, patients with Alzheimer's disease (AD) develop disorders of the respiratory system, such as sleep apnea, shortness of breath, and arrhythmias. These symptoms are aggravated with the progression of the disease. However, the cause and nature of these disturbances are not well understood. Here, we treated animals with intracerebroventricular streptozotocin (STZ, 2 mg/kg), a drug that has been described to cause Alzheimer-like behavioral and histopathological impairments. We measured ventilation (V̇E), electroencephalography, and electromyography during normocapnia, hypercapnia, and hypoxia in Wistar rats. In addition, we performed western blot analyses for phosphorylated tau, total tau, and amyloid-β (Aβ) peptide in the locus coeruleus (LC), retrotrapezoid nucleus, medullary raphe, pre-Bötzinger/Bötzinger complex, and hippocampus, and evaluated memory and learning acquisition using the Barnes maze. STZ treatment promoted memory and learning deficits and increased the percentage of total wakefulness during normocapnia and hypercapnia due to a reduction in the length of episodes of wakefulness. CO2-drive to breathe during wakefulness was increased by 26% in STZ-treated rats due to an enhanced tidal volume, but no changes in V̇E were observed in room air or hypoxic conditions. The STZ group also showed a 70% increase of Aβ in the LC and no change in tau protein phosphorylation. In addition, no alteration in body temperature was observed. Our findings suggest that AD animals present an increased sensitivity to CO2 during wakefulness, enhanced Aβ in the LC, and sleep disruption.

%B J Alzheimers Dis %V 65 %P 1159-1174 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30124447?dopt=Abstract %R 10.3233/JAD-180397 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Imaging Biomarkers of Neurodegeneration in Alzheimer's Disease: Distinct Contributions of Cortical MRI Atrophy and FDG-PET Hypometabolism. %A Benvenutto, Agnès %A Giusiano, Bernard %A Koric, Lejla %A Gueriot, Claude %A Didic, Mira %A Felician, Olivier %A Guye, Maxime %A Guedj, Eric %A Ceccaldi, Mathieu %X

BACKGROUND: Neurodegeneration biomarkers are routinely used in the diagnosis of Alzheimer's disease (AD).

OBJECTIVE: To evaluate the respective contributions of two neuroimaging biomarkers, structural MRI and 18FDG-PET, in the assessment of neurodegeneration in AD dementia.

METHODS: Patients with mild AD dementia diagnosed based on clinical and cerebrospinal fluid criteria and cognitively healthy subjects, from the Marseille cohort ADAge with cognitive, structural MRI and 18FDG-PET assessments, were included. Extent of atrophy on MRI and of hypometabolism on 18FDG-PET were individually evaluated in each patient using a voxel-based analysis on whole-brain approach and compared to healthy subjects. Patients were divided in distinct groups according to their atrophy extent on the one hand and to their hypometabolism extent on the other, then, to their imaging profile combining the extent of the two biomarkers.

RESULTS: Fifty-two patients were included. The MMSE score was significantly lower in the "Extensive hypometabolism" group than in the "Limited hypometabolism" group (respectively 19.5/30 versus 23/30). A lower Innotest Amyloid Tau Index was associated with an extensive hypometabolism (p = 0.04). There were more patients with low educational level in the "Extensive atrophy" group, while a higher educational level was more found in the "Limited atrophy" group (p = 0.005).

CONCLUSION: 18FDG-PET hypometabolism extent is associated with the pathological processes and clinical severity of AD, while MRI atrophy seems to be influenced by the cognitive reserve. In the context of mild AD dementia, these two biomarkers of neurodegeneration are thus not interchangeable and require to be considered in combination rather than in isolation.

%B J Alzheimers Dis %V 65 %P 1147-1157 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30124446?dopt=Abstract %R 10.3233/JAD-180292 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Immunohistochemical Analysis of Activin Receptor-Like Kinase 1 (ACVRL1/ALK1) Expression in the Rat and Human Hippocampus: Decline in CA3 During Progression of Alzheimer's Disease. %A Adams, Stephanie L %A Benayoun, Laurent %A Tilton, Kathy %A Mellott, Tiffany J %A Seshadri, Sudha %A Blusztajn, Jan Krzysztof %A Delalle, Ivana %X

The pathophysiology of Alzheimer's disease (AD) includes signaling defects mediated by the transforming growth factor β-bone morphogenetic protein-growth and differentiation factor (TGFβ-BMP-GDF) family of proteins. In animal models of AD, administration of BMP9/GDF2 improves memory and reduces amyloidosis. The best characterized type I receptor of BMP9 is ALK1. We characterized ALK1 expression in the hippocampus using immunohistochemistry. In the rat, ALK1 immunoreactivity was found in CA pyramidal neurons, most frequently and robustly in the CA2 and CA3 fields. In addition, there were sporadic ALK1-immunoreactive cells in the stratum oriens, mainly in CA1. The ALK1 expression pattern in human hippocampus was similar to that of rat. Pyramidal neurons within the CA2, CA3, and CA4 were strongly ALK1-immunoreactive in hippocampi of cognitively intact subjects with no neurofibrillary tangles. ALK1 signal was found in the axons of alveus and fimbria, and in the neuropil across CA fields. Relatively strongest ALK1 neuropil signal was observed in CA1 where pyramidal neurons were occasionally ALK1-immunoractive. As in the rat, horizontally oriented neurons in the stratum oriens of CA1 were both ALK1- and GAD67-immunoreactive. Analysis of ALK1 immunoreactivity across stages of AD pathology revealed that disease progression was characterized by overall reduction of the ALK1 signal in CA3 in advanced, but not early, stages of AD. These data suggest that the CA3 pyramidal neurons may remain responsive to the ALK1 ligands, e.g., BMP9, during initial stages of AD and that ALK1 may constitute a therapeutic target in early and moderate AD.

%B J Alzheimers Dis %V 63 %P 1433-1443 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843236?dopt=Abstract %R 10.3233/JAD-171065 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impact of a Virtual Dementia Experience on Medical and Pharmacy Students' Knowledge and Attitudes Toward People with Dementia: A Controlled Study. %A Gilmartin-Thomas, Julia F-M %A McNeil, John %A Powell, Anne %A Malone, Daniel T %A Wolfe, Rory %A Larson, Ian C %A O'Reilly, Claire L %A Kirkpatrick, Carl M %A Kipen, Eva %A Petrovich, Tanya %A Bell, J Simon %K Australia %K Curriculum %K Dementia %K Female %K Health Knowledge, Attitudes, Practice %K Humans %K Male %K Students, Medical %K Students, Pharmacy %K Virtual Reality %K Young Adult %X

BACKGROUND: Clinical practice guidelines for dementia highlight the importance of providing patient-centered care. This can be achieved by improving health professionals' attitudes and knowledge toward people with dementia.

OBJECTIVE: Quantitatively evaluate the impact of a virtual dementia experience on medical and pharmacy students' knowledge and attitudes toward people with dementia.

METHODS: A non-randomized controlled study from September-October 2016. The intervention group received a 1.5-hour multisensory, virtual simulation of light, sound, color, and visual content to experience the cognitive and perceptual difficulties faced by people with dementia. Controls participated in the standard curriculum only. All students were invited to complete the 20-item Dementia Attitudes Scale (DAS) pre- and post-intervention.

RESULTS: A total of 278 students (n = 64 medical, n = 214 pharmacy) were analyzed (n = 80 intervention, n = 198 control). The majority of students were female (n = 184, 66.2%), with an average age of 22.5 years. The intervention improved the DAS total score and subdomains of comfort and knowledge (p < 0.001).

CONCLUSION: The intervention had a positive impact on medical and pharmacy students' knowledge and attitudes toward people with dementia.

%B J Alzheimers Dis %V 62 %P 867-876 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480198?dopt=Abstract %R 10.3233/JAD-170982 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impact of Amyloid PET Imaging in the Memory Clinic: A Systematic Review and Meta-Analysis. %A Shea, Yat-Fung %A Barker, Warren %A Greig-Gusto, Maria T %A Loewenstein, David A %A Duara, Ranjan %A DeKosky, Steven T %X

BACKGROUND: Patients with cognitive impairment or dementias of uncertain etiology are frequently referred to a memory disorders specialty clinic. The impact of and role for amyloid PET imaging (Aβ-PET) may be most appropriate in this clinical setting.

OBJECTIVE: The primary objective of this study was to perform a systematic review and meta-analysis of the impact of Aβ-PET on etiological diagnosis and clinical management in the memory clinic setting.

METHODS: A search of the literature on the impact of Aβ-PET in the memory clinic setting between 1 January 2004 and 12 February 2018 was conducted. Meta-analysis using a random effects model was performed to determine the pooled estimate of the impact of Aβ-PET in the changes of diagnoses and changes in management plan.

RESULTS: After rigorous review, results from 13 studies were extracted, involving 1,489 patients. Meta-analysis revealed a pooled effect of change in diagnoses of 35.2% (95% CI 24.6-47.5). Sub-analyses showed that the pooled effect in change in diagnoses if Aβ-PET was used under the appropriate use criteria (AUC) or non-AUC criteria were 47.8% (95% CI 25.9-70.5) and 29.6% (95% CI: 21.5-39.3), respectively. The pooled effect of a change of diagnosis from Alzheimer's disease (AD) to non-AD and from non-AD to AD were 22.7% (95% CI: 17.1-29.5) and 25.6% (95% CI: 17.6-35.8), respectively. The pooled effect leading to a change of management was 59.6% (95% CI 39.4-77.0).

CONCLUSIONS: Aβ-PET has a highly significant impact on both changes in diagnosis and management among patients being seen at a specialty memory clinic.

%B J Alzheimers Dis %V 64 %P 323-335 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889075?dopt=Abstract %R 10.3233/JAD-180239 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Impact of Creative Arts in Alzheimer's Disease and Dementia Public Health Education. %A Burns, Nicole C %A Watts, Amber %A Perales, Jaime %A Montgomery, Robert Neal %A Morris, Jill K %A Mahnken, Jonathan D %A Lowther, Johnna %A Vidoni, Eric D %X

Previous research involving dramatic performances about Alzheimer's disease and dementia perception have targeted health care workers or caretakers. We examined the influence of a theater performance on the emotional affect of a general audience to determine the utility of this type of theater in large-scale public health education efforts. Our study included 147 participants that attended a self-revelatory theater performance based on the social/relationship experiences of those with dementia and those who care for them. This type of theater engages the audience and actors in a dual transformative process, supporting the emotional growth of all involved. Participants completed pre- and post-performance questionnaires regarding their beliefs and feelings surrounding the topic of dementia and the importance of the Arts for educating on issues surrounding dementia care. We tested for change in emotional affect pre- and post-performance using sensitivity and center of gravity statistical analyses. We found a significant change in emotional affect from an initial strong negative affect to slightly more positive/relaxed view after viewing the performance. Findings support self-revelatory theater as a resource to destigmatize preconceived notions of dementia. Large-scale community health education efforts could benefit from using this style of theater to elicit a change in audience perception of disease realities.

%B J Alzheimers Dis %V 63 %P 457-463 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578491?dopt=Abstract %R 10.3233/JAD-180092 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impact of Mild Cognitive Impairment on Mortality and Cause of Death in the Elderly. %A Bae, Jong Bin %A Han, Ji Won %A Kwak, Kyung Phil %A Kim, Bong Jo %A Kim, Shin Gyeom %A Kim, Jeong Lan %A Kim, Tae Hui %A Ryu, Seung-Ho %A Moon, Seok Woo %A Park, Joon Hyuk %A Youn, Jong Chul %A Lee, Dong Young %A Lee, Dong Woo %A Lee, Seok Bum %A Lee, Jung Jae %A Jhoo, Jin Hyeong %A Kim, Ki Woong %X

BACKGROUND: Mild cognitive impairment (MCI) is a cognitive state that lies on the continuum between normal aging and dementia, and the prevalence of MCI is higher than dementia. However, the risk for mortality of people with MCI has been far less studied than that of people with dementia, and the population attributable risk percent (PAR%) of death attributable to MCI has not been estimated yet.

OBJECTIVE: To investigate the impact of MCI on mortality and the cause of death in the elderly, and to estimate the PAR% of deaths attributable to MCI.

METHODS: Data came from 7,315 elderly subjects aged ≥60 years without dementia from two cohort studies with diagnostic assessments of MCI at baseline. Deaths among participants were confirmed through the nationwide mortality database of Statistics Korea.

RESULTS: MCI increased the risk of mortality in a multivariate Cox proportional model adjusting for age, sex, education, smoking, alcohol drinking, chronic illness, depression, vascular components, and cohort (hazard ratio = 1.59, 95% confidence interval 1.30, 1.94). PAR% of death attributable to MCI was 10.7% for age 65-74 years, 16.0% for age 75-84 years, and 24.2% for age ≥85 years. In the elderly with MCI, mortality risks from cerebrovascular disease, respiratory disease, and external causes were higher than in the cognitively normal elderly.

CONCLUSIONS: Our results suggest that the mortality risk of MCI in Asian countries may be comparable to that in Western countries, and MCI can contribute to the death of the elderly as much as dementia.

%B J Alzheimers Dis %V 64 %P 607-616 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914024?dopt=Abstract %R 10.3233/JAD-171182 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Impact of Music on the Self in Dementia. %A Baird, Amee %A Thompson, William Forde %K Consciousness %K Dementia %K Humans %K Music %K Music Therapy %K Personality %X

In this review, we consider how the onset and progression of dementia can disrupt one's sense of self, and propose that music is an ideal tool for alleviating this distressing symptom. Various aspects of the self can be impaired in people with dementia, depending on how the self is defined. There are anecdotal reports that music can 'bring people back to themselves' in the face of dementia, but there have been scarce empirical investigations of this topic. Motivated by a consideration of the existing literature, we outline a novel theoretical framework that accounts for the relationship between music and the self in people with dementia. We propose that music has a number of 'design features' that make it uniquely equipped to engage multiple aspects of the self. We suggest that each design feature interacts with different aspects of the self to varying degrees, promoting overall wellbeing. We discuss how existing research on music and dementia fits within this framework, and describe two case studies in which music was an ideal stimulus for reaffirming their sense of self. Our framework may be useful for the diagnosis and treatment of impairments of self in people with dementia, and highlights how music, given its ability to engage all aspects of the self simultaneously, can result in an overall enhanced sense of self.

%B J Alzheimers Dis %V 61 %P 827-841 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332051?dopt=Abstract %R 10.3233/JAD-170737 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impact of Untimely Access to Formal Care on Costs and Quality of Life in Community Dwelling People with Dementia. %A Janssen, Niels %A Handels, Ron L %A Sköldunger, Anders %A Woods, Bob %A Jelley, Hannah %A Edwards, Rhiannon Tudor %A Orrell, Martin %A Selbæk, Geir %A Røsvik, Janne %A Gonçalves-Pereira, Manuel %A Marques, Maria J %A Zanetti, Orazio %A Portolani, Elisa %A Irving, Kate %A Hopper, Louise %A Meyer, Gabriele %A Bieber, Anja %A Stephan, Astrid %A Kerpershoek, Liselot %A Wolfs, Claire A G %A de Vugt, Marjolein E %A Verhey, Frans R J %A Wimo, Anders %X

BACKGROUND: Access to formal care is not always timely and a better understanding on the impact of untimely access is needed.

OBJECTIVE: To examine, from a societal perspective, the impact of untimely access to formal care in terms of total costs and quality of life over one year in community dwelling people with dementia.

METHODS: Within the Actifcare study, needs, resource use, and quality of life were observed for one year in a cohort of 451 community dwelling people with dementia in 8 European countries. Untimely access to care was operationalized as having at least one unmet need for care identified by the Camberwell Assessment of Need for the Elderly (CANE) instrument. Two regression models were built for both total costs and quality of life measured by the EQ-5D-5L, one using sum of unmet needs and one using a predefined selection of need items.

RESULTS: Unmet needs were not associated with higher total costs but they were associated with a lower quality of life of people with dementia. Of all CANE items, only an unmet need for "company" was significantly related to lower total costs.

CONCLUSION: Total costs did not seem to differ between participants with unmet and met needs. Only few associations between specific unmet needs and costs and quality of life were found. Furthermore, quality of life of people with dementia decreases when multiple unmet needs are experienced, indicating that assessing and meeting needs is important to improve quality of life.

%B J Alzheimers Dis %V 66 %P 1165-1174 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400096?dopt=Abstract %R 10.3233/JAD-180531 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impaired Spike Timing Dependent Cortico-Cortical Plasticity in Alzheimer's Disease Patients. %A Di Lorenzo, Francesco %A Ponzo, Viviana %A Motta, Caterina %A Bonní, Sonia %A Picazio, Silvia %A Caltagirone, Carlo %A Bozzali, Marco %A Martorana, Alessandro %A Koch, Giacomo %X

BACKGROUND: Mechanisms of cortical plasticity have been recently investigated in Alzheimer's disease (AD) patients with transcranial magnetic stimulation protocols showing a clear impairment of long-term potentiation (LTP) cortical-like plasticity mechanisms.

OBJECTIVE: We aimed to investigate mechanisms of cortico-cortical spike-timing dependent plasticity (STDP) in AD patients investigating the connections between posterior parietal cortex (PPC) and primary motor cortex (M1).

METHODS: We used a cortico-cortical paired associative stimulation (cc-PAS) protocol to repeatedly activate the connection between PPC and M1 of the left-dominant hemisphere in a sample of fifteen AD patients and ten age-matched healthy subjects. PPC transcranial magnetic stimulation preceded (ccPAS +5) or followed M1 stimulation (ccPAS - 5) by 5 ms. Motor-evoked potentials (MEPs) were collected to assess the time course of the after effects of cc-PAS protocol measuring MEP amplitude as index of cortico-cortical associative plasticity.

RESULTS: In healthy subjects, ccPAS - 5 protocol induced the expected long-lasting increase of MEP amplitude compatible with LTP-like cortical plasticity while PAS +5 protocol induced the opposite effect. AD patients did not show any significant modification of the amplitude of MEP after both ccPAS protocols.

CONCLUSIONS: Our study shows that in AD patients the time-locked activation of human cortico-cortical connections is not able to form STDP, reflecting an impairment of a multi-factor plasticity process.

%B J Alzheimers Dis %V 66 %P 983-991 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30372679?dopt=Abstract %R 10.3233/JAD-180503 %0 Journal Article %J J Alzheimers Dis %D 2018 %T In Vitro Potency and Preclinical Pharmacokinetic Comparison of All-D-Enantiomeric Peptides Developed for the Treatment of Alzheimer's Disease. %A Schartmann, Elena %A Schemmert, Sarah %A Niemietz, Nicole %A Honold, Dominik %A Ziehm, Tamar %A Tusche, Markus %A Elfgen, Anne %A Gering, Ian %A Brener, Oleksandr %A Shah, Nadim Joni %A Langen, Karl-Josef %A Kutzsche, Janine %A Willbold, Dieter %A Willuweit, Antje %X

Diffusible amyloid-β (Aβ) oligomers are currently presumed to be the most cytotoxic Aβ assembly and held responsible to trigger the pathogenesis of Alzheimer's disease (AD). Thus, Aβ oligomers are a prominent target in AD drug development. Previously, we reported on our solely D-enantiomeric peptide D3 and its derivatives as AD drug candidates. Here, we compare one of the most promising D3 derivatives, ANK6, with its tandem version (tANK6), and its head-to-tail cyclized isoform (cANK6r). In vitro tests investigating the D-peptides' potencies to inhibit Aβ aggregation, eliminate Aβ oligomers, and reduce Aβ-induced cytotoxicity revealed that all three D-peptides efficiently target Aβ. Subsequent preclinical pharmacokinetic studies of the three all-D-peptides in wildtype mice showed promising blood-brain barrier permeability with cANK6r yielding the highest levels in brain. The peptides' potencies to lower Aβ toxicity and their remarkable brain/plasma ratios make them promising AD drug candidates.

%B J Alzheimers Dis %V 64 %P 859-873 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966196?dopt=Abstract %R 10.3233/JAD-180165 %0 Journal Article %J J Alzheimers Dis %D 2018 %T In vivo Depiction of α7 Nicotinic Receptor Loss for Cognitive Decline in Alzheimer's Disease. %A Nakaizumi, Kyoko %A Ouchi, Yasuomi %A Terada, Tatsuhiro %A Yoshikawa, Etsuji %A Kakimoto, Akihiro %A Isobe, Takashi %A Bunai, Tomoyasu %A Yokokura, Masamichi %A Suzuki, Katsuaki %A Magata, Yasuhiro %K Adult %K Aged %K alpha7 Nicotinic Acetylcholine Receptor %K Alzheimer Disease %K Brain %K Case-Control Studies %K Cognitive Dysfunction %K Female %K Humans %K Male %K Middle Aged %K Positron-Emission Tomography %K Young Adult %X

BACKGROUND: The α7 subtype of the nicotinic acetylcholine receptor (nAChR) is considered important in higher cognitive functions, and cholinergic loss underpins the pathophysiology of Alzheimer's disease (AD). However, the relationships between α7 nAChR function and clinical functions or amyloid-β (Aβ) deposition remain to be explored in the living AD brain.

OBJECTIVE: We aimed to elucidate the relationship between α7 nAChR availability in the specific cholinergic region and cognitive decline in the Aβ-confirmed AD brain.

METHODS: Twenty AD patients and ten age-matched healthy subjects were examined. The α7-nAChR availability and Aβ deposition were evaluated using positron emission tomography with an α7 nAChR radiotracer 11C-(R)-MeQAA and 11C-Pittsburg compound B (11C-PiB), respectively. Semi-quantified values of tracer binding were estimated with a simplified reference tissue method for BPND of 11C-(R)-MeQAA and a tissue ratio method for SUVR of 11C-PiB. These parameters and clinical scores were compared voxel-wise using a statistical parametric mapping method.

RESULTS: The levels of 11C-(R)-MeQAA BPND in the temporal and prefrontal cholinergic projection regions were significantly lower in AD, and negative correlations were found between 11C-PiB SUVR and 11C-(R)-MeQAA BPND in the region of the nucleus basalis magnocellularis and medial prefrontal cortex. Levels of 11C-(R)-MeQAA BPND were significantly correlated with memory and frontal function scores in AD.

CONCLUSION: The association between Aβ burden and α7-nAChR reduction in the basal forebrain cholinergic system was highlighted in relation to cognitive decline in AD. This suggests that Aβ-linked α7-nAChR reduction is clinico-pathophyisologically important for considering a good therapeutic target in AD.

%B J Alzheimers Dis %V 61 %P 1355-1365 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376856?dopt=Abstract %R 10.3233/JAD-170591 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Increased Albumin Oxidation in Cerebrospinal Fluid and Plasma from Alzheimer's Disease Patients. %A Costa, Montserrat %A Horrillo, Raquel %A Ortiz, Ana María %A Pérez, Alba %A Mestre, Anna %A Ruiz, Agustin %A Boada, Merce %A Grancha, Salvador %X

BACKGROUND: Oxidative stress in the brain and peripheral systems is considered a major player in Alzheimer's disease (AD). Albumin is the main transporter and the main extracellular antioxidant in the human body.

OBJECTIVE: Here we explore for the first time the oxidation status of cerebrospinal fluid (CSF) and plasma albumin in AD in comparison to healthy subjects.

METHODS: Plasma and CSF samples were obtained from mild-moderate AD patients and control healthy age-matched donors. Albumin redox state forms (reduced: HMA; reversibly oxidized: HNA1; irreversibly oxidized: HNA2) were determined by HPLC. Albumin post-translational modifications (PTM) analysis was performed by mass spectrometry.

RESULTS: HPLC showed less HMA in AD plasma than in controls (54.1% versus 65.2% ; p < 0.0001), mainly at expense of HNA1 (42.8% versus 32.5% ; p < 0.0001). In AD CSF, HMA was drastically decreased compared to controls (9.6% versus 77.4% ; p < 0.0001), while HNA2 was increased (52.8% versus 7.4% ; p < 0.0001). In AD patients but not in healthy controls, CSF albumin was much more irreversibly oxidized than in plasma (close to 20-fold increase in HNA2). PTM analysis showed that AD CSF albumin samples behave as a differentiated cluster, thus confirming the albumin oxidative pattern observed by HPLC.

CONCLUSION: CSF albumin oxidation in AD patients was dramatically increased comparing to healthy controls, while in plasma this increase was smaller. CSF albumin in AD patients was much more oxidized than in plasma, but this effect was not observed in healthy controls. These results suggest that albumin oxidation, especially in CSF, and its role in AD deserves further investigation.

%B J Alzheimers Dis %V 63 %P 1395-1404 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782326?dopt=Abstract %R 10.3233/JAD-180243 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Increased Prevalence of Obesity/Type 2 Diabetes and Lower Levels of Lithium in Rural Texas Counties May Explain Greater Alzheimer's Disease Risk. %A Baranowski, Bradley J %A Hayward, Grant C %A Fajardo, Val A %A MacPherson, Rebecca E K %X

BACKGROUND/OBJECTIVE: To compare Alzheimer's disease (AD) mortality rates and coinciding risk factors in rural and urban Texas populations.

METHODS: 155 Texas counties were divided into 73 rural and 82 urban areas using the U.S. Census Bureau definition of rurality. Changes in age-adjusted AD mortality across these counties were calculated using a 7-year aggregation model from 2000-2006 and 2009-2015. Data pertaining to gender, race, education, obesity, diabetes, physical inactivity, and lithium concentrations in tap water were also collected from readily available databases.

RESULTS: Change in age-adjusted AD mortality was higher in rural counties (9.5±1.4) versus urban (5.9±1.1) over the time period examined. Similarly, obesity (30.2±0.2% ), diabetes (11.0±0.1% ), and physical inactivity (29.4±0.2% ) levels were significantly higher in rural populations compared to urban (29.1±0.2%, 9.7±0.1%, and 26.7±0.3, respectively). In contrast, the percent of population with some college education (40.1±0.7% ) was lower compared to urban (29.4±0.2% and 44.4±0.9%, respectively). Lithium concentrations in tap water was significantly lower in rural counties compared to urban (63.3±8.2 and 33.4±4.7μg/L, respectively). No significant differences were observed among females and however, we did find significant differences in the percent of African American and Hispanics. Correlational analysis uncovered a negative association between education status and AD mortality over time (r = -0.17). Further analysis controlling for physical inactivity, education, and trace lithium concentrations results in a loss of statistical significance.

CONCLUSIONS: AD mortality rates are higher in rural counties when compared to urban counties, and this may be linked to greater physical inactivity, obesity, and diabetes, as well as lower trace lithium levels in tap water.

%B J Alzheimers Dis %V 64 %P 303-308 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865052?dopt=Abstract %R 10.3233/JAD-171150 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Increasing Diagnostic Accuracy of Mild Cognitive Impairment due to Alzheimer's Disease by User-Independent, Web-Based Whole-Brain Volumetry. %A Hedderich, Dennis M %A Spiro, Judith E %A Goldhardt, Oliver %A Kaesmacher, Johannes %A Wiestler, Benedikt %A Yakushev, Igor %A Zimmer, Claus %A Boeckh-Behrens, Tobias %A Grimmer, Timo %X

BACKGROUND: Volumetric quantification of structural MRI has been shown to increase the diagnostic accuracy of patients with mild cognitive impairment (MCI); however, its implementation in clinical routine is usually technically difficult and time-consuming.

OBJECTIVE: The purpose of this study was to investigate whether volumetric information obtained from the free and easy-to-use online tool volBrain can improve correct identification of MCI patients with Alzheimer's disease (AD) compared to visual reading.

METHODS: The study cohort consisted of 27 patients with MCI due to AD (AD positive) as determined by biomarker information and 26 cognitively normal controls (CN). Three blinded readers, 2 radiologists and 1 clinical dementia expert, assessed the patients' MRI regarding brain atrophy and probability of underlying AD two times, without and with supporting volumetric information from volBrain. To assess diagnostic accuracy of volBrain measures alone, a simple sum score based on basic volumetric measures was developed and tested.

RESULTS: Correct patient classification by readers 1, 2, and 3 without a volumetric report was 73.6%, 77.4%, and 83.0%. With a volumetric report, correct classification increased for the radiological readers to 77.4% and 81.1%, respectively and decreased to 77.4% for reader 3. Usage of the volumetric report alone yielded the highest diagnostic accuracy of 84.9%. Diagnostic confidence increased significantly for radiological readers.

CONCLUSION: Volumetric information from volBrain increases the radiologist's diagnostic performance and confidence in identifying MCI patients with AD. We propose that such tools may be implemented in the routine diagnostic work-up of patients with suspected AD.

%B J Alzheimers Dis %V 65 %P 1459-1467 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30175976?dopt=Abstract %R 10.3233/JAD-180532 %0 Journal Article %J J Alzheimers Dis %D 2018 %T INDEL Length and Haplotypes in the β-Synuclein Gene: A Key to Differentiate Dementia with Lewy Bodies? %A Gámez-Valero, Ana %A Canet-Pons, Julia %A Urbizu, Aintzane %A Anillo, Ana %A Santos, Cristina %A Ariza, Aurelio %A Beyer, Katrin %X

Lewy body diseases (LBD) include Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and together with Alzheimer's disease (AD) they show an important neuropathological and clinical overlap. The human alpha- and beta-synuclein genes (SNCA and SNCB) are key factors for the development of Lewy body diseases. Here, we aimed to analyze the genotype distribution of potentially functional SNPs in SNCA and SNCB, perform haplotype analysis for SNCB, and to identify functional insertion and deletion (INDEL) variations within the regulatory region of SNCB which might be responsible for the drastically diminished beta-synuclein levels reported for pure DLB. Thus, we genotyped brain samples from AD, DLB, PD, and healthy controls for two SNCA and four SNCB SNPs. We also analyzed INDEL variations upstream of SNCB, determined SNCB expression levels, and correlated INDEL lengths with expression levels. Applying Fisher's exact, chi-square, ANOVA tests, and the ΔΔCt method, we found disease-specific genotype distribution of SNCA and SNCB SNPs. Additionally, we identified three INDEL variations upstream of SNCB and showed that the INDEL allele lengths were associated with SNCB expression levels. INDEL alleles associated with low SNCB expression were accumulated in pure DLB. Finally, one major and four minor DLB specific SNCB haplotypes were identified with Haploview and Arlequin. In summary, our study showed that different SNCA and SNCB genotypes are associated with the development of either PD or DLB, and that the frequencies of genotypes associated with low SNCB expression are elevated in DLB.

%B J Alzheimers Dis %V 65 %P 207-219 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040713?dopt=Abstract %R 10.3233/JAD-180074 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Independent Associations of Physical Activity and Sleep with Cognitive Function in Older Adults. %A Falck, Ryan S %A Best, John R %A Davis, Jennifer C %A Liu-Ambrose, Teresa %X

BACKGROUND: Current evidence suggests physical activity (PA) and sleep are important for cognitive health; however, few studies examining the role of PA and sleep for cognitive health have measured these behaviors objectively.

OBJECTIVE: We cross-sectionally examined whether 1) higher PA is associated with better cognitive performance independently of sleep quality; 2) higher sleep quality is associated with better cognitive performance independently of PA; and 3) whether higher PA is associated with better sleep quality.

METHODS: We measured PA, subjective sleep quality using the Pittsburgh Sleep Quality Index (PSQI), and objective sleep quality (i.e., fragmentation, efficiency, duration, and latency) using the MotionWatch8© in community-dwelling adults (N = 137; aged 55+). Cognitive function was indexed using the Alzheimer's Disease Assessment Scale-Plus. Correlation analyses were performed to determine relationships between PA, sleep quality, and cognitive function. We then used latent variable modelling to examine the relationships of PA with cognitive function independently of sleep quality, sleep quality with cognitive function independently of PA, and PA with sleep quality.

RESULTS: We found greater PA was associated with better cognitive performance independently of 1) PSQI (β= -0.03; p < 0.01); 2) sleep fragmentation (β= -0.02; p < 0.01); 3) sleep duration (β= -0.02; p < 0.01); and 4) sleep latency (β= -0.02; p < 0.01). In addition, better sleep efficiency was associated with better cognitive performance independently of PA (β= -0.01; p = 0.04). We did not find any associations between PA and sleep quality.

CONCLUSIONS: PA is associated with better cognitive performance independently of sleep quality, and sleep efficiency is associated with better cognitive performance independently of PA. However, PA is not associated with sleep quality and thus PA and sleep quality may be related to cognitive performance through independent mechanisms.

%B J Alzheimers Dis %V 63 %P 1469-1484 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782311?dopt=Abstract %R 10.3233/JAD-170936 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Induction of Amyloid-β42 Production by Fipronil and Other Pyrazole Insecticides. %A Cam, Morgane %A Durieu, Emilie %A Bodin, Marion %A Manousopoulou, Antigoni %A Koslowski, Svenja %A Vasylieva, Natalia %A Barnych, Bogdan %A Hammock, Bruce D %A Bohl, Bettina %A Koch, Philipp %A Omori, Chiori %A Yamamoto, Kazuo %A Hata, Saori %A Suzuki, Toshiharu %A Karg, Frank %A Gizzi, Patrick %A Haber, Vesna Erakovic %A Bencetic Mihaljevic, Vlatka %A Tavcar, Branka %A Portelius, Erik %A Pannee, Josef %A Blennow, Kaj %A Zetterberg, Henrik %A Garbis, Spiros D %A Auvray, Pierrick %A Gerber, Hermeto %A Fraering, Jeremy %A Fraering, Patrick C %A Meijer, Laurent %X

Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer's disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the 'human chemical exposome' contains products able to favor the production of Aβ42/Aβ43 over Aβ40 and shorter Aβs. To detect such products, we screened a library of 3500 + compounds in a cell-based assay for enhanced Aβ42/Aβ43 production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3-10-fold increase in the production of extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase toward Aβ42/Aβ43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42/Aβ43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ42/Aβ43 peptides, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.

%B J Alzheimers Dis %V 62 %P 1663-1681 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504531?dopt=Abstract %R 10.3233/JAD-170875 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Influence of Butyrylcholinesterase in Progression of Mild Cognitive Impairment to Alzheimer's Disease. %A Gabriel, António José %A Almeida, Maria Rosário %A Ribeiro, Maria Helena %A Carneiro, Diogo %A Valério, Daniela %A Pinheiro, Ana Cristina %A Pascoal, Rui %A Santana, Isabel %A Baldeiras, Ines %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Biomarkers %K Butyrylcholinesterase %K Cognitive Dysfunction %K Disease Progression %K Female %K Genetic Predisposition to Disease %K Humans %K Kaplan-Meier Estimate %K Male %K Middle Aged %K Risk Factors %K tau Proteins %X

BACKGROUND: Several demographic and genetic prognostic factors of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) have been recognized so far. The most frequent polymorphism of butyrylcholinesterase (BuChE), the K-variant, has been proposed as a risk factor for AD, but data regarding its influence on early disease progression is still limited.

OBJECTIVE: To investigate the influence of the BuChE-K variant in MCI progression to AD.

METHODS: 96 MCI patients were included in the study and were genotyped for BuChE-K variant and Apolipoprotein E (ApoE). Cerebrospinal fluid (CSF) BuChE activity, as well as the levels of AD biomarkers amyloid-β 42 (Aβ42), total and hyperphosphorylated tau (t-tau and p-tau) were also determined.

RESULTS: No significant differences were found in either BuChE-K variant or BuChE activity between MCI patients that progressed to AD (MCI-AD) and patients that remained stable during clinical follow-up (MCI-St). As expected, baseline CSF levels of Aβ42 were significantly lower and t-Tau, p-Tau, and ApoE ɛ4 allele frequency were significantly higher in MCI-AD patients. An association between the ApoE ɛ4 allele and the BuChE-K variant in MCI-AD, but not in MCI-St patients, was found with patients carrying both alleles presenting the highest incidence of progression and the lowest estimated time of progression to AD.

CONCLUSION: Although BuChE-K alone does not seem to play a major role in progression to AD in MCI patients, a synergistic effect with the ApoE ɛ4 allele was found, highlighting the importance of assessing these combined genotypes for evaluating risk progression in MCI patients.

%B J Alzheimers Dis %V 61 %P 1097-1105 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254094?dopt=Abstract %R 10.3233/JAD-170695 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Influence of Polypharmacy on the Initiation of Anti-Dementia Therapy in Germany. %A Bohlken, Jens %A Jacob, Louis %A van den Bussche, Hendrik %A Kostev, Karel %X

The goal of the present retrospective study was to focus on the potential influence of polypharmacy on the initiation of antidementia therapy in patients diagnosed with dementia in general practices in Germany. The current study sample included patients diagnosed with dementia in 1,217 general practices in Germany between 2014 and 2016 (index date). The primary outcome measure was the rate of prescription of anti-dementia drugs within one year following the index date. The explanatory variable was the number of different drugs prescribed at baseline per patient. Independent variables included age, sex, and type of dementia. Logistic regression analyses were conducted to study the impact of the number of different drugs prescribed at baseline per participant on the odds of receiving anti-dementia therapy (in all patients and in patients diagnosed with Alzheimer's disease). The study included 21,888 patients with all-cause dementia. Mean age was 80.2 years (SD = 7.3 years) and 61.4% of the study population were women. Individuals receiving six drugs or more at baseline were significantly less likely to be prescribed anti-dementia treatment when compared to those without any drug at baseline (6- 9 drugs: odds ratio [OR] = 0.75;≥10 drugs: OR = 0.58). In the subgroup of patients with Alzheimer's disease, the odds of being prescribed anti-dementia therapy were lower in individuals with four drugs or more, compared to patients who had not been prescribed any drugs at baseline (4- 5 drugs: OR = 0.60; 6- 9 drugs: OR = 0.49;≥10 drugs: OR = 0.36). There is a negative association between polypharmacy and antidementia therapy initiation in general practices in Germany.

%B J Alzheimers Dis %V 64 %P 827-833 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29889071?dopt=Abstract %R 10.3233/JAD-180382 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Influence of the Val66Met Polymorphism of Brain-Derived Neurotrophic Factor on Neurological Function after Traumatic Brain Injury. %A Finan, John D %A Udani, Shreya V %A Patel, Vimal %A Bailes, Julian E %X

Functional outcomes after traumatic brain injury (TBI) vary widely across patients with apparently similar injuries. This variability hinders prognosis, therapy, and clinical innovation. Recently, single nucleotide polymorphism (SNPs) that influence outcome after TBI have been identified. These discoveries create opportunities to personalize therapy and stratify clinical trials. Both of these changes would propel clinical innovation in the field. This review focuses on one of most well-characterized of these SNPs, the Val66Met SNP in the brain-derived neurotrophic factor (BDNF) gene. This SNP influences neurological function in healthy subjects as well as TBI patients and patients with similar acute insults to the central nervous system. A host of other patient-specific factors including ethnicity, age, gender, injury severity, and post-injury time point modulate this influence. These interactions confound efforts to define a simple relationship between this SNP and TBI outcomes. The opportunities and challenges associated with personalizing TBI therapy around this SNP and other similar SNPs are discussed in light of these results.

%B J Alzheimers Dis %V 65 %P 1055-1064 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149456?dopt=Abstract %R 10.3233/JAD-180585 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Innovative Biomarkers for Alzheimer's Disease: Focus on the Hidden Disease Biomarkers. %A Ghidoni, Roberta %A Squitti, Rosanna %A Siotto, Mariacristina %A Benussi, Luisa %X

The criteria for the clinical diagnosis of AD include the analysis of biomarkers of the underlying brain disease pathology; a set of cerebrospinal fluid (CSF) tests, amyloid-β1-42 (Aβ42), total-tau (t-tau), and phosphorylated tau (p-tau), are available and their performance in a clinical setting has been assessed in several studies. Thus, in dementia research, great advances have been made in the discovery of putative biomarkers; however, disappointingly, few of them have been translated into clinically applicable assays. To find biomarkers able to reliably detect AD pathology already at prodromal stages and in blood is even more important. Recent technical breakthroughs have provided ultrasensitive methods that allow the detection of brain-specific proteins in blood. In the present review, we will focus on the usefulness of ultrasensitive technologies for biomarker discovery and trace elements detection; moreover, we will review studies on circulating nano-compartments, a promising novel source of material for molecular diagnostics.

%B J Alzheimers Dis %V 62 %P 1507-1518 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504534?dopt=Abstract %R 10.3233/JAD-170953 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Interactions between Atrial Fibrillation, Cardiovascular Risk Factors, and ApoE Genotype in Promoting Cognitive Decline in Patients with Alzheimer's Disease: A Prospective Cohort Study. %A Falsetti, Lorenzo %A Viticchi, Giovanna %A Buratti, Laura %A Grigioni, Francesco %A Capucci, Alessandro %A Silvestrini, Mauro %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Atherosclerosis %K Atrial Fibrillation %K Carotid Intima-Media Thickness %K Cognitive Dysfunction %K Disease Progression %K Female %K Humans %K Logistic Models %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Prospective Studies %K Risk Factors %K Tomography, X-Ray Computed %X

BACKGROUND: An association between non-valvular atrial fibrillation (NVAF) and cognitive impairment has been hypothesized.

OBJECTIVE: We sought to evaluate whether and how permanent NVAF (pNVAF) is associated with progression of cognitive impairment in patients with Alzheimer's disease (AD) in the presence of vascular or genetic risk factors.

METHODS: 310 consecutive patients affected by mild-moderate AD were included and followed for a 24-month period. At the end of the follow-up, based on the results of the neuropsychological evaluation patients were classified as stable or deteriorated to severe AD. Clinical history, therapy, time in therapeutic range for anticoagulation, Framingham cardiovascular risk profile (FCRP), CHA2DS2-VASc score, Mini-Mental State Examination (MMSE), ApoE genotype, brain CT-scan, carotid ultrasound, and ECG were collected. Binary logistic and path analysis were adopted to assess relationships between pNVAF, ApoE, and cognitive outcome.

RESULTS: Despite anticoagulant therapy, pNVAF was associated with lower entry MMSE, higher mean intima-media thickness (mIMT) and higher FCRP. Among patients carrying ApoE ɛ4 allele and affected by pNVAF, the lowest MMSE (14.90±7.62) and the highest mIMT (1.16±0.17 mm) and FCRP (26.24±3.96) values were detected. In this group, the risk of cognitive deterioration reached the highest probability. pNVAF was associated with an increased cognitive deterioration in subjects with high FCRP, CHA2DS2-VASc, or mIMT.

CONCLUSIONS: pNVAF seems to identify AD patients with a significant atherosclerotic burden and reduced cognitive performances. The interaction between pNVAF and ApoE ɛ4 genotype, especially with aggregated risk factors and an advanced stage of vascular damage is associated with higher risk of fast cognitive deterioration.

%B J Alzheimers Dis %V 62 %P 713-725 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480173?dopt=Abstract %R 10.3233/JAD-170544 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Intracellular Targeting of Heat Shock Proteins in Differentiated Human Neuronal Cells Following Proteotoxic Stress. %A Deane, Catherine A S %A Brown, Ian R %X

HSPA6 (Hsp70B') is an inducible member of the Hsp70 (HSPA) family of heat shock proteins that is present in the human genome and not found in mouse and rat. Hence it is lacking in current animal models of neurodegenerative diseases. To advance knowledge of the little studied HSPA6, differentiated human neuronal SH-SY5Y cells were treated with the proteotoxic stress-inducing agent MG132. A robust induction of HSPA6 was apparent which localized to the periphery of MG132-induced protein aggregates in the neuronal cytoplasm. Components of the protein disaggregation/refolding machine that co-operate with Hsp70 also targeted the periphery of cytoplasmic protein aggregates, including DNAJB1 (Hsp40-1), HSPH1 (Hsp105α), and HSPB1 (Hsp27). These data suggest that HSPA6 is involved in the response of human neuronal cells to proteotoxic stress that is a feature of neurodegenerative diseases which have been characterized as protein misfolding disorders. Constitutively expressed HSPA8 (Hsc70) also localized tothe periphery of cytoplasmic protein aggregates following the treatment of differentiated human neuronal cells with MG132. HSPA8 could provide a rapid response to proteotoxic stress in neuronal cells, circumventing the time required to upregulate inducible Hsps.

%B J Alzheimers Dis %V 66 %P 1295-1308 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412487?dopt=Abstract %R 10.3233/JAD-180536 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Intracranial Transplantation of Pancreatic Islets Attenuates Cognitive and Peripheral Metabolic Dysfunctions in a Rat Model of Sporadic Alzheimer's Disease. %A Bloch, Konstantin %A Gil-Ad, Irit %A Vanichkin, Alexey %A Hornfeld, Shay Henry %A Taler, Michal %A Dar, Shira %A Azarov, Dmitry %A Vardi, Pnina %A Weizman, Abraham %X

BACKGROUND: Alzheimer's disease (AD) is often associated with brain insulin resistance and peripheral metabolic dysfunctions. Recently, we developed a model of sporadic AD associated with obesity-related peripheral metabolic abnormalities in Lewis rats using intracerebroventricular administration of streptozotocin (icv-STZ).

OBJECTIVE: We aimed to assess the effect of intracranially grafted pancreatic islets on cognitive and peripheral metabolic dysfunctions in the icv-STZ Lewis rats.

METHODS: AD-like dementia associated with obesity was induced in inbred Lewis rats using a single icv-STZ. Two months after icv-STZ, syngeneic islets (100 islets per recipient) were implanted in the cranial subarachnoid cavity of icv-STZ rats. Morris water maze and marble burying tests were used for studying cognitive and behavioral functions. Central and peripheral metabolic alterations were assessed by histological and biochemical assays.

RESULTS: The icv-STZ induced increases in food intake, body weight, and blood levels of insulin and leptin without alteration of glucose homeostasis. Grafted islets reduced body weight gain, food consumption, peripheral insulin resistance, and hyperleptinemia. Biochemical and histological analysis of the brain revealed viable grafted islets expressing insulin and glucagon. The grafted islets did not affect expression of brain insulin receptors and peripheral glucose homeostasis. Two months after islet transplantation, cognitive and behavioral functioning in transplanted rats were significantly better than the sham-operated icv-STZ rats. No significant differences in the locomotor activity between transplanted and non-transplanted icv-STZ rats were found.

CONCLUSIONS: Intracranial islet transplantation attenuates cognitive decline and peripheral metabolic dysfunctions providing a novel therapeutic approach for sporadic AD associated with peripheral metabolic dysfunctions.

%B J Alzheimers Dis %V 65 %P 1445-1458 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30175977?dopt=Abstract %R 10.3233/JAD-180623 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Involvement of the Cingulate Cortex in Anosognosia: A Multimodal Neuroimaging Study in Alzheimer's Disease Patients. %A Guerrier, Laura %A Le Men, Johanne %A Gane, Anaıs %A Planton, Mélanie %A Salabert, Anne-Sophie %A Payoux, Pierre %A Dumas, Hervé %A Bonneville, Fabrice %A Péran, Patrice %A Pariente, Jérémie %X

BACKGROUND: Anosognosia is a frequent symptom of Alzheimer's disease (AD), but its neural substrates remain in question.

OBJECTIVE: In this study, we combined neuroimaging with a neuropsychological evaluation to assess neural substrates of anosognosia.

METHODS: We prospectively recruited 30 patients with probable early-stage AD and matched healthy controls. Participants underwent MRI, FDG-PET, and a neuropsychological evaluation that includes an assessment of anosognosia. In the AD group, correlations between the anosognosia score, neuroimaging modalities, and neuropsychological performance were performed.

RESULTS: Atrophy and hypometabolism were correlated with the anosognosia score in the left dorsal anterior cingulate cortex. The anosognosia score was also correlated with atrophy of the cerebellar vermis, the left postcentral gyrus, and the right fusiform gyrus. No relation was found between anosognosia and the neuropsychological assessment.

DISCUSSION: Structural and metabolic alteration in the dorsal anterior cingulate cortex seems to be associated with a diminution of awareness in patients with early-stage AD.

%B J Alzheimers Dis %V 65 %P 443-453 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056422?dopt=Abstract %R 10.3233/JAD-180324 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Iron and Alzheimer's Disease: An Update on Emerging Mechanisms. %A Lane, Darius J R %A Ayton, Scott %A Bush, Ashley I %X

Iron is a crucial transition metal for life and is the most abundant transition metal in the brain. However, iron's biological utility as an effective redox cycling metal also endows it with the potential to catalyze production of noxious free radicals. This "Janus-faced" nature of iron demands a tight regulation of cellular its metabolism. This regulation is crucial in the CNS, where iron plays myriad keystone roles in CNS processes, including mitochondrial energy transduction, enzyme catalysis, mitochondrial function, myelination, neurotransmitter anabolism and catabolism. Aberrations in brain iron homeostasis can elevate levels of this redox-active metal, leading to mislocalization of the metal and catastrophic oxidative damage to sensitive cellular and subcellular structures. Iron dyshomeostasis has been strongly linked to the pathogenesis of Alzheimer's disease (AD), as well as other major neurodegenerative diseases. Despite the growing societal burden of AD, no disease-modifying therapy exists, necessitating continued investment into both drug-development and the fundamental science investigating the disease-causing mechanisms. Targeting iron dyshomeostasis in the brain represents a rational approach to treat the underlying disease. Here we provide an update on known and emerging iron-associated mechanisms involved in AD. We conclude with an overview of evidence suggesting that, in addition to apoptosis, neuronal loss in AD involves "ferroptosis", a newly discovered iron- and lipid-peroxidation-dependent form of regulated necrosis. The ferroptosis field is rapidly progressing and may provide key insights for future drug-development with disease-modifying potential in AD.

%B J Alzheimers Dis %V 64 %P S379-S395 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865061?dopt=Abstract %R 10.3233/JAD-179944 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Joint Assessment of Quantitative 18F-Florbetapir and 18F-FDG Regional Uptake Using Baseline Data from the ADNI. %A Ben Bouallègue, Fayçal %A Mariano-Goulart, Denis %A Payoux, Pierre %X

Joint analysis of amyloid and metabolic PET patterns across healthy, mild cognitive impairment (MCI), and Alzheimer's disease (AD) subjects was performed using baseline 18F-florbetapir and 18F-FDG PET of 684 subjects from the ADNI (251 normal, 204 stable MCI, 85 AD converters, and 144 AD). Correlation between regional amyloid and metabolic uptake was measured and predictive value of PET profile regarding AD conversion in cognitively impaired subjects was assessed using survival analysis and support vector machine classification (SVM). The highest correlations were found in the temporal cortex, precuneus, and posterior cingulum. With respect to normal controls, amyloid load increase was diffuse and early in MCI subjects, whereas metabolism decrease occurred later and predominated in temporo-parietal, precuneus, and cingulate cortices. Five-year AD conversion rates in cognitively impaired subjects were 5%, 22%, 42%, and 78% in amyloid-/FDG-, amyloid-/FDG+, amyloid+/FDG-, and amyloid+/FDG+ subjects respectively (mean follow-up 37±14 months). Using SVM, the combination of ADAS-cog score, amyloid PET, and FDG PET yielded better performance in predicting AD conversion (77% accuracy; 58% positive predictive value; 88% negative predictive value) than ADAS-cog (72%; 52%; 86%), amyloid PET (72%; 52%; 87%), and FDG PET (67%; 47%; 84%). This study attests the complementary value of amyloid and FDG PET in MCI assessment and the efficiency of combined cognitive, amyloid, and metabolic scores to predict AD conversion.

%B J Alzheimers Dis %V 62 %P 399-408 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439345?dopt=Abstract %R 10.3233/JAD-170833 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Ketogenic Medium Chain Triglycerides Increase Brain Energy Metabolism in Alzheimer's Disease. %A Croteau, Etienne %A Castellano, Christian-Alexandre %A Richard, Marie Anne %A Fortier, Mélanie %A Nugent, Scott %A Lepage, Martin %A Duchesne, Simon %A Whittingstall, Kevin %A Turcotte, Éric E %A Bocti, Christian %A Fülöp, Tamás %A Cunnane, Stephen C %X

BACKGROUND: In Alzheimer's disease (AD), it is unknown whether the brain can utilize additional ketones as fuel when they are derived from a medium chain triglyceride (MCT) supplement.

OBJECTIVE: To assess whether brain ketone uptake in AD increases in response to MCT as it would in young healthy adults.

METHODS: Mild-moderate AD patients sequentially consumed 30 g/d of two different MCT supplements, both for one month: a mixture of caprylic (55%) and capric acids (35%) (n = 11), followed by a wash-out and then tricaprylin (95%; n = 6). Brain ketone (11C-acetoacetate) and glucose (FDG) uptake were quantified by PET before and after each MCT intervention.

RESULTS: Brain ketone consumption doubled on both types of MCT supplement. The slope of the relationship between plasma ketones and brain ketone uptake was the same as in healthy young adults. Both types of MCT increased total brain energy metabolism by increasing ketone supply without affecting brain glucose utilization.

CONCLUSION: Ketones from MCT compensate for the brain glucose deficit in AD in direct proportion to the level of plasma ketones achieved.

%B J Alzheimers Dis %V 64 %P 551-561 %8 2018 Jun 19 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914035?dopt=Abstract %R 10.3233/JAD-180202 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Lentivirus-Mediated HDAC3 Inhibition Attenuates Oxidative Stress in APPswe/PS1dE9 Mice. %A Yu, Linjie %A Liu, Yi %A Jin, Yuexinzi %A Cao, Xiang %A Chen, Jian %A Jin, Jiali %A Gu, Yue %A Bao, Xinyu %A Ren, Zhuoying %A Xu, Yun %A Zhu, Xiaolei %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Disease Models, Animal %K Hippocampus %K Histone Deacetylases %K Lentivirus %K Male %K Maze Learning %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Neurons %K Oxidative Stress %K Plaque, Amyloid %K Primary Cell Culture %K Reactive Oxygen Species %K Spatial Memory %K tau Proteins %X

Amyloid-β (Aβ) induces a burst of oxidative stress and plays a critical role in the pathogenesis of Alzheimer's disease (AD). Our previous results have shown that histone deacetylase 3 (HDAC3) inhibition ameliorates spatial memory deficits and decreases the Aβ burden in the brains of 9-month-old APPswe/PS1dE9 (APP/PS1) mice. In this study, we investigated the role of HDAC3 inhibition in oxidative stress in vivo and in vitro models of AD. HDAC3 was detected mainly in the neurons, and HDAC3 inhibition significantly decreased reactive oxygen species generation and improved primary cortical neuron viability. In addition, HDAC3 inhibition attenuated spatial memory dysfunction in 6-month-old APP/PS1 mice, and decreased the apoptotic rate in the hippocampi as demonstrated by TUNEL staining. HDAC3 inhibition also reduced markers of lipid peroxidation, protein oxidation, and DNA/RNA oxidation in the hippocampi of APP/PS1 mice. Moreover, HDAC3 inhibition inactivated the c-Abl/MST1/YAP signaling pathway in the hippocampi of APP/PS1 mice. In conclusion, our data show that HDAC3 inhibition can attenuate spatial memory deficits and inhibit oxidative stress in APP/PS1 mice; these results indicate a potential strategy for AD treatment.

%B J Alzheimers Dis %V 61 %P 1411-1424 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376873?dopt=Abstract %R 10.3233/JAD-170844 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Lifetime Risk Factors for Functional and Cognitive Outcomes in Patients with Alzheimer's Disease. %A de Oliveira, Fabricio Ferreira %A de Almeida, Sandro Soares %A Chen, Elizabeth Suchi %A Smith, Marilia Cardoso %A Naffah-Mazzacoratti, Maria da Graça %A Bertolucci, Paulo Henrique Ferreira %X

Lifetime risk factors for cognitive and functional decline in Alzheimer's disease (AD) are not fully understood, and were prospectively evaluated in patients with low mean schooling from São Paulo, Brazil. Consecutive outpatients with late-onset AD were assessed for APOE haplotypes and the following potential baseline predictors: gender, schooling, age at dementia onset, lifetime urban living and sanitary conditions, occupational complexity, cognitive and physical activities, cerebrovascular risk factors (obesity, lifetime alcohol use and smoking, length of arterial hypertension, diabetes mellitus, and a dyslipidemic profile), use of a pacemaker, creatinine clearance, body mass index, waist circumference, head traumas with unconsciousness, treated systemic bacterial infections, amount of surgical procedures under general anesthesia, and family history of AD. Participants were followed from October 2010 to May 2017 for baseline risk factor associations with time since dementia onset for Clinical Dementia Rating and Mini-Mental State Examination score changes. For 227 patients (154 women, 119 APOE ε 4 carriers), later AD onset (mean 73.60±6.4 years-old, earlier for APOE ε 4/ε 4 carriers, p < 0.001) was the only variable hastening all endpoints, baseline creatinine clearance and lifetime alcohol use were hazardous for earlier cognitive and functional endpoints, women had earlier cognitive endpoints only, and schooling had a cumulative protective effect over later cognitive endpoints, particularly for carriers of APOE ε 4. Exclusively for carriers of APOE ε 4, head traumas with unconsciousness were hazardous for earlier cognitive endpoints, while lifetime sanitary conditions were protective regarding later cognitive endpoints. Functional and cognitive outcomes in AD represent probable interactions between effects of brain reserve and cerebral perfusion over neurodegeneration.

%B J Alzheimers Dis %V 65 %P 1283-1299 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149448?dopt=Abstract %R 10.3233/JAD-180303 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Long Journey into Aging, Brain Aging, and Alzheimer's Disease Following the Oxidative Stress Tracks. %A Mecocci, Patrizia %A Boccardi, Virginia %A Cecchetti, Roberta %A Bastiani, Patrizia %A Scamosci, Michela %A Ruggiero, Carmelinda %A Baroni, Marta %K Aging %K Alzheimer Disease %K Animals %K Brain %K Humans %K Oxidative Stress %X

The Editors of the Journal of Alzheimer's Disease invited Professor Patrizia Mecocci to contribute a review article focused on the importance and implications of her research on aging, brain aging, and senile dementias over the last years. This invitation was based on an assessment that she was one of the journal's top authors and a strong supporter of the concept that oxidative stress is a major contributor to several alterations observed in age-related conditions (sarcopenia, osteoporosis) and, more significantly, in brain aging suggesting a pivotal role in the pathogenesis and progression of one of the most dramatic age-related diseases, Alzheimer's disease (AD). Her first pioneering research was on the discovery of high level of 8-hydroxy-2'-deoxyguanosine (OH8dG), a marker of oxidation in nucleic acids, in mitochondrial DNA isolated from cerebral cortex. This molecule increases progressively with aging and more in AD brain, supporting the hypothesis that oxidative stress, a condition of unbalance between the production of reactive oxygen species and antioxidants, gives a strong contribution to the high incidence of AD in old age subjects. OH8dG also increases in peripheral lymphocyte from AD subjects, suggesting that AD is not only a cerebral but also a systemic disease. The role of antioxidants, particularly vitamin E and zinc, were also studied in longevity and in cognitive decline and dementia. This review shows the main findings from Mecocci's laboratory related to oxidative stress in aging, brain aging, and AD and discusses the importance and implications of some of the major achievements in this field of research.

%B J Alzheimers Dis %V 62 %P 1319-1335 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad170732?id=journal-of-alzheimers-disease%2Fjad170732 %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562533?dopt=Abstract %R 10.3233/JAD-170732 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Longitudinal Changes in Serum Glucose Levels are Associated with Metabolic Changes in Alzheimer's Disease Related Brain Regions. %A Burns, Christine M %A Kaszniak, Alfred W %A Chen, Kewei %A Lee, Wendy %A Bandy, Daniel J %A Caselli, Richard J %A Reiman, Eric M %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Blood Glucose %K Brain %K Brain Mapping %K Female %K Fluorodeoxyglucose F18 %K Heterozygote %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Positron-Emission Tomography %K Prospective Studies %K Radiopharmaceuticals %X

BACKGROUND: The association between longitudinal changes in serum glucose level and longitudinal changes in [18F] Fluorodeoxyglucose-PET (FDG PET) measurements of Alzheimer's disease (AD) risk are unknown.

OBJECTIVE: To investigate whether variation in serum glucose levels across time are associated with changes in FDG PET measurements of cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer's disease (AD).

METHODS: Participants are a subset of a prospective cohort study investigating FDG PET, apolipoprotein E (APOE) ɛ4, and risk for AD which includes data from baseline, interim, and follow up visits over 4.4±1.0-years. An automated brain-mapping algorithm was utilized to characterize and compare associations between longitudinal changes in serum glucose levels and longitudinal changes in rCMRgl.

RESULTS: This study included 80 adults aged 61.5±5 years, including 38 carriers and 42 non-carriers of the APOE ɛ4 allele. Longitudinal increases in serum glucose levels were associated with longitudinal CMRgl decline in the vicinity of parietotemporal, precuneus/posterior cingulate, and prefrontal brain regions preferentially affected by AD (p < 0.05, corrected for multiple comparisons). Findings remained significant when controlled for APOE ɛ4 status and baseline and advancing age.

CONCLUSIONS: Additional studies are needed to clarify and confirm the relationship between longitudinal changes in peripheral glucose and FDG PET measurements of AD risk. Future findings will set the stage on the use of FDG PET in the evaluation of possible interventions that target risk factors for the development of AD.

%B J Alzheimers Dis %V 62 %P 833-840 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480176?dopt=Abstract %R 10.3233/JAD-170767 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Longitudinal Modeling of Functional Decline Associated with Pathologic Alzheimer's Disease in Older Persons without Cognitive Impairment. %A Wang, Dai %A Schultz, Tim %A Novak, Gerald P %A Baker, Susan %A Bennett, David A %A Narayan, Vaibhav A %X

BACKGROUND: Therapeutic research on Alzheimer's disease (AD) has moved to intercepting the disease at the preclinical phase. Most drugs in late development have focused on the amyloid hypothesis.

OBJECTIVE: To understand the magnitude of amyloid-related functional decline and to identify the functional domains sensitive to decline in a preclinical AD population.

METHODS: Data were from the Religious Orders Study and the Rush Memory and Aging Project. Cognitive decline was measured by a modified version of the Alzheimer's Disease Cooperative Study Preclinical Alzheimer Cognitive Composite. The trajectories of functional decline, as measured by the instrumental and basic activities of daily living, were longitudinally modeled in 484 participants without cognitive impairment at baseline and having both a final clinical and a postmortem neuropathology assessment of AD.

RESULTS: Individuals with different final clinical diagnoses had different trajectories of cognitive and functional decline. Individuals with AD dementia, minor cognitive impairment, and no cognitive impairment had the most, intermediate, and least declines. While individuals with pathologic AD had significantly more cognitive decline over time than those without, the magnitude of difference in functional decline between these two groups was small. Functional domains such as handling finance and handling medications were more sensitive to decline.

CONCLUSION: Demonstrating the functional benefit of an amyloid-targeting drug represents a significant challenge as elderly people experience functional decline due to a wide range of reasons with limited manifestation attributable to AD neuropathology. More sensitive functional scales focusing on the functional domains sensitive to decline in preclinical AD are needed.

%B J Alzheimers Dis %V 62 %P 855-865 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480187?dopt=Abstract %R 10.3233/JAD-170903 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer's Disease Patients Treated with Plasma Exchange with 5% Human Albumin. %A Cuberas-Borrós, Gemma %A Roca, Isabel %A Boada, Merce %A Tárraga, Lluís %A Hernandez, Isabel %A Buendia, Mar %A Rubio, Lourdes %A Torres, Gustavo %A Bittini, Ángel %A Guzmán-de-Villoria, Juan A %A Pujadas, Francesc %A Torres, Mireia %A Núñez, Laura %A Castell, Joan %A Páez, Antonio %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Female %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuroimaging %K Plasma Exchange %K Serum Albumin, Human %K Time Factors %K Tomography, Emission-Computed, Single-Photon %K Treatment Outcome %X

BACKGROUND: Recently, modifications of Aβ1-42 levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer's disease (AD) treated with plasma exchange (PE) with albumin replacement.

OBJECTIVE: To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial.

METHODS: Patients received between 3 and 18 PE with albumin (Albutein® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam®) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline.

RESULTS: 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls.

CONCLUSIONS: Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion.

%B J Alzheimers Dis %V 61 %P 321-332 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154283?dopt=Abstract %R 10.3233/JAD-170693 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer's Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study. %A Salloway, Stephen P %A Sperling, Reisa %A Fox, Nick C %A Sabbagh, Marwan N %A Honig, Lawrence S %A Porsteinsson, Anton P %A Rofael, Hany %A Ketter, Nzeera %A Wang, Daniel %A Liu, Enchi %A Carr, Stephen %A Black, Ronald S %A Brashear, H Robert %X

BACKGROUND: A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer's disease dementia (apolipoprotein (APOE) ɛ4 carriers and noncarriers) is summarized.

OBJECTIVES: The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab.

METHODS: A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the parent studies.

RESULTS: A total of 1,462 (688 were APOEɛ4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups.

CONCLUSIONS: Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies.

%B J Alzheimers Dis %V 64 %P 689-707 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914022?dopt=Abstract %R 10.3233/JAD-171157 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Low Cerebrospinal Fluid Aβ42 and Aβ40 are Related to White Matter Lesions in Cognitively Normal Elderly. %A Skoog, Ingmar %A Kern, Silke %A Zetterberg, Henrik %A Östling, Svante %A Börjesson-Hanson, Anne %A Guo, Xinxin %A Blennow, Kaj %X

BACKGROUND: Low cerebrospinal fluid (CSF) levels of Aβ42 may be the earliest manifestation of Alzheimer's disease (AD). Knowledge on how CSF Aβ interacts with different brain pathologies early in the disease process is limited. We examined how CSF Aβ markers relate to brain atrophy and white matter lesions (WMLs) in octogenarians with and without dementia to explore the earliest pathogenetic pathways of AD in the oldest old.

OBJECTIVE: To study CSF amyloid biomarkers in relation to brain atrophy and WMLs in 85-year-olds with and without dementia.

METHODS: 53 octogenarians took part in neuropsychiatric examinations and underwent both a lumbar puncture and a brain CT scan. CSF levels of Aβ42 and Aβ40 were examined in relation to cerebral atrophy and WMLs. Dementia was diagnosed.

RESULTS: In 85-year-olds without dementia, lower levels of both CSF Aβ42 and CSF Aβ40 were associated with WMLs. CSF Aβ42 also correlated with measures of central atrophy, but not with cortical atrophy. In participants with dementia, lower CSF levels of Aβ42 were related to frontal, temporal, and parietal cortical atrophy but not to WMLs.

CONCLUSIONS: Our findings may suggest that there is an interrelationship between Aβ and subcortical WMLs in older persons without dementia. After onset of dementia, low CSF Aβ42, probably representing amyloid deposition in plaques, is associated with cortical atrophy. WMLs may be an earlier manifestation of Aβ deposition than cortical degeneration.

%B J Alzheimers Dis %V 62 %P 1877-1886 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614655?dopt=Abstract %R 10.3233/JAD-170950 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Lower Serum Antibodies Against Tau Protein and Heavy Neurofilament in Alzheimer's Disease. %A Bartos, Ales %A Fialová, Lenka %A Švarcová, Jana %X

BACKGROUND: Unlike antibodies against amyloid-β, little is known about serum antibodies to neuron-specific cytoskeletal proteins in patients with Alzheimer's disease (AD).

OBJECTIVE: We aimed to study IgG autoantibodies against tau protein, light (NFL) and heavy subunits (NFH) of neurofilaments in serum of AD patients and elderly controls and to explore the evolution of antineurocytoskeletal antibody levels over time.

METHODS: Antibodies against three targets (tau, NFL, and NFH) were measured using ELISA in 100 serum samples from 51 cognitively normal elderly controls and 49 patients with AD. Our primary cross-sectional design was further extended to monitor fluctuations over 1-2 years in a subset of individuals.

RESULTS: The AD patients had lower levels of anti-tau antibodies (p = 0.03) and even lower anti-NFH antibodies (p = 0.005) than those in the control group at baseline. On the contrary, anti-NFL antibodies or total IgG concentrations in serum did not differ. All three antibodies remained stable in both groups except for a selective and significant anti-tau decline in AD patients (p = 0.03).

CONCLUSIONS: The different responses to these antigens suggest some antibody selectivity in AD. The significant decline was observed for only serum anti-tau antibodies in AD patients over time and it corresponds to lower anti-tau levels in these patients. Our findings indicate a special feature of disease-relevant antigens and humoral autoimmunity in AD.

%B J Alzheimers Dis %V 64 %P 751-760 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966192?dopt=Abstract %R 10.3233/JAD-180039 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Mechanism of Tau Hyperphosphorylation Involving Lysosomal Enzyme Asparagine Endopeptidase in a Mouse Model of Brain Ischemia. %A Basurto-Islas, Gustavo %A Gu, Jin-Hua %A Tung, Yunn Chyn %A Liu, Fei %A Iqbal, Khalid %X

Dementias including Alzheimer's disease (AD) are multifactorial disorders that involve several different etiopathogenic mechanisms. Cerebral ischemia has been suspected in the altered regulation of protein kinases and phosphatases that leads to hyperphosphorylation of tau and further neurofibrillary pathology, a key hallmark of AD and related neurodegenerative diseases. However, the deregulation of these enzymes and their relationship with ischemia and AD remain unclear. Previously, we reported a mechanism by which the lysosomal enzyme asparagine endopeptidase (AEP) is associated with brain acidosis and AD. In this study, we subjected mice to middle cerebral artery occlusion and found that compared with wild type mice, the ischemia-induced brain injury and motor deficit in AEP-knockout mice are reduced, probably because ischemia activates AEP. AEP cleaves inhibitor 2 of protein phosphatase 2A (I2PP2A), which translocates from the neuronal nucleus to the cytoplasm and produces hyperphosphorylation of tau through inhibition of PP2A. These findings suggest a possible mechanism of tau pathology associated with ischemia.

%B J Alzheimers Dis %V 63 %P 821-833 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689717?dopt=Abstract %R 10.3233/JAD-170715 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Memantine for the Treatment of Dementia: A Review on its Current and Future Applications. %A Folch, Jaume %A Busquets, Oriol %A Ettcheto, Miren %A Sánchez-López, Elena %A Castro-Torres, Ruben Dario %A Verdaguer, Ester %A Garcia, Maria Luisa %A Olloquequi, Jordi %A Casadesus, Gemma %A Beas-Zarate, Carlos %A Pelegri, Carme %A Vilaplana, Jordi %A Auladell, Carme %A Camins, Antoni %X

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered.

%B J Alzheimers Dis %V 62 %P 1223-1240 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254093?dopt=Abstract %R 10.3233/JAD-170672 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Memory Binding Test Predicts Incident Dementia: Results from the Einstein Aging Study. %A Mowrey, Wenzhu B %A Lipton, Richard B %A Katz, Mindy J %A Ramratan, Wendy S %A Loewenstein, David A %A Zimmerman, Molly E %A Buschke, Herman %X

BACKGROUND: The Memory Binding Test (MBT) demonstrated good cross-sectional discriminative validity and predicted incident aMCI.

OBJECTIVE: To assess whether the MBT predicts incident dementia better than a conventional list learning test in a longitudinal community-based study.

METHODS: As a sub-study in the Einstein Aging Study, 309 participants age≥70 initially free of dementia were administered the MBT and followed annually for incident dementia for up to 13 years. Based on previous work, poor memory binding was defined using an optimal empirical cut-score of≤17 on the binding measure of the MBT, Total Items in the Paired condition (TIP). Cox proportional hazards models were used to assess predictive validity adjusting for covariates. We compared the predictive validity of MBT TIP to that of the free and cued selective reminding test free recall score (FCSRT-FR; cut-score:≤24) and the single list recall measure of the MBT, Cued Recalled from List 1 (CR-L1; cut-score:≤12).

RESULTS: Thirty-five of 309 participants developed incident dementia. When assessing each test alone, the hazard ratio (HR) for dementia was significant for MBT TIP (HR = 8.58, 95% CI: (3.58, 20.58), p < 0.0001), FCSRT-FR (HR = 4.19, 95% CI: (1.94, 9.04), p = 0.0003) and MBT CR-L1 (HR = 2.91, 95% CI: (1.37, 6.18), p = 0.006). MBT TIP remained a significant predictor of dementia (p = 0.0002) when adjusting for FCSRT-FR or CR-L1.

CONCLUSIONS: Older adults with poor memory binding as measured by the MBT TIP were at increased risk for incident dementia. This measure outperforms conventional episodic memory measures of free and cued recall, supporting the memory binding hypothesis.

%B J Alzheimers Dis %V 62 %P 293-304 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439336?dopt=Abstract %R 10.3233/JAD-170714 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Meta-Analysis of Personality Traits in Alzheimer's Disease: A Comparison with Healthy Subjects. %A D'Iorio, Alfonsina %A Garramone, Federica %A Piscopo, Fausta %A Baiano, Chiara %A Raimo, Simona %A Santangelo, Gabriella %K Alzheimer Disease %K Case-Control Studies %K Humans %K Personality %K Personality Inventory %X

BACKGROUND: The role of specific personality traits as factor risks of Alzheimer's disease (AD) has been consistently found, whereas personality traits specifically related to AD (after the diagnosis) have not been outlined yet.

OBJECTIVE: A meta-analysis of published studies was performed to determine whether AD patients have a distinctive personality trait profile compared to healthy subjects (HC), similar to or different from a premorbid personality profile consistently reported in previous studies.

METHODS: A systematic literature search was performed using PsycInfo (PROQUEST), PubMed, and Scopus. The meta-analysis pooled results from primary studies using Hedges' g unbiased approach.

RESULTS: The meta-analysis included 10 primary studies and revealed that, when the personality was evaluated by informant-rated measures, AD patients had significantly higher levels of Neuroticism, lower levels of Openness, Agreeableness, Conscientiousness, and Extraversion than HCs. When the personality was evaluated by self-rated measures, the results obtained from informants were confirmed for Neuroticism, Openness, and Extraversion but not for Agreeableness and Conscientiousness where AD patients and HCs achieved similar scores.

CONCLUSIONS: The meta-analysis revealed that high Neuroticism and low Openness and Extraversion are distinctive personality traits significantly associated with a diagnosis of AD when evaluated both self-rated and informant-rated measures. This personality trait profile is similar to premorbid one, which contributes to development of AD over time. Therefore, our findings indirectly support the idea of specific premorbid personality traits as harbingers of AD.

%B J Alzheimers Dis %V 62 %P 773-787 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480186?dopt=Abstract %R 10.3233/JAD-170901 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Metabolic Syndrome and Amyloid Accumulation in the Aging Brain. %A Gomez, Gabriela %A Beason-Held, Lori L %A Bilgel, Murat %A An, Yang %A Wong, Dean %A Studenski, Stephanie %A Ferrucci, Luigi %A Resnick, Susan M %X

BACKGROUND: Recent studies show links between metabolic syndrome and Alzheimer's disease (AD) neuropathology. Understanding the link between vascular-related health conditions and dementia will help target at risk populations and inform clinical strategies for early detection and prevention of AD.

OBJECTIVE: To determine whether metabolic syndrome is associated with global cerebral amyloid-β (Aβ) positivity and longitudinal Aβ accumulation.

METHODS: Prospective study of 165 participants who underwent (11)C-Pittsburgh compound B (PiB) PET neuroimaging to measure Aβ, from June 2005 to May 2016. Metabolic syndrome was defined using the revised Third Adults Treatment Panel of the National Cholesterol Education Program criteria. Participants were classified as PiB+/- . Linear mixed effects models assessed the relationships between baseline metabolic syndrome and PiB status and regional Aβ change over time.

RESULTS: A total of 165 cognitively normal participants of the Baltimore Longitudinal Study of Aging (BLSA) Neuroimaging substudy, aged 55-92 years (mean baseline age = 76.4 years, 85 participants were male), received an average of 2.5 PET-PiB scans over an average interval of 2.6 (3.08 SD) years between first and last visits. Metabolic syndrome was not associated with baseline PiB positivity or concurrent regional Aβ. Metabolic syndrome was associated with increased rates of Aβ accumulation in superior parietal and precuneus regions over time in the PiB+ group. Elevated fasting glucose and blood pressure showed individual associations with accelerated Aβ accumulation.

CONCLUSION: Metabolic syndrome was associated with accelerated Aβ accumulation in PiB+ individuals and may be an important factor in the progression of AD pathology.

%B J Alzheimers Dis %V 65 %P 629-639 %8 2018 Jul 30 %G eng %N 2 %& 629 %R 10.3233/JAD-180297 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Metals and Alzheimer's Disease: How Far Have We Come in the Clinic? %A Adlard, Paul A %A Bush, Ashley I %X

It is estimated that by the year 2050 there will be more than 1.5 billion people globally over the age of 65 years. Aging is associated with changes to a number of different cellular processes which are driven by a variety of factors that contribute to the characteristic decline in function that is seen across multiple physiological domains/tissues in the elderly (including the brain). Importantly, aging is also the primary risk factor for the development of neurodegenerative disorders such as Alzheimer's disease. As such, there is an urgent need to provide a greater understanding of both the pathogenesis and treatment of these devastating neurodegenerative disorders. One of the key cellular processes that becomes dysregulated with age and participates both directly and indirectly in age-related dysfunction, is metal homeostasis and the neurochemistry of metalloproteins, the basic science of which has been extensively reviewed in the past. In this review, we will focus on the human clinical intervention trials that have been conducted over approximately the last four decades that have attempted to establish the efficacy of targeting metal ions in the treatment of AD.

%B J Alzheimers Dis %V 62 %P 1369-1379 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562528?dopt=Abstract %R 10.3233/JAD-170662 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis. %A Campbell, Jared M %A Stephenson, Matthew D %A de Courten, Barbora %A Chapman, Ian %A Bellman, Susan M %A Aromataris, Edoardo %X

BACKGROUND: Metformin, a first line antihyperglycemic medication, is an AMPK activator and has been hypothesized to act as a geroprotective agent. Studies on its association with various classifications of age-related cognitive decline have shown mixed results with positive and negative findings.

OBJECTIVE: To synthesize the best available evidence on the association of metformin-use with risk, progression, and severity of dementia.

METHOD: Eligible research investigated the effect of metformin on dementia, Alzheimer's disease, or any measure of cognitive impairment compared to any control group who were not receiving metformin. The initial search resulted in 862 citations from which 14 studies (seven cohort, four cross-sectional, two RCTs, and one case control) were included.

RESULTS: Meta-analysis of three studies showed that cognitive impairment was significantly less prevalent in diabetic metformin (Odds ratio = 0.55, 95% CI 0.38 to 0.78), while six studies showed that dementia incidence was also significantly reduced (Hazard ratio = 0.76, 95% CI 0.39 to 0.88). Mini-Mental State Examination scores were not significantly affected by metformin-use, although both RCTs showed that metformin had a neuroprotective effect compared to placebo. Some studies found negative or neutral effects for metformin use by people with diabetes; the potential mechanism of metformin-induced vitamin B12 deficiency is discussed.

CONCLUSIONS: Metformin should continue to be used as a first line therapy for diabetes in patients at risk of developing dementia or Alzheimer's disease. The use of metformin by individuals without diabetes for the prevention of dementia is not supported by the available evidence.

%B J Alzheimers Dis %V 65 %P 1225-1236 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149446?dopt=Abstract %R 10.3233/JAD-180263 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Methylenetetrahydrofolate Reductase Deficiency Deregulates Regional Brain Amyloid-β Protein Precursor Expression and Phosphorylation Levels. %A Hoffman, Alexander %A Taleski, Goce %A Qian, Helena %A Wasek, Brandi %A Arning, Erland %A Bottiglieri, Teodoro %A Sontag, Jean-Marie %A Sontag, Estelle %X

Deregulation of the amyloid-β protein precursor (AβPP) plays a critical role in the neurodegenerative cascade of Alzheimer's disease (AD). Significantly, common functional polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene are a risk factor for the development of late-onset AD. Reduced MTHFR activity is associated with alterations in folate and homocysteine metabolism. Here, we first show that in young MTHFR knockout mice, mild and severe MTHFR deficiency markedly increase cortical and hippocampal AβPP phosphorylation at the regulatory Thr668 site. However, the hippocampus is especially vulnerable to the effects of aging and mild MTHFR deficiency. Notably, the effects of severe MTHFR deficiency in young mice are recapitulated by prolonged dietary folate deficiency in old mice, which leads to regional brain accumulation of cystathionine due to impaired methylation of homocysteine. The incremental AβPP phosphorylation at Thr668 mediated by severe genetic-or diet-induced impairment of the folate cycle correlates with enhanced accumulation of demethylated protein phosphatase 2A (PP2A), and activation of glycogen synthase kinase-3β (GSK-3β). Lastly, we show that severe disturbances in folate metabolism can also affect AβPP expression levels in a brain region specific manner. Together our findings identify a novel link between genetic MTHFR deficiency, activation of GSK-3β, demethylation of PP2A, and enhanced phosphorylation of AβPP at Thr668, which is known to critically influence neuronal AβPP function and pathological amyloidogenic processing. Deregulation of AβPP provides a novel mechanism by which common human MTHFR polymorphisms may interact with dietary folate deficiency to alter neuronal homeostasis and increase the risk for sporadic AD.

%B J Alzheimers Dis %V 64 %P 223-237 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865064?dopt=Abstract %R 10.3233/JAD-180032 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Midlife Physical Activity, Psychological Distress, and Dementia Risk: The HUNT Study. %A Zotcheva, Ekaterina %A Bergh, Sverre %A Selbæk, Geir %A Krokstad, Steinar %A Håberg, Asta Kristine %A Strand, Bjørn Heine %A Ernstsen, Linda %X

BACKGROUND: Physical activity (PA) is associated with a decreased dementia risk, whereas psychological distress (distress) is linked to an increased dementia risk.

OBJECTIVE: We investigated independent and joint associations of midlife moderate-to-vigorous PA (MVPA) and distress with incident dementia.

METHODS: Our study comprised 28,916 participants aged 30-60 years from the Nord-Trøndelag Health Study (HUNT1, 1984-1986). Data on MVPA and distress from HUNT1 was linked to the Health and Memory Study in Nord-Trøndelag for dementia case identification. Participants were followed from 1995 until 2011. We used adjusted Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI).

RESULTS: In fully adjusted analyses, MVPA was associated with a reduced dementia risk (HR 0.81, 95% CI 0.62-1.06), compared to no MVPA. Distress was associated with an increased dementia risk (HR 1.30, 95% CI 0.99-1.70). Compared to distressed participants not taking part in MVPA, non-distressed no-MVPA participants had a reduced dementia risk (HR 0.72, 95% CI 0.54-0.96). The same applied to distressed MVPA participants (HR 0.50, 95% CI 0.22-1.14), and non-distressed MVPA participants (HR 0.63, 95% CI 0.44-0.90). Our results indicated an additive interaction between MVPA and distress on dementia risk.

CONCLUSION: Our results suggest that midlife MVPA reduces risk of incident dementia among both distressed and non-distressed individuals.

%B J Alzheimers Dis %V 66 %P 825-833 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320592?dopt=Abstract %R 10.3233/JAD-180768 %0 Journal Article %J J Alzheimers Dis %D 2018 %T miRNA 933 Expression by Endothelial Cells is Increased by 27-Hydroxycholesterol and is More Prevalent in Plasma from Dementia Patients. %A Dias, Irundika H K %A Brown, Caroline L %A Shabir, Kiran %A Polidori, M Cristina %A Griffiths, Helen R %X

Alzheimer's disease (AD) etiology is complex; gene and environmental risk factors may interact to predispose to disease. From single nucleotide polymorphism analyses and genome-wide association studies, a number of candidate risk genes for the onset of AD have been identified and cluster around lipid metabolism and inflammation. We hypothesized that endothelial cells which line the blood-brain barrier are likely to be critical mediators of systemic metabolism within the brain. Therefore, we have studied the effect of 27 hydroxycholesterol (27-OHC) on microvascular endothelial cell (HMVEC) redox state, inflammatory cytokine secretion, and microRNA (miR) expression. Using a transwell method, we have studied directional secretion profiles for the proinflammatory cytokines TNFα and IL-6 and confirmed that 27-OHC induces discrete and directional inflammatory molecular signatures from HMVEC. The lipids caused depletion of cellular glutathione and cytokine secretion is HMVEC-redox state-dependent. Discovery miR expression change in HMVEC with and without 27-OHC treatment was undertaken. We selected three genes for further analysis by qPCR; miR-144 and 146 expression, which are anti-inflammatory and redox regulating modulators, were not affected significantly by 27-OHC. However, increased expression of a putative neurotrophic regulatory factor miR933 in HMVEC with 27-OHC was confirmed by qPCR. In plasma from patients with dementia, all three miR were found at significantly elevated levels compared to healthy older adults. These data highlight that 27-OHC has an important regulatory effect on endothelial microvascular cells to increase expression of a miR (-933) and secretion of inflammatory cytokines that are elevated in plasma from dementia patients.

%B J Alzheimers Dis %V 64 %P 1009-1017 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966198?dopt=Abstract %R 10.3233/JAD-180201 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Mitochondrial Translocase of the Outer Membrane Alterations May Underlie Dysfunctional Oxidative Phosphorylation in Alzheimer's Disease. %A Chai, Yuek Ling %A Xing, Huayang %A Chong, Joyce R %A Francis, Paul T %A Ballard, Clive G %A Chen, Christopher P %A Lai, Mitchell K P %K Aged, 80 and over %K Alzheimer Disease %K Autopsy %K Brain %K Female %K Humans %K Male %K Mitochondria %K Mitochondrial Membrane Transport Proteins %K Multivariate Analysis %K Oxidative Phosphorylation %X

BACKGROUND: The translocase of the outer membrane (TOM) is a vital mitochondrial transport system facilitating the importation of nuclear encoded proteins into the organelle. While mitochondrial dysfunction, including perturbation of oxidative phosphorylation (OXPHOS) complex, is evident in Alzheimer's disease (AD), it remains unclear whether the observed OXPHOS deficits may be associated with TOM alterations.

OBJECTIVES: To correlate TOM subunits with OXPHOS complex proteins in AD.

METHODS: Postmortem neocortex (BA40) from AD and age-matched controls were processed to obtain mitochondrial enriched homogenates for the measurement of Tom20, Tom22, Tom40, and Tom70 as well as components of OXPHOS complex I-V by immunoblotting.

RESULTS: Tom20 and Tom70 immunoreactivities were significantly reduced in AD, as were components of OXPHOS complex I and III. Both Tom20 and Tom70 positively correlated with complex III and V, while Tom20 also correlated withcomplex IV.

CONCLUSION: Reductions in certain TOM subunits and their correlations with specific OXPHOS complex proteins suggest that an impaired mitochondrial transportation system may contribute to previously observed oxidative phosphorylation deficits in AD. Follow-up studies are needed to corroborate the present correlative study.

%B J Alzheimers Dis %V 61 %P 793-801 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254089?dopt=Abstract %R 10.3233/JAD-170613 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Montreal Cognitive Assessment: Normative Data from a German-Speaking Cohort and Comparison with International Normative Samples. %A Thomann, Alessandra E %A Goettel, Nicolai %A Monsch, Raphael J %A Berres, Manfred %A Jahn, Thomas %A Steiner, Luzius A %A Monsch, Andreas U %X

BACKGROUND: The Montreal Cognitive Assessment (MoCA) is used to evaluate multiple cognitive domains in elderly individuals. However, it is influenced by demographic characteristics that have yet to be adequately considered.

OBJECTIVE: The aim of our study was to investigate the effects of age, education, and sex on the MoCA total score and to provide demographically adjusted normative values for a German-speaking population.

METHODS: Subjects were recruited from a registry of healthy volunteers. Cognitive health was defined using the Mini-Mental State Examination (score ≥27/30 points) and the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (total score ≥85.9 points). Participants were assessed with the German version of the MoCA. Normative values were developed based on regression analysis. Covariates were chosen using the Predicted Residual Sums of Squares approach.

RESULTS: The final sample consisted of 283 participants (155 women, 128 men; mean (SD) age = 73.8 (5.2) years; education = 13.6 (2.9) years). Thirty-one percent of participants scored below the original cut-off (<26/30 points). The MoCA total score was best predicted by a regression model with age, education, and sex as covariates. Older age, lower education, and male sex were associated with a lower MoCA total score (p < 0.001).

CONCLUSION: We developed a formula to provide demographically adjusted standard scores for the MoCA in a German-speaking population. A comparison with other MoCA normative studies revealed considerable differences with respect to selection of volunteers and methods used to establish normative data.

%B J Alzheimers Dis %V 64 %P 643-655 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29945351?dopt=Abstract %R 10.3233/JAD-180080 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Moringa Oleifera Alleviates Homocysteine-Induced Alzheimer's Disease-Like Pathology and Cognitive Impairments. %A Mahaman, Yacoubou Abdoul Razak %A Huang, Fang %A Wu, Mengjuan %A Wang, Yuman %A Wei, Zhen %A Bao, Jian %A Salissou, Maibouge Tanko Mahamane %A Ke, Dan %A Wang, Qun %A Liu, Rong %A Wang, Jian-Zhi %A Zhang, Bin %A Chen, Dan %A Wang, Xiaochuan %X

Alzheimer's disease (AD) is multifactorial with unclear etiopathology. Due to the complexity of AD, many attempted single therapy treatments, like Aβ immunization, have generally failed. Therefore, there is a need for drugs with multiple benefits. Naturally occurring phytochemicals with neuroprotective, anti-amyloidogenic, antioxidative, and anti-inflammatory properties could be a possible way out. In this study, the effect of Moringa oleifera (MO), a naturally occurring plant with high antioxidative, anti-inflammatory, and neuroprotective effects, was evaluated on hyperhomocysteinemia (HHcy) induced AD-like pathology in rats. Homocysteine (Hcy) injection for 14 days was used to induce AD-like pathology. Simultaneous MO extract gavage followed the injection as a preventive treatment or, after injection completion, MO gavage was performed for another 14 days as a curative treatment. MO was found to not only prevent but also rescue the oxidative stress and cognitive impairments induced by Hcy treatment. Moreover, MO recovered the decreased synaptic proteins PSD93, PSD95, Synapsin 1 and Synaptophysin, and improved neurodegeneration. Interestingly, MO decreased the Hyc-induced tau hyperphosphorylation at different sites including S-199, T-231, S-396, and S-404, and at the same time decreased Aβ production through downregulation of BACE1. These effects in HHcy rats were accompanied by a decrease in calpain activity under MO treatment, supporting that calpain activation might be involved in AD pathogenesis in HHcy rats. Taken together, our data, for the first time, provided evidence that MO alleviates tau hyperphosphorylation and Aβ pathology in a HHcy AD rat model. This and previous other studies support MO as a good candidate for, and could provide new insights into, the treatment of AD and other tauopathies.

%B J Alzheimers Dis %V 63 %P 1141-1159 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710724?dopt=Abstract %R 10.3233/JAD-180091 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Multicenter Resting State Functional Connectivity in Prodromal and Dementia Stages of Alzheimer's Disease. %A Teipel, Stefan J %A Metzger, Coraline D %A Brosseron, Frederic %A Buerger, Katharina %A Brueggen, Katharina %A Catak, Cihan %A Diesing, Dominik %A Dobisch, Laura %A Fliebach, Klaus %A Franke, Christiana %A Heneka, Michael T %A Kilimann, Ingo %A Kofler, Barbara %A Menne, Felix %A Peters, Oliver %A Polcher, Alexandra %A Priller, Josef %A Schneider, Anja %A Spottke, Annika %A Spruth, Eike J %A Thelen, Manuela %A Thyrian, René J %A Wagner, Michael %A Düzel, Emrah %A Jessen, Frank %A Dyrba, Martin %X

BACKGROUND: Alterations of intrinsic networks from resting state fMRI (rs-fMRI) have been suggested as functional biomarkers of Alzheimer's disease (AD).

OBJECTIVE: To determine the diagnostic accuracy of multicenter rs-fMRI for prodromal and preclinical stages of AD.

METHODS: We determined rs-fMRI functional connectivity based on Pearson's correlation coefficients and amplitude of low-frequency fluctuation in people with subjective cognitive decline, people with mild cognitive impairment, and people with AD dementia compared with healthy controls. We used data of 247 participants of the prospective DELCODE study, a longitudinal multicenter observational study, imposing a unified fMRI acquisition protocol across sites. We determined cross-validated discrimination accuracy based on penalized logistic regression to account for multicollinearity of predictors.

RESULTS: Resting state functional connectivity reached significant cross-validated group discrimination only for the comparison of AD dementia cases with healthy controls, but not for the other diagnostic groups. AD dementia cases showed alterations in a large range of intrinsic resting state networks, including the default mode and salience networks, but also executive and language networks. When groups were stratified according to their CSF amyloid status that was available in a subset of cases, diagnostic accuracy was increased for amyloid positive mild cognitive impairment cases compared with amyloid negative controls, but still inferior to the accuracy of hippocampus volume.

CONCLUSION: Even when following a strictly harmonized data acquisition protocol and rigorous scan quality control, widely used connectivity measures of multicenter rs-fMRI do not reach levels of diagnostic accuracy sufficient for a useful biomarker in prodromal stages of AD.

%B J Alzheimers Dis %V 64 %P 801-813 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914027?dopt=Abstract %R 10.3233/JAD-180106 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Multi-Faceted Role of Melatonin in Neuroprotection and Amelioration of Tau Aggregates in Alzheimer's Disease. %A Balmik, Abhishek Ankur %A Chinnathambi, Subashchandrabose %X

Alzheimer's disease (AD) is one of the major age related neurodegenerative diseases whose pathology arises due to the presence of two distinct protein aggregates, viz., amyloid-β plaques in extracellular matrix and tau neurofibrillary tangles in neurons. Multiple factors play a role in AD pathology, which includes familial mutations, oxidative stress, and post-translational modifications. Melatonin is an endocrine hormone, secreted during darkness, derived from tryptophan, and produced mainly by the pineal gland. It is an amphipathic molecule, which makes it suitable to cross not only blood-brain barrier, but also to enter several other subcellular compartments like mitochondria and endoplasmic reticulum. In this context, the neuroprotective effect of melatonin may be attributed to its role as an antioxidant. Melatonin's pleiotropic function as an antioxidant and neuroprotective agent has been widely studied. However, its direct effect on the aggregation of tau and amyloid-β needs to be explored. Furthermore, an important aspect of its function is its ability to regulate the process of phosphorylation of tau by affecting the function of kinases and phosphatases. In this review, we are focusing on the pleiotropic function of melatonin on the aspect of its neuroprotective function in tau pathology, which includes antioxidant function, regulation of enzymes, including kinases and enzymes involved in free radical scavenging and mitochondrial protection.

%B J Alzheimers Dis %V 62 %P 1481-1493 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562506?dopt=Abstract %R 10.3233/JAD-170900 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Multisensory Stimulation and Individualized Music Sessions on Older Adults with Severe Dementia: Effects on Mood, Behavior, and Biomedical Parameters. %A Maseda, Ana %A Cibeira, Nuria %A Lorenzo-López, Laura %A González-Abraldes, Isabel %A Buján, Ana %A de Labra, Carmen %A Millán-Calenti, José Carlos %X

BACKGROUND: Multisensory stimulation and individualized music have shown to be good in handling the psychological and behavioral symptoms in people with severe dementia.

OBJECTIVE: Explore the effects of two nonpharmacological interventions, multisensory stimulation environment (MSSE) in a Snoezelen room and individualized music sessions, on mood, behavior, and biomedical parameters of institutionalized elderly patients with severe dementia.

METHODS: Randomized trial of 21 patients aged ≥65 years randomly assigned to two groups (MSSE and individualized music). Interventions administered in two-weekly sessions lasted 30 minutes for a period of 12 weeks. Main outcomes were recorded before, during, and at the end of the intervention.

RESULTS: Both groups had immediate positive effects on mood and behavior. Participants were more happy/more content (p < 0.001), talked more spontaneously (p = 0.009), related to people better (p = 0.002), were more attentive to/focused on their environment (p < 0.001), enjoyed themselves (p = 0.003), were less bored/inactive (p = 0.004), and more relaxed/content (p = 0.003). The MSSE group performed a better visual follow-up of the stimuli (p = 0.044), and the music group were more relaxed and happy (p = 0.003). A decrease in heart rate (p = 0.013) and an increase in oxygen saturation (p = 0.011) were observed from before to after interventions in both groups, with no significant differences between them.

CONCLUSIONS: Both interventions seem to be effective at managing mood and behavioral disturbances in the short term and at improving physiological rates, highlighting the efficacy of nonpharmacological treatments in patients with severe dementia.

%B J Alzheimers Dis %V 63 %P 1415-1425 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843244?dopt=Abstract %R 10.3233/JAD-180109 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Nailfold Capillary Morphology in Alzheimer's Disease Dementia. %A Cousins, Clara C %A Alosco, Michael L %A Cousins, Henry C %A Chua, Alicia %A Steinberg, Eric G %A Chapman, Kimberly R %A Bing-Canar, Hanaan %A Tripodis, Yorghos %A Knepper, Paul A %A Stern, Robert A %A Pasquale, Louis R %X

BACKGROUND: Cerebrovascular disease (CVD) is highly comorbid with Alzheimer's disease (AD), yet its role is not entirely understood. Nailfold video capillaroscopy (NVC) is a noninvasive method of live imaging the capillaries near the fingernail's cuticle and may help to describe further vascular contributions to AD.

OBJECTIVE: To examine finger nailfold capillary morphology using NVC in subjects with AD dementia, mild cognitive impairment (MCI), and normal cognition (NC).

METHODS: We evaluated nailfold capillary hemorrhages, avascular zones ≥100 microns, and degree of tortuosity in 28 NC, 15 MCI, and 18 AD dementia subjects using NVC. Tortuosity was measured with a semi-quantitative rating scale. To assess the relation between nailfold capillary morphological features and diagnostic grouping, univariate and multivariable logistic regression models were fit to the data.

RESULTS: 56% of subjects with AD dementia compared to 14% with NC and 13% with MCI displayed moderate to severe tortuosity. Greater severity of tortuosity was associated with 10.6-fold (95% confidence interval [CI]: 2.4, 46.2; p = 0.0018) and 7.4-fold (95% CI: 1.3, 41.3; p = 0.023) increased odds of AD dementia relative to NC and MCI, respectively, after adjusting for multiple covariates.

CONCLUSION: Greater nailfold capillary tortuosity was found in participants with AD dementia compared to those with MCI or NC. These data provide preliminary evidence of a systemic microvasculopathy in AD that may be noninvasively and inexpensively evaluated through NVC.

%B J Alzheimers Dis %V 66 %P 601-611 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320588?dopt=Abstract %R 10.3233/JAD-180658 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Natural Benzofuran from the Patagonic Aleurodiscus vitellinus Fungus has Potent Neuroprotective Properties on a Cellular Model of Amyloid-β Peptide Toxicity. %A González-Ramírez, Mariela %A Gavilán, Javiera %A Silva-Grecchi, Tiare %A Cajas-Madriaga, Daniel %A Triviño, Sergio %A Becerra, José %A Saez-Orellana, Francisco %A Pérez, Claudia %A Fuentealba, Jorge %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Basidiomycota %K Benzofurans %K Cell Survival %K Hippocampus %K Neurons %K Neuroprotective Agents %K PC12 Cells %K Plaque, Amyloid %K Rats %X

Alzheimer's disease (AD) is characterized by amyloid plaques that form due to an increase in amyloid-β peptide (Aβ) aggregation. One strategy in the search of new treatments for AD focuses on compounds that decrease Aβ accumulation. Compounds containing a benzofuran ring have been described to play an important role in decreasing Aβ-induced toxicity; however, only synthetic benzofurans have been tested thus far. The aim of the present study was to examine the in vitro neuroprotective properties of fomannoxin (Fx), a natural benzofuran isolated from cultures of the Andean-Patagonian fungi Aleurodiscus vitellinus, and evaluate its effect on Aβ peptide. We tested the effect of Fx at a wide concentration range (10-11-10-4 M) in PC-12 cells, and found the compound did not alter cellular viability. Fx also showed a concentration-dependent effect on the Aβ-induced toxicity in PC12 cells, showing viability above 100% at 10-6 M. We then measured the effect of Fx (10-7-10-5 M) on the frequency of cytosolic Ca2+ transients in rat hippocampal neurons at both acute and chronic (24 h) times. Acute incubation with Fx increased the frequency of cytosolic Ca2+ transients to values around 200%, whereas chronic incubation with Fx increased the frequency of Ca2+ transients. Finally, the Aβ-induced decrease in intracellular Ca2+ transients was prevented when Fx (10-6 M) was co-incubated with Aβ (5×10-6 M). The results suggest a potent neuroprotective effect of this naturally occurring benzofuran against Aβ peptide toxicity that could be mediated by an interference with it binding to plasma membrane, and lead Fx as new chemical entity to develop pharmacological tools against Aβ peptide neurotoxicity.

%B J Alzheimers Dis %V 61 %P 1463-1475 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376877?dopt=Abstract %R 10.3233/JAD-170958 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Naturalistic Driving Study Investigating Self-Regulation Behavior in Early Alzheimer's Disease: A Pilot Study. %A Paire-Ficout, Laurence %A Lafont, Sylviane %A Conte, Fanny %A Coquillat, Amandine %A Fabrigoule, Colette %A Ankri, Joël %A Blanc, Frédéric %A Gabel, Cécilia %A Novella, Jean-Luc %A Morrone, Isabella %A Mahmoudi, Rachid %X

BACKGROUND: Because cognitive processes decline in the earliest stages of Alzheimer's disease (AD), the driving abilities are often affected. The naturalistic driving approach is relevant to study the driving habits and behaviors in normal or critical situations in a familiar environment of participants.

OBJECTIVE: This pilot study analyzed in-car video recordings of naturalistic driving in patients with early-stage AD and in healthy controls, with a special focus on tactical self-regulation behavior.

METHODS: Twenty patients with early-stage AD (Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria), and 21 healthy older adults were included in the study. Data collection equipment was installed in their personal vehicles. Two expert psychologists assessed driving performance using a specially designed Naturalistic Driving Assessment Scale (NaDAS), paying particular attention to tactical self-regulation behavior, and they recorded all critical safety events.

RESULTS: Poorer driving performance was observed among AD drivers: their tactical self-regulation behavior was of lower quality. AD patients had also twice as many critical events as healthy drivers and three times more "unaware" critical events.

CONCLUSION: This pilot study used a naturalistic approach to accurately show that AD drivers have poorer tactical self-regulation behavior than healthy older drivers. Future deployment of assistance systems in vehicles should specifically target tactical self-regulation components.

%B J Alzheimers Dis %V 63 %P 1499-1508 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782312?dopt=Abstract %R 10.3233/JAD-171031 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuroanatomical Comparison of the "Word" and "Picture" Versions of the Free and Cued Selective Reminding Test in Alzheimer's Disease. %A Slachevsky, Andrea %A Barraza, Paulo %A Hornberger, Michael %A Muñoz-Neira, Carlos %A Flanagan, Emma %A Henriquez, Fernando %A Bravo, Eduardo %A Farías, Mauricio %A Delgado, Carolina %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Cues %K Female %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Male %K Memory, Episodic %K Mental Recall %K Middle Aged %K Neuropsychological Tests %K Photic Stimulation %X

Episodic memory tests with cued recall, such as the Free and Cued Selective Reminding Test (FCSRT), allow for the delineation of hippocampal and prefrontal atrophy contributions to memory performance in Alzheimer's disease (AD). Both Word and Picture versions of the test exist but show different profiles, with the Picture version usually scoring higher across different cohorts. One possible explanation for this divergent performance between the different modality versions of the test might be that they rely on different sets of neural correlates. The current study explores this by contrasting the neural correlates of the Word and Picture versions of the FCSRT with voxel-based morphometry (VBM) in AD and healthy subjects. We predicted that the Picture version would be associated with different cortical regions than the Word version, which might be more hippocampal-centric. When comparing 35 AD patients and 34 controls, AD patients exhibited impairments on both versions of the FCSRT and both groups performed higher in the Picture version. A region of interest analysis based on prior work revealed significant correlations between free recall of either version with atrophy of the temporal pole and hippocampal regions. Thus, contrary to expectations, performance on both the Word and the Picture version of the FCSRT is associated with largely overlapping networks. Free recall is associated with hippocampal volume and might be properly considered as an indicator of hippocampal structural integrity.

%B J Alzheimers Dis %V 61 %P 589-600 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226861?dopt=Abstract %R 10.3233/JAD-160973 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuroepigenetics and Alzheimer's Disease: An Update. %A Zusso, Morena %A Barbierato, Massimo %A Facci, Laura %A Skaper, Stephen D %A Giusti, Pietro %X

Epigenetics is the study of changes in gene expression which may be triggered by both genetic and environmental factors, and independent from changes to the underlying DNA sequence-a change in phenotype without a change in genotype-which in turn affects how cells read genes. Epigenetic changes represent a regular and natural occurrence but can be influenced also by factors such as age, environment, and disease state. Epigenetic modifications can manifest themselves not only as the manner in which cells terminally differentiate, but can have also deleterious effects, resulting in diseases such as cancer. At least three systems including DNA methylation, histone modification, and non-coding RNA (ncRNA)-associated gene silencing are thought to initiate and sustain epigenetic change. For example, in Alzheimer's disease (AD), both genetic and non-genetic factors contribute to disease etiopathology. While over 250 gene mutations have been related to familial AD, less than 5% of AD cases are explained by known disease genes. More than likely, non-genetic factors, probably triggered by environmental factors, are causative factors of late-onset AD. AD is associated with dysregulation of DNA methylation, histone modifications, and ncRNAs. Among the classes of ncRNA, microRNAs (miRNAs) have a well-established regulatory relevance. MicroRNAs are highly expressed in CNS neurons, where they play a major role in neuron differentiation, synaptogenesis, and plasticity. MicroRNAs impact higher cognitive functions, as their functional impairment is involved in the etiology of neurological diseases, including AD. Alterations in the miRNA network contribute to AD disease processes, e.g., in the regulation of amyloid peptides, tau, lipid metabolism, and neuroinflammation. MicroRNAs, both as biomarkers for AD and therapeutic targets, are in the early stages of exploration. In addition, emerging data suggest that altered transcription of long ncRNAs, endogenous, ncRNAs longer than 200 nucleotides, may be involved in an elevated risk for AD.

%B J Alzheimers Dis %V 64 %P 671-688 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29991138?dopt=Abstract %R 10.3233/JAD-180259 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neurotoxic Effects of Aβ6-42 Peptides Mimicking Putative Products Formed by the Angiotensin Converting Enzyme. %A Medvedev, Alexei E %A Radko, Sergey P %A Yurinskaya, Marina M %A Vinokurov, Maxim G %A Buneeva, Olga A %A Kopylov, Arthur T %A Kozin, Sergey A %A Mitkevich, Vladimir A %A Makarov, Alexander A %X

Angiotensin converting enzyme (ACE) is involved in proteolytic processing of the amyloid-β(Aβ) peptide implicated in the development of Alzheimer's disease (AD) and known products of ACE-based processing of Aβ42 are characterized by reduced aggregability and cytotoxicity. Recently it has been demonstrated that ACE can act as an arginine specific endopeptidase cleaving the N-terminal pentapeptide (Aβ1-5) from synthetic Aβ peptide analogues. In the context of proteolytic processing of full length Aβ42, this suggests possible formation of Aβ6-42 species. The aim of this study was to test a hypothesis that some N-terminally truncated Aβ peptide(s) could retain aggregability and neurotoxic properties typical for Aβ42. We have investigated aggregability of two amyloid-β peptides, Aβ6-42 and isoD7-Aβ6-42, mimicking potential proteolytic products of Aβ42 and isoD7-Aβ42, and evaluated their effects on the repertoire of brain Aβ binding proteins, and cytotoxicity towards neuroblastoma SH-SY5Y cells. Aggregability of isoD7-Aβ6-42 and Aβ6-42 was higher than that of full-length peptides Aβ42 and isoD7-Aβ42, while the repertoire of mouse brain Aβ binding proteins dramatically decreased. Aβ6-42 and isoD7-Aβ6-42 exhibited higher neurotoxicity towards SH-SY5Y cells than Aβ42 and isoD7-Aβ42, respectively. They effectively stimulated production of ROS and NO, and also TNFα secretion by cells. Thus, our results suggest that ACE-dependent processing of full-length Aβs could result in formation of more pathogenic peptides.

%B J Alzheimers Dis %V 66 %P 263-270 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282362?dopt=Abstract %R 10.3233/JAD-180500 %0 Journal Article %J J Alzheimers Dis %D 2018 %T New Beginnings in Alzheimer's Disease: The Most Prevalent Tauopathy. %A Hernández, Félix %A Llorens-Martín, María %A Bolós, Marta %A Pérez, Mar %A Cuadros, Raquel %A Pallas-Bazarra, Noemí %A Zabala, Juan C %A Avila, Jesús %X

Alzheimer's disease (AD) is characterized by the presence of two aberrant structures: namely senile plaques, composed of amyloid-β peptide (Aβ), and neurofibrillary tangles, composed of tau protein. In this regard, Aβ and tau protein have been widely studied in research efforts aiming to find a therapy for AD. Aβ and tau pathologies do not always overlap. The precursor of Aβ is expressed in peripheral tissues and in the central nervous system (CNS), whereas tau is mainly a neuronal protein. Since AD is a disease of the CNS, it has been proposed that Aβ may initiate the disease process, with tau being the executor. In this review, we will focus on future studies of tau pathology, although we will comment on new beginnings for AD, as other molecules other than Aβ and tau may be involved in the onset of dementia.

%B J Alzheimers Dis %V 64 %P S529-S534 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562521?dopt=Abstract %R 10.3233/JAD-179916 %0 Journal Article %J J Alzheimers Dis %D 2018 %T New Insights into the Spontaneous Human Alzheimer's Disease-Like Model Octodon degus: Unraveling Amyloid-β Peptide Aggregation and Age-Related Amyloid Pathology. %A Cisternas, Pedro %A Zolezzi, Juan M %A Lindsay, Carolina %A Rivera, Daniela S %A Martinez, Alexis %A Bozinovic, Francisco %A Inestrosa, Nibaldo C %X

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Despite advances in our understanding of the molecular milieu driving AD pathophysiology, no effective therapy is currently available. Moreover, various clinical trials have continued to fail, suggesting that our approach to AD must be revised. Accordingly, the development and validation of new models are highly desirable. Over the last decade, we have been working with Octodon degus (degu), a Chilean rodent, which spontaneously develops AD-like neuropathology, including increased amyloid-β (Aβ) aggregates, tau hyperphosphorylation, and postsynaptic dysfunction. However, for proper validation of degu as an AD model, the aggregation properties of its Aβ peptide must be analyzed. Thus, in this study, we examined the capacity of the degu Aβ peptide to aggregate in vitro. Then, we analyzed the age-dependent variation in soluble Aβ levels in the hippocampus and cortex of third- to fifth-generation captive-born degu. We also assessed the appearance and spatial distribution of amyloid plaques in O. degus and compared them with the plaques in two AD transgenic mouse models. In agreement with our previous studies, degu Aβ was able to aggregate, forming fibrillar species in vitro. Furthermore, amyloid plaques appeared in the anterior brain structures of O. degus at approximately 32 months of age and in the whole brain at 56 months, along with concomitant increases in Aβ levels and the Aβ42/Aβ40 ratio, indicating that O. degus spontaneously develops AD-like pathology earlier than other spontaneous models. Based on these results, we can confirm that O. degus constitutes a valuable model to improve AD research.

%B J Alzheimers Dis %V 66 %P 1145-1163 %8 2018 %G eng %N 3 %R 10.3233/JAD-180729 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Non-Genetic Risk Factors for Degenerative and Vascular Young Onset Dementia: Results from the INSPIRED and KGOW Studies. %A Cations, Monica %A Draper, Brian %A Low, Lee-Fay %A Radford, Kylie %A Trollor, Julian %A Brodaty, Henry %A Sachdev, Perminder %A Gonski, Peter %A Broe, Gerald Anthony %A Withall, Adrienne %X

BACKGROUND: Several brain reserve, vascular risk, and other modifiable factors have been associated with late-onset dementia, but their association with young onset dementia (YOD) has not been adequately explored.

OBJECTIVE: To examine the association of cognitive reserve enhancing factors, cardiovascular risk factors (including smoking), depression, alcohol use, and traumatic brain injury (TBI) with non-autosomal dominant degenerative and/or vascular YOD.

METHODS: Data for this matched case-control study were taken from two larger studies conducted in NSW, Australia. One comprised all people with YOD within a geographical region, while the other exclusively included Aboriginal and Torres Strait Islander participants. Dementia diagnosis was confirmed by clinical consensus, and risk exposure was retrospectively self- and/or informant-reported.

RESULTS: Participants were 96 people with YOD (58.4% with probable Alzheimer's disease) and 175 age-group, sex, and sample matched control participants. Poor educational attainment, low participation in cognitive leisure activity, stroke, transient ischemic attack, and self-reported very heavy alcohol use were related to the risk of primary degenerative and/or vascular YOD. The effect of hypertension and depression varied depending on when they occurred relative to dementia onset. Current smoking was significantly associated with risk in univariate analyses but did not retain significance in multivariate modelling. There was no association with hypercholesterolemia, diabetes, or TBI of any kind. Some compensation for low educational attainment was possible via a complex occupation later in life.

CONCLUSION: Non-genetic factors have a role in YOD, though the relative importance of each factor may be different to late onset dementia. The timing and severity of exposure, as well as the potential for compensation with later protective exposures, are important considerations for potential prevention strategies.

%B J Alzheimers Dis %V 62 %P 1747-1758 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614682?dopt=Abstract %R 10.3233/JAD-171027 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Novel Antibody Targeting Tau Phosphorylated at Serine 235 Detects Neurofibrillary Tangles. %A Brici, David %A Götz, Jürgen %A Nisbet, Rebecca M %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Animals %K Antibodies, Monoclonal %K Antibody Specificity %K Brain %K Disease Models, Animal %K Humans %K Mice %K Neurofibrillary Tangles %K Phosphorylation %K Plaque, Amyloid %K tau Proteins %X

Alzheimer's disease is characterized by two main pathological hallmarks in the human brain: the extracellular deposition of amyloid-β as plaques and the intracellular accumulation of the hyperphosphorylated protein tau as neurofibrillary tangles (NFTs). Phosphorylated tau (p-tau) specific-antibodies and silver staining have been used to reveal three morphological stages of NFT formation: pre-NFTs, intraneuronal NFTs (iNFTs), and extraneuronal NFTs (eNFTs). Here we characterize a novel monoclonal antibody, RN235, which is specific for tau phosphorylated at serine 235, and detects iNFTs and eNFTs in brain tissue, suggesting that phosphorylation at this site is indicative of late stage changes in tau.

%B J Alzheimers Dis %V 61 %P 899-905 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332046?dopt=Abstract %R 10.3233/JAD-170610 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Novel GRN Mutations in Alzheimer's Disease and Frontotemporal Lobar Degeneration. %A Piaceri, Irene %A Imperiale, Daniele %A Ghidoni, Enrico %A Atzori, Cristiana %A Bagnoli, Silvia %A Ferrari, Camilla %A Ungari, Silvana %A Ambrogio, Luca %A Sorbi, Sandro %A Nacmias, Benedetta %X

BACKGROUND: During the twentieth century, frontotemporal dementia (FTD) was often misdiagnosed, confused with Alzheimer's disease or psychiatric disorders, jeopardizing care and research.

OBJECTIVE: To analyze the FTD genes in the DNA samples of patients belonging to families clinically classified as probable Alzheimer's disease (FAD) in the early 1990s and not carrying mutation in the three main genes linked to FAD (Presenilin 1, Presenilin 2, and Amyloid precursor protein).

METHODS: The genetic screening was performed on 63 probands diagnosed as FAD before the early 2000s.

RESULTS: Four patients out of the 63 studied (4/63, 6.3%) resulted as carrying four different GRN genetic variations: p.T272SfsX10, p.R110X, p.C149LfsX10, and p.W304C. The first two mutations (p.T272SfsX10, p.R110X) are the most frequent ones in Italy in FTD patients; the latter two (p.C149LfsX10 and p.W304C) are not described in the scientific literature.

CONCLUSION: Our data suggest that it can be important to re-examine FAD patients diagnosed when the FTD spectrum was not well recognized and the causative FTD genes had not yet been identified. Moreover, we propose initially analyzing genes associated with the first form of suspected dementia and, if the results are negative, studying genes implicated in the other form of dementia.

%B J Alzheimers Dis %V 62 %P 1683-1689 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614680?dopt=Abstract %R 10.3233/JAD-170989 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Novel Lipidized Analog of Prolactin-Releasing Peptide Improves Memory Impairment and Attenuates Hyperphosphorylation of Tau Protein in a Mouse Model of Tauopathy. %A Popelová, Andrea %A Pražienková, Veronika %A Neprašová, Barbora %A Kasperová, Barbora Judita %A Hrubá, Lucie %A Holubová, Martina %A Zemenová, Jana %A Blum, David %A Železná, Blanka %A Galas, Marie-Christine %A Kuneš, Jaroslav %A Maletínská, Lenka %X

Obesity and type 2 diabetes mellitus (T2DM) were characterized as risk factors for Alzheimer's disease (AD) development. Subsequently, T2DM drugs, such as liraglutide, were proven to be neuroprotective compounds attenuating levels of amyloid deposits, and tau hyperphosphorylation, both hallmarks of AD. The central anorexigenic effects of liraglutide inspired us to examine the potential neuroprotective effects of palm11-PrRP31, a strong anorexigenic analog with glucose-lowering properties, in THY-Tau22 mice overexpressing mutated human tau, a model of AD-like tau pathology. Seven-month-old THY-Tau22 mice were subcutaneously infused with palm11-PrRP31 for 2 months. Spatial memory was tested before and after the treatment, using a Y-maze. At the end of the treatment, mice were sacrificed by decapitation and hippocampi were dissected and analyzed by immunoblotting with specific antibodies. Treatment with palm11-PrRP31 resulted in significantly improved spatial memory. In the hippocampi of palm11-PrRP31-treated THY-Tau22 mice, tau protein phosphorylation was attenuated at Thr231, Ser396, and Ser404, the epitopes linked to AD progression. The mechanism of this attenuation remains unclear, since the activation of those kinases most implicated in tau hyperphosphorylation, such as GSK-3β, JNK, or MAPK/ERK1/2, remained unchanged by palm11-PrRP31 treatment. Furthermore, we observed a significant increase in the amount of postsynaptic density protein PSD95, and a non-significant increase of synaptophysin, both markers of increased synaptic plasticity, which could also result in improved spatial memory of THY-Tau22 mice treated with palm11-PrRP31. Palm11-PrRP31 seems to be a potential tool for the attenuation of neurodegenerative disorders in the brain. However, the exact mechanism of its action must be elucidated.

%B J Alzheimers Dis %V 62 %P 1725-1736 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614684?dopt=Abstract %R 10.3233/JAD-171041 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Novel Therapeutic Approach to Treat Alzheimer's Disease by Neurotrophic Support During the Period of Synaptic Compensation. %A Baazaoui, Narjes %A Iqbal, Khalid %X

Alzheimer's disease (AD), at present, is considered an incurable disease and a major dilemma with no drug to stop or slow down its progression. Drugs that are currently available in the market are able to only transiently improve the clinical symptoms. The repeated failures in developing an effective drug has led to the suggestion that the medical intervention was probably too late to be effective since the pathology starts many years before the appearance of the clinical symptoms. Probably, at the time of the appearance of clinical symptoms the brain has undergone major neuronal and synaptic loss. Because of the uncertainty on when to use a prevention therapy, especially targeting amyloid-β (Aβ) and tau pathologies, interventions that rely on the regenerative capacity of the brain such as the modulation of the inherent neurogenesis and neuronal plasticity represent a promising therapeutic strategy. Such an approach can act both at early as well as late stages of the disease and remove the barrier of the time of intervention. In this article, we review studies mainly from our laboratory that show the merit of early intervention during the synaptic and neuronal compensation period where the brain still has the capacity to self-repair by offering neurotrophic support in reversing cognitive impairment, neuronal and synaptic deficits, Aβ, and tau pathologies and decreasing mortality in a transgenic mouse model of AD.

%B J Alzheimers Dis %V 62 %P 1211-1218 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562539?dopt=Abstract %R 10.3233/JAD-170839 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Nutrition: Review on the Possible Treatment for Alzheimer's Disease. %A Botchway, Benson O A %A Moore, Masania K %A Akinleye, Faith O %A Iyer, Ishwari C %A Fang, Marong %K Alzheimer Disease %K Curcumin %K Diet, Mediterranean %K Dietary Supplements %K Humans %K Nutritional Status %K Risk Factors %K Vitamins %X

Since its discovery some hundred years ago, Alzheimer's disease (AD), a neurodegenerative disease and an eminent cause of most dementia, continues to pose problems for affected families and society, especially in developed countries. With the approved medications by the Food and Drugs Administration in the United States, effectual treatment of AD apropos to the complete eradication of the disease continues to be elusive due to complexities relating to the pathophysiology of the disease. Nutrition has and continues to play a salient role in the survival of living organisms with no exception for human beings. Herein, we report the connection between nutrition and AD with particular attention to vitamins, curcumin, and the Mediterranean diet.

%B J Alzheimers Dis %V 61 %P 867-883 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254101?dopt=Abstract %R 10.3233/JAD-170874 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Nutritional Intervention as a Preventive Approach for Cognitive-Related Outcomes in Cognitively Healthy Older Adults: A Systematic Review. %A Solfrizzi, Vincenzo %A Agosti, Pasquale %A Lozupone, Madia %A Custodero, Carlo %A Schilardi, Andrea %A Valiani, Vincenzo %A Sardone, Rodolfo %A Dibello, Vittorio %A Di Lena, Luca %A Lamanna, Angela %A Stallone, Roberta %A Bellomo, Antonello %A Greco, Antonio %A Daniele, Antonio %A Seripa, Davide %A Sabbá, Carlo %A Logroscino, Giancarlo %A Panza, Francesco %X

The link diet-cognitive function/dementia has been largely investigated in observational studies; however, there was a lack of evidence from randomized clinical trials (RCTs) on the prevention of late-life cognitive disorders though dietary intervention in cognitively healthy older adults. In the present article, we systematically reviewed RCTs published in the last four years (2014-2017) exploring nutritional intervention efficacy in preventing the onset of late-life cognitive disorders and dementia in cognitively healthy subjects aged 60 years and older using different levels of investigation (i.e., dietary pattern changes/medical food/nutraceutical supplementation/multidomain approach and dietary macro- and micronutrient approaches) as well as possible underlying mechanisms of nutritional prevention. From the 35 included RCTs, there was moderate evidence that intervention through dietary pattern changes, medical food/nutraceutical supplementation, and multidomain approach improved specific cognitive domains or cognitive-related blood biomarkers. There was high evidence that protein supplementation improved specific cognitive domains or functional status in prefrail older adults without effect.

%B J Alzheimers Dis %V 64 %P S229-S254 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865058?dopt=Abstract %R 10.3233/JAD-179940 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease. %A Wezyk, Michalina %A Szybinska, Aleksandra %A Wojsiat, Joanna %A Szczerba, Marcelina %A Day, Kelly %A Ronnholm, Harriet %A Kele, Malin %A Berdynski, Mariusz %A Peplonska, Beata %A Fichna, Jakub Piotr %A Ilkowski, Jan %A Styczyńska, Maria %A Barczak, Anna %A Zboch, Marzena %A Filipek-Gliszczyńska, Anna %A Bojakowski, Krzysztof %A Skrzypczak, Magdalena %A Ginalski, Krzysztof %A Kabza, Michal %A Makalowska, Izabela %A Barcikowska-Kotowicz, Maria %A Wojda, Urszula %A Falk, Anna %A Zekanowski, Cezary %X

 The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer's disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1). Accordingly, the iPSC-derived FAD neurons showed increased content of BRCA1(Ser1524) colocalized with degraded PS1, accompanied by an enhanced immunostaining pattern of amyloid-β. Finally, overactivation of BRCA1 was followed by an increased content of Cdc25C phosphorylated on Ser216, likely triggering cell cycle re-entry in FAD neurons. This study suggests that overactivated BRCA1 could both influence PS1 turnover leading to amyloid-β pathology and promote cell cycle re-entry-driven cell death of postmitotic neurons in AD.

%B J Alzheimers Dis %V 62 %P 175-202 %8 2018 %G eng %N 1 %R 10.3233/JAD-170830 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Oxidative Stress, Amyloid-β Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer's Disease. %A Butterfield, D Allan %A Boyd-Kimball, Debra %X

Oxidative stress is implicated in the pathogenesis and progression of Alzheimer's disease (AD) and its earlier stage, amnestic mild cognitive impairment (aMCI). One source of oxidative stress in AD and aMCI brains is that associated with amyloid-β peptide, Aβ1-42 oligomers. Our laboratory first showed in AD elevated oxidative stress occurred in brain regions rich in Aβ1-42, but not in Aβ1-42-poor regions, and was among the first to demonstrate Aβ peptides led to lipid peroxidation (indexed by HNE) in AD and aMCI brains. Oxidatively modified proteins have decreased function and contribute to damaged key biochemical and metabolic pathways in which these proteins normally play a role. Identification of oxidatively modified brain proteins by the methods of redox proteomics was pioneered in the Butterfield laboratory. Four recurring altered pathways secondary to oxidative damage in brain from persons with AD, aMCI, or Down syndrome with AD are interrelated and contribute to neuronal death. This "Quadrilateral of Neuronal Death" includes altered: glucose metabolism, mTOR activation, proteostasis network, and protein phosphorylation. Some of these pathways are altered even in brains of persons with preclinical AD. We opine that targeting these pathways pharmacologically and with lifestyle changes potentially may provide strategies to slow or perhaps one day, prevent, progression or development of this devastating dementing disorder. This invited review outlines both in vitro and in vivo studies from the Butterfield laboratory related to Aβ1-42 and AD and discusses the importance and implications of some of the major achievements of the Butterfield laboratory in AD research.

%B J Alzheimers Dis %V 62 %P 1345-1367 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562527?dopt=Abstract %R 10.3233/JAD-170543 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Palmitoylethanolamide Blunts Amyloid-β42-Induced Astrocyte Activation and Improves Neuronal Survival in Primary Mouse Cortical Astrocyte-Neuron Co-Cultures. %A Beggiato, Sarah %A Borelli, Andrea Celeste %A Ferraro, Luca %A Tanganelli, Sergio %A Antonelli, Tiziana %A Tomasini, Maria Cristina %K Amyloid beta-Peptides %K Analysis of Variance %K Animals %K Animals, Newborn %K Anti-Inflammatory Agents, Non-Steroidal %K Astrocytes %K Cell Survival %K Cells, Cultured %K Cerebral Cortex %K Coculture Techniques %K Ethanolamines %K Mice %K Mice, Inbred C57BL %K Microtubule-Associated Proteins %K Neurons %K Palmitic Acids %K Peptide Fragments %K Time Factors %X

BACKGROUND: Based on the pivotal role of astrocytes in brain homeostasis and the strong metabolic cooperation existing between neurons and astrocytes, it has been suggested that astrocytic dysfunctions might cause and/or contribute to neuroinflammation and neurodegenerative processes. Therapeutic approaches aimed at both neuroprotection and neuroinflammation reduction may prove particularly effective in slowing the progression of these diseases. The endogenous lipid mediator palmitoylethanolamide (PEA) displayed neuroprotective and anti(neuro)inflammatory properties, and demonstrated interesting potential as a novel treatment for Alzheimer's disease.

OBJECTIVE AND METHODS: We firstly evaluated whether astrocytes could participate in regulating the Aβ42-induced neuronal damage, by using primary mouse astrocytes cell cultures and mixed astrocytes-neurons cultures. Furthermore, the possible protective effects of PEA against Aβ42-induced neuronal toxicity have also been investigated by evaluating neuronal viability, apoptosis, and morphometric parameters.

RESULTS: The presence of astrocytes pre-exposed to Aβ42 (0.5μM; 24 h) induced a reduction of neuronal viability in primary mouse astrocytes-neurons co-cultures. Furthermore, under these experimental conditions, an increase in the number of neuronal apoptotic nuclei and a decrease in the number of MAP-2 positive neurons were observed. Finally, astrocytic Aβ42 pre-exposure induced an increase in the number of neurite aggregations/100μm as compared to control (i.e., untreated) astrocytes-neurons co-cultures. These effects were not observed in neurons cultured in the presence of astrocytes pre-exposed to PEA (0.1μM), applied 1 h before and maintained during Aβ42 treatment.

CONCLUSION: Astrocytes contribute to Aβ42-induced neurotoxicity and PEA, by blunting Aβ42-induced astrocyte activation, improved neuronal survival in mouse astrocyte-neuron co-cultures.

%B J Alzheimers Dis %V 61 %P 389-399 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154284?dopt=Abstract %R 10.3233/JAD-170699 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Parietal Involvement in the Semantic Variant of Primary Progressive Aphasia with Alzheimer's Disease Cerebrospinal Fluid Profile. %A Bera, Géraldine %A Migliaccio, Raffaella %A Michelin, Thibaut %A Lamari, Foudil %A Ferrieux, Sophie %A Nogues, Marie %A Bertin, Hugo %A Habert, Marie Odile %A Dubois, Bruno %A Teichmann, Marc %A Kas, Aurélie %X

Semantic variant of primary progressive aphasia (svPPA) is typically associated with non-Alzheimer's disease (AD) pathology. However, some anatomopathological studies have found AD lesions in those patients. We compared brain perfusion SPECT of 18 svPPA patients with cerebrospinal fluid (CSF) biomarkers indicative of non-AD pathology (svPPA-nonAD) and three svPPA patients with CSF biomarkers indicative of underlying AD (svPPA-AD). All svPPA patients had severe left temporopolar hypoperfusion. SvPPA-nonAD had additional anterior cingulate and mediofrontal hypoperfusion, whereas svPPA-AD had greater left parietal and posterior cingulate involvement. Parietal damage in svPPA constitutes a biomarker for underlying Alzheimer pathology thus refining the classification of this PPA variant.

%B J Alzheimers Dis %V 66 %P 271-280 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282352?dopt=Abstract %R 10.3233/JAD-180087 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Past and the Future of Alzheimer's Disease Fluid Biomarkers. %A Blennow, Kaj %A Zetterberg, Henrik %K Alzheimer Disease %K Animals %K Biomarkers %K Humans %X

Following the development of the first methods to measure the core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers total-tau (T-tau), phosphorylated tau (P-tau) and the 42 amino acid form of amyloid-β (Aβ42), there has been an enormous expansion of this scientific research area. Today, it is generally acknowledged that these biochemical tests reflect several central pathophysiological features of AD and contribute diagnostically relevant information, also for prodromal AD. In this article in the 20th anniversary issue of the Journal of Alzheimer's Disease, we review the AD biomarkers, from early assay development to their entrance into diagnostic criteria. We also summarize the long journey of standardization and the development of assays on fully automated instruments, where we now have high precision and stable assays that will serve as the basis for common cut-off levels and a more general introduction of these diagnostic tests in clinical routine practice. We also discuss the latest expansion of the AD CSF biomarker toolbox that now also contains synaptic proteins such as neurogranin, which seemingly is specific for AD and predicts rate of future cognitive deterioration. Last, we are at the brink of having blood biomarkers that may be implemented as screening tools in the early clinical management of patients with cognitive problems and suspected AD. Whether this will become true, and whether it will be plasma Aβ42, the Aβ42/40 ratio, or neurofilament light, or a combination of these, remains to be established in future clinical neurochemical studies.

%B J Alzheimers Dis %V 62 %P 1125-1140 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad170773?id=journal-of-alzheimers-disease%2Fjad170773 %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562534?dopt=Abstract %R 10.3233/JAD-170773 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Past to Future: What Animal Models Have Taught Us About Alzheimer's Disease. %A Martini, Alessandra C %A Forner, Stefania %A Trujillo-Estrada, Laura %A Baglietto-Vargas, David %A LaFerla, Frank M %X

Alzheimer's disease (AD) impairs memory and causes significant cognitive deficits. The disease course is prolonged, with a poor prognosis, and thus exacts an enormous economic and social burden. Over the past two decades, genetically engineered mouse models have proven indispensable for understanding AD pathogenesis, as well as for discovering new therapeutic targets. Here we highlight significant studies from our laboratory that have helped advance the AD field by elucidating key pathogenic processes operative in AD and exploring a variety of aspects of the disease which may yield novel therapeutic strategies for combatting this burdensome disease.

%B J Alzheimers Dis %V 64 %P S365-S378 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504540?dopt=Abstract %R 10.3233/JAD-179917 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Patient Characteristics and Outcomes Associated with Receiving an Earlier Versus Later Diagnosis of Probable Alzheimer's Disease. %A Kirson, Noam Y %A Scott Andrews, J %A Desai, Urvi %A King, Sarah B %A Schonfeld, Sophie %A Birnbaum, Howard G %A Ball, Daniel E %A Kahle-Wrobleski, Kristin %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition Disorders %K Cohort Studies %K Datasets as Topic %K Disease Progression %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Statistics, Nonparametric %K Time Factors %X

BACKGROUND: Effectiveness of Alzheimer's disease (AD) treatments may depend critically on the timeliness of intervention.

OBJECTIVE: To compare characteristics and outcomes of patients diagnosed with probable AD (prAD) based on time elapsed from first onset of cognitive decline.

METHODS: Patients with ≥1 prAD diagnosis and ≥1 follow-up visit were selected from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS; 9/2005-6/2015) and stratified based on the time between the perceived onset of cognitive decline at baseline and first prAD diagnosis (i.e., earlier versus later diagnosis). Characteristics at baseline and prAD diagnosis, clinically meaningful progression, and medication use following prAD diagnosis were compared.

RESULTS: Median time from perceived onset of cognitive decline to prAD diagnosis was 4.5 years (earlier diagnosis: ≤3.46; later diagnosis: >5.71). Earlier-diagnosed patients (n = 1,476) were younger at baseline (74.3 versus 76.3 years) and had better cognitive and functional scores than later-diagnosed patients (n = 1,474). At first prAD diagnosis, earlier-diagnosed patients had lower mean global Clinical Dementia Rating (CDR) score (0.8 versus 1.1), higher mean Mini-Mental State Examination (MMSE) (22.6 versus 20.0), and lower mean Functional Activities Questionnaire (11.6 versus 17.3). Earlier- and later-diagnosed patients experienced similar time to a decrease of ≥3 points in MMSE (median 23.2 versus 23.1 months, p = 0.83), but earlier-diagnosed patients had longer time to a CDR score of ≥2 points, and longer times to initiation of AD medication and antipsychotic agents (all p < 0.01).

CONCLUSION: Earlier prAD diagnosis in NACC data is associated with higher cognitive function and lower functional impairment at diagnosis.

%B J Alzheimers Dis %V 61 %P 295-307 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154268?dopt=Abstract %R 10.3233/JAD-170078 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Patient Engagement: The Fundació ACE Framework for Improving Recruitment and Retention in Alzheimer's Disease Research. %A Boada, Merce %A Santos-Santos, Miguel A %A Rodríguez-Gómez, Octavio %A Alegret, Montserrat %A Cañabate, Pilar %A Lafuente, Asunción %A Abdelnour, Carla %A Buendia, Mar %A de Dios, Maria José %A Morera, Amèrica %A Sanabria, Ángela %A Campo, Laura %A Ruiz, Agustin %A Tárraga, Lluís %X

Alzheimer's disease (AD) research is at a critical time. The global society is increasingly aware of the frightening rate of growth of the human and financial burden caused by this condition and of the urgent need to halt its progression. Consequently, the scientific community holds great responsibility to quickly put in place and optimize the machinery necessary for testing new treatments or interventions. In this context demand for participants for AD research is at an all-time high. In this review, we will focus on a methodological factor that is increasingly recognized as a key factor that shapes trial populations and affects validity of results in clinical trials: patient engagement, recruitment, and retention. We outline specific problems relevant to patient engagement in AD including recruiting enough participants, difficulties in participant retention, ensuring the recruited sample is representative of the general AD population, the burden of screening failures, and new challenges related to recruiting in preclinical disease. To address the urgent need for more research studying the applicability and cost-effectiveness of different recruitment strategies across different settings and nationalities, we describe the Models of Patient Engagement for Alzheimer's Disease (MOPEAD) project, a public-private partnership promoted by the Innovative Medicine Initiative (IMI), which will provide a large multinational quantitative analysis comparing different innovative recruitment models. We also discuss strategies that address each problem and draw on the experience of Fundació ACE to argue that focusing resources on comprehensive AD centers that offer coordinated clinical and social care and participate in basic and clinical research, is an effective and efficient way of implementing many of the discussed strategies.

%B J Alzheimers Dis %V 62 %P 1079-1090 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562541?dopt=Abstract %R 10.3233/JAD-170866 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Patterns of Neuropsychological Dysfunction and Cortical Volume Changes in Logopenic Aphasia. %A Owens, Tyler E %A Machulda, Mary M %A Duffy, Joseph R %A Strand, Edythe A %A Clark, Heather M %A Boland, Sarah %A Martin, Peter R %A Lowe, Val J %A Jack, Clifford R %A Whitwell, Jennifer L %A Josephs, Keith A %X

BACKGROUND: Neuropsychological assessment can add essential information to the characterization of individuals presenting with the logopenic variant of primary progressive aphasia (lvPPA).

OBJECTIVE: This study examined the neuropsychological characteristics of lvPPA patients. We also examined differences in regional and whole brain atrophy based on neuropsychological profiles.

METHODS: We conducted a hierarchical cluster analysis on memory, executive functioning, and visuospatial neuropsychological test data for 56 individuals with lvPPA. We then compared resultant clusters to left middle temporal, inferior parietal, and superior parietal regions-of-interest using multivariate analysis of covariance. We also performed voxel-level analyses.

RESULTS: We identified three clusters characterized as lvPPA with no neurocognitive impairment (n = 5), lvPPA with mild neurocognitive deficits (n = 23), and lvPPA with marked cognitive deficits (n = 28). WAB-AQ was associated with left middle temporal volume. Superior parietal volumes were smaller for the lvPPA group with marked cognitive symptoms compared to the less severe groups. Voxel-level analyses showed greater atrophy in temporal, parietal, lateral occipital, and frontal regions, left worse than right. Age, disease duration, gender, WAB-AQ, and PiB-PET did not account for differences between groups.

CONCLUSIONS: LvPPA patients without cognitive deficits in other domains were relatively uncommon while 50% of our sample exhibited pronounced neurocognitive deficits outside the language domain. Pronounced cognitive deficits in lvPPA are associated with widespread atrophy, left worse than right. Our study underscores the importance of examining neuropsychological function in addition to language in patients with lvPPA.

%B J Alzheimers Dis %V 66 %P 1015-1025 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30372673?dopt=Abstract %R 10.3233/JAD-171175 %0 Journal Article %J J Alzheimers Dis %D 2018 %T PCSK9 Concentrations in Cerebrospinal Fluid Are Not Specifically Increased in Alzheimer's Disease. %A Courtemanche, Hélène %A Bigot, Edith %A Pichelin, Matthieu %A Guyomarch, Béatrice %A Boutoleau-Bretonnière, Claire %A Le May, Cédric %A Derkinderen, Pascal %A Cariou, Bertrand %X

The role of PCSK9 in Alzheimer's disease (AD) is controversial. We compared cerebrospinal fluid (CSF) PCSK9 concentrations in 36 AD and 31 non-AD patients. CSF PCSK9 levels did not differ between AD and non-AD groups (2.80 versus 2.62 ng/mL). However, PCSK9 CSF levels were increased in AD and non-AD patients with other neurodegenerative process (non-AD ND, n = 20) compared to patients without neurodegenerative disorders (non-ND, n = 11): 2.80 versus 2.30 (p < 0.005) and 2.83 versus 2.30 ng/mL (p = NS), respectively. CSF PCSK9 were positively correlated with AD biomarkers (Aβ1-42, T-tau, and P-tau). PCSK9 concentrations in CSF are increased in neurodegenerative disorders rather than specifically in AD.

%B J Alzheimers Dis %V 62 %P 1519-1525 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562508?dopt=Abstract %R 10.3233/JAD-170993 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Periodontal Pathogens and Associated Intrathecal Antibodies in Early Stages of Alzheimer's Disease. %A Laugisch, Oliver %A Johnen, Andreas %A Maldonado, Alejandra %A Ehmke, Benjamin %A Bürgin, Walter %A Olsen, Ingar %A Potempa, Jan %A Sculean, Anton %A Duning, Thomas %A Eick, Sigrun %X

BACKGROUND: Recent studies suggest a link between periodontitis and Alzheimer's disease (AD).

OBJECTIVE: Verification of the presence of periodontal pathogens and the intrathecal generation of pathogen-specific antibodies in 20 patients with AD and 20 with other forms of dementia (DEM-noAD).

METHODS: Clinical periodontal indices were recorded. Cerebrospinal fluid (CSF) was analyzed for total tau protein (T-tau) and amyloid-β (Aβ1-42). In serum and CSF, antibody levels against Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Treponema species were quantified. The presence of selected bacteria and inflammatory biomarkers were determined in periodontium, serum, and CSF.

RESULTS: In line with diagnoses, CSF-levels of Aβ1-42 were significantly lower in AD than DEM-noAD patients. Periodontal destruction and inflammation were omnipresent with no difference between groups. P. gingivalis, T. forsythia, and Treponema species were detected in more than 50% of subgingival biofilm samples, but neither in serum nor in the CSF. Elevated levels of anti-pathogen antibodies in CSF of 16 patients (7 AD; 9 DEM-noAD) compared to serum highlight a possibility of the intrathecal immune response to pathogens. There was no significant difference in antibodies levels against selected bacteria in CSF and serum between groups. Multivariate regression analysis and general linear models revealed an association of the T-tau level in AD group with both serum levels of anti-P. gingivalis antibodies and MCP-1/CCL-2.

CONCLUSION: Periodontal pathogens may enter the brain and stimulate a local immune response. However, in patients with dementia at the age up to 70 years, periodontal pathogens do not act as a trigger for developing AD.

%B J Alzheimers Dis %V 66 %P 105-114 %8 2018 Oct 16 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30223397?dopt=Abstract %R 10.3233/JAD-180620 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Perspectives on Communicating Biomarker-Based Assessments of Alzheimer's Disease to Cognitively Healthy Individuals. %A Milne, Richard %A Bunnik, Eline %A Diaz, Ana %A Richard, Edo %A Badger, Shirlene %A Gove, Dianne %A Georges, Jean %A Fauria, Karine %A Molinuevo, Jose-Luis %A Wells, Katie %A Ritchie, Craig %A Brayne, Carol %K Adult %K Aged %K Alzheimer Disease %K Biomarkers %K Caregivers %K Disclosure %K Female %K Focus Groups %K Humans %K Male %K Middle Aged %K Qualitative Research %K Risk Factors %K Spain %K United Kingdom %X

In clinical trials which target pathophysiological mechanisms associated with Alzheimer's disease, research participants who are recruited based on biomarker test results should be informed about their increased risk of developing Alzheimer's dementia. This paper presents the results of a qualitative focus group study of attitudes and concerns toward learning information about biomarker-based risk status among healthy research participants in the United Kingdom and Spain and people with dementia and their supporters/caregivers from countries represented in the European Working Group of People with Dementia of Alzheimer Europe. The study identified expectations related to learning risk status and preferences related to the content, quality, and follow-up of the disclosure process. The latter emphasize distinctions between risk and diagnoses, the importance of clear information about risk, and suggestions for risk reduction, as well as expectations for follow up and support. The implications of these preferences for practice are discussed. Providing details of research participants' experience and views may serve as a guide for the development of processes for the responsible disclosure of Alzheimer's disease biomarkers.

%B J Alzheimers Dis %V 62 %P 487-498 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad170813?id=journal-of-alzheimers-disease%2Fjad170813 %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480179?dopt=Abstract %R 10.3233/JAD-170813 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Perspectives on Oxidative Stress in Alzheimer's Disease and Predictions of Future Research Emphases. %A Butterfield, D Allan %X

Oxidative stress, an overproduction of free radicals or a diminution of free radical scavenging ability relative to those of cognitively aged-matched controls, is widely recognized as a critical component of the pathogenesis and progression of Alzheimer's disease (AD). This recognition arose in significant part from the work in the author's laboratory, complemented by research from others' laboratories. The Butterfield laboratory discovered the oxidative stress associated with oligomeric amyloid-β peptide manifested primarily as elevated oxidative modification of proteins and peroxidation of lipids. Such oxidative damage caused neuronal death, which undoubtedly underlies the progressive loss of cognition in AD. Identification of specific oxidatively modified brain proteins in subjects with AD or amnestic mild cognitive impairment was achieved by the methods of redox proteomics, pioneered in the author's laboratory. The importance and significance of the research emanating from the Butterfield laboratory rest on the paradigm shift of thinking regarding the roles of oxidative stress and resulting damage to key proteins and biochemical pathways in the pathogenesis and progression of AD. Predictions of future research directions also are presented. Given the enormous financial and personal burden placed upon citizens (and governments) of the US from AD, and the surety that the number of AD patients will greatly increase over the next 20-30 years, greater understanding of the molecular basis of pathogenesis and progression of AD is essential. Our laboratory is privileged to have contributed to better understanding of AD and provided rationales to identify effective therapeutic targets for this devastating dementing disorder.

%B J Alzheimers Dis %V 64 %P S469-S479 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504538?dopt=Abstract %R 10.3233/JAD-179912 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Physical Activity and Hippocampal Sub-Region Structure in Older Adults with Memory Complaints. %A Siddarth, Prabha %A Rahi, Berna %A Emerson, Natacha D %A Burggren, Alison C %A Miller, Karen J %A Bookheimer, Susan %A Lavretsky, Helen %A Dobkin, Bruce %A Small, Gary %A Merrill, David A %K Aged %K Aged, 80 and over %K Cognition %K Cross-Sectional Studies %K Executive Function %K Exercise %K Female %K Geriatric Assessment %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Male %K Memory %K Memory Disorders %K Middle Aged %K Neuropsychological Tests %X

BACKGROUND: Physical activity (PA) plays a major role in maintaining cognition in older adults. PA has been shown to be correlated with total hippocampal volume, a memory-critical region within the medial temporal lobe (MTL). However, research on associations between PA and MTL sub-region integrity is limited.

OBJECTIVE: To examine the relationship between PA, MTL thickness, and its sub-regions, and cognitive function in non-demented older adults with memory complaints.

METHODS: Twenty-nine subjects aged ≥60 years, with memory complaints were recruited for this cross-sectional study. PA was tracked for 7 days using accelerometers, and average number of steps/day determined. Subjects were categorized into two groups: those who walked ≤4000 steps/day (lower PA) and those with >4000 steps/day (higher PA). Subjects received neuropsychological testing and 3T MRI scans. Nonparametric ANCOVAs controlling for age examined differences between the two groups.

RESULTS: Twenty-six subjects aged 72.7(8.1) years completed the study. The higher PA group (n = 13) had thicker fusiform gyrus (median difference = 0.11 mm, effect size (ES) = 1.43, p = 0.001) and parahippocampal cortex (median difference = 0.12 mm, ES = 0.93, p = 0.04) compared to the lower PA group. The higher PA group also exhibited superior performance in attention and information-processing speed (median difference = 0.90, ES = 1.61, p = 0.003) and executive functioning (median difference = 0.97, ES = 1.24, p = 0.05). Memory recall was not significantly different between the two groups.

CONCLUSION: Older non-demented individuals complaining of memory loss who walked >4000 steps each day had thicker MTL sub-regions and better cognitive functioning than those who walked ≤4000 steps. Future studies should include longitudinal analyses and explore mechanisms mediating hippocampal related atrophy.

%B J Alzheimers Dis %V 61 %P 1089-1096 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254088?dopt=Abstract %R 10.3233/JAD-170586 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Phytochemicals from Achillea fragrantissima are Modulators of AβPP Metabolism. %A Bartolotti, Nancy %A Disouky, Ahmed %A Kalinski, Arthur %A Elmann, Anat %A Lazarov, Orly %X

Plant derivatives offer a novel and natural source of therapeutics. The desert plant Achillea fragrantissima (Forssk) Sch. Bip (Af) is characterized by protective antioxidative and anti-inflammatory properties. Here, we examined the effect of two Af-derived phytochemicals on learning and memory, amyloid-β protein precursor (AβPP) metabolism, and tau phosphorylation in the familial Alzheimer's disease-linked APPswe/PS1ΔE9 mouse model. We observed that mice that were injected with the phytochemicals showed a trend of improvement, albeit statistically insignificant, in the Novel Object Recognition task. However, we did not observe improvement in contextual fear conditioning, suggesting that the benefits of treatment may be either indirect or task-specific. In addition, we observed an increase in the full-length form of AβPP in the brains of mice treated with Af-derived phytochemicals. Interestingly, both in vivo and in vitro, there was no change in levels of soluble Aβ, oligomeric Aβ, or the carboxyl terminus fragments of AβPP (APP-CTFs), suggesting that the increase in full length AβPP does not exacerbate AβPP pathology, but may stabilize the full-length form of the molecule. Together, our data suggest that phytochemicals present in Af may have a modest positive impact on the progression of Alzheimer's disease.

%B J Alzheimers Dis %V 66 %P 1425-1435 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400087?dopt=Abstract %R 10.3233/JAD-180068 %0 Journal Article %J J Alzheimers Dis %D 2018 %T PICALM Gene Methylation in Blood of Alzheimer's Disease Patients Is Associated with Cognitive Decline. %A Mercorio, Roberta %A Pergoli, Laura %A Galimberti, Daniela %A Favero, Chiara %A Carugno, Michele %A Dalla Valle, Elisabetta %A Barretta, Francesco %A Cortini, Francesca %A Scarpini, Elio %A Valentina, Valentina Bollati %A Pesatori, Angela Cecilia %X

Epigenetic mechanisms might be involved in Alzheimer's disease (AD). Genetic polymorphisms in several genes, including APOE (Apolipoprotein E), PSEN1 (Presenilin 1), CR1 (Complement receptor 1), and PICALM (Phosphatidylinositol binding clathrin assembly protein), have been associated to an increased AD risk. However, data regarding methylation of these specific genes are lacking. We evaluated DNA methylation measured by quantitative bisulfite-PCR pyrosequencing in 43 AD patients and 38 healthy subjects (HS). In a multivariate age- and gender-adjusted model, PICALM methylation was decreased in AD compared to HS (mean = 3.54 and 4.63, respectively, p = 0.007). In AD, PICALM methylation level was also positively associated to Mini-Mental Scale Examination (MMSE) score (percent change 3.48%, p = 0.008). Moreover, a negative association between PICALM methylation and age was observed only in HS (percent change - 2.29%, p = 0.002). In conclusion, our data suggest a possible role of PICALM methylation in AD, particularly related to cognitive function. Given the small study sample and the associative nature of our study, further prospective investigations are required to assess the dynamics of DNA methylation in the early stages of AD development.

%B J Alzheimers Dis %V 65 %P 283-292 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040717?dopt=Abstract %R 10.3233/JAD-180242 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Plasma Amyloid-β (Aβ42) Correlates with Cerebrospinal Fluid Aβ42 in Alzheimer's Disease. %A Teunissen, Charlotte E %A Chiu, Ming-Jang %A Yang, Che-Chuan %A Yang, Shieh-Yueh %A Scheltens, Philip %A Zetterberg, Henrik %A Blennow, Kaj %X

The 42 amino acid form of amyloid-β (Aβ42) plays a key role in the pathogenesis of Alzheimer's disease (AD) and is a core biomarker for the diagnosis of AD. Numerous studies have shown that cerebrospinal fluid (CSF) Aβ42 concentrations are decreased in AD, when measured by enzyme-linked immunosorbent assay (ELISA) and other conventional immunoassays. While most studies report no change in plasma Aβ42, independent studies using the immunomagnetic reduction (IMR) technique report an increase in plasma Aβ42 levels in AD. To confirm the opposite changes of Aβ42 levels in CSF and plasma for AD, we assayed the levels of Aβ42 in plasma of subjects with known CSF Aβ42 levels. In total 43 controls and 63 AD patients were selected at two sites: the VU University Medical Center (n = 55) and Sahlgrenska University Hospital (n = 51). IMR and ELISA were applied to assay Aβ42 in plasma and CSF, respectively. We found a moderately negative correlation between plasma and CSF Aβ42 levels in AD patients (r = -0.352), and a weakly positive correlation in controls (r = 0.186). These findings further corroborate that there are opposite changes of Aβ42 levels in CSF and plasma in AD. The possible causes for the negative correlation are discussed by taken assay technologies, Aβ42 transport from brain to peripheral blood, and sample matrix into account.

%B J Alzheimers Dis %V 62 %P 1857-1863 %8 2018 Mar 27 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614646?dopt=Abstract %R 10.3233/JAD-170784 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Post Traumatic Stress Disorder Heralding the Onset of Semantic Frontotemporal Dementia. %A Bonanni, Laura %A Franciotti, Raffaella %A Martinotti, Giovanni %A Vellante, Federica %A Flacco, Maria Elena %A Di Giannantonio, Massimo %A Thomas, Astrid %A Onofrj, Marco %X

BACKGROUND: Post traumatic stress disorder (PTSD) is associated with cognitive decline. The dementia type following PTSD is unclear.

OBJECTIVE: To assess whether PTSD is associated with a specific dementia.

METHODS: Prospective study: 46 PTSD patients (DSM-IV-TR) were followed for 6-10 years with clinical, neuropsychological, imaging evaluations for possible development of dementia.Retrospective study:849 dementia patients followed during 1999-2014 (509 Alzheimer's disease, AD; 207 dementia with Lewy bodies, DLB; 90 vascular dementia, VaD; 43 frontotemporal dementia, FTD) and 287 patients with any neurological condition (including patients with/without dementia) were evaluated for the presence of PTSD in their history.

RESULTS: Prospective study: 8 patients developed dementia; 1 AD, 1 DLB, 6 semantic FTD (13.0% of the PTSD population). Retrospective study: 38 patients (4.5%) had a history of PTSD; 3.5% of AD, 4.3% of DLB, 14.0% of FTD, 5.6% of VaD. The percentage was higher in FTD than in AD or DLB (χ2 = 10, p = 0.001, and χ2 = 6, p = 0.02). At difference with AD, DLB, or VaD, FTD incidence among dementia patients with PTSD history (38 patients) was higher than in the dementia population overall (16% versus 5%, χ2 = 8, p = 0.005). The impact of possible demographical/clinical confounders (age, gender, MMSE) was excluded by Poisson regression. PTSD prevalence in the comparative group without dementia matched the prevalence in the Italian general population (1.1%). PTSD prevalence in the demented comparative group matched the prevalence in our dementia retrospective cohort, 3.7%).

DISCUSSION: PTSD was associated with the development of semantic FTD.

%B J Alzheimers Dis %V 63 %P 203-215 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614666?dopt=Abstract %R 10.3233/JAD-171134 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Postmortem T2*- Weighted MRI Imaging of Cortical Iron Reflects Severity of Alzheimer's Disease. %A Bulk, Marjolein %A Kenkhuis, Boyd %A Graaf, Linda M van der %A Goeman, Jelle J %A Natté, Remco %A Weerd, Louise van der %X

The value of iron-based MRI changes for the diagnosis and staging of Alzheimer's disease (AD) depends on an association between cortical iron accumulation and AD pathology. Therefore, this study determined the cortical distribution pattern of MRI contrast changes in cortical regions selected based on the known distribution pattern of tau pathology and investigated whether MRI contrast changes reflect the underlying AD pathology in the different lobes. T2*-weighted MRI was performed on postmortem cortical tissue of controls, late-onset AD (LOAD), and early-onset AD (EOAD) followed by histology and correlation analyses. Combining ex vivo high-resolution MRI and histopathology revealed that: 1) LOAD and EOAD have a different distribution pattern of AD pathological hallmarks and MRI contrast changes over the cortex, with EOAD showing more severe MRI changes; 2) per lobe, severity of AD pathological hallmarks correlates with iron accumulation, and hence with MRI. Therefore, iron-sensitive MRI sequences allow detection of the cortical distribution pattern of AD pathology ex vivo.

%B J Alzheimers Dis %8 2018 Aug 07 %G eng %R 10.3233/JAD-180317 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Postsynaptic Proteome of Non-Demented Individuals with Alzheimer's Disease Neuropathology. %A Zolochevska, Olga %A Bjorklund, Nicole %A Woltjer, Randall %A Wiktorowicz, John E %A Taglialatela, Giulio %X

Some individuals, here referred to as Non-Demented with Alzheimer's Neuropathology (NDAN), retain their cognitive function despite the presence of amyloid plaques and tau tangles typical of symptomatic Alzheimer's disease (AD). In NDAN, unlike AD, toxic amyloid-β oligomers do not localize to the postsynaptic densities (PSDs). Synaptic resistance to amyloid-β in NDAN may thus enable these individuals to remain cognitively intact despite the AD-like pathology. The mechanism(s) responsible for this resistance remains unresolved and understanding such protective biological processes could reveal novel targets for the development of effective treatments for AD. The present study uses a proteomic approach to compare the hippocampal postsynaptic densities of NDAN, AD, and healthy age-matched persons to identify protein signatures characteristic for these groups. Subcellular fractionation followed by 2D gel electrophoresis and mass spectrometry were used to analyze the PSDs. We describe fifteen proteins which comprise the unique proteomic signature of NDAN PSDs, thus setting them apart from control subjects and AD patients.

%B J Alzheimers Dis %8 2018 Jul 30 %G eng %R 10.3233/JAD-180179 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer's Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial. %A Wilcock, Gordon K %A Gauthier, Serge %A Frisoni, Giovanni B %A Jia, Jianping %A Hardlund, Jiri H %A Moebius, Hans J %A Bentham, Peter %A Kook, Karin A %A Schelter, Bjoern O %A Wischik, Damon J %A Davis, Charles S %A Staff, Roger T %A Vuksanovic, Vesna %A Ahearn, Trevor %A Bracoud, Luc %A Shamsi, Kohkan %A Marek, Ken %A Seibyl, John %A Riedel, Gernot %A Storey, John M D %A Harrington, Charles R %A Wischik, Claude M %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Antipsychotic Agents %K Cohort Studies %K Double-Blind Method %K Female %K Humans %K International Cooperation %K Male %K Mental Status and Dementia Tests %K Methylene Blue %K Middle Aged %K Treatment Outcome %X

BACKGROUND: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation.

OBJECTIVES: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD.

METHODS: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error.

RESULTS: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy.

CONCLUSIONS: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.

%B J Alzheimers Dis %V 61 %P 435-457 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154277?dopt=Abstract %R 10.3233/JAD-170560 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Pramlintide: The Effects of a Single Drug Injection on Blood Phosphatidylcholine Profile for Alzheimer's Disease. %A Tao, Qiushan %A Zhu, Haihao %A Chen, Xi %A Stern, Robert A %A Kowall, Neil %A Au, Rhoda %A Blusztajn, Jan Krzysztof %A Qiu, Wei Qiao %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognitive Dysfunction %K Female %K Humans %K Islet Amyloid Polypeptide %K Logistic Models %K Male %K Middle Aged %K Phosphatidylcholines %K ROC Curve %K tau Proteins %X

Studies suggest that a single injection of pramlintide, an amylin analog, induces changes in Alzheimer's disease (AD) biomarkers in the blood of AD mouse models and AD patients. The aim of this study was to examine whether a pramlintide challenge combined with a phosphatidylcholine (PC) profile diagnoses of AD and mild cognitive impairment (MCI) better than PC alone. Non-diabetic subjects with cognitive status were administered a single subcutaneous injection of 60 mcg of pramlintide under fasting condition. A total of 71 PCs, amyloid-β peptide (Aβ), and total tau (t-tau) in plasma at different time points were measured and treated as individual variables. A single injection of pramlintide altered the levels of 7 PCs in the blood, while a pramlintide injection plus food modulated the levels of 10 PCs in the blood (p < 0.05). The levels of 2 PCs in MCI and 12 PCs in AD in the pramlintide challenge were significantly lower than the ones in controls. We found that while some PCs were associated with only Aβ levels, other PCs were associated with both Aβ and t-tau levels. A receiver operating characteristic analysis of the PCs was combined with the Aβ and t-tau data to produce an area under the curve predictive value of 0.9799 between MCI subjects and controls, 0.9794 between AD subjects and controls, and 0.9490 between AD and MCI subjects. A combination of AD biomarkers and a group of PCs post a pramlintide challenge may provide a valuable diagnostic and prognostic test for AD and MCI.

%B J Alzheimers Dis %V 62 %P 597-609 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480193?dopt=Abstract %R 10.3233/JAD-170948 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Predicting and Tracking Short Term Disease Progression in Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer's Disease: Structural Brain Biomarkers. %A Marizzoni, Moira %A Ferrari, Clarissa %A Jovicich, Jorge %A Albani, Diego %A Babiloni, Claudio %A Cavaliere, Libera %A Didic, Mira %A Forloni, Gianluigi %A Galluzzi, Samantha %A Hoffmann, Karl-Titus %A Molinuevo, José Luis %A Nobili, Flavio %A Parnetti, Lucilla %A Payoux, Pierre %A Ribaldi, Federica %A Rossini, Paolo Maria %A Schönknecht, Peter %A Soricelli, Andrea %A Hensch, Tilman %A Tsolaki, Magda %A Visser, Pieter Jelle %A Wiltfang, Jens %A Richardson, Jill C %A Bordet, Régis %A Blin, Olivier %A Frisoni, Giovanni B %X

BACKGROUND: Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients.

OBJECTIVE: To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression.

METHODS: APOE ɛ4 specific CSF Aβ42/P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42/P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with Aβ42/P-tau status, time, and Aβ42/P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers.

RESULTS: Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients who declined faster (interaction, p = 0.003). Lateral ventricle volume and medial temporal lobe measures were the biomarkers most sensitive to disease progression (interaction, p≤0.042). Enrichment through ventricular volume reduced the sample size that a clinical trial would require from 13 to 76%, depending on structural outcome variable. The biomarker needing the lowest sample size was the hippocampal subfield GC-ML-DG (granule cells of molecular layer of the dentate gyrus) (n = 82 per arm to demonstrate a 20% atrophy reduction).

CONCLUSION: MRI structural biomarkers can enrich prodromal AD with fast progressors and significantly decrease group size in clinical trials of disease modifying drugs.

%B J Alzheimers Dis %8 2018 Jun 09 %G eng %R 10.3233/JAD-180152 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prediction and Early Detection of Alzheimer's Dementia: Professional Disclosure Practices and Ethical Attitudes. %A Schweda, Mark %A Kögel, Anna %A Bartels, Claudia %A Wiltfang, Jens %A Schneider, Anja %A Schicktanz, Silke %X

BACKGROUND: Biomarker-supported testing for preclinical and prodromal Alzheimer's disease (AD) finds its way into clinical practice. Professional attitudes and practices regarding disclosure and ethical issues are controversial in many countries.

OBJECTIVES: Against this background, the objective was to survey the actual practice and the attitudes of physicians in German hospitals and memory clinics in order to explore possible practical insecurities and ethical concerns.

METHODS: A detailed survey with 37 items was conducted among medical professionals at German hospitals and memory clinics (n = 108). Analyses were performed using SPSS 21.0 (IBM). Findings were based on frequency and percentage distribution.

RESULTS: Nearly half of the respondents stated that persons with mild cognitive impairment and pathological cerebrospinal fluid biomarkers were informed they had or would soon develop AD. While 81% acknowledged a 'right not to know', 75% said that results were always communicated. A majority agreed there was a benefit of prediction or later life planning [end-of-life, financial, family, housing (73-75%)] but also expected high psychological stress (82%) and self-stigmatization (70%) for those tested.

CONCLUSIONS: There is considerable heterogeneity and insecurity regarding prediction and early detection in the context of AD in Germany. Information of professionals and standardization of professional testing and disclosure practices are needed.

%B J Alzheimers Dis %V 62 %P 145-155 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439325?dopt=Abstract %R 10.3233/JAD-170443 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prediction of Alzheimer's Dementia in Patients with Amnestic Mild Cognitive Impairment in Clinical Routine: Incremental Value of Biomarkers of Neurodegeneration and Brain Amyloidosis Added Stepwise to Cognitive Status. %A Lange, Catharina %A Suppa, Per %A Pietrzyk, Uwe %A Makowski, Marcus R %A Spies, Lothar %A Peters, Oliver %A Buchert, Ralph %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloidosis %K Brain %K Cognitive Dysfunction %K Female %K Fluorodeoxyglucose F18 %K Humans %K Imaging, Three-Dimensional %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %K Survival Analysis %K tau Proteins %X

The aim of this study was to evaluate the incremental benefit of biomarkers for prediction of Alzheimer's disease dementia (ADD) in patients with mild cognitive impairment (MCI) when added stepwise in the order of their collection in clinical routine. The model started with cognitive status characterized by the ADAS-13 score. Hippocampus volume (HV), cerebrospinal fluid (CSF) phospho-tau (pTau), and the FDG t-sum score in an AD meta-region-of-interest were compared as neurodegeneration markers. CSF-Aβ1-42 was used as amyloidosis marker. The incremental prognostic benefit from these markers was assessed by stepwise Kaplan-Meier survival analysis in 402 ADNI MCI subjects. Predefined cutoffs were used to dichotomize patients as 'negative' or 'positive' for AD characteristic alteration with respect to each marker. Among the neurodegeneration markers, CSF-pTau provided the best incremental risk stratification when added to ADAS-13. FDG PET outperformed HV only in MCI subjects with relatively preserved cognition. Adding CSF-Aβ provided further risk stratification in pTau-positive subjects, independent of their cognitive status. Stepwise integration of biomarkers allows stepwise refinement of risk estimates for MCI-to-ADD progression. Incremental benefit strongly depends on the patient's status according to the preceding diagnostic steps. The stepwise Kaplan-Meier curves might be useful to optimize diagnostic workflow in individual patients.

%B J Alzheimers Dis %V 61 %P 373-388 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154285?dopt=Abstract %R 10.3233/JAD-170705 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Predictors of Age of Diagnosis and Survival of Alzheimer's Disease in Down Syndrome. %A Sinai, Amanda %A Mokrysz, Claire %A Bernal, Jane %A Bohnen, Ingrid %A Bonell, Simon %A Courtenay, Ken %A Dodd, Karen %A Gazizova, Dina %A Hassiotis, Angela %A Hillier, Richard %A McBrien, Judith %A McCarthy, Jane %A Mukherji, Kamalika %A Naeem, Asim %A Perez-Achiaga, Natalia %A Rantell, Khadija %A Sharma, Vijaya %A Thomas, David %A Walker, Zuzana %A Whitham, Sarah %A Strydom, Andre %K Age of Onset %K Alzheimer Disease %K Down Syndrome %K England %K Female %K Humans %K Male %K Middle Aged %K Risk Factors %K Survival Analysis %X

BACKGROUND: People with Down syndrome (DS) are an ultra-high risk population for Alzheimer's disease (AD). Understanding the factors associated with age of onset and survival in this population could highlight factors associated with modulation of the amyloid cascade.

OBJECTIVE: This study aimed to establish the typical age at diagnosis and survival associated with AD in DS and the risk factors associated with these.

METHODS: Data was obtained from the Aging with Down Syndrome and Intellectual Disabilities (ADSID) research database, consisting of data extracted from clinical records of patients seen by Community Intellectual Disability Services (CIDS) in England. Survival times when considering different risk factors were calculated.

RESULTS: The mean age of diagnosis was 55.80 years, SD 6.29. Median survival time after diagnosis was 3.78 years, and median age at death was approximately 60 years. Survival time was associated with age of diagnosis, severity of intellectual disability, living status, anti-dementia medication status, and history of epilepsy. Age at diagnosis and treatment status remained predictive of survival time following adjustment.

CONCLUSION: This study provides the best estimate of survival in dementia within the DS population to date, and is in keeping with previous estimates from smaller studies in the DS population. This study provides important estimates and insights into possible predictors of survival and age of diagnosis of AD in adults with DS, which will inform selection of participants for treatment trials in the future.

%B J Alzheimers Dis %V 61 %P 717-728 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226868?dopt=Abstract %R 10.3233/JAD-170624 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prevalence and Determinants of Agonistic Autoantibodies Against α1-Adrenergic Receptors in Patients Screened Positive for Dementia: Results from the Population-Based DelpHi-Study. %A Thyrian, Jochen René %A Hertel, Johannes %A Schulze, Lara N %A Dörr, Marcus %A Prüss, Harald %A Hempel, Petra %A Bimmler, Marion %A Kunze, Rudolf %A Grabe, Hans Jörgen %A Teipel, Stefan %A Hoffmann, Wolfgang %X

BACKGROUND: There is a need to assess promising biomarkers for diagnosis and treatment response in real-life settings. Despite the important role of vascular risk factors, cardiovascular biomarkers have played a minor role in dementia research. Agonistic autoantibodies (agAAB) directed against G-protein-coupled receptors (GPCR) are discussed as modulators of pathology and clinical manifestation.

OBJECTIVE: 1) Describe prevalence of agAAB directed against GPCR, especially agABB against α1-adrenergic receptors (α1-AR-agAAB) and agABB directed against β2-adrenergic receptors (β2-AR-agAAB) and 2) identify factors associated with agAAB in people with dementia during routine care.

METHODS: Blood samples and data from 95 subjects who screened positive for dementia from a primary care cohort, analyzed using an enzyme-linked immunosorbent assay (ELISA) for detecting agAAB. Sociodemographic and clinical data were assessed, and medical records checked.

RESULTS: In 40 (42%) samples, agAAB was detected, with n = 29 (31%) representing α1-AR-agAAB and n = 21 (22%) β2-AR-agAAB. There was no association between the presence of any antibody and a formal diagnosis of dementia. However, patients with coronary heart disease were more likely (OR = 4.23) to have α1-AR-agAAB than those without coronary heart disease. There were no associations between agAAB and age, sex, education, or cognitive impairment.

DISCUSSION: For the first time, we show that autoantibodies have a significant prevalence in people with dementia in a routine care setting. Previous findings were restricted to highly selective samples. We replicated the association between α1-AR-agAAB in patients with coronary heart diseases but were not able to find other factors associated with the presence of agAAB.

%B J Alzheimers Dis %V 64 %P 1091-1097 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010118?dopt=Abstract %R 10.3233/JAD-171096 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prevalence of Delirium in a Population of Elderly Outpatients with Dementia: A Retrospective Study. %A Addesi, Desirée %A Maio, Raffaele %A Smirne, Nicoletta %A Laganà, Valentina %A Altomari, Natalia %A Puccio, Gianfranco %A Colao, Rosanna %A Cupidi, Chiara %A Perticone, Francesco %A Bruni, Amalia Cecilia %K Aged %K Aged, 80 and over %K Antipsychotic Agents %K Cohort Studies %K Delirium %K Dementia %K Female %K Geriatric Assessment %K Humans %K Male %K Outpatients %K Prevalence %K Severity of Illness Index %X

BACKGROUND: Delirium is a multifactorial geriatric syndrome and often occurs in patients with cognitive impairment. It also remains under-recognized, specifically in elderly outpatients, because signs of delirium might overlap with symptoms of dementia.

OBJECTIVE: The aim of the present study is to retrospectively apply the chart-based delirium instrument on a cohort of elderly outpatients with dementia, to assess prevalence and features of delirium in this population.

METHODS: We randomly selected 650 medical records of outpatients referred to the "Neurogenetic Regional Centre" (CRN) of Lamezia Terme. Each evaluation included demographics, medical history, drugs, type and severity of dementia, and cognitive and functional status. Delirium was identified by the application of the chart-based delirium instrument.

RESULTS: The prevalence of delirium was 13.3%. The study population was divided, according to the presence of delirium, into two subgroups. Compared to the no delirium group, the delirium group was significantly older and had greater cognitive impairment with lower MMSE scores both at baseline and at the end of the follow up. They also had a significant lower score on the ADL and IADL. In this group, a higher intake of antihypertensive and antipsychotic drugs, together with a lower intake of cholinesterase inhibitors and memantine, was observed.

CONCLUSIONS: In this study, the chart-based delirium instrument was applied to an outpatient population affected by dementia and followed for a long time. Our data confirm the importance that age and frailty play on the genesis of delirium and suggest attention should be paid to the pharmacological treatment of these patients.

%B J Alzheimers Dis %V 61 %P 251-257 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171993?dopt=Abstract %R 10.3233/JAD-170339 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prevalence, Safety, and Effectiveness of Oral Anticoagulant Use in People with and without Dementia or Cognitive Impairment: A Systematic Review and Meta-Analysis. %A Fanning, Laura %A Ryan-Atwood, Taliesin E %A Bell, J Simon %A Meretoja, Atte %A McNamara, Kevin P %A Dārziņš, Pēteris %A Wong, Ian C K %A Ilomäki, Jenni %X

BACKGROUND: Differences in management and outcomes of oral anticoagulant (OAC) use may exist for people with and without dementia or cognitive impairment (CI).

OBJECTIVE: To systematically review the prevalence and safety and effectiveness outcomes of OAC use in people with and without dementia or CI.

METHODS: MEDLINE, EMBASE, and CINAHL were searched for studies reporting prevalence or safety and effectiveness outcomes of OAC use for people with and without dementia, published between 2000 to September 2017. Study selection, data extraction, and quality assessment were performed by two reviewers.

RESULTS: studies met pre-specified inclusion criteria (21 prevalence studies, 6 outcomes studies). People with dementia had 52% lower odds of receiving OAC compared to people without dementia. Mean OAC prevalence was 32% for people with dementia, compared to 48% without dementia. There was no difference in the composite outcome of embolic events, myocardial infarction, and all-cause death between dementia and non-dementia groups (adjusted hazard ratio (HR) 0.72, 95% CI, 0.45-1.14, p = 0.155). Bleeding rate was lower for people without dementia (HR 0.56, 95% CI, 0.37-0.85). Adverse warfarin events were more common for residents of long-term care with dementia (adjusted incidence rate ratio 1.48, 95% CI, 1.20-1.82). Community-dwelling people with dementia treated with warfarin had poorer anticoagulation control than those without dementia (mean time in therapeutic range (TTR) % ±SD, 38±26 (dementia), 61±27 (no dementia), p < 0.0001).

CONCLUSION: A lower proportion of people with dementia received oral anticoagulation compared with people without dementia. People with dementia had higher bleeding risk and poorer anticoagulation control when treated with warfarin.

%B J Alzheimers Dis %V 65 %P 489-517 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056420?dopt=Abstract %R 10.3233/JAD-180219 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prevalence, Semiology, and Risk Factors of Epilepsy in Alzheimer's Disease: An Ambulatory EEG Study. %A Horváth, András %A Szűcs, Anna %A Hidasi, Zoltán %A Csukly, Gábor %A Barcs, Gábor %A Kamondi, Anita %X

BACKGROUND: Alzheimer's disease (AD) is the primary cause of cognitive decline. A growing body of evidence suggests that AD patients have a higher risk to develop epileptic seizures; however, results are contradictory due to different methodological approaches of previous studies.

OBJECTIVE: We aimed to identify the prevalence, semiology, and risk factors of epilepsy in AD using long-term EEG.

METHODS: We selected forty-two AD patients and examined them using 24-hour ambulatory EEG. Neurological and epileptological data were collected with retro- and prospective methods. We analyzed the semiology of the identified seizures and the possible risk factors using logistic regression analysis.

RESULTS: We identified seizures confirmed by EEG in 24%. The majority of the seizures were aware focal (72%) without any motor activity (55%). We found epileptiform discharges without seizures in 28%. Patients with seizures and only with epileptic EEG activity showed similar clinical and demographical features. Higher education (OR:1.8) and lower Addenbrooke Examination Score (OR: 0.9) were identified as risk factors of epilepsy. Increase of 0.1 point in the Verbal-Language/Orientation-Memory ratio (VLOM) was associated with higher epilepsy risk as well (OR:2.9).

CONCLUSION: Epilepsy is a frequent comorbidity of AD. Since most of the seizures are aware non-motor focal seizures, sensitive EEG techniques are required for precise diagnosis of epilepsy. Long-term ambulatory EEG is a safe and well-tolerated option. Epileptiform EEG in AD signals the presence of concomitant epilepsy. Clinicians have to pay attention to comorbid epilepsy in dementia patients with high education, with high VLOM ratio and severe stage.

%B J Alzheimers Dis %V 63 %P 1045-1054 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710705?dopt=Abstract %R 10.3233/JAD-170925 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Price of Stress: High Bedtime Salivary Cortisol Levels Are Associated with Brain Atrophy and Cognitive Decline in Stroke Survivors. Results from the TABASCO Prospective Cohort Study. %A Tene, Oren %A Hallevi, Hen %A Korczyn, Amos D %A Shopin, Ludmila %A Molad, Jeremy %A Kirschbaum, Clemens %A Bornstein, Natan M %A Shenhar-Tsarfaty, Shani %A Kliper, Efrat %A Auriel, Eitan %A Usher, Sali %A Stalder, Tobias %A Ben Assayag, Einor %X

BACKGROUND AND OBJECTIVE: Previous studies suggest that excessive cortisol levels after stroke are associated with cognitive dysfunction. However, limited data exist regarding associations between post-stroke cortisol levels, brain abnormalities, genetic factors, and cognitive outcome. We sought to study these issues in a longitudinal stroke survivors cohort.

METHODS: Data from 182 cognitively intact ischemic stroke patients from the TABASCO study were available. Saliva cortisol levels (bedtime and post-awakening) and cognitive assessments were obtained on admission, and 6, 12, and 24 months thereafter. During hospitalization, patients underwent 3T MRI scans and APOE genotyping.

RESULTS: Higher bedtime cortisol levels immediately post-stroke were associated with larger neurological deficits (p < 0.001), brain atrophy (p = 0.025), worse white matter integrity (p = 0.003), and worse cognitive results up to 24 months post-stroke. These findings remained significant when adjusted for age, gender, education, smoking, stroke severity, apolipoprotein E4 (ApoE4) status, and body mass index. ApoE4 negatively modified the relation between cortisol and memory. As a group, participants who presented with high admission bedtime cortisol levels continued to present relatively elevated bedtime levels across all examined time-points, and this group had inferior memory and executive functioning scores compared to the lower cortisol group 24 months post-stroke (p = 0.05, p = 0.035, respectively). Post-awakening cortisol levels were not associated with neuroimaging findings or cognitive scores.

CONCLUSIONS: High bedtime salivary cortisol levels post-stroke may provide information about dysregulation of diurnal HPA-axis activity under acute challenge conditions, and predict worse cognitive outcome. ApoE4 genotype might modify this association. These findings call for specific stress management interventions in stroke survivors.

%B J Alzheimers Dis %V 65 %P 1365-1375 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149451?dopt=Abstract %R 10.3233/JAD-180486 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prodromal Alzheimer's Disease Demonstrates Increased Errors at a Simple and Automated Anti-Saccade Task. %A Holden, John G %A Cosnard, Alexandre %A Laurens, Brice %A Asselineau, Julien %A Biotti, Damien %A Cubizolle, Stéphanie %A Dupouy, Sandrine %A Formaglio, Maıté %A Koric, Lejla %A Seassau, Magali %A Tilikete, Caroline %A Vighetto, Alain %A Tison, François %X

Saccade alterations are potential early signs of Alzheimer's disease. However, uncertainty persists in how early and reliably automated saccade recording systems detect impairments. This multicenter pathophysiological case-control transversal study explored saccade execution in carefully diagnosed amnestic mild cognitive impairment patients fulfilling research criteria for prodromal Alzheimer's disease (n = 29), as compared to both aged-matched mild Alzheimer's disease patients (n = 23) and controls (n = 27). Auto-coded saccades from horizontal (gap) vertical (step) stimulus elicited pro-saccades, and anti-saccade (gap) tasks were compared across the 3 groups. Mild cognitive impairment patients committed significantly more anti-saccade errors compared to controls (46.9 versus 24.3%, p < 0.001). Conventional analyses of the auto-coded stimulus elicited saccades parameters did not distinguish the amnestic mild cognitive impairment from controls or the mild Alzheimer's disease group. However, an offline analysis of manually coded saccade latencies, using resampling statistics did reveal subtle differences among the groups. Analysis of the manually coded data revealed that the mild Alzheimer's disease group had a reliably larger self-corrected error-rate than in amnestic mild cognitive impairment and controls (p = 0.003). Analysis of the manually coded saccade latencies, using more sensitive lognormal bootstrap analysis revealed a continuum, from amnestic mild cognitive impairment to mild Alzheimer's disease, of an increased severity of impaired inhibition of stimulus elicited saccades and correct voluntary saccade initiation. Anti-saccade error rates and psychometric measures of executive and several other cognitive functions were moderately and negatively correlated. Overall, inhibitory impairments in stimulus elicited saccades, characteristic of Alzheimer's disease, may be detected early in presumed prodromal patients using a simple, automated anti-saccade task.

%B J Alzheimers Dis %V 65 %P 1209-1223 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149445?dopt=Abstract %R 10.3233/JAD-180082 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Progression of Alzheimer's Disease: A Longitudinal Study in Norwegian Memory Clinics. %A Eldholm, Rannveig Sakshaug %A Barca, Maria Lage %A Persson, Karin %A Knapskog, Anne-Brita %A Kersten, Hege %A Engedal, Knut %A Selbæk, Geir %A Brækhus, Anne %A Skovlund, Eva %A Saltvedt, Ingvild %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Disease Progression %K Female %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Memory %K Neuropsychological Tests %K Norway %X

BACKGROUND: The course of Alzheimer's disease (AD) varies considerably between individuals. There is limited evidence on factors important for disease progression.

OBJECTIVE: The primary aim was to study the progression of AD, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Secondary aims were to investigate whether baseline characteristics are important for differences in progression, and to examine the correlation between progression assessed using three different instruments: CDR-SB (0-18), the cognitive test Mini-Mental State Examination (MMSE, 0-30), and the functional measure Instrumental Activities of Daily Living (IADL, 0-1).

METHODS: The Progression of AD and Resource use (PADR) study is a longitudinal observational study in three Norwegian memory clinics.

RESULTS: In total, 282 AD patients (mean age 73.3 years, 54% female) were followed for mean 24 (16-37) months. The mean annual increase in CDR-SB was 1.6 (SD 1.8), the mean decrease in MMSE score 1.9 (SD 2.6), and the mean decrease in IADL score 0.13 (SD 0.14). Of the 282 patients, 132 (46.8%) progressed slowly, with less than 1 point yearly increase in CDR-SB. Cognitive test results at baseline predicted progression rate, and together with age, ApoE, history of hypertension, and drug use could explain 17% of the variance in progression rate. The strongest correlation of change was found between CDR-SB and IADL scores, the weakest between MMSE and IADL scores.

CONCLUSION: Progression rate varied considerably among AD patients; about half of the patients progressed slowly. Cognitive test results at baseline were predictors of progression rate.

%B J Alzheimers Dis %V 61 %P 1221-1232 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254085?dopt=Abstract %R 10.3233/JAD-170436 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Progression of Dementia and Cognitive Decline in a Dutch 2-Year Cohort Study of People with Young-Onset Dementia. %A Gerritsen, Adrie A J %A Bakker, Christian %A Verhey, Frans R J %A Bor, Hans %A Pijnenburg, Yolande A L %A de Vugt, Marjolein E %A Koopmans, Raymond T C M %X

BACKGROUND: The progression of dementia in people with young-onset dementia (YOD) is relatively unknown.

OBJECTIVE: To investigate the progression of dementia and cognitive decline in the three most common subtypes in YOD and to explore which factors are associated with this course.

METHODS: The course of dementia was examined in 198 people with YOD. The primary outcomes were cognitive function, as assessed by the Mini-Mental State Examination (MMSE) and dementia severity, as assessed by the Global Deterioration Scale (GDS). Mixed-model analyses were used to explore factors associated with the course of dementia of the diagnostic sub-types.

RESULTS: The mean overall two-year progression of dementia severity was 0.9 GDS points, this was a statistically significant change (p = 0.012) and was not significant different for the three dementia subtypes. The mean overall two-year decline in cognitive function was 1.6 points on the MMSE. The differences in cognitive decline were statistically significant (p = 0.046) among the three diagnosis groups, AD participants showed the greatest decline, of 2.3 points. In addition to lower education (p = 0.010), higher scores on the Neuropsychiatric Inventory (NPI) sub-syndromes psychosis (p < 0.001) and hyperactivity (p = 0.002) were associated with higher rates of cognitive decline. In contrast, higher scores on the NPI affect cluster were associated with lower levels of cognitive decline (p < 0.001).

CONCLUSION: Different YOD subtypes show different rates of decline in cognitive functioning, and this decline seems less progressive compared to those observed in studies in late-onset AD. Further research is needed to evaluate whether managing neuropsychiatric symptoms can positively influence the decline of cognitive function.

%B J Alzheimers Dis %V 63 %P 343-351 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614650?dopt=Abstract %R 10.3233/JAD-170859 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer's Disease. %A Reddy, P Hemachandra %A Manczak, Maria %A Yin, XiangLing %A Grady, Mary Catherine %A Mitchell, Andrew %A Tonk, Sahil %A Kuruva, Chandra Sekhar %A Bhatti, Jasvinder Singh %A Kandimalla, Ramesh %A Vijayan, Murali %A Kumar, Subodh %A Wang, Rui %A Pradeepkiran, Jangampalli Adi %A Ogunmokun, Gilbert %A Thamarai, Kavya %A Quesada, Kandi %A Boles, Annette %A Reddy, Arubala P %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Blood-Brain Barrier %K Curcumin %K Disease Models, Animal %K Humans %K Mice %K Neuroprotective Agents %K Randomized Controlled Trials as Topic %K Spices %X

The purpose of our article is to assess the current understanding of Indian spice, curcumin, against amyloid-β (Aβ)-induced toxicity in Alzheimer's disease (AD) pathogenesis. Natural products, such as ginger, curcumin, and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes, and neurological disorders. Products derived from plants are known to have protective effects, including anti-inflammatory, antioxidant, anti-arthritis, pro-healing, and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of AD. Recent research on Aβ and curcumin has revealed that curcumin prevents Aβ aggregation and crosses the blood-brain barrier, reach brain cells, and protect neurons from various toxic insults of aging and Aβ in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin's bioavailability and urgent need for new formulations to increase its brain levels to treat patients with AD.

%B J Alzheimers Dis %V 61 %P 843-866 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332042?dopt=Abstract %R 10.3233/JAD-170512 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Putative Gonadotropin-Releasing Hormone Agonist Therapy and Dementia: An Application of Medicare Hospitalization Claims Data. %A Smith, Mark A %A Bowen, Richard L %A Nguyen, Richard Q %A Perry, George %A Atwood, Craig S %A Rimm, Alfred A %X

BACKGROUND: Estrogen and hormone replacement therapies to reduce Alzheimer's disease (AD) have yielded conflicting results. However, this study proposes that the well-characterized increase in serum gonadotropins following menopause or andropause are accountable for the increased risk of developing AD among the elderly population.

OBJECTIVE: To determine the role of gonadotropins in the development of AD and investigate gonadotropin-releasing hormone (GnRH) agonist therapy as a potential preventative and/or disease-modifying approach to AD management.

METHODS: Male Medicare beneficiaries aged 67 to 75 and hospitalized with prostate cancer (n = 115,789) were compared to three control groups: men of the same demographics undergoing a cholecystectomy (n = 97,267), herniorrhaphy (n = 68,778), or transurethral prostatectomy (n = 267,691). A proportion of the patients hospitalized with prostate cancer were assumed to have low concentrations of serum gonadotropins and sex steroids as a result of GnRH agonist therapy, while those in the control groups were assumed to have elevated gonadotropin but lowered sex steroid levels that are associated with andropause in this age group.

RESULTS: The rates of development of select diagnoses of dementia, including AD, over a twelve-year follow-up period following surgery. When compared to control patients, men hospitalized with prostate cancer have a protection against dementia after twelve years of follow-up, with relative risks ranging from 0.48 to 0.83.

CONCLUSION: Patients with prostate cancer are treated with the GnRH analogue leuprolide acetate, our data suggest that leuprolide acetate may be therapeutic for AD via its downregulation of serum gonadotropins.

%B J Alzheimers Dis %V 63 %P 1269-1277 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782310?dopt=Abstract %R 10.3233/JAD-170847 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quality of Life, Care Resource Use, and Costs of Dementia in 8 European Countries in a Cross-Sectional Cohort of the Actifcare Study. %A Handels, Ron L H %A Sköldunger, Anders %A Bieber, Anja %A Edwards, Rhiannon Tudor %A Gonçalves-Pereira, Manuel %A Hopper, Louise %A Irving, Kate %A Jelley, Hannah %A Kerpershoek, Liselot %A Marques, Maria J %A Meyer, Gabriele %A Michelet, Mona %A Portolani, Elisa %A Røsvik, Janne %A Selbaek, Geir %A Stephan, Astrid %A de Vugt, Marjolein %A Wolfs, Claire %A Woods, Bob %A Zanetti, Orazio %A Verhey, Frans %A Wimo, Anders %X

BACKGROUND: With 10.5 million people with dementia in Europe and $301 billion associated costs, governments face challenges organizing access to care.

OBJECTIVE: To examine the costs related to formal and informal care use and quality of life for people with dementia in eight European countries, and explore the association with unmet needs.

METHODS: Cross-sectional data from 451 persons with dementia and their informal caregivers of the Actifcare cohort study were obtained. Formal and informal care use was multiplied by country specific unit prices of services. Needs were measured using the CANE and health-related quality of life (HRQOL) of the person with dementia (both self- and proxy-rated) and informal caregiver's quality of life using EQ-5D-5L, ICECAP-O, DEMQOL-U, and CarerQol utility scores. The association between costs and country, European region, and unmet needs was assessed using multi-level linear regression.

RESULTS: Self-rated EQ-5D-5L utility score was higher than proxy-rated (0.84 and 0.71, respectively). Informal caregivers' utility score was 0.84. Across eight countries annual mean costs of formal and informal care were approximately € 17,000. Unmet needs were not associated with annual costs of care, nor with proxy-rated HRQOL, but were associated with self-rated HRQOL.

CONCLUSION: We found varying relationships between unmet needs and quality of life, and no association between unmet needs and care costs, although the results were sensitive to various factors. Future research should further investigate the relation between unmet needs, quality of life and costs to generate a better understanding of the effects of (un)timely access to care.

%B J Alzheimers Dis %V 66 %P 1027-1040 %8 2018 %G eng %N 3 %R 10.3233/JAD-180275 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quantifying the Diagnostic Pathway for Patients with Cognitive Impairment: Real-World Data from Seven European and North American Countries. %A Ritchie, Craig W %A Black, Christopher M %A Khandker, Rezaul K %A Wood, Robert %A Jones, Eddie %A Hu, Xiaohan %A Ambegaonkar, Baishali M %X

To ensure that patients with dementia and their caregivers receive appropriate treatment and support, early diagnosis is essential but remains challenging. Real-world data from a multi-national, cross-sectional survey of physicians and their patients were analyzed to quantify the diagnostic pathway for dementia, including a focus on severity of patients' cognitive impairment (CI) at the time of symptom onset, referral and subsequent diagnosis. Data were collected for 7,620 patients with CI. Most patients saw a healthcare professional within 1 year of first symptoms and received a diagnosis within 3-7 months of initial consultation. However, only 20% of patients received a diagnosis before their disease progressed beyond the prodromal stage and 23.5% already had moderate CI at diagnosis. These findings show that the goal of identifying and diagnosing CI at the earliest stages of disease is, for many patients, not achieved. Efforts toward public awareness and proactive, earlier detection and intervention, must be maintained-indeed where possible invigorated.

%B J Alzheimers Dis %V 62 %P 457-466 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439347?dopt=Abstract %R 10.3233/JAD-170864 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers. %A Ramos de Matos, Mafalda %A Ferreira, Catarina %A Herukka, Sanna-Kaisa %A Soininen, Hilkka %A Janeiro, André %A Santana, Isabel %A Baldeiras, Ines %A Almeida, Maria Rosário %A Lleo, Alberto %A Dols-Icardo, Oriol %A Alcolea, Daniel %A Benussi, Luisa %A Binetti, Giuliano %A Paterlini, Anna %A Ghidoni, Roberta %A Nacmias, Benedetta %A Meulenbroek, Olga %A van Waalwijk van Doorn, Linda J C %A Kuiperi, H Bea J %A Hausner, Lucrezia %A Waldemar, Gunhild %A Simonsen, Anja Hviid %A Tsolaki, Magda %A Gkatzima, Olymbia %A Resende de Oliveira, Catarina %A Verbeek, Marcel M %A Clarimón, Jordi %A Hiltunen, Mikko %A de Mendonça, Alexandre %A Martins, Madalena %X

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

%B J Alzheimers Dis %V 66 %P 639-652 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320580?dopt=Abstract %R 10.3233/JAD-180512 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quantitative Magnetization Transfer of White Matter Tracts Correlates with Diffusion Tensor Imaging Indices in Predicting the Conversion from Mild Cognitive Impairment to Alzheimer's Disease. %A Makovac, Elena %A Serra, Laura %A Di Domenico, Carlotta %A Marra, Camillo %A Caltagirone, Carlo %A Cercignani, Mara %A Bozzali, Marco %X

Patients with amnestic mild cognitive impairment (aMCI) have higher probability to develop Alzheimer's disease (AD) than elderly controls. The detection of subtle changes in brain structure associated with disease progression and the development of tools to identify patients at high risk for dementia in a short time is crucial. Here, we used probabilistic white matter (WM) tractography to explore microstructural alterations within the main association, limbic, and commissural pathways in aMCI patients who converted to AD after 1 year follow-up (MCIconverters) and those who remained stable (MCIstable). Both diffusion tensor imaging (DTI) and quantitative magnetization transfer (qMT) parameters have been considered for a comprehensive pathophysiological characterization of the WM damage. Overall, tract-specific parameters derived from qMT and DTI at baseline were able to differentiate aMCI patients who converted to AD from those who remained stable in time. In particular, the qMT exchange rate, RMB0, of the right uncinate fasciculus was significantly decreased in MCIconverters, whereas fractional anisotropy was significantly decreased in the bilateral superior cingulum in MCIconverters compared to MCIstable. These results confirm the involvement of WM and particularly of association fibers in the progression of AD, highlighting disconnection as a potential mechanism.

%B J Alzheimers Dis %V 63 %P 561-575 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689722?dopt=Abstract %R 10.3233/JAD-170995 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quantitative PET and Histology of Brain Biopsy Reveal Lack of Selective Pittsburgh Compound-B Binding to Intracerebral Amyloidoma. %A Groot, Colin %A Tolboom, Nelleke %A Ikonomovic, Milos D %A Lammertsma, Adriaan A %A Boon, Baayla D C %A Barkhof, Frederik %A Scheltens, Philip %A Klunk, William E %A Rozemuller, Annemieke J M %A Ossenkoppele, Rik %A van Berckel, Bart N M %X

This single case study examines selective Pittsburgh compound-B (PiB) binding to an intracerebral light-chain amyloidoma using a 90-minute dynamic [11C]PiB-PET scan and brain biopsy tissue. Parametric non-displaceable binding potential (BPND) images showed low specific binding in the amyloidoma (BPND = 0.23), while relative tracer delivery was adequate (R1 = 0.44). Histology of the tissue revealed strong coloring with Congo-red, thioflavin-S, and X-34, indicating presence of amyloid. However, immunological staining with 6F/3D revealed absence of amyloid-β and histofluorescence of 6-CN-PiB, a highly fluorescent derivative of PiB, was at background levels. Our results suggest that PiB does not detect the atypical amyloid pathology associated with an intracerebral light-chain amyloidoma. These findings are of interest to clinicians and researchers applying [11C]PiB-PET to detect atypical forms of amyloid pathology.

%B J Alzheimers Dis %8 2018 Jul 18 %G eng %R 10.3233/JAD-180316 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quantitative Susceptibility Mapping of Amyloid-β Aggregates in Alzheimer's Disease with 7T MR. %A Tiepolt, Solveig %A Schäfer, Andreas %A Rullmann, Michael %A Roggenhofer, Elisabeth %A Gertz, Hermann-Josef %A Schroeter, Matthias L %A Patt, Marianne %A Bazin, Pierre-Louis %A Jochimsen, Thies H %A Turner, Robert %A Sabri, Osama %A Barthel, Henryk %X

BACKGROUND: PET imaging is an established technique to detect cerebral amyloid-β (Aβ) plaques in vivo. Some preclinical and postmortem data report an accumulation of redox-active iron near Aβ plaques. Quantitative susceptibility mapping (QSM) at high-field MRI enables iron deposits to be depicted with high spatial resolution.

OBJECTIVE: Aim of this study was to examine whether iron and Aβ plaque accumulation is related and thus, whether 7T MRI might be an additive diagnostic tool to Aβ PET imaging.

METHODS: Postmortem human Alzheimer's disease (AD) and healthy control (HC) frontal gray matter (GM) was imaged with 7T MRI which resulted in T1 maps and QSM. Aβ plaque load was determined by histopathology. In vivo, 10 Aβ PET-positive AD patients (74.1±6.0a) and 10 Aβ PET-negative HCs (67.1±4.4a) underwent 7T MR examination and QSM maps were analyzed. Severity of cognitive deficits was determined by MMSE.

RESULTS: Postmortem, the susceptibility of Aβ plaque-containing GM were higher than those of Aβ plaque-free GM (0.011±0.002 versus - 0.008±0.003 ppm, p < 0.001). In vivo, only the bilateral globus pallidus showed significantly higher susceptibility in AD patients compared to HCs (right: 0.277±0.018 versus - 0.009±0.009 ppm; left: 0.293±0.014 versus - 0.007±0.012 ppm, p < 0.0001). The pallidal QSM values were negatively correlated with those of the MMSE (r = - 0.69, p = 0.001).

CONCLUSION: The postmortem study revealed significant susceptibility differences between the Aβ plaque-containing and Aβ plaque-free GM, whereas in vivo only the QSM values of the globus pallidus differed significantly between AD and HC group. The pallidal QSM values correlated with the severity of cognitive deficits. These findings encourage efforts to optimize the 7T-QSM methodology.

%B J Alzheimers Dis %V 64 %P 393-404 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865069?dopt=Abstract %R 10.3233/JAD-180118 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Rationale and Design of the Mechanistic Potential of Antihypertensives in Preclinical Alzheimer's (HEART) Trial. %A Wharton, Whitney %A Goldstein, Felicia C %A Tansey, Malú G %A Brown, Alexandra L %A Tharwani, Sonum D %A Verble, Danielle D %A Cintron, Amarallys %A Kehoe, Patrick G %K African Americans %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Antihypertensive Agents %K Biomarkers %K Blood Pressure %K Brain %K Clinical Trials, Phase I as Topic %K Female %K Georgia %K Humans %K Linear Models %K Male %K Middle Aged %K Randomized Controlled Trials as Topic %K Renin-Angiotensin System %K Telmisartan %X

Research indicates that certain antihypertensive medications alter Alzheimer's disease (AD) biomarkers in Caucasians. The renin angiotensin system (RAS) regulates blood pressure (BP) in the body and the brain and may directly influence AD biomarkers, including amyloid-β (Aβ) neuropathology, cerebral blood flow (CBF), and inflammatory markers. This hypothesis is supported by studies, including ours, showing that antihypertensives targeting the RAS reduce the risk and slow the progression of AD in Caucasians. While mounting evidence supports a protective role of RAS medications in Caucasians, this mechanism has not been explored in African Americans. To assess the mechanism by which RAS medications modify the brain RAS, cerebrospinal fluid (CSF) Aβ, CBF, and inflammatory markers in African Americans, we are conducting an eight month, Phase Ib randomized, placebo controlled trial, enrolling 60 middle-aged (45-70 years), non-demented individuals, at risk for AD by virtue of a parental history. Participants include normotensive and treated hypertensives that have never been exposed to a RAS medication. Participants are randomized (1 : 1:1) by gender and BP medication use (yes/no) to one of three groups: placebo, or 20 mg, or 40 mg telmisartan (Micardis), to determine the dose required to penetrate the CNS. Our overarching hypothesis is that, compared to placebo, both doses of telmisartan will penetrate the CNS and produce salutary, dose dependent effects on the brain RAS as well as CSF Aβ, CBF, and CSF inflammatory markers in African Americans, over eight months. This manuscript describes the trial rationale and design.

%B J Alzheimers Dis %V 61 %P 815-824 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254080?dopt=Abstract %R 10.3233/JAD-161198 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Rationale and Design of the Reducing Pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR) Trial. %A Kehoe, Patrick G %A Blair, Peter S %A Howden, Beth %A Thomas, David L %A Malone, Ian B %A Horwood, Jeremy %A Clement, Clare %A Selman, Lucy E %A Baber, Hannah %A Lane, Athene %A Coulthard, Elizabeth %A Passmore, Anthony Peter %A Fox, Nick C %A Wilkinson, Ian B %A Ben-Shlomo, Yoav %K Activities of Daily Living %K Alzheimer Disease %K Antihypertensive Agents %K Atrophy %K Blood Pressure Monitors %K Brain %K Clinical Trials, Phase II as Topic %K Disease Progression %K Double-Blind Method %K Female %K Humans %K Losartan %K Magnetic Resonance Imaging %K Male %K Multivariate Analysis %K Quality of Life %K Randomized Controlled Trials as Topic %K Regression Analysis %K Renin-Angiotensin System %X

BACKGROUND: Anti-hypertensives that modify the renin angiotensin system may reduce Alzheimer's disease (AD) pathology and reduce the rate of disease progression.

OBJECTIVE: To conduct a phase II, two arm, double-blind, placebo-controlled, randomized trial of losartan to test the efficacy of Reducing pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR).

METHODS: Men and women aged at least 55 years with mild-to-moderate AD will be randomly allocated 100 mg encapsulated generic losartan or placebo once daily for 12 months after successful completion of a 2-week open-label phase and 2-week placebo washout to establish drug tolerability. 228 participants will provide at least 182 subjects with final assessments to provide 84% power to detect a 25% difference in atrophy rate (therapeutic benefit) change over 12 months at an alpha level of 0.05. We will use intention-to-treat analysis, estimating between-group differences in outcomes derived from appropriate (linear or logistic) multivariable regression models adjusting for minimization variables.

RESULTS: The primary outcome will be rate of whole brain atrophy as a surrogate measure of disease progression. Secondary outcomes will include changes to 1) white matter hyperintensity volume and cerebral blood flow; 2) performance on a standard series of assessments of memory, cognitive function, activities of daily living, and quality of life. Major assessments (for all outcomes) and relevant safety monitoring of blood pressure and bloods will be at baseline and 12 months. Additional cognitive assessment will also be conducted at 6 months along with safety blood pressure and blood monitoring. Monitoring of blood pressure, bloods, and self-reported side effects will occur during the open-label phase and during the majority of the post-randomization dispensing visits.

CONCLUSION: This study will identify whether losartan is efficacious in the treatment of AD and whether definitive Phase III trials are warranted.

%B J Alzheimers Dis %V 61 %P 803-814 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226862?dopt=Abstract %R 10.3233/JAD-170101 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Real-World, Multinational, Retrospective Observational Survey of the ADAS-Cog and Associations with Healthcare Resource Utilization in Patients with Alzheimer's Disease. %A Ritchie, Craig W %A Khandker, Rezaul K %A Pike, James %A Black, Christopher M %A Jones, Eddie %A Ambegaonkar, Baishali M %X

BACKGROUND: Alzheimer's disease (AD) is one of the most costly conditions, both economically and regarding patient disability and dependency. The huge costs coupled with the predicted increase in prevalence worldwide are likely to challenge healthcare systems in the future. The classic version of the Alzheimer's Disease Assessment Scale-Cognition subscale (ADAS-Cog) is generally seen as the current gold standard primary outcome measure of cognitive symptom progression in dementia clinical trials.

OBJECTIVE: This study evaluated the relationship between ADAS-Cog scores as a measure of clinical progression and the healthcare resource utilization (HCRU)-measured burden of cognitive impairment in patients with mild cognitive impairment, AD, or suspected AD in the real world.

METHODS: A retrospective observational survey of physicians and their consulting patients with multiple ADAS-Cog scores. Regression models were constructed for HCRU variables (e.g., consultations, hospitalizations, caregiving requirements) with ADAS-Cog rate of change, baseline ADAS-Cog, and their interaction included as exposure variables.

RESULTS: 651 patient records were completed by 154 physicians. Approximately 70% of patients had mild to moderate dementia. In 56.7% of patients, clinical progression was maintained/stable from baseline. Mean change in ADAS-Cog (adjusted to 12 months) was 2.8 points and change scores increased with increasing dementia severity. Most HCRU variables increased significantly (p < 0.05; joint test) with increasing ADAS-Cog scores (indexing clinical deterioration).

CONCLUSION: The results suggest that further understanding the relationship between HCRU and ADAS-Cog changes in real-world clinical practice could potentially provide a baseline upon which the success of disease-modifying, as well as newer symptomatic, dementia therapies can be judged.

%B J Alzheimers Dis %V 64 %P 899-910 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966202?dopt=Abstract %R 10.3233/JAD-180306 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Reappraisal of Aβ40 and Aβ42 Peptides Measurements in Cerebrospinal Fluid of Patients with Alzheimer's Disease. %A Fiorini, Michele %A Bongianni, Matilde %A Benedetti, Maria Donata %A Monaco, Salvatore %A Zanusso, Gianluigi %X

Cerebrospinal fluid (CSF) biomarkers are currently included in the diagnostic criteria for Alzheimer's disease (AD), in particular, decreased concentrations of amyloid-β peptide 1-42 (Aβ42) in the CSF, coupled with increased levels of tau and phosphorylated tau proteins, are supportive of AD diagnosis. To date, the quantification of Aβ42 levels with antibody-dependent immunoassay shows a marked variability among different laboratories and is also affected by different pre-analytical factors, suggesting that part of Aβ42 peptides might be aggregated and thus undetected by antibodies. To bypass an antibody-dependent measurement, we determined the Aβ40 and Aβ42 levels by immunoblot. We analyzed CSF samples from 35 patients with clinical diagnosis of probable AD and from 15 age-matched normal controls; CSF Aβ levels were determined by two different ELISA kits and by immunoblot analysis. Aβ40 levels measured by ELISA were comparable to those obtained by immunoblot, whereas CSF concentrations of Aβ42 measured by ELISA were significantly lower compared to values obtained by immunoblot quantification. Biochemical analysis, following 1D- and 2D-PAGE analysis, showed that the qualitative composition of Aβ peptides in the CSF is similar in AD and controls but different from that of AD brain tissues. Moreover, sedimentation velocity in sucrose gradient of CSF and brain homogenate from AD demonstrated that Aβ42 in CSF is different from Aβ42 in brain in terms of solubility and aggregation state.

%B J Alzheimers Dis %V 66 %P 219-227 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282368?dopt=Abstract %R 10.3233/JAD-180616 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Reduced Gray Matter Volume of the Thalamus and Hippocampal Region in Elderly Healthy Adults with no Impact of APOE ɛ4: A Longitudinal Voxel-Based Morphometry Study. %A Squarzoni, Paula %A Duran, Fabio Luis Souza %A Busatto, Geraldo F %A Alves, Tania Correa Toledo de Ferraz %K Aged %K Aging %K Apolipoprotein E4 %K Atrophy %K Cross-Sectional Studies %K Female %K Gray Matter %K Healthy Volunteers %K Hippocampus %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Organ Size %K Thalamus %X

BACKGROUND: Many cross-sectional voxel-based morphometry (VBM) investigations have shown significant inverse correlations between chronological age and gray matter (GM) volume in several brain regions in healthy humans. However, few VBM studies have documented GM decrements in the healthy elderly with repeated MRI measurements obtained in the same subjects. Also, the extent to which the APOE ɛ4 allele influences longitudinal findings of GM reduction in the healthy elderly is unclear.

OBJECTIVE: Verify whether regional GM changes are associated with significant decrements in cognitive performance taking in account the presence of the APOE ɛ4 allele.

METHODS: Using structural MRI datasets acquired in 55 cognitively intact elderly subjects at two time-points separated by approximately three years, we searched for voxels showing significant GM reductions taking into account differences in APOE genotype.

RESULTS: We found global GM reductions as well as regional GM decrements in the right thalamus and left parahippocampal gyrus (p < 0.05, family-wise error corrected for multiple comparisons over the whole brain). These findings were not affected by APOE ɛ4.

CONCLUSIONS: Irrespective of APOE ɛ4, longitudinal VBM analyses show that the hippocampal region and thalamus are critical sites where GM shrinkage is greater than the degree of global volume reduction in healthy elderly subjects.

%B J Alzheimers Dis %V 62 %P 757-771 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480170?dopt=Abstract %R 10.3233/JAD-161036 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Relationship Between Body Mass Index, ApoE4 Status, and PET-Based Amyloid and Neurodegeneration Markers in Amyloid-Positive Subjects with Normal Cognition or Mild Cognitive Impairment. %A Blautzik, Janusch %A Kotz, Sebastian %A Brendel, Matthias %A Sauerbeck, Julia %A Vettermann, Franziska %A Winter, Yaroslav %A Bartenstein, Peter %A Ishii, Kazunari %A Rominger, Axel %X

Body weight loss in late-life is known to occur at a very early stage of Alzheimer's disease (AD). Apolipoprotein E4 (ApoE4) represents a major genetic risk factor for AD and is linked to an increased cortical amyloid-β (Aβ) accumulation. Since the relationship between body weight, ApoE4, and AD pathology is poorly investigated, we aimed to evaluate whether ApoE4 allelic status modifies the association of body mass index (BMI) with markers of AD pathology. A total of 368 Aβ-positive cognitively healthy or mild cognitive impaired subjects had undergone [18F]-AV45-PET, [18F]-FDG-PET, and T1w-MRI examinations. Composite cortical [18F]-AV45 uptake and [18F]-FDG uptake in posterior cingulate cortex were calculated as surrogates of cortical Aβ load and glucose metabolism, respectively. Multiple linear regressions were performed to assess the relationships between these PET biomarkers with BMI, present cognitive performance, and cognitive changes over time. Multivariate analysis of covariance was conducted to test for statistical differences between ApoE4/BMI categories on the PET markers and cognitive scores. In carriers of the ApoE4 allele only, BMI was inversely associated with cortical amlyoid load (β= -0.193, p < 0.005) and recent cognitive decline (β= -0.209, p < 0.05), and positively associated with cortical glucose metabolism in an AD-vulnerable region (β= 0.145, p < 0.05). ApoE4/BMI category analyses demonstrated lower Aβ load, higher posterior cingulate glucose metabolism, improved cognitive performance, and lower progression of cognitive decline in obese ApoE4 carriers. The effect of ApoE4 in promoting the accumulation of cortical amyoid, which may itself be a driver for weight loss, may be moderated by altering leptin signaling in the hypothalamus.

%B J Alzheimers Dis %V 65 %P 781-791 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697560?dopt=Abstract %R 10.3233/JAD-170064 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Relationship between Obstructive Sleep Apnea and Alzheimer's Disease. %A Andrade, Andreia G %A Bubu, Omonigho M %A Varga, Andrew W %A Osorio, Ricardo S %X

Obstructive sleep apnea (OSA) and Alzheimer's disease (AD) are highly prevalent conditions with growing impact on our aging society. While the causes of OSA are now better characterized, the mechanisms underlying AD are still largely unknown, challenging the development of effective treatments. Cognitive impairment, especially affecting attention and executive functions, is a recognized clinical consequence of OSA. A deeper contribution of OSA to AD pathogenesis is now gaining support from several lines of research. OSA is intrinsically associated with disruptions of sleep architecture, intermittent hypoxia and oxidative stress, intrathoracic and hemodynamic changes as well as cardiovascular comorbidities. All of these could increase the risk for AD, rendering OSA as a potential modifiable target for AD prevention. Evidence supporting the relevance of each of these mechanisms for AD risk, as well as a possible effect of AD in OSA expression, will be explored in this review.

%B J Alzheimers Dis %V 64 %P S255-S270 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782319?dopt=Abstract %R 10.3233/JAD-179936 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Relevance of Coded Prodromal Mild Cognitive Impairment in the Routine Treatment of Patients with Dementia in Germany. %A Bohlken, Jens %A Kostev, Karel %X

Little is known about the impact of prior mild cognitive impairment (MCI, ICD-10: F06.7) diagnosis on the time to dementia diagnosis, anti-dementia drug therapy, and treatment persistence in patients with dementia (PWD). Patients with dementia diagnoses who started anti-dementia therapy between January 2010 and December 2016 were selected from 203 neurological/psychiatric practices in the Disease Analyzer databank (IQVIA). Patients with a history of MCI were compared to non-MCI controls in terms of demographic characteristics, anti-dementia therapy, and the rate of persistence with anti-dementia drugs. For persistence analyses, a 1:1 matching procedure was used based on age, gender, type of residence, and depression and dementia diagnosis. Persistence was represented using Kaplan-Meier curves. A Cox regression analysis was used to determine the influence of MCI diagnosis on persistence with anti-dementia drugs. 339 PWD with MCI diagnoses and 339 controls were available for analysis. PWD with MCI were younger (78.9 versus 80.4 years), less likely to live in a nursing home (8.5% versus 22.5%), more frequently received donepezil (40.1% versus 33.7%), and more likely to exhibit comorbid depression (29.6% versus 16.9%). There was no association between the risk of treatment discontinuation and prior MCI diagnosis. After 24 months, 40% versus 41.1% of patients had discontinued treatment. The prior MCI diagnosis presumably led to an earlier diagnosis of dementia and earlier anti-dementia treatment. Treatment continuity did not differ, which would suggest that it does not depend on prior MCI diagnosis but on the behavior of patients and their caregiving relatives.

%B J Alzheimers Dis %V 65 %P 393-399 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056428?dopt=Abstract %R 10.3233/JAD-180567 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Religious Orders Study and Rush Memory and Aging Project. %A Bennett, David A %A Buchman, Aron S %A Boyle, Patricia A %A Barnes, Lisa L %A Wilson, Robert S %A Schneider, Julie A %X

BACKGROUND: The Religious Orders Study and Rush Memory and Aging Project are both ongoing longitudinal clinical-pathologic cohort studies of aging and Alzheimer's disease (AD).

OBJECTIVES: To summarize progress over the past five years and its implications for understanding neurodegenerative diseases.

METHODS: Participants in both studies are older adults who enroll without dementia and agree to detailed longitudinal clinical evaluations and organ donation. The last review summarized findings through the end of 2011. Here we summarize progress and study findings over the past five years and discuss new directions for how these studies can inform on aging and AD in the future.

RESULTS: We summarize 1) findings on the relation of neurobiology to clinical AD; 2) neurobiologic pathways linking risk factors to clinical AD; 3) non-cognitive AD phenotypes including motor function and decision making; 4) the development of a novel drug discovery platform.

CONCLUSION: Complexity at multiple levels needs to be understood and overcome to develop effective treatments and preventions for cognitive decline and AD dementia.

%B J Alzheimers Dis %V 64 %P S161-S189 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865057?dopt=Abstract %R 10.3233/JAD-179939 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Reproducibility of Alzheimer's Disease Cerebrospinal Fluid-Biomarker Measurements under Clinical Routine Conditions. %A Vogelgsang, Jonathan %A Wedekind, Dirk %A Bouter, Caroline %A Klafki, Hans-W %A Wiltfang, Jens %X

Analysis of cerebrospinal fluid (CSF) is one of the key tools for the state-of-the-art differential diagnosis of dementias. Dementia due to Alzheimer's disease (AD) is characterized by elevated CSF levels of total Tau (tTau) and phospho-181-Tau (pTau) and low CSF amyloid-β42 (Aβ42). Discrepancies in the laboratory analysis of human materials are well known and much effort has been put into harmonization procedures. In this study, we measured CSF biomarkers of more than 100 patients obtained under clinical routine conditions in two different clinical laboratories. The CSF biomarker levels obtained from the two different sites were significantly correlated: R2 = 0.7129 (tTau, p < 0.001), 0.7914 (pTau, p < 0.001), 0.5078 (Aβ42, p < 0.001), 0.5739 (Aβ40, p < 0.001), and 0.4308 (Aβ42/40, p < 0.001). However, the diagnostic classifications of the Aβ42, tTau, and pTau levels of identical subjects into normal versus pathological range made by the two different sites showed substantial discrepancies (31.5%, 29.6%, and 25.0% discordant cases, respectively). Applying Aβ42/40, instead of CSF Aβ42 alone, lead to a reduction of the discordant cases to 16.8%. Our findings suggest that CSF Aβ42/40 can outperform Aβ42 as a biomarker for AD neuropathology, not only under well-controlled study conditions but also in real life clinical routine. Thus, we recommend the inclusion of Aβ42/40 as a CSF biomarker in the diagnostic procedure.

%B J Alzheimers Dis %V 62 %P 203-212 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439341?dopt=Abstract %R 10.3233/JAD-170793 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Rethinking the Reserve with a Translational Approach: Novel Ideas on the Construct and the Interventions. %A Serra, Laura %A Gelfo, Francesca %A Petrosini, Laura %A Di Domenico, Carlotta %A Bozzali, Marco %A Caltagirone, Carlo %X

The concept of brain, cognitive, and neural reserves has been introduced to account for the apparent discrepancies between neurological damage and clinical manifestations. However, these ideas are yet theoretical suggestions that are not completely assimilated in the clinical routine. The mechanisms of the reserves have been extensively studied in neurodegenerative pathologies, in particular in Alzheimer's disease. Both human and animal studies addressed this topic by following two parallel pathways. The specific aim of the present review is to attempt to combine the suggestions derived from the two different research fields to deepen the knowledge about reserves. In fact, the achievement of a comprehensive theoretical framework on reserve mechanisms is an essential step to propose well-timed interventions tailored to the clinical characteristics of patients. The present review highlights the importance of addressing three main aspects: the definition of reserve proxy measures, the interaction between reserve level and therapeutic interventions, and the specific time-window of reserve efficacy.

%B J Alzheimers Dis %V 65 %P 1065-1078 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149458?dopt=Abstract %R 10.3233/JAD-180609 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Retrospective Belgian Multi-Center MRI Biomarker Study in Alzheimer's Disease (REMEMBER). %A Niemantsverdriet, Ellis %A Ribbens, Annemie %A Bastin, Christine %A Benoit, Florence %A Bergmans, Bruno %A Bier, Jean-Christophe %A Bladt, Roxanne %A Claes, Lene %A De Deyn, Peter Paul %A Deryck, Olivier %A Hanseeuw, Bernard %A Ivanoiu, Adrian %A Lemper, Jean-Claude %A Mormont, Eric %A Picard, Gaëtane %A Salmon, Eric %A Segers, Kurt %A Sieben, Anne %A Smeets, Dirk %A Struyfs, Hanne %A Thiery, Evert %A Tournoy, Jos %A Triau, Eric %A Vanbinst, Anne-Marie %A Versijpt, Jan %A Bjerke, Maria %A Engelborghs, Sebastiaan %X

BACKGROUND: Magnetic resonance imaging (MRI) acquisition/processing techniques assess brain volumes to explore neurodegeneration in Alzheimer's disease (AD).

OBJECTIVE: We examined the clinical utility of MSmetrix and investigated if automated MRI volumes could discriminate between groups covering the AD continuum and could be used as a predictor for clinical progression.

METHODS: The Belgian Dementia Council initiated a retrospective, multi-center study and analyzed whole brain (WB), grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), cortical GM (CGM) volumes, and WM hyperintensities (WMH) using MSmetrix in the AD continuum. Baseline (n = 887) and follow-up (FU, n = 95) T1-weighted brain MRIs and time-linked neuropsychological data were available.

RESULTS: The cohort consisted of cognitively healthy controls (HC, n = 93), subjective cognitive decline (n = 102), mild cognitive impairment (MCI, n = 379), and AD dementia (n = 313). Baseline WB and GM volumes could accurately discriminate between clinical diagnostic groups and were significantly decreased with increasing cognitive impairment. MCI patients had a significantly larger change in WB, GM, and CGM volumes based on two MRIs (n = 95) compared to HC (FU>24months, p = 0.020). Linear regression models showed that baseline atrophy of WB, GM, CGM, and increased CSF volumes predicted cognitive impairment.

CONCLUSION: WB and GM volumes extracted by MSmetrix could be used to define the clinical spectrum of AD accurately and along with CGM, they are able to predict cognitive impairment based on (decline in) MMSE scores. Therefore, MSmetrix can support clinicians in their diagnostic decisions, is able to detect clinical disease progression, and is of help to stratify populations for clinical trials.

%B J Alzheimers Dis %V 63 %P 1509-1522 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782314?dopt=Abstract %R 10.3233/JAD-171140 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology. %A Hampel, Harald %A Toschi, Nicola %A Babiloni, Claudio %A Baldacci, Filippo %A Black, Keith L %A Bokde, Arun L W %A Bun, René S %A Cacciola, Francesco %A Cavedo, Enrica %A Chiesa, Patrizia A %A Colliot, Olivier %A Coman, Cristina-Maria %A Dubois, Bruno %A Duggento, Andrea %A Durrleman, Stanley %A Ferretti, Maria-Teresa %A George, Nathalie %A Genthon, Remy %A Habert, Marie-Odile %A Herholz, Karl %A Koronyo, Yosef %A Koronyo-Hamaoui, Maya %A Lamari, Foudil %A Langevin, Todd %A Lehéricy, Stéphane %A Lorenceau, Jean %A Neri, Christian %A Nisticò, Robert %A Nyasse-Messene, Francis %A Ritchie, Craig %A Rossi, Simone %A Santarnecchi, Emiliano %A Sporns, Olaf %A Verdooner, Steven R %A Vergallo, Andrea %A Villain, Nicolas %A Younesi, Erfan %A Garaci, Francesco %A Lista, Simone %K Alzheimer Disease %K Animals %K Brain %K Humans %K Neurology %K Neurophysiology %K Precision Medicine %K Systems Biology %K Translational Medical Research %X

The Precision Neurology development process implements systems theory with system biology and neurophysiology in a parallel, bidirectional research path: a combined hypothesis-driven investigation of systems dysfunction within distinct molecular, cellular, and large-scale neural network systems in both animal models as well as through tests for the usefulness of these candidate dynamic systems biomarkers in different diseases and subgroups at different stages of pathophysiological progression. This translational research path is paralleled by an "omics"-based, hypothesis-free, exploratory research pathway, which will collect multimodal data from progressing asymptomatic, preclinical, and clinical neurodegenerative disease (ND) populations, within the wide continuous biological and clinical spectrum of ND, applying high-throughput and high-content technologies combined with powerful computational and statistical modeling tools, aimed at identifying novel dysfunctional systems and predictive marker signatures associated with ND. The goals are to identify common biological denominators or differentiating classifiers across the continuum of ND during detectable stages of pathophysiological progression, characterize systems-based intermediate endophenotypes, validate multi-modal novel diagnostic systems biomarkers, and advance clinical intervention trial designs by utilizing systems-based intermediate endophenotypes and candidate surrogate markers. Achieving these goals is key to the ultimate development of early and effective individualized treatment of ND, such as Alzheimer's disease. The Alzheimer Precision Medicine Initiative (APMI) and cohort program (APMI-CP), as well as the Paris based core of the Sorbonne University Clinical Research Group "Alzheimer Precision Medicine" (GRC-APM) were recently launched to facilitate the passageway from conventional clinical diagnostic and drug development toward breakthrough innovation based on the investigation of the comprehensive biological nature of aging individuals. The APMI movement is gaining momentum to systematically apply both systems neurophysiology and systems biology in exploratory translational neuroscience research on ND.

%B J Alzheimers Dis %V 64 %P S47-S105 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad179932?id=journal-of-alzheimers-disease%2Fjad179932 %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562524?dopt=Abstract %R 10.3233/JAD-179932 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Risk Factors Associated with Cortical Thickness and White Matter Hyperintensities in Dementia Free Okinawan Elderly. %A Silbert, Lisa C %A Lahna, David %A Promjunyakul, Nutta-On %A Boespflug, Erin %A Ohya, Yusuke %A Higashiuesato, Yasushi %A Nishihira, Junko %A Katsumata, Yuriko %A Tokashiki, Takashi %A Dodge, Hiroko H %X

BACKGROUND: Cortical gray matter (GM) and white matter (WM) deterioration are signals of neurodegeneration and increased dementia risk; however, their specific etiologies in dementia-free aging is unclear.

OBJECTIVE: The objective of this study was to examine potentially modifiable risk factors of GM and WM degeneration in a well-characterized cohort of dementia-free elderly.

METHODS: 96 Okinawan elderly participants (age 83.6) from the Keys to Optimal Cognitive Aging Project (KOCOA) underwent MRI and cognitive evaluation. Serum markers of inflammation (interleukin-6 (IL-6), high sensitivity C-reactive protein), cerebrovascular disease (systolic blood pressure (SBP) 140+, hemoglobin A1C (HgbA1C), total cholesterol), and essential minerals (copper (Cu), magnesium, and calcium) were examined in relation to mean cortical thickness (MCT) and white matter hyperintensities (WMH), adjusting for age and gender. Voxel-based morphometry (VBM) analyses identified relationships between regional GM density and the above markers.

RESULTS: Decreased MCT was associated with SBP 140 + (p = 0.029) and increased serum IL-6 (p = 0.036), HgbA1C (p = 0.002), and Cu (p = 0.025). In VBM analyses, increased IL-6, HgbA1C, and Cu were associated with decreased GM density in temporal lobe regions. HgbA1C (p = 0.004) was associated with greater WMH volume.

CONCLUSIONS: Peripheral markers of Cu, CVD risk, and inflammation are associated with MRI-markers of decreased brain health in dementia-free Okinawan elderly, with regional cortical thinning in areas involved in early accumulation of Alzheimer's disease pathology. Results identify potentially modifiable biomarkers as targets in the prevention of dementia in older individuals.

%B J Alzheimers Dis %V 63 %P 365-372 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578488?dopt=Abstract %R 10.3233/JAD-171153 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Role of Amyloid-β and Tau Proteins in Alzheimer's Disease: Confuting the Amyloid Cascade. %A Gulisano, Walter %A Maugeri, Daniele %A Baltrons, Marian A %A Fà, Mauro %A Amato, Arianna %A Palmeri, Agostino %A D'Adamio, Luciano %A Grassi, Claudio %A Devanand, D P %A Honig, Lawrence S %A Puzzo, Daniela %A Arancio, Ottavio %X

The "Amyloid Cascade Hypothesis" has dominated the Alzheimer's disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of Aβ and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms between the two proteins in all of these phenomena. We discuss novel findings showing binding of both Aβ and tau oligomers to amyloid-β protein precursor (AβPP), and the requirement for the presence of this protein for both Aβ and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of Aβ and tau act in parallel and upstream of AβPP. Such a view will call for a reconsideration of therapeutic approaches directed against Aβ and tau, paving the way to an increased interest toward AβPP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies.

%B J Alzheimers Dis %V 64 %P S611-S631 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865055?dopt=Abstract %R 10.3233/JAD-179935 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Role of Neuroinflammation in the Trajectory of Alzheimer's Disease and in vivo Quantification Using PET. %A Edison, Paul %A Brooks, David J %X

Recent evidence suggests that neuroinflammation and immunity play a significant role in Alzheimer's disease and other neurodegenerative diseases. It has also been observed that, independent of the presence of aggregated proteins, neuroinflammation could be present in different neurodegenerative diseases. It has also been suggested that neuroinflammation could occur well ahead of amyloid deposition in AD. Recent genetic studies and other preclinical studies specifically point to a role of neuroinflammation and, in this review, we evaluate the evidence of neuroinflammation in the Alzheimer's disease trajectory and the different imaging modalities by which we could monitor neuroinflammation in vivo in humans.

%B J Alzheimers Dis %V 64 %P S339-S351 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865053?dopt=Abstract %R 10.3233/JAD-179929 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Role of Verb Fluency in the Detection of Early Cognitive Impairment in Alzheimer's Disease. %A Alegret, Montserrat %A Peretó, Mar %A Pérez, Alba %A Valero, Sergi %A Espinosa, Ana %A Ortega, Gemma %A Hernandez, Isabel %A Mauleón, Ana %A Rosende-Roca, Maitee %A Vargas, Liliana %A Rodríguez-Gómez, Octavio %A Abdelnour, Carla %A Berthier, Marcelo L %A Bak, Thomas H %A Ruiz, Agustin %A Tárraga, Lluís %A Boada, Merce %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Cognitive Dysfunction %K Cross-Sectional Studies %K Early Diagnosis %K Executive Function %K Female %K Humans %K Language Tests %K Logistic Models %K Longitudinal Studies %K Male %K Middle Aged %K Proportional Hazards Models %K Sensitivity and Specificity %K Spain %X

BACKGROUND: Verb fluency (VF) is the less commonly used fluency test, despite several studies suggesting its potential as a neuropsychological assessment tool.

OBJECTIVE: To investigate the presence of VF deficits in mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) dementia; to assess the usefulness of VF in the detection of cognitively healthy (CH) people who will convert to MCI, and from MCI to dementia; and to establish the VF cut-offs useful in the cognitive assessment of Spanish population.

METHODS: 568 CH, 885 MCI, and 367 mild AD dementia individuals were administered the VF test and a complete neuropsychological battery. Longitudinal analyses were performed in 231 CH and 667 MCI subjects to search for VF predictors of diagnosis conversion.

RESULTS: A worsening on VF performance from CH, MCI to AD dementia groups was found. Lower performances on VF were significantly related to conversion from CH to MCI/MCI to dementia. When the effect of time to conversion was analyzed, a significant effect of VF was found on the faster conversion from CH to MCI, but not from MCI to dementia. Moreover, VF cut-off scores and sensitivity/specificity values were calculated for 6 conditions (3 age ranges by 2 educational levels).

CONCLUSION: The VF test may be a useful tool for the differential diagnosis of cognitive failure in the elderly. Since VF deficits seem to take place in early stages of the disease, it is a suitable neuropsychological tool for the detection not only of CH people who will convert to MCI, but also from MCI to dementia.

%B J Alzheimers Dis %V 62 %P 611-619 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480180?dopt=Abstract %R 10.3233/JAD-170826 %0 Journal Article %J J Alzheimers Dis %D 2018 %T S-[18F]THK-5117-PET and [11C]PIB-PET Imaging in Idiopathic Normal Pressure Hydrocephalus in Relation to Confirmed Amyloid-β Plaques and Tau in Brain Biopsies. %A Leinonen, Ville %A Rauramaa, Tuomas %A Johansson, Jarkko %A Bottelbergs, Astrid %A Tesseur, Ina %A van der Ark, Peter %A Pemberton, Darrel %A Koivisto, Anne M %A Jääskeläinen, Juha E %A Hiltunen, Mikko %A Herukka, Sanna-Kaisa %A Blennow, Kaj %A Zetterberg, Henrik %A Jokinen, Pekka %A Rokka, Johanna %A Helin, Semi %A Haaparanta-Solin, Merja %A Solin, Olof %A Okamura, Nobuyuki %A Kolb, Hartmuth C %A Rinne, Juha O %X

BACKGROUND: Detection of pathological tau aggregates could facilitate clinical diagnosis of Alzheimer's disease (AD) and monitor drug effects in clinical trials. S-[18F]THK-5117 could be a potential tracer to detect pathological tau deposits in brain. However, no previous study have correlated S-[18F]THK-5117 uptake in PET with brain biopsy verified tau pathology in vivo.

OBJECTIVE: Here we aim to evaluate the association between cerebrospinal fluid (CSF) AD biomarkers, S-[18F]THK-5117, and [11C]PIB PET against tau and amyloid lesions in brain biopsy.

METHODS: Fourteen patients with idiopathic normal pressure hydrocephalus (iNPH) with previous shunt surgery including right frontal cortical brain biopsy and CSF Aβ1 - 42, total tau, and P-tau181 measures, underwent brain MRI, [11C]PIB PET, and S-[18F]THK-5117 PET imaging.

RESULTS: Seven patients had amyloid-β (Aβ, 4G8) plaques, two both Aβ and phosphorylated tau (Pτ, AT8) and one only Pτ in biopsy. As expected, increased brain biopsy Aβ was well associated with higher [11C]PIB uptake in PET. However, S-[18F]THK-5117 uptake did not show any statistically significant correlation with either brain biopsy Pτ or CSF P-tau181 or total tau.

CONCLUSIONS: S-[18F]THK-5117 lacked clear association with neuropathologically verified tau pathology in brain biopsy probably, at least partially, due to off-target binding. Further studies with larger samples of patients with different tau tracers are urgently needed. The detection of simultaneous Aβ and tau pathology in iNPH is important since that may indicate poorer and especially shorter response for CSF shunt surgery compared with no pathology.

%B J Alzheimers Dis %V 64 %P 171-179 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865068?dopt=Abstract %R 10.3233/JAD-180071 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Secular Trends in Dementia Prevalence and Incidence Worldwide: A Systematic Review. %A Stephan, Blossom C M %A Birdi, Ratika %A Tang, Eugene Yee Hing %A Cosco, Theodore D %A Donini, Lorenzo M %A Licher, Silvan %A Ikram, M Arfan %A Siervo, Mario %A Robinson, Louise %X

BACKGROUND: Time trends for dementia prevalence and incidence rates have been reported over the past seven decades in different countries and some have reported a decline.

OBJECTIVE: To undertake a systematic review to critically appraise and provide an evidence-based summary of the magnitude and direction of the global changes in dementia prevalence and incidence across time.

METHODS: Medline, EMBASE, and PsychINFO were searched for studies focused on secular trends in dementia prevalence and/or incidence until 18 December 2017. In total, 10,992 articles were identified and 43 retained.

RESULTS: Overall, prevalence rates are largely increasing (evidence primarily from record-based surveys and cohort studies in Japan, Canada, and France) or have remained stable (evidence primarily from cohort studies in Sweden, Spain and China). A significant decline in prevalence has however been reported in more recent studies (i.e., from 2010 onwards) from Europe (e.g., UK and Sweden) and the USA. Incidence rates have generally remained stable or decreased in China, Canada, France, Germany, Denmark, Sweden, the Netherlands, UK, and USA. An increase has only been reported in five countries: Italy, Japan, Wales, Germany, and the Netherlands. Only one study reported findings (stability in incidence) from a low and middle-income country using data from Nigeria.

CONCLUSIONS: The evidence on secular trends in the prevalence and incidence of dementia is mixed including contradictory findings using different (and in some cases the same) datasets in some countries (e.g., the USA, UK, and Sweden). This making it difficult to draw concrete conclusions. However, declining trends recently observed in some high-income Western countries in the most recent two decades including the UK, USA, and Sweden are encouraging. Updated dementia prevalence and incidence estimates will inform public health and financial planning as well as development of prevention strategies.

%B J Alzheimers Dis %V 66 %P 653-680 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30347617?dopt=Abstract %R 10.3233/JAD-180375 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Self- and Informant-Reported Memory Complaints: Frequency and Severity in Cognitively Intact Individuals and those with Mild Cognitive Impairment and Neurodegenerative Dementias. %A Rahman-Filipiak, Annalise M %A Giordani, Bruno %A Heidebrink, Judith %A Bhaumik, Arijit %A Hampstead, Benjamin M %X

BACKGROUND: Subjective memory complaints (SMCs) are incorporated into the diagnosis of mild cognitive impairment (MCI) and neurodegenerative dementias; however, the relative frequency of SMCs in cognitively intact older adults and those with different types of dementia is poorly understood. Similarly, the concordance between self- versus informant-reported SMCs has not been compared across different diagnostic groups.

OBJECTIVE: This study aimed to evaluate the frequency of self-reported (Objective 1) and informant-reported (Objective 2) SMCs in cognitively intact adults or those diagnosed with MCI or a neurodegenerative dementia. Agreement between participant and informant complaints was also evaluated (Objective 3).

METHODS: Baseline evaluation data were drawn from 488 participants (Mage = 70.49 years; Medu = 15.62 years) diagnosed as cognitively intact, non-amnestic MCI, amnestic single domain MCI, amnestic multi-domain MCI, possible/probable Alzheimer's disease, dementia with Lewy bodies, or frontotemporal dementia. Participants and their informants completed the Memory Assessment Clinic Questionnaire.

RESULTS: One-way ANCOVAs controlling for age, education, and depression revealed no group differences in severity of self-reported SMCs. In contrast, informant memory ratings followed the expected clinical pattern, with comparable and most impaired ratings given to participants with any dementia diagnosis, followed by those with any MCI diagnosis, followed by cognitively intact participants. There was inconsistent agreement between self- and informant-reported SMC ratings in any of the impaired groups.

CONCLUSIONS: Given greater diagnostic specificity and internal consistency of informant report, clinicians should weigh this information more heavily than self-report in the diagnostic process.

%B J Alzheimers Dis %V 65 %P 1011-1027 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30124444?dopt=Abstract %R 10.3233/JAD-180083 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Self-Reported Physical Activity is Associated with Tau Burden Measured by Positron Emission Tomography. %A Brown, Belinda M %A Rainey-Smith, Stephanie R %A Doré, Vincent %A Peiffer, Jeremiah J %A Burnham, Samantha C %A Laws, Simon M %A Taddei, Kevin %A Ames, David %A Masters, Colin L %A Rowe, Christopher C %A Martins, Ralph N %A Villemagne, Victor L %X

Numerous animal studies have reported exercise reduces the accumulation of Alzheimer's disease pathology, including amyloid-β (Aβ) and tau. Furthermore, we previously reported a relationship between higher levels of physical activity (PA) and lower brain Aβ burden in a human population. The recent advent of tau positron emission tomography (PET) tracers enables us to extend our investigations into the evaluation of the relationship between PA and brain tau burden. Utilizing data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we have examined the cross-sectional relationship between habitual PA and PET-quantified tau burden. Forty-three cognitively healthy older adults were categorized into low-moderate PA (LMPA; n = 16) or high PA (HPA; n = 27), based on self-reported PA levels. Tau PET imaging with the AV1451 tracer was conducted on all participants. The LMPA group had significantly higher neocortical tau burden (presented as a z-score; 1.22±1.98), compared to the HPA group (z-score: - 0.28±1.18). The difference between the LMPA and HPA groups was also evident when examining regional tau burden in the temporoparietal cortex and the prefrontal cortex. Our results suggest an association between self-reported PA level and brain tau burden. Future longitudinal and interventional studies utilizing larger samples sizes are vital to further investigate the nature of the relationship between tau and PA.

%B J Alzheimers Dis %V 63 %P 1299-1305 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758940?dopt=Abstract %R 10.3233/JAD-170998 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Serotonin Selective Reuptake Inhibitor Treatment Improves Cognition and Grey Matter Atrophy but not Amyloid Burden During Two-Year Follow-Up in Mild Cognitive Impairment and Alzheimer's Disease Patients with Depressive Symptoms. %A Brendel, Matthias %A Sauerbeck, Julia %A Greven, Sonja %A Kotz, Sebastian %A Scheiwein, Franziska %A Blautzik, Janusch %A Delker, Andreas %A Pogarell, Oliver %A Ishii, Kazunari %A Bartenstein, Peter %A Rominger, Axel %X

Late-life depression, even when of subsyndromal severity, has shown strong associations with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Preclinical studies have suggested that serotonin selective reuptake inhibitors (SSRIs) can attenuate amyloidogenesis. Therefore, we aimed to investigate the effect of SSRI medication on amyloidosis and grey matter volume in subsyndromal depressed subjects with MCI and AD during an interval of two years. 256 cognitively affected subjects (225 MCI/ 31 AD) undergoing [18F]-AV45-PET and MRI at baseline and 2-year follow-up were selected from the ADNI database. Subjects with a positive depression item (DEP(+); n = 73) in the Neuropsychiatric Inventory Questionnaire were subdivided to those receiving SSRI medication (SSRI(+); n = 24) and those without SSRI treatment (SSRI(-); n = 49). Longitudinal cognition (Δ-ADAS), amyloid deposition rate (standardized uptake value, using white matter as reference region (SUVRWM), and changes in grey matter volume were compared using common covariates. Analyses were performed separately in all subjects and in the subgroup of amyloid-positive subjects. Cognitive performance in DEP(+)/SSRI(+) subjects (Δ-ADAS: -5.0%) showed less deterioration with 2-year follow-up when compared to DEP(+)/SSRI(-) subjects (Δ-ADAS: +18.6%, p < 0.05), independent of amyloid SUVRWM at baseline. With SSRI treatment, the progression of grey matter atrophy was reduced (-0.9% versus -2.7%, p < 0.05), notably in fronto-temporal cortex. A slight trend towards lower amyloid deposition rate was observed in DEP(+)/SSRI(+) subjects versus DEP(+)/SSRI(-). Despite the lack of effect to amyloid PET, SSRI medication distinctly rescued the declining cognitive performance in cognitively affected patients with depressive symptoms, and likewise attenuated grey matter atrophy.

%B J Alzheimers Dis %V 65 %P 793-806 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010116?dopt=Abstract %R 10.3233/JAD-170387 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Serum Copper is not Altered in Frontotemporal Lobar Degeneration. %A Squitti, Rosanna %A Fostinelli, Silvia %A Siotto, Mariacristina %A Ferrari, Clarissa %A Binetti, Giuliano %A Benussi, Luisa %A Rongioletti, Mauro %A Ghidoni, Roberta %X

Meta-analyses show copper dyshomeostasis in Alzheimer's disease. However, a study evaluating copper changes in other neurodegenerative forms of dementia has not yet been performed. In this study, we assessed copper, ceruloplasmin, copper not bound to ceruloplasmin, and copper to ceruloplasmin ratio in 85 patients affected by frontotemporal lobar degeneration (FTLD) and 55 healthy controls. Data were analyzed through multivariate ANOVA models taking into account age and sex as covariates and the stratification for FTLD variants, after calculating power analysis to ensure the reliability of the conclusions drawn. The study revealed no difference between the groups.

%B J Alzheimers Dis %V 63 %P 1427-1432 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843237?dopt=Abstract %R 10.3233/JAD-171074 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Serum C-Peptide, Visfatin, Resistin, and Ghrelin are Altered in Sporadic and GRN-Associated Frontotemporal Lobar Degeneration. %A Zanardini, Roberta %A Benussi, Luisa %A Fostinelli, Silvia %A Saraceno, Claudia %A Ciani, Miriam %A Borroni, Barbara %A Padovani, Alessandro %A Binetti, Giuliano %A Ghidoni, Roberta %K Aged %K Biomarkers %K C-Peptide %K Female %K Frontotemporal Lobar Degeneration %K Ghrelin %K Humans %K Kaplan-Meier Estimate %K Male %K Middle Aged %K Mutation %K Nicotinamide Phosphoribosyltransferase %K Progranulins %K Resistin %X

Frontotemporal lobar degeneration (FTLD) is a group of complex neurodegenerative disease characterized by progressive deterioration of the frontal and anterior temporal lobes of the brain resulting in different heterogeneous conditions, mainly characterized by personality changes, behavioral disturbances, such as binge eating, and deficits in language and executive functions. Null mutations in progranulin gene (GRN) are one of the most frequent genetic determinants in familial frontotemporal dementia. Recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance revealing its metabolic function. Increasing evidence suggests that neurodegenerative dementias are associated with a higher prevalence of metabolic changes than in the general population. According to these findings, the aim of this study is to investigate putative alterations in markers linked to metabolic functions (i.e., C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucagon, insulin, resistin, and three adipokines as visfatin, leptin, and plasminogen activator inhibitor-1 total) in sporadic and GRN-related FTLD. We found that 1) C-peptide is increased in sporadic and GRN-mutated FTLD patients; in addition, we demonstrated an anticipation of the disease in patients with the highest C-peptide concentrations; 2) visfatin is slightly reduced in the whole FTLD group; 3) resistin, an adipokine involved in inflammatory-related diseases, is specifically increased in FTLD due to GRN null mutations; 4) ghrelin concentration is specifically increased in pre-symptomatic subjects and FTLD patients with GRN mutations. These findings support the hypothesis that alterations in metabolic pattern are involved in FTLD progression highlighting novel putative targets for the development of preventive and personalized therapies.

%B J Alzheimers Dis %V 61 %P 1053-1060 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226876?dopt=Abstract %R 10.3233/JAD-170747 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Sex Influences the Accuracy of Subjective Memory Complaint Reporting in Older Adults. %A Sundermann, Erin E %A Edmonds, Emily C %A Delano-Wood, Lisa %A Galasko, Douglas R %A Salmon, David P %A Rubin, Leah H %A Bondi, Mark W %K Aged %K Cognitive Dysfunction %K Female %K Humans %K Logistic Models %K Male %K Memory Disorders %K Mental Recall %K Neuropsychological Tests %K Self Report %K Sex Factors %X

Subjective memory complaints (SMC) are required when diagnosing amnestic mild cognitive impairment (aMCI), although their relationship with objective memory performance and Alzheimer's disease (AD) pathology remains unclear. We investigated whether the sex of the patient/participant moderates these associations. Participants were 940 normal control (NC) and aMCI participants from the Alzheimer's Disease Neuroimaging Initiative. SMC were assessed via the memory scale of the Everyday Cognition questionnaire. Discrepancy scores were calculated between self- and informant-reports and categorized into "overestimates," "comparable estimates", and "underestimates" of SMC. We conducted linear and logistic regressions to examine the interaction of sex with self- and informant-reported SMC and discrepancy group on the Rey Auditory Verbal Learning Test (RAVLT) Immediate and Delayed Recall and on PET measures of amyloid-β (Aβ) positivity. Diagnosis-stratified analyses were also conducted. Overall, there were sex by self- and informant-reported SMC interactions for Immediate and Delayed Recall. Despite a higher proportion of "overestimates" in women, greater self- and informant-reported SMC showed a stronger relationship to poorer RAVLT scores in women versus men. Diagnosis-stratified analyses revealed that results were driven by aMCI participants. Conversely, overall, greater self- and informant-reported SMC related to greater odds of Aβ positivity regardless of sex. In diagnosis-stratified analyses, only informant-reported SMC related to Aβ positivity in aMCI. Relative to "comparable estimates," "underestimates" of SMC were associated with poorer RAVLT scores across sexes in the overall sample and in aMCI. The predictive utility of self-report SMC may be limited to women in aMCI. Sex differences should be considered when evaluating SMC.

%B J Alzheimers Dis %V 61 %P 1163-1178 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332038?dopt=Abstract %R 10.3233/JAD-170425 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Sex Moderates the Impact of Diagnosis and Amyloid PET Positivity on Hippocampal Subfield Volume. %A Caldwell, Jessica Z K %A Berg, Jody-Lynn %A Shan, Guogen %A Cummings, Jeffrey L %A Banks, Sarah J %X

We examined moderation effects of sex and diagnosis on the effect of positive florbetapir positron emission tomography (PET) amyloid-β (Aβ) scan (A+) on hippocampus subfield volumes in 526 normal control (NC) and early mild cognitive impairment (eMCI) participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI2; ADNI-GO). Regression moderation models showed that women- but not men- with NC designation did not show reduced subiculum volumes despite A+. At the eMCI stage, A+ was detrimental across sexes. Findings were significant while accounting for the effects of age, cognition at screening, education, and APOE4 carrier status. These findings suggest that women with A+ have early neural resistance to Alzheimer's disease-related amyloid burden.

%B J Alzheimers Dis %V 64 %P 79-89 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865063?dopt=Abstract %R 10.3233/JAD-180028 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Single Subject Classification of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Using Anatomical, Diffusion Tensor, and Resting-State Functional Magnetic Resonance Imaging. %A Bouts, Mark J R J %A Möller, Christiane %A Hafkemeijer, Anne %A van Swieten, John C %A Dopper, Elise %A van der Flier, Wiesje M %A Vrenken, Hugo %A Wink, Alle Meije %A Pijnenburg, Yolande A L %A Scheltens, Philip %A Barkhof, Frederik %A Schouten, Tijn M %A de Vos, Frank %A Feis, Rogier A %A van der Grond, Jeroen %A de Rooij, Mark %A Rombouts, Serge A R B %X

BACKGROUND/OBJECTIVE: Overlapping clinical symptoms often complicate differential diagnosis between patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Magnetic resonance imaging (MRI) reveals disease specific structural and functional differences that aid in differentiating AD from bvFTD patients. However, the benefit of combining structural and functional connectivity measures to-on a subject-basis-differentiate these dementia-types is not yet known.

METHODS: Anatomical, diffusion tensor (DTI), and resting-state functional MRI (rs-fMRI) of 30 patients with early stage AD, 23 with bvFTD, and 35 control subjects were collected and used to calculate measures of structural and functional tissue status. All measures were used separately or selectively combined as predictors for training an elastic net regression classifier. Each classifier's ability to accurately distinguish dementia-types was quantified by calculating the area under the receiver operating characteristic curves (AUC).

RESULTS: Highest AUC values for AD and bvFTD discrimination were obtained when mean diffusivity, full correlations between rs-fMRI-derived independent components, and fractional anisotropy (FA) were combined (0.811). Similarly, combining gray matter density (GMD), FA, and rs-fMRI correlations resulted in highest AUC of 0.922 for control and bvFTD classifications. This, however, was not observed for control and AD differentiations. Classifications with GMD (0.940) and a GMD and DTI combination (0.941) resulted in similar AUC values (p = 0.41).

CONCLUSION: Combining functional and structural connectivity measures improve dementia-type differentiations and may contribute to more accurate and substantiated differential diagnosis of AD and bvFTD patients. Imaging protocols for differential diagnosis may benefit from also including DTI and rs-fMRI.

%B J Alzheimers Dis %V 62 %P 1827-1839 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614652?dopt=Abstract %R 10.3233/JAD-170893 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Small Vessel Cerebrovascular Pathology Identified by Magnetic Resonance Imaging Is Prevalent in Alzheimer's Disease and Mild Cognitive Impairment: A Potential Target for Intervention. %A Scott, Tammy M %A Bhadelia, Rafeeque A %A Qiu, Wei Qiao %A Folstein, Marshal F %A Rosenberg, Irwin H %X

BACKGROUND: There is evidence that Alzheimer's disease (AD) has significant cerebrovascular etiopathogenesis. Understanding potentially modifiable risk factors for vascular disease can help design long-term intervention strategies for controlling or preventing cognitive dysfunction attributable to cerebrovascular disease.

OBJECTIVE: To evaluate the presence and severity of markers of cerebrovascular pathology, its relationship to diagnostic categories of dementia, including AD, and association with the metabolic biomarker homocysteine.

METHODS: In a cross-sectional observational study, 340 community-dwelling elders received a clinical evaluation including brain MRI and neuropsychological tests. Dementia and mild cognitive impairment (MCI) were diagnosed by consensus committee. Fasting total plasma homocysteine was measured. Statistical analyses were adjusted for demographics and cerebrovascular risk factors.

RESULTS: Nearly 25% of those diagnosed with AD had small vessel infarcts (SVI). Periventricular white matter hyperintensity (pvWMHI) was prevalent in participants with AD (61%) or MCI (amnesic 61% and non-amnesic 54%, respectively). Participants with SVI and/or pvWMHI also had greater brain atrophy. Homocysteine concentrations were higher in individuals with cerebrovascular findings than in those without. In individuals with cerebrovascular disease, homocysteine was inversely related to executive function (p = 0.022) and directly related to degree of brain atrophy (p = 0.009).

CONCLUSIONS: We demonstrated a significant prevalence of small vessel markers of cerebrovascular pathology in individuals diagnosed with AD, with a significant concurrence between cerebrovascular disease and brain and ventricular atrophy. While current research on AD has focused on amyloid-βpeptide deposition, tau-pathology, and microglial activation and inflammation, greater attention to the cerebrovascular contribution to this neurodegenerative disease presents an additional target for therapeutic prevention and intervention.

%B J Alzheimers Dis %V 65 %P 293-302 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040728?dopt=Abstract %R 10.3233/JAD-180366 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Social Dysfunction in Older Age and Relationships with Cognition, Depression, and Apathy: The GreatAGE Study. %A Lozupone, Madia %A Panza, Francesco %A Piccininni, Marco %A Copetti, Massimiliano %A Sardone, Rodolfo %A Imbimbo, Bruno P %A Stella, Eleonora %A D'Urso, Francesca %A Barulli, Maria Rosaria %A Battista, Petronilla %A Grasso, Alessandra %A Tortelli, Rosanna %A Capozzo, Rosa %A Coppola, Francesco %A Abbrescia, Daniela Isabel %A Bellomo, Antonello %A Giannelli, Gianluigi %A Quaranta, Nicola %A Seripa, Davide %A Logroscino, Giancarlo %X

BACKGROUND: Most studies focused on only one measure of social dysfunction in older age, without proper validation and distinction across different dimensions including subjectivity, structural, and functional aspects.

OBJECTIVE: We sought to validate the Social Dysfunction Rating Scale (SDRS) and its factorial structure, also determining the association of SDRS with cognitive functions, global psychopathology, and social deprivation.

METHODS: The SDRS was administered to 484 Italian community-dwelling elderly, recruited in the GreatAGE study, a population-based study on aging conducted in Castellana Grotte, Bari, Southern Italy. We determined objective and subjective psychometric properties of SDRS against the gold standard evaluation of social dysfunction according to the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders (SCID-I) criterion.

RESULTS: The SDRS showed a moderate accuracy with an optimal cut-off of 26 maximized with higher sensitivity (0.74,95% CI:0.63-0.84) than specificity (0.57,95% CI:0.50-0.64). A five-factor structure was carried out and five dimensions of SDRS were identified (loneliness; social isolation; feeling of contribution/uselessness; lack of leisure activities; anxiety for the health). Education and global cognitive functions were inversely correlated to SDRS, while a direct association with global psychopathology, depression, and apathy was found. The prevalence of higher SDRS scores was major in subjects with current psychiatric disorders versus other subjects.∥Conclusion: The SDRS could be a valid instrument to capture both size and quality of social dysfunction, both in subjects with psychiatric disorders and in normal subjects. Several categories of social dysfunction differed only in the degree of health deprivation, not in social or material deprivation.

%B J Alzheimers Dis %V 65 %P 989-1000 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103335?dopt=Abstract %R 10.3233/JAD-180466 %0 Journal Article %J J Alzheimers Dis %D 2018 %T SPARCL1 Accelerates Symptom Onset in Alzheimer's Disease and Influences Brain Structure and Function During Aging. %A Seddighi, Sahba %A Varma, Vijay R %A An, Yang %A Varma, Sudhir %A Beason-Held, Lori L %A Tanaka, Toshiko %A Kitner-Triolo, Melissa H %A Kraut, Michael A %A Davatzikos, Christos %A Thambisetty, Madhav %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Brain %K Calcium-Binding Proteins %K Cerebrovascular Circulation %K Cognition Disorders %K Extracellular Matrix Proteins %K Female %K Humans %K Independent Living %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Polymorphism, Single Nucleotide %K Positron-Emission Tomography %X

We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer's disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed incident AD showed accelerated memory loss prior to disease onset. Next, we compared longitudinal changes in brain volumes (MRI; n = 120 participants; follow-up = 6.4 years; 826 scans) and resting-state cerebral blood flow (rCBF; 15O-water PET; n = 81 participants; follow-up = 7.7 years; 664 scans) in cognitively normal participants. Cognitively normal minor allele carriers of rs9998212 showed accelerated atrophy in several global, lobar, and regional brain volumes. Minor allele carriers of both SNPs showed longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology. Our findings suggest that SPARCL1 accelerates AD pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging.

%B J Alzheimers Dis %V 61 %P 401-414 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154276?dopt=Abstract %R 10.3233/JAD-170557 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Spatial Navigation in the Elderly with Alzheimer's Disease: A Cross-Sectional Study. %A Zanco, Marcos %A Plácido, Jessica %A Marinho, Valeska %A Ferreira, José Vinicius %A de Oliveira, Felipe %A Monteiro-Junior, Renato %A Barca, Maria %A Engedal, Knut %A Laks, Jerson %A Deslandes, Andrea %X

BACKGROUND: Spatial navigation is a fundamental cognitive ability that allows an individual to maintain independence by facilitating the safe movement from one place to another. It emerges as one of the first deficits in patients with Alzheimer's disease (AD).

OBJECTIVE: To compare spatial navigation performance in the healthy elderly and AD patients through use of the Floor Maze Test (FMT)- an easy-to-apply two-dimensional (2D) maze- and determine which cognitive and functional capacities were associated with performance in this task.

METHODS: The FMT was administered to 24 AD patients and 36 healthy controls. Spatial navigation was evaluated through the FMT. Functional capacity was evaluated through the Senior Fitness Test battery of tests. Cognitive functions were evaluated through the Mini-Mental State Examination (MMSE), verbal fluency, digit span test, and the Rey Auditory Verbal Learning Test (RAVLT).

RESULTS: The group with AD was significantly slower and presented more errors at all stages of the FMT. Planning Time (PT) performance was associated with cardiorespiratory resistance (Step test) and delayed memory according to the RAVLT (R2 = 0.395, p < 0.001). Performance in the Immediate Maze Time (IMT) and Delayed Maze Time (DMT) was associated with global cognitive status (MMSE) (R2 = 0.509) and delayed memory (R2 = 0.540).

CONCLUSION: Patients with AD present significant spatial navigation deficits. Their performance on the FMT is influenced by cardiorespiratory capacity, memory, and global cognitive function. As exercise helps to improve executive function and functional capacity, future intervention studies should be carried out to analyze the possible effects of physical exercise on spatial navigation.

%B J Alzheimers Dis %V 66 %P 1683-1694 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30507580?dopt=Abstract %R 10.3233/JAD-180819 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Structural Anatomical Investigation of Long-Term Memory Deficit in Behavioral Frontotemporal Dementia. %A Bertoux, Maxime %A Flanagan, Emma C %A Hobbs, Matthew %A Ruiz-Tagle, Amparo %A Delgado, Carolina %A Miranda, Marcelo %A Ibáñez, Agustín %A Slachevsky, Andrea %A Hornberger, Michael %X

Although a growing body of work has shown that behavioral variant frontotemporal dementia (bvFTD) could present with severe amnesia in approximately half of cases, memory assessment is currently the clinical standard to distinguish bvFTD from Alzheimer's disease (AD). Thus, the concept of "relatively preserved episodic memory" in bvFTD remains the basis of its clinical distinction from AD and a criterion for bvFTD's diagnosis. This view is supported by the idea that bvFTD is not characterized by genuine amnesia and hippocampal degeneration, by contrast to AD. In this multicenter study, we aimed to investigate the neural correlates of memory performance in bvFTD as assessed by the Free and Cued Selective Reminding Test (FCSRT). Imaging explorations followed a two-step procedure, first relying on a visual rating of atrophy of 35 bvFTD and 34 AD patients' MRI, contrasted with 29 controls; and then using voxel-based morphometry (VBM) in a subset of bvFTD patients. Results showed that 43% of bvFTD patients presented with a genuine amnesia. Data-driven analysis on visual rating data showed that, in bvFTD, memory recall & storage performances were significantly predicted by atrophy in rostral prefrontal and hippocampal/perihippocampal regions, similar to mild AD. VBM results in bvFTD (pFWE<0.05) showed similar prefrontal and hippocampal regions in addition to striatal and lateral temporal involvement. Our findings showed the involvement of prefrontal as well as medial/lateral temporal atrophy in memory deficits of bvFTD patients. This contradicts the common view that only frontal deficits explain memory impairment in this disease and plead for an updated view on memory dysfunctions in bvFTD.

%B J Alzheimers Dis %V 62 %P 1887-1900 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614645?dopt=Abstract %R 10.3233/JAD-170771 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Subtypes Based on Neuropsychological Performance Predict Incident Dementia: Findings from the Rush Memory and Aging Project. %A Zammit, Andrea R %A Muniz-Terrera, Graciela %A Katz, Mindy J %A Hall, Charles B %A Ezzati, Ali %A Bennett, David A %A Lipton, Richard B %X

BACKGROUND: In a previous report, we used latent class analysis (LCA) to identify natural subgroups of older adults in the Einstein Aging Study (EAS) based on neuropsychological performance. These subgroups differed in demographics, genetic profile, and prognosis. Herein, we assess the generalizability of these findings to an independent sample, the Rush Memory and Aging Project (MAP), which used an overlapping, but distinct neuropsychological battery.

OBJECTIVE: Our aim was to identify the association of natural subgroups based on neuropsychological performance in the MAP cohort with incident dementia and compare them with the associations identified in the EAS.

METHODS: MAP is a community-dwelling cohort of older adults living in the northeastern Illinois, Chicago. Latent class models were applied to baseline scores of 10 neuropsychological measures across 1,662 dementia-free MAP participants. Results were compared to prior findings from the EAS.

RESULTS: LCA resulted in a 5-class model: Mixed-Domain Impairment (n = 71, 4.3%), Memory-specific-Impairment (n = 274, 16.5%), Average (n = 767, 46.1%), Frontal Impairment (n = 222, 13.4%), and a class of Superior Cognition (n = 328, 19.7%). Similar to the EAS, the Mixed-Domain Impairment, the Memory-Specific Impairment, and the Frontal Impairment classes had higher risk of incident Alzheimer's disease when compared to the Average class. By contrast, the Superior Cognition had a lower risk of Alzheimer's disease when compared to the Average class.

CONCLUSIONS: Natural cognitive subgroups in MAP are similar to those identified in EAS. These similarities, despite study differences in geography, sampling strategy, and cognitive tests, suggest that LCA is capable of identifying classes that are not limited to a single sample or a set of cognitive tests.

%B J Alzheimers Dis %8 2018 Nov 29 %G eng %R 10.3233/JAD-180737 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Supplemental Retinal Carotenoids Enhance Memory in Healthy Individuals with Low Levels of Macular Pigment in A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. %A Power, Rebecca %A Coen, Robert F %A Beatty, Stephen %A Mulcahy, Riona %A Moran, Rachel %A Stack, Jim %A Howard, Alan N %A Nolan, John M %K Adult %K Cognition %K Dietary Supplements %K Double-Blind Method %K Executive Function %K Female %K Healthy Volunteers %K Humans %K Lutein %K Macular Pigment %K Male %K Memory, Episodic %K Middle Aged %K Retina %K Vision Tests %K Zeaxanthins %X

BACKGROUND: There is a biologically plausible rationale whereby the dietary carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ), which are collectively referred to as macular pigment (MP) in the central retina (macula), support the maintenance of cognition via their antioxidant and anti-inflammatory properties.

OBJECTIVE: To investigate the impact of supplemental L, Z, and MZ on memory, executive function, and verbal fluency among healthy individuals with low MP levels.

METHODS: In this double-blind, placebo-controlled, randomized clinical trial, subjects (n = 91; mean±SD age = 45.42±12.40; % male = 51.6) consumed a daily formulation of 10 mg L, 10 mg MZ, and 2 mg Z (n = 45) or placebo (n = 46) for 12 months. Cognitive domains assessed included verbal and visual learning, immediate and delayed memory, executive function, and verbal fluency. MP and serum carotenoid concentrations of L, Z, and MZ were also measured.

RESULTS: Following 12-month supplementation, individuals in the active group exhibited statistically significant improvements in memory when compared to the placebo group (paired associated learning [PAL] memory score [rANOVA, p = 0.009]; PAL errors [rANOVA, p = 0.017]). Furthermore, the observed reduction in the number of errors made in the PAL task among those in the intervention group was positively and significantly related to observed increases in MP volume (p = 0.005) and observed increases in serum concentrations of L (p = 0.009).

CONCLUSION: This randomized, double-blind, placebo-controlled clinical trial demonstrates a memory-enhancing effect of daily supplementation with L, Z, and MZ in healthy subjects with low MP at baseline. The implications of these findings for intellectual performance throughout life, and for risk of cognitive decline in later life, warrant further study.

%B J Alzheimers Dis %V 61 %P 947-961 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332050?dopt=Abstract %R 10.3233/JAD-170713 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Synthetic Fragment of Receptor for Advanced Glycation End Products Prevents Memory Loss and Protects Brain Neurons in Olfactory Bulbectomized Mice. %A Volpina, Olga M %A Samokhin, Alexandr N %A Koroev, Dmitriy O %A Nesterova, Inna V %A Volkova, Tatyana D %A Medvinskaya, Natalia I %A Nekrasov, Pavel V %A Tatarnikova, Olga G %A Kamynina, Anna V %A Balasanyants, Samson M %A Voronina, Tamara A %A Kulikov, Alexey M %A Bobkova, Natalia V %K Administration, Intranasal %K Animals %K Behavior, Animal %K Brain %K Disease Models, Animal %K Male %K Maze Learning %K Memory Disorders %K Mice %K Mice, Transgenic %K Neurons %K Olfactory Bulb %K Peptide Fragments %K Receptor for Advanced Glycation End Products %X

Activation of receptor for advanced glycation end products (RAGE) plays an essential role in the development of Alzheimer's disease (AD). It is known that the soluble isoform of the receptor binds to ligands and prevents negative effects of the receptor activation. We proposed that peptide fragments from RAGE prevent negative effects of the receptor activation during AD neurodegeneration. We have synthesized peptide fragments from surface-exposed regions of RAGE. Peptides were intranasally administrated into olfactory bulbectomized (OBX) mice, which developed some characteristics similar to AD neurodegeneration. We have found that only insertion of fragment (60-76) prevents the memory of OBX mice. Immunization of OBX mice with peptides showed that again only (60-76) peptide protected the memory of animals. Both intranasal insertion and immunization decreased the amyloid-β (Aβ) level in the brain. Activity of shortened fragments of (60-76) peptide was tested and showed only the (60-70) peptide is responsible for manifestation of activity. Intranasal administration of (60-76) peptide shows most protective effect on morpho-functional characteristics of neurons in the cortex and hippocampal areas. Using Flu-(60-76) peptide, we revealed its penetration in the brain of OBX mice as well as colocalization of Flu-labeled peptide with Aβ in the brain regions in transgenic mice. Flu-(60-76) peptide complex with trimer of Aβ was detected by SDS-PAGE. These data indicate that Aβ can be one of the molecular target of (60-70) peptide. These findings provide a new peptide molecule for design of anti-AD drug and for investigation of RAGE activation ways in progression of AD neurodegeneration.

%B J Alzheimers Dis %V 61 %P 1061-1076 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332040?dopt=Abstract %R 10.3233/JAD-170483 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Systematic Review and Aggregated Analysis on the Impact of Amyloid PET Brain Imaging on the Diagnosis, Diagnostic Confidence, and Management of Patients being Evaluated for Alzheimer's Disease. %A Fantoni, Enrico R %A Chalkidou, Anastasia %A O' Brien, John T %A Farrar, Gill %A Hammers, Alexander %X

BACKGROUND: Amyloid PET (aPET) imaging could improve patient outcomes in clinical practice, but the extent of impact needs quantification.

OBJECTIVE: To provide an aggregated quantitative analysis of the value added by aPET in cognitively impaired subjects.

METHODS: Systematic literature searches were performed in Embase and Medline until January 2017. 1,531 cases over 12 studies were included (1,142 cases over seven studies in the primary analysis where aPET was the key biomarker; the remaining cases included as defined groups in the secondary analysis). Data was abstracted by consensus among two observers and assessed for bias. Clinical utility was measured by diagnostic change, diagnostic confidence, and patient management before and after aPET. Three groups were further analyzed: control patients for whom feedback of aPET scan results was delayed; aPET Appropriate Use Criteria (AUC+) cases; and patients undergoing additional FDG/CSF testing.

RESULTS: For 1,142 cases with only aPET, 31.3% of diagnoses were revised, whereas 3.2% of diagnoses changed in the delayed aPET control group (p < 0.0001). Increased diagnostic confidence following aPET was found for 62.1% of 870 patients. Management changes with aPET were found in 72.2% of 740 cases and in 55.5% of 299 cases in the control group (p < 0.0001). The diagnostic value of aPET in AUC+ patients or when FDG/CSF were additionally available did not substantially differ from the value of aPET alone in the wider population.

CONCLUSIONS: Amyloid PET contributed to diagnostic revision in almost a third of cases and demonstrated value in increasing diagnostic confidence and refining management plans.

%B J Alzheimers Dis %V 63 %P 783-796 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29689725?dopt=Abstract %R 10.3233/JAD-171093 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Systematic Review and Meta-Analysis on the Prevalence of Dementia in Europe: Estimates from the Highest-Quality Studies Adopting the DSM IV Diagnostic Criteria. %A Bacigalupo, Ilaria %A Mayer, Flavia %A Lacorte, Eleonora %A Di Pucchio, Alessandra %A Marzolini, Fabrizio %A Canevelli, Marco %A Di Fiandra, Teresa %A Vanacore, Nicola %X

BACKGROUND: Dementia, including Alzheimer's disease (AD), is one of the most burdensome medical conditions. Usually, the reviews that aim at calculating the prevalence of dementia include estimates from studies without assessing their methodological quality. Alzheimer's Disease International (ADI) proposed a score to assess the methodological quality of population-based studies aimed at estimating the prevalence of dementia. During the last three years, the European Commission has funded three projects (Eurodem, EuroCoDe, and ALCOVE) in order to estimate the prevalence of dementia in Europe.

OBJECTIVE: The aim of this study was to perform a systematic review and meta-analysis of data on the prevalence of dementia in Europe derived from studies that included only subjects with a diagnosis of dementia according to the DSM IV criteria, and that had a high quality score according to ADI criteria.

METHODS: We considered the studies selected by the two projects EuroCoDe (1993-2007) and Alcove (2008-2011), and we performed a new bibliographic search. For the systematic review, we only selected the subset of articles that included subjects with a diagnosis of dementia according to the DSM IV criteria. The studies were qualitatively assessed using the ADI tool.

RESULTS: The meta-analysis considered 9 studies that were carried out in Europe between 1993 and 2018 including a total of 18,263 participants, of which 2,137 were diagnosed with dementia. The prevalence rate standardized for age and sex resulted 7.1%.

DISCUSSION: This is the first systematic review on the prevalence of dementia in Europe considering only high-quality studies adopting the same diagnostic criteria (i.e., DSM IV).

%B J Alzheimers Dis %V 66 %P 1471-1481 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412486?dopt=Abstract %R 10.3233/JAD-180416 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Targeted Assessment of Enlargement of the Perivascular Space in Alzheimer's Disease and Vascular Dementia Subtypes Implicates Astroglial Involvement Specific to Alzheimer's Disease. %A Boespflug, Erin L %A Simon, Matthew J %A Leonard, Emmalyn %A Grafe, Marjorie %A Woltjer, Randall %A Silbert, Lisa C %A Kaye, Jeffrey A %A Iliff, Jeffrey J %X

Waste clearance from the brain parenchyma occurs along perivascular pathways. Enlargement of the perivascular space (ePVS) is associated with pathologic features of Alzheimer's disease (AD), although the mechanisms and implications of this dilation are unclear. Fluid exchange along the cerebral vasculature is dependent on the perivascular astrocytic water channel aquaporin-4 (AQP4) and loss of perivascular AQP4 localization is found in AD. We directly measured ePVS in postmortem samples of pathologically characterized tissue from participants who were cognitively intact or had AD or mixed dementia (vascular lesions with AD). We found that both AD and mixed dementia groups had significantly increased ePVS compared to cognitively intact subjects. In addition, we found increased global AQP4 expression of the AD group over both control and mixed dementia groups and a qualitative reduction in perivascular localization of AQP4 in the AD group. Among these cases, increasing ePVS burden was associated with the presence of tau and amyloid-β pathology. These findings are consistent with the existing evidence of ePVS in AD and provide novel information regarding differences in AD and vascular dementia and the potential role of astroglial pathology in ePVS.

%B J Alzheimers Dis %V 66 %P 1587-1597 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30475760?dopt=Abstract %R 10.3233/JAD-180367 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Tau and Amyloid Positron Emission Tomography Imaging Predict Driving Performance Among Older Adults with and without Preclinical Alzheimer's Disease. %A Roe, Catherine M %A Babulal, Ganesh M %A Mishra, Shruti %A Gordon, Brian A %A Stout, Sarah H %A Ott, Brian R %A Carr, David B %A Ances, Beau M %A Morris, John C %A Benzinger, Tammie L S %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid %K Automobile Driving %K Biomarkers %K Carbolines %K Female %K Humans %K Logistic Models %K Male %K Neuroimaging %K Positron-Emission Tomography %K tau Proteins %X

Abnormal levels of Alzheimer's disease (AD) biomarkers, measured by positron emission tomography imaging using amyloid-based radiotracers and cerebrospinal fluid, are associated with impaired driving performance in older adults. We examined whether preclinical AD staging, defined using amyloid imaging and tau imaging using the radiotracer T807 (AKA flortaucipir or AV-1451), was associated with receiving a marginal/fail rating on a standardized road test (n = 42). Participants at Stage 2 (positive amyloid and tau scans) of preclinical AD were more likely to receive a marginal/fail rating compared to participants at Stage 0 or 1. Stage 2 preclinical AD may manifest in worse driving performance.

%B J Alzheimers Dis %V 61 %P 509-513 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171997?dopt=Abstract %R 10.3233/JAD-170521 %0 Journal Article %J J Alzheimers Dis %D 2018 %T TDP-43 and Alzheimer's Disease Pathologic Subtype in Non-Amnestic Alzheimer's Disease Dementia. %A Sahoo, Aradhana %A Bejanin, Alexandre %A Murray, Melissa E %A Tosakulwong, Nirubol %A Weigand, Stephen D %A Serie, Amanda M %A Senjem, Matthew L %A Machulda, Mary M %A Parisi, Joseph E %A Boeve, Bradley F %A Knopman, David S %A Petersen, Ronald C %A Dickson, Dennis W %A Whitwell, Jennifer L %A Josephs, Keith A %X

BACKGROUND: TDP-43 has been shown to be strongly associated with memory loss, smaller hippocampal volumes, and faster rates of hippocampal atrophy in Alzheimer's disease (AD) patients with an amnestic presentation. Whether TDP-43 has any clinical or anatomical associations in AD patients with non-amnestic phenotype is unknown.

OBJECTIVE: To determine whether TDP-43 plays a significant role in the clinic-anatomic features of non-amnestic AD.

METHODS: All cases with pathologically confirmed intermediate-high probability AD from 1996-2012 were identified and retrospectively sub-classified into amnestic versus non-amnestic dementia at the time of presentation. Neurofibrillary tangle counts were performed in those with a non-amnestic presentation using thioflavin-S microscopy in the hippocampus and three neocortical regions, and all cases were subtyped into hippocampal-sparing, limbic-predominant, and typical AD pathology. TDP-43 immunoreactivity was used to assess for the presence of TDP-43. Statistical analyses helped determine whether pathologic subtype or TDP-43 was more strongly associated with clinico-imaging features.

RESULTS: Out of 172 pathologically confirmed AD cases, 36 (19%) were classified as non-amnestic. Twenty-five of these 36 (69%) had typical pathology, 0 limbic-predominant pathology, and 11 (31%) hippocampal-sparing pathology. Eleven (44%) of the 25 cases with typical pathology were TDP-43+. Of the 11 cases with hippocampal-sparing pathology, 4 (36%) were TDP-43+. There were no differences in demographic, clinical, or neuroimaging features in those with TDP-43 versus those without except for older age at onset (p = 0.02) and age at death (p = 0.02) in those with TDP-43. AD pathological subtype accounted for slightly more of the variances in the neocortex than TDP-43.

CONCLUSION: In non-amnestic AD, we find little evidence that clinical or anatomical features of the disease are related to TDP-43.

%B J Alzheimers Dis %V 64 %P 1227-1233 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010126?dopt=Abstract %R 10.3233/JAD-180169 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Testamentary Capacity Assessment Tool (TCAT): A Brief Instrument for Patients with Dementia. %A Papageorgiou, Sokratis G %A Voskou, Panagiota %A Economou, Alexandra %A Beratis, Ion %A Douzenis, Athanasios %K Adult %K Aged %K Cognition Disorders %K Dementia %K Female %K Humans %K Male %K Memory %K Mental Competency %K Middle Aged %K Neuropsychological Tests %K Reproducibility of Results %K Sensitivity and Specificity %K Wills %X

BACKGROUND: In current practice, it is common for the medical practitioner to assess a person's testamentary capacity (TC) and give evidence to the Courts about a potential will contest. TC is an advanced cognitive activity that is both situation- and task-specific.

OBJECTIVE: The aim of the present study was the development of a brief, specialized instrument for TC assessment in patients with dementia.

METHOD: We developed a short tool consisting of four subtests, assessing the person's core functions which are required for TC: memory (orientation, autobiographical memory and realistic perception of beneficiaries), absence of serious psychopathology, knowledge of financial parameters (value of assets, everyday life products, bills), and intention (vignettes, theory of mind). For its validation, we examined 64 outpatients from the Cognitive Disorders/Dementia Unit, 2nd Department of Behavioral Neurology, University of Athens. The decision of the expert served as the gold standard for the evaluation of TC.

RESULTS: Of the 64 participants, 39 were judged by the expert as capable of TC and the remaining 25 as incapable. For the total scale (maximum score of 48), the best combination of sensitivity (82.6%) and specificity (100%) was obtained for a cut-off score of 32/33. Cronbach's alpha showed high levels of internal reliability for the scale (α= 0.86) and the point-biserial correlation coefficients showed high levels of criterion-related validity (rbp = 0.797, p < 0.001).

CONCLUSION: The new instrument appears to be a reliable screening tool for the evaluation of TC in dementia, which can be used by both the expert and the non-expert. Further research is needed to confirm these promising findings.

%B J Alzheimers Dis %V 61 %P 985-994 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254082?dopt=Abstract %R 10.3233/JAD-170297 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Testing Hippocampal Memory in Prodromal Dementia with Lewy Bodies. %A Bussè, Cinzia %A Caffarra, Paolo %A Rossi, Alice %A Zorzi, Giovanni %A Fragiacomo, Federica %A Camporese, Giulia %A Pompanin, Sara %A Di Bernardo, Gian Antonio %A Cagnin, Annachiara %X

The Free and Cued Selective Reminding test (FCSRT) was used to assess memory in 19 patients with prodromal dementia with Lewy bodies (DLB) and 25 Alzheimer's disease (AD) patients. DLB scored better than AD in selective measures of the FCSRT: immediate total recall (p = 0.01) and index of sensitivity of cueing (p = 0.001), while free delayed and total memory scores were similarly impaired. The index of sensitivity of cueing held a sensitivity of 76% and specificity of 79% in distinguishing DLB. FCSRT could help in disentangling hippocampal memory deficits from memory impairment due to ineffective recall strategies.

%B J Alzheimers Dis %V 64 %P 349-353 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914032?dopt=Abstract %R 10.3233/JAD-180166 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Three Decades of Dementia Research: Insights from One Small Community of Indomitable Rotterdammers. %A Wolters, Frank J %A Adams, Hieab H H %A Bos, Daniel %A Licher, Silvan %A Ikram, M Arfan %X

The most commonly encountered opening sentence in scientific publications about dementia undoubtedly relates to the overwhelming burden of disease. Finding an effective preventive or therapeutic intervention against dementia has been considered the most important unmet need in contemporary medicine. While efforts on tackling this devastating disease have increased exponentially, it is difficult to imagine that in the 1980s and early-1990s, the disease did not feature prominently on any public health report. Yet, it was already then that epidemiologists recognized the growing societal burden of dementia and rationalized that dementia is not necessarily part of aging. Indeed, the conviction that dementia is pathologically distinct from aging led to various efforts in search of unravelling its risk factors and understanding its pre-clinical phase. Among the early pioneers, the population-based Rotterdam Study was initiated in 1990 clearly aiming on chronic diseases including dementia, and among this Alzheimer's disease, as one of its focus points. Ever since, the Rotterdam Study has been an important cornerstone in increasing our knowledge about dementia from an epidemiological perspective. Here, we summarize the main findings originating from this study, and put these into perspective with previous and current work in the field. With an expanding scope of the Rotterdam Study over the years, we discuss findings on occurrence, modifiable risk factors, imaging, and its genetic underpinnings. Importantly, we conclude with recommendations- or, perhaps better stated, a wish list- for future research which may help us reach our finish line: finding an effective preventive or therapeutic intervention against dementia.

%B J Alzheimers Dis %V 64 %P S145-S159 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843240?dopt=Abstract %R 10.3233/JAD-179938 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Three-Factor Structure of Cognitive Functioning Among Unimpaired Carriers and Non-Carriers of Autosomal-Dominant Alzheimer's Disease. %A Guzmán-Vélez, Edmarie %A Jaimes, Sehily %A Aguirre-Acevedo, Daniel C %A Norton, Daniel J %A Papp, Kathryn V %A Amariglio, Rebecca %A Rentz, Dorene %A Baena, Ana %A Henao, Eliana %A Tirado, Victoria %A Munoz, Claudia %A Giraldo, Margarita %A Sperling, Reisa A %A Lopera, Francisco %A Quiroz, Yakeel T %X

BACKGROUND: There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer's disease (AD), and that can be used to reliably measure cognitive decline.

OBJECTIVE: We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members.

METHODS: 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol).

RESULTS: The three-factor model provided an excellent fit for all participants (p = 0.24; RMSEA = 0.01). Further, the episodic memory (p = 0.0004, d = 0.25) and executive functioning (p = 0.001, d = 0.18) factors distinguished cognitively unimpaired carriers from non-carriers. The episodic memory factor provided the earliest indication of preclinical cognitive decline at 35 years of age, nine years before individuals' estimated age of clinical onset.

CONCLUSIONS: The three theoretically derived cognitive factors provide a reliable measure of cognition and may be useful for the early detection of AD, as well as for measuring disease progression. However, longitudinal studies are needed to confirm that these factors can be used to track the progression of cognitive decline in preclinical AD.

%B J Alzheimers Dis %V 65 %P 107-115 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040714?dopt=Abstract %R 10.3233/JAD-180078 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Total MRI Small Vessel Disease Burden Correlates with Cognitive Performance, Cortical Atrophy, and Network Measures in a Memory Clinic Population. %A Banerjee, Gargi %A Jang, Hyemin %A Kim, Hee Jin %A Kim, Sung Tae %A Kim, Jae Seung %A Lee, Jae Hong %A Im, Kiho %A Kwon, Hunki %A Lee, Jong Min %A Na, Duk L %A Seo, Sang Won %A Werring, David John %X

BACKGROUND: Recent evidence suggests that combining individual imaging markers of cerebral small vessel disease (SVD) may more accurately reflect its overall burden and better correlate with clinical measures.

OBJECTIVE: We wished to establish the clinical relevance of the total SVD score in a memory clinic population by investigating the association with SVD score and cognitive performance, cortical atrophy, and structural network measures, after adjusting for amyloid-β burden.

METHODS: We included 243 patients with amnestic mild cognitive impairment (MCI), Alzheimer's disease dementia, subcortical vascular MCI, or subcortical vascular dementia. All underwent MR and [11C] PiB-PET scanning and had standardized cognitive testing. Multiple linear regression was used to evaluate the relationships between SVD score and cognition, cortical thickness, and structural network measures. Path analyses were performed to evaluate whether network disruption mediates the effects of SVD score on cortical thickness and cognition.

RESULTS: Total SVD score was associated with the performance of frontal (β - 4.31, SE 2.09, p = 0.040) and visuospatial (β - 0.95, SE 0.44, p = 0.032) tasks, and with reduced cortical thickness in widespread brain regions. Total SVD score was negatively correlated with nodal efficiency, as well as changes in brain network organization, with evidence of reduced integration and increasing segregation. Path analyses showed that the associations between SVD score and frontal and visuospatial scores were partially mediated by decreases in their corresponding nodal efficiency and cortical thickness.

CONCLUSION: Total SVD burden has clinical relevance in a memory clinic population and correlates with cognition, and cortical atrophy, as well as structural network disruption.

%B J Alzheimers Dis %V 63 %P 1485-1497 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843234?dopt=Abstract %R 10.3233/JAD-170943 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Transcranial Sonography in Neurodegenerative Diseases with Cognitive Decline. %A Favaretto, Silvia %A Walter, Uwe %A Baracchini, Claudio %A Cagnin, Annachiara %K Cognition Disorders %K Humans %K Neurodegenerative Diseases %K Ultrasonography, Doppler, Transcranial %X

Transcranial sonography (TCS) of the brain parenchyma detects alterations in the substantia nigra (SN), raphe nuclei and basal ganglia; this technique has been established as a tool for the early diagnosis of Parkinson's disease and differential diagnosis from atypical parkinsonian syndromes. Here, we aimed to review the main applications of TCS in neurodegenerative diseases presenting with dementia syndrome, focusing on Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration, idiopathic normal pressure hydrocephalus, and atypical and secondary parkinsonisms. The finding of bilaterally marked hyperechogenicity of the SN appears as a characteristic feature of DLB, while it is found only in a minority of AD patients. SN hyperechogenicity is also detected in most patients with corticobasal degeneration and in about one third of patients with progressive supranuclear palsy, in which is constantly associated with hyperechogenic alterations of the basal ganglia. In conclusion, TCS is a valid supportive tool in the diagnostic workup of patients with dementia due to different neurodegenerative conditions. A promising new application is the differentiation of DLB from AD even at the early stages of these diseases.

%B J Alzheimers Dis %V 61 %P 29-40 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103031?dopt=Abstract %R 10.3233/JAD-170382 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Treatment of Atrial Fibrillation in Patients with Dementia: A Cohort Study from the Swedish Dementia Registry. %A Subic, Ana %A Cermakova, Pavla %A Religa, Dorota %A Han, Shuang %A von Euler, Mia %A Kåreholt, Ingemar %A Johnell, Kristina %A Fastbom, Johan %A Bognandi, Liselia %A Winblad, Bengt %A Kramberger, Milica G %A Eriksdotter, Maria %A Garcia-Ptacek, Sara %K Aged %K Aged, 80 and over %K Anticoagulants %K Atrial Fibrillation %K Dementia %K Female %K Hemorrhage %K Humans %K Longitudinal Studies %K Male %K Registries %K Risk Factors %K Stroke %K Survival Analysis %K Sweden %K Warfarin %X

BACKGROUND: Patients with dementia might have higher risk for hemorrhagic complications with anticoagulant therapy prescribed for atrial fibrillation (AF).

OBJECTIVE: This study assesses the risks and benefits of warfarin, antiplatelets, and no treatment in patients with dementia and AF.

METHODS: Of 49,792 patients registered in the Swedish Dementia Registry 2007-2014, 8,096 (16%) had a previous diagnosis of AF. Cox proportional hazards models were used to calculate the risk for ischemic stroke (IS), nontraumatic intracranial hemorrhage, any-cause hemorrhage, and death.

RESULTS: Out of the 8,096 dementia patients with AF, 2,143 (26%) received warfarin treatment, 2,975 (37%) antiplatelet treatment, and 2,978 (37%) had no antithrombotic treatment at the time of dementia diagnosis. Patients on warfarin had fewer IS than those without treatment (5.2% versus 8.7%; p < 0.001) with no differences compared to antiplatelets. In adjusted analyses, warfarin was associated with a lower risk for IS (HR 0.76, CI 0.59-0.98), while antiplatelets were associated with increased risk (HR 1.25, CI 1.01-1.54) compared to no treatment. For any-cause hemorrhage, there was a higher risk with warfarin (HR 1.28, CI 1.03-1.59) compared to antiplatelets. Warfarin and antiplatelets were associated with a lower risk for death compared to no treatment.

CONCLUSIONS: Warfarin treatment in Swedish patients with dementia is associated with lower risk of IS and mortality, and a small increase in any-cause hemorrhage. This study supports the use of warfarin in appropriate cases in patients with dementia. The low percentage of patients on warfarin treatment indicates that further gains in stroke prevention are possible.

%B J Alzheimers Dis %V 61 %P 1119-1128 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29286925?dopt=Abstract %R 10.3233/JAD-170575 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Ubisol-Q10 (a Nanomicellar Water-Soluble Formulation of CoQ10) Treatment Inhibits Alzheimer-Type Behavioral and Pathological Symptoms in a Double Transgenic Mouse (TgAPEswe, PSEN1dE9) Model of Alzheimer's Disease. %A Muthukumaran, Krithika %A Kanwar, Annie %A Vegh, Caleb %A Marginean, Alexandra %A Elliott, Austin %A Guilbeault, Nicholas %A Badour, Alexander %A Sikorska, Marianna %A Cohen, Jerome %A Pandey, Siyaram %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Disease Models, Animal %K Male %K Maze Learning %K Memory %K Memory Disorders %K Mice %K Mice, Transgenic %K Microglia %K Mutation %K Nerve Tissue Proteins %K Peptide Fragments %K Presenilin-1 %K Ubiquinone %K Vitamins %X

 Alzheimer's disease (AD) is one of the most common neurodegenerative pathologies for which there are no effective therapies to halt disease progression. Given the increase in the incidence of this disorder, there is an urgent need for pharmacological intervention. Unfortunately, recent clinical trials produced disappointing results. Molecular mechanisms of AD are converging on the notion that mitochondrial dysfunction, oxidative stress, and accumulation of dysfunctional proteins are involved in AD pathology. Previously, we have shown that a water-soluble formulation of Coenzyme Q10 (Ubisol-Q10), an integral part of the electron transport chain, stabilizes mitochondria and prevents neuronal cell death caused by neurotoxins or oxidative stress both in vitro and in vivo. In this study, we evaluated the neuroprotective effects of Ubisol-Q10 treatment in double transgenic AD mice. In the present study, we report that providing Ubisol-Q10 in drinking water (at a dose of ∼6 mg/kg/day) reduced circulating amyloid-β (Aβ) peptide, improved long term memory, preserved working spatial memory, and drastically inhibited Aβ plaque formation in 18-month-old transgenic mice compared to an untreated transgenic group. Thus Ubisol-Q10 supplementation has the potential to inhibit the progression of neurodegeneration, leading to a better quality of life for humans suffering with AD.

%B J Alzheimers Dis %V 61 %P 221-236 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154270?dopt=Abstract %R 10.3233/JAD-170275 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Underlying Biological Processes in Mild Cognitive Impairment: Amyloidosis Versus Neurodegeneration. %A Santana, Isabel %A Baldeiras, Ines %A Santiago, Beatriz %A Duro, Diana %A Freitas, Sandra %A Pereira, Miguel Tábuas %A Almeida, Maria Rosário %A Oliveira, Catarina Resende %X

The amyloid cascade hypothesis proposes amyloid-β (Aβ) as the earliest and key pathological hallmark of Alzheimer's disease (AD), but this mandatory "amyloid-first pathway" has been contested. Longitudinal studies of mild cognitive impairment (MCI) patients represent an opportunity to investigate the intensity of underlying biological processes (amyloidosis versus neurodegeneration) and their relevance for progression to AD. We re-examined our cohort of amnestic MCI, grouped according to cerebrospinal fluid (CSF) biomarkers, aiming at establishing their prognostic value for Alzheimer-type dementia and testing the hypothetical model of biomarkers sequence, based on the amyloid cascade. Our baseline population consisted of 217 MCI patients, 63% with neurodegeneration markers and 47% with amyloidosis. Within the longitudinal study-group (n = 165), 85 progressed to AD and 80 remained cognitively stable. Age, CSF Aβ42, and t-Tau were identified as the best single predictors of conversion to AD. Regarding MCI classification according to the NIA-AA criteria, the high-AD-likelihood group (HL-both amyloid and neurodegeneration markers) was the most frequent (42%); followed by the Suspected Non-Alzheimer Pathophysiology group (SNAP-26%), the low-AD-likelihood group (LL-negative biomarkers-22%), and the Isolated Amyloid Pathology group (IAP-10%). Risk of progression to AD was higher in HL in relation to the LL group (HR = 6.1, 95% CI = 2.1-18.0, p = 0.001). SNAP and IAP groups were equivalent in terms of risk of progression to AD (IAP: HR = 2.6, 95% CI = 0.7-9.3, p = 0.141; SNAP: HR = 3.1, 95% CI = 1.1-9.6; p = 0.046), but only SNAP was significantly different from the LL group. These results support different neurobiological pathways to AD beyond the amyloid hypothesis, highlighting the alternative "neurodegeneration-first pathway" for further investigation.

%B J Alzheimers Dis %V 64 %P S647-S657 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562515?dopt=Abstract %R 10.3233/JAD-179908 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Uniform Data Set, Czech Version: Normative Data in Older Adults from an International Perspective. %A Nikolai, Tomas %A Stepankova, Hana %A Kopecek, Miloslav %A Sulc, Zdenek %A Vyhnálek, Martin %A Bezdicek, Ondrej %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition %K Czech Republic %K Female %K Humans %K Internationality %K Male %K Middle Aged %K National Institute on Aging (U.S.) %K Neuropsychological Tests %K Psychometrics %K Reference Values %K Regression Analysis %K United States %X

BACKGROUND: Outside of the United States, international perspectives on normative data for neuropsychological test performance, within diverse populations, have been scarce. The neuropsychological test battery from the Uniform Data Set (UDS) of the Alzheimer's Disease Centers (ADC) program of the United States National Institute on Aging (NIA) is one of the most sensitive batteries for the evaluation of both normal cognitive aging and pathological cognitive decline.

OBJECTIVE: This study aimed to determine the feasibility of the Czech Neuropsychological Test Battery from the Uniform Data Set (UDS-Cz 2.0), while also evaluating the results obtained from an international perspective.

METHODS: This paper describes data from 520 cognitively normal participants. Regression analyses were used to describe the influence of demographic variables on UDS-Cz test performance.

RESULTS: Cognitive performance on all measures declined with age, with patient education level serving as a protective factor. Therefore, the present study provides normative data for the UDS-Cz, adjusted for the demographic variables of age and education.

CONCLUSION: The present study determines the psychometric properties of the UDS-Cz and establishes normative values in the aging Czech population, which can be used in clinical settings.

%B J Alzheimers Dis %V 61 %P 1233-1240 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332045?dopt=Abstract %R 10.3233/JAD-170595 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Untold New Beginnings: Adult Hippocampal Neurogenesis and Alzheimer's Disease. %A Teixeira, Catia M %A Pallas-Bazarra, Noemí %A Bolós, Marta %A Terreros-Roncal, Julia %A Avila, Jesús %A Llorens-Martín, María %X

Neurogenesis occurs in a limited number of brain regions during adulthood. Of these, the hippocampus has attracted great interest due to its involvement in memory processing. Moreover, both the hippocampus and the main area that innervates this structure, namely the entorhinal cortex, show remarkable atrophy in patients with Alzheimer's disease (AD). Adult hippocampal neurogenesis is a process that continuously gives rise to newborn granule neurons in the dentate gyrus. These cells coexist with developmentally generated granule neurons in this structure, and both cooperative and competition phenomena regulate the communication between these two types of cells. Importantly, it has been revealed that GSK-3β and tau proteins, which are two of the main players driving AD pathology, are cornerstones of adult hippocampal neurogenesis regulation. We have shown that alterations either promoting or impeding the actions of these two proteins have detrimental effects on the structural plasticity of granule neurons. Of note, these impairments occur both under basal conditions and in response to detrimental and neuroprotective stimuli. Thus, in order to achieve the full effectiveness of future therapies for AD, we propose that attention be turned toward identifying the pathological and physiological actions of the proteins involved in the pathogenesis of this condition.

%B J Alzheimers Dis %V 64 %P S497-S505 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562522?dopt=Abstract %R 10.3233/JAD-179918 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Unusual Clinical Presentations Challenging the Early Clinical Diagnosis of Creutzfeldt-Jakob Disease. %A Baiardi, Simone %A Capellari, Sabina %A Bartoletti Stella, Anna %A Parchi, Piero %X

The introduction of prion RT-QuIC, an ultrasensitive specific assay for the in vivo detection of the abnormal prion protein, has significantly increased the potential for an early and accurate clinical diagnosis of Creutzfeldt-Jakob disease (CJD). However, in the clinical setting, the early identification of patients with possible CJD is often challenging. Indeed, CJD patients may present with isolated symptoms that remain the only clinical manifestation for some time, or with neurological syndromes atypical for CJD. To enhance awareness of unusual disease presentations and promote earlier diagnosis, we reviewed the entire spectrum of atypical early manifestations of CJD, mainly reported to date as case descriptions or small case series. They included sensory either visual or auditory disturbances, seizures, isolated psychiatric manifestations, atypical parkinsonian syndromes (corticobasal syndrome, progressive supranuclear palsy-like), pseudobulbar syndrome, isolated involuntary movements (dystonia, myoclonus, chorea, blepharospasm), acute or subacute onsets mimicking a stroke, isolated aphasia, and neuropathy. Since CJD is a rare disease and its clinical course rapidly progressive, an in-depth understanding and awareness of early clinical features are mandatory to enhance the overall diagnostic accuracy in its very early stages and to recruit optimal candidates for future therapeutic trials.

%B J Alzheimers Dis %V 64 %P 1051-1065 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010123?dopt=Abstract %R 10.3233/JAD-180123 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Use of Mobile Games to Assess Cognitive Function of Elderly with and without Cognitive Impairment. %A Bonnechère, Bruno %A Van Vooren, Mélissa %A Bier, Jean-Christophe %A De Breucker, Sandra %A Van Hove, Olivier %A Van Sint Jan, Serge %A Feipel, Véronique %A Jansen, Bart %X

BACKGROUND: In the past few years numerous mobile games have been developed to train the brain. There is a lack of information about the relation between the scores obtained in these games and the cognitive abilities of the patients.

OBJECTIVE: The aim of this study was to determine whether or not mobile games can be used to assess cognitive abilities of elderly.

METHODS: Twenty healthy young adults, 29 old patients with cognitive impairments (Mini-Mental State Exam (MMSE) [20- 24]) and 27-aged controls participated in this study. Scores obtained in 7 mobile games were correlated with MMSE and the Addenbrooke's Cognitive Evaluation revised (ACE-R).

RESULTS: Statistically significant differences were found for all games between patients with cognitive impairments and the aged controls. Correlations between the average scores of the games and the MMSE and ACE-R are significant (R = 0.72 [p < 0.001] and R = 0.81 [p < 0.001], respectively).

CONCLUSION: Scores of cognitive mobile games could be used as an alternative to MMSE and ACE-R to evaluate cognitive function of aged people with and without cognitive impairment at least when MMSE is higher than 20/30.

%B J Alzheimers Dis %V 64 %P 1285-1293 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29991133?dopt=Abstract %R 10.3233/JAD-180224 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Using Neuropsychological Process Scores to Identify Subtle Cognitive Decline and Predict Progression to Mild Cognitive Impairment. %A Thomas, Kelsey R %A Edmonds, Emily C %A Eppig, Joel %A Salmon, David P %A Bondi, Mark W %X

BACKGROUND: We previously operationally-defined subtle cognitive decline (SCD) in preclinical Alzheimer's disease (AD) using total scores on neuropsychological (NP) tests. NP process scores (i.e., provide information about how a total NP score was achieved) may be a useful tool for identifying early cognitive inefficiencies prior to objective impairment seen in mild cognitive impairment (MCI) and dementia.

OBJECTIVE: We aimed to integrate process scores into the SCD definition to identify stages of SCD and improve early detection of those at risk for decline.

METHODS: Cognitively "normal" participants from the Alzheimer's Disease Neuroimaging Initiative were classified as "early" SCD (E-SCD; >1 SD below norm-adjusted mean on 2 process scores or on 1 process score plus 1 NP total score), "late" SCD (L-SCD; existing SCD criteria of >1 SD below norm-adjusted mean on 2 NP total scores in different domains), or "no SCD" (NC). Process scores considered in the SCD criteria were word-list intrusion errors, retroactive interference, and learning slope. Cerebrospinal fluid AD biomarkers were used to examine pathologic burden across groups.

RESULTS: E-SCD and L-SCD progressed to MCI 2.5-3.4 times faster than the NC group. Survival curves for E-SCD and L-SCD converged at 7-8 years after baseline. The combined (E-SCD+L-SCD) group had improved sensitivity to detect progression to MCI relative to L-SCD only. AD biomarker positivity increased across NC, SCD, and MCI groups.

CONCLUSIONS: Process scores can be integrated into the SCD criteria to allow for increased sensitivity and earlier identification of cognitively normal older adults at risk for decline prior to frank impairment on NP total scores.

%B J Alzheimers Dis %V 64 %P 195-204 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865077?dopt=Abstract %R 10.3233/JAD-180229 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Utility of Amyloid and FDG-PET in Clinical Practice: Differences Between Secondary and Tertiary Care Memory Units. %A Lage, Carmen %A Suarez, Andrea Gonzalez %A Pozueta, Ana %A Riancho, Javier %A Kazimierczak, Martha %A Bravo, María %A Jimenez Bonilla, Julio %A de Arcocha Torres, Marıa %A Quirce, Remedios %A Banzo, Ignacio %A Vázquez-Higuera, José Luis %A Rabinovici, Gil D %A Rodriguez-Rodriguez, Eloy %A Sánchez-Juan, Pascual %X

The clinical utility of amyloid positron emission tomography (PET) has not been fully established. Our aim was to evaluate the effect of amyloid imaging on clinical decision making in a secondary care unit and compare our results with a previous study in a tertiary center following the same methods. We reviewed retrospectively 151 cognitively impaired patients who underwent amyloid (Pittsburgh compound B [PiB]) PET and were evaluated clinically before and after the scan in a secondary care unit. One hundred and fifty concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed changes between the pre- and post-PET clinical diagnosis and Alzheimer's disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using χ2 and multivariate logistic regression. Concordance between classification based on scan readings and baseline diagnosis was 66% for PiB and 47% for FDG. The primary diagnosis changed after PET in 17.2% of cases. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (p = 0.0002). Changes in treatment were associated with concordant PiB (p = 0.009) while FDG had no effect on treatment decisions. Based on our regression model, patients with diagnostic dilemmas, a suspected non-amyloid syndrome, and Clinical Dementia Rating <1 were more likely to benefit from amyloid PET due to a higher likelihood of diagnostic change. We found that changes in diagnosis after PET in our secondary center almost doubled those of our previous analysis of a tertiary unit (9% versus 17.2%). Our results offer some clues about the rational use of amyloid PET in a secondary care memory unit stressing its utility in mild cognitive impairment patients.

%B J Alzheimers Dis %V 63 %P 1025-1033 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710706?dopt=Abstract %R 10.3233/JAD-170985 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Utility of Amyloid PET Scans in the Evaluation of Patients Presenting with Diverse Cognitive Complaints. %A Shea, Yat-Fung %A Barker, Warren %A Greig-Gusto, Maria T %A Loewenstein, David A %A DeKosky, Steven T %A Duara, Ranjan %X

BACKGROUND: The impact of amyloid positron emission tomography (Aβ-PET) in a "real-world" memory disorders clinic remains poorly studied.

OBJECTIVE: We studied the impact of Aβ-PET in diagnosis and management in the memory clinic and factors making the most impact in diagnosis and management.

METHODS: We studied 102 patients who had presented at a memory disorders clinic (the Wien Center for Alzheimer's Disease and Memory Disorders, Miami Beach, FL) and had a diagnostic work-up for cognitive complaints, including Aβ-PET scans.

RESULTS: Following Aβ-PET, changes were made in diagnosis (37.3%), in specific treatments for Alzheimer's disease (26.5%) and in psychiatric treatments (25.5%). The agreement between diagnosis pre-Aβ-PET versus post-Aβ-PET diagnosis was only fair, with a Cohen's kappa of 0.23 (95% CI 0-0.42). Patients with MRI findings suggestive of AD (medial temporal and/or parietal atrophy) were more frequently amyloid positive than amyloid negative (66.2% versus 33.8%, p = 0.04). Among patients with atypical clinical features for AD, but with MRI findings suggestive of AD, an amyloid negative PET scan had a greater impact than an amyloid positive PET scan on diagnosis (84.2% versus 17.1%, p < 0.001), management (84.2% versus 40%, p < 0.01) and discussion of results and advice on lifestyle (73.7% versus 22.9%, p < 0.001).

CONCLUSIONS: We conclude that MRI features suggestive of AD predict a positive amyloid PET scan. However, among those with MRI features suggestive of AD but with atypical clinical features of AD, the clinical impact on diagnosis and management is greater for an amyloid negative than an amyloid positive Aβ-PET scans.

%B J Alzheimers Dis %V 66 %P 1599-1608 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30475766?dopt=Abstract %R 10.3233/JAD-180683 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Utility of an Alzheimer's Disease Risk-Weighted Polygenic Risk Score for Predicting Rates of Cognitive Decline in Preclinical Alzheimer's Disease: A Prospective Longitudinal Study. %A Porter, Tenielle %A Burnham, Samantha C %A Milicic, Lidija %A Savage, Greg %A Maruff, Paul %A Lim, Yen Ying %A Li, Qiao-Xin %A Ames, David %A Masters, Colin L %A Rainey-Smith, Stephanie %A Rowe, Christopher C %A Salvado, Olivier %A Groth, David %A Verdile, Giuseppe %A Villemagne, Victor L %A Laws, Simon M %X

BACKGROUND: With the exception of APOE, genetic variants associated with increased Alzheimer's disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood.

OBJECTIVE: To validate associations of a 22-variant AD-risk-weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline.

METHODS: The PRS was evaluated with respect to brain amyloid-β (Aβ) burden, cerebrospinal fluid (CSF) Aβ42, total-tau, and phospho-tau, and decline in cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer's Cognitive Composite (PACC).

RESULTS: PRS, both with and without APOE, were positively correlated with brain Aβ burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Aβhigh) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Aβhigh CN older adults is due to a saturating effect of APOE genotype.

CONCLUSIONS: An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline.

%B J Alzheimers Dis %V 66 %P 1193-1211 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412495?dopt=Abstract %R 10.3233/JAD-180713 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Ventral Tegmental Area in Prodromal Alzheimer's Disease: Bridging the Gap between Mice and Humans. %A D'Amelio, Marcello %A Serra, Laura %A Bozzali, Marco %X

Alzheimer's disease (AD) is a progressive neurological disorder characterized by several cognitive and non-cognitive symptoms, with episodic memory being the earliest and most prominently impaired cognitive function. Dopaminergic signals are required for encoding hippocampal memory for new events and the ventral tegmental area (VTA), together with the locus coeruleus, are the primary sources of dopamine acting on dopaminergic receptors in the hippocampus. With this in mind, a recent study on a validated mouse model of AD highlighted on the hippocampal dysfunction and its correlation with an early degeneration of dopaminergic neurons in the VTA. In this issue, De Marco and Venneri test the hypothesis that the volume of the VTA nucleus in humans might be associated with cognitive features of AD.

%B J Alzheimers Dis %V 63 %P 181-183 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29630556?dopt=Abstract %R 10.3233/JAD-180094 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Visual Processing during Short-Term Memory Binding in Mild Alzheimer's Disease. %A Fernández, Gerardo %A Orozco, David %A Agamennoni, Osvaldo %A Schumacher, Marcela %A Sañudo, Silvana %A Biondi, Juan %A Parra, Mario A %X

Patients with Alzheimer's disease (AD) typically present with attentional and oculomotor abnormalities that can have an impact on visual processing and associated cognitive functions. Over the last few years, we have witnessed a shift toward the analyses of eye movement behaviors as a means to further our understanding of the pathophysiology of common disorders such as AD. However, little work has been done to unveil the link between eye moment abnormalities and poor performance on cognitive tasks known to be markers for AD patients, such as the short-term memory-binding task. We analyzed eye movement fixation behaviors of thirteen healthy older adults (Controls) and thirteen patients with probable mild AD while they performed the visual short-term memory binding task. The short-term memory binding task asks participants to detect changes across two consecutive arrays of two bicolored object whose features (i.e., colors) have to be remembered separately (i.e., Unbound Colors), or combined within integrated objects (i.e., Bound Colors). Patients with mild AD showed the well-known pattern of selective memory binding impairments. This was accompanied by significant impairments in their eye movements only when they processed Bound Colors. Patients with mild AD remarkably decreased their mean gaze duration during the encoding of color-color bindings. These findings open new windows of research into the pathophysiological mechanisms of memory deficits in AD patients and the link between its phenotypic expressions (i.e., oculomotor and cognitive disorders). We discuss these findings considering current trends regarding clinical assessment, neural correlates, and potential avenues for robust biomarkers.

%B J Alzheimers Dis %V 63 %P 185-194 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614644?dopt=Abstract %R 10.3233/JAD-170728 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Visualization of Focal Thinning of the Ganglion Cell-Inner Plexiform Layer in Patients with Mild Cognitive Impairment and Alzheimer's Disease. %A Shao, Yi %A Jiang, Hong %A Wei, Yantao %A Shi, Yingying %A Shi, Ce %A Wright, Clinton B %A Sun, Xiaoyan %A Vanner, Elizabeth A %A Rodriguez, Anny D %A Lam, Byron L %A Rundek, Tatjana %A Baumel, Barry S %A Gameiro, Giovana Rosa %A Dong, Chuanhui %A Wang, Jianhua %X

BACKGROUND: A detailed analysis of the tomographic thickness of intraretinal layers may provide more information on neurodegeneration in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD).

OBJECTIVE: The goal was to analyze tomographic thickness patterns of intraretinal layers in patients with AD andMCI.

METHOD: Forty-nine patients (25 AD and 24 MCI) and 21 cognitively normal (CN) controls were imaged using ultra-high-resolution optical coherence tomography to obtain volumetric data centered on the fovea. The segmented intraretinal layers were retinal nerve fiber layer (RNFL), ganglion cell- inner plexiform layer (GCIPL), inner nuclear layer (INL), outer nuclear layer (ONL), outer plexiform layer (OPL), and retinal photoreceptor (PR), in addition to the total retinal thickness(TRT).

RESULTS: The thickness differences were negative (thinning) mainly in TRT, RNFL, and GCIPL in both AD and MCI groups in comparison to CN, while the thickness differences were positive (thickening) mainly in ONL and PR in AD. GCIPL of AD and MCI was thinner in superior, nasal superior, and temporal superior quadrants, compared to CN (p < 0.05). GCIPL of the inner superior, inner nasal superior, inner temporal superior, and outer nasal superior sectors was significantly thinner in AD than CN (p < 0.05). GCIPL of the outer superior, inner temporal superior, outer nasal, and temporal superior sectors was significantly thinner in MCI than CN (p < 0.05).

CONCLUSION: Focal thinning of the GCIPL was visualized and quantified by detailed partitions in AD and MCI, which provides specific information about neurodegeneration in MCI and AD.

%B J Alzheimers Dis %V 64 %P 1261-1273 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040712?dopt=Abstract %R 10.3233/JAD-180070 %0 Journal Article %J J Alzheimers Dis %D 2018 %T What Do We Know About Behavioral Crises in Dementia? A Systematic Review. %A Backhouse, Tamara %A Camino, Julieta %A Mioshi, Eneida %X

BACKGROUND: Behavioral crises in dementia are represented by a wide variety of symptoms, regularly require external intervention from professionals, and are reported as a risk factor for hospital admission. Little is known about the factors that are associated with them.

OBJECTIVE: To determine the factors associated with dementia-related behavioral crises.

METHODS: We searched MEDLINE, CINAHL, PsycINFO, EMBASE, and AMED databases. An additional lateral search including reference lists was conducted. Two researchers screened all records for potential eligibility. Narrative synthesis was used to bring together the findings.

RESULTS: Out of the 5,544 records identified, 24 articles (18 distinct studies) met the eligibility criteria. Aggression and agitation were the most common behaviors present at crises. Delusions, wandering/absconding, and hallucinations were also key behaviors contributing to crises. Behavioral crises predominantly happened in the severe stages of dementia (according to MMSE scores), in people with dementia residing in their own homes and in long-term care, and were the catalyst for admissions to psychiatric inpatient settings, specialist-care units, long-term care settings, or for referrals to psychiatric community services. Lack of consistency in assessment of behavior, and management of agitation/aggression in dementia crises were evident.

CONCLUSION: Interventions to reduce the likelihood of people with dementia-related behaviors reaching crisis point need to focus on both family and care home settings and incorporate aggression and agitation management. Future research should focus on determining the factors that could be addressed to prevent behavioral crises and the interventions and models of care that may help to prevent crises.

%B J Alzheimers Dis %V 62 %P 99-113 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439334?dopt=Abstract %R 10.3233/JAD-170679 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Which Risk Factors Causally Influence Dementia? A Systematic Review of Mendelian Randomization Studies. %A Kuźma, Elżbieta %A Hannon, Eilis %A Zhou, Ang %A Lourida, Ilianna %A Bethel, Alison %A Levine, Deborah A %A Lunnon, Katie %A Thompson-Coon, Jo %A Hyppönen, Elina %A Llewellyn, David J %X

BACKGROUND: Numerous risk factors for dementia are well established, though the causal nature of these associations remains unclear.

OBJECTIVE: To systematically review Mendelian randomization (MR) studies investigating causal relationships between risk factors and global cognitive function or dementia.

METHODS: We searched five databases from inception to February 2017 and conducted citation searches including MR studies investigating the association between any risk factor and global cognitive function, all-cause dementia or dementia subtypes. Two reviewers independently assessed titles and abstracts, full-texts, and study quality.

RESULTS: We included 18 MR studies investigating education, lifestyle factors, cardiovascular factors and related biomarkers, diabetes related and other endocrine factors, and telomere length. Studies were of predominantly good quality, however eight received low ratings for sample size and statistical power. The most convincing causal evidence was found for an association of shorter telomeres with increased risk of Alzheimer's disease (AD). Causal evidence was weaker for smoking quantity, vitamin D, homocysteine, systolic blood pressure, fasting glucose, insulin sensitivity, and high-density lipoprotein cholesterol. Well-replicated associations were not present for most exposures and we cannot fully discount survival and diagnostic bias, or the potential for pleiotropic effects.

CONCLUSIONS: Genetic evidence supported a causal association between telomere length and AD, whereas limited evidence for other risk factors was largely inconclusive with tentative evidence for smoking quantity, vitamin D, homocysteine, and selected metabolic markers. The lack of stronger evidence for other risk factors may reflect insufficient statistical power. Larger well-designed MR studies would therefore help establish the causal status of these dementia risk factors.

%B J Alzheimers Dis %V 64 %P 181-193 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865062?dopt=Abstract %R 10.3233/JAD-180013 %0 Journal Article %J J Alzheimers Dis %D 2018 %T White Matter Hyperintensities and Cognition in Mild Cognitive Impairment and Alzheimer's Disease: A Domain-Specific Meta-Analysis. %A van den Berg, Esther %A Geerlings, Mirjam I %A Biessels, Geert Jan %A Nederkoorn, Paul J %A Kloppenborg, Raoul P %X

BACKGROUND: White matter hyperintensities (WMHs) are related to cognitive dysfunction in the general population. The clinical relevance of WMHs in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) is, however, unclear.

OBJECTIVE: This meta-analysis aimed to quantify the association of WMHs and specific cognitive domains in patients with MCI or AD.

METHODS: PubMed (January 1990-January 2017) was searched for studies that used MRI to quantify WMHs, and measured cognitive functioning (≥1 predefined cognitive domain with ≥1 test) in a well-defined population of persons diagnosed with MCI or AD. Fischer's Z was used as the common metric for effect size. Modifying effects of demographics, MMSE, and WMH location were examined.

RESULTS: Twelve cross-sectional studies on AD (total n = 1,370, median age 75 years) and 10 studies on MCI (9 cross-sectional, 1 longitudinal; total n = 2,286, median age 73 years) were included. The association between WMHs and overall cognition was significantly stronger for MCI (-0.25, -0.36 to -0.14) than for AD (-0.11, -0.14 to -0.08; QM = 10.7, p < 0.05). For both groups, largest effect sizes were found in attention and executive functions (-0.26, -0.36 to -0.15) and processing speed (-0.21, -0.35 to -0.12). No significant modifying effects of age and gender were found.

CONCLUSION: WMHs have a medium-sized association with different cognitive functions in patients with MCI and a small, but statistically significant, association with cognition in AD. These result underscore the role of co-occurring vascular brain damage in MCI and AD.

%B J Alzheimers Dis %V 63 %P 515-527 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29630548?dopt=Abstract %R 10.3233/JAD-170573 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Word and Picture Version of the Free and Cued Selective Reminding Test (FCSRT): Is There Any Difference? %A Arighi, Andrea %A Carandini, Tiziana %A Mercurio, Matteo %A Carpani, Giovanni %A Pietroboni, Anna Margherita %A Fumagalli, Giorgio %A Ghezzi, Laura %A Basilico, Paola %A Calvi, Alberto %A Scarioni, Marta %A De Riz, Milena %A Fenoglio, Chiara %A Scola, Elisa %A Triulzi, Fabio %A Galimberti, Daniela %A Scarpini, Elio %K Aged %K Aged, 80 and over %K Association Learning %K Cognitive Dysfunction %K Cues %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Recall %K Middle Aged %K Neuropsychological Tests %K Photic Stimulation %K Vocabulary %X

The Free and Cued Selective Reminding Test (FCSRT) is the most commonly used neuropsychological test to evaluate episodic memory. Two variants of FCSRT exist, using the recall of words (FCSRT-w) or pictures (FCSRT-p). Fourteen patients with mild cognitive impairment underwent neuropsychological evaluation and brain magnetic resonance. We found differences in FCSRT-w and FCSRT-p variants scores. FCSRT-p was correlated with atrophy in areas involved in visual stimuli processing while FCSRT-w was correlated to hippocampal atrophy. Our study suggests that FCSRT-w and FCSRT-p scores are not equivalent, but a larger cohort of patients is needed to validate these results.

%B J Alzheimers Dis %V 61 %P 47-52 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125489?dopt=Abstract %R 10.3233/JAD-170712 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The 2002 NIMH Provisional Diagnostic Criteria for Depression of Alzheimer's Disease (PDC-dAD): Gauging their Validity over a Decade Later. %A Sepehry, Amir A %A Lee, Philip E %A Hsiung, Ging-Yuek R %A Beattie, B Lynn %A Feldman, Howard H %A Jacova, Claudia %X

Presented herein is evidence for criterion, content, and convergent/discriminant validity of the NIMH-Provisional Diagnostic Criteria for depression of Alzheimer's Disease (PDC-dAD) that were formulated to address depression in Alzheimer's disease (AD). Using meta-analytic and systematic review methods, we examined criterion validity evidence in epidemiological and clinical studies comparing the PDC-dAD to Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV), and International Classification of Disease (ICD 9) depression diagnostic criteria. We estimated prevalence of depression by PDC, DSM, and ICD with an omnibus event rate effect-size. We also examined diagnostic agreement between PDC and DSM. To gauge content validity, we reviewed rates of symptom endorsement for each diagnostic approach. Finally, we examined the PDC's relationship with assessment scales (global cognition, neuropsychiatric, and depression definition) for convergent validity evidence. The aggregate evidence supports the validity of the PDC-dAD. Our findings suggest that depression in AD differs from other depressive disorders including Major Depressive Disorder (MDD) in that dAD is more prevalent, with generally a milder presentation and with unique features not captured by the DSM. Although the PDC are the current standard for diagnosis of depression in AD, we identified the need for their further optimization based on predictive validity evidence.

%B J Alzheimers Dis %V 58 %P 449-462 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453472?dopt=Abstract %R 10.3233/JAD-161061 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A 3-Month Aerobic Training Program Improves Brain Energy Metabolism in Mild Alzheimer's Disease: Preliminary Results from a Neuroimaging Study. %A Castellano, Christian-Alexandre %A Paquet, Nancy %A Dionne, Isabelle J %A Imbeault, Hélène %A Langlois, Francis %A Croteau, Etienne %A Tremblay, Sébastien %A Fortier, Mélanie %A Matte, J Jacques %A Lacombe, Guy %A Fülöp, Tamás %A Bocti, Christian %A Cunnane, Stephen C %X

BACKGROUND: Aerobic training has some benefits for delaying the onset or progression of Alzheimer's disease (AD). Little is known about the implication of the brain's two main fuels, glucose and ketones (acetoacetate), associated with thesebenefits.

OBJECTIVE: To determine whether aerobic exercise training modifies brain energy metabolism in mild AD.

METHODS: In this uncontrolled study, ten patients with mild AD participated in a 3-month, individualized, moderate-intensity aerobic training on a treadmill (Walking). Quantitative measurement of brain uptake of glucose (CMRglu) and acetoacetate (CMRacac) using neuroimaging and cognitive testing were done before and after the Walking program.

RESULTS: Four men and six women with an average global cognitive score (MMSE) of 26/30 and an average age of 73 y completed the Walking program. Average total distance and treadmill speed were 8 km/week and 4 km/h, respectively. Compared to the Baseline, after Walking, CMRacac was three-fold higher (0.6±0.4 versus 0.2±0.1 μmol/100 g/min; p = 0.01). Plasma acetoacetate concentration and the blood-to-brain acetoacetate influx rate constant were also increased by 2-3-fold (all p≤0.03). CMRglu was unchanged after Walking (28.0±0.1 μmol/100 g/min; p = 0.96). There was a tendency toward improvement in the Stroop-color naming test (-10% completion time, p = 0.06). Performance on the Trail Making A&B tests was also directly related to plasma acetoacetate and CMRacac (all p≤0.01).

CONCLUSION: In mild AD, aerobic training improved brain energy metabolism by increasing ketone uptake and utilization while maintaining brain glucose uptake, and could potentially be associated with some cognitive improvement.

%B J Alzheimers Dis %V 56 %P 1459-1468 %G eng %N 4 %R 10.3233/JAD-161163 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Abnormalities of Cerebral Deep Medullary Veins on 7 Tesla MRI in Amnestic Mild Cognitive Impairment and Early Alzheimer's Disease: A Pilot Study. %A Bouvy, Willem H %A Kuijf, Hugo J %A Zwanenburg, Jaco J M %A Koek, Huiberdina L %A Kappelle, L Jaap %A Luijten, Peter R %A Ikram, M Kamran %A Biessels, Geert Jan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Brain %K Cerebral Small Vessel Diseases %K Cognitive Dysfunction %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %X

Cerebral small vessel disease (SVD) contributes to cognitive impairment and dementia. SVD may affect veins, but veins are difficult to detect with 1.5 and 3T MRI. We compared deep medullary veins (DMVs) visualized on 7T-MRI between patients with early Alzheimer's disease (eAD; n = 17) or amnestic MCI (aMCI; n = 12) and controls (n = 40). The number and density of DMVs was similar in patients and controls, but tortuosity was higher in eAD (Cohen's d = 0.7, 95% CI: 0.1-1.2, p = 0.02) and aMCI (Cohen's d = 0.8, 95% CI: 0.2-1.5, p = 0.01), independent of brain atrophy. Venous changes provide a new perspective on vascular involvement in dementia.

%B J Alzheimers Dis %V 57 %P 705-710 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28282806?dopt=Abstract %R 10.3233/JAD-160952 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Abnormalities of Cortical Neural Synchronization Mechanisms in Subjects with Mild Cognitive Impairment due to Alzheimer's and Parkinson's Diseases: An EEG Study. %A Babiloni, Claudio %A Del Percio, Claudio %A Lizio, Roberta %A Noce, Giuseppe %A Cordone, Susanna %A Lopez, Susanna %A Soricelli, Andrea %A Ferri, Raffaele %A Pascarelli, Maria Teresa %A Nobili, Flavio %A Arnaldi, Dario %A Famá, Francesco %A Aarsland, Dag %A Orzi, Francesco %A Buttinelli, Carla %A Giubilei, Franco %A Onofrj, Marco %A Stocchi, Fabrizio %A Stirpe, Paola %A Fuhr, Peter %A Gschwandtner, Ute %A Ransmayr, Gerhard %A Caravias, Georg %A Garn, Heinrich %A Sorpresi, Fabiola %A Pievani, Michela %A D'Antonio, Fabrizia %A de Lena, Carlo %A Güntekin, Bahar %A Hanoğlu, Lutfu %A Başar, Erol %A Yener, Görsev %A Emek-Savaş, Derya Durusu %A Triggiani, Antonio Ivano %A Franciotti, Raffaella %A Frisoni, Giovanni B %A Bonanni, Laura %A De Pandis, Maria Francesca %X

The aim of this retrospective and exploratory study was that the cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms might reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and Parkinson's disease (PDMCI) as compared to healthy subjects. Clinical and rsEEG data of 75 ADMCI, 75 PDMCI, and 75 cognitively normal elderly (Nold) subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) was matched between the ADMCI and PDMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROC) classified these sources across individuals. Results showed that compared to the Nold group, the posterior alpha2 and alpha3 source activities were more abnormal in the ADMCI than the PDMCI group, while the parietal delta source activities were more abnormal in the PDMCI than the ADMCI group. The parietal delta and alpha sources correlated with MMSE score and correctly classified the Nold and diseased individuals (area under the ROC = 0.77-0.79). In conclusion, the PDMCI and ADMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test these rsEEG markers for clinical applications and drug discovery.

%B J Alzheimers Dis %V 59 %P 339-358 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28621693?dopt=Abstract %R 10.3233/JAD-160883 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Acceleration of Amyloidosis by Inflammation in the Amyloid-Beta Marmoset Monkey Model of Alzheimer's Disease. %A Philippens, Ingrid H %A Ormel, Paul R %A Baarends, Guus %A Johansson, Maja %A Remarque, Ed J %A Doverskog, Magnus %X

BACKGROUND: The immune system is increasingly mentioned as a potential target for Alzheimer's disease (AD) treatment.

OBJECTIVE: In the present pilot study, the effect of (neuro)inflammation on amyloidopathy was investigated in the marmoset monkey, which has potential as an AD animal model due to its natural cerebral amyloidosis similar to humans.

METHODS: Six adult/aged marmosets (Callithrix jacchus) were intracranial injected with amyloid-beta (Aβ) fibrils at three cortical locations in the right hemisphere. Additionally, in half of the monkeys, lipopolysaccharide (LPS) was co-injected with the Aβ fibrils and injected in the other hemisphere without Aβ fibrils. The other three monkeys received phosphate buffered saline instead of LPS, as a control for the inflammatory state. The effect of inflammation on amyloidopathy was also investigated in an additional monkey that suffered from chronic inflammatory wasting syndrome. Mirror histology sections were analyzed to assess amyloidopathy and immune reaction, and peripheral blood for AD biomarker expression.

RESULTS: All LPS-injected monkeys showed an early AD immune blood cell expression profile on CD95 and CD45RA. Two out of three monkeys injected with Aβ and LPS and the additional monkey, suffering from chronic inflammation, developed plaques. None of the controls, injected with Aβ only, developed any plaques.

CONCLUSION: This study shows the importance of immune modulation on the susceptibility for amyloidosis, a hallmark of AD, which offers new perspectives for disease modifying approaches in AD.

%B J Alzheimers Dis %V 55 %P 101-113 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662314?dopt=Abstract %R 10.3233/JAD-160673 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Accuracy of Clinical Diagnosis of Dementia with Lewy Bodies versus Neuropathology. %A Skogseth, Ragnhild %A Hortobágyi, Tibor %A Soennesyn, Hogne %A Chwiszczuk, Luiza %A Ffytche, Dominic %A Rongve, Arvid %A Ballard, Clive %A Aarsland, Dag %X

BACKGROUND: The first consensus criteria for dementia with Lewy bodies (DLB) published in 1996 were revised in 2005, partly because the original clinical criteria had suboptimal sensitivity. Few studies have assessed the accuracy of the 2005 criteria applied prospectively in newly diagnosed patients who have been followed longitudinally.

OBJECTIVE: To explore the correlation between clinical and pathological diagnoses in patients with DLB and Parkinson's disease with dementia (PDD).

METHODS: From a prospective referral cohort study with enriched recruitment of patients with DLB and PDD, we included the first 56 patients coming to autopsy. Patients had mild dementia at inclusion and were followed annually until death with standardized clinical assessments. Pathological assessment was performed blind to clinical information according to standardized protocols and consensus criteria for DLB.

RESULTS: 20 patients received a pathological diagnosis of Lewy body disease; the corresponding clinical diagnoses were probable DLB (n = 11), PDD (n = 5), probable (n = 2) or possible (n = 2) Alzheimer's disease (AD). Of 14 patients with a clinical diagnosis of probable DLB, 11 had DLB/PDD and 3 had AD at pathology. One patient with clinically possible DLB fulfilled criteria for pathological AD. Sensitivity, specificity, positive predictive value, and negative predictive values for probable DLB were 73%, 93%, 79%, and 90%.

CONCLUSION: Our findings suggest that the international clinical consensus criteria for DLB perform reasonably well. However, false positive and false negative diagnoses still occur, indicating that the criteria need to be improved, that biomarkers may be needed, and that neuropathological feedback is vital to improve accuracy.

%B J Alzheimers Dis %V 59 %P 1139-1152 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731443?dopt=Abstract %R 10.3233/JAD-170274 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Adult-Onset Epilepsy in Presymptomatic Alzheimer's Disease: A Retrospective Study. %A DiFrancesco, Jacopo C %A Tremolizzo, Lucio %A Polonia, Valeria %A Giussani, Giorgia %A Bianchi, Elisa %A Franchi, Carlotta %A Nobili, Alessandro %A Appollonio, Ildebrando %A Beghi, Ettore %A Ferrarese, Carlo %X

BACKGROUND: The prevalence of epilepsy with onset in adulthood increases with age, mainly due to the accumulation of brain damage. However, a significant proportion of patients experience seizures of unknown cause. Alzheimer's disease (AD) is associated with an increased risk of seizures. Seizure activity is interpreted as a secondary event related to hyperexcitability caused by amyloid-β aggregation.

OBJECTIVE: Since neurodegenerative processes begin several years before clinical symptoms, epilepsy could be more frequent in the presymptomatic stages of dementia.

METHODS: We retrospectively reviewed the prevalence of epilepsy of unknown origin with adult onset before cognitive decline in a large cohort of AD patients (EPS-AD) recruited based on clinical and neuropsychological data. Data of patients with epilepsy followed by AD were compared with two control groups: patients with AD without seizures (no EPS-AD) and a large reference population (RP).

RESULTS: In AD patients, the prevalence of epilepsy of unknown origin, with onset in the adulthood before cognitive decline is 17.1 times higher compared with the RP (95% CI: 10.3-28.3). In EPS-AD, seizures begin on average 4.6 years (median 2.0) before the onset of cognitive symptoms and cognitive decline starts 3.6 years earlier compared with noEPS-AD.

CONCLUSIONS: Neurodegenerative processes of dementia could play a key role in the pathogenesis of epilepsy in a subgroup of individuals intended to develop cognitive decline. Adult-onset epilepsy of undefined cause could thus represent a risk factor for the ongoing neurodegenerative damage, even preceding by years the onset of clinical symptoms of dementia.

%B J Alzheimers Dis %V 60 %P 1267-1274 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28968234?dopt=Abstract %R 10.3233/JAD-170392 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Aerosol Delivery of Curcumin Reduced Amyloid-β Deposition and Improved Cognitive Performance in a Transgenic Model of Alzheimer's Disease. %A McClure, Richard %A Ong, Henry %A Janve, Vaibhab %A Barton, Shawn %A Zhu, Meiying %A Li, Bo %A Dawes, Mary %A Jerome, W Gray %A Anderson, Adam %A Massion, Pierre %A Gore, John C %A Pham, Wellington %X

We report a novel approach for the delivery of curcumin to the brain via inhalation of the aerosol for the potential treatment of Alzheimer's disease. The percentage of plaque fraction in the subiculum and hippocampus reduced significantly when young 5XFAD mice were treated with inhalable curcumin over an extended period of time compared to age-matched nontreated counterparts. Further, treated animals demonstrated remarkably improved overall cognitive function, no registered systemic or pulmonary toxicity associated with inhalable curcumin observed during the course of this work.

%B J Alzheimers Dis %V 55 %P 797-811 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802223?dopt=Abstract %R 10.3233/JAD-160289 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alcohol Intake and Cognitively Healthy Longevity in Community-Dwelling Adults: The Rancho Bernardo Study. %A Richard, Erin L %A Kritz-Silverstein, Donna %A Laughlin, Gail A %A Fung, Teresa T %A Barrett-Connor, Elizabeth %A McEvoy, Linda K %X

To better understand the association of alcohol intake with cognitively healthy longevity (CHL), we explored the association between amount and frequency of alcohol intake and CHL among 1,344 older community-dwelling adults. Alcohol intake was assessed by questionnaire in 1984-1987. Cognitive function was assessed in approximate four-year intervals between 1988 and 2009. Multinomial logistic regression, adjusting for multiple lifestyle and health factors, was used to examine the association between alcohol consumption and CHL (living to age 85 without cognitive impairment), survival to age 85 with cognitive impairment (MMSE score >1.5 standard deviations below expectation for age, sex, and education), or death before age 85. Most participants (88%) reported some current alcohol intake; 49% reported a moderate amount of alcohol intake, and 48% reported drinking near-daily. Relative to nondrinkers, moderate and heavy drinkers (up to 3 drinks/day for women and for men 65 years and older, up to 4 drinks/day for men under 65 years) had significantly higher adjusted odds of survival to age 85 without cognitive impairment (p's < 0.05). Near-daily drinkers had 2-3 fold higher adjusted odds of CHL versus living to at least age 85 with cognitive impairment (odds ratio (OR) = 2.06; 95% confidence interval (CI): 1.21, 3.49) or death before 85 (OR = 3.24; 95% CI: 1.92, 5.46). Although excessive drinking has negative health consequences, these results suggest that regular, moderate drinking may play a role in cognitively healthy longevity.

%B J Alzheimers Dis %V 59 %P 803-814 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671111?dopt=Abstract %R 10.3233/JAD-161153 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alterations in the Balance of Amyloid-β Protein Precursor Species in the Cerebrospinal Fluid of Alzheimer's Disease Patients. %A Lopez-Font, Inmaculada %A Boix, Claudia P %A Zetterberg, Henrik %A Blennow, Kaj %A Sáez-Valero, Javier %X

We recently demonstrated that soluble forms of the amyloid-β protein precursor (sAβPP) assemble into multimeric complexes in cerebrospinal fluid (CSF), which contributes to the underestimation of specific sAβPP species when assessed by ELISA. To circumvent this issue, we analyzed by SDS-PAGE large fragments of sAβPP and their variants in the CSF from Alzheimer's disease (AD; n = 20) and control (n = 20) subjects, probing with specific antibodies against particular domains. Similar levels of sAβPPα and sAβPPβ protein were found in CSF samples from AD and controls, yet there appeared to be a shift in the balance of the soluble full-length AβPP (sAβPPf) species in AD samples, with a decrease in the proportion of the lower (∼100 kDa) band relative to the upper (∼120 kDa) band. Similar differences were observed in the contribution of the major KPI-immunoreactive AβPP species. CSF samples also displayed differences in the correlations of AβPP species with classical AD biomarkers, particularly with respect to the Aβ42 peptide. The differences reveal alterations that probably reflect pathophysiological changes in the brain.

%B J Alzheimers Dis %V 57 %P 1281-1291 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372336?dopt=Abstract %R 10.3233/JAD-161275 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alterations in the Peripheral Immune System in Dementia. %A Busse, Mandy %A Michler, Enrico %A von Hoff, Franz %A Dobrowolny, Henrik %A Hartig, Roland %A Frodl, Thomas %A Busse, Stefan %X

Alterations in the immune response that result in inflammation might play a role in the pathology of dementias. In order to analyze changes of the peripheral immune system associated with different types of dementias, we determined several innate and adaptive cell populations in whole blood using flow cytometry. We included patients with Alzheimer's disease (AD; n = 60), vascular dementia (VaD; n = 20), and frontotemporal dementia (FTD; n = 12) at the time point of diagnosis and 24 age-matched neuropsychiatric healthy persons. Monocytes and NK cells were diminished in VaD, but not in AD and FTD. B cell and T cell numbers were decreased in all investigated forms of dementia. Changes in the contribution of naïve/memory T cells were only present in AD. Correlation and regression analyses revealed associations between altered immune cell populations and Q Albumin as marker for the integrity of the blood-cerebrospinal fluid-barrier, Mini-Mental State Examination values, and age. The peripheral immune system is altered in AD, VaD, and FTD. However, each disorder presents unique changes in the investigated cell types indicating different mechanisms underlying the pathology.

%B J Alzheimers Dis %V 58 %P 1303-1313 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582858?dopt=Abstract %R 10.3233/JAD-161304 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alterations of Clock Gene RNA Expression in Brain Regions of a Triple Transgenic Model of Alzheimer's Disease. %A Bellanti, Francesco %A Iannelli, Giuseppina %A Blonda, Maria %A Tamborra, Rosanna %A Villani, Rosanna %A Romano, Adele %A Calcagnini, Silvio %A Mazzoccoli, Gianluigi %A Vinciguerra, Manlio %A Gaetani, Silvana %A Giudetti, Anna Maria %A Vendemiale, Gianluigi %A Cassano, Tommaso %A Serviddio, Gaetano %X

A disruption to circadian rhythmicity and the sleep/wake cycle constitutes a major feature of Alzheimer's disease (AD). The maintenance of circadian rhythmicity is regulated by endogenous clock genes and a number of external Zeitgebers, including light. This study investigated the light induced changes in the expression of clock genes in a triple transgenic model of AD (3×Tg-AD) and their wild type littermates (Non-Tg). Changes in gene expression were evaluated in four brain areas¾suprachiasmatic nucleus (SCN), hippocampus, frontal cortex and brainstem¾of 6- and 18-month-old Non-Tg and 3×Tg-AD mice after 12 h exposure to light or darkness. Light exposure exerted significant effects on clock gene expression in the SCN, the site of the major circadian pacemaker. These patterns of expression were disrupted in 3×Tg-AD and in 18-month-old compared with 6-month-old Non-Tg mice. In other brain areas, age rather than genotype affected gene expression; the effect of genotype was observed on hippocampal Sirt1 expression, while it modified the expression of genes regulating the negative feedback loop as well as Rorα, Csnk1ɛ and Sirt1 in the brainstem. In conclusion, during the early development of AD, there is a disruption to the normal expression of genes regulating circadian function after exposure to light, particularly in the SCN but also in extra-hypothalamic brain areas supporting circadian regulation, suggesting a severe impairment of functioning of the clock gene pathway. Even though this study did not demonstrate a direct association between these alterations in clock gene expression among brain areas with the cognitive impairments and chrono-disruption that characterize the early onset of AD, our novel results encourage further investigation aimed at testing this hypothesis.

%B J Alzheimers Dis %V 59 %P 615-631 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671110?dopt=Abstract %R 10.3233/JAD-160942 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Altered Gut Microbiome Composition and Tryptic Activity of the 5xFAD Alzheimer's Mouse Model. %A Brandscheid, Carolin %A Schuck, Florian %A Reinhardt, Sven %A Schäfer, Karl-Herbert %A Pietrzik, Claus U %A Grimm, Marcus %A Hartmann, Tobias %A Schwiertz, Andreas %A Endres, Kristina %X

The regulation of physiological gut functions such as peristalsis or secretion of digestive enzymes by the central nervous system via the Nervus vagus is well known. Recent investigations highlight that pathological conditions of neurological or psychiatric disorders might directly interfere with the autonomous neuronal network of the gut - the enteric nervous system, or even derive from there. By using a murine Alzheimer's disease model, we investigated a potential influence of disease-associated changes on gastrointestinal properties. 5xFAD mice at three different ages were compared to wild type littermates in regard to metabolic parameters and enzymes of the gut by fluorimetric enzyme assay and western blotting. Overexpression of human amyloid-β protein precursor (AβPP) within the gut was assessed by qPCR and IHC; fecal microbiome analysis was conducted by 16SrRNA quantitation of selected phyla and species. While general composition of fecal samples, locomotion, and food consumption of male 5xFAD animals were not changed, we observed a reduced body weight occurring at early pathological stages. Human AβPP was not only expressed within the brain of these mice but also in gut tissue. Analysis of fecal proteins revealed a reduced trypsin amount in the 5xFAD model mice as compared to the wild type. In addition, we observed changes in fecal microbiota composition along with age. We therefore suggest that the presence of the mutated transgenes (AβPP and PS1), which are per se the basis for the genetic form of Alzheimer's disease in humans, directly interferes with gut function as shown here for the disease model mice.

%B J Alzheimers Dis %V 56 %P 775-788 %G eng %N 2 %R 10.3233/JAD-160926 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease as the Product of a Progressive Energy Deficiency Syndrome in the Central Nervous System: The Neuroenergetic Hypothesis. %A Blonz, Edward R %X

The decreased availability of metabolizable energy resources in the central nervous system is hypothesized to be a key factor in the pathogenesis of Alzheimer's disease. More specifically, the age-related decline in the ability of glucose to cross the blood-brain barrier creates a metabolic stress that shifts the normal, benign processing of amyloid-β protein precursor toward pathways associated with the production of amyloid-β plaques and tau-containing neurofibrillary tangles that are characteristic of the disease. The neuroenergetic hypothesis provides insight into the etiology of Alzheimer's disease and illuminates new approaches for diagnosis, monitoring, and treatment.

%B J Alzheimers Dis %V 60 %P 1223-1229 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28946565?dopt=Abstract %R 10.3233/JAD-170549 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease Biomarkers and Future Decline in Cognitive Normal Older Adults. %A Dumurgier, Julien %A Hanseeuw, Bernard J %A Hatling, Frances B %A Judge, Kelly A %A Schultz, Aaron P %A Chhatwal, Jasmeer P %A Blacker, Deborah %A Sperling, Reisa A %A Johnson, Keith A %A Hyman, Bradley T %A Gómez-Isla, Teresa %X

BACKGROUND: Identifying older adults at risk of cognitive decline represents a challenge as Alzheimer's disease (AD) modifying therapies move toward preclinical stages.

OBJECTIVE: To investigate the relationship between AD biomarkers and subsequent change in cognition in a cohort of cognitively intact older adults.

METHODS: 84 cognitively normal subjects (mean age 72.0 years, 59% women) were recruited through the Massachusetts Alzheimer's Disease Research Center and the Harvard Aging Brain Study and followed over 3 years. Measurements of amyloid-β 1-42 (Aβ42), total Tau (t-Tau), and Tau phosphorylated at threonine 181 (p-Tau181) in the cerebrospinal fluid (CSF) at study entry were available in all cases. Baseline brain MRI, FDG-PET, and PiB-PET data were available in the majority of participants. Relationship between baseline AD biomarkers and longitudinal change in cognition was assessed using Cox proportional hazard regression and linear mixed models.

RESULTS: 14% participants increased their global Clinical Dementia Rating (CDR) score from 0 to 0.5 during follow-up. A CDR score increase was associated with higher baseline CSF t-Tau and p-Tau181, higher global cortical PiB retention, and lower hippocampal volume. The combination of high CSF t-Tau and low Aβ42 or low hippocampal volume was more strongly related to cognitive outcome than each single biomarker. Higher CSF t-Tau was the only biomarker associated with subsequent decline in MMSE score.

CONCLUSIONS: Baseline CSF t-Tau and p-Tau181, in vivo amyloid load, and hippocampal volume were all independently associated with future decline in cognition. The discriminatory ability of these biomarkers to predict risk of cognitive decline, however, was only modest.

%B J Alzheimers Dis %V 60 %P 1451-1459 %G eng %N 4 %R 10.3233/JAD-170511 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease: Characterization of the Brain Sites of the Initial Tau Cytoskeletal Pathology Will Improve the Success of Novel Immunological Anti-Tau Treatment Approaches. %A Rüb, Udo %A Stratmann, Katharina %A Heinsen, Helmut %A Seidel, Kay %A Bouzrou, Mohamed %A Korf, Horst-Werner %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Humans %K Immunotherapy %K tau Proteins %X

Alzheimer's disease (AD) represents the most frequent neurodegenerative disease of the human brain worldwide. Currently practiced treatment strategies for AD only include some less effective symptomatic therapeutic interventions, which unable to counteract the disease course of AD. New therapeutic attempts aimed to prevent, reduce, or remove the extracellular depositions of the amyloid-β protein did not elicit beneficial effects on cognitive deficits or functional decline of AD. In view of the failure of these amyloid-β-based therapeutic trials and the close correlation between the brain pathology of the cytoskeletal tau protein and clinical AD symptoms, therapeutic attention has since shifted to the tau cytoskeletal protein as a novel drug target. The abnormal hyperphosphorylation and intraneuronal aggregation of this protein are early events in the evolution of the AD-related neurofibrillary pathology, and the brain spread of the AD-related tau aggregation pathology may possibly follow a corruptive protein templating and seeding-like mechanism according to the prion hypothesis. Accordingly, immunotherapeutic targeting of the tau aggregation pathology during the very early pre-tangle phase is currently considered to represent an effective and promising therapeutic approach for AD. Recent studies have shown that the initial immunoreactive tau aggregation pathology already prevails in several subcortical regions in the absence of any cytoskeletal changes in the cerebral cortex. Thus, it may be hypothesized that the subcortical brain regions represent the "port of entry" for the pathogenetic agent from which the disease ascends anterogradely as an "interconnectivity pathology".

%B J Alzheimers Dis %V 57 %P 683-696 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269779?dopt=Abstract %R 10.3233/JAD-161102 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Alzheimer's Disease-Associated Cerebrospinal Fluid (CSF) Biomarkers do not Correlate with CSF Volumes or CSF Production Rate. %A Edsbagge, Mikael %A Andreasson, Ulf %A Ambarki, Khalid %A Wikkelsø, Carsten %A Eklund, Anders %A Blennow, Kaj %A Zetterberg, Henrik %A Tullberg, Mats %X

BACKGROUND: Neuropathologically, Alzheimer's disease (AD) is characterized by accumulation of a 42 amino acid peptide called amyloid-β (Aβ42) in extracellular senile plaques together with intraneuronal inclusions of hyperphosphorylated tau protein in neurofibrillary tangles and neuronal degeneration. These changes are reflected in the cerebrospinal fluid (CSF), the volumes and production rates of which vary considerably between individuals, by reduced concentration of Aβ42, increased concentration of phosphorylated tau (P-tau) protein, and increased concentration of total tau (T-tau) protein, respectively.

OBJECTIVE: To examine the outstanding question if CSF concentrations of AD associated biomarkers are influenced by variations in CSF volumes, CSF production rate, and intracranial pressure in healthy individuals.

METHODS: CSF concentrations of Aβ42, P-tau, and T-tau, as well as a number of other AD-related CSF biomarkers were analyzed together with intracranial subarachnoid, ventricular, and spinal CSF volumes, as assessed by magnetic resonance imaging volumetric measurements, and CSF production rate in 19 cognitively normal healthy subjects (mean age 70.6, SD 3.6 years).

RESULTS: Negative correlations were seen between the concentrations of three CSF biomarkers (albumin ratio, Aβ38, and Aβ40), and ventricular CSF volume, but apart from this finding, no significant correlations were observed.

CONCLUSION: These results speak against inter-individual variations in CSF volume and production rate as important confounds in the AD biomarker research field.

%B J Alzheimers Dis %V 58 %P 821-828 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505972?dopt=Abstract %R 10.3233/JAD-161257 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Amylin Treatment Reduces Neuroinflammation and Ameliorates Abnormal Patterns of Gene Expression in the Cerebral Cortex of an Alzheimer's Disease Mouse Model. %A Wang, Erming %A Zhu, Haihao %A Wang, Xiaofan %A Gower, Adam %A Wallack, Max %A Blusztajn, Jan Krzysztof %A Kowall, Neil %A Qiu, Wei Qiao %X

Our recent study has demonstrated that peripheral amylin treatment reduces the amyloid pathology in the brain of Alzheimer's disease (AD) mouse models, and improves their learning and memory. We hypothesized that the beneficial effects of amylin for AD was beyond reducing the amyloids in the brain, and have now directly tested the actions of amylin on other aspects of AD pathogenesis, especially neuroinflammation. A 10-week course of peripheral amylin treatment significantly reduced levels of cerebral inflammation markers, Cd68 and Iba1, in amyloid precursor protein (APP) transgenic mice. Mechanistic studies indicated the protective effect of amylin required interaction with its cognate receptor because silencing the amylin receptor expression blocked the amylin effect on Cd68 in microglia. Using weighted gene co-expression network analysis, we discovered that amylin treatment influenced two gene modules linked with amyloid pathology: 1) a module related to proinflammation and transport/vesicle process that included a hub gene of Cd68, and 2) a module related to mitochondria function that included a hub gene of Atp5b. Amylin treatment restored the expression of most genes in the APP cortex toward levels observed in the wild-type (WT) cortex in these two modules including Cd68 and Atp5b. Using a human dataset, we found that the expression levels of Cd68 and Atp5b were significantly correlated with the neurofibrillary tangle burden in the AD brain and with their cognition. These data suggest that amylin acts on the pathological cascade in animal models of AD, and further supports the therapeutic potential of amylin-type peptides for AD.

%B J Alzheimers Dis %V 56 %P 47-61 %G eng %N 1 %R 10.3233/JAD-160677 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Amyloid Burden in Obstructive Sleep Apnea. %A Yun, Chang-Ho %A Lee, Ho-Young %A Lee, Seung Ku %A Kim, Hyun %A Seo, Hyung Suk %A Bang, Seong Ae %A Kim, Sang Eun %A Greve, Douglas N %A Au, Rhoda %A Shin, Chol %A Thomas, Robert J %X

To test the hypothesis that excessive amyloid deposition is a biological link between obstructive sleep apnea (OSA) and Alzheimer's disease, we determined whether OSA increases cerebral amyloid burden, relative to controls, using Pittsburgh Compound B (PiB) PET imaging. The subjects were adult participants (age 50-65 years) from the Korean Genome and Epidemiology Study. Polysomnography, brain MRI including 3D images, and a detailed neuro-cognitive function test battery were done in 2011-2012. Nineteen OSA subjects (Apnea-Hypopnea Index [AHI] ≥15/h, 21.2±5.1/h; age 58.5±4.1 years; 9 male) and 19 controls (AHI 1.8±1.3/h; age 58.5±4.2 years; 9 male) underwent 60-min dynamic 11C-PiB PET. All subjects were right-handed with normal cognitive function and brain MRI. Controls were matched by age, gender, education, and APOE genotype. A voxel-wise comparison of PiB-PET images between the two groups was performed after spatial and count normalization with cerebellar gray matter as a reference. Covariates included the status of sleep duration, hypertension, diabetes, body mass index, exercise, depressive mood, smoking, and alcohol drinking. Cortical thickness on 3D MRI was also measured and compared between the two groups. The OSA group showed a higher PiB deposition in the right posterior cingulate gyrus and right temporal cortex (corrected p < 0.05). There was no area of higher uptake in the control compared with OSA. Regional differences in cortical thickness were not significant. The study suggests that OSA accelerates amyloid deposition and may contribute to the development or progression of Alzheimer's disease.

%B J Alzheimers Dis %V 59 %P 21-29 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550245?dopt=Abstract %R 10.3233/JAD-161047 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Antihypertensive Treatment is associated with MRI-Derived Markers of Neurodegeneration and Impaired Cognition: A Propensity-Weighted Cohort Study. %A Edwards, Jodi D %A Ramirez, Joel %A Callahan, Brandy L %A Tobe, Sheldon W %A Oh, Paul %A Berezuk, Courtney %A Lanctôt, Krista %A Swardfager, Walter %A Nestor, Sean %A Kiss, Alexander %A Strother, Stephen %A Black, Sandra E %X

BACKGROUND: Hypertension is an important risk factor for Alzheimer's disease (AD) and cerebral small vessel disease. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are common anti-hypertensive treatments, but have differential effects on cortical amyloid.

OBJECTIVE: The objective of this study was to evaluate associations between anti-hypertensive treatment, brain volume, and cognition, using a propensity-weighted analysis to account for confounding by indication.

METHODS: We identified a cohort of normal elderly adults and individuals with mild cognitive impairment (MCI) or AD (N = 886; mean age = 75.0) from the Alzheimer's Disease Neuroimaging Initiative. Primary outcomes were brain parenchymal fraction, total hippocampal volume, and white matter hyperintensity (WMH) volume. Secondary outcomes were standardized scores on neuropsychological tests. Propensity-weighted adjusted multivariate linear regression was used to estimate associations between anti-hypertensive treatment class and MRI volumes and cognition.

RESULTS: Individuals treated with ARBs showed larger hippocampal volumes (R2 = 0.83, p = 0.05) and brain parenchymal fraction (R2 = 0.83, p = 0.01) than those treated with ACEIs. When stratified by diagnosis, this effect remained only in normal elderly adults and MCI patients, and a significant association between ARBs and lower WMH volume (R2 = 0.83, p = 0.03) emerged for AD patients only. ARBs were also associated with significantly better performance on tests of episodic and verbal memory, language, and executive function (all p < 0.05).

CONCLUSIONS: Findings are consistent with evidence for a neuroprotective effect of treatment with ARBs for brain structure and cognition. This study has potential implications for the treatment of hypertension, particularly in elderly adults at risk of cognitive decline and AD.

%B J Alzheimers Dis %V 59 %P 1113-1122 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731439?dopt=Abstract %R 10.3233/JAD-170238 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Aortic Valve Calcification and the Risk of dementia: A Population-Based Study. %A Wolters, Frank J %A Bos, Daniel %A Vernooij, Meike W %A Franco, Oscar H %A Hofman, Albert %A Koudstaal, Peter J %A van der Lugt, Aad %A Ikram, M Arfan %X

The association of aortic valve calcification (AVC) with dementia remains unknown. In 2,428 non-demented participants from the population-based Rotterdam Study, we investigated the association of CT-assessed AVC with risk of dementia and cognitive decline. AVC was present in 33.1% of the population. During a median follow-up of 9.3 years, 160 participants developed dementia. We found no association between presence of AVC and risk of all-cause dementia [hazard ratio (HR): 0.89 (95% confidence interval (CI):0.63;1.26)]. Presence of AVC was not associated with cognitive decline on any of the cognitive tests, nor with a measure of global cognition.

%B J Alzheimers Dis %V 55 %P 893-897 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767996?dopt=Abstract %R 10.3233/JAD-160871 %0 Journal Article %J J Alzheimers Dis %D 2017 %T APOE ε4 Modulation of Training Outcomes in Several Cognitive Domains in a Sample of Cognitively Intact Older Adults. %A López-Higes, Ramón %A Rodríguez-Rojo, Inmaculada C %A Prados, José M %A Montejo, Pedro %A Del-Río, David %A Delgado-Losada, María Luisa %A Montenegro, Mercedes %A López-Sanz, David %A Barabash, Ana %X

BACKGROUND: Most research points to the ɛ4 allele of the apolipoprotein E (APOE) gene as the most recognizable genetic risk factor associated with Alzheimer's disease pathogenesis. It has been also suggested that the APOEɛ4 allele has a negative influence on cognitive functioning, which begins long before cognitive impairment becomes manifest. However, still, little is known about the APOEɛ4 interaction with cognitive intervention programs.

OBJECTIVE: The main goal of this study was to explore whether there was a differential APOE genotype modulation effect after cognitive training in different domains, such as language comprehension, executive functions, and memory. Contrary to other studies, hippocampal volume was controlled for.

METHODS: Fifty older adults (65+ years; 30 women and 20 men) participated in a multi-domain cognitive training that involved 30 sessions taking place over 12 weeks. Half of the participants were APOEɛ4 carriers. The control group was matched in age, gender, normalized hippocampal volume, cognitive reserve, Mini-Mental State Examination score, and Geriatric Depression Scale-Short Version.

RESULTS: The study revealed that there were consistent treatment benefits in complex sentence comprehension (noncanonical sentences and sentences with two propositions), a domain that was not directly trained, but only in the A POEɛ4 noncarrier group.

CONCLUSION: Genetic profile modulates training outcomes in sentence comprehension.

%B J Alzheimers Dis %V 58 %P 1201-1215 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550244?dopt=Abstract %R 10.3233/JAD-161014 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Apolipoprotein A1 in Cerebrospinal Fluid and Plasma and Progression to Alzheimer's Disease in Non-Demented Elderly. %A Slot, Rosalinde E R %A Van Harten, Argonde C %A Kester, Maartje I %A Jongbloed, Wesley %A Bouwman, Femke H %A Teunissen, Charlotte E %A Scheltens, Philip %A Veerhuis, Robert %A van der Flier, Wiesje M %X

BACKGROUND: HDL-cholesterol transporter Apolipoprotein A1 (ApoA1) holds neuroprotective properties, such as inhibition of amyloid-β aggregation. Low plasma ApoA1 concentrations are associated with Alzheimer's disease (AD). Little is known about ApoA1 levels in the pre-dementia stages of AD.

OBJECTIVE: To investigate associations between cerebrospinal fluid (CSF) and plasma ApoA1 levels and clinical progression toward AD in non-demented elderly.

METHODS: From the Amsterdam Dementia Cohort, we included 429 non-demented elderly with subjective cognitive decline (SCD; n = 206, 61±9 years, Mini-Mental State Exam (MMSE) 28±2) and mild cognitive impairment (MCI; n = 223, 67±8 years, MMSE 27±2), with a mean follow-up of 2.5±1.6 years. We used Cox proportional hazard models to investigate relations between CSF and plasma ApoA1 concentrations and clinical progression, defined as progression to MCI or AD for SCD, and progression to AD for MCI. Analyses were adjusted for age, gender, MMSE, and plasma cholesterol levels. Analyses were stratified for diagnosis and APOEɛ4 carriership.

RESULTS: 117 patients (27%) showed clinical progression. One standard deviation increase of CSF ApoA1 was associated with a 30% increased risk of clinical progression (hazard ratio (HR) (95% CI)  = 1.3(1.0-1.6)). The effect appeared to be attributable to the APOEɛ4 carriers with SCD (HR 3.3(1.0-10.9)). Lower plasma ApoA1 levels were associated with an increased risk of clinical progression in APOEɛ4 carriers with SCD (HR 5.0(1.3-18.9)).

CONCLUSION: Higher CSF and lower plasma ApoA1 levels were associated with an increased risk of clinical progression in APOEɛ4 carriers with SCD; suggesting that ApoA1 may be involved in the earliest stages of AD.

%B J Alzheimers Dis %V 56 %P 687-697 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035918?dopt=Abstract %R 10.3233/JAD-151068 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Apolipoprotein E Isoforms Differentially Regulate Alzheimer's Disease and Amyloid-β-Induced Inflammatory Response in vivo and in vitro. %A Dorey, Evan %A Bamji-Mirza, Michelle %A Najem, Dema %A Li, Yan %A Liu, Hong %A Callaghan, Debbie %A Walker, Douglas %A Lue, Lih-Fen %A Stanimirovic, Danica %A Zhang, Wandong %X

Neuroinflammation plays a critical role in neuronal dysfunction and death of Alzheimer's disease (AD). ApoE4 is a major risk factor of AD, while ApoE2 is neuroprotective. Little is known about the roles of ApoE isoforms in the neuroinflammation seen in AD. Their roles and mechanisms in Aβ-induced/neuroinflammation were investigated in this study using in vivo and in vitro models. Rat astrocytes were treated with lipid-poor recombinant hApoE and/or Aβ42. Mouse astrocyte lines-expressing lipidated hApoE were treated with Aβ42 and/or vitamin D receptor (VDR) agonist, 1α,25-dihydroxyvitamin D3. Cells and media were harvested for cytokine ELISA, RNA isolated for qRT-PCR, and nuclear protein for transcription factor (TF) arrays and EMSA. hApoE-transgenic and AD mice were mated to generate hApoE2/AD and hApoE4/AD mice. Mice were euthanized at 6 months of age. Brain tissues were collected for cytokine ELISA array, Aβ ELISA, immunoblotting, and immunohistochemistry. hApoE4/AD mice had significantly higher levels of inflammatory cytokines than hApoE2/AD mice. Lipidated hApoE4 significantly promoted inflammatory gene expression induced by Aβ42 but not recombinant hApoE4 in astrocytes as compared to controls. Lipidated hApoE3 provided a certain degree of protection against Aβ42-induced inflammatory response but not recombinant hApoE3 as compared to controls. Both lipidated and recombinant hApoE2 provided protection against Aβ42-induced inflammatory response compared to controls. TF array revealed that ApoE2 strongly activated VDR in Aβ42-treated astrocytes. Application of 1α,25-dihydroxyvitamin D3 completely inhibited Aβ-induced inflammatory gene expression in hApoE4-expressing astrocytes. The results suggest that ApoE4 promotes, but ApoE2 inhibits, AD/Aβ-induced neuroinflammation via VDR signaling. Targeting VDR signaling or active form of VD3 may relieve AD neuroinflammation or/and neurodegeneration.

%B J Alzheimers Dis %V 57 %P 1265-1279 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372324?dopt=Abstract %R 10.3233/JAD-160133 %0 Journal Article %J J Alzheimers Dis %D 2017 %T An Arabic Version of the Cognitive Subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog): Reliability, Validity, and Normative Data. %A Ben Jemaa, Sonia %A Attia Romdhane, Neila %A Bahri-Mrabet, Amel %A Jendli, Adel %A Le Gall, Didier %A Bellaj, Tarek %X

The Alzheimer's Disease Assessment Scale's cognitive subscale (ADAS-Cog) is the most widely used instrument for screening cognitive dysfunction in Alzheimer's disease. The aim of the present study was to develop an Arabic version of this scale (A-ADAS-Cog), examine its psychometric properties (reliability and validity), and provide normative data. The A-ADAS-Cog), an Arabic version of the Mini-Mental State Examination (A-MMSE), and a Standardized Clinical Dementia Rating Scale (CDR) were administered to three Tunisian groups: 124 normal controls (NC), 33 patients with non-Alzheimer dementia (N-AD), and 25 patients with Alzheimer's disease (AD). The A-ADAS-Cog scores were significantly affected by age and education. A correction table was constructed to control these effects. The results showed that the A-ADAS-Cog has good internal consistency and reliability (α= 0.82 for AD). The test-retest reliability of the A-ADAS-Cog was stable over time (r = 0.97). An evaluation of the construct validity of the A-ADAS-Cog using principal component analysis led to a solution with three factors (memory, language and praxis), which explained 72% of the variance. The concurrent validity of the A-ADAS-Cog was established using the A-MMSE score (r = -0.86), CDR Sum of Boxes score (CDR-SB; r = 0.87), and global CDR score (CDR-Global; r = 0.74). Finally, the A-ADAS-Cog has an excellent discriminating power in the diagnosis of AD (ROC area = 0.92). A cut-off score of 10 (sensitivity = 84% and specificity = 91%) is indicated for the screening of the AD. Overall, the results indicated that the A-ADAS-Cog is psychometrically reliable and valid and provides promising results for screening of dementia in Arabic speaking patients.

%B J Alzheimers Dis %V 60 %P 11-21 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505978?dopt=Abstract %R 10.3233/JAD-170222 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association between Anti-Dementia Treatment Persistence and Daily Dosage of the First Prescription: A Retrospective Analysis in Neuropsychiatric Practices in Germany. %A Bohlken, Jens %A Jacob, Louis %A Kostev, Karel %X

BACKGROUND: High adherence and persistence are important for the efficacy of anti-dementia treatments.

OBJECTIVE: The goal of this study was to analyze the association between anti-dementia treatment persistence and daily dosage of the first prescription in patients treated in neuropsychiatric practices in Germany.

METHODS: This study included patients aged 60 years or over who were diagnosed with Alzheimer's disease and received anti-dementia prescriptions (galantamine, donepezil, memantine, and rivastigmine) for the first time between 2005 and 2014. The main outcome measure was the treatment persistence rate within 12 months after the index date as a function of the first dose. Cox proportional hazards regression models were used to estimate the relation between persistence and daily dosages after adjusting for age, gender, and residence in nursing homes.

RESULTS: In this study, 2,442, 5,669, 4,416, 642, and 2,334 patients received galantamine, donepezil, memantine, oral rivastigmine, and patch rivastigmine, respectively. After 12 months of follow-up, continuation rates were similar for individuals using different doses of galantamine, donepezil, oral rivastigmine, and patch rivastigmine, but were significantly different for those taking memantine. Patients using 20 mg of memantine were less likely to discontinue their treatment than patients using 10 mg (HR = 0.88, 95% CI: 0.80-0.96). There was no significant association between daily dosages and persistence for the other drugs (HRs ranging from 0.86 to 1.15).

CONCLUSIONS: There was no significant association between treatment persistence and daily dosages in patients with Alzheimer's disease in Germany who were treated with galantamine, donepezil, or rivastigmine.

%B J Alzheimers Dis %V 58 %P 37-44 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372337?dopt=Abstract %R 10.3233/JAD-170091 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association between Cholesterol Exposure and Neuropathological Findings: The ACT Study. %A Bettcher, Brianne M %A Ard, M Colin %A Reed, Bruce R %A Benitez, Andreana %A Simmons, Amanda %A Larson, Eric B %A Sonnen, Josh A %A Montine, Thomas J %A Li, Ge %A Keene, C Dirk %A Crane, Paul K %A Mungas, Dan %X

We characterized the relationship between late life cholesterol exposure and neuropathological outcomes in a community-based, older adult cohort. Adult Changes in Thought (ACT) is a cohort study that enrolls consenting, randomly selected, non-demented people aged ≥65 from a healthcare delivery system. We used late life HDL and total cholesterol lab values from Group Health computerized records, and calculated HDL and non-HDL levels. We evaluated neuropathological outcomes of Alzheimer's disease, cerebral amyloid angiopathy, vascular brain injury, and Lewy body disease. Using linear mixed models with age and antilipemic medication as predictors, we obtained predicted cholesterol values at age 70 and 10 years prior to death for individuals with available cholesterol data in 10-year exposure windows. We used logistic regression to determine whether predicted late life cholesterol levels were associated with neuropathological outcomes controlling for age at death, APOE genotype, sex, and their interactions with cholesterol levels. 525 decedents came to autopsy by 08/2014. Of these, plasma cholesterol concentration was available for 318 (age 70, model 1) and 396 (10 years prior to death, model 2) participants. We did not find associations between late life cholesterol and Alzheimer's disease neuropathological changes, and there were no associations between cholesterol levels and amyloid angiopathy or vascular brain injury. We observed an association between predicted non-HDL cholesterol at age 70 and Lewy body disease. Our study suggests an association between late life non-HDL cholesterol exposure and Lewy body disease. We did not observe associations between late life cholesterol levels and Braak stage or CERAD score.

%B J Alzheimers Dis %V 59 %P 1307-1315 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731431?dopt=Abstract %R 10.3233/JAD-161224 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association between Cognitive Status before Surgery and Outcomes in Elderly Patients with Hip Fracture in a Dedicated Orthogeriatric Care Pathway. %A Zerah, Lorene %A Cohen-Bittan, Judith %A Raux, Mathieu %A Meziere, Anthony %A Tourette, Cendrine %A Neri, Christian %A Verny, Marc %A Riou, Bruno %A Khiami, Frederic %A Boddaert, Jacques %X

BACKGROUND: Dementia is associated with a worse prognosis of hip fracture, but the impact of a dedicated geriatric care pathway on the prognosis of these patients has not been evaluated.

OBJECTIVE: According to the cognitive status before surgery, our main objective was to compare mortality rate at 6 months; secondary outcomes were to compare in-hospital complications, the risk of new institutionalization, and the ability to walk at 6 months.

METHODS: Between 2009 and 2015, all patients (>70 years) admitted after hip fracture surgery into a dedicated unit of peri-operative geriatric care were included: patients with dementia (DP), without dementia (NDP), and with cognitive status not determined (CSND). Data are expressed as hazard ratio (HR) for multivariate cox analysis or odds ratio (OR) for multivariate logistic regression analysis and their 95% confidence interval (CI).

RESULTS: We included 650 patients (86±6 years): 168 DP, 400 NDP, and 82 CSND. After adjustment for age, sex, comorbidities, polypharmacy, pre-fracture autonomy, time-to-surgery, and delirium, there were no significant differences for 6-month mortality (DP versus NDP: HR = 0.7[0.4-1.2], DP versus CSND: HR = 0.6[0.3-1.4], CSND versus NDP: HR = 0.8[0.4-1.7]); but DP and CSND were more likely to be newly institutionalized after 6 months compared to NDP (OR DP = 2.6[1.4-4.9], p = 0.003, OR CSND = 2.9[1.4-6.1], p = 0.004). 92% of population was walking after 6 months (63% with assistance): no difference was found between the three groups.

CONCLUSION: In a dedicated geriatric care pathway, DP and CSND undergoing hip surgery have the same 6-month mortality and walking ability as NDP.

%B J Alzheimers Dis %V 56 %P 145-156 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911302?dopt=Abstract %R 10.3233/JAD-160655 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Association between Montreal Cognitive Assessment Memory Scores and Hippocampal Volume in a Neurodegenerative Disease Sample. %A Ritter, Aaron %A Hawley, Nanako %A Banks, Sarah J %A Miller, Justin B %X

Despite widespread use, there have been few investigations into the neuroanatomical correlates of the Montreal Cognitive Assessment (MoCA). In a sample of 138 consecutive patients presenting with cognitive complaints, we report significant correlations between lower MoCA memory scores and smaller hippocampal volumes (r = 0.36-0.41, p < 0.001). We also report that the newly devised memory index score, designed to better capture encoding deficits than the standard delayed recall score, was not significantly better for predicting hippocampal volume. These initial results suggest that poor performance on the MoCA's memory section should prompt further evaluation for hippocampal atrophy.

%B J Alzheimers Dis %V 58 %P 695-699 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453481?dopt=Abstract %R 10.3233/JAD-161241 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association of Cancer History with Alzheimer's Disease Dementia and Neuropathology. %A Yarchoan, Mark %A James, Bryan D %A Shah, Raj C %A Arvanitakis, Zoe %A Wilson, Robert S %A Schneider, Julie %A Bennett, David A %A Arnold, Steven E %X

BACKGROUND: Cancer and Alzheimer's disease (AD) are common diseases of aging and share many risk factors. Surprisingly, however, epidemiologic data from several recent independent cohort studies suggest that there may be an inverse association between these diseases.

OBJECTIVE: To determine the relationship between history of cancer and odds of dementia proximate to death and neuropathological indices of AD.

METHODS: Using data from two separate clinical-pathologic cohort studies of aging and AD, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP), we compared odds of AD dementia proximate to death among participants with and without a history of cancer. We then examined the relation of history of cancer with measures of AD pathology at autopsy, i.e., paired helical filament tau (PHFtau) neurofibrillary tangles and amyloid-β load.

RESULTS: Participants reporting a history of cancer had significantly lower odds of AD (OR 0.70 [0.55-0.89], p = 0.0040) proximate to death as compared to participants reporting no prior history of cancer. The results remained significant after adjusting for multiple risk factors including age, sex, race, education, and presence of an APOEɛ4 allele. At autopsy, participants with a history of cancer had significantly fewer PHFtau tangles (p < 0.001) than participants without a history of cancer, but similar levels of amyloid-β.

CONCLUSIONS: Cancer survivors have reduced odds of developing AD and a lower burden of neurofibrillary tangle deposition.

%B J Alzheimers Dis %V 56 %P 699-706 %G eng %N 2 %R 10.3233/JAD-160977 %0 Journal Article %J J Alzheimers Dis %D 2017 %T BACE1 Dynamics Upon Inhibition with a BACE Inhibitor and Correlation to Downstream Alzheimer's Disease Markers in Elderly Healthy Participants. %A Timmers, Maarten %A Barão, Soraia %A Van Broeck, Bianca %A Tesseur, Ina %A Slemmon, John %A de Waepenaert, Katja %A Bogert, Jennifer %A Shaw, Leslie M %A Engelborghs, Sebastiaan %A Moechars, Dieder %A Mercken, Marc %A Van Nueten, Luc %A Tritsmans, Luc %A De Strooper, Bart %A Streffer, Johannes Rolf %X

The β-site amyloid-β protein precursor (AβPP) cleaving enzyme-1 (BACE1) is the rate limiting enzyme in the generation of amyloid-β peptide (Aβ) from AβPP, one of the major pathways in Alzheimer's disease (AD) pathology. Increased BACE1 levels and activity have been reported in the brain of patients with sporadic AD. Therefore, changes of BACE1 levels in the cerebrospinal fluid (CSF) have also been investigated as a possible biomarker of the disease. We analyzed BACE1 levels in CSF of elderly healthy participants before and after chronic treatment with a BACE inhibitor (BACEi) and evaluated the correlation between BACE1 levels and downstream AD markers. Overall, BACE1 CSF levels showed strong correlations to all downstream AD markers investigated. This is the first reported finding that shows BACE1 levels in CSF were well correlated to its end product Aβ1 - 42. As previously described, BACE1 levels were strongly correlated to total-tau and phosphorylated tau levels in CSF. Generally, chronic BACE inhibition did not influence BACE1 CSF protein levels. Follow-up studies including early-stage AD pathophysiology and prodromal AD patients will help to understand the importance of measuring BACE1 routinely in daily clinical practice and AD clinical trials.

%B J Alzheimers Dis %V 56 %P 1437-1449 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157093?dopt=Abstract %R 10.3233/JAD-160829 %0 Journal Article %J J Alzheimers Dis %D 2017 %T BDNF Responses in Healthy Older Persons to 35 Minutes of Physical Exercise, Cognitive Training, and Mindfulness: Associations with Working Memory Function. %A Håkansson, Krister %A Ledreux, Aurélie %A Daffner, Kirk %A Terjestam, Yvonne %A Bergman, Patrick %A Carlsson, Roger %A Kivipelto, Miia %A Winblad, Bengt %A Granholm, Ann-Charlotte %A Mohammed, Abdul Kadir H %X

Brain-derived neurotrophic factor (BDNF) has a central role in brain plasticity by mediating changes in cortical thickness and synaptic density in response to physical activity and environmental enrichment. Previous studies suggest that physical exercise can augment BDNF levels, both in serum and the brain, but no other study has examined how different types of activities compare with physical exercise in their ability to affect BDNF levels. By using a balanced cross over experimental design, we exposed nineteen healthy older adults to 35-minute sessions of physical exercise, cognitive training, and mindfulness practice, and compared the resulting changes in mature BDNF levels between the three activities. We show that a single bout of physical exercise has significantly larger impact on serum BDNF levels than either cognitive training or mindfulness practice in the same persons. This is the first study on immediate BDNF effects of physical activity in older healthy humans and also the first study to demonstrate an association between serum BDNF responsivity to acute physical exercise and working memory function. We conclude that the BDNF increase we found after physical exercise more probably has a peripheral than a central origin, but that the association between post-intervention BDNF levels and cognitive function could have implications for BDNF responsivity in serum as a potential marker of cognitive health.

%B J Alzheimers Dis %V 55 %P 645-657 %G ENG %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716670?dopt=Abstract %R 10.3233/JAD-160593 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Bimanual Gesture Imitation in Alzheimer's Disease. %A Sanin, G Nter %A Benke, Thomas %X

BACKGROUND/OBJECTIVE: Unimanual gesture production or imitation has often been studied in Alzheimer's disease (AD) during apraxia testing. In the present study, it was hypothesized that bimanual motor tasks may be a sensitive method to detect impairments of motor cognition in AD due to increased demands on the cognitive system.

METHODS: We investigated bimanual, meaningless gesture imitation in 45 AD outpatients, 38 subjects with mild cognitive impairment (MCI), and 50 normal controls (NC) attending a memory clinic. Participants performed neuropsychological background testing and three tasks: the Interlocking Finger Test (ILF), Imitation of Alternating Hand Movements (AHM), and Bimanual Rhythm Tapping (BRT).

RESULTS: The tasks were short and easy to administer. Inter-rater reliability was high across all three tests. AD patients performed significantly poorer than NC and MCI participants; a deficit to imitate bimanual gestures was rarely found in MCI and NC participants. Sensitivity to detect AD ranged from 0.5 and 0.7, specificity beyond 0.9. ROC analyses revealed good diagnostic accuracy (0.77 to 0.92). Impairment to imitate bimanual gestures was mainly predicted by diagnosis and disease severity.

CONCLUSION: Our findings suggest that an impairment to imitate bimanual, meaningless gestures is a valid disease marker of mild to moderate AD and can easily be assessed in memory clinic settings. Based on our preliminary findings, it appears to be a separate impairment which can be distinguished from other cognitive deficits.

%B J Alzheimers Dis %V 57 %P 53-59 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222504?dopt=Abstract %R 10.3233/JAD-160680 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Bipolar Disorder and Frontotemporal Dementia: An Intriguing Association. %A Papazacharias, Apostolos %A Lozupone, Madia %A Barulli, Maria Rosaria %A Capozzo, Rosa %A Imbimbo, Bruno P %A Veneziani, Federica %A De Blasi, Roberto %A Nardini, Marcello %A Seripa, Davide %A Panza, Francesco %A Logroscino, Giancarlo %X

Bipolar disorder (BD) could represent a prodromal state of frontotemporal dementia (FTD). Two patients affected by lifelong BD with a progressive decline of cognitive functions, behavioral, and neurological signs, reached the early diagnosis of FTD before the age of 60. They were diagnosed as affected by primary progressive aphasia and FTD with parkinsonism, respectively. A diagnosis of FTD should therefore be taken into account, in case of unexpected cognitive and behavioral decline in patients with a long history of BD. Follow-up studies with genetic, neuropsychological, and neuroimaging markers of these BD/FTD patients could further explore some of the underlying association, opening new viable therapeutic options.

%B J Alzheimers Dis %V 55 %P 973-979 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802240?dopt=Abstract %R 10.3233/JAD-160860 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Brain Biomarkers in Familial Alzheimer's Disease Mouse Models. %A Kuttner-Hirshler, Yafit %A Venkatasubramanian, Palamadai N %A Apolinario, Joan %A Bonds, Jacqueline %A Wyrwicz, Alice M %A Lazarov, Orly %X

Alzheimer's disease (AD) is characterized by progressive loss of memory and cognitive deterioration. It is thought that the onset of the disease takes place several decades before memory deficits are apparent. Reliable biomarkers for the diagnosis or prognostication of the disease are highly desirable. Neural stem cells (NSC) exist in the adult brain throughout life and give rise to neural progenitor cells (NPC), which differentiate into neurons or glia. The level of NPC proliferation and new neuron formation is significantly compromised in mouse models of familial Alzheimer's disease (FAD). These deficits are readily detected in young adults, at 2-3 months of age, preceding amyloid deposition and cognitive impairments, which may indicate that impaired neurogenesis can be an early biomarker for cognitive deficits in AD. Recent studies suggest that NSC can be detected in live rodents, noninvasively, using proton magnetic resonance spectroscopy (1H-MRS) signal at 1.28 ppm. Here we examined the use of 1H-MRS for determining the extent of neurogenesis in the brains of FAD mice. We observed that the reduction in neurogenesis in the FAD mice as observed by immunohistochemistry, was not manifested by a reduction in the 1.28 ppm signal, suggesting that this marker is either not specific for neurogenesis or not sensitive enough for the detection of alterations in hippocampal neurogenesis in the brains of FAD mice.

%B J Alzheimers Dis %V 60 %P 949-958 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922152?dopt=Abstract %R 10.3233/JAD-170269 %0 Journal Article %J J Alzheimers Dis %D 2017 %T CD44 Splice Variants as Potential Players in Alzheimer's Disease Pathology. %A Pinner, Elhanan %A Gruper, Yaron %A Ben Zimra, Micha %A Kristt, Don %A Laudon, Moshe %A Naor, David %A Zisapel, Nava %X

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, deposition of amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles, and neuronal cell death. Neuroinflammation is commonly believed to participate in AD pathogenesis. CD44 is an inflammation-related gene encoding a widely-distributed family of alternatively spliced cell surface glycoproteins that have been implicated in inflammation, metastases, and inflammation-linked neuronal injuries. Here we investigated the expression patterns of CD44S (which does not contain any alternative exon) and CD44 splice variants in postmortem hippocampal samples from AD patients and matched non-AD controls. The expression of CD44S and CD44 splice variants CD44V3, CD44V6, and CD44V10 was significantly higher in AD patients compared to non-AD controls. Immunohistochemistry of human hippocampal sections revealed that CD44S differentially localized to neuritic plaques and astrocytes, whereas CD44V3, CD44V6, and CD44V10 expression was mostly neuronal. Consistent with these findings, we found that the expression of CD44V6 and CD44V10 was induced by Aβ peptide in neuroblastoma cells and primary neurons. Furthermore, in loss of function studies we found that both CD44V10-specific siRNA and CD44V10 antibody protected neuronal cells from Aβ-induced toxicity, suggesting a causal relationship between CD44V10 and neuronal cell death. These data indicate that certain CD44 splice variants contribute to AD pathology and that CD44V10 inhibition may serve as a new neuroprotective treatment strategy for this disease.

%B J Alzheimers Dis %V 58 %P 1137-1149 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550248?dopt=Abstract %R 10.3233/JAD-161245 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Central Review of Amyloid-Related Imaging Abnormalities in Two Phase III Clinical Trials of Bapineuzumab in Mild-To-Moderate Alzheimer's Disease Patients. %A Ketter, Nzeera %A Brashear, H Robert %A Bogert, Jennifer %A Di, Jianing %A Miaux, Yves %A Gass, Achim %A Purcell, Derk D %A Barkhof, Frederik %A Arrighi, H Michael %X

BACKGROUND: Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]).

OBJECTIVES: To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimer's disease randomized to bapineuzumab IV or placebo during two Phase III trials (APOE ɛ4 allele carriers or noncarriers).

METHODS: Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE ɛ4 noncarriers and 1,121 carriers by independent neuroradiologists. Assessment of ARIA-E, ARIA-H, intracerebral hemorrhages, and age-related white matter changes is described.

RESULTS: In the Final Read, treatment-emergent ARIA-E were identified in 242 patients including 76 additional cases not noted previously in real time. Overall, incidence proportion of ARIA-E was higher in carriers (active 21.2%; placebo 1.1%) than in noncarriers (pooled active 11.3%; placebo 0.6%), and was more often identified in homozygote APOE ɛ4 carriers than heterozygotes (34.5% versus 16.9%). Incidence rate of ARIA-E increased with increased dose in noncarriers. Frequency of ARIA-E first episodes was highest after the first and second bapineuzumab infusion and declined after repeated infusions. Incidence of total HDs <10 mm (cerebral microhemorrhages) was higher in active groups versus placebo.

CONCLUSION: ARIA was detected more often on MRI scans when every scan was reviewed by trained neuroradiologists and results adjudicated. There was increased incidence of ARIA-E in bapineuzumab-treated carriers who had a microhemorrhage at baseline. ARIA-E was a risk factor for incident ARIA-H and late onset ARIA-E was milder radiologically. Age-related white matter changes did not progress during the study.

%B J Alzheimers Dis %V 57 %P 557-573 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269765?dopt=Abstract %R 10.3233/JAD-160216 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebral Hemodynamics in Mild Cognitive Impairment: A Systematic Review. %A Beishon, Lucy %A Haunton, Victoria J %A Panerai, Ronney B %A Robinson, Thompson G %X

BACKGROUND: The incidence of dementia is projected to rise over the coming decades, but with no sensitive diagnostic tests available. Vascular pathology precedes the deposition of amyloid and is an attractive early target.

OBJECTIVE: The aim of this review was to investigate the use of cerebral hemodynamics and oxygenation as a novel biomarker for mild cognitive impairment (MCI), focusing on transcranial Doppler ultrasonography (TCD) and near-infrared spectroscopy (NIRS).

METHODS: 2,698 articles were identified from Medline, Embase, PsychINFO, and Web of Science databases. 306 articles were screened and quality assessed independently by two reviewers; 26 met the inclusion criteria. Meta-analyses were performed for each marker with two or more studies and limited heterogeneity.

RESULTS: Eleven studies were TCD, 8 NIRS, 5 magnetic resonance imaging, and 2 positron/single photon emission tomography. Meta-analyses showed reduced tissue oxygenation index, cerebral blood flow and velocity, with higher pulsatility index, phase and cerebrovascular resistance in MCI compared to controls. The majority of studies found reduced CO2 reactivity in MCI, with mixed findings in neuroactivation studies.

CONCLUSION: Despite small sample sizes and heterogeneity, meta-analyses demonstrate clear abnormalities in cerebral hemodynamic and oxygenation parameters, even at an early stage of cognitive decline. Further work is required to investigate the use of cerebral hemodynamic and oxygenation parameters as a sensitive biomarker for dementia.

%B J Alzheimers Dis %V 59 %P 369-385 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671118?dopt=Abstract %R 10.3233/JAD-170181 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebrospinal Fluid Amyloid-β 42, Total Tau and Phosphorylated Tau are Low in Patients with Normal Pressure Hydrocephalus: Analogies and Differences with Alzheimer's Disease. %A Santangelo, Roberto %A Cecchetti, Giordano %A Bernasconi, Maria Paola %A Cardamone, Rosalinda %A Barbieri, Alessandra %A Pinto, Patrizia %A Passerini, Gabriella %A Scomazzoni, Francesco %A Comi, Giancarlo %A Magnani, Giuseppe %X

Co-existence of Alzheimer's disease (AD) in normal pressure hydrocephalus (NPH) is a frequent finding, thus a common pathophysiological basis between AD and NPH has been postulated. We measured CSF amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) concentrations in a sample of 294 patients with different types of dementia and 32 subjects without dementia. We then compared scores on neuropsychological tests of NPH patients with pathological and normal CSF Aβ42 values. Aβ42 levels were significantly lower in NPH than in control patients, with no significant differences between AD and NPH. On the contrary, t-tau and p-tau levels were significantly lower in NPH than in AD, with no differences between NPH and controls. NPH patients with pathological Aβ42 levels did not perform worse than NPH patients with normal Aβ42 levels in any cognitive domains. Our data seem to support the hypothesis of amyloid accumulation in brains of NPH patients. Nevertheless, amyloid does not seem to play a pathogenetic role in the development of cognitive deficits in NPH.

%B J Alzheimers Dis %V 60 %P 183-200 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826180?dopt=Abstract %R 10.3233/JAD-170186 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Cerebrospinal Fluid Aβ1-42/Aβ1-40 Ratio Improves Concordance with Amyloid-PET for Diagnosing Alzheimer's Disease in a Clinical Setting. %A Niemantsverdriet, Ellis %A Ottoy, Julie %A Somers, Charisse %A De Roeck, Ellen %A Struyfs, Hanne %A Soetewey, Femke %A Verhaeghe, Jeroen %A Van den Bossche, Tobi %A Van Mossevelde, Sara %A Goeman, Johan %A De Deyn, Peter Paul %A Mariën, Peter %A Versijpt, Jan %A Sleegers, Kristel %A Van Broeckhoven, Christine %A Wyffels, Leonie %A Albert, Adrien %A Ceyssens, Sarah %A Stroobants, Sigrid %A Staelens, Steven %A Bjerke, Maria %A Engelborghs, Sebastiaan %X

BACKGROUND: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-β (Aβ) increases when the CSF Aβ1-42/Aβ1-40 ratio is used as compared to CSF Aβ1-42 levels alone.

OBJECTIVE: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting.

METHODS: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [18F]Florbetapir ([18F]AV45) PET scan, [18F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (Aβ1-42, Aβ1-40, T-tau, P-tau181).

RESULTS: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [18F]AV45 PET measures when the CSF Aβ1-42/Aβ1-40 was applied compared to Aβ1-42 alone. CSF biomarkers were stronger associated to [18F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matterConclusions:The concordance between CSF Aβ and [18F]AV45 PET increases when the CSF Aβ1-42/Aβ1-40 ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.

%B J Alzheimers Dis %V 60 %P 561-576 %8 2017 %G eng %N 2 %R 10.3233/JAD-170327 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebrospinal Fluid Aβ42/40 Corresponds Better than Aβ42 to Amyloid PET in Alzheimer's Disease. %A Lewczuk, Piotr %A Matzen, Anja %A Blennow, Kaj %A Parnetti, Lucilla %A Molinuevo, José Luis %A Eusebi, Paolo %A Kornhuber, Johannes %A Morris, John C %A Fagan, Anne M %X

BACKGROUND: Decreased concentrations of amyloid-β 1-42 (Aβ42) in cerebrospinal fluid (CSF) and increased retention of Aβ tracers in the brain on positron emission tomography (PET) are considered the earliest biomarkers of Alzheimer's disease (AD). However, a proportion of cases show discrepancies between the results of the two biomarker modalities which may reflect inter-individual differences in Aβ metabolism. The CSF Aβ42/40 ratio seems to be a more accurate biomarker of clinical AD than CSF Aβ42 alone.

OBJECTIVE: We tested whether CSF Aβ42 alone or the Aβ42/40 ratio corresponds better with amyloid PET status and analyzed the distribution of cases with discordant CSF-PET results.

METHODS: CSF obtained from a mixed cohort (n = 200) of cognitively normal and abnormal research participants who had undergone amyloid PET within 12 months (n = 150 PET-negative, n = 50 PET-positive according to a previously published cut-off) was assayed for Aβ42 and Aβ40 using two recently developed immunoassays. Optimal CSF cut-offs for amyloid positivity were calculated, and concordance was tested by comparison of the areas under receiver operating characteristic (ROC) curves (AUC) and McNemar's test for paired proportions.

RESULTS: CSF Aβ42/40 corresponded better than Aβ42 with PET results, with a larger proportion of concordant cases (89.4% versus 74.9%, respectively, p < 0.0001) and a larger AUC (0.936 versus 0.814, respectively, p < 0.0001) associated with the ratio. For both CSF biomarkers, the percentage of CSF-abnormal/PET-normal cases was larger than that of CSF-normal/PET-abnormal cases.

CONCLUSION: The CSF Aβ42/40 ratio is superior to Aβ42 alone as a marker of amyloid-positivity by PET. We hypothesize that this increase in performance reflects the ratio compensating for general between-individual variations in CSF total Aβ.

%B J Alzheimers Dis %V 55 %P 813-822 %G ENG %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27792012?dopt=Abstract %R 10.3233/JAD-160722 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebrospinal Fluid Biomarkers as a Diagnostic Tool of the Underlying Pathology of Primary Progressive Aphasia. %A Paraskevas, George P %A Kasselimis, Dimitrios %A Kourtidou, Evie %A Constantinides, Vasilios %A Bougea, Anastasia %A Potagas, Costas %A Evdokimidis, Ioannis %A Kapaki, Elisabeth %X

BACKGROUND: Primary progressive aphasia (PPA) may present with three main clinical variants, namely nonfluent agrammatic (nfaPPA), semantic (sPPA), and logopenic (lPPA) subtypes. Frontotemporal lobar degenerations (FTLD) or Alzheimer's disease (AD) are the most common etiologies.

OBJECTIVE: To study the potential of cerebrospinal fluid (CSF) biomarkers for identifying the underlying pathology in patients with PPA.

METHODS: CSF levels of total tau protein (τT), amyloid-β peptide (Aβ42), and tau phosphorylated at threonine-181 (τP - 181) were measured by double sandwich, enzyme-linked immunosorbent assay (ELISA) in 43 patients with PPA, 26 patients with AD, and 17 healthy controls.

RESULTS: All patients could be classified as compatible with the AD or non-AD biomarker profile, either with the three biomarkers (90.7%) or their ratios, especially the τP - 181/Aβ42 ratio (9.3%). An AD-compatible biomarker profile was present in 39.5% of all PPA patients, specifically 22.2%, 35.7%, and 75% of nfaPPA, sPPA, and lPPA, respectively. In PPA patients with a non-AD profile (presumably FTLD), two different clusters could be identified according to the τP - 181/τT ratio, possibly corresponding to the two major FTLD pathologies (tau and TDP-43).

CONCLUSION: CSF biomarkers may be a valuable tool for the discrimination between PPA patients with AD and non-AD pathophysiology and possibly between FTLD patients with tau and TDP-43 pathology.

%B J Alzheimers Dis %V 55 %P 1453-1461 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858708?dopt=Abstract %R 10.3233/JAD-160494 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebrospinal Fluid Biomarkers for Alzheimer's Disease: A View of the Regulatory Science Qualification Landscape from the Coalition Against Major Diseases CSF Biomarker Team. %A Arnerić, Stephen P %A Batrla-Utermann, Richard %A Beckett, Laurel %A Bittner, Tobias %A Blennow, Kaj %A Carter, Leslie %A Dean, Robert %A Engelborghs, Sebastiaan %A Genius, Just %A Gordon, Mark Forrest %A Hitchcock, Janice %A Kaplow, June %A Luthman, Johan %A Meibach, Richard %A Raunig, David %A Romero, Klaus %A Samtani, Mahesh N %A Savage, Mary %A Shaw, Leslie %A Stephenson, Diane %A Umek, Robert M %A Vanderstichele, Hugo %A Willis, Brian %A Yule, Susan %X

Alzheimer's disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development.

%B J Alzheimers Dis %V 55 %P 19-35 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662307?dopt=Abstract %R 10.3233/JAD-160573 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebrospinal Fluid Neurogranin as a Biomarker of Neurodegenerative Diseases: A Cross-Sectional Study. %A Lista, Simone %A Toschi, Nicola %A Baldacci, Filippo %A Zetterberg, Henrik %A Blennow, Kaj %A Kilimann, Ingo %A Teipel, Stefan J %A Cavedo, Enrica %A Dos Santos, Antonio Melo %A Epelbaum, Stéphane %A Lamari, Foudil %A Dubois, Bruno %A Nisticò, Robert %A Floris, Roberto %A Garaci, Francesco %A Hampel, Harald %X

We investigated cerebrospinal fluid (CSF) concentrations of the postsynaptic biomarker neurogranin at baseline in cognitively healthy controls (HC) compared to individuals with mild cognitive impairment (MCI), patients with Alzheimer's disease (AD) dementia, and patients with frontotemporal dementia (FTD). CSF neurogranin was quantified using an in-house immunoassay in a cross-sectional multicenter study of 108 participants [AD dementia (n = 35), FTD (n = 9), MCI (n = 41), cognitively HC (n = 23)]. CSF neurogranin concentrations were significantly higher in AD patients compared with both HC subjects and FTD patients, suggesting that increased CSF neurogranin concentrations may indicate AD-related pathophysiology. CSF neurogranin was independently associated with both total tau and hyperphosphorylated tau proteins, whereas a non-significant correlation with the 42-amino acid-long amyloid-β peptide was evident. CSF neurogranin, however, was not superior to core AD biomarkers in differentiating HC from the three diagnostic groups, and it did not improve their diagnostic accuracy. We conclude that further classification and longitudinal studies are required to shed more light into the potential role of neurogranin as a pathophysiological biomarker of neurodegenerative diseases.

%B J Alzheimers Dis %V 59 %P 1327-1334 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731449?dopt=Abstract %R 10.3233/JAD-170368 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Challenges and Considerations Related to Studying Dementia in Blacks/African Americans. %A Ighodaro, Eseosa T %A Nelson, Peter T %A Kukull, Walter A %A Schmitt, Frederick A %A Abner, Erin L %A Caban-Holt, Allison %A Bardach, Shoshana H %A Hord, Derrick C %A Glover, Crystal M %A Jicha, Gregory A %A Van Eldik, Linda J %A Byrd, Alexander X %A Fernander, Anita %X

Blacks/African Americans have been reported to be ∼2-4 times more likely to develop clinical Alzheimer's disease (AD) compared to Whites. Unfortunately, study design challenges (e.g., recruitment bias), racism, mistrust of healthcare providers and biomedical researchers, confounders related to socioeconomic status, and other sources of bias are often ignored when interpreting differences in human subjects categorized by race. Failure to account for these factors can lead to misinterpretation of results, reification of race as biology, discrimination, and missed or delayed diagnoses. Here we provide a selected historical background, discuss challenges, present opportunities, and suggest considerations for studying health outcomes among racial/ethnic groups. We encourage neuroscientists to consider shifting away from using biologic determination to interpret data, and work instead toward a paradigm of incorporating both biological and socio-environmental factors known to affect health outcomes with the goal of understanding and improving dementia treatments for Blacks/African Americans and other underserved populations.

%B J Alzheimers Dis %V 60 %P 1-10 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731440?dopt=Abstract %R 10.3233/JAD-170242 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Challenges in Screening and Recruitment for a Neuroimaging Study in Cognitively Impaired Geriatric Inpatients. %A Apostolova, Ivayla %A Lange, Catharina %A Roberts, Anna %A Igel, Hans Joachim %A Mäurer, Anja %A Liese, Stephanie %A Estrella, Melanie %A Prasad, Vikas %A Stechl, Elisabeth %A Lämmler, Gernot %A Steinhagen-Thiessen, Elisabeth %A Buchert, Ralph %X

BACKGROUND: Neuroimaging-based biomarkers have the potential to improve etiological diagnosis of cognitive impairment in elderly inpatients. However, there is a relative lack of studies on neuroimaging-based biomarkers in hospitalized geriatric patients, as the vast majority of neuroimaging studies in dementia have focused on memory clinic outpatients. An important aspect of study planning is a priori estimation of the rate of screen failures.

OBJECTIVE: To report on the rate and causes of screen failures in a prospective study on the utility of neuroimaging (PET, MRI) for the etiological diagnosis of newly manifested cognitive impairment in acutely hospitalized geriatric patients.

METHODS: Ten acute care geriatrics clinics with 802 beds participated in the study. The potential recruitment rate had been estimated to 5 patients/100 beds/week.

RESULTS: Seventeen months of pre-screening resulted in 322 potential participants. 109 of these patients were enrolled, i.e., the screen failure rate was 66%. 58% of the screen failures were due to refusal of participation by the patient, most often due to lack of interest in clarifying the cause of the cognitive impairment or due to reluctance to engage in additional diagnostic procedures associated with physical stress. 42% of pre-screened patients were excluded because of violation of the eligibility criteria.

CONCLUSION: Enrollment for neuroimaging studies presents considerable additional challenges in acutely hospitalized geriatric patients compared to outpatient settings. Low rate of approaching potential candidates by attending geriatricians and a high rate of screen failures have to be anticipated in the study design.

%B J Alzheimers Dis %V 56 %P 197-204 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911313?dopt=Abstract %R 10.3233/JAD-160797 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Change in Odor Identification Impairment is Associated with Improvement with Cholinesterase Inhibitor Treatment in Mild Cognitive Impairment. %A Devanand, D P %A Lentz, Cody %A Chunga, Richard E %A Ciarleglio, Adam %A Scodes, Jennifer M %A Andrews, Howard %A Schofield, Peter W %A Stern, Yaakov %A Huey, Edward D %A Bell, Karen %A Pelton, Gregory H %X

BACKGROUND: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease pathology.

OBJECTIVE: To determine if decline in odor identification ability with anticholinergic challenge can predict improvement with donepezil, a cholinesterase inhibitor (ChEI), in patients with mild cognitive impairment (MCI).

METHODS: At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and then the dose was kept constant for 52 weeks. Main outcomes were change in Selective Reminding Test (SRT) total immediate recall and ADAS-Cog total score from baseline to 26 and 52 weeks.

RESULTS: In 37 participants, mean age 70.4 (SD 9.8) y, greater atropine-induced decrease in UPSIT score at baseline was associated with greater improvement in SRT total recall score from baseline to 26 and 52 weeks (p < 0.03). This effect remained after adjusting for time, age, education, gender, APOE ɛ4 status, and baseline cognitive score (p < 0.05). Decrease in UPSIT score was associated with global improvement (CIBIC-plus) over 52 weeks (p < 0.02). After excluding patients with congential anosmia, increase in UPSIT score from 0 to 8 weeks showed a trend-level association with improvement on the ADAS-Cog (p = 0.07).

CONCLUSIONS: Anticholinergic challenge-induced odor identification decline was associated with cognitive improvement, and short-term improvement in odor identification tended to predict longer term cognitive improvement. These simple inexpensive strategies have the potential to improve selection of patients with MCI for ChEI treatment.

%B J Alzheimers Dis %V 60 %P 1525-1531 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29081417?dopt=Abstract %R 10.3233/JAD-170497 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Changes of Cerebrospinal Fluid Peptides due to Tauopathy. %A Majerova, Petra %A Barath, Peter %A Michalicova, Alena %A Katina, Stanislav %A Novak, Michal %A Kovac, Andrej %X

Alzheimer's disease (AD) and progressive supranuclear palsy are two common neurodegenerative tauopathies, and the most common cause of progressive brain dementia in elderly affecting more than 35 million people. The tauopathies are characterized by abnormal deposition of microtubule associated protein tau into intracellular neurofibrillary tangles composed mainly of the hyperphosphorylated form of the protein. The diagnosis of tauopathies is based on the presence of clinical features and pathological changes. Over the last decade, there has been an intensive search for novel biochemical markers for clinical diagnosis of AD and other tauopathies. In the present study, we used transgenic rat model for tauopathy expressing human truncated tau protein (aa 151-391/4R) to analyze the cerebrospinal fluid (CSF) peptidome using liquid chromatography - matrix assisted laser desorption/ionization mass spectrometry (LC-MALDI TOF/TOF). From 345 peptides, we identified a total of 175 proteins. Among them, 17 proteins were significantly altered in the CSF of transgenic rats. The following proteins were elevated in the CSF of transgenic rats when compared to the control animals: neurofilament light and medium chain, apolipoprotein E, gamma-synuclein, chromogranin A, reticulon-4, secretogranin-2, calsyntein-1 and -3, endothelin-3, neuroendocrine protein B72A, alpha-1-macroglobulin, and augurin. Interestingly most of the identified proteins were previously linked to AD and other tauopathies, indicating the significance of transgenic animals in biomarker validation.

%B J Alzheimers Dis %V 58 %P 507-520 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453489?dopt=Abstract %R 10.3233/JAD-170110 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Chronic Neurodegenerative Illnesses and Epilepsy in Danish Adventists and Baptists: A Nationwide Cohort Study. %A Thygesen, Lau Caspar %A Gimsing, Louise NØrreslet %A Bautz, Andrea %A Hvidt, Niels Christian %A Johansen, Christoffer %X

BACKGROUND: Limited knowledge of the influence of lifestyle risk factors and religious living on chronic neurological diseases exist. Seventh-day Adventists (SDA) do not consume tobacco, alcohol, or pork, and many adhere to lacto-ovo-vegetarian diet, and Baptists discourage excessive use of alcohol and tobacco.

OBJECTIVE: We investigated whether the incidence of four common chronic neurological illnesses: dementia, Alzheimer's disease, Parkinson's disease, and epilepsy in a large cohort of Danish Adventists and Baptists was different compared to the general Danish population. Three of the illnesses are neurodegenerative, whereas epilepsy can occur at any age.

METHODS: We compared hospital admission rates for some major neurological diseases among members of the Danish Religious Societies Health Study comprising 6,532 SDA and 3,720 Baptists with the general Danish population. Standardized incidence rates (SIR) stratified by sex, age, and calendar time were calculated.

RESULTS: SIR of dementia or Alzheimer's disease was significantly decreased for members of both communities (SDA, 0.78; 95% CI, 0.67-#x2013;0.90 and Baptists, 0.59; 0.47-#x2013;0.73). The SIRs of Parkinson's disease and epilepsy were not significantly different compared to the general population.

CONCLUSIONS: We observe reduced incidence for dementia or Alzheimer's disease in a large cohort of members of two religious communities characterized by lifestyle recommendations. More studies are needed to disentangle the interaction between such lifestyle and other components of the religious belief system.

%B J Alzheimers Dis %V 56 %P 1429-1435 %G eng %N 4 %R 10.3233/JAD-160710 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Chronotropic Response and Cognitive Function in a Cohort at Risk for Alzheimer's Disease. %A Law, Lena L %A Schultz, Stephanie A %A Boots, Elizabeth A %A Einerson, Jean A %A Dougherty, Ryan J %A Oh, Jennifer M %A Korcarz, Claudia E %A Edwards, Dorothy F %A Koscik, Rebecca L %A Dowling, N Maritza %A Gallagher, Catherine L %A Bendlin, Barbara B %A Carlsson, Cynthia M %A Asthana, Sanjay %A Hermann, Bruce P %A Sager, Mark A %A Johnson, Sterling C %A Cook, Dane B %A Stein, James H %A Okonkwo, Ozioma C %X

The objective of this study was to examine the association of chronotropic response (CR) and heart rate (HR) recovery- two indices of cardiovascular function within the context of a graded exercise test- with cognitive performance in a cognitively healthy, late-middle-aged cohort at risk for Alzheimer's disease (AD). Ninety participants (age = 63.52±5.86 years; 65.6% female) from the Wisconsin Registry for Alzheimer's Prevention participated in this study. They underwent graded exercise testing and a comprehensive neuropsychological assessment that assessed the following four cognitive domains: Immediate Memory, Verbal & Learning Memory, Working Memory, and Speed & Flexibility. Regression analyses, adjusted for age, sex, and education, were used to examine the association between CR, HR recovery, and cognition. We found significant associations between CR and cognitive performance in the domains of Immediate Memory, Verbal Learning & Memory, and Speed & Flexibility. In contrast, HR recovery was not significantly associated with cognitive function. The association between CR and cognition persisted even after controlling for HR recovery. Together, these findings indicatethat, in a cognitively normal, late-middle-aged cohort, CR is a stronger correlate of cognitive performance than HR recovery. Overall, this study reinforces the idea that cardiovascular health plays an important role in cognitive function, specifically in a cohort at risk for AD; and that interventions that promote vascular health may be a viable pathway to preventing or slowing cognitive decline due to AD.

%B J Alzheimers Dis %V 56 %P 351-359 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911299?dopt=Abstract %R 10.3233/JAD-160642 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Classification of Alzheimer's Disease and Prediction of Mild Cognitive Impairment Conversion Using Histogram-Based Analysis of Patient-Specific Anatomical Brain Connectivity Networks. %A Beheshti, Iman %A Maikusa, Norihide %A Daneshmand, Morteza %A Matsuda, Hiroshi %A Demirel, Hasan %A Anbarjafari, Gholamreza %X

In this study, we investigated the early detection of Alzheimer's disease (AD) and mild cognitive impairment (MCI) conversion to AD through individual structural connectivity networks using structural magnetic resonance imaging (sMRI) data. In the proposed method, the cortical morphometry of individual gray matter images were used to construct structural connectivity networks. A statistical feature generation approach based on histogram-based feature generation procedure was proposed to represent a statistical-pattern of connectivity networks from a high-dimensional space into low-dimensional feature vectors. The proposed method was evaluated on numerous samples including 61 healthy controls (HC), 42 stable-MCI (sMCI), 45 progressive-MCI (pMCI), and 83 AD subjects at the baseline from the J-ADNI data-set using support vector machine classifier. The proposed method yielded a classification accuracy of 84.17%, 70.38%, and 61.05% in identifying AD/HC, MCIs/HCs, and sMCI/pMCI, respectively. The experimental results show that the proposed method performed in a comparable way to alternative methods using MRI data.

%B J Alzheimers Dis %V 60 %P 295-304 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28800325?dopt=Abstract %R 10.3233/JAD-161080 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Clinical Effectiveness and Tolerability of Electroconvulsive Therapy in Patients with Neuropsychiatric Symptoms of Dementia. %A Isserles, Moshe %A Daskalakis, Zafiris J %A Kumar, Sanjeev %A Rajji, Tarek K %A Blumberger, Daniel M %X

BACKGROUND: Dementia frequently presents with aggression, agitation, and disorganized behavior for which current treatment is partially effective and is associated with significant adverse effects.

OBJECTIVE: The aim of this study was to retrospectively assess the clinical effectiveness and tolerability of electroconvulsive therapy (ECT) in a sample of patients with neuropsychiatric symptoms of dementia (NPS) and to explore factors associated with response and with cognitive adverse effects.

METHODS: We examined the clinical records of 25 patients with dementia and a pre-existing psychiatric disorder treated with ECT at an academic mental health hospital between April 1, 2010 and January 28, 2016. Twenty-nine acute ECT courses and fifteen maintenance courses were reviewed. We assessed treatment effectiveness and cognitive adverse effects as well as factors associated with response to treatment, including pre-existing psychiatric disorders, concomitant pharmacological treatment and types of dementia.

RESULTS: ECT resulted in a clinically meaningful response in 72% of acute treatment courses. Cognitive adverse effects affecting functioning were reported in 7% of the acute treatment courses. Maintenance treatment was effective in sustaining the response in 87% of treatment courses with two reports of significant cognitive adverse effects. One patient fell and experienced a hip fracture a day after treatment. Use of antipsychotic or antidepressant medications, pre-existing psychiatric disorder, or gender were not associated with response.

CONCLUSION: This study shows meaningful clinical effectiveness and good tolerability of ECT in patients with severe NPS of dementia. Furthermore, maintenance ECT was effective in sustaining treatment response.

%B J Alzheimers Dis %V 57 %P 45-51 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222513?dopt=Abstract %R 10.3233/JAD-161000 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Clinical Response to Donepezil in Mild and Moderate Dementia: Relationship to Drug Plasma Concentration and CYP2D6 and APOE Genetic Polymorphisms. %A Miranda, Luís F J R %A Gomes, Karina B %A Tito, Pedro A L %A Silveira, Josianne N %A Pianetti, Gerson A %A Byrro, Ricardo M D %A Peles, Patrícia R H %A Pereira, Fernando H %A Santos, Thiago R %A Assini, Arthur G %A Ribeiro, Valéria V %A Moraes, Edgar N %A Caramelli, Paulo %X

The clinical response to donepezil in patients with mild and moderate dementia was investigated in relation to the drug plasma concentration and APOE and CYP2D6 polymorphisms. In a prospective naturalistic observational study, 42 patients with Alzheimer's disease (AD) and AD with cerebrovascular disease who took donepezil (10 mg) for 12 months were evaluated. Their DNA was genotyped, and the donepezil plasma concentrations were measured after 3, 6, and 12 months. Good responders scored ≥-1 on the Mini-Mental State Examination at 12 months in comparison to the baseline score. The study results indicated the good response pattern was influenced by the concentration of donepezil, but not by APOE and CYP2D6 polymorphisms.

%B J Alzheimers Dis %V 55 %P 539-549 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716659?dopt=Abstract %R 10.3233/JAD-160164 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Clinical Use of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease Diagnosis: The Italian Selfie. %A Sancesario, Giulia M %A Toniolo, Sofia %A Chiasserini, Davide %A Di Santo, Simona G %A Zegeer, Josh %A Bernardi, Gaetano %A Musicco, Massimo %A Caltagirone, Carlo %A Parnetti, Lucilla %A Bernardini, Sergio %X

Although the use of cerebrospinal fluid (CSF) amyloid β1-42 (Aβ42), tau (T-tau), and phosphorylated tau (p-tau181) gives added diagnostic and prognostic values, the diffusion is still limited in clinical practice and only a restricted number of patients receive an integrated clinico-biological diagnosis. By a survey, we aimed to do a "selfie" of the use and diffusion of CSF biomarkers of dementia in Italy, the standardization of pre-analytical procedures, the harmonization of ranges, and the participation to Quality Control programs. An online questionnaire was sent to the members of SIBioC and SINdem-ITALPLANED and to main neurological clinics all over Italy. In Italy, 25 laboratories provide biomarkers analysis in addition to a network of 15 neighboring hospitals. In sum, 40 neurological centers require CSF analyses. 7/20 regions (35%) lack CSF laboratories. Standardization of pre-analytical procedures is present in 62.02% of the laboratories; only 56.00% of the laboratories participate in International Quality Control. There is no harmonization of cut-offs. In Italy, the use of CSF biomarkers is still limited in clinical practice. Standardization and harmonization of normal ranges are needed. To optimize and expand the use of CSF biomarkers, a cost-benefit analysis should be promoted by scientific societies and national health services.

%B J Alzheimers Dis %V 55 %P 1659-1666 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911328?dopt=Abstract %R 10.3233/JAD-160975 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive Change in Rehabilitation Patients with Dementia: Prevalence and Association with Rehabilitation Success. %A Dutzi, Ilona %A Schwenk, Michael %A Kirchner, Marietta %A Bauer, Jürgen M %A Hauer, Klaus %X

BACKGROUND: Dementia is a frequent diagnosis in geriatric rehabilitation. Studies in patients with dementia on the development of their cognitive status during rehabilitation and its relation to functional outcomes have been scarce.

OBJECTIVES: To describe the changes in cognitive status in patients with dementia during inpatient rehabilitation and to determine its association with patient characteristics and rehabilitation outcome.

METHODS: Cohort study in a geriatric rehabilitation center with data collection at admission and discharge. Outcome measures were change in global and domain-related cognitive functioning and its association with activities of daily living (ADL) and discharge home.

RESULTS: 154 patients (mean age 83.7 years) diagnosed with mild to moderate dementia were included. Cognitive performance significantly improved from admission to discharge for all cognitive variables tested (p < 0.001 to 0.03). Change in global cognitive functioning, executive functions, and episodic memory were positively associated with ADL recovery. Change in global cognitive functioning predicted ADL improvements (β= 0.32; p = 0.006). Only 7.8% of patients, characterized by worse ADL and motor abilities as well as higher frailty scores at admission, deteriorated in global cognitive scores. In comparison to patients with stable or improved cognition, these patients showed least improvements in ADL-scores (4.1 versus 12.5) and a trend for higher institutionalization (50% versus 26.5%).

CONCLUSIONS: The findings highlight the potential of patients with dementia to recover cognitive functioning during rehabilitation. Cognitive change represents an independent rehabilitation outcome and a prognostic factor for successful rehabilitation suggesting that specific interventions are indicated to maintain and enhance cognitive functioning in these highly vulnerable patients.

%B J Alzheimers Dis %V 60 %P 1171-1182 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984597?dopt=Abstract %R 10.3233/JAD-170401 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive Composites Domain Scores Related to Neuroimaging Biomarkers within Probable-Amnestic Mild Cognitive Impairment-Storage Subtype. %A Espinosa, Ana %A Alegret, Montserrat %A Pesini, Pedro %A Valero, Sergi %A Lafuente, Asunción %A Buendia, Mar %A San José, Itziar %A Ibarria, Marta %A Tejero, Miguel A %A Giménez, Joan %A Ruiz, Susana %A Hernandez, Isabel %A Pujadas, Francesc %A Martínez-Lage, Pablo %A Munuera, Josep %A Arbizu, Javier %A Tárraga, Lluís %A Hendrix, Suzanne B %A Ruiz, Agustin %A Becker, James T %A Landau, Susan M %A Sotolongo-Grau, Oscar %A Sarasa, Manuel %A Boada, Merce %X

The probable-amnestic (Pr-a) mild cognitive impairment (MCI)-storage subtype is a phenotype with 8.5 times more risk of conversion to dementia, mainly Alzheimer's disease (AD), than the possible non-amnestic (Pss-na) MCI. The aim of this study was to find the optimized cognitive composites (CCs) domain scores most related to neuroimaging biomarkers within Pr-aMCI-storage subtype patients. The Fundació ACE (ACE) study with 20 Pr-aMCI-storage subtype subjects (MCI) were analyzed. All subjects underwent a neuropsychological assessment, a structural MRI, FDG-PET, and PIB-PET. The adjusted hippocampal volume (aHV) on MRI, the standard uptake value ratio (SUVR) on FDG-PET and PIB-PET SUVR measures were analyzed. The construction of the CCs domain scores, and the aHV on MRI and FDG-PET SUVR measures, were replicated in the parental AB255 study database (n = 133 MCI). Partial correlations adjusted by age, gender, and education were calculated with the associated p-value among every CC domain score and the neuroimaging biomarkers. The results were replicated in the "MCI due to AD" with memory storage impairments from ADNI. Delayed Recall CC domain score was significantly correlated with PIB-PET SUVR (β= -0.61, p = 0.003) in the ACE study and also with aHV on MRI (β= 0.27, p = 0.01) and FDG-PET SUVR (β= 0.27, p = 0.01) in the AB255 study. After a median survival time of 20.6 months, 85% from the ACE MCI converted to AD. The replication of our results in the ADNI dataset also confirmed our findings. Delayed Recall is the CC domain score best correlated with neuroimaging biomarkers associated with prodromal AD diagnosis.

%B J Alzheimers Dis %V 57 %P 447-459 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269787?dopt=Abstract %R 10.3233/JAD-161223 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive Event-Related Potential, an Early Diagnosis Biomarker in Frail Elderly Subjects: The ERP-MAPT-PLUS Ancillary Study. %A Bennys, Karim %A Gabelle, Audrey %A Berr, Claudine %A De Verbizier, Delphine %A Andrieu, Sandrine %A Vellas, Bruno %A Touchon, Jacques %X

BACKGROUND: By analyzing brain synaptic function, cognitive event-related potentials (ERPs) could provide powerful and innovative tools for early Alzheimer's disease (AD) diagnosis.

OBJECTIVE: We investigated the relevance of the ERP-P300 component as a potential diagnosis marker in elderly subjects at risk of developing AD.

METHODS: ERP-P300 was analyzed on 85 subjects recruited from the Multidomain Alzheimer Preventive Trial (MAPT). PET-AV45 brain imaging was available from 36 subjects.

RESULTS: Two ERP-P300 subgroups were identified according to their PET-AV45 status: PET-Aβ positive (n = 15) and PET-Aβ negative (n = 21). In the amyloid positive group, we observed a highly significant increase in P3b latency in parietal brain regions (p = 0.0052). P3b in parietal regions correctly categorized 69.4% elderly subjects from the P300-PET Aβ positive group. Combined analysis of parietal P3b latencies and category fluency correctly classified 75% subjects from the P300-PET Aβ positive group.

CONCLUSIONS: The P300 ERP presents good predictive measure of brain amyloid load and has the potential to be used as a screening instrument for preclinical AD. The incorporation of P3b latency may be used as an adjunctive tool with neuropsychological assessment (i.e., verbal category fluency) as a specific and sensitive method for preclinical assessment of AD.

%B J Alzheimers Dis %V 58 %P 87-97 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372327?dopt=Abstract %R 10.3233/JAD-161012 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive Rehabilitation in Alzheimer's Disease: A Controlled Intervention Trial. %A Brueggen, Katharina %A Kasper, Elisabeth %A Ochmann, Sina %A Pfaff, Henrike %A Webel, Steffi %A Schneider, Wolfgang %A Teipel, Stefan %X

BACKGROUND: Cognitive Rehabilitation for Alzheimer's disease (AD) is an integrative multimodal intervention. It aims to maintain autonomy and quality of life by enhancing the patients' abilities to compensate for decreased cognitive functioning.

OBJECTIVE: We evaluated the feasibility of a group-based Cognitive Rehabilitation approach in mild AD dementia and assessed its effect on activities of daily living (ADL).

METHODS: We included 16 patients with AD dementia in a controlled partial-randomized design. We adapted the manual-guided Cognitive Rehabilitation program (CORDIAL) to a group setting. Over the course of three months, one group received the Cognitive Rehabilitation intervention (n = 8), while the other group received a standardized Cognitive Training as an active control condition (n = 8). ADL-competence was measured as primary outcome. The secondary outcome parameters included cognitive abilities related to daily living, functional cognitive state, and non-cognitive domains, e.g., quality of life. For each scale, we assessed the interaction effect 'intervention by time', i.e., from pre-to post-intervention.

RESULTS: We found no significant interaction effect of intervention by time on the primary outcome ADL-competence. The interaction effect was significant for quality of life (Cohen's d: -1.43), showing an increase in the intervention group compared with the control group.

CONCLUSIONS: Our study demonstrates the feasibility of a group-based Cognitive Rehabilitation program for patients with mild AD dementia. The Cognitive Rehabilitation showed no significant effect on ADL, possibly reflecting a lack of transfer between the therapy setting and real life. However, the group setting enhanced communication skills and coping mechanisms. Effects on ADL may not have reached statistical significance due to a limited sample size. Furthermore, future studies might use an extended duration of the intervention and integrate caregivers to a greater extent to increase transfer to activities of daily living.

%B J Alzheimers Dis %V 57 %P 1315-1324 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372325?dopt=Abstract %R 10.3233/JAD-160771 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive Status, Gray Matter Atrophy, and Lower Orthostatic Blood Pressure in Older Adults. %A O'Hare, Celia %A Kenny, Rose-Anne %A Aizenstein, Howard %A Boudreau, Robert %A Newman, Anne %A Launer, Lenore %A Satterfield, Suzanne %A Yaffe, Kristine %A Rosano, Caterina %X

BACKGROUND: Associations between orthostatic blood pressure and cognitive status (CS) have been described with conflicting results.

OBJECTIVE: We hypothesize that long-term exposure to lower orthostatic blood pressure is related to having worse CS later in life and that atrophy of regions involved in central regulation of autonomic function mediate these associations.

METHODS: Three-to-four measures of orthostatic blood pressure were obtained from 1997-2003 in a longitudinal cohort of aging, and average systolic orthostatic blood pressure response (ASOBPR) was computed as % change in systolic blood pressure from sit-to-stand measured at one minute post stand. CS was determined in 2010-2012 by clinician-adjudication (n = 240; age = 87.1±2.6; 59% women; 37% black) with a subsample also undergoing concurrent structural neuroimaging (n = 129). Gray matter volume of regions related to autonomic function was measured. Multinomial regression was used to compare ASOBPR in those who were cognitively intact versus those with a diagnosis of mild cognitive impairment or dementia, controlling for demographics, trajectories of seated blood pressure, incident cardiovascular risk/events and medications measured from 1997 to 2012. Models were repeated in the subsample with neuroimaging, before and after adjustment for regional gray matter volume.

RESULTS: There was an inverse association between ASOBPR and probability of dementia diagnosis (9% lower probability for each % point higher ASOBPR: OR 0.91, CI95%  = 0.85-0.98; p = 0.01). Associations were similar in the subgroup with neuroimaging before and after adjustment for regional gray matter volume.

CONCLUSION: ASOBPR may be an early marker of risk of dementia in older adults living in the community.

%B J Alzheimers Dis %V 57 %P 1239-1250 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28339397?dopt=Abstract %R 10.3233/JAD-161228 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive-Enhancing Effects of a Polyphenols-Rich Extract from Fruits without Changes in Neuropathology in an Animal Model of Alzheimer's Disease. %A Dal-Pan, Alexandre %A Dudonné, Stéphanie %A Bourassa, Philippe %A Bourdoulous, Morgane %A Tremblay, Cyntia %A Desjardins, Yves %A Calon, Frederic %X

No effective preventive treatment is available for age-related cognitive decline and Alzheimer's disease (AD). Epidemiological studies indicate that a diet rich in fruit is associated with cognitive improvement. It was thus proposed that high polyphenol concentrations found in berries can prevent cognitive impairment associated with aging and AD. Therefore, the Neurophenols project aimed at investigating the effects of a polyphenolic extract from blueberries and grapes (PEBG) in the triple-transgenic (3xTg-AD) mouse model of AD, which develops AD neuropathological markers, including amyloid-β plaques and neurofibrillary tangles, leading to memory deficits. In this study, 12-month-old 3xTg-AD and NonTg mice were fed a diet supplemented with standardized PEBG (500 or 2500 mg/kg) for 4 months (n = 15-20/group). A cognitive evaluation with the novel object recognition test was performed at 15 months of age and mice were sacrificed at 16 months of age. We observed that PEBG supplementation with doses of 500 or 2500 mg/kg prevented the decrease in novel object recognition observed in both 15-month-old 3xTg-AD mice and NonTg mice fed a control diet. Although PEBG treatment did not reduce Aβ and tau pathologies, it prevented the decrease in mature BDNF observed in 16-month-old 3xTg-AD mice. Finally, plasma concentrations of phenolic metabolites, such as dihydroxyphenyl valerolactone, a microbial metabolite of epicatechin, positively correlated with memory performances in supplemented mice. The improvement in object recognition observed in 3xTg-AD mice after PEBG administration supports the consumption of polyphenols-rich extracts to prevent memory impairment associated with age-related disease, without significant effects on classical AD neuropathology.

%B J Alzheimers Dis %V 55 %P 115-135 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662290?dopt=Abstract %R 10.3233/JAD-160281 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Combinatorial Treatment Effects in a Cell Culture Model of Alzheimer's Disease. %A Beesley, Stephen %A Olcese, James %A Saunders, Charles %A Bienkiewicz, Ewa A %X

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia, and as its prevalence increases, so does its detrimental impact on society. The currently available therapies have limited efficacy, leaving AD patients on an irrevocably fatal path of this disease.

OBJECTIVE: The purpose of this study was to test efficacy of a novel combinatorial treatment approach to alleviate AD-like pathology.

METHODS: We selected four naturally occurring compounds and used them in different combinations to test their effect on AD-like pathology. Employing a well-established cell culture AD model system, we evaluated levels of several diverse biomarkers associated with a number of cellular pathways associated with AD. The readouts included: amyloid-β peptides, anti-inflammatory and anti-apoptotic proteins, oxidative enzymes, and reactive oxygen species.

RESULTS: Using this approach, we demonstrated that the compounds delivered in combination had higher efficacy than individual treatments. Specifically, we observed significant reduction in levels of the amyloid-β peptides, as well as pro-inflammatory proteins and reactive oxygen species. Similarly, delivery of compounds in combination resulted in an increased expression of anti-apoptotic proteins and anti-oxidative enzymes. Collectively, these modifications in AD pathology biomarkers reflect a promising therapeutic and preventive strategy to combat this disease.

CONCLUSION: The above findings support a novel therapeutic approach to address a currently unmet medical need, which would benefit not only AD patients and their caregivers, but also society as a whole.

%B J Alzheimers Dis %V 55 %P 1155-1166 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27814295?dopt=Abstract %R 10.3233/JAD-160459 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Combined Creutzfeldt-Jakob/ Alzheimer's Disease Cases are Important in Search for Microbes in Alzheimer's Disease. %A Bastian, Frank O %X

The question whether Alzheimer's disease is infectious as brought up in the recent editorial published in the Journal of Alzheimer's Disease is complicated by the controversy whether the causal agent is a microbe or a misfolded host protein (amyloid). The replicating amyloid (prion) theory, based upon data from studies of Creutzfeldt-Jakob disease (CJD) and other transmissible spongiform encephalopathies (TSEs), has been challenged since the prion can be separated from TSE infectivity, and spiroplasma, a wall-less bacterium, has been shown to be involved in the pathogenesis of CJD. Further support for a microbial cause for AD comes from occurrence of mixed CJD/AD cases involving up to 15% of AD brains submitted to brain banks. The association of CJD with AD suggests a common etiology rather than simply being a medical curiosity. A co-infection with the transmissible agent of CJD, which we propose to be a Spiroplasma sp., would explain the diversity of bacteria shown to be associated with cases of AD.

%B J Alzheimers Dis %V 56 %P 867-873 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059790?dopt=Abstract %R 10.3233/JAD-160999 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Common Variant in the MC1R Gene (p.V92M) is associated with Alzheimer's Disease Risk. %A Tell-Marti, Gemma %A Puig-Butille, Joan Anton %A Potrony, Miriam %A Plana, Estel %A Badenas, Celia %A Antonell, Anna %A Sánchez-Valle, Raquel %A Molinuevo, José L %A Lleo, Alberto %A Alcolea, Daniel %A Fortea, Juan %A Fernández-Santiago, Rubén %A Clarimón, Jordi %A Lladó, Albert %A Puig, Susana %X

Despite the recent identification of some novel risk genes for Alzheimer's disease (AD), the genetic etiology of late-onset Alzheimer's disease (LOAD) remains largely unknown. The inclusion of these novel risk genes to the risk attributable to the APOE gene accounts for roughly half of the total genetic variance in LOAD. The evidence indicates that undiscovered genetic factors may contribute to AD susceptibility. In the present study, we sequenced the MC1R gene in 525 Spanish LOAD patients and in 160 controls. We observed that a common MC1R variant p.V92M (rs2228479), not related to pigmentation traits, was present in 72 (14%) patients and 15 (9%) controls and confers increased risk of developing LOAD (OR: 1.99, 95% CI: 1.08-3.64, p = 0.026), especially in those patients whose genetic risk could not be explained by APOE genotype. This association remains and even increased in the subset of 69 patients with typical AD cerebrospinal fluid profile (OR: 3.40 95% CI: 1.40-8.27, p = 0.007). We did not find an association between p.V92M and age of onset of AD. Further studies are necessary to elucidate the role of MC1R in brain cells through the different MC1R pathways.

%B J Alzheimers Dis %V 56 %P 1065-1074 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059796?dopt=Abstract %R 10.3233/JAD-161113 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer's Disease Brains. %A Haddick, Patrick C G %A Larson, Jessica L %A Rathore, Nisha %A Bhangale, Tushar R %A Phung, Qui T %A Srinivasan, Karpagam %A Hansen, David V %A Lill, Jennie R %A Pericak-Vance, Margaret A %A Haines, Jonathan %A Farrer, Lindsay A %A Kauwe, John S %A Schellenberg, Gerard D %A Cruchaga, Carlos %A Goate, Alison M %A Behrens, Timothy W %A Watts, Ryan J %A Graham, Robert R %A Kaminker, Joshua S %A van der Brug, Marcel %X

The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer's disease subjects in an IL6R allele dependent manner. We conducted a screen to identify variants associated with the age of onset of Alzheimer's disease in APOE ɛ4 carriers. Across five datasets, p.D358A had a meta P = 3 ×10-4 and an odds ratio = 1.3, 95% confidence interval 1.12 -1.48. Our study suggests that a common coding region variant of the IL-6 receptor results in neuroinflammatory changes that may influence the age of onset of Alzheimer's disease in APOE ɛ4 carriers.

%B J Alzheimers Dis %V 56 %P 1037-1054 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106546?dopt=Abstract %R 10.3233/JAD-160524 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Comparison of Gait Parameters for Predicting Cognitive Decline: The Mayo Clinic Study of Aging. %A Savica, Rodolfo %A Wennberg, Alexandra M V %A Hagen, Clinton %A Edwards, Kelly %A Roberts, Rosebud O %A Hollman, John H %A Knopman, David S %A Boeve, Bradley F %A Machulda, Mary M %A Petersen, Ronald C %A Mielke, Michelle M %X

BACKGROUND: Previous studies reported that slower gait speed might predict cognitive impairment and dementing illnesses, supporting the role of gait speed as a possible subclinical marker of cognitive impairment. However, the predictive value of other gait parameters for cognitive decline is unclear.

OBJECTIVE: To investigate and compare the association with, and prediction of, specific gait parameters for cognition in a population-based sample.

METHODS: The analysis included 3,426 cognitively normal participants enrolled in the Mayo Clinic Study of Aging. At baseline and every 15 months (mean follow-up = 1.93 years), participants had a study coordinator evaluation, neurological examination, and a neuropsychological assessment using nine tests that covered four domains. Gait parameters were assessed with the GAITRite® instrument. General linear mixed effects models were used to compute the annualized rate of change in cognitive domain z-scores, controlling for age, sex, education, depression, comorbidities, body mass index, APOE ɛ4 allele, and visit number, and excluding individuals with a history of stroke, alcoholism, Parkinson's disease, subdural hematoma, and normal pressure hydrocephalus.

RESULTS: Spatial (stride length), temporal (ambulatory time, gait speed, step count, cadence, double support time), and spatiotemporal (cadence) gait parameters, and greater intraindividual variability in stride length, swing time, and stance time were associated with a significant decline in global cognition and in specific domains including memory, executive function, visuospatial, and language.

CONCLUSIONS: Spatial, temporal, and spatiotemporal measures of gait and greater variability of gait parameters were associated with and predictive of both global- and domain-specific cognitive decline.

%B J Alzheimers Dis %V 55 %P 559-567 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662317?dopt=Abstract %R 10.3233/JAD-160697 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Comprehensive Quantitative Profiling of Tau and Phosphorylated Tau Peptides in Cerebrospinal Fluid by Mass Spectrometry Provides New Biomarker Candidates. %A Russell, Claire L %A Mitra, Vikram %A Hansson, Karl %A Blennow, Kaj %A Gobom, Johan %A Zetterberg, Henrik %A Hiltunen, Mikko %A Ward, Malcolm %A Pike, Ian %X

Aberrant tau phosphorylation is a hallmark in Alzheimer's disease (AD), believed to promote formation of paired helical filaments, the main constituent of neurofibrillary tangles in the brain. While cerebrospinal fluid (CSF) levels of total tau and tau phosphorylated at threonine residue 181 (pThr181) are established core biomarkers for AD, the value of alternative phosphorylation sites, which may have more direct relevance to pathology, for early diagnosis is not yet known, largely due to their low levels in CSF and lack of standardized detection methods. To overcome sensitivity limitations for analysis of phosphorylated tau in CSF, we have applied an innovative mass spectrometry (MS) workflow, TMTcalibratortrademark, to enrich and enhance the detection of phosphoproteome components of AD brain tissue in CSF, and enable the quantitation of these analytes. We aimed to identify which tau species present in the AD brain are also detectable in CSF and which, if any, are differentially regulated with disease. Over 75% coverage of full-length (2N4R) tau was detected in the CSF with 47 phosphopeptides covering 31 different phosphorylation sites. Of these, 11 phosphopeptides were upregulated by at least 40%, along with an overall increase in tau levels in the CSF of AD patients relative to controls. Use of the TMTcalibratortrademark workflow dramatically improved our ability to detect tau-derived peptides that are directly related to human AD pathology. Further validation of regulated tau peptides as early biomarkers of AD is warranted and is currently being undertaken.

%B J Alzheimers Dis %V 55 %P 303-313 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636850?dopt=Abstract %R 10.3233/JAD-160633 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cortical Cerebral Microinfarcts on 3 Tesla MRI in Patients with Vascular Cognitive Impairment. %A Ferro, Doeschka A %A van Veluw, Susanne J %A Koek, Huiberdina L %A Exalto, Lieza G %A Biessels, Geert Jan %X

BACKGROUND: Cerebral microinfarcts (CMIs) are small ischemic lesions that are a common neuropathological finding in patients with stroke or dementia. CMIs in the cortex can now be detected in vivo on 3 Tesla MRI.

OBJECTIVE: To determine the occurrence of CMIs and associated clinical features in patients with possible vascular cognitive impairment (VCI).

METHOD: 182 memory-clinic patients (mean age 71.4±10.6, 55% male) with vascular injury on brain MRI (i.e., possible VCI) underwent a standardized work-up including 3 Tesla MRI and cognitive assessment. A control group consisted of 70 cognitively normal subjects (mean age 70.6±4.7, 60% male). Cortical CMIs and other neuroimaging markers of vascular brain injury were rated according to established criteria.

RESULT: Occurrence of CMIs was higher (20%) in patients compared to controls (10%). Among patients, the presence of CMIs was associated with male sex, history of stroke, infarcts, and white matter hyperintensities. CMI presence was also associated with a diagnosis of vascular dementia and reduced performance in multiple cognitive domains.

CONCLUSION: CMIs on 3 Tesla MRI are common in patients with possible VCI and co-occur with imaging markers of small and large vessel disease, likely reflecting a heterogeneous etiology. CMIs are associated with worse cognitive performance, independent of other markers of vascular brain injury.

%B J Alzheimers Dis %V 60 %P 1443-1450 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036822?dopt=Abstract %R 10.3233/JAD-170481 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cortical Iron Reflects Severity of Alzheimer's Disease. %A van Duijn, Sara %A Bulk, Marjolein %A van Duinen, Sjoerd G %A Nabuurs, Rob J A %A van Buchem, Mark A %A van der Weerd, Louise %A Natté, Remco %X

Abnormal iron distribution in the isocortex is increasingly recognized as an in vivo marker for Alzheimer's disease (AD). However, the contribution of iron accumulation to the AD pathology is still poorly understood. In this study, we investigated: 1) frontal cortical iron distribution in AD and normal aging and 2) the relation between iron distribution and degree of AD pathology. We used formalin fixed paraffin embedded frontal cortex from 10 AD patients, 10 elder, 10 middle aged, and 10 young controls and visualized iron with a modified Perl's histochemical procedure. AD and elderly subjects were not different with respect to age and sex distribution. Iron distribution in the frontal cortex was not affected by normal aging but was clearly different between AD and controls. AD showed accumulation of iron in plaques, activated microglia, and, in the most severe cases, in the mid-cortical layers along myelinated fibers. The degree of altered iron accumulations was correlated to the amount of amyloid-β plaques and tau pathology in the same block, as well as to Braak stage (p < 0.001). AD and normal aging show different iron and myelin distribution in frontal cortex. These changes appear to occur after the development of the AD pathological hallmarks. These findings may help the interpretation of high resolution in vivo MRI and suggest the potential of using changes in iron-based MRI contrast to indirectly determine the degree of AD pathology in the frontal cortex.

%B J Alzheimers Dis %V 60 %P 1533-1545 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29081415?dopt=Abstract %R 10.3233/JAD-161143 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cross-Sectional and Longitudinal Cognitive Correlates of FDDNP PET and CSF Amyloid-β and Tau in Parkinson's Disease1. %A Buongiorno, Mariateresa %A Antonelli, Francesca %A Compta, Yaroslau %A Fernandez, Yolanda %A Pavía, Javier %A Lomeña, Francisco %A Ríos, José %A Ramírez, Isabel %A García, José Ramón %A Soler, Marina %A Cámara, Ana %A Fernández, Manel %A Basora, Misericòrdia %A Salazar, Fàtima %A Sanchez-Etayo, Gerard %A Valldeoriola, Francesc %A Barrio, Jorge Raúl %A Marti, Maria Jose %X

Tau and amyloid-β (Aβ) aggregates have been suggested to play a role in the development of dementia in Parkinson's disease (PD). Positron emission tomography (PET) with [18F]FDDNP and the determination of cerebrospinal fluid (CSF) levels of these proteins constitute a means to visualize in vivo Aβ and tau brain accumulation. Information about longitudinal changes of these CSF and PET biomarkers in PD with regard to progression to dementia is lacking. We assessed the cross-sectional and longitudinal associations of CSF and PET biomarkers of tau and Aβ with PD-related cognitive dysfunction in 6 healthy-controls (HC), 16 patients with PD without dementia (PDND), and 8 PD with dementia (PDD). All subjects underwent comprehensive neuropsychological testing, [18F]FDDNP PET, and CSF Aβ-tau determination. After 18 months, the PDND group was re-assessed clinically and by neuropsychological, PET, and CSF determinations. Cross-sectionally, PDD had higher [18F]FDDNP binding in lateral temporal regions and lower levels of CSF Aβ levels compared to PDND, with a congruent correlation between the [18F]FDDNP binding and CSF Aβ levels. Longitudinally, higher baseline lateral temporal [18F]FDDNP binding was associated to longitudinal worsening in cognitive performances and progression to dementia among subjects classified as PDND at baseline, who additionally disclosed at follow-up an increase in lateral-temporal FDDNP binding, as well as a reduction in CSF Aβ and an increase in CSF tau levels. These results confirm the relevance of these CSF and PET biomarkers to PDD, being specifically the first to show [18F]FDDNP PET as a dementia risk biomarker in PD, along with longitudinal CSF and PET changes over time.

%B J Alzheimers Dis %V 55 %P 1261-1272 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27814297?dopt=Abstract %R 10.3233/JAD-160698 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Cross-Validation of FDG- and Amyloid-PET Biomarkers in Mild Cognitive Impairment for the Risk Prediction to Dementia due to Alzheimer's Disease in a Clinical Setting. %A Iaccarino, Leonardo %A Chiotis, Konstantinos %A Alongi, Pierpaolo %A Almkvist, Ove %A Wall, Anders %A Cerami, Chiara %A Bettinardi, Valentino %A Gianolli, Luigi %A Nordberg, Agneta %A Perani, Daniela %X

Assessments of brain glucose metabolism (18F-FDG-PET) and cerebral amyloid burden (11C-PiB-PET) in mild cognitive impairment (MCI) have shown highly variable performances when adopted to predict progression to dementia due to Alzheimer's disease (ADD). This study investigates, in a clinical setting, the separate and combined values of 18F-FDG-PET and 11C-PiB-PET in ADD conversion prediction with optimized data analysis procedures. Respectively, we investigate the accuracy of an optimized SPM analysis for 18F-FDG-PET and of standardized uptake value ratio semiquantification for 11C-PiB-PET in predicting ADD conversion in 30 MCI subjects (age 63.57±7.78 years). Fourteen subjects converted to ADD during the follow-up (median 26.5 months, inter-quartile range 30 months). Receiver operating characteristic analyses showed an area under the curve (AUC) of 0.89 and of 0.81 for, respectively, 18F-FDG-PET and 11C-PiB-PET. 18F-FDG-PET, compared to 11C-PiB-PET, showed higher specificity (1.00 versus 0.62, respectively), but lower sensitivity (0.79 versus 1.00). Combining the biomarkers improved classification accuracy (AUC = 0.96). During the follow-up time, all the MCI subjects positive for both PET biomarkers converted to ADD, whereas all the subjects negative for both remained stable. The difference in survival distributions was confirmed by a log-rank test (p = 0.002). These results indicate a very high accuracy in predicting MCI to ADD conversion of both 18F-FDG-PET and 11C-PiB-PET imaging, the former showing optimal performance based on the SPM optimized parametric assessment. Measures of brain glucose metabolism and amyloid load represent extremely powerful diagnostic and prognostic biomarkers with complementary roles in prodromal dementia phase, particularly when tailored to individual cases in clinical settings.

%B J Alzheimers Dis %V 59 %P 603-614 %G eng %N 2 %R 10.3233/JAD-170158 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Curcumin Ameliorates Neuroinflammation, Neurodegeneration, and Memory Deficits in p25 Transgenic Mouse Model that Bears Hallmarks of Alzheimer's Disease. %A Sundaram, Jeyapriya Raja %A Poore, Charlene Priscilla %A Sulaimee, Noor Hazim Bin %A Pareek, Tej %A Cheong, Wei Fun %A Wenk, Markus R %A Pant, Harish C %A Frautschy, Sally A %A Low, Chian-Ming %A Kesavapany, Sashi %X

Several studies have indicated that neuroinflammation is indeed associated with neurodegenerative disease pathology. However, failures of recent clinical trials of anti-inflammatory agents in neurodegenerative disorders have emphasized the need to better understand the complexity of the neuroinflammatory process in order to unravel its link with neurodegeneration. Deregulation of Cyclin-dependent kinase 5 (Cdk5) activity by production of its hyperactivator p25 is involved in the formation of tau and amyloid pathology reminiscent of Alzheimer's disease (AD). Recent studies show an association between p25/Cdk5 hyperactivation and robust neuroinflammation. In addition, we recently reported the novel link between the p25/Cdk5 hyperactivation-induced inflammatory responses and neurodegenerative changes using a transgenic mouse that overexpresses p25 (p25Tg). In this study, we aimed to understand the effects of early intervention with a potent natural anti-inflammatory agent, curcumin, on p25-mediated neuroinflammation and the progression of neurodegeneration in p25Tg mice. The results from this study showed that curcumin effectively counteracted the p25-mediated glial activation and pro-inflammatory chemokines/cytokines production in p25Tg mice. Moreover, this curcumin-mediated suppression of neuroinflammation reduced the progression of p25-induced tau/amyloid pathology and in turn ameliorated the p25-induced cognitive impairments. It is widely acknowledged that to treat AD, one must target the early-stage of pathological changes to protect neurons from irreversible damage. In line with this, our results demonstrated that early intervention of inflammation could reduce the progression of AD-like pathological outcomes. Moreover, our data provide a rationale for the potential use of curcuminoids in the treatment of inflammation associated neurodegenerative diseases.

%B J Alzheimers Dis %V 60 %P 1429-1442 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036814?dopt=Abstract %R 10.3233/JAD-170093 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Curcumin Inhibits Tau Aggregation and Disintegrates Preformed Tau Filaments in vitro. %A Rane, Jitendra Subhash %A Bhaumik, Prasenjit %A Panda, Dulal %X

The pathological aggregation of tau is a common feature of most of the neuronal disorders including frontotemporal dementia, Parkinson's disease, and Alzheimer's disease. The inhibition of tau aggregation is considered to be one of the important strategies for treating these neurodegenerative diseases. Curcumin, a natural polyphenolic molecule, has been reported to have neuroprotective ability. In this work, curcumin was found to bind to adult tau and fetal tau with a dissociation constant of 3.3±0.4 and 8±1 μM, respectively. Molecular docking studies indicated a putative binding site of curcumin in the microtubule-binding region of tau. Using several complementary techniques, including dynamic light scattering, thioflavin S fluorescence, 90° light scattering, electron microscopy, and atomic force microscopy, curcumin was found to inhibit the aggregation of tau. The dynamic light scattering analysis and atomic force microscopic images revealed that curcumin inhibits the oligomerization of tau. Curcumin also disintegrated preformed tau oligomers. Using Far-UV circular dichroism, curcumin was found to inhibit the β-sheets formation in tau indicating that curcumin inhibits an initial step of tau aggregation. In addition, curcumin inhibited tau fibril formation. Furthermore, the effect of curcumin on the preformed tau filaments was analyzed by atomic force microscopy, transmission electron microscopy, and 90° light scattering. Curcumin treatment disintegrated preformed tau filaments. The results indicated that curcumin inhibited the oligomerization of tau and could disaggregate tau filaments.

%B J Alzheimers Dis %V 60 %P 999-1014 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984591?dopt=Abstract %R 10.3233/JAD-170351 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Current Approaches and Clinician Attitudes to the Use of Cerebrospinal Fluid Biomarkers in Diagnostic Evaluation of Dementia in Europe. %A Miller, Anne-Marie %A Balasa, Mircea %A Blennow, Kaj %A Gardiner, Mary %A Rutkowska, Aleksandra %A Scheltens, Philip %A Teunissen, Charlotte E %A Visser, Pieter Jelle %A Winblad, Bengt %A Waldemar, Gunhild %A Lawlor, Brian %X

BACKGROUND: BIOMARKAPD seeks to diminish the barriers associated with the clinical use of cerebrospinal fluid (CSF) biomarker analysis by reducing variation in CSF laboratory methodologies and generating consensus recommendations on their clinical interpretation and application for dementia diagnosis.

OBJECTIVE: To examine the disparity in practitioner attitudes and clinical practice relating to the use of CSF biomarkers for dementia diagnosis across Europe.

METHODS: Clinical dementia experts were surveyed on the prevalence of national consensus guidelines and analytical reimbursement across Europe, their biomarker platform preferences, lumbar puncture methodologies and application of reference values and cut-offs for CSF analysis.

RESULTS: 74% of respondents (total n = 51) use CSF biomarkers in clinical practice and 69% perform lumbar punctures on an outpatient basis. Most use CSF biomarkers to diagnose atypical (84%) and early-onset cases of cognitive impairment (71%) and for the differential diagnosis of other dementias (69%). 82% state they are sufficiently informed about CSF biomarkers yet 61% report a lack of national consensus guidelines on their use for dementia diagnosis. 48% of countries represented do not reimburse clinical CSF analysis costs. 43% report using normal reference ranges derived from publications.

CONCLUSION: Variations in attitude and practice relating to CSF biomarkers, widely recognised as barriers to their clinical acceptance, remain evident within and between countries across Europe, even in expert centres. These shortcomings must be addressed by developing consensus guidelines on CSF-related methodologies and their clinical application, to further their use for the diagnostic evaluation of dementia.

%B J Alzheimers Dis %V 60 %P 201-210 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826189?dopt=Abstract %R 10.3233/JAD-170502 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Damage to the Frontal Aslant Tract Accounts for Visuo-Constructive Deficits in Alzheimer's Disease. %A Serra, Laura %A Gabrielli, Giulia Bechi %A Tuzzi, Elisa %A Spanò, Barbara %A Giulietti, Giovanni %A Failoni, Virginia %A Marra, Camillo %A Caltagirone, Carlo %A Koch, Giacomo %A Cercignani, Mara %A Bozzali, Marco %X

The frontal aslant tract (FAT) has been described as a bundle connecting the Broca's area to the supplementary motor area (SMA) and the pre-SMA in both hemispheres. The functional properties of this tract and its role in degenerative dementia, such as Alzheimer's disease (AD), still need to be fully clarified. The aim of this study was to explore the microstructural integrity of the FAT in patients with AD and its potential relationship with cognitive functioning. Twenty-three patients with AD and 25 healthy subjects (HS) were enrolled. All subjects underwent cognitive and MRI examination. MRI, including diffusion sequences, was used for probabilistic tractography analysis. We reconstructed individual FATs bilaterally and assessed their microstructural integrity using fractional anisotropy (FA), computed as both mean tract value and voxel-wise using SPM-8. Mean FA values were then used to test for correlations with cognitive measures. Mean tract FA and voxel-wise analyses revealed that patients with AD, compared to HS, had decreased FA in the FAT bilaterally. In addition, positive associations were found between FA in the FATs and patients' performance at tests for constructional praxis and visuospatial logical reasoning. The present results reveal a bilateral damage of FAT in AD patients. The association between FATs' microscopic abnormalities and constructive abilities fits well with the knowledge of a functional involvement of SMA and pre-SMA in movement sequences when executing constructive praxis tasks. The FAT is an associative bundle critically involved in the network sub-serving constructional praxis in patients with AD.

%B J Alzheimers Dis %V 60 %P 1015-1024 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984608?dopt=Abstract %R 10.3233/JAD-170638 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Decreased Glucose Metabolism in Medial Prefrontal Areas is Associated with Nutritional Status in Patients with Prodromal and Early Alzheimer's Disease. %A Sugimoto, Taiki %A Nakamura, Akinori %A Kato, Takashi %A Iwata, Kaori %A Saji, Naoki %A Arahata, Yutaka %A Hattori, Hideyuki %A Bundo, Masahiko %A Ito, Kengo %A Niida, Shumpei %A Sakurai, Takashi %X

BACKGROUND: Weight loss is frequently observed in patients with Alzheimer's disease (AD); however, the underlying mechanisms are not well understood.

OBJECTS: To clarify the associations between nutritional status and AD-related brain changes using Pittsburgh Compound-B (PiB)-PET, fluorodeoxyglucose (FDG)-PET, and structural MRI.

METHODS: The subjects were 34 amyloid-β (Aβ)-positive individuals with mild cognitive impairment or early AD (prodromal/early AD), and 55 Aβ-negative cognitively normal (CN) subjects who attended the Multimodal Neuroimaging for AD Diagnosis (MULNIAD) study. Nutritional status of the subjects was assessed by body mass index and waist to height ratio (waist circumference/height). The associations between nutritional status and brain changes were examined by multiple regression analysis using statistical parametric mapping.

RESULTS: In the prodromal/early AD group, nutritional status was significantly positively correlated with regional cerebral glucose metabolism (rCGM) in the medial prefrontal cortices, while different topographical associations were seen in the CN group, suggesting these changes were AD-specific. Aβ deposition and gray matter volume were not significantly associated with nutritional status. Sub-analysis in the prodromal/early AD group demonstrated that fat mass index, but not fat-free mass index, was positively correlated with rCGM in the medial prefrontal areas.

CONCLUSION: This present study provides preliminary results suggesting that hypometabolism in the medial prefrontal areas is specifically associated with AD-related weight loss, and decrease in fat mass may have a key role.

%B J Alzheimers Dis %V 60 %P 225-233 %G eng %N 1 %R 10.3233/JAD-170257 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Deep Brain Stimulation for Alzheimer's Disease: Ethical Challenges for Clinical Research. %A Siegel, Andrew M %A Barrett, Marna S %A Bhati, Mahendra T %X

Deep brain stimulation (DBS) is an invasive neuromodulation modality that has shown early promise as a novel treatment of Alzheimer's disease (AD). Further clinical research is warranted on the basis of positive results from animal and human studies, as well as the inadequacy of existing treatments in reducing the enormous medical and financial costs of untreated AD. Nevertheless, unique ethical challenges require particular attention to elements of subject enrollment and informed consent. Study protocols should specify robust assessment and regular monitoring of subject decision-making capacity to consent to trial participation. Investigators should also assess for and mitigate therapeutic misconception (the phenomenon whereby a research participant conflates the goals of research with those of clinical treatment) and ensure that all prospective trial participants have adequate post-trial access to treatment and DBS device maintenance. In the following discussion, each issue is summarized and followed by recommendations for proper ethical procedure. We conclude by assimilating relevant ethical considerations into a decision-making algorithm designed to aid future clinical investigators of DBS for AD with the task of ethical subject enrollment.

%B J Alzheimers Dis %V 56 %P 429-439 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27983548?dopt=Abstract %R 10.3233/JAD-160356 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Deficit in Central Auditory Processing as a Biomarker of Pre-Clinical Alzheimer's Disease. %A Tuwaig, Miranda %A Savard, Mélissa %A Jutras, Benoît %A Poirier, Judes %A Collins, D Louis %A Rosa-Neto, Pedro %A Fontaine, David %A Breitner, John C S %X

Prevention of dementia due to Alzheimer's disease (d/AD) requires interventions that slow the disease process prior to symptom onset. To develop such interventions, one needs metrics that assess pre-symptomatic disease progression. Familiar measures of progression include cerebrospinal fluid (CSF) biochemical and imaging analyses, as well as cognitive testing. Changes in the latter can sometimes be difficult to distinguish from effects of "normal" aging. A different approach involves testing of "central auditory processing" (CAP), which enables comprehension of auditory stimuli amidst a distracting background (e.g., conversation in a noisy bar or restaurant). Such comprehension is often impaired in d/AD. Similarly, effortful or diminished auditory comprehension is sometimes reported by cognitively healthy elders, raising the possibility that CAP deficit may be a marker of pre-symptomatic AD. In 187 cognitively and physically healthy members of the aging, AD family history-positive PREVENT-AD cohort, we therefore evaluated whether CAP deficits were associated with known markers of AD neurodegeneration. Such markers included CSF tau concentrations and magnetic resonance imaging volumetric and cortical thickness measures in key AD-related regions. Adjusting for age, sex, education, pure-tone hearing, and APOEɛ4 status, we observed a persistent relationship between CAP scores and CSF tau levels, entorhinal and hippocampal cortex volumes, cortical thickness, and deficits in cognition (Repeatable Battery for Assessment of Neuropsychological Status total score, and several of its index scales). These cross-sectional observations suggest that CAP may serve as a novel metric for pre-symptomatic AD pathogenesis. They are therefore being followed up longitudinally with larger samples.

%B J Alzheimers Dis %V 60 %P 1589-1600 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984583?dopt=Abstract %R 10.3233/JAD-170545 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Delayed Recall and Working Memory MMSE Domains Predict Delirium following Cardiac Surgery. %A Price, Catherine C %A Garvan, Cynthia %A Hizel, Loren P %A Lopez, Marcos G %A Billings, Frederic T %X

BACKGROUND: Reduced preoperative cognition is a risk factor for postoperative delirium. The significance for type of preoperative cognitive deficit, however, has yet to be explored and could provide important insights into mechanisms and prediction of delirium.

OBJECTIVE: Our goal was to determine if certain cognitive domains from the general cognitive screener, the Mini-Mental State Exam (MMSE), predict delirium after cardiac surgery.

METHODS: Patients completed a preoperative MMSE prior to undergoing elective cardiac surgery. Following surgery, delirium was assessed throughout ICU stay using the Confusion Assessment Method for ICU delirium and the Richmond Agitation and Sedation Scale.

RESULTS: Cardiac surgery patients who developed delirium (n = 137) had lower total MMSE scores than patients who did not develop delirium (n = 457). In particular, orientation to place, working memory, delayed recall, and language domain scores were lower. Of these, only the working memory and delayed recall domains predicted delirium in a regression model adjusting for history of chronic obstructive pulmonary disease, age, sex, and duration of cardiopulmonary bypass. For each word not recalled on the three-word delayed recall assessment, the odds of delirium increased by 50%. For each item missed on the working memory index, the odds of delirium increased by 36%. Of the patients who developed delirium, 47% had a primary impairment in memory, 21% in working memory, and 33% in both domains. The area under the receiver operating characteristics curve using only the working memory and delayed recall domains was 0.75, compared to 0.76 for total MMSE score.

CONCLUSION: Delirium risk is greater for individuals with reduced MMSE scores on the delayed recall and working memory domains. Research should address why patients with memory and executive vulnerabilities are more prone to postoperative delirium than those with other cognitive limitations.

%B J Alzheimers Dis %V 59 %P 1027-1035 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697572?dopt=Abstract %R 10.3233/JAD-170380 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Depressive Symptoms and Tau Accumulation in the Inferior Temporal Lobe and Entorhinal Cortex in Cognitively Normal Older Adults: A Pilot Study. %A Gatchel, Jennifer R %A Donovan, Nancy J %A Locascio, Joseph J %A Schultz, Aaron P %A Becker, J Alex %A Chhatwal, Jasmeer %A Papp, Kathryn V %A Amariglio, Rebecca E %A Rentz, Dorene M %A Blacker, Deborah %A Sperling, Reisa A %A Johnson, Keith A %A Marshall, Gad A %X

BACKGROUND: Depressive symptoms are common in older adults and associated with increased morbidity and cognitive decline. These symptoms occur during preclinical and prodromal stages of Alzheimer's disease (AD), but their relationship to tau, one of the main AD proteinopathies, is poorly understood.

OBJECTIVE: The objective of this study was to investigate the cross-sectional association between depressive symptoms and cerebral tau [18F T807 (also known as 18F-AV-1451) tau positron emission tomography (PET) imaging] in cognitively normal (CN) older adults.

METHODS: We measured depressive symptoms using the Geriatric Depression Scale (GDS), and in vivo cerebral tau using T807 PET in 111 CN older adults. We employed general linear regression models to evaluate the relationship of GDS score regressed on entorhinal cortex (EC) or inferior temporal (IT) tau in separate backward elimination models. Other predictors included age, sex, and in secondary analyses, amyloid (Pittsburgh Compound B PET).

RESULTS: Higher GDS was significantly associated with greater IT tau (partial r = 0.188, p = 0.050) and marginally associated with greater EC tau (partial r = 0.183, p = 0.055). In additional analyses including both linear and quadratic age terms, we found a significant U-shaped relation of GDS to age (p = 0.001).

CONCLUSIONS: Results suggest that IT and EC tau are modestly associated with depressive symptoms in CN older adults. Findings suggest a link between depressive symptoms and tau-mediated neurodegeneration in a region vulnerable in AD. Future longitudinal studies examining the association of more severe depressive symptoms and cerebral tau accumulation are needed to substantiate this finding and to guide prevention and treatment in AD.

%B J Alzheimers Dis %V 59 %P 975-985 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697559?dopt=Abstract %R 10.3233/JAD-170001 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Detecting At-Risk Alzheimer's Disease Cases. %A Fladby, Tormod %A Pålhaugen, Lene %A Selnes, Per %A Waterloo, Knut %A Bråthen, Geir %A Hessen, Erik %A Almdahl, Ina Selseth %A Arntzen, Kjell-Arne %A Auning, Eirik %A Eliassen, Carl Fredrik %A Espenes, Ragna %A Grambaite, Ramune %A Grøntvedt, Gøril Rolfseng %A Johansen, Krisztina Kunszt %A Johnsen, Stein Harald %A Kalheim, Lisa Flem %A Kirsebom, Bjørn-Eivind %A Müller, Kai Ivar %A Nakling, Arne Exner %A Rongve, Arvid %A Sando, Sigrid Botne %A Siafarikas, Nikias %A Stav, Ane Løvli %A Tecelao, Sandra %A Timon, Santiago %A Bekkelund, Svein Ivar %A Aarsland, Dag %X

While APOEɛ4 is the major genetic risk factor for Alzheimer's disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aβ42 (pAβ) and APOEɛ4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pAβ and APOEɛ4 frequency compared to NC. Also, NCFD had higher APOEɛ4 frequencies without increased fraction of pAβ compared to NC, and cases recruited from memory clinics had higher fractions of pAβ and APOEɛ4 frequency than self-referred. This study shows that memory clinic referrals are pAβ enriched, whereas self-referred and NCFD cases more frequently are pAβ negative but at risk (APOEɛ4 positive), suitable for primary intervention.

%B J Alzheimers Dis %V 60 %P 97-105 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826181?dopt=Abstract %R 10.3233/JAD-170231 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Development of Nasal Lipid Nanocarriers Containing Curcumin for Brain Targeting. %A Vaz, Gustavo Richter %A Hädrich, Gabriela %A Bidone, Juliana %A Rodrigues, Jamile Lima %A Falkembach, Mariana Corrêa %A Putaux, Jean-Luc %A Hort, Mariana Appel %A Monserrat, José Maria %A Varela Junior, Antônio Sergio %A Teixeira, Helder Ferreira %A Muccillo-Baisch, Ana Luiza %A Horn, Ana Paula %A Dora, Cristiana Lima %X

BACKGROUND: Curcumin (CUR) has properties that can be useful for the treatment of Alzheimer's disease. Such properties are the inhibition of amyloid-β-protein (Aβ) aggregation, Aβ-induced inflammation, and activities of β-secretase and acetylcholinesterase. However, previous studies have revealed that CUR exhibited low bioavailability and difficulties in reaching the brain.

OBJECTIVE: To overcome such drawbacks, this study aims at developing nasal lipid nanocarriers loaded with CUR to effectively target the brain.

METHODS: The lipid nanocarriers (NE) were prepared using the hot solvent diffusion associated with the phase inversion temperature methods. Physico-chemical and morphological characterizations and in vitro drug release of the nanocarriers were carried out. The CUR permeation/retention was analyzed in Franz-type diffusion cell using porcine nasal mucosa. Confocal laser scan and histopathological studies were also performed.

RESULTS: The results showed that the NE sizes ranged between 18 nm and 44 nm with negative zeta potential. The CUR content ranged from 0.24 to 1.50 mg/mL with an encapsulation efficiency of 99%. The profiles of CUR release indicated a biphasic kinetics. CUR-NE permeation across the porcine nasal mucosa was higher when compared to free CUR. These results have also been validated through an analysis on a confocal microscopy. In addition, no toxicity on the nasal mucosa has been observed in a histopathological analysis.

CONCLUSION: These results suggest that it is possible to develop NEs with a high content of CUR and small particle size. Such an encapsulation increases the potential of CUR permeation across the porcine nasal mucosa.

%B J Alzheimers Dis %V 59 %P 961-974 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731428?dopt=Abstract %R 10.3233/JAD-160355 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Diagnostic and Prognostic Value of Neuropsychological Assessment in Memory Clinic Patients. %A Jansen, Willemijn J %A Handels, Ron L H %A Visser, Pieter Jelle %A Aalten, Pauline %A Bouwman, Femke %A Claassen, Jurgen %A van Domburg, Peter %A Hoff, Erik %A Hoogmoed, Jan %A Leentjens, Albert F G %A Rikkert, Marcel Olde %A Oleksik, Ania M %A Smid, Machiel %A Scheltens, Philip %A Wolfs, Claire %A Verhey, Frans %A Ramakers, Inez H G B %X

BACKGROUND: Neuropsychological testing has long been embedded in daily clinical practice at memory clinics but the added value of a complete neuropsychological assessment (NPA) to standard clinical evaluation is unknown.

OBJECTIVE: To evaluate the added diagnostic and prognostic value of NPA to clinical evaluation only in memory clinic patients.

METHODS: In 221 memory clinic patients of a prospective cohort study, clinical experts diagnosed clinical syndrome (subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or dementia) and etiology (Alzheimer's disease (AD) or no AD), and provided a prognosis of disease course (decline or no decline) before and after results of NPA were made available. The reference standard was a panel consensus based on all clinical information at baseline and up to 2 follow-up assessments.

RESULTS: With NPA data available, clinicians changed their initial syndromal diagnosis in 22% of patients, and the etiological diagnosis as well as the prognosis in 15%. This led to an increase in correctly classified cases of 18% for syndromal diagnosis, 5% for etiological diagnosis, and 1% for prognosis. NPA data resulted in the largest improvement in patients initially classified as SCI (syndrome: 93.3% (n = 14) correctly reclassified, etiology: net reclassification improvement [NRI] = 0.61, prognosis: NRI = 0.13) or MCI (syndrome: 89.3% (n = 23) correctly reclassified, etiology: NRI = 0.17, prognosis: NRI = 0.14), while there was no improvement in patients with dementia (syndrome: 100% (n = 1) correctly reclassified, etiology: NRI = -0.05, prognosis: NRI = -0.06). Overall, inclusion of NPA in the diagnostic process increased confidence in all diagnoses with 6-7%.

CONCLUSION: Administration of a complete NPA after standard clinical evaluation has added value for diagnosing cognitive syndrome and its underlying etiology in patients regarded as non-demented based on the first clinical impression.

%B J Alzheimers Dis %V 55 %P 679-689 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716658?dopt=Abstract %R 10.3233/JAD-160126 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Diagnostic and Prognostic Value of the Combination of Two Measures of Verbal Memory in Mild Cognitive Impairment due to Alzheimer's Disease. %A Sala, Isabel %A Illán-Gala, Ignacio %A Alcolea, Daniel %A Sánchez-Saudinós, Ma Belén %A Salgado, Sergio Andrés %A Morenas-Rodriguez, Estrella %A Subirana, Andrea %A Videla, Laura %A Clarimón, Jordi %A Carmona-Iragui, María %A Ribosa-Nogué, Roser %A Blesa, Rafael %A Fortea, Juan %A Lleo, Alberto %X

BACKGROUND: Episodic memory impairment is the core feature of typical Alzheimer's disease.

OBJECTIVE: To evaluate the performance of two commonly used verbal memory tests to detect mild cognitive impairment due to Alzheimer's disease (MCI-AD) and to predict progression to Alzheimer's disease dementia (AD-d).

METHODS: Prospective study of MCI patients in a tertiary memory disorder unit. Patients underwent an extensive neuropsychological battery including two tests of declarative verbal memory: The Free and Cued Selective Reminding Test (FCSRT) and the word list learning task from the Consortium to Establish a Registry for Alzheimer's disease (CERAD-WL). Cerebrospinal fluid (CSF) was obtained from all patients and MCI-AD was defined by means of the t-Tau/Aβ1-42 ratio. Logistic regression analyses tested whether the combination of FCSRT and CERAD-WL measures significantly improved the prediction of MCI-AD. Progression to AD-d was analyzed in a Cox regression model.

RESULTS: A total of 202 MCI patients with a mean follow-up of 34.2±24.2 months were included and 98 (48.5%) met the criteria for MCI-AD. The combination of FCSRT and CERAD-WL measures improved MCI-AD classification accuracy based on CSF biomarkers. Both tests yielded similar global predictive values (59.9-65.3% and 59.4-62.8% for FCSRT and CERAD-WL, respectively). MCI-AD patients with deficits in both FCSRT and CERAD-WL had a faster progression to AD-d than patients with deficits in only one test.

CONCLUSIONS: The combination of FCSRT and CERAD-WL improves the classification of MCI-AD and defines different prognostic profiles. These findings have important implications for clinical practice and the design of clinical trials.

%B J Alzheimers Dis %V 58 %P 909-918 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527215?dopt=Abstract %R 10.3233/JAD-170073 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Diagnostic Biomarkers of Alzheimer's Disease as Identified in Saliva using 1H NMR-Based Metabolomics. %A Yilmaz, Ali %A Geddes, Tim %A Han, BeomSoo %A Bahado-Singh, Ray O %A Wilson, George %A Imam, Khaled %A Maddens, Michael %A Graham, Stewart F %X

Using 1H NMR metabolomics, we biochemically profiled saliva samples collected from healthy-controls (n = 12), mild cognitive impairment (MCI) sufferers (n = 8), and Alzheimer's disease (AD) patients (n = 9). We accurately identified significant concentration changes in 22 metabolites in the saliva of MCI and AD patients compared to controls. This pilot study demonstrates the potential for using metabolomics and saliva for the early diagnosis of AD. Given the ease and convenience of collecting saliva, the development of accurate and sensitive salivary biomarkers would be ideal for screening those at greatest risk of developing AD.

%B J Alzheimers Dis %V 58 %P 355-359 %G eng %N 2 %R 10.3233/JAD-161226 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Discovery and Confirmation of Diagnostic Serum Lipid Biomarkers for Alzheimer's Disease Using Direct Infusion Mass Spectrometry. %A Anand, Swati %A Barnes, Justin M %A Young, Sydney A %A Garcia, Diana M %A Tolley, H Dennis %A Kauwe, John S K %A Graves, Steven W %X

Alzheimer's disease (AD) is a neurodegenerative disorder lacking early biochemical diagnosis and treatment. Lipids have been implicated in neurodegenerative disorders including AD. A shotgun lipidomic approach was undertaken to determine if lipid biomarkers exist that can discriminate AD cases from controls. The discovery study involved sera from 29 different stage AD cases and 32 controls. Lipid extraction was performed using organic solvent and the samples were directly infused into a time-of-flight mass spectrometer. Differences between AD cases and controls were detected with 87 statistically significant lipid candidate markers found. These potential lipid markers were reevaluated in a second confirmatory study involving 27 cases and 30 controls. Of the 87 candidates from the first study, 35 continued to be statistically significant in the second confirmatory set. Tandem MS studies were performed and almost all confirmed markers were characterized and classified. Using a Bayesian lasso probit regression model on the confirmed markers, a multi-marker set with AUC = 0.886 was developed comparing all stages of AD with controls. Additionally, using confirmed biomarkers, multi-marker sets with AUCs >0.90 were developed for each specific AD Clinical Dementia Rating versus controls, including the earliest stage of AD. More conservative and likely more realistic statistical analyses still found multi-marker sets that appeared useful in diagnosing AD. Finally, using ordinal modeling a set of markers was developed that staged AD accurately 70% of the time, p = 0.0079. These results suggest that these serum lipidomic biomarkers may help diagnose and perhaps even stage AD.

%B J Alzheimers Dis %V 59 %P 277-290 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598845?dopt=Abstract %R 10.3233/JAD-170035 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Discriminative Properties of Hippocampal Hypoperfusion in Marijuana Users Compared to Healthy Controls: Implications for Marijuana Administration in Alzheimer's Dementia. %A Amen, Daniel G %A Darmal, Borhan %A Raji, Cyrus A %A Bao, Weining %A Jorandby, Lantie %A Meysami, Somayeh %A Raghavendra, Cauligi S %X

BACKGROUND: Few studies have evaluated the impact of marijuana use on regional cerebral blood flow.

OBJECTIVE: To determine whether perfusion in specific brain regions on functional neuroimaging, including those affected by Alzheimer's disease pathology, are abnormal in marijuana users compared to controls.

METHOD: Persons with a diagnosis of cannabis use disorder by DSM-IV and DSM-V criteria (n = 982) were compared to controls (n = 92) with perfusion neuroimaging with SPECT at rest and at a concentration task. Perfusion estimates were quantified using a standard atlas. Cerebral perfusion differences were calculated using one-way ANOVA. Diagnostic separation was determined with discriminant analysis of all subjects. Feature selection with a minimum redundancy maximum relevancy (mRMR) identified predictive regions in a subset of marijuana users (n = 436) with reduced psychiatric co-morbidities.

RESULTS: Marijuana users showed lower cerebral perfusion on average (p < 0.05). Discriminant analysis distinguished marijuana users from controls with correct classification of 96% and leave one out cross-validation of 92%. With concentration SPECT regions, there was correct classification of 95% with a leave-one-out cross validation of 90%. AUC analysis for concentration SPECT regions showed 95% accuracy, 90% sensitivity, and 83% specificity. The mRMR analysis showed right hippocampal hypoperfusion on concentration SPECT imaging was the most predictive in separating marijuana subjects from controls.

CONCLUSION: Multiple brain regions show low perfusion on SPECT in marijuana users. The most predictive region distinguishing marijuana users from healthy controls, the hippocampus, is a key target of Alzheimer's disease pathology. This study raises the possibility of deleterious brain effects of marijuana use.

%B J Alzheimers Dis %V 56 %P 261-273 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27886010?dopt=Abstract %R 10.3233/JAD-160833 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Disinhibition in Alzheimer's Disease is Associated with Reduced Right Frontal Pole Cortical Thickness. %A Finger, Elizabeth %A Zhang, Jing %A Dickerson, Bradford %A Bureau, Yves %A Masellis, Mario %X

Neuropsychiatric symptoms in Alzheimer's disease are among the most disabling and difficult aspects for caregivers and treating health professionals to manage. Despite the high prevalence of these behaviors, little is known about the factors which lead some patients to develop florid behavioral symptoms while others may progress to severe dementia without such phenomenon. We examined whether regional brain volumes as measured by cortical thickness would predict the presence or absence of disinhibition in patients with Alzheimer's disease. Using data from the ADNI, we identified 758 patients with caregiver ratings on the Neuropsychiatric Inventory and a volumetric MRI scan with cortical thickness measurements completed in FreeSurfer by the UCSF core. Of these, 177 patients were found to have disinhibition. Logistic regression models demonstrated that reduced cortical thickness in the right frontal pole was associated with the presence of disinhibition even when controlling for age, disease severity, total intracranial volume, gender, and APOE genotype. The results are considered in the context of leading models of the functions of frontopolar cortex.

%B J Alzheimers Dis %V 60 %P 1161-1170 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984590?dopt=Abstract %R 10.3233/JAD-170348 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Do Cancer Drugs Counteract Neurodegeneration? Repurposing for Alzheimer's Disease. %A Monacelli, Fiammetta %A Cea, Michele %A Borghi, Roberta %A Odetti, Patrizio %A Nencioni, Alessio %X

In spite of in depth investigations in the field of the amyloid cascade hypothesis, so far, no disease modifying therapy has been developed for Alzheimer's disease (AD). The pathophysiology provides some evidence of the inverse correlation between cancer and AD. Both AD and cancer are characterized by abnormal cellular behaviors; trigger factors along with a meta synchronously action is expected to drive cancer or neurodegeneration, supporting, respectively, progressive neuronal loss or uncontrolled cell proliferation in cancer cells. So far, cancer and AD are seemingly two opposite ends of the same biological spectrum. Basic science increasingly indicates shared molecular mechanisms between cancer and AD and gives weight to key relevant biological theories; according to them, the inverse tuning of clustered gene expression, the sharing of mutual independent pathway or the deregulated unfolded proteins system (UPR) may count for this inverse association. Additionally, the common biological background gave credibility to the recent discovery of a repurposing role for cancer drugs in AD. It refers to the development of new uses for existing pharmaceuticals having the same role as the original mechanism or to the discovery of a new drug action with disease modifying effects. The present review summarizes the most important biological theories that link neurodegeneration and cancer and provides an up-to-date revision of the repurposing cancer agents for AD. The review also addresses the gap of knowledge, since drug cancer repositioning holds an important promise but further investigations are warranted to ascertain the clinical relevance of such attractive clinical candidate compounds for AD.

%B J Alzheimers Dis %V 55 %P 1295-1306 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27834781?dopt=Abstract %R 10.3233/JAD-160840 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Do Hearing Aids Influence Behavioral and Psychological Symptoms of Dementia and Quality of Life in Hearing Impaired Alzheimer's Disease Patients and Their Caregivers? %A Adrait, Arnaud %A Perrot, Xavier %A Nguyen, Marie-France %A Gueugnon, Marine %A Petitot, Charles %A Collet, Lionel %A Roux, Adeline %A Bonnefoy, Marc %X

BACKGROUND: It has been suggested that age-related hearing loss (ARHL) and Alzheimer's disease (AD) are commonly associated.

OBJECTIVE: The Alzheimer Disease, Presbycusis and Hearing Aids (ADPHA) clinical trial assessed the influence of hearing aids (HAs) on patients affected by ARHL and AD, as judged by behavioral symptoms and functional abilities, as well as patient and caregiver quality of life (QoL).

METHODS: A multicenter double-blind randomized placebo-controlled trial, with a semi-crossover procedure over 12 months, was conducted from 2006 to 2012. For the first 6 months, the active group was treated with active HAs and the placebo group with inactive HAs. For the last 6 months, HAs in the placebo group were activated. Assessment was conducted at baseline, 6 months, and 12 months. We performed intergroup and intragroup comparisons. Behavioral symptoms were assessed by neuropsychiatric inventory (NPI), functional abilities by instrumental activities of daily living, and QoL by Zarit, Alzheimer's disease related quality of life, and simplified Duke scales.

RESULTS: Fifty-one patients were included and randomized: 22 in active group (mean NPI 17.6; mean age 83±6.2) and 26 in placebo group (mean NPI 25.8; mean age 82.3±7.2) were fitted with HAs. At 6-month follow-up, all scores worsened without significant difference between the two groups. In placebo group, activation of HAs had no effect on the change of these scores.

CONCLUSION: These findings do not provide evidence of improvement in behavioral symptoms, functional status, or QoL of hearing impaired AD patients and their caregivers after 6 months of HA use. However, we cannot exclude that HAs may have a positive effect in patients aged less than 75 years.

%B J Alzheimers Dis %V 58 %P 109-121 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269769?dopt=Abstract %R 10.3233/JAD-160792 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Does the Female Advantage in Verbal Memory Contribute to Underestimating Alzheimer's Disease Pathology in Women versus Men? %A Sundermann, Erin E %A Biegon, Anat %A Rubin, Leah H %A Lipton, Richard B %A Landau, Susan %A Maki, Pauline M %X

There is a growing recognition of sex differences in Alzheimer's disease (AD). Females show an advantage over males on tests of verbal memory, which are used to diagnose AD and its precursor, amnestic mild cognitive impairment (aMCI). Women retain this advantage in aMCI despite reduced hippocampal volume and temporal lobe glucose metabolism. Here we examined whether this female advantage endures despite evidence of AD-specific pathology, cortical amyloid-β (Aβ) deposition measured with [18F]AV45 (florbetapir) positron emission tomography. Participants with normal cognition (N = 304), aMCI (N = 515), and AD dementia (N = 175) were drawn from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Across and within diagnostic groups, we conducted linear regressions to examine the interaction of sex with cortical Aβ burden on immediate and delayed recall on the Rey Auditory Verbal Learning Test (RAVLT) adjusting for age, education, and APOE4. In the overall group, sex by cortical Aβ interaction was significant for delayed recall only. Overall, delayed recall performance was significantly better in women versus men among those with low to moderate Aβ burden, but women and men performed similarly among those with high Aβ burden. In diagnosis-stratified analyses, a significant sex by cortical Aβ interaction was observed for delayed recall in the aMCI group, but not in the normal or AD dementia groups. Thus, women maintain a verbal memory advantage over men in aMCI despite similar levels of AD pathology. Although this advantage may benefit women by delaying verbal memory impairment until more advanced pathology, it may also delay diagnosis of aMCI and treatment intervention.

%B J Alzheimers Dis %V 56 %P 947-957 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106548?dopt=Abstract %R 10.3233/JAD-160716 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Down Syndrome, Partial Trisomy 21, and Absence of Alzheimer's Disease: The Role of APP. %A Doran, Eric %A Keator, David %A Head, Elizabeth %A Phelan, Michael J %A Kim, Ron %A Totoiu, Minodora %A Barrio, Jorge R %A Small, Gary W %A Potkin, Steven G %A Lott, Ira T %X

Overexpression of the amyloid precursor protein (APP) gene on chromosome 21 in Down syndrome (DS) has been linked to increased brain amyloid levels and early-onset Alzheimer's disease (AD). An elderly man with phenotypic DS and partial trisomy of chromosome 21 (PT21) lacked triplication of APP affording an opportunity to study the role of this gene in the pathogenesis of dementia. Multidisciplinary studies between ages 66-72 years comprised neuropsychological testing, independent neurological exams, amyloid PET imaging with 11C-Pittsburgh compound-B (PiB), plasma amyloid-β (Aβ) measurements, and a brain autopsy examination. The clinical phenotype was typical for DS and his intellectual disability was mild in severity. His serial neuropsychological test scores showed less than a 3% decline as compared to high functioning individuals with DS who developed dementia wherein the scores declined 17-28% per year. No dementia was detected on neurological examinations. On both PiB-PET scans, the patient with PT21 had lower PiB standard uptake values than controls with typical DS or sporadic AD. Plasma Aβ42 was lower than values for demented or non-demented adults with DS. Neuropathological findings showed only a single neuritic plaque and neurofibrillary degeneration consistent with normal aging but not AD. Taken together the findings in this rare patient with PT21 confirm the obligatory role of APP in the clinical, biochemical, and neuropathological findings of AD in DS.

%B J Alzheimers Dis %V 56 %P 459-470 %G eng %N 2 %R 10.3233/JAD-160836 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Dual Mechanism of Toxicity for Extracellular Injection of Tau Oligomers versus Monomers in Human Tau Mice. %A Manassero, Giusi %A Guglielmotto, Michela %A Monteleone, Debora %A Vasciaveo, Valeria %A Butenko, Olena %A Tamagno, Elena %A Arancio, Ottavio %A Tabaton, Massimo %X

The mechanism of tau toxicity is still unclear. Here we report that recombinant tau oligomers and monomers, intraventricularly injected in mice with a pure human tau background, foster tau pathology through different mechanisms. Oligomeric forms of tau alter the conformation of tau in a paired helical filament-like manner. This effect occurs without tau hyperphosphorylation as well as activation of specific kinases, suggesting that oligomers of tau induce tau assembly through a nucleation effect. Monomers, in turn, induce neurodegeneration through a calpain-mediated tau cleavage that leads to accumulation of a 17 kDa neurotoxic peptide and induction of apoptotic cell death.

%B J Alzheimers Dis %V 59 %P 743-751 %G eng %N 2 %R 10.3233/JAD-170298 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Dynamics of the Complement, Cytokine, and Chemokine Systems in the Regulation of Synaptic Function and Dysfunction Relevant to Alzheimer's Disease. %A Jiang, Shanya %A Bhaskar, Kiran %X

Alzheimer's disease (AD) is the most common form of dementia affecting nearly 45 million people worldwide. However, the etiology of AD is still unclear. Accumulations of amyloid-β plaques and tau tangles, neuroinflammation, and synaptic and neuronal loss are the major neuropathological hallmarks of AD, with synaptic loss being the strongest correlating factor with memory and cognitive impairment in AD. Many of these pathological hallmarks influence each other during the onset and progression of the disease. Recent genetic evidence suggests the possibility of a causal link between altered immune pathways and synaptic dysfunction in AD. Emerging studies also suggest that immune system-mediated synaptic pruning could initiate early-stage pathogenesis of AD. This comprehensive review is toward understanding the crosstalk of neuron-microglia-astrocyte and dynamics of complement, cytokine, and chemokine systems in the regulation of synaptic function and dysfunction relevant to AD. We start with summarizing several immune pathways, involving complements, MHC-I and CX3CL1, which mediate synaptic elimination during development and in AD. We then will discuss the potential of targeting these molecules as therapeutic interventions or as biomarkers for AD.

%B J Alzheimers Dis %V 57 %P 1123-1135 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372329?dopt=Abstract %R 10.3233/JAD-161123 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect of a Comprehensive Intervention on Plasma BDNF in Patients with Alzheimer's Disease. %A Balietti, Marta %A Giuli, Cinzia %A Fattoretti, Patrizia %A Fabbietti, Paolo %A Papa, Roberta %A Postacchini, Demetrio %A Conti, Fiorenzo %X

A comprehensive intervention (CI) on patients with Alzheimer's disease was assessed by measuring plasmabrain-derived neurotrophic factor (pBDNF) and ADAS-Cog score (ADAS-Cogscore) before, immediately after (FU1), and 6 (FU2) and 24 months (FU3) after the CI. Baseline pBDNF was higher in patients with moderate AD (but not mild AD) than in healthy controls. At FU1, pBDNF and ADAS-Cogscore decreased significantly. At FU2 and FU3, patients' cognitive status worsened and pBDNF further increased versus baseline, suggesting that CI interruption may be a stress event that prevents return to homeostasis. CI exerted positive short-term effects, but more information is needed on long-term consequences.

%B J Alzheimers Dis %V 57 %P 37-43 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222525?dopt=Abstract %R 10.3233/JAD-161168 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect of APOE Genotype on Amyloid Deposition, Brain Volume, and Memory in Cognitively Normal Older Individuals. %A Lim, Yen Ying %A Williamson, Robert %A Laws, Simon M %A Villemagne, Victor L %A Bourgeat, Pierrick %A Fowler, Christopher %A Rainey-Smith, Stephanie %A Salvado, Olivier %A Martins, Ralph N %A Rowe, Christopher C %A Masters, Colin L %A Maruff, Paul %X

BACKGROUND: The association between the apolipoprotein E (APOE) ɛ4 allele and high risk of developing Alzheimer's disease (AD) dementia before the age of 80 has been recognized for over 30 years. However, the timing and mode of action of APOE is not understood, nor has there been a detailed analysis of the effect of APOE genotype on memory, hippocampal volume, and amyloid-β (Aβ) levels in cognitively normal adults.

OBJECTIVE: Examine the effect of APOE allelic genotype on the relationship between Aβ levels, hippocampal volume, and memory in cognitively normal adults.

METHODS: This is a cross-sectional study of 989 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, all of whom underwent APOE genotyping and memory assessment. A subset of this group underwent PET neuroimaging for Aβ (n = 585) and MRI for hippocampal volume (n = 303).

RESULTS: APOEɛ4 homozygotes (ɛ4/ɛ4) showed significantly worse episodic memory and higher Aβ levels than ɛ4 heterozygotes. The relationship between increasing Aβ levels and worse episodic memory was significant for ɛ3 homozygotes (ɛ3/ɛ3), ɛ4 heterozygotes, and strongest for ɛ4 homozygotes. There were no differences in hippocampal volume between APOE groups; the relationship between smaller hippocampal volume and worse episodic memory was significant only for ɛ4 homozygotes.

CONCLUSION: APOE acts in a co-dominant fashion on Aβ levels, episodic memory, and hippocampal volume in cognitively normal older adults. APOEɛ4 is central to the events that lead to AD in cognitively normal older adults, likely through a quantitative role in the disruption of Aβ clearance.

%B J Alzheimers Dis %V 58 %P 1293-1302 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550258?dopt=Abstract %R 10.3233/JAD-170072 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect of APOE ε4 Genotype on Metabolic Biomarkers in Aging and Alzheimer's Disease. %A Morris K, Jill %A Uy, Roxanne Adeline Z %A Vidoni, Eric D %A Wilkins, Heather M %A Archer, Ashley E %A Thyfault, John P %A Miles, John M %A Burns, Jeffrey M %X

Alzheimer's disease (AD) may have heterogeneous pathophysiological underpinnings, with risk factors including apolipoprotein rmvarep4 (APOE4) genotype and insulin resistance. We hypothesized that distinct phenotypes exist within AD. We examined APOE4 and metabolic biomarkers in 338 subjects (n = 213 nondemented (ND), n = 125 AD). We further characterized steady state free fatty acid (FFA) levels in a subset of 45 participants who had also participated in a hyperinsulinemic-euglycemic clamp. Insulin resistance (HOMA-IR) was elevated in AD versus ND (p = 0.04) and in APOE4 noncarriers versus carriers (p < 0.01). This was driven by increased fasting insulin in AD versus ND (p < 0.01) and in APOE4 non-carriers versus carriers (p = 0.01). Fasting glucose was not different. In subjects who underwent a clamp, there was a group x genotype interaction on FFA levels during hyperinsulinemia (p = 0.03). APOE4 non-carriers with AD had higher FFA levels, while APOE4 carriers with AD exhibited lower FFA levels. Metabolic dysfunction is overrepresented in individuals with AD dementia who do not carry the APOE4 allele. This suggests that important subsets of AD phenotypes may exist that diverge metabolically.

%B J Alzheimers Dis %V 58 %P 1129-1135 %G eng %N 4 %R 10.3233/JAD-170148 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect of Spinal Manometers on Cerebrospinal Fluid Amyloid-β Concentration. %A Toombs, Jamie %A Foiani, Martha S %A Paterson, Ross W %A Heslegrave, Amanda %A Wray, Selina %A Schott, Jonathan M %A Fox, Nick C %A Lunn, Michael P %A Blennow, Kaj %A Zetterberg, Henrik %X

The effect of spinal manometers on cerebrospinal fluid (CSF) amyloid-β (Aβ) concentration was investigated. Pooled human CSF samples were divided in two, one half passed through a manometer into a collection tube, the other transferred directly to a collection tube. CSF was analyzed for Aβ38/40/42 using an electrochemiluminescence immunoassay. Relative to control, use of a manometer decreased Aβ38/40/42 concentration by 5.6% (±1.5SE), 4.4% (±1.7SE), and 4.3% (±2.4SE), respectively. The ratios of Aβ42 :40, Aβ42 :38, and Aβ40 :38 were not affected by manometer treatment. Factors which artificially lower CSF Aβ concentrations are relevant to clinical diagnosis for AD and study design.

%B J Alzheimers Dis %V 56 %P 885-891 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059797?dopt=Abstract %R 10.3233/JAD-161126 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect of Vascular Risk Factors on the Progression of Mild Alzheimer's Disease and Lewy Body Dementia. %A Bergland, Anne Katrine %A Dalen, Ingvild %A Larsen, Alf Inge %A Aarsland, Dag %A Soennesyn, Hogne %X

BACKGROUND: Vascular risk factors (VRF) are associated with an increased risk of neurodegenerative disease.

OBJECTIVE: To examine the association between VRF and cognitive decline in patients with Alzheimer's disease (AD) and Lewy body dementia (LBD).

METHODS: We included consecutive referrals with mild AD or LBD to dementia clinics in western Norway from 2005 to 2013. The Mini-Mental Status Exam (MMSE) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) were administered at baseline and then annually for up to five years. The VRF include diabetes mellitus, hypertension, hypercholesterolemia, overweight and smoking. Generalized Estimating Equations (GEE) were used to examine the potential association between VRF scores and the change in MMSE and CDR-SB scores, adjusting for age, sex, and the apolipoprotein ɛ4 allele (APOE4).

RESULTS: A total of 200 patients were included (113 AD, 87 LBD) (mean age 76 years, mean baseline MMSE 24.0, mean follow-up time 3.5 years). Smoking was the only VRF significantly associated with a more rapid cognitive decline, however only in the AD group. Being overweight at baseline was associated with a slower cognitive decline. Moreover, hypertension at baseline predicted a slower decline in MMSE scores. In the LBD group diabetes mellitus was found to be associated with a slower increase in CDR-SB scores.

CONCLUSION: With the exception of smoking, VRF at time of dementia diagnosis were not associated with a more rapid cognitive decline.

%B J Alzheimers Dis %V 56 %P 575-584 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035932?dopt=Abstract %R 10.3233/JAD-160847 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect Size Analyses of Souvenaid in Patients with Alzheimer's Disease. %A Cummings, Jeffrey %A Scheltens, Philip %A McKeith, Ian %A Blesa, Rafael %A Harrison, John E %A Bertolucci, Paulo H F %A Rockwood, Kenneth %A Wilkinson, David %A Wijker, Wouter %A Bennett, David A %A Shah, Raj C %X

BACKGROUND: Souvenaid® (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium), was developed to support the formation and function of neuronal membranes.

OBJECTIVE: To determine effect sizes observed in clinical trials of Souvenaid and to calculate the number needed to treat to show benefit or harm.

METHODS: Data from all three reported randomized controlled trials of Souvenaid in Alzheimer's disease (AD) dementia (Souvenir I, Souvenir II, and S-Connect) and an open-label extension study were included in analyses of effect size for cognitive, functional, and behavioral outcomes. Effect size was determined by calculating Cohen's d statistic (or Cramér's V method for nominal data), number needed to treat and number needed to harm. Statistical calculations were performed for the intent-to-treat populations.

RESULTS: In patients with mild AD, effect sizes were 0.21 (95% confidence intervals: -0.06, 0.49) for the primary outcome in Souvenir II (neuropsychological test battery memory z-score) and 0.20 (0.10, 0.34) for the co-primary outcome of Souvenir I (Wechsler memory scale delayed recall). No effect was shown on cognition in patients with mild-to-moderate AD (S-Connect). The number needed to treat (6 and 21 for Souvenir I and II, respectively) and high number needed to harm values indicate a favorable harm:benefit ratio for Souvenaid versus control in patients with mild AD.

CONCLUSIONS: The favorable safety profile and impact on outcome measures converge to corroborate the putative mode of action and demonstrate that Souvenaid can achieve clinically detectable effects in patients with early AD.

%B J Alzheimers Dis %V 55 %P 1131-1139 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767993?dopt=Abstract %R 10.3233/JAD-160745 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Exercise on Cognitive Function in Older People with Dementia: A Randomized Controlled Trial. %A Toots, Annika %A Littbrand, Håkan %A Boström, Gustaf %A Hörnsten, Carl %A Holmberg, Henrik %A Lundin-Olsson, Lillemor %A Lindelöf, Nina %A Nordström, Peter %A Gustafson, Yngve %A Rosendahl, Erik %X

BACKGROUND: Although physical exercise has been suggested to influence cognitive function, previous exercise studies show inconsistent results in people with dementia.

OBJECTIVES: To investigate effects of exercise on cognitive function in people with dementia.

METHOD: The Umeå Dementia and Exercise (UMDEX) study, a cluster-randomized controlled trial, was set in 16 nursing homes in Umeå, Sweden. One hundred-and-forty-one women and 45 men with dementia; mean age of 85 y and mean Mini-Mental State Examination (MMSE) score of 15, were randomized to a High-Intensity Functional Exercise program or a seated attention control activity. Blinded assessors measured global cognitive function using the MMSE and the Alzheimer's disease Assessment Scale - Cognitive subscale (ADAS-Cog), and executive function using Verbal fluency (VF) at baseline and 4 months (directly after intervention completion), and MMSE and VF at 7 months.

RESULTS: Linear mixed models showed no between-group effects in mean difference from baseline (95% confidence intervals, CI) at 4 months in MMSE (-0.27; 95% CI -1.4 to 0.87, p = 0.644), ADAS-Cog (-1.04, 95% CI -4 to 1.92, p = 0.491), or VF (-0.53, 95% CI -1.42 to 0.35, p = 0.241) or at 7 months in MMSE (-1.15, 95% CI -2.32 to 0.03, p = 0.056) or VF (-0.18, 95% CI -1.09 to 0.74, p = 0.707).

CONCLUSION: A 4-month, high-intensity functional exercise program had no superior effects on global cognition or executive function in people with dementia living in nursing homes when compared with an attention control activity.

%B J Alzheimers Dis %V 60 %P 323-332 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28800328?dopt=Abstract %R 10.3233/JAD-170014 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Effects of Gene Mutations on Default Mode Network in Familial Alzheimer's Disease. %A Li, Xiaozhen %A Westman, Eric %A Thordardottir, Steinunn %A Ståhlbom, Anne Kinhult %A Almkvist, Ove %A Blennow, Kaj %A Wahlund, Lars-Olof %A Graff, Caroline %X

Familial Alzheimer's disease (FAD) mutations have very high penetrance but age at onset and rate of disease progression differ. Neuroimaging and cerebrospinal fluid (CSF) examinations in mutation carriers (MCs) may provide an opportunity to identify early biomarkers that can be used to track disease progression from presymptomatic to the dementia stages of disease. The default mode network (DMN) is a resting state neuronal network composed of regions known to associate with amyloid deposition in AD. We hypothesized that functional connectivity in the DMN might change at pre-clinical stages in FAD MCs and correlate with changes in CSF biomarkers as a consequence of AD brain pathology. To test the hypothesis, we compared the functional connectivity in DMN between pre-MCs/MCs and non-carriers (NCs). No significant differences between pre-MCs and NCs were observed. When comparing all MCs with NCs, significant decreased functional connectivity in the right inferior parietal lobule, right precuneus, and left posterior cingulate cortex were found. We also found statistically significant correlations between CSF amyloid-β 42 and tau protein levels and average Z-score, a resting-state functional MRI measurement reflecting the degree of the correlation between a given voxel's time courses and the time courses corresponding to DMN, from the region with statistical difference. The observed disruption of DMN and pathological levels of AD CSF-biomarkers in FAD MCs are similar to the changes described in sporadic AD, which give further support that amyloid and tau pathology impairs neuronal and synaptic function.

%B J Alzheimers Dis %V 56 %P 327-334 %G eng %N 1 %R 10.3233/JAD-160730 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Healthy Aging and Mild Cognitive Impairment on a Real-Life Decision-Making Task. %A Pertl, Marie-Theres %A Benke, Thomas %A Zamarian, Laura %A Delazer, Margarete %X

In this study, we investigated the effects of age and of mild cognitive impairment (MCI) on decision making under risk by adopting a task representing real-life health-related situations and involving complex numerical information. Moreover, we assessed the relationship of real-life decision making to other cognitive functions such as number processing, executive functions, language, memory, and attention. For this reason, we compared the performance of 19 healthy, relatively younger adults with that of 18 healthy older adults and the performance of the 18 healthy older adults with that of 17 patients with MCI. Results indicated difficulties in real-life decision making for the healthy older adults compared with the healthy, relatively younger adults. Difficulties of patients with MCI relative to the healthy older adults arose in particular in difficult items requiring processing of frequencies and fractions. Significant effects of age and of MCI in processing frequencies were also evident in a ratio number comparison task. Decision-making performance of healthy participants and of the patient group correlated significantly with number processing. There was a further significant correlation with executive functions for the healthy participants and with reading comprehension for the patients. Our results suggest that healthy older individuals and patients with MCI make less advantageous decisions when the information is complex and high demands are put on executive functions and numerical abilities. Moreover, we show that executive functions and numerical abilities are not only essential in laboratory gambling tasks but also in more realistic and ecological decision situations within the health context.

%B J Alzheimers Dis %V 58 %P 1077-1087 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527216?dopt=Abstract %R 10.3233/JAD-170119 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia. %A Ferrari, Raffaele %A Grassi, Mario %A Graziano, Francesca %A Palluzzi, Fernando %A Archetti, Silvana %A Bonomi, Elisa %A Bruni, Amalia C %A Maletta, Raffaele G %A Bernardi, Livia %A Cupidi, Chiara %A Colao, Rosanna %A Rainero, Innocenzo %A Rubino, Elisa %A Pinessi, Lorenzo %A Galimberti, Daniela %A Scarpini, Elio %A Serpente, Maria %A Nacmias, Benedetta %A Piaceri, Irene %A Bagnoli, Silvia %A Rossi, Giacomina %A Giaccone, Giorgio %A Tagliavini, Fabrizio %A Benussi, Luisa %A Binetti, Giuliano %A Ghidoni, Roberta %A Singleton, Andrew %A Hardy, John %A Momeni, Parastoo %A Padovani, Alessandro %A Borroni, Barbara %X

In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95% CI: -4.64 to -3.07, p < 2×10-16) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.

%B J Alzheimers Dis %V 56 %P 1271-1278 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28128768?dopt=Abstract %R 10.3233/JAD-160949 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer's Disease Biomarkers: A Pilot Clinical Trial. %A Craft, Suzanne %A Claxton, Amy %A Baker, Laura D %A Hanson, Angela J %A Cholerton, Brenna %A Trittschuh, Emily H %A Dahl, Deborah %A Caulder, Erin %A Neth, Bryan %A Montine, Thomas J %A Jung, Youngkyoo %A Maldjian, Joseph %A Whitlow, Christopher %A Friedman, Seth %X

BACKGROUND: Long acting insulin detemir administered intranasally for three weeks enhanced memory for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). The investigation of longer-term administration is necessary to determine whether benefits persist, whether they are similar to benefits provided by regular insulin, and whether either form of insulin therapy affects AD biomarkers.

OBJECTIVE: The present study aimed to determine whether four months of treatment with intranasal insulin detemir or regular insulin improves cognition, daily functioning, and AD biomarkers for adults with MCI or AD.

METHODS: This randomized, double-blind, placebo-controlled trial included an intent-to-treat sample consisting of 36 adults diagnosed with MCI or mild to moderate AD. Participants received placebo (n = 12), 40 IU of insulin detemir (n = 12), or 40 IU of regular insulin (n = 12) daily for four months, administered with a nasal delivery device. A cognitive battery was administered at baseline and after two and four months of treatment. MRI was administered for all participants and lumbar puncture for a subset (n = 20) at baseline and four months. The primary outcome was change from baseline to four months on a memory composite (sum of Z scores for delayed list and story recall). Secondary outcomes included: global cognition (Alzheimer's Disease Assessment Scale-Cognition), daily functioning (Dementia Severity Rating Scale), MRI volume changes in AD-related regions of interest, and cerebrospinal fluid AD markers.

RESULTS: The regular insulin treated group had better memory after two and four months compared with placebo (p < 0.03). No significant effects were observed for the detemir-assigned group compared with the placebo group, or for daily functioning for either group. Regular insulin treatment was associated with preserved volume on MRI. Regular insulin treatment was also associated with reduction in the tau-P181/Aβ42 ratio.

CONCLUSION: Future research is warranted to examine the mechanistic basis of treatment differences, and to further assess the efficacy and safety of intranasal insulin.

%B J Alzheimers Dis %V 57 %P 1325-1334 %G eng %N 4 %R 10.3233/JAD-161256 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Risperidone and Galantamine Treatment on Alzheimer's Disease Biomarker Levels in Cerebrospinal Fluid. %A Bloniecki, Victor %A Aarsland, Dag %A Blennow, Kaj %A Cummings, Jeffrey %A Falahati, Farshad %A Winblad, Bengt %A Freund-Levi, Yvonne %X

BACKGROUND: Treatment for neuropsychiatric symptoms (NPS) in dementia is insufficient. Antipsychotics and acetylcholinesterase inhibitors are used generating symptomatic improvements in behavior and cognition, but few studies have investigated their effect on Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF).

OBJECTIVE: This is a secondary analysis based on an earlier clinical trial comparing the treatment effects on NPS. The aim of this study was to examine whether treatment with risperidone and galantamine affect levels of the biomarkers T-Tau, P-Tau, Aβ1-42, and Aβ42/40-ratio in CSF. The secondary aim was to test if baseline levels of these biomarkers are associated with the clinical course of NPS.

METHODS: 83 patients (mean + SD 77.9.6±7.7 years) with dementia and NPS were randomized to galantamine (n = 44) or risperidone (n = 39) treatment. CSF samples were collected at baseline and after 12 weeks.

RESULTS: Changes in levels of biomarkers between the two treatment groups did not differ significantly. Low baseline levels of Aβ1 - 42 was significantly associated with reduction of irritability at follow up. Low baseline levels of Aβ1-42, Aβ42/40, and P-Tau were significant correlates of reduction in appetite and eating disorders. CSF Aβ1-42 levels in patients treated with risperidone were significantly decreased at follow up, showing an 8% (40 pg/mL) reduction as compared with baseline (p = 0.03).

CONCLUSIONS: Our results suggest that risperidone may affect the CSF profile of AD biomarkers indicating more amyloid pathology. Treatment with galantamine did not affect the CSF biomarkers in any direction. The AD CSF biomarkers displayed correlations with specific NPS suggesting potential research questions to be pursued.

%B J Alzheimers Dis %V 57 %P 387-393 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269767?dopt=Abstract %R 10.3233/JAD-160758 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Efficacy and Safety of Plasma Exchange with 5% Albumin to Modify Cerebrospinal Fluid and Plasma Amyloid-β Concentrations and Cognition Outcomes in Alzheimer's Disease Patients: A Multicenter, Randomized, Controlled Clinical Trial. %A Boada, Merce %A Anaya, Fernando %A Ortiz, Pilar %A Olazarán, Javier %A Shua-Haim, Joshua R %A Obisesan, Thomas O %A Hernandez, Isabel %A Muñoz, Joan %A Buendia, Mar %A Alegret, Montserrat %A Lafuente, Asunción %A Tárraga, Lluís %A Núñez, Laura %A Torres, Mireia %A Grifols, Joan Ramon %A Ferrer, Isidre %A Lopez, Oscar L %A Páez, Antonio %X

BACKGROUND: Studies conducted in animal models and humans suggest the presence of a dynamic equilibrium of amyloid-β (Aβ) peptide between cerebrospinal fluid (CSF) and plasma compartments.

OBJECTIVE: To determine whether plasma exchange (PE) with albumin replacement was able to modify Aβ concentrations in CSF and plasma as well as to improve cognition in patients with mild-moderate Alzheimer's disease (AD).

METHODS: In a multicenter, randomized, patient- and rater-blind, controlled, parallel-group, phase II study, 42 AD patients were assigned (1 : 1) to PE treatment or control (sham) groups. Treated patients received a maximum of 18 PE with 5% albumin (Albutein®, Grifols) with three different schedules: two PE/weekly (three weeks), one PE/weekly (six weeks), and one PE/bi- weekly (12 weeks), plus a six-month follow-up period. Plasma and CSF Aβ1-40 and Aβ1-42 levels, as well as cognitive, functional, and behavioral measures were determined.

RESULTS: CSF Aβ1-42 levels after the last PE compared to baseline were marginally higher in PE-treated group versus controls (adjusted means of variation: 75.3 versus -45.5 pg/mL; 95% CI: -19.8, 170.5 versus 135.1, 44.2; p = 0.072). Plasma Aβ1-42 levels were lower in the PE-treated group after each treatment period (p < 0.05). Plasma Aβ1-40 levels showed a saw-tooth pattern variation associated with PE. PE-treated patients scored better in the Boston Naming Test and Semantic Verbal Fluency (p < 0.05) throughout the study. Neuropsychiatric Inventory scores were higher in controls during the PE phase (p < 0.05).

CONCLUSION: PE with human albumin modified CSF and plasma Aβ1-42 levels. Patients treated with PE showed improvement in memory and language functions, which persisted after PE was discontinued.

%B J Alzheimers Dis %V 56 %P 129-143 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911295?dopt=Abstract %R 10.3233/JAD-160565 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Efficacy of Hearing Aids on the Cognitive Status of Patients with Alzheimer's Disease and Hearing Loss: A Multicenter Controlled Randomized Trial. %A Nguyen, Marie-France %A Bonnefoy, Marc %A Adrait, Arnaud %A Gueugnon, Marine %A Petitot, Charles %A Collet, Lionel %A Roux, Adeline %A Perrot, Xavier %X

BACKGROUND/OBJECTIVE: This study evaluated the cognitive benefit of hearing aids (HA) in older patients with Alzheimer's disease (AD) and hearing loss (HL) after a 6- and 12-month period of utilization.

METHODS: A multicenter double-blind randomized placebo-controlled trial was conducted in patients aged more than 65 years. A group was equipped with active HA for 6 months (active group) and a second group had placebo HA for 6 months (placebo group) followed by a secondary activation phase for a further 6 months (semi crossover procedure). Both groups were retested after a 12-month period. The primary endpoint was the change from baseline of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS Cog) after a 6-month period in both groups and after 6 months of secondary HA activation in the placebo group. A smaller cognitive decline should be obtained with HA use; an increase in ADAS Cog score of less than 6 points was defined a success.

RESULTS: Fifty-one patients aged 68 to 99 years were included; 38 attended the 6-month visit: 18 in the active group and 20 in the placebo group. At 6 months, 14 (82.4%) successes were noticed in the active group, and 15 (88.2%) in the placebo group (p = 1.0); delta ADAS Cog in the active group was 1.8±5.3 and 1.3±5.3 in the placebo group (p = 0.8). In the placebo group, after the secondary HA activation, no significant improvement was observed.

CONCLUSION: No significant effect of HA use was observed after 6 months of follow-up in patients with AD and HL.

%B J Alzheimers Dis %V 58 %P 123-137 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387664?dopt=Abstract %R 10.3233/JAD-160793 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Epidemiological Approaches to Understanding the Link Between Type 2 Diabetes and Dementia. %A Sutherland, Greg T %A Lim, Julia %A Srikanth, Velandai %A Bruce, David G %X

Diabetes and dementia are two diseases that increased dramatically in most societies in direct proportion to increases in average life expectancy. The two conditions are strongly associated and there is much hope that understanding this association will unlock the enigma that is the pathogenesis of dementia. Previous studies suggest that type 2 diabetes is a risk factor for all-cause dementia, vascular dementia and Alzheimer's disease. However these estimates may not necessarily have taken into account the overlap in dementia pathologies or the competing risk of death. Although the link between diabetes and vascular disease is intuitive, it is now becoming clear that type 2 diabetes is also associated with reduced brain volumes and with progression of brain atrophy, apparently independent of its relation with cerebrovascular disease. This raises the possibility that type 2 diabetes may also contribute to neurodegeneration, and particularly tau pathology. Prospective studies that record extensive multimodal in-vivo biomarkers and conduct rigorous postmortem neuropathological examination are certainly required to tease apart these complex pathways. However monitoring cognitive outcomes from current observational studies and randomized clinical trials of new diabetes treatments could be equally valuable in reducing the dementia epidemic.

%B J Alzheimers Dis %V 59 %P 393-403 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372332?dopt=Abstract %R 10.3233/JAD-161194 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Ethical Considerations for Deep Brain Stimulation Trials in Patients with Early-Onset Alzheimer's Disease. %A Viaña, John Noel M %A Bittlinger, Merlin %A Gilbert, Frederic %X

Several studies of deep brain stimulation (DBS) of the fornix or the nucleus basalis of Meynert have been recently conducted in people with Alzheimer's disease, with several recruiting participants <65 and thus have early-onset Alzheimer's disease (EOAD). Although EOAD accounts for less than 5.5% of AD cases, ethical considerations must still be made when performing DBS trials including these participants since a portion of people with EOAD, especially those possessing autosomal-dominant mutations, have an atypical and more aggressive disease progression. These considerations include appropriate patient selection and signing of an informed consent for genetic testing; appropriate study design; potential outcomes that people with EOAD could expect; and accurate interpretation and balanced discussion of trial results. Finally, recommendations for future DBS for AD trials will be made to ensure that EOAD patients will not experience avoidable harms should they be enrolled in these experimental studies.

%B J Alzheimers Dis %V 58 %P 289-301 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28436389?dopt=Abstract %R 10.3233/JAD-161073 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Ethnic Variations in Prognosis of Patients with Dementia: A Prospective Nationwide Registry Linkage Study in The Netherlands. %A Agyemang, Charles %A van de Vorst, Irene E %A Koek, Huiberdina L %A Bots, Michiel L %A Seixas, Azizi %A Norredam, Marie %A Ikram, Umar %A Stronks, Karien %A Vaartjes, Ilonca %X

BACKGROUND: Data on dementia prognosis among ethnic minority groups are limited in Europe.

OBJECTIVE: We assessed differences in short-term (1-year) and long-term (3-year) mortality and readmission risk after a first hospitalization or first ever referral to a day clinic for dementia between ethnic minority groups and the ethnic Dutch population in the NetherlandsMethods: Nationwide prospective cohorts of first hospitalized dementia patients (N = 55,827) from January 1, 2000 to December 31, 2010 were constructed. Differences in short-term and long-term mortality and readmission risk following hospitalization or referral to the day clinic between ethnic minority groups (Surinamese, Turkish, Antilleans, Indonesians) and the ethnic Dutch population were investigated using Cox proportional hazard regression models with adjustment for age, sex, and comorbidities.

RESULTS: Age-sex-adjusted short-term and long-term risks of death following a first hospitalization with dementia were comparable between the ethnic minority groups and the ethnic Dutch. Age- and sex-adjusted risk of admission was higher only in Turkish compared with ethnic Dutch (HR 1.57, 95% CI,1.08-2.29). The difference between Turkish and the Dutch attenuated and was no longer statistically significant after further adjustment for comorbidities. There were no ethnic differences in short-term and long-term risk of death, and risk of readmission among day clinic patients.

CONCLUSION: Compared with Dutch patients with a comparable comorbidity rate, ethnic minority patients with dementia did not have a worse prognosis. Given the poor prognosis of dementia, timely and targeted advance care planning is essential, particularly in ethnic minority groups who are mired by cultural barriers and where uptake of advance care planning is known to be low.

%B J Alzheimers Dis %V 56 %P 205-213 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911320?dopt=Abstract %R 10.3233/JAD-160897 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Evidence of a Cardiovascular Function for Microtubule-Associated Protein Tau. %A Betrie, Ashenafi H %A Ayton, Scott %A Bush, Ashley I %A Angus, James A %A Lei, Peng %A Wright, Christine E %X

Aggregation of tau protein into intracellular deposits is a pathognomonic feature of tauopathies such as Alzheimer's disease (AD) and lowering tau is a prominent therapeutic strategy under development. However, the physiological function of tau protein is not well known, particularly in the periphery. Lowering tau protein risks disrupting its physiological role leading to unwanted effects. In this study, the presence of tau protein in cardiac tissue is confirmed and the functional role in the cardiovascular system and the consequences of its loss were explored. Isolated right and left atria and small mesenteric arteries from wild type and tau deficient (KO) mice of two age groups (13 and 23 months old) were used to assess cardiovascular phenotypes. Tau KO mice showed an increased systolic blood pressure and cardiac hypertrophy at 13 months, which was accompanied by a significantly lower right atrial rate and a subtle decrease in the maximum contractility to calcium, isoprenaline, and electrical sympathetic nerve stimulation. Aging tau KO mice to 23 months resulted in cardiac hypertrophy with significantly attenuated left atrial contractility, increased blood pressure, and sensitivity of isolated mesenteric arteries to angiotensin II contraction and isoprenaline relaxation compared to their younger counterparts. This study supports a functional role of tau in the heart and loss of this protein leads to a deterioration in cardiovascular performance which worsens with age. Taken together, these results provide insight into the peripheral function of tau protein, and give caution to the therapeutic strategy of lowering tau protein.

%B J Alzheimers Dis %V 56 %P 849-860 %8 Jan 2017 %G eng %N 2 %R 10.3233/JAD-161093 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Evidence that the Human Innate Immune Peptide LL-37 may be a Binding Partner of Amyloid-β and Inhibitor of Fibril Assembly. %A De Lorenzi, Ersilia %A Chiari, Marcella %A Colombo, Raffaella %A Cretich, Marina %A Sola, Laura %A Vanna, Renzo %A Gagni, Paola %A Bisceglia, Federica %A Morasso, Carlo %A Lin, Jennifer S %A Lee, Moonhee %A McGeer, Patrick L %A Barron, Annelise E %X

BACKGROUND: Identifying physiologically relevant binding partners of amyloid-β (Aβ) that modulate in vivo fibril formation may yield new insights into Alzheimer's disease (AD) etiology. Human cathelicidin peptide, LL-37, is an innate immune effector and modulator, ubiquitous in human tissues and expressed in myriad cell types.

OBJECTIVE: We present in vitro experimental evidence and discuss findings supporting a novel hypothesis that LL-37 binds to Aβ42 and can modulate Aβ fibril formation.

METHODS: Specific interactions between LL-37 and Aβ (with Aβ in different aggregation states, assessed by capillary electrophoresis) were demonstrated by surface plasmon resonance imaging (SPRi). Morphological and structural changes were investigated by transmission electron microscopy (TEM) and circular dichroism (CD) spectroscopy. Neuroinflammatory and cytotoxic effects of LL-37 alone, Aβ42 alone, and LL-37/Aβ complexes were evaluated in human microglia and neuroblastoma cell lines (SH-SY5Y).

RESULTS: SPRi shows binding specificity between LL-37 and Aβ, while TEM shows that LL-37 inhibits Aβ42 fibril formation, particularly Aβ's ability to form long, straight fibrils characteristic of AD. CD reveals that LL-37 prevents Aβ42 from adopting its typical β-type secondary structure. Microglia-mediated toxicities of LL-37 and Aβ42 to neurons are greatly attenuated when the two peptides are co-incubated prior to addition. We discuss the complementary biophysical characteristics and AD-related biological activities of these two peptides.

CONCLUSION: Based on this body of evidence, we propose that LL-37 and Aβ42 may be natural binding partners, which implies that balanced (or unbalanced) spatiotemporal expression of the two peptides could impact AD initiation and progression.

%B J Alzheimers Dis %V 59 %P 1213-1226 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731438?dopt=Abstract %R 10.3233/JAD-170223 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Extracellular Tau Oligomers Induce Invasion of Endogenous Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction. %A Swanson, Eric %A Breckenridge, Leigham %A McMahon, Lloyd %A Som, Sreemoyee %A McConnell, Ian %A Bloom, George S %X

Aggregates composed of the microtubule associated protein, tau, are a hallmark of Alzheimer's disease and non-Alzheimer's tauopathies. Extracellular tau can induce the accumulation and aggregation of intracellular tau, and tau pathology can be transmitted along neural networks over time. There are six splice variants of central nervous system tau, and various oligomeric and fibrillar forms are associated with neurodegeneration in vivo. The particular extracellular forms of tau capable of transferring tau pathology from neuron to neuron remain ill defined, however, as do the consequences of intracellular tau aggregation on neuronal physiology. The present study was undertaken to compare the effects of extracellular tau monomers, oligomers, and filaments comprising various tau isoforms on the behavior of cultured neurons. We found that 2N4R or 2N3R tau oligomers provoked aggregation of endogenous intracellular tau much more effectively than monomers or fibrils, or of oligomers made from other tau isoforms, and that a mixture of all six isoforms most potently provoked intracellular tau accumulation. These effects were associated with invasion of tau into the somatodendritic compartment. Finally, we observed that 2N4R oligomers perturbed fast axonal transport of membranous organelles along microtubules. Intracellular tau accumulation was often accompanied by increases in the run length, run time and instantaneous velocity of membranous cargo. This work indicates that extracellular tau oligomers can disrupt normal neuronal homeostasis by triggering axonal tau accumulation and loss of the polarized distribution of tau, and by impairing fast axonal transport.

%B J Alzheimers Dis %V 58 %P 803-820 %G eng %N 3 %R 10.3233/JAD-170168 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Feasibility of Lumbar Puncture in the Study of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease in Subjects with Down Syndrome. %A Carmona-Iragui, María %A Santos, Telma %A Videla, Sebastián %A Fernández, Susana %A Benejam, Bessy %A Videla, Laura %A Alcolea, Daniel %A Blennow, Kaj %A Blesa, Rafael %A Lleo, Alberto %A Fortea, Juan %X

BACKGROUND: Alzheimer's disease (AD) is the main medical problem in older adults with Down syndrome (DS). Studies of cerebrospinal fluid (CSF) AD biomarkers are limited and the feasibility of lumbar puncture (LP) is controversial in this population.

OBJECTIVE: To analyze the frequency of complications after a LP in DS.

METHODS: We collected data from 80 adults with DS that underwent a LP within the Down Alzheimer Barcelona Neuroimaging Initiative. Demographics, cognitive status, headache history, and presence of complications after the LP were recorded in every subject. In 53 of them (active group), this information was collected following a semi-structured and validated protocol that actively looks for complications. Other variables related to the LP procedure were also recorded. A telephone interview to the caregiver was performed 5-7 days after the procedure to ask about complications. Data from 27 subjects (clinical practice group), from whom the presence of complications was obtained in a medical follow-up visit within the three months after the LP, were also included.

RESULTS: There were no adverse events in 90% of our participants. The most frequent complication was headache (6.25%); only one subject reported a typical post-lumbar puncture headache with moderate severity that required analgesic treatment. Dizziness (3.75%) and back pain (1.25%) were also reported. All the participants that reported complications belonged to the active group.

CONCLUSION: LP can be safely performed to study CSF biomarkers in DS. The reported complications are qualitatively similar to the general population, but are less frequently reported, even when actively searched for.

%B J Alzheimers Dis %V 55 %P 1489-1496 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858714?dopt=Abstract %R 10.3233/JAD-160827 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Financial and Health Literacy Predict Incident Alzheimer's Disease Dementia and Pathology. %A Yu, Lei %A Wilson, Robert S %A Schneider, Julie A %A Bennett, David A %A Boyle, Patricia A %X

BACKGROUND: Domain specific literacy is a multidimensional construct that requires multiple resources including cognitive and non-cognitive factors.

OBJECTIVE: We test the hypothesis that domain specific literacy is associated with Alzheimer's disease (AD) dementia and AD pathology after controlling for cognition.

METHODS: Participants were community-based older persons who completed a baseline literacy assessment, underwent annual clinical evaluations for up to 8 years, and agreed to organ donation after death. Financial and health literacy was measured using 32 questions and cognition was measured using 19 tests. Annual diagnosis of AD dementia followed standard criteria. AD pathology was examined postmortem by quantifying plaques and tangles. Cox models examined the association of literacy with incident AD dementia. Performance of model prediction for incident AD dementia was assessed using indices for integrated discrimination improvement and continuous net reclassification improvement. Linear regression models examined the independent association of literacy with AD pathology in autopsied participants.

RESULTS: All 805 participants were free of dementia at baseline and 102 (12.7%) developed AD dementia during the follow-up. Lower literacy was associated with higher risk for incident AD dementia (p < 0.001), and the association persisted after controlling for cognition (hazard ratio = 1.50, p = 0.004). The model including the literacy measure had better predictive performance than the one with demographics and cognition only. Lower literacy also was associated with higher burden of AD pathology after controlling for cognition (β= 0.07, p = 0.035).

CONCLUSION: Literacy predicts incident AD dementia and AD pathology in community-dwelling older persons, and the association is independent of traditional measures of cognition.

%B J Alzheimers Dis %V 56 %P 1485-1493 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157101?dopt=Abstract %R 10.3233/JAD-161132 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Finger-to-Nose Test Findings in Alzheimer's Disease. %A Bergeron, David %A Vermette, Antoine %A De La Sablonnière, Justine %A Cayer, Anne-Marie %A Laforce, Robert %A Bouchard, Rémi W %X

The finger-to-nose test is routinely performed during the clinical assessment of patients with cognitive impairments. Although widely known to screen for cerebellar dysfunction by unmasking appendicular ataxia, we have found that this test could also be interpreted from a cognitive perspective. We describe two typical signs observed at the finger-to-nose test in Alzheimer's disease (AD) patients: the "second finger syndrome" and the "distal pressure sign". By retrospectively reviewing the medical records 461 patients followed at our academic memory clinic, we found that these signs are commonplace in AD, but not in vascular dementia or subjective cognitive impairment.

%B J Alzheimers Dis %V 55 %P 1335-1337 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858718?dopt=Abstract %R 10.3233/JAD-160941 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Framingham Risk Score and the Risk of Progression from Mild Cognitive Impairment to Dementia. %A Viticchi, Giovanna %A Falsetti, Lorenzo %A Buratti, Laura %A Sajeva, Giulia %A Luzzi, Simona %A Bartolini, Marco %A Provinciali, Leandro %A Silvestrini, Mauro %X

BACKGROUND: Mild cognitive impairment (MCI) often represents the clinical manifestation of cognitive deterioration preceding Alzheimer's disease (AD). Currently, there are no reliable approaches for an objective evaluation of the risk of developing AD in MCI patients.

OBJECTIVE: The aim of this study was to verify whether the Framingham cardiovascular risk profile (FCRP) could be useful to identify patients at the highest risk of conversion from MCI to AD.

METHODS: Patients with amnestic MCI (aMCI) were carefully investigated to assess their vascular risk profile. They were also submitted to a comprehensive neuropsychological evaluation. The FCRP was calculated for each patient and the apolipoprotein E (ApoE) genotype was determined from peripheral blood cells. The main outcome was defined as a conversion to AD within 24 months after inclusion.

RESULTS: 385 consecutive aMCI subjects were included. Age, FCRP, and vascular age showed a fairly predictive value on conversion to AD. Selecting the subpopulation of ApoE ɛ4 carriers, we observed that FCRP had an increased performance in predicting the conversion. The rate of conversion increased from 12.5% in the FCRP low-risk group to 43.2% in the high-risk group (p < 0.0001). ApoE ɛ4 carriers had a 3.7-times increased probability of conversion with respect to the other subjects (p < 0.0001).

CONCLUSIONS: FCRP assessment could be considered a reliable approach to predict conversion to AD in aMCI subjects. The presence of ApoE ɛ4 increases significantly the risk of conversion. These data confirm the narrow relationship between genetic and vascular risk factors in influencing the evolution of cognitive impairment.

%B J Alzheimers Dis %V 59 %P 67-75 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582863?dopt=Abstract %R 10.3233/JAD-170160 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Frequency-Dependent Changes in the Amplitude of Low-Frequency Fluctuations in Mild Cognitive Impairment with Mild Depression. %A Li, Yuxia %A Jing, Bin %A Liu, Han %A Li, Yifan %A Gao, Xuan %A Li, Yongqiu %A Mu, Bin %A Yu, Haikuo %A Cheng, Jinbo %A Barker, Peter B %A Wang, Hongxing %A Han, Ying %X

BACKGROUND: Depression is a potential marker of preclinical Alzheimer's disease (AD). However, little is known about the abnormal characteristics revealed by resting-state functional magnetic resonance imaging (rs-fMRI) in mild cognitive impairment (MCI) subjects with depressive symptoms (MCI-d).

OBJECTIVE: The study was to examine whether abnormalities in amplitudes of low-frequency oscillation occurred in MCI-d and tried to find the possible spectrum showed higher recognition ability to the diagnosis by utilizing functional MRI (fMRI).

METHODS: The amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) within full frequency (0.01-0.1 Hz), slow-5 (0.01-0.027 Hz), and slow-4 (0.027-0.073 Hz) were computed using resting-state fMRI data of 27 MCI without depressive symptoms, 19 MCI-d, and 32 well-matched healthy controls (HC). Analysis of covariance was performed on ALFF and fALFF among MCI, MCI-d, and HC groups.

RESULTS: Several brain regions showed significant differences in ALFF and fALFF within full frequency, slow-5, and slow-4 bands among three groups. Importantly, receiver operating characteristic analysis revealed that the ALFF values in the full frequency band in the left parahippocampal gyrus and the left precuneus, Slow 5 value in ALFF in the left inferior frontal gyrus, and Slow 4 value in ALFF in the left precuneus could effectively differentiate MCI-d from MCI patients.

CONCLUSION: In this study, we found that several changes in special brain regions are associated with MCI and MCI-d patients. And the differences depend on the studied frequency bands of rs-fMRI data. The affective network and the default-mode network might be damaged simultaneously in MCI-d patients.

%B J Alzheimers Dis %V 58 %P 1175-1187 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550250?dopt=Abstract %R 10.3233/JAD-161282 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Frontotemporal Dementia due to the Novel GRN Arg161GlyfsX36 Mutation. %A Gazzina, Stefano %A Archetti, Silvana %A Alberici, Antonella %A Bonomi, Elisa %A Cosseddu, Maura %A Di Lorenzo, Diego %A Padovani, Alessandro %A Borroni, Barbara %X

Progranulin is a multifunctional growth factor mainly expressed in neurons and microglia. Loss-of-function mutations in the Granulin (GRN) gene are causative of frontotemporal dementia with TAR DNA-binding protein-43 inclusions. We reported the case of a 51-year-old male patient affected by sporadic agrammatic variant of primary progressive aphasia, in whom we identified a novel heterozygous deletion in the exon 6 (g.10338_39delAG, p.Arg161GlyfsX36). Plasma progranulin levels were significantly reduced and in silico analysis predicted a premature termination codon. This case expands our knowledge on GRN mutations in frontotemporal dementia.

%B J Alzheimers Dis %V 57 %P 1185-1189 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304311?dopt=Abstract %R 10.3233/JAD-170066 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Fully Automatic MRI-Based Hippocampus Volumetry Using FSL-FIRST: Intra-Scanner Test-Retest Stability, Inter-Field Strength Variability, and Performance as Enrichment Biomarker for Clinical Trials Using Prodromal Target Populations at Risk for Alzheimer's %A Cavedo, Enrica %A Suppa, Per %A Lange, Catharina %A Opfer, Roland %A Lista, Simone %A Galluzzi, Samantha %A Schwarz, Adam J %A Spies, Lothar %A Buchert, Ralph %A Hampel, Harald %X

BACKGROUND: MRI-based hippocampus volume is a core clinical biomarker for identification of Alzheimer's disease (AD).

OBJECTIVE: To assess robustness of automatic hippocampus volumetry with the freely available FSL-FIRST software with respect to short-term repeat and across field strength imaging. FSL-FIRST hippocampus volume (FIRST-HV) was also evaluated as enrichment biomarker for mild cognitive impairment (MCI) trials.

METHODS: Robustness of FIRST-HV was assessed in 51 healthy controls (HC), 74 MCI subjects, and 28 patients with AD dementia from ADNI1, each with two pairs of back-to-back scans, one at 1.5T one at 3T. Enrichment performance was tested in a second sample of 287 ADNI MCI subjects.

RESULTS: FSL-FIRST worked properly in all four scans in 147 out of 153 subjects of the first sample (49 HC, 72 MCI, 26 AD). In these subjects, FIRST-HV did not differ between the first and the second scan within an imaging session, neither at 1.5T nor at 3T (p≥0.302). FIRST-HV was on average 0.78% larger at 3T compared to 1.5T (p = 0.012). The variance of the FIRST-HV difference was larger in the inter-field strength setting than in the intra-scanner settings (p < 0.0005). Computer simulations suggested that the additional variability encountered in the inter-field strength scenario does not cause a relevant degradation of FIRST-HV's prognostic performance in MCI. FIRST-HV based enrichment resulted in considerably increased effect size of the 2-years change of cognitive measures.

CONCLUSION: The impact of intra-scanner test-retest and inter-field strength variability of FIRST-HV on clinical tasks is negligible. In addition, FIRST-HV is useful for enrichment in clinical MCI trials.

%B J Alzheimers Dis %V 60 %P 151-164 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28777748?dopt=Abstract %R 10.3233/JAD-161108 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Functional Connectivity in the Default Mode Network is Reduced in Association with Nocturnal Awakening in Mild Cognitive Impairment. %A McKinnon, Andrew C %A Duffy, Shantel L %A Cross, Nathan E %A Terpening, Zoe %A Grunstein, Ron R %A Lagopoulos, Jim %A Batchelor, Jennifer %A Hickie, Ian B %A Lewis, Simon J G %A Shine, James M %A Naismith, Sharon L %X

BACKGROUND: Sleep disturbance is prevalent in MCI, and is a risk factor for cognitive deterioration.

OBJECTIVE: To identify functional connectivity deficits in the default mode network (DMN) in patients with mild cognitive impairment (MCI) and sleep disturbance, relative to MCIs with intact sleep.

METHODS: Participants comprised 47 adults aged 55 years and over, recruited from the Healthy Brain Ageing Clinic at the Brain and Mind Centre, Sydney, Australia. This sample contained 15 controls and 32 participants meeting criteria for MCI. Participants underwent resting-state fMRI and actigraphy, along with comprehensive neuropsychological, medical and psychiatric assessment. MCIs were split into two groups according to average wake after sleep onset (WASO) per night. WASO equal to or greater than 1 standard deviation (SD) above the control mean was deemed to reflect disturbed sleep. There were 11 patients in the MCI sleep-disturbed group, and 21 in the MCI sleep-intact group.

RESULTS: Relative to controls, MCIs demonstrated significant connectivity reductions between parietal and temporoparietal regions, and between temporal regions. Relative to MCIs with intact sleep, MCIs with sleep disturbance demonstrated reductions in functional connectivity between temporal and parietal regions, and between temporal and temporoparietal regions.

CONCLUSIONS: MCIs with nocturnal awakenings demonstrate reductions in DMN connectivity. These reductions comprise brain regions that are crucially involved in sleep and memory processes. These results strengthen our previous findings, which found reduced connectivity in MCIs with self-reported sleep disturbances. Future studies may build on these findings through incorporating complementary neuroimaging techniques and experimental manipulations of sleep.

%B J Alzheimers Dis %V 56 %P 1373-1384 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157095?dopt=Abstract %R 10.3233/JAD-160922 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Functional Reserve: Experience Participating in Instrumental Activities of Daily Living is Associated with Gender and Functional Independence in Mild Cognitive Impairment. %A Berezuk, Courtney %A Zakzanis, Konstantine K %A Ramirez, Joel %A Ruocco, Anthony C %A Edwards, Jodi D %A Callahan, Brandy L %A Black, Sandra E %X

BACKGROUND: Gender differences in instrumental activities of daily living (IADLs) in mild cognitive impairment (MCI) and Alzheimer's disease may be explained by gender differences in IADL involvement.

OBJECTIVE: We introduce a novel theoretical construct, termed functional reserve, and empirically examine gender differences in IADL experience as a proxy of this reserve.

METHODS: We cross-sectionally examined men (n = 502) and women (n = 340) with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Demographic factors, depressive symptoms, neuropsychological scores, and IADL experience were included as independent variables and total Functional Activities Questionnaire (FAQ) scores as the dependent variable. Regression analyses were performed on the full cohort and stratified by gender to identify differential predictive relationships for men and women.

RESULTS: Gender was associated with total FAQ (p < 0.05) until adjusting for IADL experience. Furthermore, the combination of cognitive measures accounted for the most variance in functional dependence (12% explained, p < 0.001), although IADL experience was the most important single variable (4.8% explained, p < 0.001). Stratification by gender revealed that IADL experience accounted for 6.6% of the variance in FAQ score in men (p < 0.001) but only 2.4% in women (p = 0.001); however, the interaction between gender and experience was not statistically significant.

DISCUSSION: A small effect of men showing greater functional dependence in MCI may be explained by lower IADL experience. Additionally, IADL experience was associated with superior functioning in all analyses, potentially through increased functional reserve. This concept of functional reserve may have implications for identifying individuals at risk for IADL dependence, preventing or delaying decline, and potentially treating functional impairment.

%B J Alzheimers Dis %V 58 %P 425-434 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453478?dopt=Abstract %R 10.3233/JAD-161227 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Generation and Partial Characterization of Rabbit Monoclonal Antibody to Amyloid-β Peptide 1-37 (Aβ37). %A Mehta, Pankaj D %A Blain, Jean-Francois %A Freeman, Emily A %A Patrick, Bruce A %A Barshatzky, Marc %A Hrdlicka, Lori A %A Mehta, Sangita P %A Frackowiak, Janusz %A Mazur-Kolecka, Bozena %A Wegiel, Jerzy %A Patzke, Holger %A Miller, David L %X

Secreted soluble amyloid-β 1-37 (Aβ37) peptide is one of the prominent Aβ forms next to Aβ40, and is found in cerebrospinal fluid (CSF) and blood. Recent studies have shown the importance of quantitation of CSF Aβ37 levels in combination with Aβ38, Aβ40, and Aβ42 to support the diagnosis of patients with probable Alzheimer's disease (AD), and the value of antibody to Aβ37 to facilitate drug discovery studies. However, the availability of reliable and specific monoclonal antibody to Aβ37 is very limited. Our aims were: 1) to generate and partially characterize rabbit monoclonal antibody (RabmAb) to Aβ37, and 2) to determine whether the antibody detects changes in Aβ37 levels produced by a γ-secretase modulator (GSM). Our generated RabmAb to Aβ37 was found to be specific to Aβ37, since it did not react with Aβ36, Aβ38, Aβ39, Aβ40, and Aβ42 in an ELISA or immunoblotting. The epitope of the antibody was contained in the seven C-terminal residues of Aβ37. The antibody was sensitive enough to measure CSF and plasma Aβ37 levels in ELISA. Immunohistological studies showed the presence of Aβ37-positive deposits in the brain of AD, and Down syndrome persons diagnosed with AD. Our studies also showed that the antibody detected Aβ37 increases in CSF and brains of rodents following treatment with a GSM. Thus, our antibody can be widely applied to AD research, and in a panel based approach it may have potential to support the diagnosis of probable AD, and in testing the effect of GSMs to target AD.

%B J Alzheimers Dis %V 57 %P 135-145 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222530?dopt=Abstract %R 10.3233/JAD-161207 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Genetic Prion Disease Caused by PRNP Q160X Mutation Presenting with an Orbitofrontal Syndrome, Cyclic Diarrhea, and Peripheral Neuropathy. %A Fong, Jamie C %A Rojas, Julio C %A Bang, Jee %A Legati, Andrea %A Rankin, Katherine P %A Forner, Sven %A Miller, Zachary A %A Karydas, Anna M %A Coppola, Giovanni %A Grouse, Carrie K %A Ralph, Jeffrey %A Miller, Bruce L %A Geschwind, Michael D %X

Patients with pathogenic truncating mutations in the prion gene (PRNP) usually present with prolonged disease courses with severe neurofibrillary tangle and cerebral amyloidosis pathology, but more atypical phenotypes also occur, including those with dysautonomia and peripheral neuropathy. We describe the neurological, cognitive, neuroimaging, and electrophysiological features of a 31-year-old man presenting with an orbitofrontal syndrome, gastrointestinal symptoms, and peripheral neuropathy associated with PRNP Q160X nonsense mutation, with symptom onset at age 27. The mutation was also detected in his asymptomatic father and a symptomatic paternal cousin; several members of prior generations died from early onset dementia. This is the first report of a family affected with the nonsense PRNP mutation Q160X displaying clear autosomal dominant disease in multiple family members and reduced penetrance. This case strengthens the evidence suggesting an association between PRNP truncating mutations and prion systemic amyloidosis. PRNP gene testing should be considered in any patient with atypical dementia, especially with early onset and neuropathy, even in the absence of a family history.

%B J Alzheimers Dis %V 55 %P 249-258 %G ENG %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716661?dopt=Abstract %R 10.3233/JAD-160300 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Genetically-Predicted Adult Height and Alzheimer's Disease. %A Larsson, Susanna C %A Traylor, Matthew %A Burgess, Stephen %A Markus, Hugh S %X

BACKGROUND: Observational studies have linked increased adult height with better cognitive performance and reduced risk of Alzheimer's disease (AD). It is unclear whether the associations are due to shared biological processes that influence height and AD or due to confounding by early life exposures or environmental factors.

OBJECTIVE: To use a genetic approach to investigate the association between adult height and AD.

METHODS: We selected 682 single nucleotide polymorphisms (SNPs) associated with height at genome-wide significance (p < 5×10-8) in the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Summary statistics for each of these SNPs on AD were obtained from the International Genomics of Alzheimer's Project (IGAP) of 17,008 individuals with AD and 37,154 controls. The estimate of the association between genetically predicted height and AD was calculated using the inverse-variance weighted method.

RESULTS: The odds ratio of AD was 0.91 (95% confidence interval, 0.86-0.95; p = 9.8×10-5) per one standard deviation increase (about 6.5 cm) in genetically predicted height based on 682 SNPs, which were clustered in 419 loci. In an analysis restricted to one SNP from each height-associated locus (n = 419 SNPs), the corresponding OR was 0.92 (95% confidence interval, 0.86-0.97; p = 4.8×10-3).

CONCLUSIONS: This finding suggests that biological processes that influence adult height may have a role in the etiology of AD.

%B J Alzheimers Dis %V 60 %P 691-698 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869480?dopt=Abstract %R 10.3233/JAD-170528 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Glutathione Conformations and Its Implications for in vivo Magnetic Resonance Spectroscopy. %A Mandal, Pravat K %A Shukla, Deepika %A Govind, Varan %A Boulard, Yves %A Ersland, Lars %X

Glutathione (GSH) is a major antioxidant in humans that is involved in the detoxification of reactive radicals and peroxides. The molecular structural conformations of GSH depend on the surrounding micro-environment, and it has been experimentally evaluated using NMR and Raman spectroscopic techniques as well as by molecular dynamics simulation studies. The converging report indicates that GSH exists mainly in two major conformations, i.e., "extended" and "folded". The NMR-derived information on the GSH conformers is essential to obtain optimal acquisition parameters in in vivo MRS experiments targeted for GSH detection. To further investigate the implications of GSH conformers in in vivo MRS studies and their relative proportions in healthy and pathological conditions, a multi-center clinical research study is necessary with a common protocol for GSH detection and quantification.

%B J Alzheimers Dis %V 59 %P 537-541 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527221?dopt=Abstract %R 10.3233/JAD-170350 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Growth Arrest Specific 6 Concentration is Increased in the Cerebrospinal Fluid of Patients with Alzheimer's Disease. %A Sainaghi, Pier Paolo %A Bellan, Mattia %A Lombino, Franco %A Alciato, Federica %A Carecchio, Miryam %A Galimberti, Daniela %A Fenoglio, Chiara %A Scarpini, Elio %A Cantello, Roberto %A Pirisi, Mario %A Comi, Cristoforo %X

Growth arrest specific 6 (Gas6) has neurotrophic and neuroinflammatory functions, and may play a role in Alzheimer's disease (AD). In keeping with this hypothesis, we observed that cerebrospinal fluid (CSF) Gas6 is increased in AD patients compared to controls (63 versus 67 subjects; median value 13.3 versus 9.1 ng/ml; p < 0.0001). Thereafter, we assessed whether CSF Gas6 concentration was correlated to the following parameters: disease duration, MMSE score two years after clinical diagnosis, AD CSF biomarkers, and years of formal schooling. We detected an inverse correlation between CSF Gas6 levels at diagnosis and both disease duration (p < 0.0001) and decrease in the MMSE score two years later (p < 0.0001). Conversely, we found no correlation between CSF Gas6 and both AD biomarkers and years of formal schooling. In conclusion, our results suggest that upregulation of CSF Gas6 may be part of a defensive response aimed at counteracting AD progression.

%B J Alzheimers Dis %V 55 %P 59-65 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636849?dopt=Abstract %R 10.3233/JAD-160599 %0 Journal Article %J J Alzheimers Dis %D 2017 %T High Sensitivity Cardiac Troponin T and Cognitive Function in the Oldest Old: The Leiden 85-Plus Study. %A Bertens, Anne Suzanne %A Sabayan, Behnam %A de Craen, Anton J M %A Van der Mast, Roos C %A Gussekloo, Jacobijn %X

BACKGROUND: Impaired cardiac function has been related to accelerated cognitive decline in late-life.

OBJECTIVE: To investigate whether higher levels of high sensitivity cardiac troponin T (hs-cTnT), a sensitive marker for myocardial injury, are associated with worse cognitive function in the oldest old.

METHODS: In 455 participants of the population-based Leiden 85-plus Study, hs-cTnT was measured at 86 years. Cognitive function was measured annually during four years with the Mini-Mental State Examination (MMSE).

RESULTS: Participants in the highest gender-specific tertile of hs-cTnT had a 2.0-point lower baseline MMSE score than participants in the lowest tertile (95% confidence interval (CI) (95% CI 0.73-3.3), and had a 0.58-point steeper annual decline in MMSE during follow-up (95% CI 0.06-1.1). The associations remained after adjusting for sociodemographic and cardiovascular risk factors excluding those without a history of overt cardiac disease.

CONCLUSION: In a population-based sample of the oldest old, higher levels of hs-cTnT were associated with worse cognitive function and faster cognitive decline, independently from cardiovascular risk factors and a history of overt cardiac disease.

%B J Alzheimers Dis %V 60 %P 235-242 %G eng %N 1 %R 10.3233/JAD-170171 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A High-Cholesterol Diet Increases 27-Hydroxycholesterol and Modifies Estrogen Receptor Expression and Neurodegeneration in Rabbit Hippocampus. %A Brooks, Sylwia W %A Dykes, Ava C %A Schreurs, Bernard G %X

Hypercholesterolemia has been implicated in numerous health problems from cardiovascular disease to neurodegeneration. High serum cholesterol levels in midlife have been associated with an increased risk of developing Alzheimer's disease (AD) later in life which suggests that the pathways leading to AD pathology might be activated decades before the symptoms of the disease are detected. Cholesterol-fed animals, particularly cholesterol-fed rabbits, exhibit brain pathology similar to the changes found in brains of AD patients. Dietary cholesterol, which cannot pass the blood-brain barrier, is thought to influence central nervous system homeostasis by increased transport of its circulatory breakdown product, 27-hydroxycholesterol (27-OHC), into the brain. 27-OHC is an endogenous selective estrogen receptor modulator. Estrogen-mediated non-reproductive functions require estrogen receptors (ERs) and include modulation of mitochondrial function and structure, as well as regulation of synaptogenesis in the brain. ERs are located in brain areas affected early in AD pathogenesis, including the hippocampus. Here we report that increase in serum cholesterol, induced by feeding rabbits a high-cholesterol diet, is associated with higher levels of 27-OHC in the brain as well as increased levels of neurodegeneration in the hippocampus. Furthermore, these results are accompanied by changes in expression of ERs in the hippocampus as well as a decrease in hippocampal mitochondria. These findings provide an important insight into one of the possible mechanisms involved in the development of AD, and shed light on the processes that may antedate amyloid-β and tau phosphorylation changes currently hypothesized to cause AD symptomology and pathology.

%B J Alzheimers Dis %V 56 %P 185-196 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911307?dopt=Abstract %R 10.3233/JAD-160725 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Histogram-Based Feature Extraction from Individual Gray Matter Similarity-Matrix for Alzheimer's Disease Classification. %A Beheshti, Iman %A Maikusa, Norihide %A Matsuda, Hiroshi %A Demirel, Hasan %A Anbarjafari, Gholamreza %X

Automatic computer-aided diagnosis (CAD) systems have been widely used in classification of patients who suffer from Alzheimer's disease (AD). This paper presents an automatic CAD system based on histogram feature extraction from single-subject gray matter similarity-matrix for classifying the AD patients from healthy controls (HC) using structural magnetic resonance imaging (MRI) data. The proposed CAD system is composed of five stages. In the first stage, segmentation is employed to perform pre-processing on the MRI images, and segment into gray matter, white matter, and cerebrospinal fluid using the voxel-based morphometric toolbox procedure. In the second stage, gray matter MRI scans are used to construct similarity-matrices. In the third stage, a novel statistical feature-generation process is proposed, utilizing the histogram of the individual similarity-matrix to represent statistical patterns of the respective similarity-matrices of different size and order into fixed-size feature-vectors. In the fourth stage, we propose to combine MRI measures with a neuropsychological test, the Functional Assessment Questionnaire (FAQ), to improve the classification accuracy. Finally, the classification is performed using a support vector machine and evaluated with the 10-fold cross-validation strategy. We evaluated the proposed method on 99 AD and 102 HC subjects from the J-ADNI. The proposed CAD system yields an 84.07% classification accuracy using MRI measures and 97.01% for combining MRI measures with FAQ scores, respectively. The experimental results indicate that the performance of the proposed system is competitive with respect to state-of-the-art techniques reported in the literature.

%B J Alzheimers Dis %V 55 %P 1571-1582 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27886012?dopt=Abstract %R 10.3233/JAD-160850 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Histopathology and Florbetaben PET in Patients Incorrectly Diagnosed with Alzheimer's Disease. %A Sabbagh, Marwan N %A Schäuble, Barbara %A Anand, Keshav %A Richards, Danielle %A Murayama, Shigeo %A Akatsu, Hiroyasu %A Takao, Masaki %A Rowe, Christopher C %A Masters, Colin L %A Barthel, Henryk %A Gertz, Hermann-Josef %A Peters, Oliver %A Rasgon, Natalie %A Jovalekic, Aleksandar %A Sabri, Osama %A Schulz-Schaeffer, Walter J %A Seibyl, John %X

Of 57 individuals diagnosed with Alzheimer's disease (AD) in a phase III study, 13 (23%) had amyloid-β (Aβ) levels on postmortem histopathology that did not explain the dementia. Based on postmortem histopathology, a wide range of different non-AD conditions was identified, including frontotemporal dementia, hippocampal sclerosis, and dementia with Lewy bodies. Of the histopathologically Aβ negative scored cases ante-mortem Florbetaben PET scans were classified as negative for Aβ in 11 patients based on visual analysis and in all 12 quantifiable cases based on composite standardized uptake value ratios. Thus, florbetaben PET can assist physicians in the differential diagnosis of neurodegenerative disorders by reliably excluding Aβ pathology.

%B J Alzheimers Dis %V 56 %P 441-446 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27983552?dopt=Abstract %R 10.3233/JAD-160821 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Home-Based Exercise Program Improves Balance and Fear of Falling in Community-Dwelling Older Adults with Mild Alzheimer's Disease: A Pilot Study. %A Padala, Kalpana P %A Padala, Prasad R %A Lensing, Shelly Y %A Dennis, Richard A %A Bopp, Melinda M %A Roberson, Paula K %A Sullivan, Dennis H %X

BACKGROUND/OBJECTIVE: Balance problems are common in older adults with Alzheimer's disease (AD). The objective was to study the effects of a Wii-Fit interactive video-game-led physical exercise program to a walking program on measures of balance in older adults with mild AD.

METHODS: A prospective randomized controlled parallel-group trial (Wii-Fit versus walking) was conducted in thirty community-dwelling older adults (73±6.2 years) with mild AD. Home-based exercises were performed under caregiver supervision for 8 weeks. Primary (Berg Balance Scale, BBS) and secondary outcomes (fear of falls and quality of life) were measured at baseline, 8 weeks (end of intervention), and 16 weeks (8-weeks post-intervention).

RESULTS: At 8 weeks, there was a significantly greater improvement (average inter-group difference [95% CI]) in the Wii-Fit group compared to the walking group in BBS (4.8 [3.3-6.2], p < 0.001), after adjusting for baseline. This improvement was sustained at 16 weeks (3.5 [2.0-5.0], p < 0.001). Analyses of the secondary outcome measures indicated that there was a significantly greater improvement in the Wii-Fit group compared to walking group in Activity-specific Balance Confidence scale (6.5 [3.6-9.4], p < 0.001) and Falls Efficacy Scale (-4.8 [-7.6 to -2.0], p = 0.002) at 8 weeks. However, this effect was not sustained at 16 weeks. Quality of life improved in both groups at 8 weeks; however, there were no inter-group differences (p = 0.445).

CONCLUSION: Home-based, caregiver-supervised Wii-Fit exercises improve balance and may reduce fear of falling in community-dwelling older adults with mild AD.

%B J Alzheimers Dis %V 59 %P 565-574 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28655135?dopt=Abstract %R 10.3233/JAD-170120 %0 Journal Article %J J Alzheimers Dis %D 2017 %T How Studies of the Serotonin System in Macaque Models of Menopause Relate to Alzheimer's Disease1. %A Bethea, Cynthia L %A Reddy, Arubala P %A Christian, Fernanda Lima %X

Serotonin plays a key role in mood or affect, and dysfunction of the serotonin system has been linked to depression in humans and animal models. Depression appears prior to or coincident with overt symptoms of Alzheimer's disease (AD) in about 50% of patients, and some experts consider it a risk factor for the development of AD. In addition, AD is more prevalent in women, who also show increased incidence of depression. Indeed, it has been proposed that mechanisms underlying depression overlap the mechanisms thought to hasten AD. Women undergo ovarian failure and cessation of ovarian steroid production in middle age and the postmenopausal period correlates with an increase in the onset of depression and AD. This laboratory has examined the many actions of ovarian steroids in the serotonin system of non-human primates using a rhesus macaque model of surgical menopause with short or long-term estradiol (E) or estradiol plus progesterone (E+P) replacement therapy. In this mini-review, we present a brief synopsis of the relevant literature concerning AD, depression, and serotonin. We also present some of our data on serotonin neuron viability, the involvement of the caspase-independent pathway, and apoptosis-inducing factor in serotonin-neuron viability, as well as gene expression related to neurodegeneration and neuron viability in serotonin neurons from adult and aged surgical menopausal macaques. We show that ovarian steroids, particularly E, are crucial for serotonin neuron function and health. In the absence of E, serotonin neurons are endangered and deteriorating toward apoptosis. The possibility that this scenario may proceed or accompany AD in postmenopausal women seems likely.

%B J Alzheimers Dis %V 57 %P 1001-1015 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662311?dopt=Abstract %R 10.3233/JAD-160601 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Humanin Specifically Interacts with Amyloid-β Oligomers and Counteracts Their in vivo Toxicity. %A Romeo, Margherita %A Stravalaci, Matteo %A Beeg, Marten %A Rossi, Alessandro %A Fiordaliso, Fabio %A Corbelli, Alessandro %A Salmona, Mario %A Gobbi, Marco %A Cagnotto, Alfredo %A Diomede, Luisa %K Amyloid beta-Peptides %K Animals %K Animals, Genetically Modified %K Caenorhabditis elegans %K Caenorhabditis elegans Proteins %K Circular Dichroism %K Disease Models, Animal %K Dose-Response Relationship, Drug %K Gene Expression Regulation %K Humans %K Intracellular Signaling Peptides and Proteins %K Microscopy, Atomic Force %K Microscopy, Electron, Transmission %K Neprilysin %K Paralysis %K Peptide Fragments %K Surface Plasmon Resonance %X

The 24-residue peptide humanin (HN) has been proposed as a peptide-based inhibitor able to interact directly with amyloid-β (Aβ) oligomers and interfere with the formation and/or biological properties of toxic Aβ species. When administered exogenously, HN, or its synthetic S14G-derivative (HNG), exerted multiple cytoprotective effects, counteracting the Aβ-induced toxicity. Whether these peptides interact directly with Aβ, particularly with the soluble oligomeric assemblies, remains largely unknown. We here investigated the ability of HN and HNG to interact directly with highly aggregating Aβ42, and interfere with the formation and toxicity of its oligomers. Experiments were run in cell-free conditions and in vivo in a transgenic C. elegans strain in which the Aβ toxicity was specifically due to oligomeric species. Thioflavin-T assay indicated that both HN and HNG delay the formation and reduce the final amount of Aβ42 fibrils. In vitro surface plasmon resonance studies indicated that they interact with Aβ42 oligomers favoring the formation of amorphous larger assemblies, observed with turbidity and electron microscopy. In vivo studies indicated that both HN and HNG decrease the relative abundance of A11-positive prefibrillar oligomers as well as OC-positive fibrillar oligomers and had similar protective effects. However, while HN possibly decreased the oligomers by promoting their assembly into larger aggregates, the reduction of oligomers caused by HNG can be ascribed to a marked decrease of the total Aβ levels, likely the consequence of the HNG-induced overexpression of the Aβ-degrading enzyme neprilysin. These findings provide information on the mechanisms underlying the anti-oligomeric effects of HN and HNG and illustrate the role of S14G substitution in regulating the in vivo mechanism of action.

%B J Alzheimers Dis %V 57 %P 857-871 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28282805?dopt=Abstract %R 10.3233/JAD-160951 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits. %A Fried, Peter J %A Schilberg, Lukas %A Brem, Anna-Katharine %A Saxena, Sadhvi %A Wong, Bonnie %A Cypess, Aaron M %A Horton, Edward S %A Pascual-Leone, Alvaro %X

BACKGROUND: Type-2 diabetes mellitus (T2DM) accelerates cognitive aging and increases risk of Alzheimer's disease. Rodent models of T2DM show altered synaptic plasticity associated with reduced learning and memory. Humans with T2DM also show cognitive deficits, including reduced learning and memory, but the relationship of these impairments to the efficacy of neuroplastic mechanisms has never been assessed.

OBJECTIVE: Our primary objective was to compare mechanisms of cortical plasticity in humans with and without T2DM. Our secondary objective was to relate plasticity measures to standard measures of cognition.

METHODS: A prospective cross-sectional cohort study was conducted on 21 adults with T2DM and 15 demographically-similar non-diabetic controls. Long-term potentiation-like plasticity was assessed in primary motor cortex by comparing the amplitude of motor evoked potentials (MEPs) from single-pulse transcranial magnetic stimulation before and after intermittent theta-burst stimulation (iTBS). Plasticity measures were compared between groups and related to neuropsychological scores.

RESULTS: In T2DM, iTBS-induced modulation of MEPs was significantly less than controls, even after controlling for potential confounds. Furthermore, in T2DM, modulation of MEPs 10-min post-iTBS was significantly correlated with Rey Auditory Verbal Learning Task (RAVLT) performance.

CONCLUSION: Humans with T2DM show abnormal cortico-motor plasticity that is correlated with reduced verbal learning. Since iTBS after-effects and the RAVLT are both NMDA receptor-dependent measures, their relationship in T2DM may reflect brain-wide alterations in the efficacy of NMDA receptors. These findings offer novel mechanistic insights into the brain consequences of T2DM and provide a reliable means to monitor brain health and evaluate the efficacy of clinical interventions.

%B J Alzheimers Dis %V 55 %P 89-100 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636847?dopt=Abstract %R 10.3233/JAD-160505 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Impact of Alzheimer's Disease on the Resting State Functional Connectivity of Brain Regions Modulating Pain: A Cross Sectional Study. %A Monroe, Todd B %A Beach, Paul A %A Bruehl, Stephen P %A Dietrich, Mary S %A Rogers, Baxter P %A Gore, John C %A Atalla, Sebastian W %A Cowan, Ronald L %X

BACKGROUND: It is currently unknown why people with Alzheimer's disease (AD) receive less pain medication and report pain less frequently.

OBJECTIVE: The purpose of this study was to determine the impact of AD on thermal psychophysics and resting-state functional connectivity (RSFC) among sensory, affective, descending modulatory, and default mode structures.

METHODS: Controls (n = 23, 13 = female) and age-matched people with AD (n = 23, 13 = females) underwent psychophysical testing to rate perceptions of warmth, mild, and moderate pain and then completed resting-state fMRI. Between groups analysis in psychophysics and RSFC were conducted among pre-defined regions of interest implicated in sensory and affective dimensions of pain, descending pain modulation, and the default mode network.

RESULTS: People with AD displayed higher thermal thresholds for warmth and mild pain but similar moderate pain thresholds to controls. No between-group differences were found for unpleasantness at any percept. Relative to controls, people with AD demonstrated reduced RSFC between the right posterior insula and left anterior cingulate and also between right amygdala and right secondary somatosensory cortex. Moderate pain unpleasantness reports were associated with increased RSFC between right dorsolateral prefrontal cortex and left ACC in controls only.

CONCLUSIONS: While AD had little effect on unpleasantness, people with AD had increased thermal thresholds, altered RSFC, and no association of psychophysics with RSFC in pain regions. Findings begin to elucidate that in people with AD, altered integration of pain sensation, affect, and descending modulation may, in part, contribute to decreased verbal pain reports and thus decreased analgesic administration.

%B J Alzheimers Dis %V 57 %P 71-83 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222526?dopt=Abstract %R 10.3233/JAD-161187 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Impact of Recruitment Methods in Subjective Cognitive Decline. %A Abdelnour, Carla %A Rodríguez-Gómez, Octavio %A Alegret, Montserrat %A Valero, Sergi %A Moreno-Grau, Sonia %A Sanabria, Ángela %A Hernandez, Isabel %A Rosende-Roca, Maitee %A Vargas, Liliana %A Mauleón, Ana %A Sánchez, Domingo %A Espinosa, Ana %A Ortega, Gemma %A Pérez-Cordón, Alba %A Diego, Susana %A Gailhajanet, Anna %A Guitart, Marina %A Sotolongo-Grau, Oscar %A Ruiz, Agustin %A Tárraga, Lluís %A Boada, Merce %X

BACKGROUND: Recruitment methods can determine sample characteristics in mild cognitive impairment and Alzheimer's disease dementia, but little is known about its influence in subjective cognitive decline (SCD).

OBJECTIVE: To determine the influence of two types of recruitment methods in the characteristics of individuals with SCD.

METHODS: We select and compare clinical and neuropsychological features, and frequency of APOE ɛ4 allele of 326 subjects with SCD from two cohorts: Open House Initiative (OHI) versus Memory Unit (MU). A logistic regression analysis (LRA), using gender and years of education as covariates, was used to examine the neuropsychological variables.

RESULTS: The OHI sample were mostly women (75.9% versus 64.5%, p < 0.05), with higher educational level (12.15 [3.71] versus 10.70 [3.80] years, p = 0.001), and more family history of dementia (138 [62.7%] versus 44 [41.5%], p < 0.001) than the MU sample. Also, the OHI sample showed better overall neuropsychological performance than the MU sample, and after a LRA, this trend continued in automatic response inhibition capacity, abstract reasoning, and recognition memory. We did not find differences in age, depression history, and/or APOE ɛ4 allele frequency.

CONCLUSION: SCD subjects showed different demographic and neuropsychological characteristics depending on the recruitment method, which should be taken into account in the design of research studies with this target population.

%B J Alzheimers Dis %V 57 %P 625-632 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269773?dopt=Abstract %R 10.3233/JAD-160915 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Impact of the Relationship of Stress and the Immune System in the Appearance of Alzheimer's Disease. %A de la Rubia Ortí, Jose Enrique %A Sancho Castillo, Sandra %A Benlloch, Maria %A Julián Rochina, Mariano %A Corchón Arreche, Silvia %A García-Pardo, María Pilar %X

The understanding of how the immune system works, as well as its relationship with the stress level, seems to be important at the start of the Alzheimer's disease (AD). To analyze this, immunoglobulin A (IgA) and cortisol in saliva were measured using ELISA in patients with mild AD and healthy volunteers, and the production of both biomarkers was compared and correlated. In participants without AD, IgA was higher when cortisol was lower, and the opposite happened in participants with AD, with the quantification in saliva being a suitable method to determine it.

%B J Alzheimers Dis %V 55 %P 899-903 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767997?dopt=Abstract %R 10.3233/JAD-160903 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Implication of the APP Gene in Intellectual Abilities. %A Myrum, Craig %A Nikolaienko, Oleksii %A Bramham, Clive R %A Haavik, Jan %A Zayats, Tetyana %X

BACKGROUND: Cognitive functions are highly heritable and polygenic, though the source of this genetic influence is unclear. On the neurobiological level, these functions rely on effective neuroplasticity, in which the activity-regulated cytoskeleton associated protein (ARC) plays an essential role.

OBJECTIVES: To examine whether the ARC gene complex may contribute to the genetic components of intellectual function given the crucial role of ARC in brain plasticity and memory formation.

METHODS: The ARC complex was tested for association with intelligence (IQ) in children from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 5,165). As Alzheimer's disease (AD) shares genetics with cognitive functioning, the association was followed up in an AD sample (17,008 cases, 37,154 controls).

RESULTS: The ARC complex revealed association with verbal and total IQ (empirical p = 0.027 and 0.041, respectively) in the ALSPAC. The strongest single variant signal (rs2830077; empirical p = 0.018), within the APP gene, was confirmed in the AD sample (p = 2.76E-03). Functional analyses of this variant showed its preferential binding to the transcription factor CP2.

DISCUSSION: This study implicates APP in childhood IQ. While follow-up studies are needed, this observation could help elucidate the etiology of disorders associated with cognitive dysfunction, such as AD.

%B J Alzheimers Dis %V 59 %P 723-735 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671113?dopt=Abstract %R 10.3233/JAD-170049 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer's Disease Patients and Controls after Correction for Ventricular Volumes. %A van Waalwijk van Doorn, Linda J C %A Gispert, Juan D %A Kuiperij, H Bea %A Claassen, Jurgen A H R %A Arighi, Andrea %A Baldeiras, Ines %A Blennow, Kaj %A Bozzali, Marco %A Castelo-Branco, Miguel %A Cavedo, Enrica %A Emek-Savaş, Derya D %A Eren, Erden %A Eusebi, Paolo %A Farotti, Lucia %A Fenoglio, Chiara %A Ormaechea, Juan Fortea %A Freund-Levi, Yvonne %A Frisoni, Giovanni B %A Galimberti, Daniela %A Genc, Sermin %A Greco, Viviana %A Hampel, Harald %A Herukka, Sanna-Kaisa %A Liu, Yawu %A Lladó, Albert %A Lleo, Alberto %A Nobili, Flavio M %A Oguz, Kader K %A Parnetti, Lucilla %A Pereira, João %A Picco, Agnese %A Pikkarainen, Maria %A de Oliveira, Catarina Resende %A Saka, Esen %A Salvadori, Nicola %A Sánchez-Valle, Raquel %A Santana, Isabel %A Scarpini, Elio %A Scheltens, Philip %A Soininen, Hilkka %A Tarducci, Roberto %A Teunissen, Charlotte %A Tsolaki, Magda %A Urbani, Andrea %A Vilaplana, Eduard %A Visser, Pieter Jelle %A Wallin, Asa K %A Yener, Görsev %A Molinuevo, José L %A Meulenbroek, Olga %A Verbeek, Marcel M %X

Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aβ42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aβ42 levels inversely correlated to VV/TIV in the whole study population (Aβ42: r = -0.28; p < 0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: r = -0.15; p-tau: r = -0.13; both p < 0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF Aβ42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aβ42 levels.

%B J Alzheimers Dis %V 56 %P 543-555 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059783?dopt=Abstract %R 10.3233/JAD-160668 %0 Journal Article %J J Alzheimers Dis %D 2017 %T In Vivo Detection of Gray Matter Neuropathology in the 3xTg Mouse Model of Alzheimer's Disease with Diffusion Tensor Imaging. %A Snow, Wanda M %A Dale, Ryan %A O'Brien-Moran, Zoe %A Buist, Richard %A Peirson, Danial %A Martin, Melanie %A Albensi, Benedict C %X

A diagnosis of Alzheimer's disease (AD), a neurodegenerative disorder accompanied by severe functional and cognitive decline, is based on clinical findings, with final confirmation of the disease at autopsy by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles. Given that microstructural brain alterations occur years prior to clinical symptoms, efforts to detect brain changes early could significantly enhance our ability to diagnose AD sooner. Diffusion tensor imaging (DTI), a type of MRI that characterizes the magnitude, orientation, and anisotropy of the diffusion of water in tissues, has been used to infer neuropathological changes in vivo. Its utility in AD, however, is still under investigation. The current study used DTI to examine brain regions susceptible to AD-related pathology; the cerebral cortex, entorhinal cortex, and hippocampus, in 12-14-month-old 3xTg AD mice that possess both Aβ plaques and neurofibrillary tangles. Mean diffusivity did not differ between 3xTg and control mice in any region. Decreased fractional anisotropy (p < 0.01) and axial diffusivity (p < 0.05) were detected only in the hippocampus, in which both congophilic Aβ plaques and hyperphosphorylated tau accumulation, consistent with neurofibrillary tangle formation, were detected. Pathological tau accumulation was seen in the cortex. The entorhinal cortex was largely spared from AD-related neuropathology. This is the first study to demonstrate DTI abnormalities in gray matter in a mouse model of AD in which both pathological hallmarks are present, suggesting the feasibility of DTI as a non-invasive means of detecting brain pathology in vivo in early-stage AD.

%B J Alzheimers Dis %V 58 %P 841-853 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505976?dopt=Abstract %R 10.3233/JAD-170136 %0 Journal Article %J J Alzheimers Dis %D 2017 %T In vivo Patterns of Tau Pathology, Amyloid-β Burden, and Neuronal Dysfunction in Clinical Variants of Alzheimer's Disease. %A Dronse, Julian %A Fliessbach, Klaus %A Bischof, Gérard N %A von Reutern, Boris %A Faber, Jennifer %A Hammes, Jochen %A Kuhnert, Georg %A Neumaier, Bernd %A Onur, Oezguer A %A Kukolja, Juraj %A van Eimeren, Thilo %A Jessen, Frank %A Fink, Gereon R %A Klockgether, Thomas %A Drzezga, Alexander %X

The clinical heterogeneity of Alzheimer's disease is not reflected in the rather diffuse cortical deposition of amyloid-β. We assessed the relationship between clinical symptoms, in vivo tau pathology, amyloid distribution, and hypometabolism in variants of Alzheimer's disease using novel multimodal PET imaging techniques. Tau pathology was primarily observed in brain regions related to clinical symptoms and overlapped with areas of hypometabolism. In contrast, amyloid-β deposition was diffusely distributed over the entire cortex. Tau PET imaging may thus serve as a valuable biomarker for the localization of neuronal injury in vivo and may help to validate atypical subtypes of Alzheimer's disease.

%B J Alzheimers Dis %V 55 %P 465-471 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802224?dopt=Abstract %R 10.3233/JAD-160316 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Incident Cerebral Microbleeds Detected by Susceptibility Weight-Imaging Help to Identify Patients with Mild Cognitive Impairment Progressing to Alzheimer's Disease. %A Basselerie, Hubert %A Bracoud, Luc %A Zeestraten, Eva %A Bouguen, Eva %A Kiyasova, Vera %A Pueyo, Maria %A Cognard, Christophe %A Dumas, Hervé %A Gramada, Raluca %A Ousset, Pierre Jean %A Vellas, Bruno %A Bonneville, Fabrice %X

BACKGROUND: The relationship between cerebral microbleeds (CMB) and Alzheimer's disease (AD) has not yet been clearly determined, particularly with susceptibility weight-imaging (SWI).

OBJECTIVE: To evaluate the SWI sequence using 3T MRI for the detection of CMB, and its ability to differentiate elderly control subjects (CS), stable mild cognitive impairment patients (MCI-s), MCI patients progressing to AD (MCI-p), and AD patients.

METHODS: It was a prospective, monocentric, observational study that took place in Toulouse, France. Participants were 65 years and older, enrolled in three groups: CS, MCI, and AD. Based on the longitudinal analysis of cognitive decline, MCI subjects were retrospectively classified as MCI-s or MCI-p. Each patient had a 4-year follow-up with MRI at baseline (MRI#1) and during the fourth year (MRI#3). CMB were counted on native SWI images juxtaposed to minIP reformatted images.

RESULTS: 150 patients were enrolled: 48 CS, 25 MCI-s, 18 MCI-p, 59 AD. At MRI#1 and at MRI#3, there was no significant difference in the prevalence of CMB between groups (p = 0.75 and p = 0.87). In the MCI-p + AD group, significantly more subjects had≥4 incident CMB compared to the CS + MCI-s group (p = 0.016). In the MCI-p + AD group, the prevalence of patients with >4 CMB was significantly higher at MRI#3 than at MRI#1 (p = 0.008).

CONCLUSION: Using SWI, AD and MCI-p patients had developed significantly more new CMB than CS and MCI-s patients during the follow-up. Incident CMB might be suggested as a potential imaging marker of AD progression.

%B J Alzheimers Dis %V 60 %P 253-262 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826188?dopt=Abstract %R 10.3233/JAD-170470 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Increased Carbohydrate Intake is Associated with Poorer Performance in Verbal Memory and Attention in an APOE Genotype-Dependent Manner. %A Gardener, Samantha L %A Rainey-Smith, Stephanie R %A Sohrabi, Hamid R %A Weinborn, Michael %A Verdile, Giuseppe %A Fernando, W M A D Binosha %A Lim, Yen Ying %A Harrington, Karra %A Burnham, Samantha %A Taddei, Kevin %A Masters, Colin L %A Macaulay, Stuart L %A Rowe, Christopher C %A Ames, David %A Maruff, Paul %A Martins, Ralph N %X

Evidence suggests that a diet low in carbohydrates can impact on cognitive performance among those with Alzheimer's disease (AD). However, there is a lack of data assessing this relationship among cognitively normal (CN) older adults at increased future risk of developing AD due to carriage of the apolipoprotein E (APOE) ɛ4 allele. We assessed the cross-sectional association between carbohydrate intake, cognitive performance, and cerebral amyloid-β (Aβ) load in CN older adults, genotyped for APOEɛ4 allele carrier status. Greater carbohydrate intake was associated with poorer performance in verbal memory in APOEɛ4 allele non-carriers, and poorer performance in attention in APOEɛ4 allele carriers. There were no associations between carbohydrate intake and cerebral Aβ load. These results provide support to the idea that decreasing carbohydrate intake may offer neurocognitive benefits, with specific cognitive domains affected in an APOE genotype-dependent manner. These findings warrant further investigation utilizing a longitudinal study design.

%B J Alzheimers Dis %V 58 %P 193-201 %G eng %N 1 %R 10.3233/JAD-161158 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Increased PCSK9 Cerebrospinal Fluid Concentrations in Alzheimer's Disease. %A Zimetti, Francesca %A Caffarra, Paolo %A Ronda, Nicoletta %A Favari, Elda %A Adorni, Maria Pia %A Zanotti, Ilaria %A Bernini, Franco %A Barocco, Federica %A Spallazzi, Marco %A Galimberti, Daniela %A Ricci, Chiara %A Ruscica, Massimiliano %A Corsini, Alberto %A Ferri, Nicola %X

BACKGROUND: Alzheimer's disease (AD) has been associated with dysregulation of brain cholesterol trafficking and abnormal production of apolipoprotein E isoform 4 (apoE4). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein present in serum and cerebrospinal fluid (CSF) degrading the low-density lipoprotein receptor (LDLr) and other apoE-binding receptors involved in neuron cholesterol uptake. The role of PCSK9 in AD is controversial.

OBJECTIVE: We compared PCSK9 levels in CSF of AD patients and non-AD controls and looked at correlations with CSF total apoE and apoE4.

METHODS: CSF from AD (n = 30) and from age and sex-matched non-AD patients (n = 30) was collected by lumbar puncture for routine diagnosis. CSF PCSK9, total apoE, and apoE4 levels were measured by ELISA. AD patients showed the typical CSF neurobiomarker pattern (decreased Aβ42 and increased tau and phospho-tau) and impaired cognitive performances, as indicated by the scores of the Mini-Mental State Examination test.

RESULTS: PCSK9 levels in CSF were higher in AD than in non-AD subjects (+1.45 fold; p = 0.0049). CSF total apoE concentrations did not differ between the two groups, while apoE4 levels were higher in AD subjects (+3.34 fold; p = 0.0068). Considering all samples, a significant positive correlation was found between PCSK9 and apoE4 (r = 0.4409; p = 0.0006). PCSK9 levels were higher in APOE ɛ4 carriers, reaching statistical significance in the AD group (+1.45 fold; p = 0.0454).

CONCLUSION: These results report for the first time an alteration of CSF PCSK9 levels in AD and suggest a pathophysiological link between PCSK9, apoE4, and AD.

%B J Alzheimers Dis %V 55 %P 315-320 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662294?dopt=Abstract %R 10.3233/JAD-160411 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Increased Transforming Growth Factor β2 in the Neocortex of Alzheimer's Disease and Dementia with Lewy Bodies is Correlated with Disease Severity and Soluble Aβ42 Load. %A Chong, Joyce R %A Chai, Yuek Ling %A Lee, Jasinda H %A Howlett, David %A Attems, Johannes %A Ballard, Clive G %A Aarsland, Dag %A Francis, Paul T %A Chen, Christopher P %A Lai, Mitchell K P %X

BACKGROUND: Of the three transforming growth factor (TGF)-β isoforms known, TGFβ1 deficits have been widely reported in Alzheimer's disease (AD) and studied as a potential therapeutic target. In contrast, the status of TGFβ2, which has been shown to mediate amyloid-β (Aβ)-mediated neuronal death, are unclear both in AD and in Lewy body dementias (LBD) with differential neuritic plaque and neurofibrillary tangle burden.

OBJECTIVE: To measure neocortical TGFβ2 levels and their correlations with neuropathological and clinical markers of disease severity in a well-characterized cohort of AD as well as two clinical subtypes of LBD, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), known to manifest relatively high and low Aβ plaque burden, respectively.

METHODS: Postmortem samples from temporal cortex (BA21) were measured for TGFβ2 using a Luminex-based platform, and correlated with scores for neuritic plaques, neurofibrillary tangles, α-synuclein pathology, dementia severity (as measured by annual decline of Mini-Mental State Examination scores) as well as soluble and total fractions of brain Aβ42.

RESULTS: TGFβ2 was significantly increased in AD and DLB, but not in PDD. TGFβ2 also correlated with scores for neurofibrillary tangles, Lewy bodies (within the LBD group), dementia severity, and soluble Aβ42 concentration, but not with neuritic plaque scores, total Aβ42, or monomeric α-synuclein immunoreactivity.

CONCLUSIONS: TGFβ2 is increased in the temporal cortex of AD and DLB, and its correlations with neuropathological and clinical markers of disease severity as well as with soluble Aβ42 load suggest a potential pathogenic role in mediating the neurotoxicity of non-fibrillar Aβ. Our study also indicates the potential utility of targeting TGFβ2 in pharmacotherapeutic approaches to AD and DLB.

%B J Alzheimers Dis %V 56 %P 157-166 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911312?dopt=Abstract %R 10.3233/JAD-160781 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Individual Correspondence of Amyloid-β and Intrinsic Connectivity in the Posterior Default Mode Network Across Stages of Alzheimer's Disease. %A Pasquini, Lorenzo %A Benson, Gloria %A Grothe, Michel J %A Utz, Lukas %A Myers, Nicholas E %A Yakushev, Igor %A Grimmer, Timo %A Scherr, Martin %A Sorg, Christian %X

In Alzheimer's disease (AD), amyloid-β (Aβ) pathology and intrinsic functional connectivity (iFC) interact. Across stages of AD, we expected individual spatial correspondence of Aβ and iFC to reveal both Aβ accumulation and its detrimental effects on iFC. We used resting-state functional magnetic imaging and Aβ imaging in a cross-sectional sample of 90 subjects across stages of AD and healthy older adults. Global and local correspondence of Aβ and iFC were assessed within the posterior default mode network (pDMN) by within-subject voxel-wise correlations. Beginning at preclinical stages, global Aβ-iFC correspondence was positive for the whole pDMN, showing that Aβ accumulates in areas of high connectivity, and reached a plateau at prodromal stages. Starting at preclinical stages, local correspondence was negative in network centers, indicating that Aβ reduces connectivity of the pDMN as a function of local plaque concentration, and peaked at prodromal stages. Positive global correspondence suggests that Aβ accumulation progresses along iFC, with this effect starting in preclinical stages, and being constant along clinical periods. Negative local correspondence suggests detrimental effects of Aβ on iFC in network centers, starting at preclinical stages, and peaking when first symptoms appear. Data reveal a complex trajectory of Aβ and iFC correspondence, affecting both Aβ accumulation and iFC impairments.

%B J Alzheimers Dis %V 58 %P 763-773 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28482640?dopt=Abstract %R 10.3233/JAD-170096 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Inflammation, Amyloid, and Atrophy in The Aging Brain: Relationships with Longitudinal Changes in Cognition. %A Sala-Llonch, Roser %A Idland, Ane-Victoria %A Borza, Tom %A Watne, Leiv Otto %A Wyller, Torgeir Bruun %A Brækhus, Anne %A Zetterberg, Henrik %A Blennow, Kaj %A Walhovd, Kristine Beate %A Fjell, Anders Martin %X

Amyloid deposition occurs in aging, even in individuals free from cognitive symptoms, and is often interpreted as preclinical Alzheimer's disease (AD) pathophysiology. YKL-40 is a marker of neuroinflammation, being increased in AD, and hypothesized to interact with amyloid-β (Aβ) in causing cognitive decline early in the cascade of AD pathophysiology. Whether and how Aβ and YKL-40 affect brain and cognitive changes in cognitively healthy older adults is still unknown. We studied 89 participants (mean age: 73.1 years) with cerebrospinal fluid samples at baseline, and both MRI and cognitive assessments from two time-points separated by two years. We tested how baseline levels of Aβ42 and YKL-40 correlated with changes in cortical thickness and cognition. Thickness change correlated with Aβ42 only in Aβ42+ participants (<600 pg/mL, n = 27) in the left motor and premotor cortices. Aβ42 was unrelated to cognitive change. Increased YKL-40 was associated with less preservation of scores on the animal naming test in the total sample (r = -0.28, p = 0.012) and less preservation of a score reflecting global cognitive function for Aβ42+ participants (r = -0.58, p = 0.004). Our results suggest a role for inflammation in brain atrophy and cognitive changes in cognitively normal older adults, which partly depended on Aβ accumulation.

%B J Alzheimers Dis %V 58 %P 829-840 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505968?dopt=Abstract %R 10.3233/JAD-161146 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Insula and Inferior Frontal Gyrus' Activities Protect Memory Performance Against Alzheimer's Disease Pathology in Old Age. %A Lin, Feng %A Ren, Ping %A Lo, Raymond Y %A Chapman, Benjamin P %A Jacobs, Alanna %A Baran, Timothy M %A Porsteinsson, Anton P %A Foxe, John J %X

Apolipoprotein E (APOE) ɛ4 carriers and patients with amnestic mild cognitive impairment (MCI) have high risk of developing Alzheimer's disease (AD). The Scaffolding Theory of Aging and Cognition proposes that recruitment of additional frontal brain regions can protect cognition against aging. This thesis has yet to be fully tested in older adults at high risk for AD. In the present study, 75 older participants (mean age: 74 years) were included. Applying a voxel-wise approach, fractional amplitude of low-frequency fluctuations (fALFF) in resting-state functional neuroimaging data were analyzed as a function of APOEɛ4 status (carrier versus noncarrier) and clinical status (healthy control [HC] versus MCI) using a 2×2 analysis of covariance (ANCOVA). Measures of cognition and cerebrospinal fluid levels of amyloid- β were also obtained. Three frontal regions were identified with significant interaction effects using ANCOVA (corrected p < 0.01): left-insula, left-inferior frontal gyrus (IFG), and right-precentral gyrus. The HC/APOEɛ4 carrier group had significantly higher fALFF in all three regions than other groups. In the entire sample, for two regions (left insula and left IFG), a significant positive relationship between amyloid-β and memory was only observed among individuals with low fALFF. Our results suggest higher activity in frontal regions may explain being cognitively normal among a subgroup of APOEɛ4 carriers and protect against the negative impact of AD-associated pathology on memory. This is an observation with potential implications for AD therapeutics.

%B J Alzheimers Dis %V 55 %P 669-678 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716674?dopt=Abstract %R 10.3233/JAD-160715 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Integration of Multilocus Genetic Risk into the Default Mode Network Longitudinal Trajectory during the Alzheimer's Disease Process. %A Su, Fan %A Shu, Hao %A Ye, Qing %A Xie, Chunming %A Yuan, Baoyu %A Zhang, Zhijun %A Bai, Feng %X

The aim of the study was to investigate the cognitive significance of the changes in default mode network (DMN) during the process of Alzheimer's disease (AD) and the genetic basis that drives the alteration. Eighty-seven subjects with mild cognitive impairment (MCI) and 131 healthy controls (HC) were employed at baseline, and they had the genetic risk scores (GRS) based on the GWAS-validated AD-related top loci. Eleven MCIs who converted to AD (c-MCIs), 32 subjects who remained stable (nc-MCIs), and 56 HCs participated in the follow-up analyses after an average of 35 months. Decreased functional connectivity (FC) within temporal cortex was identified for MCIs at baseline, which was partially determined by the GRS; moreover, compensations may occur within the frontal-parietal brain to maintain relatively intact cognition. During the follow-ups, c-MCIs exhibited more FC declines within the prefrontal-parietal lobes and parahippocampal gyrus/hippocampus than the HCs and nc-MCIs. The GRS did not significantly vary among the three groups, whereas associations were identified at risky alleles and FC declines in all AD spectra. Interestingly, the influence of APOEɛ4 varied as the disease progressed; APOEɛ4 was associated with longitudinal FC decreases only for HCs in the single variance-based analyses and deteriorated DMN integration in nc-MCIs by combining the effects of other loci. However, the GRS without APOEɛ4 predicted FC decline for converters. It is suggested that the integration of multilocus genetic risk predicted the longitudinal trajectory of DMN and may be used as a clinical strategy to track AD progression.

%B J Alzheimers Dis %V 56 %P 491-507 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035927?dopt=Abstract %R 10.3233/JAD-160787 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Intracerebroventricular Streptozotocin Induces Obesity and Dementia in Lewis Rats. %A Bloch, Konstantin %A Gil-Ad, Irit %A Vanichkin, Alexey %A Hornfeld, Shay Henry %A Koroukhov, Nickolay %A Taler, Michal %A Vardi, Pnina %A Weizman, Abraham %X

BACKGROUND: Animal models of dementia associated with metabolic abnormalities play an important role in understanding the bidirectional relationships between these pathologies. Rodent strains develop cognitive dysfunctions without alteration of peripheral metabolism following intracerebroventricular administration of streptozotocin (icv-STZ).

OBJECTIVE: We aimed to estimate the effect of icv-STZ on cognitive functions and peripheral metabolism in Lewis rats, which are rarely used for the induction of cognitive abnormalities.

METHODS: Inbred adult Lewis rats were treated with single icv-STZ (3 mg/kg). Cognitive functions were assessed using Morris water maze (MWM) test and locomotion by the Open Field test. Metabolic alterations were studied using histological and biochemical analysis of brain and peripheral tissues.

RESULTS: The icv-STZ induced rapid weight decline during the first two weeks. Thereafter, the rats showed an accelerated weight gain. Three months after the icv-STZ treatment, the rats were severely obese and revealed fatty liver, pancreatic islet hypertrophy, significantly elevated levels of blood insulin, leptin, and adiponectin, but intact peripheral glucose homeostasis. The icv-STZ rats expressed amyloid-β deposits in blood vessels of leptomeningeal area, microgliosis, astrogliosis, and spongiosis in fimbria-fornix area of hippocampus. Locomotor activities of icv-STZ treated and sham-operated rats were similar. In the MWM test, the icv-STZ treated rats demonstrated severely impaired spatial learning during both acquisition and reversal phases.

CONCLUSIONS: Icv-STZ treated Lewis rats develop severe dementia associated with obesity and peripheral metabolic abnormalities. This animal model may be useful for exploring the pathophysiological relationship between obesity and dementia and provides a new tool for development of effective therapy.

%B J Alzheimers Dis %V 60 %P 121-136 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28800326?dopt=Abstract %R 10.3233/JAD-161289 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Intracranial Arterial 4D Flow in Individuals with Mild Cognitive Impairment is Associated with Cognitive Performance and Amyloid Positivity. %A Berman, Sara E %A Clark, Lindsay R %A Rivera-Rivera, Leonardo A %A Norton, Derek %A Racine, Annie M %A Rowley, Howard A %A Bendlin, Barbara B %A Blennow, Kaj %A Zetterberg, Henrik %A Carlsson, Cynthia M %A Asthana, Sanjay %A Turski, Patrick %A Wieben, Oliver %A Johnson, Sterling C %X

It is becoming increasingly recognized that cerebrovascular disease is a contributing factor in the pathogenesis of Alzheimer's disease (AD). A unique 4D-Flow magnetic resonance imaging (MRI) technique, phase contrast vastly undersampled isotropic projection imaging (PC VIPR), enables examination of angiographic and quantitative metrics of blood flow in the arteries of the Circle of Willis within a single MRI acquisition. Thirty-eight participants with mild cognitive impairment (MCI) underwent a comprehensive neuroimaging protocol (including 4D-Flow imaging) and a standard neuropsychological battery. A subset of participants (n = 22) also underwent lumbar puncture and had cerebrospinal fluid (CSF) assayed for AD biomarkers. Cut-offs for biomarker positivity in CSF resulting from a receiver operating characteristic curve analysis of AD cases and controls from the larger Wisconsin Alzheimer's Disease Research Center cohort were used to classify MCI participants as biomarker positive or negative on amyloid-β (Aβ42), total-tau and total-tau/Aβ42 ratio. Internal carotid artery (ICA) and middle cerebral artery (MCA) mean flow were associated with executive functioning performance, with lower mean flow corresponding to worse performance. MCI participants who were biomarker positive for Aβ42 had lower ICA mean flow than did those who were Aβ42 negative. In sum, mean ICA and MCA arterial flow was associated with cognitive performance in participants with MCI and lower flow in the ICA was associated with amyloid positivity. This provides further evidence for vascular health as a contributing factor in the etiopathogenesis of AD, and could represent a point to intervene in the disease process.

%B J Alzheimers Dis %V 60 %P 243-252 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826187?dopt=Abstract %R 10.3233/JAD-170402 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Intranasal Insulin Transport is Preserved in Aged SAMP8 Mice and is Altered by Albumin and Insulin Receptor Inhibition. %A Rhea, Elizabeth M %A Humann, Samantha R %A Nirkhe, Surabhi %A Farr, Susan A %A Morley, John E %A Banks, William A %X

Insulin delivered to the level of the cribriform plate (intranasal insulin) is being investigated for its ability to enhance memory in people with Alzheimer's disease (AD). Recent work has shown intranasal insulin can be detected in young CD-1 mice within 5 min and is still present 60 min after injection. The current study determined whether intranasal insulin transport and the subsequent brain distribution of insulin varies in young, healthy mice (CD-1) compared to those with an AD-like phenotype (aged SAMP8) or those pre-disposed to develop such a phenotype (young SAMP8). We showed transport does not vary among these three mouse cohorts, suggesting that intranasal uptake and brain pharmacokinetics do not differ with AD-like signs or the genetic predisposition to developing them. We found that co-administration with bovine serum albumin increased levels of insulin in most brain regions. In addition, the insulin receptor inhibitor, S961, decreases the amount of insulin transported throughout the brain after intranasal injection. These results show insulin delivery to the brain by intranasal administration can be modified with agents such as albumin, may be dependent on the insulin receptor, and is not affected by an AD-like phenotype as presented by the SAMP8 mouse.

%B J Alzheimers Dis %V 57 %P 241-252 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222522?dopt=Abstract %R 10.3233/JAD-161095 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Iron Concentration in Deep Gray Matter Structures is Associated with Worse Visual Memory Performance in Healthy Young Adults. %A Darnai, Gergely %A Nagy, Szilvia Anett %A Horváth, Réka %A Ács, Péter %A Perlaki, Gábor %A Orsi, Gergely %A Kovács, Norbert %A Altbäcker, Anna %A Plózer, Enikő %A Tényi, Dalma %A Weintraut, Rita %A Schwarcz, Attila %A John, Flóra %A Varga, Eszter %A Bereczkei, Tamás %A Clemens, Zsófia %A Komoly, Sámuel %A Janszky, József %X

Abnormally high deposition of iron can contribute to neurodegenerative disorders with cognitive impairment. Since previous studies investigating cognition-brain iron accumulation relationships focused on elderly people, our aim was to explore the association between iron concentration in subcortical nuclei and two types of memory performances in a healthy young population. Gender difference was found only in the globus pallidus. Our results showed that iron load characterized by R2* value on the MRI in the caudate and putamen was related to visual memory, while verbal memory was unrelated to iron concentration.

%B J Alzheimers Dis %V 59 %P 675-681 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671115?dopt=Abstract %R 10.3233/JAD-170118 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Kidins220 Correlates with Tau in Alzheimer's Disease Brain and Cerebrospinal Fluid. %A Gamir-Morralla, Andrea %A Belbin, Olivia %A Fortea, Juan %A Alcolea, Daniel %A Ferrer, Isidro %A Lleo, Alberto %A Iglesias, Teresa %X

Identification of neurodegeneration-monitoring biomarkers would be of great clinical value for Alzheimer's disease (AD) diagnosis. Using N- or C-terminal antibodies, we studied the pro-survival synaptic effector, Kidins220, in the brain and cerebrospinal fluid (CSF) of controls and AD patients. Only the N-terminal antibody showed a positive correlation between Kidins220 and phosphorylated tau in AD brains. Using this antibody, Kidins220 was detected in CSF from AD patients where it positively correlated with CSF phosphorylated tau and tau. This study highlights the potential of Kidins220 as a CSF biomarker in AD.

%B J Alzheimers Dis %V 55 %P 1327-1333 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858709?dopt=Abstract %R 10.3233/JAD-160639 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Left Frontal Hub Connectivity during Memory Performance Supports Reserve in Aging and Mild Cognitive Impairment. %A Franzmeier, Nicolai %A Hartmann, Julia C %A Taylor, Alexander N W %A Araque Caballero, Miguel Á %A Simon-Vermot, Lee %A Buerger, Katharina %A Kambeitz-Ilankovic, Lana M %A Ertl-Wagner, Birgit %A Mueller, Claudia %A Catak, Cihan %A Janowitz, Daniel %A Stahl, Robert %A Dichgans, Martin %A Duering, Marco %A Ewers, Michael %X

Reserve in aging and Alzheimer's disease (AD) is defined as maintaining cognition at a relatively high level in the presence of neurodegeneration, an ability often associated with higher education among other life factors. Recent evidence suggests that higher resting-state functional connectivity within the frontoparietal control network, specifically the left frontal cortex (LFC) hub, contributes to higher reserve. Following up these previous resting-state fMRI findings, we probed memory-task related functional connectivity of the LFC hub as a neural substrate of reserve. In elderly controls (CN, n = 37) and patients with mild cognitive impairment (MCI, n = 17), we assessed global connectivity of the LFC hub during successful face-name association learning, using generalized psychophysiological interaction analyses. Reserve was quantified as residualized memory performance, accounted for gender and proxies of neurodegeneration (age, hippocampus atrophy, and APOE genotype). We found that greater education was associated with higher LFC-connectivity in both CN and MCI during successful memory. Furthermore, higher LFC-connectivity predicted higher residualized memory (i.e., reserve). These results suggest that higher LFC-connectivity contributes to reserve in both healthy and pathological aging.

%B J Alzheimers Dis %V 59 %P 1381-1392 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731448?dopt=Abstract %R 10.3233/JAD-170360 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Left Ventricular Hypertrophy and Cognitive Decline in Old Age. %A Mahinrad, Simin %A Vriend, Annelotte E %A Jukema, J Wouter %A van Heemst, Diana %A Sattar, Naveed %A Blauw, Gerard Jan %A Macfarlane, Peter W %A Clark, Elaine N %A de Craen, Anton J M %A Sabayan, Behnam %X

BACKGROUND: Patients with advanced heart failure run a greater risk of dementia. Whether early cardiac structural changes also associate with cognitive decline is yet to be determined.

OBJECTIVE: We tested whether left ventricular hypertrophy (LVH) derived from electrocardiogram associates with cognitive decline in older subjects at risk of cardiovascular disease.

METHODS: We included 4,233 participants (mean age 75.2 years, 47.8% male) from PROSPER (PROspective Study of Pravastatin in the Elderly at Risk). LVH was assessed from baseline electrocardiograms by measuring the Sokolow-Lyon index. Higher levels of Sokolow-Lyon index indicate higher degrees of LVH. Cognitive domains involving selective attention, processing speed, and immediate and delayed memory were measured at baseline and repeated during a mean follow-up of 3.2 years.

RESULTS: At baseline, LVH was not associated with worse cognitive function. During follow-up, participants with higher levels of LVH had a steeper decline in cognitive function including in selective attention (p = 0.009), processing speed (p = 0.010), immediate memory (p < 0.001), and delayed memory (p = 0.002). These associations were independent of cardiovascular risk factors, co-morbidities, and medications.

CONCLUSION: LVH assessed by electrocardiogram associates with steeper decline in cognitive function of older subjects independent of cardiovascular risk factors and co-morbidities. This study provides further evidence on the link between subclinical cardiac structural changes and cognitive decline in older subjects.

%B J Alzheimers Dis %V 58 %P 275-283 %G eng %N 1 %R 10.3233/JAD-161150 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The level of 24-Hydroxycholesteryl Esters is an Early Marker of Alzheimer's Disease. %A Benussi, Luisa %A Ghidoni, Roberta %A Dal Piaz, Fabrizio %A Binetti, Giuliano %A Di Iorio, Giuseppe %A Abrescia, Paolo %X

Cholesterol (C) brain accumulation seems to play a role in the Alzheimer's disease (AD) pathogenesis. 24(S)-hydroxycholesterol (24OH-C) is the predominant metabolite of brain C and its synthesis is believed to represent a way to remove excess C from neurons. Previous studies showed that 24OH-C level is altered in patients with neurodegenerative diseases, including AD. Only one study demonstrated that 24OH-C esterification is altered in neurodegenerative diseases, i.e., amyotrophic lateral sclerosis. Herein we analyzed the level of 24OH-C esters (% 24OH-CE) in i) cerebrospinal fluid (CSF) and homologous serum of AD (n = 13) and controls (n = 8); ii) plasma from AD (n = 30), controls (n = 30), mild cognitive impairment (MCI) converting to AD (n = 34), and stable MCI (n = 40). The % 24OH-CE in CSF positively correlated with that in homologous serum and was lower in both CSF and blood from AD patients as compared to controls; moreover, the plasma value of % 24OH-CE was lower in MCI conv-AD than in non-converters. Kaplan Meier Survival curves revealed a significant anticipation of the disease onset in AD and MCI conv-AD subjects with the lowest % 24OH-CE values. In conclusion, the reduction of % 24OH-CE in AD and MCI conv-AD, as well as the anticipation of the disease in patients with the lowest % 24OH-CE, support a role of the cholesterol/lecithin-cholesterol acyltransferase axis in AD onset/progression. Thus, targeting brain cholesterol metabolism could be a valuable strategy to prevent AD associated cognitive decline.

%B J Alzheimers Dis %V 56 %P 825-833 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27983556?dopt=Abstract %R 10.3233/JAD-160930 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Link between Type 2 Diabetes and Neurodegeneration: Roles for Amyloid-β, Amylin, and Tau Proteins. %A Bharadwaj, Prashant %A Wijesekara, Nadeeja %A Liyanapathirana, Milindu %A Newsholme, Philip %A Ittner, Lars %A Fraser, Paul %A Verdile, Giuseppe %X

A wealth of evidence indicates a strong link between type 2 diabetes (T2D) and neurodegenerative diseases such as Alzheimer's disease (AD). Although the precise mechanism remains unclear, T2D can exacerbate neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism, and central nervous system insulin resistance are features of both AD and T2D. The T2D phenotype (glucose dyshomeostasis, insulin resistance, impaired insulin signaling) also promotes AD pathology, namely accumulation of amyloid-β (Aβ) and hyperphosphorylated tau and can induce other aspects of neuronal degeneration including inflammatory and oxidative processes. Aβ and hyperphosphorylated tau may also have roles in pancreatic β-cell dysfunction and in reducing insulin sensitivity and glucose uptake by peripheral tissues such as liver, skeletal muscle, and adipose tissue. This suggests a role for these AD-related proteins in promoting T2D. The accumulation of the islet amyloid polypeptide (IAPP, or amylin) within islet β-cells is a major pathological feature of the pancreas in patients with chronic T2D. Co-secreted with insulin, amylin accumulates over time and contributes to β-cell toxicity, ultimately leading to reduced insulin secretion and onset of overt (insulin dependent) diabetes. Recent evidence also suggests that this protein accumulates in the brain of AD patients and may interact with Aβ to exacerbate the neurodegenerative process. In this review, we highlight evidence indicating T2D in promoting Aβ and tau mediated neurodegeneration and the potential contributions of Aβ and tau in promoting a diabetic phenotype that could further exacerbate neurodegeneration. We also discuss underlying mechanisms by which amylin can contribute to the neurodegenerative processes.

%B J Alzheimers Dis %V 59 %P 421-432 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269785?dopt=Abstract %R 10.3233/JAD-161192 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Localization and Processing of the Amyloid-β Protein Precursor in Mitochondria-Associated Membranes. %A Del Prete, Dolores %A Suski, Jan M %A Oulès, Bénédicte %A Debayle, Delphine %A Gay, Anne Sophie %A Lacas-Gervais, Sandra %A Bussiere, Renaud %A Bauer, Charlotte %A Pinton, Paolo %A Paterlini-Bréchot, Patrizia %A Wieckowski, Mariusz R %A Checler, Frédéric %A Chami, Mounia %X

Alteration of mitochondria-associated membranes (MAMs) has been proposed to contribute to the pathogenesis of Alzheimer's disease (AD). We studied herein the subcellular distribution, the processing, and the protein interactome of the amyloid-β protein precursor (AβPP) and its proteolytic products in MAMs. We reveal that AβPP and its catabolites are present in MAMs in cellular models overexpressing wild type AβPP or AβPP harboring the double Swedish or London familial AD mutations, and in brains of transgenic mice model of AD. Furthermore, we evidenced that both β- and γ-secretases are present and harbor AβPP processing activities in MAMs. Interestingly, cells overexpressing APPswe show increased ER-mitochondria contact sites. We also document increased neutral lipid accumulation linked to Aβ production and reversed by inhibiting β- or γ-secretases. Using a proteomic approach, we show that AβPP and its catabolites interact with key proteins of MAMs controlling mitochondria and ER functions. These data highlight the role of AβPP processing and proteomic interactome in MAMs deregulation taking place in AD.

%B J Alzheimers Dis %V 55 %P 1549-1570 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911326?dopt=Abstract %R 10.3233/JAD-160953 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Logopenic Aphasia due to a Strategic Stroke: New Evidence from a Single Case. %A Riancho, Javier %A Pozueta, Ana %A Santos, Miguel %A Lage, Carmen %A Carril, José M %A Banzo, Ignacio %A Martínez-Rodriguez, Isabel %A Gorno-Tempini, Marilu %A Sánchez-Juan, Pascual %K Aphasia %K Atrophy %K Brain %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Stroke %X

Among primary progressive aphasias (PPAs), logopenic variant PPA (lv-PPA) is usually related to Alzheimer's disease. Although it has been widely clinically and pathologically evaluated, the topography in LPA is still controversial. We report a patient presenting with a logopenic syndrome due to a strategic lesion located in the superior and middle temporal gyrus and compare our findings with those of a PiB-PET positive lv-PPA patient matched by age, gender, and education. We consider that our study provides new anatomical clues to better understand the cognitive mechanisms underlying the logopenic syndrome.

%B J Alzheimers Dis %V 57 %P 717-721 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304307?dopt=Abstract %R 10.3233/JAD-161267 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Longitudinal Study on Resting State Functional Connectivity in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease. %A Hafkemeijer, Anne %A Möller, Christiane %A Dopper, Elise G P %A Jiskoot, Lize C %A van den Berg-Huysmans, Annette A %A van Swieten, John C %A van der Flier, Wiesje M %A Vrenken, Hugo %A Pijnenburg, Yolande A L %A Barkhof, Frederik %A Scheltens, Philip %A van der Grond, Jeroen %A Rombouts, Serge A R B %X

BACKGROUND/OBJECTIVE: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of early-onset dementia. We applied longitudinal resting state functional magnetic resonance imaging (fMRI) to delineate functional brain connections relevant for disease progression and diagnostic accuracy.

METHODS: We used two-center resting state fMRI data of 20 AD patients (65.1±8.0 years), 12 bvFTD patients (64.7±5.4 years), and 22 control subjects (63.8±5.0 years) at baseline and 1.8-year follow-up. We used whole-network and voxel-based network-to-region analyses to study group differences in functional connectivity at baseline and follow-up, and longitudinal changes in connectivity within and between groups.

RESULTS: At baseline, connectivity between paracingulate gyrus and executive control network, between cuneal cortex and medial visual network, and between paracingulate gyrus and salience network was higher in AD compared with controls. These differences were also present after 1.8 years. At follow-up, connectivity between angular gyrus and right frontoparietal network, and between paracingulate gyrus and default mode network was lower in bvFTD compared with controls, and lower compared with AD between anterior cingulate gyrus and executive control network, and between lateral occipital cortex and medial visual network. Over time, connectivity decreased in AD between precuneus and right frontoparietal network and in bvFTD between inferior frontal gyrus and left frontoparietal network. Longitudinal changes in connectivity between supramarginal gyrus and right frontoparietal network differ between both patient groups and controls.

CONCLUSION: We found disease-specific brain regions with longitudinal connectivity changes. This suggests the potential of longitudinal resting state fMRI to delineate regions relevant for disease progression and for diagnostic accuracy, although no group differences in longitudinal changes in the direct comparison of AD and bvFTD were found.

%B J Alzheimers Dis %V 55 %P 521-537 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662284?dopt=Abstract %R 10.3233/JAD-150695 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Long-Term Cognitive Decline in Dementia with Lewy Bodies in a Large Multicenter, International Cohort. %A Kramberger, Milica G %A Auestad, Bjørn %A Garcia-Ptacek, Sara %A Abdelnour, Carla %A Olmo, Josep Garre %A Walker, Zuzana %A Lemstra, Afina W %A Londos, Elisabet %A Blanc, Frédéric %A Bonanni, Laura %A McKeith, Ian %A Winblad, Bengt %A de Jong, Frank Jan %A Nobili, Flavio %A Stefanova, Elka %A Petrova, Maria %A Falup-Pecurariu, Cristian %A Rektorova, Irena %A Bostantjopoulou, Sevasti %A Biundo, Roberta %A Weintraub, Daniel %A Aarsland, Dag %K Aged %K Aged, 80 and over %K Analysis of Variance %K Cognition Disorders %K Cohort Studies %K Female %K Humans %K International Cooperation %K Lewy Body Disease %K Male %K Mental Status Schedule %K Middle Aged %X

BACKGROUND/OBJECTIVE: The aim of this study was to describe the rate and clinical predictors of cognitive decline in dementia with Lewy bodies (DLB), and compare the findings with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) patients.

METHODS: Longitudinal scores for the Mini-Mental State Examination (MMSE) in 1,290 patients (835 DLB, 198 PDD, and 257 AD) were available from 18 centers with up to three years longitudinal data. Linear mixed effects analyses with appropriate covariates were used to model MMSE decline over time. Several subgroup analyses were performed, defined by anti-dementia medication use, baseline MMSE score, and DLB core features.

RESULTS: The mean annual decline in MMSE score was 2.1 points in DLB, compared to 1.6 in AD (p = 0.07 compared to DLB) and 1.8 in PDD (p = 0.19). Rates of decline were significantly higher in DLB compared to AD and PDD when baseline MMSE score was included as a covariate, and when only those DLB patients with an abnormal dopamine transporter SPECT scan were included. Decline was not predicted by sex, baseline MMSE score, or presence of specific DLB core features.

CONCLUSIONS: The average annual decline in MMSE score in DLB is approximately two points. Although in the overall analyses there were no differences in the rate of decline between the three neurodegenerative disorders, there were indications of a more rapid decline in DLB than in AD and PDD. Further studies are needed to understand the predictors and mechanisms of cognitive decline in DLB.

%B J Alzheimers Dis %V 57 %P 787-795 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304294?dopt=Abstract %R 10.3233/JAD-161109 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Low Arousal Positive Emotional Stimuli Attenuate Aberrant Working Memory Processing in Persons with Mild Cognitive Impairment. %A Broster, Lucas S %A Jenkins, Shonna L %A Holmes, Sarah D %A Jicha, Gregory A %A Jiang, Yang %X

Emotional enhancement effects on memory have been reported to mitigate the pathophysiology of Alzheimer's disease (AD). However, relative to their manifestation in persons without pathologic aging, these effects may be reduced in magnitude or even deleterious, especially in tasks that more closely model ecologic memory performance. Based upon a synthesis of such reports, we hypothesized that in persons with AD low arousal positive stimuli would evoke relatively intact emotional enhancement effects, but that high arousal negative stimuli would evoke disordered emotional enhancement effects. To assess this, participants with and without mild cognitive impairment (MCI) presumed to be due to AD performed an emotionally-valenced short-term memory task while encephalography was recorded. Results indicated that for persons with MCI, high arousal negative stimuli led to working memory processing patterns previously associated with MCI presumed due to AD and dementia of the Alzheimer-type. In contrast, low arousal positive stimuli evoked a processing pattern similar to MCI participants' unaffected spouses. Our current findings suggest that low arousal positive stimuli attenuate working memory deficits of MCI due to AD.

%B J Alzheimers Dis %V 60 %P 1333-1349 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29060938?dopt=Abstract %R 10.3233/JAD-170233 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Low Cognitive Awareness, but Not Complaint, is a Good Marker of Preclinical Alzheimer's Disease. %A Cacciamani, Federica %A Tandetnik, Caroline %A Gagliardi, Geoffroy %A Bertin, Hugo %A Habert, Marie-Odile %A Hampel, Harald %A Boukadida, Laurie %A Révillon, Marie %A Epelbaum, Stéphane %A Dubois, Bruno %X

BACKGROUND: Subjective cognitive decline (SCD) may result from many conditions, including Alzheimer's disease (AD).

OBJECTIVE: In this study, we searched for a specific pattern of SCD in asymptomatic individuals at risk for AD.

METHODS: Cognitively normal older adults (N = 318) reporting SCD and their informants were enrolled in the INSIGHT-PreAD cohort. We examined the relationship between six SCD measures and both cognitive scores and AD neuroimaging markers (amyloid burden, hippocampal atrophy and brain hypometabolism). An awareness of cognitive decline index (ACDI) has been introduced based on the subject-informant discrepancy in a questionnaire of SCD and participants with low versus high awareness were compared.

RESULTS: Scores in the INSIGHT-PreAD SCD questionnaires did not correlate with AD neuroimaging markers. As well, no correlation has been found between SCD measures and cognitive scores. Comparing subjects with a low (n = 19) and high (n = 86) level of awareness, no significant difference in terms of demography, neuropsychiatric symptoms, autonomy, quality of life, cognition, and hippocampal volume was found. However, the "low awareness" group showed greater amyloid burden and lower cortical metabolism, compared to the "high awareness" group.

CONCLUSION: This study provided additional evidence that reporting SCD by itself is not a specific symptom of preclinical AD. Conversely, a low cognitive awareness (namely, when subjects report fewer difficulties than their relatives do) may represent a very early form of anosognosia and serve as a specific indicator of preclinical AD. This finding is of key importance as an enrichment factor to consider in both clinical practice and research trials.

%B J Alzheimers Dis %V 59 %P 753-762 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671134?dopt=Abstract %R 10.3233/JAD-170399 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Low Erythrocyte Levels of Proteasome and Acyl-Peptide Hydrolase (APEH) Activities in Alzheimer's Disease: A Sign of Defective Proteostasis? %A Palmieri, Gianna %A Cocca, Ennio %A Gogliettino, Marta %A Valentino, Roberta %A Ruvo, Menotti %A Cristofano, Gloria %A Angiolillo, Antonella %A Balestrieri, Marco %A Rossi, Mosè %A Di Costanzo, Alfonso %X

Alzheimer's disease (AD) is a progressive, multifactorial neurodegenerative disorder that is the main cause of dementia. To date, there are no definitive diagnostic tests that can predict or assess onset and progression of the disease. Blood biomarkers for AD are being sought for many years but their identification remains a challenging task. In this study, we investigated the potential relationship between AD and levels of acyl-peptide hydrolase (APEH) and proteasome in erythrocyte samples of 52 participants (26 AD and 26 cognitively healthy controls). A statistically significant decrease in proteasome and exopeptidase/endopeptidase APEH activities was found in AD samples compared to those of healthy controls. Moreover, in contrast to what was observed for proteasome transcripts, APEH activities reduction in AD patients was unrelated to its gene expression levels, suggesting the occurrence of posttranslational modifications or the expression of endogenous inhibitors that might impair enzyme activity. These preliminary data further support a relationship between the APEH-proteasome system and AD molecular players, providing the first evidence of its potential use as a novel blood-based indicator for the routine detection of AD.

%B J Alzheimers Dis %V 60 %P 1097-1106 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984596?dopt=Abstract %R 10.3233/JAD-170389 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Low Florbetapir PET Uptake and Normal Aβ1-42 Cerebrospinal Fluid in an APP Ala713Thr Mutation Carrier. %A Lombardi, Gemma %A Berti, Valentina %A Tedde, Andrea %A Bagnoli, Silvia %A Piaceri, Irene %A Polito, Cristina %A Lucidi, Giulia %A Ferrari, Camilla %A Ginestroni, Andrea %A Moretti, Marco %A Pupi, Alberto %A Nacmias, Benedetta %A Sorbi, Sandro %K Alanine %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Aniline Compounds %K Brain %K Ethylene Glycols %K Humans %K Male %K Middle Aged %K Mutation %K Peptide Fragments %K Positron-Emission Tomography %K Threonine %X

According to the literature, the APP Ala713Thr mutation is associated with Alzheimer's disease and cerebral amyloid angiopathy. We describe a case of dementia clinically compatible with frontotemporal dementia in an APP Ala713Thr mutation carrier in which both [18F]Florbetapir PET uptake and Aβ1-42 cerebrospinal fluid levels were normal. Further evidences are required to establish if this association is only incidental.

%B J Alzheimers Dis %V 57 %P 697-703 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304299?dopt=Abstract %R 10.3233/JAD-161170 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Macrophage Migration Inhibitory Factor is Associated with Biomarkers of Alzheimer's Disease Pathology and Predicts Cognitive Decline in Mild Cognitive Impairment and Mild Dementia. %A Oikonomidi, Aikaterini %A Tautvydaitė, Domilė %A Gholamrezaee, Mehdi M %A Henry, Hugues %A Bacher, Michael %A Popp, Julius %X

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory protein playing a regulatory role in the immune response. First evidence from in vitro and animal studies suggests that MIF may be involved in the development of Alzheimer's disease (AD) pathology.

OBJECTIVE: To address in older subjects (i) the relationships between AD pathology and MIF plasma and cerebrospinal fluid (CSF) levels; and (ii) to investigate whether increased MIF-related systemic and CNS inflammation is associated with clinical disease progression.

METHODS: CSF and plasma concentrations of MIF as well as biomarkers of amyloid, neuronal injury, and tau hyperphosphorylation (CSF Aβ1-42, tau, and ptau, respectively) were assessed in 97 subjects with MCI or mild dementia (cognitive impairment, CI) and 52 healthy volunteers with normal cognition. Clinical and neuropsychological evaluations were performed at inclusion and at follow up visits.

RESULTS: CSF MIF levels were higher in participants with CI with an AD CSF biomarker profile, but not in CI with a non-AD profile, compared to the healthy controls. Higher MIF CSF levels were associated with higher CSF tau and ptau and lower CSF Aβ1-42 after adjusting for potential confounders. In CI, MIF CSF independently predicted cognitive decline at a follow-up visit after controlling for potential confounders including CSF Aβ1-42 and tau levels.

CONCLUSION: Our study provides evidence that MIF-related inflammation is related to amyloid pathology, tau hyperphosphorylation, and neuronal injury at the early clinical stages of AD. Higher MIF CSF levels are associated with accelerated cognitive decline in MCI and mild dementia.

%B J Alzheimers Dis %V 60 %P 273-281 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826184?dopt=Abstract %R 10.3233/JAD-170335 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Memory Correlates of Alzheimer's Disease Cerebrospinal Fluid Markers: A Longitudinal Cohort Study. %A Reijs, Babette L R %A Ramakers, Inez H G B %A Köhler, Sebastian %A Teunissen, Charlotte E %A Koel-Simmelink, Marleen %A Nathan, Pradeep J %A Tsolaki, Magda %A Wahlund, Lars-Olof %A Waldemar, Gunhild %A Hausner, Lucrezia %A Vandenberghe, Rik %A Johannsen, Peter %A Blackwell, Andrew %A Vanderstichele, Hugo %A Verhey, Frans %A Visser, Pieter Jelle %X

BACKGROUND: Performance on episodic, semantic, and working memory tests is impaired in Alzheimer's disease (AD)-type dementia, but it is unclear which type of memory test is most strongly associated with early AD biomarkers in cerebrospinal fluid (CSF), and most useful for monitoring disease progression.

OBJECTIVE: To examine the association between amyloid-β 1-42 (Aβ42) and tau in CSF with performance on different memory domains at baseline, and how these CSF markers are related with memory decline.

METHODS: We included 263 individuals with normal cognition, mild cognitive impairment, AD-type dementia, and non-AD dementia from the European EDAR study. Assessment included CSF Aβ42 and t-tau analyses with INNO-BIA AlzBio3 Luminex assay, the CERAD wordlist learning and delayed recall, animal fluency test, and the CANTAB Paired Associates Learning (PAL) and Spatial Working Memory tasks. Follow-up assessments were performed within 3 years after baseline.

RESULTS: At baseline, decreased CSF Aβ42 correlated most strongly with the PAL total errors adjusted and the wordlist delayed recall and increased CSF t-tau with the wordlist delayed recall. Over time, decreased CSF Aβ42 was associated with decline on the wordlist learning, whereas increased CSF t-tau were associated with decline in scores on the wordlist learning, wordlist delayed recall, and animal fluency. Associations were independent of baseline diagnosis.

CONCLUSION: Tests assessing episodic verbal and visuospatial memory are most useful for detection of AD pathology. Tests for episodic verbal memory and semantic memory are most useful for tracking memory decline.

%B J Alzheimers Dis %V 60 %P 1119-1128 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984585?dopt=Abstract %R 10.3233/JAD-160766 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Memory is Not Enough: The Neurobiological Substrates of Dynamic Cognitive Reserve. %A Serra, Laura %A Bruschini, Michela %A Di Domenico, Carlotta %A Gabrielli, Giulia Bechi %A Marra, Camillo %A Caltagirone, Carlo %A Cercignani, Mara %A Bozzali, Marco %X

Changes in the residual memory variance are considered as a dynamic aspect of cognitive reserve (d-CR). We aimed to investigate for the first time the neural substrate associated with changes in the residual memory variance overtime in patients with amnestic mild cognitive impairment (aMCI). Thirty-four aMCI patients followed-up for 36 months and 48 healthy elderly individuals (HE) were recruited. All participants underwent 3T MRI, collecting T1-weighted images for voxel-based morphometry (VBM). They underwent an extensive neuropsychological battery, including six episodic memory tests. In patients and controls, factor analyses were used on the episodic memory scores to obtain a composite memory score (C-MS). Partial Least Square analyses were used to decompose the variance of C-MS in latent variables (LT scores), accounting for demographic variables and for the general cognitive efficiency level; linear regressions were applied on LT scores, striping off any contribution of general cognitive abilities, to obtain the residual value of memory variance, considered as an index of d-CR. LT scores and d-CR were used in discriminant analysis, in patients only. Finally, LT scores and d-CR were used as variable of interest in VBM analysis. The d-CR score was not able to correctly classify patients. In both aMCI patients and HE, LT1st and d-CR scores showed correlations with grey matter volumes in common and in specific brain areas. Using CR measures limited to assess memory function is likely less sensitive to detect the cognitive decline and predict the evolution of Alzheimer's disease. In conclusion, d-CR needs a measure of general cognition to identify conversion to Alzheimer's disease efficiently.

%B J Alzheimers Dis %V 58 %P 171-184 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387678?dopt=Abstract %R 10.3233/JAD-170086 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Metabolic and Growth Rate Alterations in Lymphoblastic Cell Lines Discriminate Between Down Syndrome and Alzheimer's Disease. %A Coskun, Pinar %A Helguera, Pablo %A Nemati, Zahra %A Bohannan, Ryan C %A Thomas, Jean %A Samuel, Schriner E %A Argueta, Jocelyn %A Doran, Eric %A Wallace, Douglas C %A Lott, Ira T %A Busciglio, Jorge %X

BACKGROUND: Deficits in mitochondrial function and oxidative stress play pivotal roles in Down syndrome (DS) and Alzheimer's disease (AD) and these alterations in mitochondria occur systemically in both conditions.

OBJECTIVE: We hypothesized that peripheral cells of elder subjects with DS exhibit disease-specific and dementia-specific metabolic features. To test this, we performed a comprehensive analysis of energy metabolism in lymphoblastic-cell-lines (LCLs) derived from subjects belonging to four groups: DS-with-dementia (DSAD), DS-without-dementia (DS), sporadic AD, and age-matched controls.

METHODS: LCLs were studied under regular or minimal feeding regimes with galactose or glucose as primary carbohydrate sources. We assessed metabolism under glycolysis or oxidative phosphorylation by quantifying cell viability, oxidative stress, ATP levels, mitochondrial membrane potential (MMP), mitochondrial calcium uptake, and autophagy.

RESULTS: DS and DSAD LCLs showed slower growth rates under minimal feeding. DS LCLs mainly dependent on mitochondrial respiration exhibited significantly slower growth and higher levels of oxidative stress compared to other groups. While ATP levels (under mitochondrial inhibitors) and mitochondrial calcium uptake were significantly reduced in DSAD and AD cells, MMP was decreased in DS, DSAD, and AD LCLs. Finally, DS LCLs showed markedly reduced levels of the autophagy marker LC3-II, underscoring the close association between metabolic dysfunction and impaired autophagy in DS.

CONCLUSION: There are significant mitochondrial functional changes in LCLs derived from DS, DSAD, and AD patients. Several parameters analyzed were consistently different between DS, DSAD, and AD lines suggesting that metabolic indicators between LCL groups may be utilized as biomarkers of disease progression and/or treatment outcomes.

%B J Alzheimers Dis %V 55 %P 737-748 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802222?dopt=Abstract %R 10.3233/JAD-160278 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Metal-Free Method for Producing MRI Contrast at Amyloid-β. %A Hilt, Silvia %A Tang, Tang %A Walton, Jeffrey H %A Budamagunta, Madhu %A Maezawa, Izumi %A Kálai, Tamás %A Hideg, Kálmán %A Singh, Vikrant %A Wulff, Heike %A Gong, Qizhi %A Jin, Lee-Way %A Louie, Angelique %A Voss, John C %X

Alzheimer's disease (AD) is characterized by depositions of the amyloid-β (Aβ) peptide in the brain. The disease process develops over decades, with substantial neurological loss occurring before a clinical diagnosis of dementia can be rendered. It is therefore imperative to develop methods that permit early detection and monitoring of disease progression. In addition, the multifactorial pathogenesis of AD has identified several potential avenues for AD intervention. Thus, evaluation of therapeutic candidates over lengthy trial periods also demands a practical, noninvasive method for measuring Aβ in the brain. Magnetic resonance imaging (MRI) is the obvious choice for such measurements, but contrast enhancement for Aβ has only been achieved using Gd(III)-based agents. There is great interest in gadolinium-free methods to image the brain. In this study, we provide the first demonstration that a nitroxide-based small-molecule produces MRI contrast in brain specimens with elevated levels of Aβ. The molecule is comprised of a  fluorene (a molecule with high affinity for Aβ) and a nitroxide spin label (a paramagnetic MRI contrast species). Labeling of brain specimens with the spin-labeled fluorene produces negative contrast in samples from AD model mice whereas no negative contrast is seen in specimens harvested from wild-type mice. Injection of spin-labeled fluorene into live mice resulted in good brain penetration, with the compound able to generate contrast 24-h post injection. These results provide a proof of concept method that can be used for early, noninvasive, gadolinium-free detection of amyloid plaques by MRI.

%B J Alzheimers Dis %V 55 %P 1667-1681 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911291?dopt=Abstract %R 10.3233/JAD-160279 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Methionine Sulfoxide Reductase-B3 (MsrB3) Protein Associates with Synaptic Vesicles and its Expression Changes in the Hippocampi of Alzheimer's Disease Patients. %A Adams, Stephanie L %A Benayoun, Laurent %A Tilton, Kathy %A Chavez, Olivia R %A Himali, Jayandra J %A Blusztajn, Jan Krzysztof %A Seshadri, Sudha %A Delalle, Ivana %X

Genome-wide association studies (GWAS) identified susceptibility loci associated with decreased hippocampal volume, and found hippocampal subfield-specific effects at MSRB3 (methionine sulfoxide reductase-B3). The MSRB3 locus was also linked to increased risk for late onset Alzheimer's disease (AD). In this study, we uncovered novel sites of MsrB3 expression in CA pyramidal layer and arteriolar walls by using automated immunohistochemistry on hippocampal sections from 23 individuals accompanied by neuropathology reports and clinical dementia rating scores. Controls, cognitively intact subjects with no hippocampal neurofibrillary tangles, exhibited MsrB3 signal as distinct but rare puncta in CA1 pyramidal neuronal somata. In CA3, however, MsrB3-immunoreactivity was strongest in the neuropil of the pyramidal layer. These patterns were replicated in rodent hippocampi where ultrastructural and immunohistofluorescence analysis revealed MsrB3 signal associated with synaptic vesicles and colocalized with mossy fiber terminals. In AD subjects, the number of CA1 pyramidal neurons with frequent, rather than rare, MsrB3-immunoreactive somatic puncta increased in comparison to controls. This change in CA1 phenotype correlated with the occurrence of AD pathological hallmarks. Moreover, the intensity of MsrB3 signal in the neuropil of CA3 pyramidal layer correlated with the signal pattern in neurons of CA1 pyramidal layer that was characteristic of cognitively intact individuals. Finally, MsrB3 signal in the arteriolar walls in the hippocampal white matter decreased in AD patients. This characterization of GWAS-implicated MSRB3 protein expression in human hippocampus suggests that patterns of neuronal and vascular MsrB3 protein expression reflect or underlie pathology associated with AD.

%B J Alzheimers Dis %V 60 %P 43-56 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28777754?dopt=Abstract %R 10.3233/JAD-170459 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Methylene Blue (Tetramethylthionine Chloride) Influences the Mobility of Adult Neural Stem Cells: A Potentially Novel Therapeutic Mechanism of a Therapeutic Approach in the Treatment of Alzheimer's Disease. %A van der Ven, Amelie T %A Pape, Julius C %A Hermann, Dirk %A Schloesser, Robert %A Genius, Just %A Fischer, Nadine %A Mößner, Rainald %A Scherbaum, Norbert %A Wiltfang, Jens %A Rujescu, Dan %A Benninghoff, Jens %X

An interest in neurogenesis in the adult human brain as a relevant and targetable process has emerged as a potential treatment option for Alzheimer's disease and other neurodegenerative conditions. The aim of this study was to investigate the effects of tetramethylthionine chloride (methylene blue, MB) on properties of adult murine neural stem cells. Based on recent clinical studies, MB has increasingly been discussed as a potential treatment for Alzheimer's disease. While no differences in the proliferative capacity were identified, a general potential of MB in modulating the migratory capacity of adult neural stem cells was indicated in a cell mobility assay. To our knowledge, this is the first time that MB could be associated with neural mobility. The results of this study add insight to the spectrum of features of MB within the central nervous system and may be helpful for understanding the molecular mechanisms underlying a potential therapeutic effect of MB.

%B J Alzheimers Dis %V 57 %P 531-540 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269766?dopt=Abstract %R 10.3233/JAD-160755 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Microglial and Neuronal TDP-43 Pathology in Anti-IgLON5-Related Tauopathy. %A Cagnin, Annachiara %A Mariotto, Sara %A Fiorini, Michele %A Gaule, Marina %A Bonetto, Nicola %A Tagliapietra, Matteo %A Buratti, Emanuele %A Zanusso, Gianluigi %A Ferrari, Sergio %A Monaco, Salvatore %X

A novel neuronal tauopathy, mainly confined to hypothalamus and brainstem tegmentum, has recently been reported in patients with autoantibodies to the neuronal cell-adhesion molecule IgLON5. We describe a patient with anti-IgLON5 syndrome, who presented with dysautonomia and sleep disorder, followed by subacute dementia. Postmortem brain examination disclosed neuronal tau pathology prevailing in the hippocampus, amygdala, and locus coeruleus, in addition to microglial/neuronal TDP-43 pathology, with overexpression of aberrantly phosphorylated forms and neurotoxic truncated fragments, in basal ganglia, nucleus basalis, thalamus, and midbrain. These findings suggest that neurodegeneration in anti-IgLON5 syndrome might also occur via a microglia-triggered non-cell autonomous pathway.

%B J Alzheimers Dis %V 59 %P 13-20 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550263?dopt=Abstract %R 10.3233/JAD-170189 %0 Journal Article %J J Alzheimers Dis %D 2017 %T MicroRNA Profile in Patients with Alzheimer's Disease: Analysis of miR-9-5p and miR-598 in Raw and Exosome Enriched Cerebrospinal Fluid Samples. %A Riancho, Javier %A Vázquez-Higuera, José Luis %A Pozueta, Ana %A Lage, Carmen %A Kazimierczak, Martha %A Bravo, María %A Calero, Miguel %A Gonalezález, Andrea %A Rodríguez, Eloy %A Lleo, Alberto %A Sánchez-Juan, Pascual %X

BACKGROUND: MicroRNAs have been postulated as potential biomarkers for Alzheimer's disease (AD). Exosomes are nanovesicles which transport microRNAs, proteins, and other cargos. It has been hypothesized that the exosome traffic might be increased in neurodegenerative disorders.

OBJECTIVE: i) To assess the cerebrospinal fluid (CSF) microRNA profile in a group of AD patients and control subjects and to validate a group of microRNAs previously reported by other authors. ii) To compare microRNA levels in whole CSF and in the exosome-enriched fraction in AD patients.

METHODS: A panel of 760 microRNAs was analyzed in the CSF of 10 AD patients and 10 healthy subjects. Among microRNAs differently expressed, we selected those that had been previously reported by other authors. Candidates were validated in a larger group by individual qPCR assays. MicroRNA expression was also evaluated in exosome-enriched CSF samples of patients with AD and controls.

RESULTS: Fifteen microRNAs were differently expressed in AD. MiR-9-5p, miR-134, and miR-598 were selected as candidates for further analysis. MiR-9-5p and miR-598 were detected in 50 and 75% of control CSF samples, respectively, while they were not detected in any AD CSF samples. We observed an opposite pattern when we evaluated the microRNA expression in the exosome-enriched CSF AD samples. No pattern variations were noted among healthy subjects.

CONCLUSION: These data propose miR-9-5p and miR-598 as potential biomarkers for AD. Further studies in plasma and other body fluids will confirm their potential role as easily accessible biomarkers. In addition, our data suggest that exosome trafficking is different between AD and control subjects raising the need to take this phenomenon into consideration in future studies of AD biomarkers.

%B J Alzheimers Dis %V 57 %P 483-491 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269782?dopt=Abstract %R 10.3233/JAD-161179 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Midlife Metabolic Profile and the Risk of Late-Life Cognitive Decline. %A Tortelli, Rosanna %A Lozupone, Madia %A Guerra, Vito %A Barulli, Maria Rosaria %A Imbimbo, Bruno P %A Capozzo, Rosa %A Grasso, Alessandra %A Tursi, Marianna %A Di Dio, Cristina %A Sardone, Rodolfo %A Giannelli, Gianluigi %A Seripa, Davide %A Misciagna, Giovanni %A Panza, Francesco %A Logroscino, Giancarlo %X

Among metabolic syndrome components, the effects of higher plasma glucose levels on cognitive decline (CD) have been considered in few studies. We evaluated the associations among midlife glycemia, total cholesterol, high-density lipoprotein cholesterol, triglycerides, midlife insulin resistance [homeostasis model assessment for insulin resistance (HOMA-index)], and CD in the older subjects of the population-based MICOL Study (Castellana Grotte, Italy) at baseline (M1) and at follow-ups seven (M2) and twenty years later (M3). At M1, a dementia risk score and a composite cardiovascular risk score for dementia were calculated. For 797 subjects out of 833, we obtained a Mini-Mental State Examination (MMSE) score at M3, subdividing these subjects in three cognitive functioning subgroups: normal cognition, mild CD, and moderate-severe CD. Mean fasting glycemia at baseline was significantly higher in moderate-severe CD subgroup (114.6±71.4 mg/dl) than in the normal cognition subgroup (101.2±20.6). Adjusting for gender, age, and other metabolic components, higher fasting glycemia values both at M1 [odds ratio (OR) = 1.31; 95% confidence interval (CI): 1.08-1.59] and M2 (OR = 1.26; 95% CI: 1.01-1.57) were associated with an increased risk of moderate-severe CD. Mean HOMA index value was significantly higher in the moderate-severe CD subgroup (5.7±9.4) compared to the normal cognition subgroup (2.9±1.4) at M1. The dementia risk probability (MMSE < 24) increased moving through higher categories of the dementia risk score and decreased as long as the cardiovascular score increased. The present findings highlighted the indication to control blood glucose levels, regardless of a diagnosis of diabetes mellitus, as early as midlife for prevention of late-life dementia.

%B J Alzheimers Dis %V 59 %P 121-130 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582862?dopt=Abstract %R 10.3233/JAD-170153 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Mild Behavioral Impairment Checklist (MBI-C): A Rating Scale for Neuropsychiatric Symptoms in Pre-Dementia Populations. %A Ismail, Zahinoor %A Agüera-Ortiz, Luis %A Brodaty, Henry %A Cieslak, Alicja %A Cummings, Jeffrey %A Fischer, Corinne E %A Gauthier, Serge %A Geda, Yonas E %A Herrmann, Nathan %A Kanji, Jamila %A Lanctôt, Krista L %A Miller, David S %A Mortby, Moyra E %A Onyike, Chiadi U %A Rosenberg, Paul B %A Smith, Eric E %A Smith, Gwenn S %A Sultzer, David L %A Lyketsos, Constantine %X

BACKGROUND: Mild behavioral impairment (MBI) is a construct that describes the emergence at ≥50 years of age of sustained and impactful neuropsychiatric symptoms (NPS), as a precursor to cognitive decline and dementia. MBI describes NPS of any severity, which are not captured by traditional psychiatric nosology, persist for at least 6 months, and occur in advance of or in concert with mild cognitive impairment. While the detection and description of MBI has been operationalized in the International Society to Advance Alzheimer's Research and Treatment - Alzheimer's Association (ISTAART-AA) research diagnostic criteria, there is no instrument that accurately reflects MBI as described.

OBJECTIVE: To develop an instrument based on ISTAART-AA MBI criteria.

METHODS: Eighteen subject matter experts participated in development using a modified Delphi process. An iterative process ensured items reflected the five MBI domains of 1) decreased motivation; 2) emotional dysregulation; 3) impulse dyscontrol; 4) social inappropriateness; and 5) abnormal perception or thought content. Instrument language was developed a priori to pertain to non-demented functionally independent older adults.

RESULTS: We present the Mild Behavioral Impairment Checklist (MBI-C), a 34-item instrument, which can easily be completed by a patient, close informant, or clinician.

CONCLUSION: The MBI-C provides the first measure specifically developed to assess the MBI construct as explicitly described in the criteria. Its utility lies in MBI case detection, and monitoring the emergence of MBI symptoms and domains over time. Studies are required to determine the prognostic value of MBI for dementia development, and for predicting different dementia subtypes.

%B J Alzheimers Dis %V 56 %P 929-938 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059789?dopt=Abstract %R 10.3233/JAD-160979 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Mitochondrial Biomarker-Based Study of S-Equol in Alzheimer's Disease Subjects: Results of a Single-Arm, Pilot Trial. %A Wilkins, Heather M %A Mahnken, Jonathan D %A Welch, Paul %A Bothwell, Rebecca %A Koppel, Scott %A Jackson, Richard L %A Burns, Jeffrey M %A Swerdlow, Russell H %X

Reductions in bioenergetic fluxes, mitochondrial enzyme activities, and mitochondrial number are observed in Alzheimer's disease (AD). Preclinical work indicates estrogen pathway signaling by either estrogen or selective β estrogen receptor (ERβ) agonists benefits these parameters. To assess whether an ERβ agonist could improve mitochondrial function in actual AD subjects, we administered S-equol (10 mg twice daily) to 15 women with AD and determined the platelet mitochondria cytochrome oxidase (COX) activity before initiating S-equol (lead-in), after two weeks of S-equol (active treatment), and two weeks after stopping S-equol (wash-out). Because the intra-individual variation of this enzyme across samples taken at different times was unknown we used a nonparametric, single-arm, dichotomous endpoint that classified subjects whose active treatment COX activity exceeded the average of their lead-in and wash-out measures as positive responders. Eleven positive responses were observed (p < 0.06). The implications of this finding on our null hypothesis (that S-equol does not influence platelet mitochondria COX activity) are discussed. To our knowledge, this is the first time a direct mitochondrial target engagement biomarker has been utilized in an AD clinical study.

%B J Alzheimers Dis %V 59 %P 291-300 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598847?dopt=Abstract %R 10.3233/JAD-170077 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Modeling the Distress of Spousal Caregivers of People with Dementia. %A Wawrziczny, Emilie %A Berna, Guillaume %A Ducharme, Francine %A Kergoat, Marie-Jeanne %A Pasquier, Florence %A Antoine, Pascal %X

BACKGROUND: The progressive mobilization of spouse caregivers who take care of a person with dementia (PWD) can lead to situations of distress.

OBJECTIVE: The current study sought to investigate the influence of the characteristics of the caregiving context on spousal caregiver distress.

METHODS: 125 spousal caregivers participated in this study. The characteristics of the caregiving context were assessed using questionnaires. We examined a moderated-mediator model (Step 1) in which we hypothesized that PWD and caregiver characteristics and dyadic determinants contribute to spousal caregiver distress. This model was compared based on the age at onset of the disease and the gender of the caregiver (Step 2).

RESULTS: The model revealed that poor self-rated health and a lack of family support accentuated spousal caregiver distress, whereas the feeling of being prepared and level of confidence decreased spousal caregiver distress. Moreover, the quality of couple adjustment affected spousal caregiver distress, and this effect was mediated by the severity of the PWD's symptoms. Regarding the age at onset of the disease, the path between Couple Adjustment and the Care recipient's impairments was more important for caregivers of person with early-onset dementia (PEOD). Female caregivers who reported poor self-rated health experienced greater distress.

CONCLUSIONS: It would be interesting to create a support program that would incorporate these three areas of intervention regarding the progression of the disease: first, "preparedness modules"; second, "dyadic modules" (especially for caregivers of PEOD); and third, "family modules". Specific attention should be given to female caregivers who report poor self-rated health.

%B J Alzheimers Dis %V 55 %P 703-716 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716667?dopt=Abstract %R 10.3233/JAD-160558 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Modeling the Relationships Among Late-Life Body Mass Index, Cerebrovascular Disease, and Alzheimer's Disease Neuropathology in an Autopsy Sample of 1,421 Subjects from the National Alzheimer's Coordinating Center Data Set. %A Alosco, Michael L %A Duskin, Jonathan %A Besser, Lilah M %A Martin, Brett %A Chaisson, Christine E %A Gunstad, John %A Kowall, Neil W %A McKee, Ann C %A Stern, Robert A %A Tripodis, Yorghos %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Autopsy %K Body Mass Index %K Cerebrovascular Disorders %K Datasets as Topic %K Female %K Humans %K Male %K National Institute on Aging (U.S.) %K Neuropathology %K Neuropsychological Tests %K Retrospective Studies %K United States %X

The relationship between late-life body mass index (BMI) and Alzheimer's disease (AD) is poorly understood due to the lack of research in samples with autopsy-confirmed AD neuropathology (ADNP). The role of cerebrovascular disease (CVD) in the interplay between late-life BMI and ADNP is unclear. We conducted a retrospective longitudinal investigation and used joint modeling of linear mixed effects to investigate causal relationships among repeated antemortem BMI measurements, CVD (quantified neuropathologically), and ADNP in an autopsy sample of subjects across the AD clinical continuum. The sample included 1,421 subjects from the National Alzheimer's Coordinating Center's Uniform Data Set and Neuropathology Data Set with diagnoses of normal cognition (NC; n = 234), mild cognitive impairment (MCI; n = 201), or AD dementia (n = 986). ADNP was defined as moderate to frequent neuritic plaques and Braak stageIII-VI. Ischemic Injury Scale (IIS) operationalized CVD. Joint modeling examined relationships among BMI, IIS, and ADNP in the overall sample and stratified by initial visit Clinical Dementia Rating score. Subject-specific random intercept for BMI was the predictor for ADNP due to minimal BMI change (p = 0.3028). Analyses controlling for demographic variables and APOE ɛ4 showed lower late-life BMI predicted increased odds of ADNP in the overall sample (p < 0.001), and in subjects with CDR of 0 (p = 0.0021) and 0.5 (p = 0.0012), but not ≥1.0 (p = 0.2012). Although higher IIS predicted greater odds of ADNP (p < 0.0001), BMI did not predict IIS (p = 0.2814). The current findings confirm lower late-life BMI confers increased odds for ADNP. Lower late-life BMI may be a preclinical indicator of underlying ADNP.

%B J Alzheimers Dis %V 57 %P 953-968 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304301?dopt=Abstract %R 10.3233/JAD-161205 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Moderate Physical Activity is Associated with Cerebral Glucose Metabolism in Adults at Risk for Alzheimer's Disease. %A Dougherty, Ryan J %A Schultz, Stephanie A %A Kirby, Taylor K %A Boots, Elizabeth A %A Oh, Jennifer M %A Edwards, Dorothy %A Gallagher, Catherine L %A Carlsson, Cynthia M %A Bendlin, Barbara B %A Asthana, Sanjay %A Sager, Mark A %A Hermann, Bruce P %A Christian, Bradley T %A Johnson, Sterling C %A Cook, Dane B %A Okonkwo, Ozioma C %X

The objective of this study was to investigate the relationship between accelerometer-measured physical activity (PA) and glucose metabolism in asymptomatic late-middle-aged adults. Ninety-three cognitively healthy late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention participated in this cross-sectional study. They underwent 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging and wore an accelerometer (ActiGraph GT3X+) to measure free-living PA. Accelerometer data yielded measures of light (LPA), moderate (MPA), and vigorous (VPA) intensity PA. FDG-PET images were scaled to the cerebellum and pons, and cerebral glucose metabolic rate was extracted from specific regions of interest (ROIs) known to be hypometabolic in AD, i.e., hippocampus, posterior cingulate, inferior temporal cortex, and angular gyrus. Regression analyses were utilized to examine the association between PA and glucose metabolism, while adjusting for potential confounds. There were associations between MPA and glucose metabolism in all ROIs examined. In contrast, LPA was not associated with glucose uptake in any ROI and VPA was only associated with hippocampal FDG uptake. Secondary analyses did not reveal associations between sedentary time and glucose metabolism in any of the ROIs. Exploratory voxel-wise analysis identified additional regions where MPA was significantly associated with glucose metabolism including the precuneus, supramarginal gyrus, amygdala, and middle frontal gyrus. These findings suggest that the intensity of PA is an important contributor to neuronal function in a late-middle-aged cohort, with MPA being the most salient. Prospective studies are necessary for fully elucidating the link between midlife engagement in PA and later life development of AD.

%B J Alzheimers Dis %V 58 %P 1089-1097 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527205?dopt=Abstract %R 10.3233/JAD-161067 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Molecular Mechanisms Underlying Neuroprotective Effect of Intranasal Administration of Human Hsp70 in Mouse Model of Alzheimer's Disease. %A Evgen'ev, Michail B %A Krasnov, George S %A Nesterova, Inna V %A Garbuz, David G %A Karpov, Vadim L %A Morozov, Alexey V %A Snezhkina, Anastasiya V %A Samokhin, Alexander N %A Sergeev, Alexander %A Kulikov, Alexei M %A Bobkova, Natalia V %X

Heat shock protein 70, encoded by the HSPA1A gene in humans, is a key component of the machinery that protects neuronal cells from various stress conditions and whose production significantly declines during the course of aging and as a result of several neurodegenerative diseases. Herein, we investigated whether sub-chronic intranasal administration of exogenous Hsp70 (eHsp70) exerts a neuroprotective effect on the temporal cortex and areas of the hippocampus in transgenic 5XFAD mice, a model of Alzheimer's disease. The quantitative analysis of neuronal pathologies in the compared groups, transgenic (Tg) versus non-transgenic (nTg), revealed high level of abnormalities in the brains of transgenic mice. Treatment with human recombinant Hsp70 had profound rejuvenation effect on both neuronal morphology and functional state in the temporal cortex and hippocampal regions in transgenic mice. Hsp70 administration had a smaller, but still significant, effect on the functional state of neurons in non-transgenic mice as well. Using deep sequencing, we identified multiple differentially expressed genes (DEGs) in the hippocampus of transgenic and non-transgenic mice. Furthermore, this analysis demonstrated that eHsp70 administration strongly modulates the spectrum of DEGs in transgenic animals, reverting to a pattern similar to that observed in non-transgenic age-matched mice, which included upregulation of genes responsible for amine transport, transmission of nerve impulses and other pathways that are impaired in 5XFAD mice. Overall, our data indicate that Hsp70 treatment may be an effective therapeutic against old age diseases of the Alzheimer's type.

%B J Alzheimers Dis %V 59 %P 1415-1426 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28759972?dopt=Abstract %R 10.3233/JAD-170398 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Montreal Cognitive Assessment: Normative Data from a Large Swedish Population-Based Cohort. %A Borland, Emma %A Nägga, Katarina %A Nilsson, Peter M %A Minthon, Lennart %A Nilsson, Erik D %A Palmqvist, Sebastian %X

BACKGROUND: The Montreal Cognitive Assessment (MoCA) has a high sensitivity for detecting cognitive dysfunction. Swedish normative data does not exist and international norms are often derived from populations where cognitive impairment has not been screened for and not been thoroughly assessed to exclude subjects with dementia or mild cognitive impairment.

OBJECTIVE: To establish norms for MoCA and develop a regression-based norm calculator based on a large, well-examined cohort.

METHODS: MoCA was administered on 860 randomly selected elderly people from a population-based cohort from the EPIC study. Cognitive dysfunction was screened for and further assessed at a memory clinic. After excluding cognitively impaired participants, normative data was derived from 758 people, aged 65-85.

RESULTS: MoCA cut-offs (-1 to -2 standard deviations) for cognitive impairment ranged from <25 to <21 for the lowest educated and <26 to <24 for the highest educated, depending on age group. Significant predictors for MoCA score were age, sex and level of education.

CONCLUSION: We present detailed normative MoCA data and cut-offs according to the DSM-5 criteria for cognitive impairment based on a large population-based cohort of elderly individuals, screened and thoroughly investigated to rule out cognitive impairment. Level of education, sex, and age should be taken in account when evaluating MoCA score, which is facilitated by our online regression-based calculator that provide percentile and z-score for a subject's MoCA score.

%B J Alzheimers Dis %V 59 %P 893-901 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697562?dopt=Abstract %R 10.3233/JAD-170203 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Motor Phenotype in Neurodegenerative Disorders: Gait and Balance Platform Study Design Protocol for the Ontario Neurodegenerative Research Initiative (ONDRI). %A Montero-Odasso, Manuel %A Pieruccini-Faria, Frederico %A Bartha, Robert %A Black, Sandra E %A Finger, Elizabeth %A Freedman, Morris %A Greenberg, Barry %A Grimes, David A %A Hegele, Robert A %A Hudson, Christopher %A Kleinstiver, Peter W %A Lang, Anthony E %A Masellis, Mario %A McLaughlin, Paula M %A Munoz, Douglas P %A Strother, Stephen %A Swartz, Richard H %A Symons, Sean %A Tartaglia, Maria Carmela %A Zinman, Lorne %A Strong, Michael J %A McIlroy, William %X

BACKGROUND: The association of cognitive and motor impairments in Alzheimer's disease and other neurodegenerative diseases is thought to be related to damage in the common brain networks shared by cognitive and cortical motor control processes. These common brain networks play a pivotal role in selecting movements and postural synergies that meet an individual's needs. Pathology in this "highest level" of motor control produces abnormalities of gait and posture referred to as highest-level gait disorders. Impairments in cognition and mobility, including falls, are present in almost all neurodegenerative diseases, suggesting common mechanisms that still need to be unraveled.

OBJECTIVE: To identify motor-cognitive profiles across neurodegenerative diseases in a large cohort of patients.

METHODS: Cohort study that includes up to 500 participants, followed every year for three years, across five neurodegenerative disease groups: Alzheimer's disease/mild cognitive impairment, frontotemporal degeneration, vascular cognitive impairment, amyotrophic lateral sclerosis, and Parkinson's disease. Gait and balance will be assessed using accelerometers and electronic walkways, evaluated at different levels of cognitive and sensory complexity, using the dual-task paradigm.

RESULTS: Comparison of cognitive and motor performances across neurodegenerative groups will allow the identification of motor-cognitive phenotypes through the standardized evaluation of gait and balance characteristics.

CONCLUSIONS: As part of the Ontario Neurodegenerative Research Initiative (ONDRI), the gait and balance platform aims to identify motor-cognitive profiles across neurodegenerative diseases. Gait assessment, particularly while dual-tasking, will help dissect the cognitive and motor contribution in mobility and cognitive decline, progression to dementia syndromes, and future adverse outcomes including falls and mortality.

%B J Alzheimers Dis %V 59 %P 707-721 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671116?dopt=Abstract %R 10.3233/JAD-170149 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Multi-Cohort Study of ApoE ɛ4 and Amyloid-β Effects on the Hippocampus in Alzheimer's Disease. %A Khan, Wasim %A Giampietro, Vincent %A Banaschewski, Tobias %A Barker, Gareth J %A Bokde, Arun L W %A Büchel, Christian %A Conrod, Patricia %A Flor, Herta %A Frouin, Vincent %A Garavan, Hugh %A Gowland, Penny %A Heinz, Anreas %A Ittermann, Bernd %A Lemaître, Hervé %A Nees, Frauke %A Paus, Tomas %A Pausova, Zdenka %A Rietschel, Marcella %A Smolka, Michael N %A Ströhle, Andreas %A Gallinat, Jeurgen %A Vellas, Bruno %A Soininen, Hilkka %A Kloszewska, Iwona %A Tsolaki, Magda %A Mecocci, Patrizia %A Spenger, Christian %A Villemagne, Victor L %A Masters, Colin L %A Muehlboeck, J-Sebastian %A Bäckman, Lars %A Fratiglioni, Laura %A Kalpouzos, Grégoria %A Wahlund, Lars-Olof %A Schumann, Gunther %A Lovestone, Simon %A Williams, Steven C R %A Westman, Eric %A Simmons, Andrew %X

The apolipoprotein E (APOE) gene has been consistently shown to modulate the risk of Alzheimer's disease (AD). Here, using an AD and normal aging dataset primarily consisting of three AD multi-center studies (n = 1,781), we compared the effect of APOE and amyloid-β (Aβ) on baseline hippocampal volumes in AD patients, mild cognitive impairment (MCI) subjects, and healthy controls. A large sample of healthy adolescents (n = 1,387) was also used to compared hippocampal volumes between APOE groups. Subjects had undergone a magnetic resonance imaging (MRI) scan and APOE genotyping. Hippocampal volumes were processed using FreeSurfer. In the AD and normal aging dataset, hippocampal comparisons were performed in each APOE group and in ɛ4 carriers with positron emission tomography Aβ who were dichotomized (Aβ+/Aβ-) using previous cut-offs. We found a linear reduction in hippocampal volumes with ɛ4 carriers possessing the smallest volumes, ɛ3 carriers possessing intermediate volumes, and ɛ2 carriers possessing the largest volumes. Moreover, AD and MCI ɛ4 carriers possessed the smallest hippocampal volumes and control ɛ2 carriers possessed the largest hippocampal volumes. Subjects with both APOE ɛ4 and Aβ+ had the lowest hippocampal volumes when compared to Aβ- ɛ4 carriers, suggesting a synergistic relationship between APOE ɛ4 and Aβ. However, we found no hippocampal volume differences between APOE groups in healthy 14-year-old adolescents. Our findings suggest that the strongest neuroanatomic effect of APOE ɛ4 on the hippocampus is observed in AD and groups most at risk of developing the disease, whereas hippocampi of old and young healthy individuals remain unaffected.

%B J Alzheimers Dis %V 56 %P 1159-1174 %8 2017 %G eng %N 3 %R 10.3233/JAD-161097 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Multifunctional Biocompatible Drug Candidate is Highly Effective in Delaying Pathological Signs of Alzheimer's Disease in 5XFAD Mice. %A Segal-Gavish, Hadar %A Danino, Ortal %A Barhum, Yael %A Ben-Zur, Tali %A Shai, Ella %A Varon, David %A Offen, Daniel %A Fischer, Bilha %X

BACKGROUND: Metal-ion-chelation was suggested to prevent zinc and copper ions-induced amyloid-β (Aβ) aggregation and oxidative stress, both implicated in the pathophysiology of Alzheimer's disease (AD). In a quest for biocompatible metal-ion chelators potentially useful for AD therapy, we previously tested a series of nucleoside 5'-phosphorothioate derivatives as agents for decomposition of Cu(I)/Cu(II)/Zn(II)-Aβ-aggregates, and as inhibitors of OH radicals formation in Cu(I) or Fe(II) /H2O2 solution. Specifically, in our recent study we have identified 2-SMe-ADP(α-S), designated as SAS, as a most promising neuroprotectant.

OBJECTIVE: To further explore SAS ability to protect the brain from Aβ toxicity both in vitro and in vivo.

METHODS: We evaluated SAS ability to decompose or inhibit the formation of Aβ42-M(II) aggregates, and rescue primary neurons and astrocytes from Aβ42 toxicity. Furthermore, we aimed at exploring the therapeutic effect of SAS on behavioral and cognitive deficits in the 5XFAD mouse model of AD.

RESULTS: We found that SAS can rescue primary culture of neurons and astrocytes from Aβ42 toxicity and to inhibit the formation and dissolve Aβ42-Zn(II)/Cu(II) aggregates. Furthermore, we show that SAS treatment can prevent behavioral disinhibition and ameliorate spatial working memory deficits in 5XFAD mice. Notably, the mice were treated at the age of 2 months, before the onset of AD symptoms, for a duration of 2 months, while the effect was demonstrated at the age of 6 months.

CONCLUSION: Our results indicate that SAS has the potential to delay progression of core pathological characteristics of AD in the 5XFAD mouse model.

%B J Alzheimers Dis %V 58 %P 389-400 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453480?dopt=Abstract %R 10.3233/JAD-161236 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Multimodal Cognitive Enhancement Therapy for Patients with Mild Cognitive Impairment and Mild Dementia: A Multi- Center, Randomized, Controlled, Double-Blind, Crossover Trial. %A Han, Ji Won %A Lee, Hyeonggon %A Hong, Jong Woo %A Kim, Kayoung %A Kim, Taehyun %A Byun, Hye Jin %A Ko, Ji Won %A Youn, Jong Chul %A Ryu, Seung-Ho %A Lee, Nam-Jin %A Pae, Chi-Un %A Kim, Ki Woong %X

We developed and evaluated the effect of Multimodal Cognitive Enhancement Therapy (MCET) consisting of cognitive training, cognitive stimulations, reality orientation, physical therapy, reminiscence therapy, and music therapy in combination in older people with mild cognitive impairment (MCI) or mild dementia. This study was a multi-center, double-blind, randomized, placebo-controlled, two-period cross-over study (two 8-week treatment phases separated by a 4-week wash-out period). Sixty-four participants with MCI or dementia whose Clinical Dementia Rating was 0.5 or 1 were randomized to the MCET group or the mock-therapy (placebo) group. Outcomes were measured at baseline, week 9, and week 21. Fifty-five patients completed the study. Mini-Mental State Examination (effect size = 0.47, p = 0.013) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (effect size = 0.35, p = 0.045) scores were significantly improved in the MCET compared with mock-therapy group. Revised Memory and Behavior Problems Checklist frequency (effect size = 0.38, p = 0.046) and self-rated Quality of Life - Alzheimer's Disease (effect size = 0.39, p = 0.047) scores were significantly improved in the MCET compared with mock-therapy. MCET improved cognition, behavior, and quality of life in people with MCI or mild dementia more effectively than conventional cognitive enhancing activities did.

%B J Alzheimers Dis %V 55 %P 787-796 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802233?dopt=Abstract %R 10.3233/JAD-160619 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Network-Based Substrate of Cognitive Reserve in Alzheimer's Disease. %A Serra, Laura %A Mancini, Matteo %A Cercignani, Mara %A Di Domenico, Carlotta %A Spanò, Barbara %A Giulietti, Giovanni %A Koch, Giacomo %A Marra, Camillo %A Bozzali, Marco %X

Cognitive reserve (CR) is known to modulate the clinical features of Alzheimer's disease (AD). This concept may be critical for the development of non-pharmacological interventions able to slow down patients' cognitive decline in the absence of disease-modifying treatments. We aimed at identifying the neurobiological substrates of CR (i.e., neural reserve) over the transition between normal aging and AD, by assessing the underlying brain networks and their topological properties. A cohort of 154 participants (n = 68 with AD, n = 61 with amnestic mild cognitive impairment (aMCI), and 25 healthy subjects) underwent resting-state functional MRI and neuropsychological testing. Within each group, participants were classified as having high or low CR, and functional connectivity measures were compared, within group, between high and low CR individuals. Network-based statistics and topological network properties derived from graph theory were explored. Connectivity differences between high and low CR were evident only for aMCI patients, with participants with high CR showing a significant increase of connectivity in a network involving mainly fronto-parietal nodes. Conversely, they showed significantly decreased connectivity in a network involving fronto-temporo-cerebellar nodes. Consistently, changes to topological measures were observed in either direction, and were associated with measures of global cognitive function. These findings support the hypothesis that CR impacts on neurodegenerative process in the early phase of AD only. In addition, they fit with the existence of a "neural reserve", characterized by specific neural networks and their efficiency. It remains to be demonstrated whether interventions later in life can modulate this "neural reserve".

%B J Alzheimers Dis %V 55 %P 421-430 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662319?dopt=Abstract %R 10.3233/JAD-160735 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neural Correlates of Self-Reference Effect in Early Alzheimer's Disease. %A Gaubert, Malo %A Villain, Nicolas %A Landeau, Brigitte %A Mézenge, Florence %A Egret, Stéphanie %A Perrotin, Audrey %A Belliard, Serge %A de la Sayette, Vincent %A Eustache, Francis %A Desgranges, Béatrice %A Chételat, Gaël %A Rauchs, Géraldine %X

Information that is processed with reference to the self (i.e., self-referential processing, SRP) is generally associated with better remembering than information processed in a semantic condition. This benefit of self on memory performance is called self-reference effect (SRE). In the present study, we assessed changes in the SRE and SRP-related brain activity in patients diagnosed with mild cognitive impairment or early Alzheimer's disease (MCI/AD). Fifteen patients with confirmed amyloid-β deposits (positive florbetapir-PET scan) and 28 healthy controls (negative florbetapir-PET scan) were included. Participants either had to judge personality trait adjectives with reference to themselves (self condition) or to a celebrity (other condition), or determine whether these adjectives were positive or not (semantic condition). These adjectives were then presented with distractors in a surprise recognition task. Functional MRI data were acquired during both the judgment and recognition tasks. The SRE was observed in controls, but reduced in patients. Both controls and patients activated cortical midline structures when judging items with reference to themselves, but patients exhibited reduced activity in the angular gyrus. In patients, activity at encoding in the angular gyrus positively correlated with subsequent recognition accuracy in the self condition (self accuracy). This region also exhibited significant hypometabolism and Aβ burden, both related to self accuracy. By contrast, there were no differences in brain activity during recognition, either between the self and semantic conditions, or between groups. These results highlight SRE impairment in patients with MCI/AD, despite intact activity in cortical midline structures, and suggest that dysfunction of the angular gyrus is related to this impairment.

%B J Alzheimers Dis %V 56 %P 717-731 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035923?dopt=Abstract %R 10.3233/JAD-160561 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neural Dynamics of Multiple Object Processing in Mild Cognitive Impairment and Alzheimer's Disease: Future Early Diagnostic Biomarkers? %A Bagattini, Chiara %A Mazza, Veronica %A Panizza, Laura %A Ferrari, Clarissa %A Bonomini, Cristina %A Brignani, Debora %X

The aim of this study was to investigate the behavioral and electrophysiological dynamics of multiple object processing (MOP) in mild cognitive impairment (MCI) and Alzheimer's disease (AD), and to test whether its neural signatures may represent reliable diagnostic biomarkers. Behavioral performance and event-related potentials [N2pc and contralateral delay activity (CDA)] were measured in AD, MCI, and healthy controls during a MOP task, which consisted in enumerating a variable number of targets presented among distractors. AD patients showed an overall decline in accuracy for both small and large target quantities, whereas in MCI patients, only enumeration of large quantities was impaired. N2pc, a neural marker of attentive individuation, was spared in both AD and MCI patients. In contrast, CDA, which indexes visual short term memory abilities, was altered in both groups of patients, with a non-linear pattern of amplitude modulation along the continuum of the disease: a reduction in AD and an increase in MCI. These results indicate that AD pathology shows a progressive decline in MOP, which is associated to the decay of visual short-term memory mechanisms. Crucially, CDA may be considered as a useful neural signature both to distinguish between healthy and pathological aging and to characterize the different stages along the AD continuum, possibly becoming a reliable candidate for an early diagnostic biomarker of AD pathology.

%B J Alzheimers Dis %V 59 %P 643-654 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671112?dopt=Abstract %R 10.3233/JAD-161274 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neurofibrillary Tangles of Aβx-40 in Alzheimer's Disease Brains. %A Lacosta, Ana-María %A Insua, Daniel %A Badi, Hassnae %A Pesini, Pedro %A Sarasa, Manuel %X

The two pathognomonic lesions in the brain of AD patients are senile plaques and intraneuronal neurofibrillary tangles (NFT). Previous studies have demonstrated that amyloid-β (Aβ) is a component of both senile plaques and NFTs, and have showed that intracellular accumulation of Aβ is toxic for cells and precedes the appearance of extracellular amyloid deposits. Here we report that there are numerous intraneuronal NFT and extraneuronal NFT immunoreactive for Aβx-40 in which there is no co-localization with tau staining suggesting the existence of two different neurodegenerating populations associated with the intracellular accumulation of either tau protein or Aβx-40 in AD.

%B J Alzheimers Dis %V 58 %P 661-667 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453491?dopt=Abstract %R 10.3233/JAD-170163 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neuroimaging and its Relevance to Understanding Pathways Linking Diabetes and Cognitive Dysfunction. %A Moran, Chris %A Beare, Richard %A Phan, Thanh %A Starkstein, Sergio %A Bruce, David %A Romina, Mizrahi %A Srikanth, Velandai %X

Diabetes mellitus is associated with an elevated risk of cognitive impairment and dementia. Cerebrovascular disease and neurodegeneration are two major pathways that may explain the effect of diabetes on the brain and therefore deserve investigation. Neuroimaging provides an effective way to investigate the contribution of these pathways in vivo, guiding further mechanistic research and providing biomarkers for clinical correlation or interventional studies. In this paper, we present a narrative review of the state of play with neuroimaging evidence in studies of people with diabetes mellitus, how these data are useful in understanding mechanistic links between diabetes and brain impairment, and possible ways that the field may develop in the future.

%B J Alzheimers Dis %V 59 %P 405-419 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527209?dopt=Abstract %R 10.3233/JAD-161166 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neurons Derived from Induced Pluripotent Stem Cells of Patients with Down Syndrome Reproduce Early Stages of Alzheimer's Disease Type Pathology in vitro. %A Dashinimaev, Erdem B %A Artyuhov, Alexander S %A Bolshakov, Alexey P %A Vorotelyak, Ekaterina A %A Vasiliev, Andrey V %X

People with Down syndrome (DS) are at high risk of developing pathology similar to Alzheimer's disease (AD). Modeling of this pathology in vitro may be useful for studying this phenomenon. In this study, we analyzed three different cultures of neural cells carrying trisomy of chromosome 21, which were generated by directed differentiation from induced pluripotent stem cells (iPS cells). We report here that in vitro generated DS neural cells have abnormal metabolism of amyloid-β (Aβ) manifested by increased secretion and accumulation of Aβ granules of Aβ42 pathological isoform with upregulated expression of the APP gene. Additionally, we found increased expression levels of genes that are considered to be associated with AD (BACE2, RCAN1, ETS2, TMED10), as compared to healthy controls. Thus, the neural cells generated from induced pluripotent stem cells with DS reproduce initial cellular signs of AD-type pathology and can be useful tools for modeling and studying this variant of AD in vitro.

%B J Alzheimers Dis %V 56 %P 835-847 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059787?dopt=Abstract %R 10.3233/JAD-160945 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neuropsychiatric Symptoms and Alzheimer's Disease Biomarkers Predict Driving Decline: Brief Report. %A Babulal, Ganesh M %A Stout, Sarah H %A Head, Denise %A Holtzman, David M %A Fagan, Anne M %A Morris, John C %A Roe, Catherine M %X

We examined whether neuropsychiatric symptoms (NPS) interact with cerebrospinal fluid (CSF) biomarkers (amyloid-β42 [Aβ42], tau, phosphorylated tau181 [ptau181], tau/Aβ42, and ptau181/Aβ42) of Alzheimer's disease pathology to predict driving decline among cognitively-normal older adults (N = 116) aged ≥65. Cox proportional hazards models examined time to receiving a rating of marginal or fail on the driving test. Age, education, and gender were adjusted in the models. Participants with more abnormal CSF (Aβ42, tau/Aβ42, ptau181/Aβ42) and NPS were faster to receive a marginal/fail on the road test compared to those without NPS. NPS interact with abnormal CSF biomarkers to impact driving performance among cognitively-normal older adults.

%B J Alzheimers Dis %V 58 %P 675-680 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453487?dopt=Abstract %R 10.3233/JAD-170067 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neuropsychiatric Symptoms and Cognitive Impairment: Understanding the Importance of Co-Morbid Symptoms. %A Mortby, Moyra E %A Burns, Richard %A Eramudugolla, Ranmalee %A Ismail, Zahinoor %A Anstey, Kaarin J %X

BACKGROUND: Neuropsychiatric symptoms (NPS) are common in older adults with cognitive impairment, yet little is known about population-based prevalence and clinical implications of co-morbid symptom presentation across the spectrum from normal cognition to dementia.

OBJECTIVE: To characterize the prevalence of NPS and explore the clinical implications of co-morbid symptom presentation.

METHODS: Cross-sectional study of 1,417 older adults (aged 73-79) with dementia (n = 40); with mild cognitive impairment (MCI; n = 133); who are 'cognitively normal, but-at-risk' (CN-AR; n = 397); and who are cognitively normal (n = 847). NPS were assessed by the Neuropsychiatric Inventory. Cluster analyses were conducted using a latent class analysis (LCA).

RESULTS: NPS are highly prevalent across the cognitive function spectrum (30.8% -80%). NPS were associated with a 3-fold increased risk of dementia, a 2-fold increased risk of MCI, and a 1.5-times increased risk of CN-AR. Each additional co-morbid symptom was associated with an additional 1.5-times increased risk of dementia, but not MCI or CN-AR. LCA revealed four distinctive sub-populations: 1) frontal/low comorbidity; 2) high prevalence/high comorbidity; 3) affective/low comorbidity; and 4) sleep/low comorbidity.

CONCLUSION: Our findings confirm previous reports on the prevalence of NPS in community-based samples and are consistent with the profiles of NPS domain characteristics of MCI and dementia. Number of co-morbid NPS and not symptom clusters are associated with increased risk of dementia. Understanding such patterns will help inform our understanding of mild behavioral disorders and assist with clinical assessment.

%B J Alzheimers Dis %V 59 %P 141-153 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598846?dopt=Abstract %R 10.3233/JAD-170050 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neuropsychological Symptoms in Sporadic Creutzfeldt-Jakob Disease Patients in Germany. %A Krasnianski, Anna %A Bohling, Geeske T %A Heinemann, Uta %A Varges, Daniela %A Meissner, Bettina %A Schulz-Schaeffer, Walter J %A Reif, Andreas %A Zerr, Inga %X

BACKGROUND: The polymorphism at codon 129 of the prion protein gene (PRNP) and the PrPSc types 1 and 2 belong to a molecular classification of sporadic Creutzfeldt-Jakob disease (sCJD) that correlates well with the clinical and neuropathological phenotype of sCJD.

OBJECTIVE: The aim of the study was to perform the first detailed evaluation of neuropsychological deficits in a large group of definite sCJD patients with known molecular subtype.

METHODS: We analyzed neuropsychological symptoms in a cohort of 248 sCJD patients with known M129 V polymorphism of PRNP and prion protein type.

RESULTS: Neuropsychological symptoms were very frequent in our patients (96%) and occurred as early as in the first third of the disease course. Besides amnesia and impaired attention (89% each), frontal lobe syndrome (75%), aphasia (63%), and apraxia (57%) were the most common neuropsychological deficits. There was no statistically significant difference with regard to frequency of neuropsychological symptoms between the subtypes. In MV2 and VV2 patients, the onset of neuropsychological symptoms was significantly later than in all other subtypes.

CONCLUSION: We provide the first detailed analysis of neuropsychological symptoms in a large group of sCJD patients with known M129 V genotype and prion protein type. We suggest that the rate of progression of neuropsychological symptoms is subtype-specific. These data may improve the diagnosis in atypical sCJD subtypes.

%B J Alzheimers Dis %V 59 %P 329-337 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598840?dopt=Abstract %R 10.3233/JAD-161129 %0 Journal Article %J J Alzheimers Dis %D 2017 %T No Genetic Overlap Between Circulating Iron Levels and Alzheimer's Disease. %A Lupton, Michelle K %A Benyamin, Beben %A Proitsi, Petroula %A Nyholt, Dale R %A Ferreira, Manuel A %A Montgomery, Grant W %A Heath, Andrew C %A Madden, Pamela A %A Medland, Sarah E %A Gordon, Scott D %A Lovestone, Simon %A Tsolaki, Magda %A Kloszewska, Iwona %A Soininen, Hilkka %A Mecocci, Patrizia %A Vellas, Bruno %A Powell, John F %A Bush, Ashley I %A Wright, Margaret J %A Martin, Nicholas G %A Whitfield, John B %X

Iron deposition in the brain is a prominent feature of Alzheimer's disease (AD). Recently, peripheral iron measures have also been shown to be associated with AD status. However, it is not known whether these associations are causal: do elevated or depleted iron levels throughout life have an effect on AD risk? We evaluate the effects of peripheral iron on AD risk using a genetic profile score approach by testing whether variants affecting iron, transferrin, or ferritin levels selected from GWAS meta-analysis of approximately 24,000 individuals are also associated with AD risk in an independent case-control cohort (n∼10,000). Conversely, we test whether AD risk variants from a GWAS meta-analysis of approximately 54,000 account for any variance in iron measures (n∼9,000). We do not identify a genetic relationship, suggesting that peripheral iron is not causal in the initiation of AD pathology.

%B J Alzheimers Dis %V 59 %P 85-99 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582860?dopt=Abstract %R 10.3233/JAD-170027 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Non-Phosphorylated Tau as a Potential Biomarker of Alzheimer's Disease: Analytical and Diagnostic Characterization. %A Lewczuk, Piotr %A Lelental, Natalia %A Lachmann, Ingolf %A Holzer, Max %A Flach, Katharina %A Brandner, Sebastian %A Engelborghs, Sebastiaan %A Teunissen, Charlotte E %A Zetterberg, Henrik %A Molinuevo, José Luis %A Mroczko, Barbara %A Blennow, Kaj %A Popp, Julius %A Parnetti, Lucilla %A Chiasserini, Davide %A Perret-Liaudet, Armand %A Spitzer, Philipp %A Maler, Juan Manuel %A Kornhuber, Johannes %X

BACKGROUND: Virtually nothing is known about a potential diagnostic role of non-phospho-epitopes of Tau (Non-P-Tau) in cerebrospinal fluid (CSF).

OBJECTIVE: To establish and analytically and clinically characterize the first assay capable to measure concentrations of Non-P-Tau in human CSF.

METHODS: An antibody (1G2) was developed that selectively binds to the Tau molecule non-phosphorylated at the positions T175 and T181, and was used in establishing a sandwich ELISA capable to measure Non-P-Tau in human CSF, following analytical and clinical validation of the method.

RESULTS: The 1G2 antibody shows decreasing reactivity to tau peptides containing phosphorylation mainly at positions T175 and T181. Detection limit of the assay is 25 pg/ml; the coefficients of variation (CVs) of the optical densities of the repeated standard curves were between 3.6-15.9%. Median intra-assay imprecision of double measurements was 4.8%; inter-assay imprecision was in the range of 11.2% - 15.3%. Non-P-Tau concentrations are stable in the CSF samples sent to distinct laboratories under ambient temperature; inter-laboratory variation was approximately 30%. The Non-P-Tau CSF concentrations were highly significantly increased in patients with Alzheimer's disease in stage of mild cognitive impairment or dementia (AD/MCI, n = 58, 109.2±32.0 pg/mL) compared to the non-demented Controls (n = 42, 62.1±9.3 pg/mL, p < 0.001). At the cut-off of 78.3 pg/mL, the sensitivity and the specificity were 94.8% and 97.6%, respectively.

CONCLUSION: For the first time, an assay is reported to reliably measure concentrations of non-phosphorylated Tau in human CSF.

%B J Alzheimers Dis %V 55 %P 159-170 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662295?dopt=Abstract %R 10.3233/JAD-160448 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Normal Vitamin Levels and Nutritional Indices in Alzheimer's Disease Patients with Mild Cognitive Impairment or Dementia with Normal Body Mass Indexes. %A Ulstein, Ingun %A Bøhmer, Thomas %X

Evidence supports an association between vitamin deficiencies and cognitive decline in Alzheimer's disease (AD). If vitamin deficiencies are causative for AD development, they should be detectable during very early stages of AD. Here we investigated nutritional factors among home-living patients diagnosed with mild cognitive impairment (MCI) or mild dementia due to AD, compared to healthy controls. Our study included 73 patients with AD (25 with MCI, 48 with dementia) and 63 cognitively intact age-matched controls. All participants underwent cognitive testing, somatic examination, and measurements of vitamins A, B1, B6, folate, B12, C, D, and E, and F2-α-isoprostane. Results are given as mean (SD). MMSE scores were 29.1 (1.0) for healthy controls, 27.4 (1.8) for patients with MCI, and 24.3 (3.2) for patients with dementia. Vitamin concentrations for the these groups, respectively, were as follows: B1 (nmol/l), 157 (29), 161 (35), and 161 (32); B6 (nmol/l), 57 (63), 71 (104), and 58 (44); folate (mmol/l), 23 (9), 26 (10), and 23 (11); B12 (pmol/l), 407 (159), 427 (116), and 397 (204); C (μmol/l), 63 (18), 61 (16), and 63 (29); A (μmol/l), 2.3 (0.6), 2.2 (0.5), and 2.3(0.5); E (μmol/l), 36 (6.3), 36 (6.9), and 36 (8.2); 25-OH vitamin D (nmol/l), 65 (18), 61 (19), and 65 (20); and 8-iso-PGFα (pg/ml), 64 (27); 60 (19), and 66 (51). These concentrations did not significantly differ (p≤0.05) between the three groups. Our results do not support the hypothesis that vitamin deficiencies play a causative role in the development of early cognitive impairment.

%B J Alzheimers Dis %V 55 %P 717-725 %8 2016 Oct 5 %G eng %N 2 %R 10.3233/JAD-160393 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Novel Blood-Based Biomarkers of Cognition, Stress, and Physical or Cognitive Training in Older Adults at Risk of Dementia: Preliminary Evidence for a Role of BDNF, Irisin, and the Kynurenine Pathway. %A Küster, Olivia C %A Laptinskaya, Daria %A Fissler, Patrick %A Schnack, Cathrin %A Zügel, Martina %A Nold, Verena %A Thurm, Franka %A Pleiner, Sina %A Karabatsiakis, Alexander %A von Einem, Björn %A Weydt, Patrick %A Liesener, André %A Borta, Andreas %A Woll, Alexander %A Hengerer, Bastian %A Kolassa, Iris-Tatjana %A von Arnim, Christine A F %X

 Psychosocial stress and physical, cognitive, and social activity predict the risk of cognitive decline and dementia. The aim of this study was to elucidate brain-derived neurotrophic factor (BDNF), irisin, and the kynurenine pathway (KP) as potential underlying biological correlates. We evaluated associations of irisin and the KP with BDNF in serum and with cognition, stress, and activities. Furthermore, changes in serum concentrations of BDNF, irisin, and KP metabolites were investigated after physical or cognitive training. Forty-seven older adults at risk of dementia were assigned to 10 weeks of physical training, cognitive training, or a wait-list control condition. Previous physical, cognitive, and social activities and stressful life events were recorded; global cognition, episodic memory, and executive functions were assessed. Serum levels of L-kynurenine, kynurenic acid, 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN) were determined by validated assays based on liquid chromatography coupled to tandem mass spectrometry. BDNF and irisin serum levels were determined with enzyme-linked immunosorbent assays. BDNF and irisin correlated positively with global cognition and episodic memory, while the neurotoxic metabolite QUIN correlated negatively with executive functions. Stressful life events were associated with reduced BDNF and increased 3-HK. 3-HK decreased after cognitive training, while BDNF tended to increase after physical training. This suggests that psychosocial stress as well as cognitive and physical training may impact BDNF serum levels and the KP. Irisin and QUIN may constitute novel serum biomarkers of cognitive impairment, in addition to BDNF. Larger scale trials are needed to replicate and extend these novel findings.

%B J Alzheimers Dis %V 59 %P 1097-1111 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731451?dopt=Abstract %R 10.3233/JAD-170447 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Novel Phospho-Tau Monoclonal Antibody Generated Using a Liposomal Vaccine, with Enhanced Recognition of a Conformational Tauopathy Epitope. %A Theunis, Clara %A Adolfsson, Oskar %A Crespo-Biel, Natalia %A Piorkowska, Kasia %A Pihlgren, Maria %A Hickman, David T %A Gafner, Valerie %A Borghgraef, Peter %A Devijver, Herman %A Pfeifer, Andrea %A Van Leuven, Fred %A Muhs, Andreas %X

The microtubule-associated protein Tau is an intrinsically unfolded, very soluble neuronal protein. Under still unknown circumstances, Tau protein forms soluble oligomers and insoluble aggregates that are closely linked to the cause and progression of various brain pathologies, including Alzheimer's disease. Previously we reported the development of liposome-based vaccines and their efficacy and safety in preclinical mouse models for tauopathy. Here we report the use of a liposomal vaccine for the generation of a monoclonal antibody with particular characteristics that makes it a valuable tool for fundamental studies as well as a candidate antibody for diagnostic and therapeutic applications. The specificity and affinity of antibody ACI-5400 were characterized by a panel of methods: (i) measuring the selectivity for a specific phospho-Tau epitope known to be associated with tauopathy, (ii) performing a combination of peptide and protein binding assays, (iii) staining of brain sections from mouse preclinical tauopathy models and from human subjects representing six different tauopathies, and (iv) evaluating the selective binding to pathological epitopes on extracts from tauopathy brains in non-denaturing sandwich assays. We conclude that the ACI-5400 antibody binds to protein Tau phosphorylated at S396 and favors a conformation that is typically present in the brain of tauopathy patients, including Alzheimer's disease.

%B J Alzheimers Dis %V 56 %P 585-599 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035925?dopt=Abstract %R 10.3233/JAD-160695 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Only White Matter Hyperintensities Predicts Post-Stroke Cognitive Performances Among Cerebral Small Vessel Disease Markers: Results from the TABASCO Study. %A Molad, Jeremy %A Kliper, Efrat %A Korczyn, Amos D %A Ben Assayag, Einor %A Ben Bashat, Dafna %A Shenhar-Tsarfaty, Shani %A Aizenstein, Orna %A Shopin, Ludmila %A Bornstein, Natan M %A Auriel, Eitan %X

BACKGROUND: White matter hyperintensities (WMH) were shown to predict cognitive decline following stroke or transient ischemic attack (TIA). However, WMH are only one among other radiological markers of cerebral small vessel disease (SVD).

OBJECTIVE: The aim of this study was to determine whether adding other SVD markers to WMH improves prediction of post-stroke cognitive performances.

METHODS: Consecutive first-ever stroke or TIA patients (n = 266) from the Tel Aviv Acute Brain Stroke Cohort (TABASCO) study were enrolled. MRI scans were performed within seven days of stroke onset. We evaluated the relationship between cognitive performances one year following stroke, and previously suggested total SVD burden score including WMH, lacunes, cerebral microbleeds (CMB), and perivascular spaces (PVS).

RESULTS: Significant negative associations were found between WMH and cognition (p < 0.05). Adding other SVD markers (lacunes, CMB, PVS) to WMH did not improve predication of post-stroke cognitive performances. Negative correlations between SVD burden score and cognitive scores were observed for global cognitive, memory, and visual spatial scores (all p < 0.05). However, following an adjustment for confounders, no associations remained significant.

CONCLUSION: WMH score was associated with poor post-stroke cognitive performance. Adding other SVD markers or SVD burden score, however, did not improve prediction.

%B J Alzheimers Dis %V 56 %P 1293-1299 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157096?dopt=Abstract %R 10.3233/JAD-160939 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Passive Assessment of Routine Driving with Unobtrusive Sensors: A New Approach for Identifying and Monitoring Functional Level in Normal Aging and Mild Cognitive Impairment. %A Seelye, Adriana %A Mattek, Nora %A Sharma, Nicole %A Witter, Phelps %A Brenner, Ariella %A Wild, Katherine %A Dodge, Hiroko %A Kaye, Jeffrey %X

BACKGROUND: Driving is a key functional activity for many older adults, and changes in routine driving may be associated with emerging cognitive decline due to early neurodegenerative disease. Current methods for assessing driving such as self-report are inadequate for identifying and monitoring subtle changes in driving patterns that may be the earliest signals of functional change in developing mild cognitive impairment (MCI).

OBJECTIVE: This proof of concept study aimed to establish the feasibility of continuous driving monitoring in a sample of cognitively normal and MCI older adults for an average of 206 days using an unobtrusive driving sensor and demonstrate that derived sensor-based driving metrics could effectively discriminate between MCI and cognitively intact groups.

METHODS: Novel objective driving measures derived from 6 months of routine driving monitoring were examined in older adults with intact cognition (n = 21) and MCI (n = 7) who were enrolled in the Oregon Center for Aging and Technology (ORCATECH) longitudinal assessment program.

RESULTS: Unobtrusive continuous monitoring of older adults' routine driving using a driving sensor was feasible and well accepted. MCI participants drove fewer miles and spent less time on the highway per day than cognitively intact participants. MCI drivers showed less day-to-day fluctuations in their driving habits than cognitively intact drivers.

CONCLUSION: Sensor-based driving measures are objective, unobtrusive, and can be assessed every time a person drives his or her vehicle to identify clinically meaningful changes in daily driving. This novel methodology has the potential to be useful for the early detection and monitoring of changes in daily functioning within individuals.

%B J Alzheimers Dis %V 59 %P 1427-1437 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731434?dopt=Abstract %R 10.3233/JAD-170116 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer's Disease. %A Darst, Burcu F %A Koscik, Rebecca L %A Racine, Annie M %A Oh, Jennifer M %A Krause, Rachel A %A Carlsson, Cynthia M %A Zetterberg, Henrik %A Blennow, Kaj %A Christian, Bradley T %A Bendlin, Barbara B %A Okonkwo, Ozioma C %A Hogan, Kirk J %A Hermann, Bruce P %A Sager, Mark A %A Asthana, Sanjay %A Johnson, Sterling C %A Engelman, Corinne D %X

Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer's disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer's Project's meta-analysis, we identified clusters of genes that grouped into pathways involved in amyloid-β (Aβ) deposition and neurodegeneration: Aβ clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aβ deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging in 168 individuals, and cerebrospinal fluid Aβ deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.

%B J Alzheimers Dis %V 55 %P 473-484 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662287?dopt=Abstract %R 10.3233/JAD-160195 %0 Journal Article %J J Alzheimers Dis %D 2017 %T PCSK9 Promotes oxLDL-Induced PC12 Cell Apoptosis Through the Bcl-2/Bax-Caspase 9/3 Signaling Pathway. %A Liu, Lu-Shan %A Bai, Xue-Qin %A Gao, Ya %A Wu, Qi %A Ren, Zhong %A Li, Qing %A Pan, Li-Hong %A He, Ni-Ya %A Peng, Juan %A Tang, Zhi-Han %K Amyloid beta-Peptides %K Analysis of Variance %K Animals %K Apoptosis %K bcl-2-Associated X Protein %K Caspases %K Culture Media, Serum-Free %K Dose-Response Relationship, Drug %K Flow Cytometry %K Lipid Metabolism %K Lipoproteins, LDL %K PC12 Cells %K Peptide Fragments %K Proprotein Convertase 9 %K Proto-Oncogene Proteins c-bcl-2 %K Rats %K RNA, Messenger %K RNA, Small Interfering %K Signal Transduction %K Transfection %X

BACKGROUND: Hyperlipidemia is a risk factor for neurodegenerative diseases. Proprotein convertase subtilisin / Kexin type 9 (PCSK9) degrades hepatic low-density lipoprotein receptor (LDLR) to regulate lipid metabolism. It is unclear if PCSK9 plays a role in neurodegenerative diseases.

OBJECTIVE: This study was designed to determine whether PCSK9 is crucial between hyperlipidemia and Alzheimer's disease. The interrelationship between PCSK9 and neuronal apoptosis was explored in PC12 cells in response to treatment with oxidized low-density lipoprotein (oxLDL).

METHODS: Cultured PC12 cells were serum-starved and incubated with different concentrations of oxLDL for 24 h. Intracytoplasmic lipid droplets were observed by oil red O staining. Morphological assessment of apoptotic cells was performed using Hoechst 33258 staining and flow cytometry analysis. The expression of mRNA and protein was detected by reverse-transcription polymerase chain reaction (RT-PCR) and western blot analyses, respectively. Transfection of small interfering RNA (siRNA) into PC12 cells was conducted using HiperFect Transfection Reagent. Concentrations of Aβ40 and Aβ42 were detected by enzyme-linked immunosorbent assay (ELISA) kit.

RESULTS: Intracellular lipid content, the number of apoptotic cells, and PCSK9 expression were increased in PC12 cells after oxLDL treatment. Transfection with PCSK9 siRNA reduced the oxLDL-induced apoptosis of PC12 cells. We further confirmed the involvement of Bcl-2/Bax-Caspase (9, 3) signaling pathway in the regulation of PC12 cells apoptosis.β-Secretase 1, another target gene of PCSK9, was downregulated in PC12 cells in response to oxLDL treatment. Aβ40 and Aβ42 contents were also decreased.

CONCLUSION: PCSK9 promotes oxLDL-induced PC12 cell apoptosis through the Bcl-2/Bax-Caspase 9/3 signaling pathway.

%B J Alzheimers Dis %V 57 %P 723-734 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304296?dopt=Abstract %R 10.3233/JAD-161136 %0 Journal Article %J J Alzheimers Dis %D 2017 %T People with Dementia Can Learn Compensatory Movement Maneuvers for the Sit-to-Stand Task: A Randomized Controlled Trial. %A Werner, Christian %A Wiloth, Stefanie %A Lemke, Nele Christin %A Kronbach, Florian %A Jansen, Carl-Philipp %A Oster, Peter %A Bauer, Jürgen M %A Hauer, Klaus %X

BACKGROUND: A complex motor skill highly relevant to mobility in everyday life (e.g., sit-to-stand [STS] transfer) has not yet been addressed in studies on motor learning in people with dementia (PwD).

OBJECTIVE: To determine whether a dementia-specific motor learning exercise program enables PwD to learn compensatory STS maneuvers commonly taught in geriatric rehabilitation therapy to enhance patients' STS ability.

METHODS: Ninety-seven patients with mild-to-moderate dementia (Mini-Mental State Examination: 21.9±2.9 points) participated in a double-blinded, randomized, placebo-controlled trial with 10-week intervention and 3-month follow-up period. The intervention group (IG, n = 51) underwent a motor learning exercise program on compensatory STS maneuvers specifically designed for PwD. The control group (CG, n = 46) performed a low-intensity motor placebo activity. Primary outcomes were scores of the Assessment of Compensatory Sit-to-stand Maneuvers in People with Dementia (ACSID), which covers the number of recalled and initiated, and of effectively performed compensatory STS maneuvers. Secondary outcomes included temporal and kinematic STS characteristics measured by a body-fixed motion sensor (BFS, DynaPort® Hybrid).

RESULTS: The IG significantly improved in all ACSID scores compared to the CG (p < 0.001). Secondary analysis confirmed learning effects for all BFS-based outcomes (p < 0.001-0.006). Learning gains were sustained during follow-up for most outcomes.

CONCLUSION: People with mild-to-moderate dementia can learn and retain compensatory STS maneuvers in response to a dementia-specific motor learning exercise program. This is the first study that demonstrated preserved motor learning abilities in PwD by using a motor skill highly relevant to everyday life.

%B J Alzheimers Dis %V 60 %P 107-120 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28759967?dopt=Abstract %R 10.3233/JAD-170258 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Perception and Reality of Cognitive Function: Information Processing Speed, Perceived Memory Function, and Perceived Task Difficulty in Older Adults. %A Torrens-Burton, Anna %A Basoudan, Nasreen %A Bayer, Antony J %A Tales, Andrea %X

This study examines the relationships between two measures of information processing speed associated with executive function (Trail Making Test and a computer-based visual search test), the perceived difficulty of the tasks, and perceived memory function (measured by the Memory Functioning Questionnaire) in older adults (aged 50+ y) with normal general health, cognition (Montreal Cognitive Assessment score of 26+), and mood. The participants were recruited from the community rather than through clinical services, and none had ever sought or received help from a health professional for a memory complaint or mental health problem. For both the trail making and the visual search tests, mean information processing speed was not correlated significantly with perceived memory function. Some individuals did, however, reveal substantially slower information processing speeds (outliers) that may have clinical significance and indicate those who may benefit most from further assessment and follow up. For the trail making, but not the visual search task, higher levels of subjective memory dysfunction were associated with a greater perception of task difficulty. The relationship between actual information processing speed and perceived task difficulty also varied with respect to the task used. These findings highlight the importance of taking into account the type of task and metacognition factors when examining the integrity of information processing speed in older adults, particularly as this measure is now specifically cited as a key cognitive subdomain within the diagnostic framework for neurocognitive disorders.

%B J Alzheimers Dis %V 60 %P 1601-1609 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984584?dopt=Abstract %R 10.3233/JAD-170599 %0 Journal Article %J J Alzheimers Dis %D 2017 %T PET Imaging of Tau Pathology and Relationship to Amyloid, Longitudinal MRI, and Cognitive Change in Down Syndrome: Results from the Down Syndrome Biomarker Initiative (DSBI). %A Rafii, Michael S %A Lukic, Ana S %A Andrews, Randolph D %A Brewer, James %A Rissman, Robert A %A Strother, Stephen C %A Wernick, Miles N %A Pennington, Craig %A Mobley, William C %A Ness, Seth %A Matthews, Dawn C %X

BACKGROUND: Adults with Down syndrome (DS) represent an enriched population for the development of Alzheimer's disease (AD), which could aid the study of therapeutic interventions, and in turn, could benefit from discoveries made in other AD populations.

OBJECTIVES: 1) Understand the relationship between tau pathology and age, amyloid deposition, neurodegeneration (MRI and FDG PET), and cognitive and functional performance; 2) detect and differentiate AD-specific changes from DS-specific brain changes in longitudinal MRI.

METHODS: Twelve non-demented adults, ages 30 to 60, with DS were enrolled in the Down Syndrome Biomarker Initiative (DSBI), a 3-year, observational, cohort study to demonstrate the feasibility of conducting AD intervention/prevention trials in adults with DS. We collected imaging data with 18F-AV-1451 tau PET, AV-45 amyloid PET, FDG PET, and volumetric MRI, as well as cognitive and functional measures and additional laboratory measures.

RESULTS: All amyloid negative subjects imaged were tau-negative. Among the amyloid positive subjects, three had tau in regions associated with Braak stage VI, two at stage V, and one at stage II. Amyloid and tau burden correlated with age. The MRI analysis produced two distinct volumetric patterns. The first differentiated DS from normal (NL) and AD, did not correlate with age or amyloid, and was longitudinally stable. The second pattern reflected AD-like atrophy and differentiated NL from AD. Tau PET and MRI atrophy correlated with several cognitive and functional measures.

CONCLUSIONS: Tau accumulation is associated with amyloid positivity and age, as well as with progressive neurodegeneration measurable using FDG and MRI. Tau correlates with cognitive decline, as do AD-specific hypometabolism and atrophy.

%B J Alzheimers Dis %V 60 %P 439-450 %8 2017 %G eng %N 2 %R 10.3233/JAD-170390 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Phenotype-Dependent Interactions between N-acetyl-L-Aspartate and Acetyl-CoA in Septal SN56 Cholinergic Cells Exposed to an Excess of Zinc. %A Zyśk, Marlena %A Bielarczyk, Hanna %A Gul-Hinc, Sylwia %A Dyś, Aleksandra %A Gapys, Beata %A Ronowska, Anna %A Sakowicz-Burkiewicz, Monika %A Szutowicz, Andrzej %X

Pyruvate dehydrogenase reaction utilizing glucose-derived pyruvate is an almost exclusive source of acetyl-CoA in different cell mitochondrial compartments of the brain. In neuronal mitochondria, the largest fraction of acetyl-CoA is utilized for energy production and the much smaller one for N-acetyl-L-aspartate (NAA) synthesis. Cholinergic neurons, unlike others, require additional amounts of acetyl-CoA for acetylcholine synthesis. Therefore, several neurotoxic signals, which inhibit pyruvate dehydrogenase, generate deeper shortages of acetyl-CoA and greater mortality of cholinergic neurons than noncholinergic ones. NAA is considered to be a marker of neuronal energy status in neuropathic brains. However, there is no data on putative differential fractional distribution of the acetyl-CoA pool between energy producing and NAA or acetylcholine synthesizing pathways in noncholinergic and cholinergic neurons, respectively. Therefore, the aim of this study was to investigate whether zinc-excess, a common excitotoxic signal, may evoke differential effects on the NAA metabolism in neuronal cells with low and high expression of the cholinergic phenotype. Differentiated SN56 neuronal cells, displaying a high activity of choline acetyltransferase and rates of acetylcholine synthesis, contained lower levels of acetyl-CoA and NAA, being more susceptible to ZnCl2 exposition that the nondifferentiated SN56 or differentiated dopaminergic SHSY5Y neuronal and astroglial C6 cells. Differentiated SN56 accumulated greater amounts of Zn2 + from extracellular space than the other ones, and displayed a stronger suppression of pyruvate dehydrogenase complex activity and acetyl-CoA, NAA, ATP, acetylcholine levels, and loss of viability. These data indicate that the acetyl-CoA synthesizing system in neurons constitutes functional unity with energy generating and NAA or acetylcholine pathways of its utilization, which are uniformly affected by neurotoxic conditions.

%B J Alzheimers Dis %V 56 %P 1145-1158 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28106547?dopt=Abstract %R 10.3233/JAD-160693 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Plasma Amyloid-β Peptides in Type 2 Diabetes: A Matched Case-Control Study. %A Peters, Kirsten E %A Davis, Wendy A %A Taddei, Kevin %A Martins, Ralph N %A Masters, Colin L %A Davis, Timothy M E %A Bruce, David G %X

BACKGROUND: Plasma amyloid-β (Aβ) levels have rarely been investigated in type 2 diabetes despite its known associations with Alzheimer's disease.

OBJECTIVE: To compare blood plasma Aβ concentrations (Aβ40 and Aβ42) in cognitively normal individuals with and without type 2 diabetes.

METHODS: Plasma Aβ40 and Aβ42 were measured in 194 participants with diabetes recruited from the community-based Fremantle Diabetes Study Phase II cohort (mean age 71 years, 59% males) and 194 age-, sex-, and APOEɛ4 allele-matched, control subjects without diabetes from the Australian Imaging, Biomarkers and Lifestyle Study using a multiplex microsphere-based immunoassay.

RESULTS: Plasma Aβ40 and Aβ42 were normally distributed in the controls but were bimodal in the participants with diabetes. Median Aβ40 and Aβ42 concentrations were significantly lower in those with type 2 diabetes (Aβ40 median [inter-quartile range]: 125.0 [52.6-148.3] versus 149.3 [134.0-165.6] pg/mL; Aβ42: 26.9 [14.5-38.3] versus 33.6 [28.0-38.9] pg/mL, both p < 0.001) while the ratio Aβ42:Aβ40 was significantly higher (0.26 [0.23-0.32] versus 0.22 [0.19-0.25], p < 0.001). After adjustment, participants with diabetes and plasma Aβ40 levels in the low peak of the bimodal distribution were significantly more likely to have normal to high estimated glomerular filtration rates (odds ratio (95% CI): 2.40 (1.20-4.80), p = 0.013) although the group with diabetes had lower renal function overall.

CONCLUSION: Type 2 diabetes is associated with altered plasma concentrations of Aβ peptides and is an important source of variation that needs to be taken into account when considering plasma Aβ peptides as biomarkers for Alzheimer's disease.

%B J Alzheimers Dis %V 56 %P 1127-1133 %G eng %N 3 %R 10.3233/JAD-161050 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Plasma Proteomic Profiles of Cerebrospinal Fluid-Defined Alzheimer's Disease Pathology in Older Adults. %A Dayon, Loïc %A Wojcik, Jérôme %A Núñez Galindo, Antonio %A Corthésy, John %A Cominetti, Ornella %A Oikonomidi, Aikaterini %A Henry, Hugues %A Migliavacca, Eugenia %A Bowman, Gene L %A Popp, Julius %X

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers of the beta-amyloid and microtubule associated protein tau metabolism have proven the capacity to improve classification of subjects developing Alzheimer's disease (AD). The blood plasma proteome was characterized to further elaborate upon the mechanisms involved and identify proteins that may improve classification of older adults developing an AD dementia.

OBJECTIVE: Identify and describe plasma protein expressions that best classify subjects with CSF-defined presence of AD pathology and cerebral amyloidosis.

METHODS: We performed a cross-sectional analysis of samples collected from community-dwelling elderly with (n = 72) or without (n = 48) cognitive impairment. CSF Aβ1-42, tau, and phosphorylated tau (P-tau181) were measured using ELISA, and mass spectrometry quantified the plasma proteomes. Presence of AD pathology was defined as CSF P-tau181/Aβ1-42 > 0.0779, and presence of amyloidosis was defined as CSF Aβ1-42 < 724 pg/mL.

RESULTS: Two hundred and forty-eight plasma proteins were quantified. Plasma proteins did not improve classification of the AD CSF biomarker profile in the whole sample. When the analysis was separately performed in the cognitively impaired individuals, the diagnosis accuracy of AD CSF profile was 88.9% with 19 plasma proteins included. Within the full cohort, there were 16 plasma proteins that improved diagnostic accuracy of cerebral amyloidosis to 92.4%.

CONCLUSION: Plasma proteins improved classification accuracy of AD pathology in cognitively-impaired older adults and appeared representative of amyloid pathology. If confirmed, those candidates could serve as valuable blood biomarkers of the preclinical stages of AD or risk of developing AD.

%B J Alzheimers Dis %V 60 %P 1641-1652 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125490?dopt=Abstract %R 10.3233/JAD-170426 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Plasma Tau Association with Brain Atrophy in Mild Cognitive Impairment and Alzheimer's Disease. %A Deters, Kacie D %A Risacher, Shannon L %A Kim, Sungeun %A Nho, Kwangsik %A West, John D %A Blennow, Kaj %A Zetterberg, Henrik %A Shaw, Leslie M %A Trojanowski, John Q %A Weiner, Michael W %A Saykin, Andrew J %X

BACKGROUND: Peripheral (plasma) and central (cerebrospinal fluid, CSF) measures of tau are higher in Alzheimer's disease (AD) relative to prodromal stages and controls. While elevated CSF tau concentrations have been shown to be associated with lower grey matter density (GMD) in AD-specific regions, this correlation has yet to be examined for plasma in a large study.

OBJECTIVE: Determine the neuroanatomical correlates of plasma tau using voxel-based analysis.

METHODS: Cross-sectional data for 508 ADNI participants were collected for clinical, plasma total-tau (t-tau), CSF amyloid (Aβ42) and tau, and MRI variables. The relationship between plasma tau and GMD and between CSF t-tau and GMD were assessed on a voxel-by-voxel basis using regression models. Age, sex, APOEɛ4 status, diagnosis, and total intracranial volume were used as covariates where appropriate. Participants were defined as amyloid positive (Aβ+) if CSF Aβ42 was <192 pg/mL.

RESULTS: Plasma tau was negatively correlated with GMD in the medial temporal lobe (MTL), precuneus, thalamus, and striatum. The associations with thalamus and striatum were independent of diagnosis. A negative correlation also existed between plasma tau and GMD in Aβ+ participants in the MTL, precuneus, and frontal lobe. When compared to CSF t-tau, plasma tau showed a notably different associated brain atrophy pattern, with only small overlapping regions in the fusiform gyrus.

CONCLUSION: Plasma tau may serve as a non-specific marker for neurodegeneration but is still relevant to AD considering low GMD was associated with plasma tau in Aβ+ participants and not Aβ-participants.

%B J Alzheimers Dis %V 58 %P 1245-1254 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550246?dopt=Abstract %R 10.3233/JAD-161114 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Polymorphonuclear Neutrophil Functions are Differentially Altered in Amnestic Mild Cognitive Impairment and Mild Alzheimer's Disease Patients. %A Le Page, Aurélie %A Lamoureux, Julie %A Bourgade, Karine %A Frost, Eric H %A Pawelec, Graham %A Witkowski, Jacek M %A Larbi, Anis %A Dupuis, Gilles %A Fülöp, Tamás %X

The mechanisms of neurodegeneration in Alzheimer's disease (AD) remain under investigation. Alterations in the blood-brain barrier facilitate exchange of inflammatory mediators and immune cells between the brain and the periphery in AD. Here, we report analysis of phenotype and functions of polymorphonuclear neutrophils (PMN) in peripheral blood from patients with amnestic mild cognitive impairment (aMCI, n = 13), patients with mild AD (mAD, n = 15), and healthy elderly controls (n = 13). Results showed an increased expression of CD177 in mAD but not in healthy or aMCI patients. IL-8 stimulated increased expression of the CD11b integrin in PMN of healthy subjects in vitro but PMN of aMCI and mAD patients failed to respond. CD14 and CD16 expression was lower in PMN of mAD but not in aMCI individuals relative to controls. Only PMN of aMCI subjects expressed lower levels of CD88. Phagocytosis toward opsonized E. coli was differentially impaired in PMN of aMCI and mAD subjects whereas the capacity to ingest Dextran particles was absent only in mAD subjects. Killing activity was severely impaired in aMCI and mAD subjects whereas free radical production was only impaired in mAD patients. Inflammatory cytokine (TNFα, IL-6, IL-1β, IL-12p70) and chemokine (MIP-1α, MIP-1β, IL-8) production in response to LPS stimulation was very low in aMCI and nearly absent in mAD subjects. TLR2 expression was low only in aMCI. Our data showed a differentially altered capacity of PMN of aMCI and mAD subjects to respond to pathological aggression that may impact impaired responses associated with AD development.

%B J Alzheimers Dis %V 60 %P 23-42 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28777750?dopt=Abstract %R 10.3233/JAD-170124 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Potentially Inappropriate Medication, Anticholinergic Burden, and Mortality in People Attending Memory Clinics. %A Cross, Amanda J %A George, Johnson %A Woodward, Michael C %A Ames, David %A Brodaty, Henry %A Wolfe, Rory %A Connors, Michael H %A Elliott, Rohan A %X

BACKGROUND: There is limited evidence regarding the association between potentially inappropriate medications (PIM) and mortality in older people with cognitive impairment.

OBJECTIVE: To examine whether use of medications considered to be potentially inappropriate in older people with cognitive impairment (PIMcog) and anticholinergic cognitive burden (ACB) were associated with mortality in people who attended memory clinics.

METHODS: Cross-sectional and longitudinal analyses of data from the Prospective Research In MEmory clinics (PRIME) study. Participants were community-dwelling people who attended nine memory clinics and had a diagnosis of mild cognitive impairment or dementia. PIMcog was defined as any medication considered potentially inappropriate for a person with cognitive impairment according to Beers or STOPP criteria. Anticholinergic burden was calculated using the ACB scale. Time-dependent Cox-proportional hazards regression was used to analyze associations between PIMcog use/ACB score and all-cause mortality over a three-year follow-up period. The regression model included the baseline variables: age, gender, education, cognitive diagnoses, total number of medications, disease-burden, cognition, physical function, and neuropsychiatric symptoms.

RESULTS: Of 964 participants, 360 (37.3%) used one or more PIMcog at some time during the study; most commonly anticholinergics and sedatives. 624 (64.7%) participants used a medication with potential or definite anticholinergic properties (ACB>0) at some point during the study. Both PIMcog use (adjusted hazard ratio: 1.42 95% CI: 1.12-1.80) and ACB score (adjusted hazard ratio: 1.18 95% CI: 1.06-1.32) were associated with mortality.

CONCLUSION: Use of PIMcogs and medications with anticholinergic properties was common among memory clinic patients and both were associated with mortality.

%B J Alzheimers Dis %V 60 %P 349-358 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869467?dopt=Abstract %R 10.3233/JAD-170265 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Preclinical Amyloid-β and Axonal Degeneration Pathology in Delirium. %A Idland, Ane-Victoria %A Wyller, Torgeir Bruun %A Støen, Randi %A Eri, Lars Magne %A Frihagen, Frede %A Ræder, Johan %A Chaudhry, Farrukh Abbas %A Hansson, Oskar %A Zetterberg, Henrik %A Blennow, Kaj %A Bogdanovic, Nenad %A Brækhus, Anne %A Watne, Leiv Otto %X

BACKGROUND: The clinical relevance of brain β-amyloidosis in older adults without dementia is not established. As delirium and dementia are strongly related, studies on patients with delirium may give pathophysiological clues.

OBJECTIVE: To determine whether the Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau) are associated with delirium in hip fracture patients with and without dementia.

METHODS: CSF was collected in conjunction to spinal anesthesia in 129 patients. Delirium was assessed using the Confusion Assessment Method once daily in all patients, both pre- and postoperatively. The diagnosis of dementia at admission was based upon clinical consensus. CSF levels of Aβ42, T-tau, and P-tau were analyzed.

RESULTS: In patients without dementia, we found lower CSF Aβ42 levels (median, 310 ng/L versus 489 ng/L, p = 0.006), higher T-tau levels (median, 505 ng/L versus 351 ng/L, p = 0.02), but no change in P-tau in patients who developed delirium (n = 16) compared to those who remained lucid (n = 49). Delirious patients also had lower ratios of Aβ42 to T-tau (p < 0.001) and P-tau (p = 0.001) relative to those without delirium. CSF Aβ42 and T-tau remained significantly associated with delirium status in adjusted analyses. In patients with dementia, CSF biomarker levels did not differ between those with (n = 54) and without delirium (n = 10).

CONCLUSION: The reduction in CSF Aβ42, indicating β-amyloidosis, and increase in T-tau, indicating neurodegeneration, in hip fracture patients without dementia developing delirium indicates that preclinical AD brain pathology is clinically relevant and possibly plays a role in delirium pathophysiology.

%B J Alzheimers Dis %V 55 %P 371-379 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662296?dopt=Abstract %R 10.3233/JAD-160461 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Precuneus Failures in Subjects of the PSEN1 E280A Family at Risk of Developing Alzheimer's Disease Detected Using Quantitative Electroencephalography. %A Ochoa, John Fredy %A Alonso, Joan Francesc %A Duque, Jon Edinson %A Tobón, Carlos Andrés %A Baena, Ana %A Lopera, Francisco %A Mañanas, Miguel Angel %A Hernández, Alher Mauricio %X

BACKGROUND: Presenilin-1 (PSEN1) mutations are the most common cause of familial early onset Alzheimer's disease (AD). The PSEN1 E280A (E280A) mutation has an autosomal dominant inheritance and is involved in the production of amyloid-β. The largest family group of carriers with E280A mutation is found in Antioquia, Colombia. The study of mutation carriers provides a unique opportunity to identify brain changes in stages previous to AD. Electroencephalography (EEG) is a low cost and minimally invasiveness technique that enables the following of brain changes in AD.

OBJECTIVE: To examine how previous reported differences in EEG for Theta and Alpha-2 rhythms in E280A subjects are related to specific regions in cortex and could be tracked across different ages.

METHODS: EEG signals were acquired during resting state from non-carriers and carriers, asymptomatic and symptomatic subjects from E280A kindred from Antioquia, Colombia. Independent component analysis (ICA) and inverse solution methods were used to locate brain regions related to differences in Theta and Alpha-2 bands.

RESULTS: ICA identified two components, mainly related to the Precuneus, where the differences in Theta and Alpha-2 exist simultaneously at asymptomatic and symptomatic stages. When the ratio between Theta and Alpha-2 is used, significant correlations exist with age and a composite cognitive scale.

CONCLUSION: Theta and Alpha-2 rhythms are altered in E280A subjects. The alterations are possible to track at Precuneus regions using EEG, ICA, and inverse solution methods.

%B J Alzheimers Dis %V 58 %P 1229-1244 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550254?dopt=Abstract %R 10.3233/JAD-161291 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Predicting Development of Amyotrophic Lateral Sclerosis in Frontotemporal Dementia. %A Van Langenhove, Tim %A Piguet, Olivier %A Burrell, James R %A Leyton, Cristian %A Foxe, David %A Abela, Melissa %A Bartley, Lauren %A Kim, Woojin S %A Jary, Eve %A Huang, Yue %A Dobson-Stone, Carol %A Kwok, John B %A Halliday, Glenda M %A Hodges, John R %X

BACKGROUND: A proportion of patients with frontotemporal dementia (FTD) also develop amyotrophic lateral sclerosis (ALS).

OBJECTIVE: We aimed to establish the risk of developing ALS in patients presenting with FTD and to identify the relevant clinical variables associated with progression from FTD to FTD-ALS.

METHODS: Of 218 consecutive patients with FTD, 10.1% had a dual FTD-ALS diagnosis at presentation. The remaining 152 FTD patients with follow-up of at least 12 months were included in the present study. We calculated the rate of progression to FTD-ALS and compared the baseline characteristics of FTD patients who developed ALS to those who did not develop ALS.

RESULTS: Five percent of FTD patients developed ALS. The incidence rate of ALS was 6.7/100 patient-years in patients with FTD symptoms since 1 year, which declined with duration of FTD symptoms. No FTD patients developed ALS after 5 years. Five out of 8 FTD patients who developed ALS had presented with a mixed behavioral variant FTD and progressive non-fluent aphasia (bvFTD+PNFA) phenotype, 2 with bvFTD, and 1 with PNFA. Progression to FTD-ALS was significantly more frequent in patients with bvFTD+PNFA compared to those without this phenotype (p < 0.0001, OR 38.3, 95% CI: 7.3 to 199.2), and in FTD patients who carried the C9orf72 repeat expansion compared to those without the repeat expansion (p = 0.02, OR 8.0, 95% CI: 1.7 to 38.6).

CONCLUSIONS: FTD patients with a mixed bvFTD+PNFA phenotype and with a C9orf72 repeat expansion should be closely monitored for the possible development of ALS. The risk of developing ALS in FTD appears to decline with the duration of FTD symptoms.

%B J Alzheimers Dis %V 58 %P 163-170 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387671?dopt=Abstract %R 10.3233/JAD-161272 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Prediction of Incipient Alzheimer's Disease Dementia in Patients with Mild Cognitive Impairment. %A Ardekani, Babak A %A Bermudez, Elaine %A Mubeen, Asim M %A Bachman, Alvin H %X

BACKGROUND: Mild cognitive impairment (MCI) is a transitional stage from normal aging to Alzheimer's disease (AD) dementia. It is extremely important to develop criteria that can be used to separate the MCI subjects at imminent risk of conversion to Alzheimer-type dementia from those who would remain stable. We have developed an automatic algorithm for computing a novel measure of hippocampal volumetric integrity (HVI) from structural MRI scans that may be useful for this purpose.

OBJECTIVE: To determine the utility of HVI in classification between stable and progressive MCI patients using the Random Forest classification algorithm.

METHODS: We used a 16-dimensional feature space including bilateral HVI obtained from baseline and one-year follow-up structural MRI, cognitive tests, and genetic and demographic information to train a Random Forest classifier in a sample of 164 MCI subjects categorized into two groups [progressive (n = 86) or stable (n = 78)] based on future conversion (or lack thereof) of their diagnosis to probable AD.

RESULTS: The overall accuracy of classification was estimated to be 82.3% (86.0% sensitivity, 78.2% specificity). The accuracy in women (89.1%) was considerably higher than that in men (78.9%). The prediction accuracy achieved in women is the highest reported in any previous application of machine learning to AD diagnosis in MCI.

CONCLUSION: The method presented in this paper can be used to separate stable MCI patients from those who are at early stages of AD dementia with high accuracy. There may be stronger indicators of imminent AD dementia in women with MCI as compared to men.

%B J Alzheimers Dis %V 55 %P 269-281 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662309?dopt=Abstract %R 10.3233/JAD-160594 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Prevalence and Correlates of Behavioral Disorders in Old Age Subjects with Cognitive Impairment: Results from the ReGAl Project. %A Boccardi, Virginia %A Conestabile Della Staffa, Manuela %A Baroni, Marta %A Ercolani, Sara %A Croce, Michele Francesco %A Ruggiero, Carmelinda %A Mecocci, Patrizia %X

BACKGROUND: Presence of behavioral and psychological symptoms of dementia (BPSD) is very common in subjects with cognitive impairment, representing an important determinant of disease progression, institutionalization, and worse prognosis. Knowledge of the prevalence and correlates of BPSD in community-living old subjects with cognitive impairment is limited so far, but it is essential for establishing specifically tailored care and cure in such a vulnerable population.

OBJECTIVE: With this study, we aimed at investigating, in a large sample of old age subjects with cognitive impairment, BPSD prevalence and correlates including the main demographic, clinical, and socio-environmental characteristics.

METHODS: Data were gathered from the ReGAl project (Rete Geriatrica Alzheimer; Geriatric Network on Alzheimer's disease), a large longitudinal Italian multicentric clinical-based study, promoted by the Italian Society of Gerontology and Geriatrics (SIGG).

RESULTS: We evaluated data from 4,157 old-age subjects affected by mild cognitive impairment (MCI) (541; 13%) or dementia (3616; 87%). 85.2% of all the population presented with at least one BPSD. Using a factor analysis, we identified four factors of BPSD: psychotic, affective, maniac, and impulse control behaviors. Logistic regression analyses revealed that among the main demographic, clinical, and socio-environmental aspects considered, only comorbidity was associated with all factors, independently of multiple covariates.

CONCLUSION: Identification of BPSD is crucial in everyday clinical practice and necessary to develop specific interventions and to define appropriate outcomes in their management. BPSD occur in a complex psychopathological context, influenced by several demographic and environmental factors that must be taken into account for a correct diagnosis and treatment.

%B J Alzheimers Dis %V 60 %P 1275-1283 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036823?dopt=Abstract %R 10.3233/JAD-170494 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Prevalence of Use of Cardiovascular Drugs in Dementia Patients Treated in General Practices in Germany. %A Jacob, Louis %A Bohlken, Jens %A Kostev, Karel %X

BACKGROUND: Dementia is a chronic disease associated with numerous cardiovascular disorders.

OBJECTIVE: To analyze the prevalence of cardiovascular drug use in dementia patients treated in general practices in Germany.

METHODS: The present study included patients who were diagnosed with dementia (Alzheimer's disease, vascular dementia, or unspecified dementia) in 2015. The main outcome measure was the proportion of patients using cardiovascular drugs. Demographical and clinical variables included age, sex, dementia type, and cardiovascular co-diagnoses. A multivariate logistic regression model was used to analyze the association between cardiovascular drug use and these variables.

RESULTS: We identified 7,987 and 1,268 dementia patients with and without prescriptions for cardiovascular drugs, respectively. The share of individuals who received cardiovascular treatments was 86.3%. Diuretics (20.9%), beta blocking agents (20.0%), and ACE inhibitors (17.4%) were the three most commonly prescribed types of medications. Patients between the ages of 71-80 (OR = 1.59), 81-90 (OR = 1.61), and over 90 years (OR = 1.48) were more likely to receive cardiovascular drugs than patients under the age of 70 years. Moreover, compared to those with unspecified dementia, individuals with Alzheimer's disease had a lower chance while those with vascular dementia had a higher chance of being prescribed these drugs (ORs equal to 0.81 and 1.22, respectively). Finally, we found a positive association between the use of cardiovascular drugs and all co-diagnoses (ORs ranging from 1.23 to 7.12).

CONCLUSION: The prevalence of cardiovascular drug use in dementia patients was around 86%. This use was significantly associated with such factors as age, type of dementia, and co-diagnoses.

%B J Alzheimers Dis %V 56 %P 1519-1524 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222532?dopt=Abstract %R 10.3233/JAD-161234 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Prevention of Amyloid-β and Tau Pathologies, Associated Neurodegeneration, and Cognitive Deficit by Early Treatment with a Neurotrophic Compound. %A Baazaoui, Narjes %A Iqbal, Khalid %X

To date, neither any effective treatment nor prevention of Alzheimer's disease (AD), a major dementia causing disorder, are available. Herein, we investigated the secondary prevention of neurodegeneration, amyloid-β (Aβ) and tau pathologies with a neurotrophic compound P021 in 3xTg-AD mice. Previous work found that P021 can rescue at mild to moderate stages Aβ and tau pathologies in 3xTg-AD mice. To determine its potential clinical application, we sought to test the preventive effect of P021 on Aβ and tau pathologies by starting the treatment during the period of synaptic compensation several months before the appearance of any overt pathology in 3xTg-AD mice. We started a continuous treatment with P021 in 3-month-old female animals and followed its effect at 9-, 15- and 18-months post-treatment. Neurodegeneration at the above time points was studied using Fluorojade C staining, and tau and Aβ pathologies both immunohistochemically and by Western blots. Cognitive performance was studied by assessing episodic memory with Novel Object Recognition task at 16-17-months post-treatment. We found that P021 treatment initiated during the synaptic compensation period can prevent neurodegeneration, Aβ and tau pathologies, rescue episodic memory impairment, and markedly reduce mortality rate. These findings for the first time show effective prevention of AD changes with a neurotrophic compound that targets neurogenesis and synaptic plasticity, suggesting that improving the health of the neuronal network can prevent AD.

%B J Alzheimers Dis %V 58 %P 215-230 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387677?dopt=Abstract %R 10.3233/JAD-170075 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Progression of Alzheimer's Disease: Are Fast Decliners Really Fast? A Four-Year Follow-Up. %A Barocco, Federica %A Spallazzi, Marco %A Concari, Letizia %A Gardini, Simona %A Pelosi, Annalisa %A Caffarra, Paolo %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Cognition Disorders %K Disease Progression %K Female %K Humans %K Longitudinal Studies %K Male %K Psychiatric Status Rating Scales %K ROC Curve %K Time Factors %X

BACKGROUND: The rate of cognitive and functional decline in Alzheimer's disease (AD) changes across individuals.

OBJECTIVES: Our purpose was to assess whether the concept of "fast decline" really fits its definition and whether cognitive and functional variables at onset can predict the progression of AD.

METHODS: 324 AD patients were included. We retrospectively examined their Mini-Mental State Examination (MMSE) total score and sub-items, Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL) at baseline and every six months for a 4-year follow-up. Patients were divided into "fast decliners" (n = 62), defined by a loss ≥5 points on the MMSE score within the first year from the baseline; "intermediate decliners" (n = 37), by a loss ≥5 points after the first year and before the 18th month; or "slow decliners" (n = 225), composed of the remaining patients.

RESULTS: At baseline, the groups did not differ on demographic, clinical, and cognitive variables. The decline at the end of the 4-year follow-up period seems to be similar among the different decline clusters. Predictors of disease progression have not been identified; only the MMSE total score at 12 months <14/30 was indicative of a poor prognosis.

CONCLUSIONS: Even with the limitation due to the small sample size, the lack of differences in the disease progression in time in the different clusters suggest the inconsistency of the so-called "fast decliners". This study was unable to show any significant difference among clusters of AD progression within a 4-year time interval. Further studies should better clarify whether a more consistent distinction exists between slow and fast decliners.

%B J Alzheimers Dis %V 57 %P 775-786 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304306?dopt=Abstract %R 10.3233/JAD-161264 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Protein Expression of BACE1 is Downregulated by Donepezil in Alzheimer's Disease Platelets. %A Sarno, Tamires Alves %A Talib, Leda Leme %A Joaquim, Helena Passarelli Giroud %A Bram, Jessyka Maria de França %A Gattaz, Wagner Farid %A Forlenza, Orestes Vicente %X

BACKGROUND: Abnormal amyloid-β protein precursor (AβPP) metabolism is a key feature of Alzheimer's disease (AD). Platelets contain most of the enzymatic machinery required for AβPP processing, and correlates of intracerebral abnormalities have been demonstrated in platelets of patients with AD. Thus, AβPP-related molecules in platelets may be regarded as peripheral markers of AD.

OBJECTIVE: We sought to determine the protein expression of the AβPP secretases (ADAM10, BACE1, and PSEN1) and AβPP ratio in platelets of patients with mild or moderate AD compared to healthy controls. We further determined whether the protein expression of these markers might be modified by chronic treatment with donepezil.

METHODS: Platelet samples were obtained from patients and controls at baseline and after 3 and 6 months of continuous treatment with therapeutic doses of donepezil. The protein expression of platelet markers was determined by western blotting.

RESULTS: AD patients had a significant decrease in AβPP ratio, ADAM10, and PSEN1 compared to controls at baseline, but these differences were not modified by the treatment. Nonetheless, a significant reduction in the protein expression of BACE1 was observed in patients treated with donepezil for 6 months.

CONCLUSION: Our results corroborate previous findings from our group and others of decreased AβPP ratio and protein expression of ADAM10 in AD. We further show that PSEN1 is decreased in AD platelets, and that the protein expression of BACE1 is downregulated by chronic treatment with donepezil. This effect may be interpreted as evidence of disease modification.

%B J Alzheimers Dis %V 55 %P 1445-1451 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858713?dopt=Abstract %R 10.3233/JAD-160813 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Psychotic Symptoms Associated with Poor Renal Function in Mild Cognitive Impairment and Dementias. %A Kunschmann, Ralf %A Busse, Stefan %A Frodl, Thomas %A Busse, Mandy %X

Patients suffering from cognitive decline such as mild cognitive impairment or neurodegenerative disorders including Alzheimer's dementia, vascular dementia, frontotemporal dementia, and Lewy body dementia are often accompanied by symptoms like psychosis, depression, agitation, and apathy. Aging increases not only the prevalence of dementia but also the development of kidney disorders, which had emerged as possible risk factor of cognitive impairment and dementia. However, a contribution of renal dysfunction to psychosis associated with cognitive decline remains to be investigated. We addressed the question whether patients diagnosed with mild cognitive impairment or dementia and co-symptoms show alterations in serum parameters. Analyzing 309 patients in total, we detected a positive correlation between the occurrence of psychotic symptoms and increased retention parameters in serum, including creatinine and urea levels and the estimated glomerular filtration rates. This was in particular detected in female patients. In male patients, psychotic symptoms were associated with an increased number of leukocytes in blood. We propose that clinicians should be aware of psychotic symptoms in patients with reduced cognitive functions that could be associated with changes in the retention parameters.

%B J Alzheimers Dis %V 58 %P 243-252 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387674?dopt=Abstract %R 10.3233/JAD-161306 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Pupillary Responses as a Biomarker of Early Risk for Alzheimer's Disease. %A Granholm, Eric L %A Panizzon, Matthew S %A Elman, Jeremy A %A Jak, Amy J %A Hauger, Richard L %A Bondi, Mark W %A Lyons, Michael J %A Franz, Carol E %A Kremen, William S %X

Task-evoked pupillary responses may be a psychophysiological biomarker of early risk for mild cognitive impairment (MCI) and Alzheimer's disease (AD). Pupil dilation during cognitive tasks reflects cognitive effort until compensatory capacity is surpassed and performance declines are manifest, and reflects activation in the locus coeruleus, where degenerative changes have been found in the earliest stages of AD. We recorded pupillary responses during digit span recall in 918 participants ages 56-66. Despite normal performance, amnestic single-domain MCI (S-MCI) participants showed greater pupil dilation than non-amnestic S-MCI and cognitively normal (CN) participants at lower cognitive loads. Multi-domain MCI (M-MCI) participants failed to modulate effort across cognitive loads and showed poorer performance. Pupillary responses differentiated MCI and CN groups. Amnestic S-MCI participants required compensatory effort to maintain performance, consistent with increased risk for decline. Greater effort in CN individuals might indicate risk for MCI. Results are consistent with dysfunction in locus coeruleus-linked brain systems. This brief task shows promise as a biomarker for early MCI and AD risk prediction.

%B J Alzheimers Dis %V 56 %P 1419-1428 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157098?dopt=Abstract %R 10.3233/JAD-161078 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice. %A Liu, Peng %A Reichl, John H %A Rao, Eshaan R %A McNellis, Brittany M %A Huang, Eric S %A Hemmy, Laura S %A Forster, Colleen L %A Kuskowski, Michael A %A Borchelt, David R %A Vassar, Robert %A Ashe, Karen H %A Zahs, Kathleen R %X

There exist several dozen lines of transgenic mice that express human amyloid-β protein precursor (AβPP) with Alzheimer's disease (AD)-linked mutations. AβPP transgenic mouse lines differ in the types and amounts of Aβ that they generate and in their spatiotemporal patterns of expression of Aβ assemblies, providing a toolkit to study Aβ amyloidosis and the influence of Aβ aggregation on brain function. More complete quantitative descriptions of the types of Aβ assemblies present in transgenic mice and in humans during disease progression should add to our understanding of how Aβ toxicity in mice relates to the pathogenesis of AD. Here, we provide a direct quantitative comparison of amyloid plaque burdens and plaque sizes in four lines of AβPP transgenic mice. We measured the fraction of cortex and hippocampus occupied by dense-core plaques, visualized by staining with Thioflavin S, in mice from young adulthood through advanced age. We found that the plaque burdens among the transgenic lines varied by an order of magnitude: at 15 months of age, the oldest age studied, the median cortical plaque burden in 5XFAD mice was already ∼4.5 times that of 21-month-old Tg2576 mice and ∼15 times that of 21-24-month-old rTg9191 mice. Plaque-size distributions changed across the lifespan in a line- and region-dependent manner. We also compared the dense-core plaque burdens in the mice to those measured in a set of pathologically-confirmed AD cases from the Nun Study. Cortical plaque burdens in Tg2576, APPSwePS1ΔE9, and 5XFAD mice eventually far exceeded those measured in the human cohort.

%B J Alzheimers Dis %V 56 %P 743-761 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059792?dopt=Abstract %R 10.3233/JAD-161027 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Quantitative Magnetic Resonance Abnormalities in Creutzfeldt-Jakob Disease and Fatal Insomnia. %A Grau-Rivera, Oriol %A Calvo, Anna %A Bargalló, Nuria %A Monté, Gemma C %A Nos, Carlos %A Lladó, Albert %A Molinuevo, José Luis %A Gelpi, Ellen %A Sánchez-Valle, Raquel %X

BACKGROUND: Quantitative neuroimaging might unveil abnormalities in prion diseases that are not perceivable at visual inspection. On the other hand, scarce studies have quantified volumetric changes in prion diseases.

OBJECTIVES: We aim to characterize volumetric and diffusion tensor imaging (DTI) changes in patients with prion diseases who presented with either Creutzfeldt-Jakob disease (CJD) or fatal insomnia (FI) phenotype.

METHODS: Twenty patients with prion diseases- 15 with CJD and 5 with fatal insomnia (FI)- and 40 healthy controls were examined with a 3-Tesla magnetic resonance imaging scanner. Images were segmented and normalized with SPM12. DTI maps were obtained with FMRIB Software Library. Whole-brain voxel-wise and region-of-interest analyses of volumetric and DTI changes were performed with SPM12. White matter (WM) changes were also analyzed with tract-based spatial statistics. Semiquantitive assessment of neuropathological parameters was compared with DTI metrics in thalamus from 11 patients.

RESULTS: Patients with CJD and FI presented significant atrophy in thalamus and cerebellum. In CJD, mean diffusivity (MD) was decreased in striatum and increased in subcortical WM, while both increased and decreased values were observed across different thalamic nuclei. In FI, MD was increased in thalamus and cerebellum. Spongiform change and PrPSc deposition were more intense in thalamus in CJD than in FI, although no significant correlations arose with MD values in the nuclei studied.

CONCLUSION: Volumetric and DTI abnormalities suggest a central common role of the thalamus in prion diseases. We report, for the first time, quantitative MRI changes in FI, and provide further evidence of WM involvement in prion diseases.

%B J Alzheimers Dis %V 55 %P 431-443 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662320?dopt=Abstract %R 10.3233/JAD-160750 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer's Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity. %A Louwersheimer, Eva %A Cohn-Hokke, Petra E %A Pijnenburg, Yolande A L %A Weiss, Marjan M %A Sistermans, Erik A %A Rozemuller, Annemieke J %A Hulsman, Marc %A van Swieten, John C %A van Duijn, Cock M %A Barkhof, Frederik %A Koene, Teddy %A Scheltens, Philip %A van der Flier, Wiesje M %A Holstege, Henne %X

BACKGROUND: The major genetic risk factor for late onset Alzheimer's disease (AD) is the APOE-ɛ4 allele. However, APOE-ɛ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants.

OBJECTIVE: To identify genetic factors that, next to APOE-ɛ4 homozygosity, contribute to the development of AD.

METHODS: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members.

RESULTS: All affected family members were homozygous for the APOE-ɛ4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE-ɛ4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with AβPP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with AβPP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities.

CONCLUSION: We hypothesize that next to APOE-ɛ4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aβ processing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family.

%B J Alzheimers Dis %V 56 %P 63-74 %G eng %N 1 %R 10.3233/JAD-160091 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Recent Progress in Alzheimer's Disease Research, Part 3: Diagnosis and Treatment. %A Hane, Francis T %A Robinson, Morgan %A Lee, Brenda Y %A Bai, Owen %A Leonenko, Zoya %A Albert, Mitchell S %K Alzheimer Disease %K Biomarkers %K Biomedical Research %K Humans %K Neuroimaging %X

The field of Alzheimer's disease (AD) research has grown exponentially over the past few decades, especially since the isolation and identification of amyloid-β from postmortem examination of the brains of AD patients. Recently, the Journal of Alzheimer's Disease (JAD) put forth approximately 300 research reports which were deemed to be the most influential research reports in the field of AD since 2010. JAD readers were asked to vote on these most influential reports. In this 3-part review, we review the results of the 300 most influential AD research reports to provide JAD readers with a readily accessible, yet comprehensive review of the state of contemporary research. Notably, this multi-part review identifies the "hottest" fields of AD research providing guidance for both senior investigators as well as investigators new to the field on what is the most pressing fields within AD research. Part 1 of this review covers pathogenesis, both on a molecular and macro scale. Part 2 review genetics and epidemiology, and part 3 covers diagnosis and treatment. This part of the review, diagnosis and treatment, reviews the latest diagnostic criteria, biomarkers, imaging, and treatments in AD.

%B J Alzheimers Dis %V 57 %P 645-665 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269772?dopt=Abstract %R 10.3233/JAD-160907 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Recovery from Proactive Semantic Interference and MRI Volume: A Replication and Extension Study. %A Loewenstein, David A %A Curiel, Rosie E %A DeKosky, Steven %A Rosselli, Monica %A Bauer, Russell %A Grieg-Custo, Maria %A Penate, Ailyn %A Li, Chunfei %A Lizagarra, Gabriel %A Golde, Todd %A Adjouadi, Malek %A Duara, Ranjan %X

BACKGROUND: The rise in incidence of Alzheimer's disease (AD) has led to efforts to advance early detection of the disease during its preclinical stages. To achieve this, the field needs to develop more sensitive cognitive tests that relate to biological markers of disease pathology. Failure to recover from proactive interference (frPSI) is one such cognitive marker that is associated with volumetric reductions in the hippocampus, precuneus, and other AD-prone regions, and to amyloid load in the brain.

OBJECTIVE: The current study attempted to replicate and extend our previous findings that frPSI is a sensitive marker of early AD, and related to a unique pattern of volumetric loss in AD prone areas.

METHODS: Three different memory measures were examined relative to volumetric loss and cortical thickness among 45 participants with amnestic mild cognitive impairment.

RESULTS: frPSI was uniquely associated with reduced volumes in the hippocampus (r = 0.50) precuneus (r = 0.41), and other AD prone regions, replicating previous findings. Strong associations between frPSI and lower entorhinal cortex volumes and cortical thickness (r≥0.60) and precuneus (r = 0.50) were also observed.

CONCLUSION: Unique and strong associations between volumetric reductions and frPSI as observed by Loewenstein and colleagues were replicated. Together with cortical thickness findings, these results indicate that frPSI is worthy of further study as a sensitive and early cognitive marker of AD.

%B J Alzheimers Dis %V 59 %P 131-139 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598850?dopt=Abstract %R 10.3233/JAD-170276 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Reduced Cerebrospinal Fluid Concentration of Apolipoprotein A-I in Patients with Alzheimer's Disease. %A Johansson, Per %A Almqvist, Erik G %A Bjerke, Maria %A Wallin, Anders %A Johansson, Jan-Ove %A Andreasson, Ulf %A Blennow, Kaj %A Zetterberg, Henrik %A Svensson, Johan %X

BACKGROUND: Apolipoprotein E (ApoE) has been extensively studied in Alzheimer's disease (AD), but little is known of apolipoprotein A-I (ApoA-I) in cerebrospinal fluid (CSF).

OBJECTIVE: Plasma lipids as well as ApoA-I and ApoE in plasma and CSF were determined and related to Mini-Mental State Examination (MMSE) score, APOE genotype, and CSF AD biomarkers.

METHODS: Consecutive patients with AD (n = 29), stable mild cognitive impairment (n = 13), other dementias (n = 14), and healthy controls (n = 18) were included at a single center.

RESULTS: AD patients had higher plasma triglycerides and lower CSF ApoA-I concentration than controls (both p < 0.05). CSF ApoE concentration was reduced in other dementias (p < 0.01). In AD as well as other dementias, the ratios between CSF and plasma concentrations of both ApoA-I and ApoE were lower than those in the controls. ApoA-I and ApoE in plasma and CSF were not influenced by APOEɛ4 allele distribution. In the total study population (n = 74), CSF ApoA-I correlated positively with MMSE score (r = 0.26, p < 0.05) and negatively with CSF P-tau (r = -0.25, p < 0.05). CSF ApoE correlated positively with CSF concentrations of T-tau and P-tau in the total study population and in AD patients.

CONCLUSION: CSF ApoA-I was reduced in AD patients and associated with measures of cognitive function and AD disease status. The mechanisms underlying the decreased CSF:plasma ratios of ApoA-I and ApoE in AD and other dementias need to be explored in further studies.

%B J Alzheimers Dis %V 59 %P 1017-1026 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697566?dopt=Abstract %R 10.3233/JAD-170226 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Reduction of RPT6/S8 (a Proteasome Component) and Proteasome Activity in the Cortex is associated with Cognitive Impairment in Lewy Body Dementia. %A Alghamdi, Amani %A Vallortigara, Julie %A Howlett, David R %A Broadstock, Martin %A Hortobágyi, Tibor %A Ballard, Clive %A Thomas, Alan J %A O'Brien, John T %A Aarsland, Dag %A Attems, Johannes %A Francis, Paul T %A Whitfield, David R %X

Lewy body dementia is the second most common neurodegenerative dementia and is pathologically characterized by α-synuclein positive cytoplasmic inclusions, with varying amounts of amyloid-β (Aβ) and hyperphosphorylated tau (tau) aggregates in addition to synaptic loss. A dysfunctional ubiquitin proteasome system (UPS), the major proteolytic pathway responsible for the clearance of short lived proteins, may be a mediating factor of disease progression and of the development of α-synuclein aggregates. In the present study, protein expression of a key component of the UPS, the RPT6 subunit of the 19S regulatory complex was determined. Furthermore, the main proteolytic-like (chymotrypsin- and PGPH-) activities have also been analyzed. The middle frontal (Brodmann, BA9), inferior parietal (BA40), and anterior cingulate (BA24) gyrus' cortex were selected as regions of interest from Parkinson's disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer's disease (AD, n = 16), and control (n = 24) brains. Clinical and pathological data available included the MMSE score. DLB, PDD, and AD were characterized by significant reductions of RPT6 (one-way ANOVA, p < 0.001; Bonferroni post hoc test) in prefrontal cortex and parietal cortex compared with controls. Strong associations were observed between RPT6 levels in prefrontal, parietal cortex, and anterior cingulate gyrus and cognitive impairment (p = 0.001, p = 0.001, and p = 0.008, respectively). These findings highlight the involvement of the UPS in Lewy body dementia and indicate that targeting the UPS may have the potential to slow down or reduce the progression of cognitive impairment in DLB and PDD.

%B J Alzheimers Dis %V 57 %P 373-386 %G eng %N 2 %R 10.3233/JAD-160946 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Relationship between Markers of Inflammation and Degeneration in the Central Nervous System and the Blood-Brain Barrier Impairment in Alzheimer's Disease. %A Muszyński, Paweł %A Kulczyńska-Przybik, Agnieszka %A Borawska, Renata %A Litman-Zawadzka, Ala %A Słowik, Agnieszka %A Klimkowicz-Mrowiec, Aleksandra %A Pera, Joanna %A Dziedzic, Tomasz %A Mroczko, Barbara %X

BACKGROUND: It is known that YKL-40- a marker of glial inflammation, and VILIP-1- a marker of neuronal injury, reflect functional and structural changes in AD brains, although there is limited data concerning their potential influence on blood-brain barrier (BBB) homeostasis.

OBJECTIVE: Therefore, the aim of our study was to investigate the relationship between markers of inflammation and degeneration in the central nervous system (CNS) of patients with AD and mild cognitive impairment (MCI) as well as immunological response in CNS and BBB function.

METHODS: Cerebrospinal fluid (CSF) concentrations of proteins tested were determined in 45 AD patients, 18 MCI subjects, and 23 non-demented controls using ELISA method.

RESULTS: CSF concentrations of YKL-40 were significantly higher in MCI and AD patients, whereas CSF levels of VILIP-1 were statistically higher in the AD group as compared to the subjects without cognitive deficits. Elevated concentrations of YKL-40 correlated significantly with increased albumin quotient and decreased Aβ42/40 ratio in AD patients and with IgG quotient in the total study group. We did not find a relationship between VILIP-1 and immunological parameters reflecting BBB dysfunction and humoral immune response.

CONCLUSION: Our findings indicate that YKL-40 may contribute to decreased stability and increased permeability of BBB in AD patients. It is assumed that YKL-40 is implicated in the development of brain barriers, although its precise mechanism of action in the BBB disruption remains unrevealed. Further studies on larger groups of patients are required to confirm our hypothesis.

%B J Alzheimers Dis %V 59 %P 903-912 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697565?dopt=Abstract %R 10.3233/JAD-170220 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Relationship of Brain Amyloid Load and APOE Status to Regional Cortical Thinning and Cognition in the ADNI Cohort. %A Li, Chunfei %A Loewenstein, David A %A Duara, Ranjan %A Cabrerizo, Mercedes %A Barker, Warren %A Adjouadi, Malek %X

BACKGROUND: Both amyloid (Aβ) load and APOE4 allele are associated with neurodegenerative changes in Alzheimer's disease (AD) prone regions and with risk for cognitive impairment.

OBJECTIVE: To evaluate the unique and independent contribution of APOE4 allele status (E4+∖E4-), Aβ status (Amy+∖Amy-), and combined APOE4 and Aβ status on regional cortical thickness (CoTh) and cognition among participants diagnosed as cognitively normal (CN, n = 251), early mild cognitive impairment (EMCI, n = 207), late mild cognitive impairment (LMCI, n = 196), and mild AD (n = 162) from the ADNI.

METHODS: A series of two-way ANCOVAs with post-hoc Tukey HSD tests, controlling independently for Aβ and APOE4 status and age were examined.

RESULTS: Among LMCI and AD participants, cortical thinning was widespread in association with Amy+ status, whereas in association with E4+ status only in the inferior temporal and medial orbito-frontal regions. Among CN and EMCI participants, E4+ status, but not Amy+ status, was independently associated with increased CoTh, especially in limbic regions [e.g., in the entorhinal cortex, CoTh was 0.123 mm greater (p = 0.002) among E4+ than E4-participants]. Among CN and EMCI, both E4+ and Amy+ status were independently associated with cognitive impairment, which was greatest among those with combined E4 + and Amy+ status.

CONCLUSION: Decreased CoTh is independently associated with Amy+ status in many brain regions, but with E4+ status in very restricted number of brain regions. Among CN and EMCI participants, E4 + status is associated with increased CoTh, in medial and inferior temporal regions, although cognitive impairment at this state is independently associated with Amy+ and E4 + status. These findings imply a unique pathophysiological mechanism for E4 + status in AD and its progression.

%B J Alzheimers Dis %V 59 %P 1269-1282 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731444?dopt=Abstract %R 10.3233/JAD-170286 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Relationships Between Components of Metabolic Syndrome and Mild Cognitive Impairment Subtypes: A Cross-Sectional Study of Japanese Older Adults. %A Bae, Seongryu %A Shimada, Hiroyuki %A Lee, Sangyoon %A Makizako, Hyuma %A Lee, Sungchul %A Harada, Kazuhiro %A Doi, Takehiko %A Tsutsumimoto, Kota %A Hotta, Ryo %A Nakakubo, Sho %A Park, Hyuntae %A Suzuki, Takao %X

BACKGROUND: The associations between components of metabolic syndrome (MetS) and mild cognitive impairment (MCI) subtypes remain unclear.

OBJECTIVE: The study aim was to identify the prevalence of MetS for MCI subtypes and to investigate sex differences in the association between MetS and MCI subtypes in older Japanese adults.

METHODS: The study analyzed data from 3,312 men and women aged 70 years or more. MetS was diagnosed according to International Diabetes Federation criteria. Participants completed cognitive tests and were categorized into normal cognition, amnestic MCI (aMCI), and non-amnestic MCI (naMCI). The associations between MetS and its components and MCI subtypes were analyzed using multiple logistic regression.

RESULTS: MetS prevalence was greater in participants with naMCI (men: p = 0.030; women: p = 0.040). Participants with naMCI showed higher odds ratios (OR) of MetS (men: 2.45, 95% confidence intervals (CI): 1.13-5.32; women: OR: 1.94, 95% CI: 1.12-3.39) compared with participants with normal cognition. MetS was not associated with aMCI. Analysis of MetS components showed that raised glucose (OR: 1.62, 95% CI: 1.19-2.22) and reduced high-density lipoprotein cholesterol (OR: 1.97, 95% CI: 1.25-3.12) were associated with naMCI in men. In women, raised blood pressure (OR: 1.42, 95% CI: 1.03-1.94) and raised glucose (OR: 1.32, 95% CI: 1.02-1.71) were associated with naMCI.

CONCLUSION: MetS was associated only with naMCI regardless of sex, which suggests etiologic differences in MCI subtypes. We also found sex differences in the relationship between naMCI risk and MetS and its components.

%B J Alzheimers Dis %V 60 %P 913-921 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922149?dopt=Abstract %R 10.3233/JAD-161230 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Relationships of Dietary Patterns, Foods, and Micro- and Macronutrients with Alzheimer's Disease and Late-Life Cognitive Disorders: A Systematic Review. %A Solfrizzi, Vincenzo %A Custodero, Carlo %A Lozupone, Madia %A Imbimbo, Bruno P %A Valiani, Vincenzo %A Agosti, Pasquale %A Schilardi, Andrea %A D'Introno, Alessia %A La Montagna, Maddalena %A Calvani, Mariapaola %A Guerra, Vito %A Sardone, Rodolfo %A Abbrescia, Daniela I %A Bellomo, Antonello %A Greco, Antonio %A Daniele, Antonio %A Seripa, Davide %A Logroscino, Giancarlo %A Sabbá, Carlo %A Panza, Francesco %X

In the last decade, the association between diet and cognitive function or dementia has been largely investigated. In the present article, we systematically reviewed observational studies published in the last three years (2014-2016) on the relationship among dietary factors and late-life cognitive disorders at different levels of investigation (i.e., dietary patterns, foods and food-groups, and dietary micro- and macronutrients), and possible underlying mechanisms of the proposed associations. From the reviewed evidence, the National Institute on Aging-Alzheimer's Association guidelines for Alzheimer's disease (AD) and cognitive decline due to AD pathology introduced some evidence suggesting a direct relation between diet and changes in the brain structure and activity. There was also accumulating evidence that combinations of foods and nutrients into certain patterns may act synergistically to provide stronger health effects than those conferred by their individual dietary components. In particular, higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline. Moreover, also other emerging healthy dietary patterns such as the Dietary Approach to Stop Hypertension (DASH) and the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diets were associated with slower rates of cognitive decline and significant reduction of AD rate. Furthermore, some foods or food groups traditionally considered harmful such as eggs and red meat have been partially rehabilitated, while there is still a negative correlation of cognitive functions with saturated fatty acids and a protective effect against cognitive decline of elevated fish consumption, high intake of monounsaturated fatty acids and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA.

%B J Alzheimers Dis %V 59 %P 815-849 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697569?dopt=Abstract %R 10.3233/JAD-170248 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Relative Incidence of Seizures and Myoclonus in Alzheimer's Disease, Dementia with Lewy Bodies, and Frontotemporal Dementia. %A Beagle, Alexander J %A Darwish, Sonja M %A Ranasinghe, Kamalini G %A La, Alice L %A Karageorgiou, Elissaios %A Vossel, Keith A %X

BACKGROUND: Patients with Alzheimer's disease (AD) are more prone to seizures and myoclonus, but relative risk of these symptoms among other dementia types is unknown.

OBJECTIVE: To determine incidence of seizures and myoclonus in the three most common neurodegenerative dementias: AD, dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD).

METHODS: Our institution's medical records were reviewed for new-onset unprovoked seizures and myoclonus in patients meeting criteria for AD (n = 1,320), DLB (n = 178), and FTD (n = 348). Cumulative probabilities of developing seizures and myoclonus were compared between diagnostic groups, whereas age-stratified incidence rates were determined relative to control populations.

RESULTS: The cumulative probability of developing seizures after disease onset was 11.5% overall, highest in AD (13.4%) and DLB (14.7%) and lowest in FTD (3.0%). The cumulative probability of developing myoclonus was 42.1% overall, highest in DLB (58.1%). The seizure incidence rates, relative to control populations, were nearly 10-fold in AD and DLB, and 6-fold in FTD. Relative seizure rates increased with earlier age-at-onset in AD (age <50, 127-fold; 50-69, 21-fold; 70+, 2-fold) and FTD (age <50, 53-fold; 50-69, 9-fold), and relative myoclonus rates increased with earlier age-at-onset in all groups. Seizures began an average of 3.9 years after the onset of cognitive or motor decline, and myoclonus began 5.4 years after onset.

CONCLUSIONS: Seizures and myoclonus occur with greater incidence in patients with AD, DLB, and FTD than in the general population, but rates vary with diagnosis, suggesting varied pathomechanisms of network hyperexcitability. Patients often experience these symptoms early in disease, suggesting hyperexcitability could be an important target for interventions.

%B J Alzheimers Dis %V 60 %P 211-223 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826176?dopt=Abstract %R 10.3233/JAD-170031 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Remyelination: A Potential Therapeutic Strategy for Alzheimer's Disease? %A Sun, Junjun %A Zhou, Hong %A Bai, Feng %A Zhang, Zhijun %A Ren, Qingguo %X

Myelin is a lipid-rich multilamellar membrane that wraps around long segments of neuronal axons and it increases the conduction of action potentials, transports the necessary trophic support to the neuronal axons, and reduces the energy consumed by the neuronal axons. Together with axons, myelin is a prerequisite for the higher functions of the central nervous system and complex forms of network integration. Myelin impairments have been suggested to lead to neuronal dysfunction and cognitive decline. Accumulating evidence, including brain imaging and postmortem and genetic association studies, has implicated myelin impairments in Alzheimer's disease (AD). Increasing data link myelin impairments with amyloid-β (Aβ) plaques and tau hyperphosphorylation, which are both present in patients with AD. Moreover, aging and apolipoprotein E (ApoE) may be involved in the myelin impairments observed in patients with AD. Decreased neuronal activity, increased Aβ levels, and inflammation further damage myelin in patients with AD. Furthermore, treatments that promote myelination contribute to the recovery of neuronal function and improve cognition. Therefore, strategies targeting myelin impairment may provide therapeutic opportunities for patients with AD.

%B J Alzheimers Dis %V 58 %P 597-612 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453483?dopt=Abstract %R 10.3233/JAD-170036 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Risk Factors for Mild Cognitive Impairment in German Primary Care Practices. %A Jacob, Louis %A Bohlken, Jens %A Kostev, Karel %X

BACKGROUND: Mild cognitive impairment (MCI) is a common mental disorder affecting around 16% of elderly people without dementia. MCI is considered an intermediate state between normal cognition and dementia.

OBJECTIVE: To analyze risk factors for the development of MCI in German primary care practices.

METHODS: In total, 3,604 MCI patients and 3,604 controls without MCI were included between January 2010 and December 2015. Several disorders potentially associated with MCI were determined. Multivariate logistic regression models were fitted with MCI as a dependent variable and other disorders as potential predictors.

RESULTS: The mean age was 75.2 years and 45.3% of patients were men. MCI development was found to be associated with 12 disorders: intracranial injury, anxiety disorder, depression, mental and behavioral disorders due to alcohol use, stroke, hyperlipidemia, obesity, hypertension, Parkinson's disease, sleep disorder, coronary heart disease, and diabetes with odds ratios ranging from 1.13 (diabetes) to 2.27 (intracranial injury).

CONCLUSION: Intracranial injury, anxiety, and depression showed the strongest association with MCI. Further analyses are needed to gain a better understanding of the MCI risk factors.

%B J Alzheimers Dis %V 56 %P 379-384 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911316?dopt=Abstract %R 10.3233/JAD-160875 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Risk Factors, Neuroanatomical Correlates, and Outcome of Neuropsychiatric Symptoms in Alzheimer's Disease. %A Poulin, Stéphane P %A Bergeron, David %A Dickerson, Bradford C %X

BACKGROUND: An integrative model of neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) is lacking.

OBJECTIVE: In this study, we investigated the risk factors, anatomy, biology, and outcomes of NPS in AD.

METHODS: 181 subjects were included from the Alzheimer's Disease Neuroimaging Study (ADNI). NPS were assessed with the Neuropsychiatric Inventory Questionnaire at baseline and 6 months. NPI >3 was used as a threshold for NPS positivity. Three NPS courses were characterized: 1) minimal/absent (negative at 0 and 6 months, n = 77); 2) fluctuating (positive only at one time point, n = 53); 3) persistent (positive at both time points, n = 51). We examined the association between NPS course and family history of dementia, personal history of psychiatric disorders, cerebrospinal fluid biomarkers, atrophy patterns, as well as longitudinal cognitive and functional measures at 12 and 24 months (MMSE, CDR-SOB, FAQ).

RESULTS: AD subjects with absent, fluctuating, or persistent NPS had similar CSF amyloid-β and tau levels. AD subjects with minimal/absent NPS had less personal history of psychiatric disorders (35%) than those with fluctuating (57%; p = 0.015) or persistent NPS (47%, not significant). At 24 months, AD subjects with persistent NPS had worse cognitive (MMSE; p = 0.05) and functional (CDR-SOB; p = 0.016) outcomes. Dorsolateral prefrontal atrophy was seen in persistent NPS, but not in fluctuating NPS.

CONCLUSIONS: Our results suggest that individuals with personal history of psychiatric disorders might be more vulnerable to develop NPS throughout the course of AD. The worst cognitive and functional outcomes associated with NPS in AD underscores the importance of monitoring NPS early in the disease course.

%B J Alzheimers Dis %V 60 %P 483-493 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869463?dopt=Abstract %R 10.3233/JAD-160767 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Road Less Traveled: Alternative Pathways for Action-Verb Processing in Parkinson's Disease. %A Abrevaya, Sofía %A Sedeño, Lucas %A Fitipaldi, Sol %A Pineda, David %A Lopera, Francisco %A Buritica, Omar %A Villegas, Andrés %A Bustamante, Catalina %A Gomez, Diana %A Trujillo, Natalia %A Pautassi, Ricardo %A Ibáñez, Agustín %A García, Adolfo M %X

Action verbs are critically embodied in motor brain networks. In Parkinson's disease (PD), damage to the latter compromises access to such words. However, patients are not fully incapable of processing them, as their performance is far from floor level. Here we tested the hypothesis that action-verb processing in PD may rely on alternative disembodied semantic circuits. Seventeen PD patients and 15 healthy controls listened to action verbs and nouns during functional MRI scanning. Using cluster-mass analysis with a permutation test, we assessed task-related functional connectivity considering seeds differentially engaged by action and non-action words (namely, putamen and M1 versus posterior superior temporal lobe, respectively). The putamen seed showed reduced connectivity within the basal ganglia in patients for both lexical categories. However, only action verbs recruited different cortical networks in each group. Specifically, the M1 seed exhibited more anterior connectivity for controls and more posterior connectivity for patients, with no differences in the temporal seed. Moreover, the patients' level of basal ganglia atrophy positively correlated with their reliance on M1-posterior connectivity during action-verb processing. PD patients seem to have processed action verbs via non-motor cortical networks subserving amodal semantics. Such circuits may afford alternative pathways to process words when default embodied mechanisms are disturbed. Moreover, the greater the level of basal ganglia atrophy, the greater the patients' reliance on this alternative route. Our findings offer new insights into differential neurofunctional mechanisms recruited to process action semantics in PD.

%B J Alzheimers Dis %V 55 %P 1429-1435 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27834777?dopt=Abstract %R 10.3233/JAD-160737 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Role of Niemann-Pick Type C Disease Mutations in Dementia. %A Cupidi, Chiara %A Frangipane, Francesca %A Gallo, Maura %A Clodomiro, Alessandra %A Colao, Rosanna %A Bernardi, Livia %A Anfossi, Maria %A Conidi, Maria Elena %A Vasso, Franca %A Curcio, Sabrina Anna Maria %A Mirabelli, Maria %A Smirne, Nicoletta %A Torchia, Giusi %A Muraca, Maria Gabriella %A Puccio, Gianfranco %A Di Lorenzo, Raffaele %A Zampieri, Stefania %A Romanello, Milena %A Dardis, Andrea %A Maletta, Raffaele Giovanni %A Bruni, Amalia Cecilia %X

BACKGROUND: Several neurological and systemic diseases can cause dementia, beyond Alzheimer's disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance.

OBJECTIVE: To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus.

METHODS: We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients.

RESULTS: Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222 S mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2.

CONCLUSIONS: Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event.

%B J Alzheimers Dis %V 55 %P 1249-1259 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27792009?dopt=Abstract %R 10.3233/JAD-160214 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Screening for Alzheimer's Disease: Cognitive Impairment in Self-Referred and Memory Clinic-Referred Patients. %A Kirsebom, Bjørn-Eivind %A Espenes, Ragna %A Waterloo, Knut %A Hessen, Erik %A Johnsen, Stein Harald %A Bråthen, Geir %A Aarsland, Dag %A Fladby, Tormod %X

BACKGROUND: Cognitive assessment is essential in tracking disease progression in AD. Presently, cohorts including preclinical at-risk participants are recruited by different means, which may bias cognitive and clinical features. We compared recruitment strategies to levels of cognitive functioning.

OBJECTIVE: We investigate recruitment source biases in self-referred and memory clinic-referred patient cohorts to reveal potential differences in cognitive performance and demographics among at-risk participants.

METHODS: We included 431 participants 40-80 years old. Participants were classified as controls (n = 132) or symptom group (n = 299). The symptom group comprised of subjective cognitive decline (SCD, n = 163) and mild cognitive impairment (MCI, n = 136). We compared cognitive performance and demographics in memory clinic-referrals (n = 86) to self-referred participants responding to advertisements and news bulletins (n = 179). Participants recruited by other means were excluded from analysis (n = 34).

RESULTS: At symptom group level, we found significant reductions in cognitive performance in memory clinic-referrals compared to self-referrals. However, here reductions were only found within the MCI group. We found no differences in cognitive performance due to recruitment within the SCD group. The MCI group was significantly impaired compared to controls on all measures. Significant reductions in learning, and executive functions were also found for the SCD group.

CONCLUSION: Regardless of recruitment method, both the SCD and MCI groups showed reductions in cognitive performance compared to controls. We found differences in cognitive impairment for memory clinic-referrals compared to self-referrals only within the MCI group, SCD-cases being equally affected irrespective of referral type.

%B J Alzheimers Dis %V 60 %P 1621-1631 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984581?dopt=Abstract %R 10.3233/JAD-170385 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Screening for Mild Cognitive Impairment and Dementia with Automated, Anonymous Online and Telephone Cognitive Self-Tests. %A Van Mierlo, Lisa D %A Wouters, Hans %A Sikkes, Sietske A M %A van der Flier, Wiesje M %A Prins, Niels D %A Bremer, Jonne A E %A Koene, Teddy %A Van Hout, Hein P J %X

BACKGROUND: Many older people worry about cognitive decline. Early cognitive screening in an anonymous and easily accessible manner may reassure older people who are unnecessarily worried about normal cognitive aging while it may also expedite help seeking in case of suspicious cognitive decline.

OBJECTIVE: To develop and validate online and telephone-based automated self-tests of cognitive function.

METHODS: We examined the feasibility and validity of the self-tests in a prospective study of 117 participants of whom 34 had subjective cognitive decline (SCD), 30 had mild cognitive impairment (MCI), and 53 had dementia. The ability of these self-tests to accurately distinguish MCI and dementia from SCD was examined with ROC curves. Convergent validity was examined by calculating rank correlations between the self-tests and neuropsychological tests.

RESULTS: Both the online and telephone cognitive self-tests were feasible, because the majority of participants (86% and 80%, respectively) were able to complete them. The online self-test had adequate diagnostic accuracy in the screening for MCI and dementia versus SCD with an Area under the Curve (AUC) of 0.86 (95% CI: 0.78-0.93). The AUC of the MMSE was 0.82 (95% CI: 0.74-0.89). By contrast, the telephone self-test had lower diagnostic accuracy (AUC = 0.75, 95% CI: 0.64-0.86). Both self-tests had good convergent validity as demonstrated by moderate to strong rank correlations with neuropsychological tests.

CONCLUSION: We demonstrated good diagnostic accuracy and convergent validity for the online self-test of cognitive function. It is therefore a promising tool in the screening for MCI and dementia.

%B J Alzheimers Dis %V 56 %P 249-259 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911296?dopt=Abstract %R 10.3233/JAD-160566 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Selenium Levels in Serum, Red Blood Cells, and Cerebrospinal Fluid of Alzheimer's Disease Patients: A Report from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL). %A Cardoso, Bárbara R %A Hare, Dominic J %A Bush, Ashley I %A Li, Qiao-Xin %A Fowler, Christopher J %A Masters, Colin L %A Martins, Ralph N %A Ganio, Katherine %A Lothian, Amber %A Mukherjee, Soumya %A Kapp, Eugene A %A Roberts, Blaine R %X

Selenium (Se) protects cells against oxidative stress damage through a range of bioactive selenoproteins. Increased oxidative stress is a prominent feature of Alzheimer's disease (AD), and previous studies have shown that Se deficiency is associated with age-related cognitive decline. In this study, we assessed Se status in different biofluids from a subgroup of participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. As Se in humans can either be an active component of selenoproteins or inactive via non-specific incorporation into other proteins, we used both size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) and tandem mass spectrometry to characterize selenoproteins in serum. We observed no differences in total Se concentration in serum or cerebrospinal fluid of AD subjects compared to mildly cognitively impairment patients and healthy controls. However, Se levels in erythrocytes were decreased in AD compared to controls. SEC-ICP-MS analysis revealed a dominant Se-containing fraction. This fraction was subjected to standard protein purification and a bottom-up proteomics approach to confirm that the abundant Se in the fraction was due, in part, to selenoprotein P. The lack of change in the Se level is at odds with our previous observations in a Brazilian population deficient in Se, and we attribute this to the Australian cohort being Se-replete.

%B J Alzheimers Dis %V 57 %P 183-193 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222503?dopt=Abstract %R 10.3233/JAD-160622 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Selenoprotein S Reduces Endoplasmic Reticulum Stress-Induced Phosphorylation of Tau: Potential Role in Selenate Mitigation of Tau Pathology. %A Rueli, Rachel H L H %A Torres, Daniel J %A Dewing, Andrea S T %A Kiyohara, Arlene C %A Barayuga, Stephanie M %A Bellinger, Miyoko T %A Uyehara-Lock, Jane H %A White, Lon R %A Moreira, Paula I %A Berry, Marla J %A Perry, George %A Bellinger, Frederick P %X

Previous studies demonstrated that selenium in the form of sodium selenate reduces neurofibrillary tangle formation in Alzheimer's disease models. Hyperphosphorylation of tau, which leads to formation of neurofibrillary tangles in Alzheimer's disease, is increased by endoplasmic reticulum (ER) stress. Selenoprotein S (SelS) is part of an ER membrane complex that removes misfolded proteins from the ER as a means to reduce ER stress. Selenate, as with other forms of selenium, will increase selenoprotein expression. We therefore proposed that increased SelS expression by selenate would contribute to the beneficial actions of selenate in Alzheimer's disease. SelS expression increased with ER stress and decreased under conditions of elevated glucose concentrations in the SH-SY5Y neuronal cell line. Reducing expression of SelS with siRNA promoted cell death in response to ER stress. Selenate increased SelS expression, which significantly correlated with decreased tau phosphorylation. Restricting SelS expression during ER stress conditions increased tau phosphorylation, and also promoted aggregation of phosphorylated tau in neurites and soma. In human postmortem brain, SelS expression coincided with neurofibrillary tangles, but not with amyloid-β plaques. These results indicate that selenate can alter phosphorylation of tau by increasing expression of SelS in Alzheimer's disease and potentially other neurodegenerative disorders.

%B J Alzheimers Dis %V 55 %P 749-762 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802219?dopt=Abstract %R 10.3233/JAD-151208 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Self-Consciousness Deficits in Alzheimer's Disease and Frontotemporal Dementia. %A Arroyo-Anlló, Eva Ma %A Bouston, Adèle Turpin %A Fargeau, Marie-Noëlle %A Orgaz Baz, Begõna %A Gil, Roger %X

Self-consciousness (SC) is multifaceted and considered to be the consciousness of one's own mental states. The main aim of this paper is to compare SC in patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Three groups (control and patient groups) of 23 subjects each were assessed using an SC questionnaire. Both types of dementia clearly induce an alteration of SC. The bvFTD group showed a greater impairment in SC than the AD and control groups. The SC score was strongly associated with frontal functions. The most significantly impaired SC aspects in the bvFTD group were Anosognosia, Introspection, and Moral Judgments. For the AD group, the significantly impaired aspects of SC were Anosognosia and Prospective Memory. The differences in SC between the AD and bvFTD groups were essentially centered on the Anosognosia, Moral Judgments, and Introspection aspects, which were highly impaired in the bvFTD patients. This suggests that SC is related to orbito-frontal functioning and thus, to the default mode network.

%B J Alzheimers Dis %V 55 %P 1437-1443 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858712?dopt=Abstract %R 10.3233/JAD-160770 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sembragiline in Moderate Alzheimer's Disease: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Trial (MAyflOwer RoAD). %A Nave, Stephane %A Doody, Rachelle S %A Boada, Merce %A Grimmer, Timo %A Savola, Juha-Matti %A Delmar, Paul %A Pauly-Evers, Meike %A Nikolcheva, Tania %A Czech, Christian %A Borroni, Edilio %A Ricci, Benedicte %A Dukart, Juergen %A Mannino, Marie %A Carey, Tracie %A Moran, Emma %A Gilaberte, Inma %A Muelhardt, Nicoletta Milani %A Gerlach, Irene %A Santarelli, Luca %A Ostrowitzki, Susanne %A Fontoura, Paulo %X

BACKGROUND: Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer's disease (AD).

OBJECTIVE: To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD.

METHODS: In this Phase II study (NCT01677754), 542 patients with moderate dementia (MMSE 13-20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1 mg, 5 mg, or placebo once daily orally for 52 weeks.

RESULTS: No differences between treated groups and placebo in adverse events or in study completion. The primary endpoint, change from baseline in ADAS-Cog11, was not met. At Week 52, the difference between sembragiline and placebo in ADAS-Cog11 change from baseline was - 0.15 (p = 0.865) and 0.90 (p = 0.312) for 1 and 5 mg groups, respectively. Relative to placebo at Week 52 (but not at prior assessment times), the 1 mg and 5 mg sembragiline groups showed differences in ADCS-ADL of 2.64 (p = 0.051) and 1.89 (p = 0.160), respectively. A treatment effect in neuropsychiatric symptoms (as assessed by the difference between sembragiline and placebo on BEHAVE-AD-FW) was also seen at Week 52 only: - 2.80 (p = 0.014; 1 mg) and - 2.64 (p = 0.019; 5 mg), respectively. A post hoc subgroup analysis revealed greater treatment effects on behavior and functioning in patients with more severe baseline behavioral symptoms (above the median).

CONCLUSIONS: This study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline.

%B J Alzheimers Dis %V 58 %P 1217-1228 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550255?dopt=Abstract %R 10.3233/JAD-161309 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sensing of Alzheimer's Disease and Multiple Sclerosis Using Nano-Bio Interfaces. %A Hajipour, Mohammad Javad %A Ghasemi, Forough %A Aghaverdi, Haniyeh %A Raoufi, Mohammad %A Linne, Uwe %A Atyabi, Fatemeh %A Nabipour, Iraj %A Azhdarzadeh, Morteza %A Derakhshankhah, Hossein %A Lotfabadi, Alireza %A Bargahi, Afshar %A Alekhamis, Zahra %A Aghaie, Afsaneh %A Hashemi, Ehsan %A Tafakhori, Abbas %A Aghamollaii, Vajiheh %A Mashhadi, Marzie Maserat %A Sheibani, Sara %A Vali, Hojatollah %A Mahmoudi, Morteza %X

It is well understood that patients with different diseases may have a variety of specific proteins (e.g., type, amount, and configuration) in their plasmas. When nanoparticles (NPs) are exposed to these plasmas, the resulting coronas may incorporate some of the disease-specific proteins. Using gold (Au) NPs with different surface properties and corona composition, we have developed a colorimetric sensor array for the discrimination and detection of two neurodegenerative diseases, Alzheimer's disease (AD) and multiple sclerosis (MS). Applying a variety of techniques, including UV-visible spectra, array response analyses and liquid chromatography-tandem mass spectrometry, we found the corona-NP complexes, obtained from different human serums, had distinct protein composition, including some specific proteins that are known as AD and MS biomarkers. The array responses, analyzed by chemometrics and statistical methods, demonstrate promising capabilities of the sensor to unambiguously identify and discriminate AD and MS. The developed sensor array might enable a simple, inexpensive and rapid detection/discrimination of neurodegenerative diseases.

%B J Alzheimers Dis %V 59 %P 1187-1202 %G eng %N 4 %R 10.3233/JAD-160206 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Severity of Depression Impacts Imminent Conversion from Mild Cognitive Impairment to Alzheimer's Disease. %A Defrancesco, Michaela %A Marksteiner, Josef %A Kemmler, Georg %A Fleischhacker, Walter Wolfgang %A Blasko, Imrich %A Deisenhammer, Eberhard A %X

BACKGROUND: Mild cognitive impairment (MCI) has been suggested to represent a prodromal stage of dementia and to confer a high risk for conversion to dementia Alzheimer's type (DAT).

OBJECTIVES: In this study, we examined the predictive value of depressive symptoms and neuropsychological variables on conversion of MCI to DAT.

METHODS: Neuropsychological and clinical follow-up data of 260 MCI patients seen at the Psychiatric Memory Clinic of the Medical University of Innsbruck between 2005 and 2015 were analyzed retrospectively. Depression was assessed using the Geriatric Depression Scale (GDS). Potential predictors of conversion from MCI to DAT were analyzed by logistic regression analyses and additional survival-analytic methods.

RESULTS: Of the 260 patients (mean age 71.5±7.7 years), 83 (32%) converted to DAT within a mean follow-up time of 3.2±2.2 years and estimated one-year conversion rate of 10.1%. The univariate analysis showed with few exceptions (gender, use of antidepressants, low GDS score) group differences at baseline in patients converted to DAT compared to stable MCI patients. Logistic regression analysis as well as survival analysis revealed moderate to severe depression together with higher age and specific cognitive deficits as predictors of conversion from MCI to DAT.

CONCLUSION: Our results support the predictive value of different neuropsychological measures on the progression of DAT. In addition, we found a strong negative influence of depression on conversion to DAT in MCI patients. These results emphasize the importance of assessing depressive symptoms in the early stages of DAT when evaluating the conversion from MCI to DAT.

%B J Alzheimers Dis %V 59 %P 1439-1448 %G eng %N 4 %R 10.3233/JAD-161135 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sex Difference in Aerobic Exercise Efficacy to Improve Cognition in Older Adults with Vascular Cognitive Impairment: Secondary Analysis of a Randomized Controlled Trial. %A Barha, Cindy K %A Hsiung, Ging-Yuek R %A Best, John R %A Davis, Jennifer C %A Eng, Janice J %A Jacova, Claudia %A Lee, Philip E %A Munkacsy, Michelle %A Cheung, Winnie %A Liu-Ambrose, Teresa %X

Aerobic training (AT) is a promising, non-pharmacological intervention to mitigate the deleterious effects of aging and disease on brain health. However, a large amount of variation exists in its efficacy. This is a secondary analysis of a randomized controlled trial of AT in 71 older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Specifically, we investigated: 1) whether sex moderates the relationship between AT and executive functions, and 2) the role of brain derived neurotrophic factor (BDNF) and gains in functional fitness capacity. Older adults were randomly assigned to either 6-month, thrice-weekly AT or to usual care plus education (CON). At baseline, trial completion, and 6-month follow-up, executive functions were assessed with the Trail Making Test (A & B), verbal digits forward and backward test, and the Stroop Test. Functional fitness capacity was assessed with the 6-Minute Walk Test. Compared with CON, AT significantly improved Trail Making Test performance in females but not males, an effect that was retained at follow-up. AT significantly increased BDNF levels in females but decreased levels in males. On the other hand, AT led to significant gains in functional fitness capacity in males only. This study provides evidence that sex differences exist in AT efficacy on brain health as well as in the biological mechanisms subserving AT.

%B J Alzheimers Dis %V 60 %P 1397-1410 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036816?dopt=Abstract %R 10.3233/JAD-170221 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sex Differences in the Psychophysical Response to Contact Heat in Moderate Cognitive Impairment Alzheimer's Disease: A Cross-Sectional Brief Report. %A Cowan, Ronald L %A Beach, Paul A %A Atalla, Sebastian W %A Dietrich, Mary S %A Bruehl, Stephen P %A Deng, Jie %A Wang, Jinjiao %A Newhouse, Paul A %A Gore, John C %A Monroe, Todd B %X

BACKGROUND: People with Alzheimer's disease (AD) report pain less frequently and receive less pain medication than people without AD. Recent studies have begun to elucidate how pain may be altered in those with AD. However, potential sex differences in pain responsiveness have never been explored in these patients. It is unclear whether sex differences found in prior studies of healthy young and older individuals extend to people with AD.

OBJECTIVE: The purpose of this study was to examine sex differences in the psychophysical response to experimental thermal pain in people with AD.

METHODS: Cross-sectional analysis of 14 male and 14 female age-matched (≥65 years of age, median = 74) and AD severity-matched (Mini-Mental State Exam score <24, median = 16) communicative people who completed thermal psychophysics.

RESULTS: There was a statistically significant main effect of sex for both temperature and unpleasantness ratings that persisted after controlling for average and current pain (mixed-effects general liner model: temperature: p = 0.004, unpleasantness: p < 0.001). Females reported sensing mild pain and moderate pain percepts at markedly lower temperatures than did males (mild: Cohen's d = 0.72, p = 0.051, moderate: Cohen's d = 0.80, p = 0.036). By contrast, males rated mild and moderate thermal pain stimuli as more unpleasant than did females (mild: Cohen's d = 0.80, p = 0.072, moderate: Cohen's d = 1.32, p = 0.006). There were no statistically significant correlations of temperature with perceived unpleasantness for mild or moderate pain (rs = 0.29 and rs = 0.20 respectively, p > 0.05).

CONCLUSIONS: Results suggest experimental pain-related sex differences persist in older adults with AD in a different manner than those previously demonstrated in cognitively intact older adults. These findings could potentially aid in developing targeted pain management approaches in this vulnerable population. Further studies are warranted to replicate the findings from this pilot work.

%B J Alzheimers Dis %V 60 %P 1633-1640 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28968238?dopt=Abstract %R 10.3233/JAD-170532 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sex Impact on Tau-Aggregation and Postsynaptic Protein Levels in the P301L Mouse Model of Tauopathy. %A Buccarello, Lucia %A Grignaschi, Giuliano %A Castaldo, Anna Maria %A Di Giancamillo, Alessia %A Domeneghini, Cinzia %A Melcangi, Roberto Cosimo %A Borsello, Tiziana %X

P301L transgenic (tg) mice well mimic features of human tauopathies and provide a good model for investigating the role of tau in neurodegenerative events. We here analyzed the possible interactions among phosphorylation of tau (p-tau), spine injury, neuronal death, and sex in the P301L mouse model of tauopathy. When compared to control mice (ctr), P301L transgenic mice (tg) presented a lower body weight, reduced survival rate, hyperphosphorylated tau, spine injury, and neuronal loss in both cerebral cortex and hippocampus at 15 months of age. Importantly, we found that pathological features were more pronounced in female than male tg mice. Recent reports underline that tau may be localized within both pre- and post-synaptic compartments, suggesting that it may possibly induce or contribute to synaptic dysfunction. Therefore, we focused our attention on tau localization at dendritic spines. We detected high levels of both tau and p-tau in dendritic spine of P301L transgenic mice. In addition, p-tau correlated with a significant reduction of post-synaptic markers, such as GluN2A, GluN2B, GluA1, GluA2, Drebrin, and PSD-95, in P301L mice. The p-tau levels are higher in female than in male mice, and the increased p-tau was consistent with a proportional decrease in the post-synaptic marker levels analyzed. The P301L-tg females showed a more severe synaptopathy compared to males. Future investigations on the postsynaptic role of p-tau will be necessary to understand its toxic effects and provide insights into new therapeutic targets for maintaining spine integrity, highlighting the importance of tau toxicity as well as the impact of sex on tau-pathology.

%B J Alzheimers Dis %V 56 %P 1279-1292 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157099?dopt=Abstract %R 10.3233/JAD-161087 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Short-Term Response is not Predictive of Long-Term Response to Acetylcholinesterase Inhibitors in Old Age Subjects with Alzheimer's Disease: A "Real World" Study. %A Boccardi, Virginia %A Baroni, Marta %A Smirne, Nicoletta %A Clodomiro, Alessandra %A Ercolani, Sara %A Longo, Annalisa %A Ruggiero, Carmelinda %A Bruni, Amalia C %A Mecocci, Patrizia %X

BACKGROUND: Most of clinical guidelines recommend discontinuing treatment with cholinesterase inhibitors (ChEIs) in patients with Alzheimer's disease (AD) who do not show an initial response to therapy as evaluated with the Mini-Mental State Examination (MMSE) scale. However, understanding the relationship between the initial response to ChEI treatment and the subsequent course of the disease is extremely important in clinical practice, but evidence is limited, particularly in the old-old population.

OBJECTIVE: We aimed at investigating the relationship between short-term and long-term response to ChEI therapy in old age subjects with AD in a "real life" setting.

METHODS: This is a retrospective longitudinal study of 628 old age subjects (≥65 years old) with AD and treated with ChEIs over three year follow-up. The sample was divided into "young-old" (≤75 years) and "old-old" (≥76 years) according to age, and as "responder" and "non-responder" according to the initial (i.e., after three months) response to treatment. Cognitive and functional evaluation was performed by means of MMSE and ADL/IADL, respectively.

RESULTS: In the long run, subjects considered as non-responders showed a lower rate of cognitive decline as compared with responders, with a mean annual decline at MMSE of 1.0 point versus 1.6 points (p < 0.0001), respectively. Old-old non-responders had a slower rate of cognitive (p < 0.0001) and functional decline (p < 0.0001) as compared with responders after three years of observation.

CONCLUSION: Discontinuing ChEI treatment solely for the absence of an initial response is not appropriate, especially in old-old subjects.

%B J Alzheimers Dis %V 56 %P 239-248 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911323?dopt=Abstract %R 10.3233/JAD-160904 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Silicic Acid and Beer Consumption Reverses the Metal Imbalance and the Prooxidant Status Induced by Aluminum Nitrate in Mouse Brain. %A González-Muñoz, María José %A Garcimartán, Alba %A Meseguer, Isabel %A Mateos-Vega, Carmen José %A Orellana, José María %A Peña-Fernández, Antonio %A Benedí, Juana %A Sánchez-Muniz, Francisco J %X

BACKGROUND: Emerging evidence suggests that by affecting mineral balance, aluminum (Al) may enhance some events associated with neurodegenerative diseases.

AIM: To examine the effect of Al(NO3)3 exposure on brain Al, cooper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), silicon (Si), and zinc (Zn) levels, and the metal-change implication in brain oxidant and inflammatory status.

METHODS: Four groups of six-week-old male NMRI mice were treated for three months: i) controls, administrated with deionized water; ii) Al, which received Al(NO3)3; iii) Al+silicic acid, which were given Al(NO3)3 plus silicic acid; and iv) Al+beer, which received Al(NO3)3 plus beer.

RESULTS: Brain Al and TBARS levels and TNFα and GPx expressions increased, while Cu, Mn, and Zn levels, and catalase and CuZn-SOD expression decreased (at least, p < 0.05) in Al versus control animals. Al, Si, and TBARS levels and TNFα expression decreased (p < 0.05) in Al+silicic acid and Al+beer specimens while Cu, Mn, and Zn levels and antioxidant expression increased versus the Al group. Brain Al levels correlated negatively with those of Cu, Fe, Mn, and Zn, and catalase, CuZn-SOD, and GPx enzyme expressions but positively with Si and TBARS levels and TNFα expression. Two components of the principal component analysis (PCA) explained 71.2% of total data variance (p < 0.001). PCA connected the pro-oxidant markers with brain Al content, while brain Zn and Cu levels were closer to antioxidant enzyme expression.

CONCLUSION: Administration of Al(NO3)3 induced metal imbalance, inflammation, and antioxidant status impairment in the brain. Those effects were blocked to a significant extent by silicic acid and beer administration.

%B J Alzheimers Dis %V 56 %P 917-927 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059788?dopt=Abstract %R 10.3233/JAD-160972 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sleep Apnea, Cognitive Profile, and Vascular Changes: An Intriguing Relationship. %A Buratti, Laura %A Viticchi, Giovanna %A Baldinelli, Sara %A Falsetti, Lorenzo %A Luzzi, Simona %A Pulcini, Alessandra %A Petrelli, Cristina %A Provinciali, Leandro %A Silvestrini, Mauro %X

BACKGROUND: Sleep breathing disorders can affect cognitive performances through complex brain anatomical and functional changes.

OBJECTIVE: Our aim was to evaluate the correlations between cognitive performances and obstructive sleep apnea syndrome (OSAS), as well as the possible influence of vascular factors.

METHODS: Thirty-four non-demented OSAS patients and 34 controls were submitted to a neuropsychological evaluation and to a vascular screening including the study of cerebrovascular reactivity by means of the breath-holding index (BHI) calculation. After 6 months, polisomnographic, neuropsychologic, and hemodynamics assessment was repeated in patients.

RESULTS: At baseline, some cognitive performances involved in executive and memory functions were significantly lower in patients with respect to controls. Significantly lower values in mean BHI were also detected in patients with respect to controls (p < 0.0001). At the 6-month evaluation, 18 patients had a reduction in OSAS severity (group 1) and 16 remained stable (group 2). Group 1 patients had a significant improvement in left and mean BHI (p < 0.001) and in short-term (p = 0.02) and long-term Rey Auditory Verbal Learning Test (p < 0.001). No change in cerebrovascular reactivity and cognitive profile was detected in group 2 patients.

CONCLUSIONS: Patients with OSAS may experience a reduced cognitive efficiency. Improvement of OSAS was associated to favorable hemodynamic changes and increased level of performances in verbal memory tasks so suggesting an involvement of vascular underlying mechanisms in sustaining cognitive dysfunctions in OSAS. Our preliminary data suggest the need for further studies to deepen the knowledge about the relationships between OSAS, cerebral hemodynamic compromise, and cognitive impairment risk.

%B J Alzheimers Dis %V 60 %P 1195-1203 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984599?dopt=Abstract %R 10.3233/JAD-170445 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Is Sleep Disruption a Risk Factor for Alzheimer's Disease? %A Macedo, Arthur Cassa %A Balouch, Sara %A Tabet, Naji %X

Sleep disturbances are routinely encountered in Alzheimer's disease (AD) and affect about 25-40% of patients in the mild-to-moderate stages of the disease. In many, sleep pathology may represent a symptom of the underlying neurodegeneration. However, a history of sleep disruption occurring years prior to onset of cognitive symptoms could represent a potential risk factor for AD. The aim of the present narrative review was to evaluate current evidence linking sleep disturbances with AD development and to understand the mechanisms that may contribute to this. Although the mechanisms by which poor sleep may contribute to AD genesis is not fully understood, emerging evidence linking disturbances in the sleep wake cycle with Aβ deposition is shedding light on the relationship between sleep pathology and the subsequent development of AD. Aβ burden appears to be enhanced by sleep-wake cycle disruptions and is suspected as being an important mechanism by which sleep disruptions contribute in AD development. Other mechanisms triggered by sleep disruption may also be involved in AD development, such as brain hypoxia, oxidative stress, circadian activity rhythms disturbances, overexpression of orexins, and blood-brain barrier impairment. Further understanding of the link between sleep disturbances and future development of AD is still needed before sleep disturbances are clearly marked as a preventable risk factor for AD. In these circumstances, early lifestyle interventions to help increase the quantity and quality of sleep may have a favorable outcome on decreasing the incidence of AD and this needs to be investigated further.

%B J Alzheimers Dis %V 58 %P 993-1002 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550253?dopt=Abstract %R 10.3233/JAD-161287 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sleep EEG Detects Epileptiform Activity in Alzheimer's Disease with High Sensitivity. %A Horváth, András %A Szűcs, Anna %A Barcs, Gábor %A Kamondi, Anita %X

BACKGROUND: The reported prevalence of epilepsy in Alzheimer's disease (AD) is variable, probably due to the different methodological approaches.

OBJECTIVE: We aimed to define the optimal electroencephalogram (EEG) settings for reliable detection of epileptiform discharges in AD patients.

METHODS: We analyzed 24-h EEGs of 5 patients living with AD and epilepsy. The sensitivity of various length EEGs in detecting epileptiform discharges in different periods of the day, the diurnal distribution of the discharges, and their relation to sleep-stages were calculated.

RESULTS: Significant high correlation was identified between the sensitivity of EEG and the length of recordings (r = 0.972, p = 0.005). The sensitivity of a 30-min EEG-epoch recorded between 8:00 and 16:00 was 0.0375 compared to 0.7 between 0:00 and 8:00 (p = 0.005). The average sensitivity of an 8-h EEG-epoch was≥0.8. 82% of epileptiform discharges occurred during sleep, mainly related to non-REM sleep (p < 0.001).

CONCLUSION: 8-h awake-, or 1-h sleep-EEG provide sufficient sensitivity in detecting epileptiform activity in AD. This needs to be considered in studies on AD-related epilepsy. Recognizing epilepsy in AD patients is essential because it might compromise cognitive functions and accelerate the progression of the disease.

%B J Alzheimers Dis %V 56 %P 1175-1183 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28128769?dopt=Abstract %R 10.3233/JAD-160994 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sleep-Wake Profile in Dementia with Lewy Bodies, Alzheimer's Disease, and Normal Aging. %A Cagnin, Annachiara %A Fragiacomo, Federica %A Camporese, Giulia %A Turco, Matteo %A Bussè, Cinzia %A Ermani, Mario %A Montagnese, Sara %X

BACKGROUND: Alterations of the sleep-wake cycle are common features of neurodegenerative dementia.

OBJECTIVES: To study differences in sleep-wake profiles in dementia with Lewy bodies (DLB), Alzheimer's disease (AD), and healthy controls.

METHODS: 30 DLB and 32 AD patients, and 33 healthy elderly participants were studied. Patients were evaluated for global cognitive impairment, extrapyramidal signs, fluctuations of attention, and behavioral disorders. A comprehensive sleep-wake profile was obtained including a set of questionnaires [Pittsburgh Sleep Quality Index (PSQI), REM Sleep Behavior Disorder Single-Question screen (RBD1Q), Epworth Sleepiness Scale (ESS)] and 12-day sleep diaries.

RESULTS: Patients were matched for age, gender, and disease severity. DLB patients showed more severe daytime somnolence/dysfunction due to somnolence, and a higher proportion of RBD-like symptoms (70%) compared to AD and controls (p < 0.001), regardless of the presence of psychoactive drug treatment. As for sleep timing, DLB patients had a greater number of daytime naps and longer night sleep, with the latter being associated with use of clonazepam. The severity of fluctuations was associated with the presence of RBD (Clinician Assessment of Fluctuation score = RBD+: 5.2±3.7; RBD-: 2.1±3.2, p = 0.04). AD patients reported the best sleep-wake profile, while healthy controls declared the poorest sleep quality, although sleep timing and the quality of wakefulness were comparable between AD and controls.

DISCUSSION: RBD and daytime fluctuations of attention may coexist in DLB and even reciprocally potentiate each other. Self-reports of sleep quality may lead to an underestimation of sleep disturbances in AD, possibly influenced by anosognosia, compared to normal elderly individuals who complain mainly of insomnia.

%B J Alzheimers Dis %V 55 %P 1529-1536 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27886007?dopt=Abstract %R 10.3233/JAD-160385 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Smoking, APOE Genotype, and Cognitive Decline: The Rotterdam Study. %A Wingbermühle, Robin %A Wen, Ke-Xin %A Wolters, Frank J %A Ikram, M Arfan %A Bos, Daniel %X

The association of smoking with preclinical cognitive decline remains unclear and may be modified by the APOEɛ4 genotype. In 5,705 participants (mean age: 63.9±9.1 years; 57.4% women) from the population-based Rotterdam Study, we investigated the relationship between smoking and cognitive decline over a 5.5-year period and examined potential effect modification by APOEɛ4 genotype. We found that current smoking was related to decline in global cognition [difference compared to never smoking: -0.06 (95% C.I.-0.10;-0.01)], as well as decline on specific cognitive tests including the Letter Digit Substitution Task, the 15-Word Learning Test, and the Purdue Pegboard. We found no evidence for effect modification by APOEɛ4 genotype on this relation.

%B J Alzheimers Dis %V 57 %P 1191-1195 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304310?dopt=Abstract %R 10.3233/JAD-170063 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Social Cognition in the Frontal Variant of Alzheimer's Disease: A Case Study. %A Duclos, Harmony %A de la Sayette, Vincent %A Bonnet, Anne-Laure %A Viard, Armelle %A Eustache, Francis %A Desgranges, Béatrice %A Laisney, Mickaël %X

Although frontal presentations of Alzheimer's disease (fv-AD) have already been described in the literature, we still know little about patients' social cognitive abilities, especially their theory of mind (ToM). We report the case of FT, a 61-year-old woman who was diagnosed with fv-AD. Two assessments of social cognition, using a false-belief task, the Reading the Mind in the Eyes test, and a task probing knowledge of social norms, were performed one year apart. FT exhibited cognitive ToM and social knowledge deficits from the onset. Affective ToM was initially preserved, but deteriorated as the disease progressed.

%B J Alzheimers Dis %V 55 %P 459-463 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662316?dopt=Abstract %R 10.3233/JAD-160690 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Social Representation of Dementia: An Analysis of 5,792 Consecutive Cases Evaluated in a Memory Clinic. %A Cañabate, Pilar %A Martínez, Gabriel %A Rosende-Roca, Maitee %A Moreno, Mariola %A Preckler, Silvia %A Valero, Sergi %A Sotolongo, Oscar %A Hernandez, Isabel %A Alegret, Montserrat %A Ortega, Gemma %A Espinosa, Ana %A Mauleón, Ana %A Vargas, Liliana %A Rodríguez, Octavio %A Abdelnour, Carla %A Sánchez, Domingo %A Martín, Elvira %A Ruiz, Agustin %A Tárraga, Lluís %A Boada, Merce %X

BACKGROUND: Different interpretations of cognitive impairment and dementia due to differences in health structures, such as cultural differences could affect the diagnosis and treatment of the condition. it is reasonable to expect that the social and family impact of the disease and coping strategies will differ among societies.

OBJECTIVE: The general aim of this study is to understand the social representations of dementia, its associated practices, and the effects they imply.

METHODS: People diagnosed with clinical dementia and their families were assessed from 2005 to 2015 in the memory clinic of the Fundació ACE, Institut Català de Neurociències Aplicades in Barcelona, Spain.

RESULTS: 9,898 people were examined and 5,792 were diagnosed with dementia. For those with a caregiver (71%), the decision-making fell on the person with dementia in 16.2% of the cases; and for those without a caregiver, in 26.4% of the cases the family did not perceive the deficits as a disease, which led to multiple risk situations (74.6%).

CONCLUSIONS: The recognition of dementia as part of aging is common among families. Consequently, risk situations may arise and diagnosis and access to treatment may be delayed. The incorporation of a social appraisal to the diagnostic process is a necessity to evaluate these situations.

%B J Alzheimers Dis %V 58 %P 1099-1108 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527206?dopt=Abstract %R 10.3233/JAD-161119 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload. %A Cascella, Roberta %A Evangelisti, Elisa %A Bigi, Alessandra %A Becatti, Matteo %A Fiorillo, Claudia %A Stefani, Massimo %A Chiti, Fabrizio %A Cecchi, Cristina %X

An altered distribution of membrane gangliosides (GM), including GM1, has recently been reported in the brains of Alzheimer's disease (AD) patients. Moreover, amyloid-positive synaptosomes obtained from AD brains were found to contain high-density GM1 clusters, suggesting a pathological significance of GM1 increase at presynaptic neuritic terminals in AD. Here, we show that membrane GM1 specifically recruits small soluble oligomers of the 42-residue form of amyloid-β peptide (Aβ42), with intracellular flux of Ca2+ ions in primary rat hippocampal neurons and in human neuroblastoma cells. Specific membrane proteins appear to be involved in the early and transient influx of Ca2+ ions induced by Aβ42 oligomers with high solvent-exposed hydrophobicity (A+), but not in the sustained late influx of the same oligomers and in that induced by Aβ42 oligomers with low solvent-exposed hydrophobicity (A-) in GM1-enriched cells. In addition, A+ oligomers accumulate in proximity of membrane NMDA and AMPA receptors, inducing the early and transient Ca2+ influx, although FRET shows that the interaction is not direct. These results suggest that age-dependent clustering of GM1 within neuronal membranes could induce neurodegeneration in elderly people as a consequence of an increased ability of the lipid bilayers to recruit membrane-permeabilizing oligomers. We also show that both lipid and protein components of the plasma membrane can contribute to neuronal dysfunction, thus expanding the molecular targets for therapeutic intervention in AD.

%B J Alzheimers Dis %V 60 %P 923-938 %G eng %N 3 %R 10.3233/JAD-170340 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Specific Verbal Memory Measures May Distinguish Alzheimer's Disease from Dementia with Lewy Bodies. %A Bussè, Cinzia %A Anselmi, Pasquale %A Pompanin, Sara %A Zorzi, Giovanni %A Fragiacomo, Federica %A Camporese, Giulia %A Di Bernardo, Gian Antonio %A Semenza, Carlo %A Caffarra, Paolo %A Cagnin, Annachiara %X

BACKGROUND: Standard measures of commonly used memory tests may not be appropriate to distinguish different neurodegenerative diseases affecting memory.

OBJECTIVE: To study whether specific measures of verbal memory obtained with the Rey Auditory Verbal Learning test (RAVLT) could help distinguish dementia with Lewy bodies (DLB) from Alzheimer's disease (AD).

METHODS: Twenty-nine DLB and 32 AD patients participated in the study and were followed longitudinally for 3 years until the diagnosis was confirmed according to standard clinical criteria. Twenty-eight healthy elderly subjects served as controls. The following verbal memory measures were evaluated: verbal learning (VL), verbal forgetting (VF), percentage of verbal forgetting (VF%), and serial position effects of the immediate recall performance.

RESULTS: DLB and AD groups have comparable performances at the RAVLT immediate and delayed recall tasks. However, VL was higher in DLB than AD while VF% was greater in AD. With a VF% cut-off ≥75%, AD and DLB patients were differently distributed, with 58% of AD versus 21% of DLB above this cut-off. The recency effect was significant higher in AD than DLB.

DISCUSSION: DLB patients had a better performance in VL than AD, but worse VF and recency effect. These specific measures of verbal memory could be used as cognitive markers in the differential diagnosis between these two conditions.

%B J Alzheimers Dis %V 59 %P 1009-1015 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697561?dopt=Abstract %R 10.3233/JAD-170154 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sphingolipid-Enriched Extracellular Vesicles and Alzheimer's Disease: A Decade of Research. %A Dinkins, Michael B %A Wang, Guanghu %A Bieberich, Erhard %X

Extracellular vesicles (EVs), particularly exosomes, have emerged in the last 10 years as a new player in the progression of Alzheimer's disease (AD) with high potential for being useful as a diagnostic and treatment tool. Exosomes and other EVs are enriched with the sphingolipid ceramide as well as other more complex glycosphingolipids such as gangliosides. At least a subpopulation of exosomes requires neutral sphingomyelinase activity for their biogenesis and secretion. As ceramide is often elevated in AD, exosome secretion may be affected as well. Here, we review the available data showing that exosomes regulate the aggregation and clearance of amyloid-beta (Aβ) and discuss the differences in data from laboratories regarding Aβ binding, induction of aggregation, and glial clearance. We also summarize available data on the role of exosomes in extracellular tau propagation, AD-related exosomal mRNA/miRNA cargo, and the use of exosomes as biomarker and gene therapy vehicles for diagnosis and potential treatment.

%B J Alzheimers Dis %V 60 %P 757-768 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662306?dopt=Abstract %R 10.3233/JAD-160567 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Subjective Memory Impairment and Gait Variability in Cognitively Healthy Individuals: Results from a Cross-Sectional Pilot Study. %A Beauchet, Olivier %A Launay, Cyrille P %A Chabot, Julia %A Levinoff, Elise J %A Allali, Gilles %X

BACKGROUND: Increased stride time variability has been associated with memory impairment in mild cognitive impairment. Subjective memory impairment (SMI) is considered the earliest clinical stage of Alzheimer's disease (AD). The association between increased stride time variability and SMI has not been reported.

OBJECTIVE: This study aims to examine the association of stride time variability while performing single and dual tasking with SMI in cognitively healthy individuals (CHI).

METHODS: A total of 126 CHI (15 without SMI, 69 with SMI expressed by participants, 10 with SMI expressed by participant's relative, and 32 with SMI expressed by both participants and their relatives) were included in this cross-sectional study. The coefficient of variation (CoV) of stride time and walking speed were recorded under usual condition and while counting backwards. Age, gender, body mass index, number of drugs taken daily, use of psychoactive drugs, fear of falling, history of previous falls, and walking speed were used as covariates.

RESULTS: The multiple linear regression models showed that greater CoV of stride time while counting backwards, but not while single tasking, was associated with a participant's relative SMI (p = 0.038).

CONCLUSION: This study found a specific association between SMI expressed by a participant's relative and a greater CoV of stride time (i.e., worse performance) while dual tasking, suggesting that the association between gait variability and memory may be present in the earliest stages of memory impairment. Thus, gait variability under dual-task in individuals with SMI expressed by their relatives can be a potential biomarker of AD.

%B J Alzheimers Dis %V 55 %P 965-971 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802231?dopt=Abstract %R 10.3233/JAD-160604 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Synaptic Compensation as a Probable Cause of Prolonged Mild Cognitive Impairment in Alzheimer's Disease: Implications from a Transgenic Mouse Model of the Disease. %A Baazaoui, Narjes %A Flory, Michael %A Iqbal, Khalid %X

Alzheimer's disease (AD) is a slow, progressive neurodegenerative disease in which cognitive decline takes place over a period of several years with a very variable period of mild cognitive impairment (MCI) and, in some cases, relatively long period before progression to dementia. The cognitive deficit during MCI is probably due to neuronal loss, an intermediate level of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT) and synaptosis, which is interrupted with a transient compensatory increase. We found impairment in reference memory accompanied by a decrease in the expression of synaptophysin, β-III tubulin, and MAP2 and a trend for GluR1, at 12 weeks of age in 3xTg-AD mice (hAPPSwe, P301L tau, PS1 [M146V] knock-in), a widely used transgenic model of AD. Past 12 weeks, the cross-sectional analysis of different age groups showed a compensatory increase in synaptic markers relative to that in wild type animals in a topographic and time-dependent manner. When studied across time we found that in 3xTg-AD mice, the compensatory phenomenon occurred in parallel in different regions of the brain. However, this attempt of the brain to repair itself was able to only partially rescue cognitive impairment. These findings for the first time raise the intriguing possibility that AD causing mutated transgenes may initially cause an increase in synaptic and dendritic markers as a compensatory mechanism for synaptic deficit, and this phenomenon, though transient, could be the biological basis of the period of MCI seen in AD.

%B J Alzheimers Dis %V 56 %P 1385-1401 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222506?dopt=Abstract %R 10.3233/JAD-160845 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Synaptic Membrane Synthesis in Rats Depends on Dietary Sufficiency of Vitamin C, Vitamin E, and Selenium: Relevance for Alzheimer's Disease. %A Cansev, Mehmet %A Turkyilmaz, Mesut %A Sijben, John W C %A Sevinc, Cansu %A Broersen, Laus M %A van Wijk, Nick %X

Chronic consumption of a diet enriched with nutritional precursors of phospholipids, including uridine and the polyunsaturated fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), was shown previously to enhance levels of brain phospholipids and synaptic proteins in rodents. Vitamin C, vitamin E, and selenium may directly affect the breakdown or synthesis of membrane phospholipids. The present study investigated the necessity of antioxidants for the effectiveness of supplementation with uridine plus DHA and EPA (as fish oil) in rats. Rats were randomized to four treatment groups and received, for 6 weeks, one of four experimental diets, i.e., a diet low in antioxidants, a diet high in antioxidants, a diet low in antioxidants supplemented with DHA+EPA+uridine, or a diet high in antioxidants supplemented with DHA+EPA+uridine. On completion of dietary treatment, rats were sacrificed, and brain levels of phospholipids, synaptic proteins, and two enzymes involved in phospholipid synthesis (choline-phosphate cytidylyltransferase, PCYT1A, and choline/ethanolamine phosphotransferase, CEPT1) were analyzed. Levels of phospholipids, the pre- and post-synaptic proteins Synapsin-1 and PSD95, and the enzymes PCYT1A and CEPT1 were significantly enhanced by combined supplementation of DHA+EPA+uridine and antioxidants and not enhanced by supplementation of DHA+EPA+uridine with insufficient antioxidant levels. Our data suggest that dietary vitamin C, vitamin E, and selenium are essential for the phospholipid precursors' effects on increasing levels of membrane phospholipids and synaptic proteins, the indirect indicators of synaptogenesis. Their concomitant supply may be relevant in Alzheimer's disease patients, because the disease is characterized by synapse loss and lower plasma and brain levels of phospholipid precursors and antioxidants.

%B J Alzheimers Dis %V 59 %P 301-311 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598848?dopt=Abstract %R 10.3233/JAD-170081 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Synthesis, Radiosynthesis, and Preliminary in vitro and in vivo Evaluation of the Fluorinated Ceramide Trafficking Inhibitor (HPA-12) for Brain Applications. %A Crivelli, Simone M %A Paulus, Andreas %A Markus, Jozef %A Bauwens, Matthias %A Berkes, Dusan %A De Vries, Helga E %A Mulder, Monique T %A Walter, Jochen %A Mottaghy, Felix M %A Losen, Mario %A Martinez-Martinez, Pilar %X

Ceramide levels are increased in blood and brain tissue of Alzheimer's disease (AD) patients. Since the ceramide transporter protein (CERT) is the only known protein able to mediate non-vesicular transfer of ceramide between organelle membranes, the modulation of CERT function may impact on ceramide accumulation. The competitive CERT inhibitor N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide (HPA-12) interferes with ceramide trafficking. To understand the role of ceramide/CERT in AD, HPA-12 can be a useful tool to modulate ceramide trafficking. Here we first report the synthesis and in vitro properties of HPA-12 radiolabeled with fluorine-18 and present preliminary in vitro and in vivo positron emission tomography (PET) imaging and biodistribution data. In vitro results demonstrated that the fluorination did not alter the biological properties of HPA-12 since the [fluorine-19]HPA-12, interferes with 5-DMB-ceramide trafficking in HeLa cells. Radiolabeled HPA-12, [fluorine-18]HPA-12, was obtained with a radiochemical yield of 90% and a specific activity of 73 MBq/μmol. PET imaging on wild-type mice showed hepatobiliary clearance and a brain uptake on the order of 0.3 standard uptake value (SUV) one hour post injection. Furthermore, the biodistribution data showed that after removal of the blood by intracardial perfusion, radioactivity was still measurable in the brain demonstrating that the [fluorine-18]HPA-12 crosses the blood brain barrier and is retained in the brain.

%B J Alzheimers Dis %V 60 %P 783-794 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922150?dopt=Abstract %R 10.3233/JAD-161231 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tailored and Adaptive Computerized Cognitive Training in Older Adults at Risk for Dementia: A Randomized Controlled Trial. %A Bahar-Fuchs, Alex %A Webb, Shannon %A Bartsch, Lauren %A Clare, Linda %A Rebok, George %A Cherbuin, Nicolas %A Anstey, Kaarin J %X

BACKGROUND: Computerized Cognitive Training (CCT) has been shown to improve cognitive function in older adults with mild cognitive impairment (MCI) or mood-related neuropsychiatric symptoms (MrNPS), but many questions remain unresolved.

OBJECTIVE: To evaluate the extent to which CCT benefits older adults with both MCI and MrNPS, and its effects on meta-cognitive and non-cognitive outcomes, as well as establish whether adapting difficulty levels and tailoring to individuals' profile is superior to generic training.

METHODS: Older adults with MCI (n = 9), MrNPS (n = 11), or both (MCI+, n = 25) were randomized into a home-based individually-tailored and adaptive CCT (n = 21) or an active control condition (AC; n = 23) in a double-blind design. Interventions lasted 8-12 weeks and outcomes were assessed after the intervention, and at a 3-month follow-up.

RESULTS: Participants in both conditions reported greater satisfaction with their everyday memory following intervention and at follow-up. However, participants in the CCT condition showed greater improvement on composite measures of memory, learning, and global cognition at follow-up. Participants with MrNPS in the CCT condition were also found to have improved mood at 3-month follow-up and reported using fewer memory strategies at the post-intervention and follow-up assessments. There was no evidence that participants with MCI+ were disadvantaged relative to the other diagnostic conditions. Finally, informant-rated caregiver burden declined at follow-up assessment in the CCT condition relative to the AC condition.

CONCLUSIONS: Home-based CCT with adaptive difficulty and personal tailoring appears superior to more generic CCT in relation to both cognitive and non-cognitive outcomes. Mechanisms of treatment effect and future directions are discussed.

%B J Alzheimers Dis %V 60 %P 889-911 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28922158?dopt=Abstract %R 10.3233/JAD-170404 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tau Oligomers in Sera of Patients with Alzheimer's Disease and Aged Controls. %A Kolarova, Michala %A Sengupta, Urmi %A Bartos, Ales %A Ricny, Jan %A Kayed, Rakez %X

Although tau protein was long regarded as an intracellular protein with several functions inside the cell, new evidence has shown tau secretion into the extracellular space. The active secretion of tau could be a physiological response of neurons to increased intracellular amounts of tau during the progression of tau pathology. We looked for potential differences in the serum levels of toxic tau oligomers in regards to cognitive impairment of subjects. We detected tau oligomers in the serum of Alzheimer's disease (AD) patients, but they were also present to some extent in the serum of healthy older subjects where the levels positively correlated with aging (Spearman r = 0.26, p = 0.016). On the contrary, we found lower levels of tau oligomers in the serum of mild cognitive impairment (MCI) (p = 0.033) and MCI-AD (p = 0.006) patients. These results could suggest that clearance of extracellular tau proteins takes place, in part, in the periphery. In the case of MCI patients, the lower levels of tau oligomers could be the result of impaired clearance of tau protein from interstitium to blood and consequent accumulation of tau aggregates in the brain.

%B J Alzheimers Dis %V 58 %P 471-478 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453485?dopt=Abstract %R 10.3233/JAD-170048 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tau Platelets Correlate with Regional Brain Atrophy in Patients with Alzheimer's Disease. %A Slachevsky, Andrea %A Guzmán-Martínez, Leonardo %A Delgado, Carolina %A Reyes, Pablo %A Farías, Gonzalo A %A Muñoz-Neira, Carlos %A Bravo, Eduardo %A Farías, Mauricio %A Flores, Patricia %A Garrido, Cristian %A Becker, James T %A Lopez, Oscar L %A Maccioni, Ricardo B %X

BACKGROUND: Intracellular neurofibrillary tangles are part of the core pathology of Alzheimer's disease (AD), which are mainly composed of hyperphosphorylated tau protein.

OBJECTIVES: The purpose of this study is to determine whether high molecular weight (HMW) or low molecular weight (LMW) tau protein levels, as well as the ratio HMW/LMW, present in platelets correlates with brain magnetic resonance imaging (MRI) structural changes in normal and cognitively impaired subjects.

METHODS: We examined 53 AD patients and 37 cognitively normal subjects recruited from two Memory Clinics at the Universidad de Chile. Tau levels in platelets were determined by immunoreactivity and the MRI scans were analyzed using voxel-based morphometry in 41 AD patients.

RESULTS: The HMW/LMW tau ratio was statistically different between controls and AD patients, and no associations were noted between HMW or LMW tau and MRI structures. In a multivariate analysis controlled for age and education level, the HMW/LMW tau ratio was associated with reduced volume in the left medial and right anterior cingulate gyri, right cerebellum, right thalamus (pulvinar), left frontal cortex, and right parahippocampal region.

CONCLUSIONS: This exploratory study showed that HMW/LMW tau ratio is significantly higher in AD patients than control subjects, and that it is associated with specific brain regions atrophy. Determination of peripheral markers of AD pathology can help understanding the pathophysiology of neurodegeneration in AD.

%B J Alzheimers Dis %V 55 %P 1595-1603 %G eng %N 4 %R 10.3233/JAD-160652 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tau Proteins Cross the Blood-Brain Barrier. %A Banks, William A %A Kovac, Andrej %A Majerova, Petra %A Bullock, Kristin M %A Shi, Min %A Zhang, Jing %X

Tauopathies are a hallmark of many neurodegenerative diseases, including Alzheimer's disease and traumatic brain injuries. It has been demonstrated that amyloid-beta peptides, alpha-synuclein, and prion proteins cross the blood-brain barrier (BBB), contributing to their abilities to induce disease. Very little is known about whether tau proteins can cross the BBB. Here we systematically characterized several key forms of tau proteins to cross the BBB, including Tau-441 (2N4R), Tau-410 (2N3R), truncated tau 151-391 (0N4R), and truncated tau 121-227. All of these tau proteins crossed the BBB readily and bidirectonally; however, only Tau-410 had a saturable component to its influx. The tau proteins also entered the blood after their injection into the brain, with Tau 121-227 having the slowest exit from brain. The tau proteins varied in regards to their enzymatic stability in brain and blood and in their peripheral pharmacokinetics. These results show that blood-borne tau proteins could contribute to brain tauopathies. The result also suggest that the CNS can contribute to blood levels of tau, raising the possibility that, as suggested for other misfolded proteins, blood levels of tau proteins could be used as a biomarker of CNS disease.

%B J Alzheimers Dis %V 55 %P 411-419 %8 2016 Sep 20 %G eng %N 1 %R 10.3233/JAD-160542 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tau Rather than TDP-43 Proteins are Potential Cerebrospinal Fluid Biomarkers for Frontotemporal Lobar Degeneration Subtypes: A Pilot Study. %A Kuiperij, H Bea %A Versleijen, Alexandra A M %A Beenes, Marijke %A Verwey, Nicolaas A %A Benussi, Luisa %A Paterlini, Anna %A Binetti, Giuliano %A Teunissen, Charlotte E %A Raaphorst, Joost %A Schelhaas, Helenius J %A Küsters, Benno %A Pijnenburg, Yolande A L %A Ghidoni, Roberta %A Verbeek, Marcel M %X

BACKGROUND: Frontotemporal dementia (FTD) is a heterogeneous disease both at the clinical, genetic, and pathobiological level. The underlying pathological spectrum (termed FTLD, frontotemporal lobar degeneration) is in most cases defined by accumulation of either tau (FTLD-tau) or TDP-43 proteins (FTLD-TDP). Biomarkers to differentiate these subtypes are not yet available, whereas these are essential requirements to study the natural course of disease and for homogeneous inclusion of patients in clinical studies.

OBJECTIVE: To study if a combination of total (t-) and phosphorylated (p-)tau, and t-TDP-43 and p-TDP-43 proteins in cerebrospinal fluid (CSF) is suitable to discriminate FTLD-tau and FTLD-TDP subtypes.

METHODS: We developed immunoassays for the quantification of t-TDP-43 and p-TDP-43 proteins and used commercially available assays for the quantification of t-tau and p-tau proteins. We quantified these proteins in ventricular CSF samples from neuropathologically defined FTLD-tau and FTLD-TDP cases to study the reflection of underlying brain pathology in CSF composition, and in lumbar CSF samples from FTLD-tau and FTLD-TDP patients to study the diagnostic potential of CSF biomarkers.

RESULTS: In ventricular CSF, t-TDP-43 and t-tau levels, when combined into one model, were significantly different between neuropathologically-defined FTLD-tau and FTLD-TDP cases. In a pilot study using lumbar CSF, the p-tau/t-tau ratio, but not t-TDP-43 levels, were significantly different between FTLD-TDP and FTLD-tau patients.

CONCLUSION: We conclude that with current available methods, CSF tau, rather than TDP-43 proteins, may have diagnostic value in the differentiation of FTLD patients with either tau or TDP-43 pathology.

%B J Alzheimers Dis %V 55 %P 585-595 %G eng %N 2 %R 10.3233/JAD-160386 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Temporal Order of Alzheimer's Disease-Related Cognitive Marker Changes in BLSA and WRAP Longitudinal Studies. %A Bilgel, Murat %A Koscik, Rebecca L %A An, Yang %A Prince, Jerry L %A Resnick, Susan M %A Johnson, Sterling C %A Jedynak, Bruno M %X

Investigation of the temporal trajectories of currently used neuropsychological tests is critical to identifying earliest changing measures on the path to dementia due to Alzheimer's disease (AD). We used the Progression Score (PS) method to characterize the temporal trajectories of measures of verbal memory, executive function, attention, processing speed, language, and mental status using data spanning normal cognition, mild cognitive impairment, and AD from 1,661 participants with a total of 7,839 visits (age at last visit 77.6 SD 9.2) in the Baltimore Longitudinal Study of Aging (BLSA) and 1510 participants with a total of 3,473 visits (age at last visit 59.5 SD 7.4) in the Wisconsin Registry for Alzheimer's Prevention (WRAP). This method aligns individuals in time based on the similarity of their longitudinal measurements to reveal temporal trajectories. As a validation of our methodology, we explored the associations between the individualized cognitive progression scores (Cog-PS) computed by our method and clinical diagnosis. Digit span tests were the first to show declines in both data sets, and were detected mainly among cognitively normal individuals. These were followed by tests of verbal memory, which were in turn followed by Trail Making Tests, Boston Naming Test, and Mini-Mental State Examination. Differences in Cog-PS across the clinical diagnosis and APOEɛ4 groups were statistically significant, highlighting the potential use of Cog-PS as individualized indicators of disease progression. Identifying cognitive measures that are changing in preclinical AD can lead to the development of novel cognitive tests that are finely tuned to detecting earliest changes.

%B J Alzheimers Dis %V 59 %P 1335-1347 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731452?dopt=Abstract %R 10.3233/JAD-170448 %0 Journal Article %J J Alzheimers Dis %D 2017 %T TFP5, a Peptide Inhibitor of Aberrant and Hyperactive Cdk5/p25, Attenuates Pathological Phenotypes and Restores Synaptic Function in CK-p25Tg Mice. %A Shukla, Varsha %A Seo, Jinsoo %A Binukumar, B K %A Amin, Niranjana D %A Reddy, Preethi %A Grant, Philip %A Kuntz, Susan %A Kesavapany, Sashi %A Steiner, Joseph %A Mishra, Santosh K %A Tsai, Li-Huei %A Pant, Harish C %X

It has been reported that cyclin-dependent kinase 5 (cdk5), a critical neuronal kinase, is hyperactivated in Alzheimer's disease (AD) and may be, in part, responsible for the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs). It has been proposed by several laboratories that hyperactive cdk5 results from the overexpression of p25 (a truncated fragment of p35, the normal cdk5 regulator), which, when complexed to cdk5, induces hyperactivity, hyperphosphorylated tau/NFTs, amyloid-β plaques, and neuronal death. It has previously been shown that intraperitoneal (i.p.) injections of a modified truncated 24-aa peptide (TFP5), derived from the cdk5 activator p35, penetrated the blood-brain barrier and significantly rescued AD-like pathology in 5XFAD model mice. The principal pathology in the 5XFAD mutant, however, is extensive amyloid plaques; hence, as a proof of concept, we believe it is essential to demonstrate the peptide's efficacy in a mouse model expressing high levels of p25, such as the inducible CK-p25Tg model mouse that overexpresses p25 in CamKII positive neurons. Using a modified TFP5 treatment, here we show that peptide i.p. injections in these mice decrease cdk5 hyperactivity, tau, neurofilament-M/H hyperphosphorylation, and restore synaptic function and behavior (i.e., spatial working memory, motor deficit using Rota-rod). It is noteworthy that TFP5 does not inhibit endogenous cdk5/p35 activity, nor other cdks in vivo suggesting it might have no toxic side effects, and may serve as an excellent therapeutic candidate for neurodegenerative disorders expressing abnormally high brain levels of p25 and hyperactive cdk5.

%B J Alzheimers Dis %V 56 %P 335-349 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28085018?dopt=Abstract %R 10.3233/JAD-160916 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Theobromine-Induced Changes in A1 Purinergic Receptor Gene Expression and Distribution in a Rat Brain Alzheimer's Disease Model. %A Mendiola-Precoma, Jesus %A Padilla, Karla %A Rodríguez-Cruz, Alfredo %A Berumen, Laura C %A Miledi, Ricardo %A García-Alcocer, Guadalupe %X

Dementia caused by Alzheimer's disease (AD) is mainly characterized by accumulation in the brain of extra- and intraneuronal amyloid-β (Aβ) and tau proteins, respectively, which selectively affect specific regions, particularly the neocortex and the hippocampus. Sporadic AD is mainly caused by an increase in apolipoprotein E, a component of chylomicrons, which are cholesterol transporters in the brain. Recent studies have shown that high lipid levels, especially cholesterol, are linked to AD. Adenosine is an atypical neurotransmitter that regulates a wide range of physiological functions by activating four P1 receptors (A1, A2A, A2B, and A3) and P2 purinergic receptors that are G protein-coupled. A1 receptors are involved in the inhibition of neurotransmitter release, which could be related to AD. The aim of the present work was to study the effects of a lard-enriched diet (LED) on cognitive and memory processes in adult rats (6 months of age) as well as the effect of theobromine on these processes. The results indicated that the fat-enriched diet resulted in a long-term deterioration in cognitive and memory functions. Increased levels of Aβ protein and IL-1β were also observed in the rats fed with a high-cholesterol diet, which were used to validate the AD animal model. In addition, the results of qPCR and immunohistochemistry indicated a decrease in gene expression and distribution of A1 purinegic receptor, respectively, in the hippocampus of LED-fed rats. Interestingly, theobromine, at both concentrations tested, restored A1 receptor levels and improved cognitive functions and Aβ levels for a dose of 30 mg/L drinking water.

%B J Alzheimers Dis %V 55 %P 1273-1283 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27792010?dopt=Abstract %R 10.3233/JAD-160569 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Toward the Automation of Diagnostic Conversation Analysis in Patients with Memory Complaints. %A Mirheidari, Bahman %A Blackburn, Daniel %A Harkness, Kirsty %A Walker, Traci %A Venneri, Annalena %A Reuber, Markus %A Christensen, Heidi %X

BACKGROUND: The early diagnosis of dementia is of great clinical and social importance. A recent study using the qualitative methodology of conversation analysis (CA) demonstrated that language and communication problems are evident during interactions between patients and neurologists, and that interactional observations can be used to differentiate between cognitive difficulties due to neurodegenerative disorders (ND) or functional memory disorders (FMD).

OBJECTIVE: This study explores whether the differential diagnostic analysis of doctor-patient interactions in a memory clinic can be automated.

METHODS: Verbatim transcripts of conversations between neurologists and patients initially presenting with memory problems to a specialist clinic were produced manually (15 with FMD, and 15 with ND). A range of automatically detectable features focusing on acoustic, lexical, semantic, and visual information contained in the transcripts were defined aiming to replicate the diagnostic qualitative observations. The features were used to train a set of five machine learning classifiers to distinguish between ND and FMD.

RESULTS: The mean rate of correct classification between ND and FMD was 93% ranging from 97% by the Perceptron classifier to 90% by the Random Forest classifier.Using only the ten best features, the mean correct classification score increased to 95%.

CONCLUSION: This pilot study provides proof-of-principle that a machine learning approach to analyzing transcripts of interactions between neurologists and patients describing memory problems can distinguish people with neurodegenerative dementia from people with FMD.

%B J Alzheimers Dis %V 58 %P 373-387 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28436388?dopt=Abstract %R 10.3233/JAD-160507 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Translational MRI Volumetry with NeuroQuant: Effects of Version and Normative Data on Relationships with Memory Performance in Healthy Older Adults and Patients with Mild Cognitive Impairment. %A Stelmokas, Julija %A Yassay, Lance %A Giordani, Bruno %A Dodge, Hiroko H %A Dinov, Ivo D %A Bhaumik, Arijit %A Sathian, K %A Hampstead, Benjamin M %X

NeuroQuant (NQ) is a fully-automated program that overcomes several existing limitations in the clinical translation of MRI-derived volumetry. The current study characterized differences between the original (NQ1) and an updated NQ version (NQ2) by 1) replicating previously identified relationships between neuropsychological test performance and medial temporal lobe volumes, 2) evaluating the level of agreement between NQ versions, and 3) determining if the addition of NQ2 age-/sex-based z-scores hold greater clinical utility for prediction of memory impairment than standard percent of intracranial volume (% ICV) values. Sixty-seven healthy older adults and 65 mild cognitive impairment patients underwent structural MRI and completed cognitive testing, including the Immediate and Delayed Memory indices from the Repeatable Battery for the Assessment of Neuropsychological Status. Results generally replicated previous relationships between key medial temporal lobe regions and memory test performance, though comparison of NQ regions revealed statistically different values that were biased toward one version or the other depending on the region. NQ2 hippocampal z-scores explained additional variance in memory performance relative to % ICV values. Findings indicate that NQ1/2 medial temporal lobe volumes, especially age- and sex-based z-scores, hold clinical value, though caution is warranted when directly comparing volumes across NQ versions.

%B J Alzheimers Dis %V 60 %P 1499-1510 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29060939?dopt=Abstract %R 10.3233/JAD-170306 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Transport of Non-Transferrin Bound Iron to the Brain: Implications for Alzheimer's Disease. %A Tripathi, Ajai K %A Karmakar, Shilpita %A Asthana, Abhishek %A Ashok, Ajay %A Desai, Vilok %A Baksi, Shounak %A Singh, Neena %X

A direct correlation between brain iron and Alzheimer's disease (AD) raises questions regarding the transport of non-transferrin-bound iron (NTBI), a toxic but less researched pool of circulating iron that is likely to increase due to pathological and/or iatrogenic systemic iron overload. Here, we compared the distribution of radiolabeled-NTBI (59Fe-NTBI) and transferrin-bound iron (59Fe-Tf) in mouse models of iron overload in the absence or presence of inflammation. Following a short pulse, most of the 59Fe-NTBI was taken up by the liver, followed by the kidney, pancreas, and heart. Notably, a strong signal of 59Fe-NTBI was detected in the brain ventricular system after 2 h, and the brain parenchyma after 24 h. 59Fe-Tf accumulated mainly in the femur and spleen, and was transported to the brain at a much slower rate than 59Fe-NTBI. In the kidney, 59Fe-NTBI was detected in the cortex after 2 h, and outer medulla after 24 hours. Most of the 59Fe-NTBI and 59Fe-Tf from the kidney was reabsorbed; negligible amount was excreted in the urine. Acute inflammation increased the uptake of 59Fe-NTBI by the kidney and brain from 2-24 hours. Chronic inflammation, on the other hand, resulted in sequestration of iron in the liver and kidney, reducing its transport to the brain. These observations provide direct evidence for the transport of NTBI to the brain, and reveal a complex interplay between inflammation and brain iron homeostasis. Further studies are necessary to determine whether transient increase in NTBI due to systemic iron overload is a risk factor for AD.

%B J Alzheimers Dis %V 58 %P 1109-1119 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550259?dopt=Abstract %R 10.3233/JAD-170097 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Treadmill Exercise Exerts Neuroprotection and Regulates Microglial Polarization and Oxidative Stress in a Streptozotocin-Induced Rat Model of Sporadic Alzheimer's Disease. %A Lu, Yujiao %A Dong, Yan %A Tucker, Donovan %A Wang, Ruimin %A Ahmed, Mohammad Ejaz %A Brann, Darrell %A Zhang, Quanguang %X

Recent work has suggested that exercise may be beneficial in preventing or ameliorating symptoms of several neurological disorders, although the mechanism is not entirely understood. The current study was designed to examine the potential beneficial effect of treadmill exercise upon cognitive function in a streptozotocin (STZ)-induced rat model of Alzheimer's disease (AD). Animals underwent treadmill exercise (30 min/day, 5 days/week) for 4 weeks after bilateral STZ intracerebroventricular injection (2.4 mg/kg). We demonstrated that treadmill exercise significantly attenuated STZ-induced neurodegeneration in the rat hippocampal CA1 region and strongly preserved hippocampal-dependent cognitive functioning. Further mechanistic investigation displayed a marked suppression of STZ-induced amyloid-β accumulation and tau phosphorylation. Intriguingly, treadmill exercise remarkably inhibited reactive gliosis following STZ insult and effectively shifted activated microglia from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype, which was correlated with a significantly reduced expression of pro-inflammatory mediators and a corresponding enhancement of anti-inflammatory cytokine expression in the hippocampus. Furthermore, treadmill exercise caused a robust suppression of oxidative damage as evidenced by significantly reduced peroxynitrite production, lipid peroxidation, and oxidized DNA damage. Finally, treadmill exercise strongly attenuated STZ-induced mitochondrial dysfunction manifested by a dramatically elevated intra-mitochondrial cytochrome c oxidase activity and ATP synthesis, and markedly inhibited neuronal apoptosis in the hippocampus. These findings demonstrate that treadmill exercise has a multifactorial effect to attenuate many of the pathological processes that play a key role in AD, and provide further support for the beneficial role of exercise as a potential therapeutic option in AD treatment.

%B J Alzheimers Dis %V 56 %P 1469-1484 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157094?dopt=Abstract %R 10.3233/JAD-160869 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Trends, Predictors, and Outcomes of Healthcare Resources Used in Patients Hospitalized with Alzheimer's Disease with at Least One Procedure: The Nationwide Inpatient Sample. %A Beydoun, May A %A Gamaldo, Alyssa A %A Beydoun, Hind A %A Shaked, Danielle %A Zonderman, Alan B %A Eid, Shaker M %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Female %K Health Resources %K Hospitalization %K Humans %K Inpatients %K Length of Stay %K Male %K Middle Aged %K Morbidity %K Outcome Assessment (Health Care) %K Predictive Value of Tests %K United States %X

We assessed trends, predictors and outcomes of resource utilization in hospital inpatient discharges with a principal diagnosis of Alzheimer's disease (AD) with at least one procedure. Using Nationwide Inpatient Sample data (NIS, 2002-2012), discharges primarily diagnosed with AD, aged ≥60 y and with ≥1 procedure, were selected (Weighted N = 92,300). Hospital resource utilization were assessed using ICD-9-CM codes, while hospitalization outcomes included total charges (TC, 2012$), length of stay (LOS, days), and mortality risk (MR, %). Brain and respiratory/gastrointestinal procedure utilization both dropped annually by 3-7%, while cardiovascular procedures/evaluations, blood evaluations, blood transfusion, and resuscitation ("CVD/Blood") as well as neurophysiological and psychological evaluation and treatment ("Neuro") procedures increased by 5-8%. Total charges, length of stay, and mortality risk were all markedly higher with use of respiratory/gastrointestinal procedures as opposed to being reduced with use of "Brain" procedures. Procedure count was positively associated with all three hospitalization outcomes. In sum, patterns of hospital resources that were used among AD inpatients changed over-time, and were associated with hospitalization outcomes such as total charges, length of stay, and mortality risk.

%B J Alzheimers Dis %V 57 %P 813-824 %8 2017 %G eng %N 3 %R 10.3233/JAD-161225 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Upregulated Expression of Heparanase and Heparanase 2 in the Brains of Alzheimer's Disease. %A Garcia, Beatriz %A Martin, Carla %A Garcia-Suarez, Olivia %A Muniz-Alonso, Barbara %A Ordiales, Helena %A Fernandez-Menendez, Santiago %A Santos-Juanes, Jorge %A Lorente-Gea, Laura %A Castanon, Sonia %A Vicente-Etxenausia, Ikerne %A Pina Batista, Kelvin Manuel %A Ruiz-Diaz, Irune %A Caballero-Martinez, Maria Cristina %A Merayo-Lloves, Jesus %A Guerra-Merino, Isabel %A Quiros, Luis M %A Fernandez-Vega, Ivan %X

BACKGROUND: Heparan sulfate proteoglycans (HSPGs) promote amyloid-β peptide and tau fibrillization in Alzheimer's disease (AD) and provide resistance against proteolytic breakdown. Heparanase (HPSE) is the only enzyme that cleaves heparan sulfate (HS). Heparanase 2 (HPSE2) lacks HS-degrading activity, although it is able to interact with HS with high affinity.

OBJECTIVE: To analyze HPSE and HPSE2 expressions at different stages of AD.

METHODS: RT-PCR was used to analyze transcription levels of both heparanases at different stages of AD, and immunohistochemistry was performed to localize each one in different parts of the brain.

RESULTS: Both proteins appeared overexpressed at different stages of AD. Immunohistochemistry indicated that the presence of the heparanases was related to AD pathology, with intracellular deposits found in degenerated neurons. At the extracellular level, HPSE was observed only in neuritic plaques with a fragmented core, while HPSE2 appeared in those with compact cores as well.

CONCLUSION: Given the involvement of HSPGs in AD pathology, there would seem to be a relationship between the regulation of heparanase expression, the features of the disease, and a possible therapeutic alternative.

%B J Alzheimers Dis %V 58 %P 185-192 %8 2017 %G eng %N 1 %R 10.3233/JAD-161298 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Validation by Magnetic Resonance Imaging of the Diagnostic Potential of a Heptapeptide-Functionalized Imaging Probe Targeted to Amyloid-β and Able to Cross the Blood-Brain Barrier. %A André, Séverine %A Ansciaux, Emilie %A Saidi, Elamine %A Larbanoix, Lionel %A Stanicki, Dimitri %A Nonclercq, Denis %A Vander Elst, Luce %A Laurent, Sophie %A Muller, Robert N %A Burtea, Carmen %X

The diagnosis of Alzheimer's disease (AD) is a critical step in the management of patients. We have developed a non-invasive diagnosis tool based on magnetic resonance molecular imaging (MRMI) of amyloid-β peptide using ultra-small particles of iron oxide (USPIO) functionalized with a disulfide constrained cyclic heptapeptide (PHO) identified by phage display (USPIO-PHO). After previously demonstrating the optimal pharmacologic properties of USPIO-PHO and its capacity to cross the blood-brain barrier (BBB), the ability of USPIO-PHO to target amyloid plaques (AP) by MRMI has been validated in the present work on AD transgenic mice. The immunohistochemistry and immunofluorescent detection of USPIO-PHO on brain sections collected after in vivo MRMI studies enabled its colocalization with AP, confirming the BBB passage and specific targeting. The AP targeting by USPIO-PHO has been moreover corroborated by the good correlation between the number of AP detected with anti-amyloid β antibody and Perls'-DAB staining. Finally, the crossing mechanism of USPIO-PHO through the BBB was elucidated, revealing the involvement of non-degradation pathway of caveolae, while the control contrast agent USPIO-PEG was not endocytosed by the human brain endothelial cells.

%B J Alzheimers Dis %V 60 %P 1547-1565 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036827?dopt=Abstract %R 10.3233/JAD-170563 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Validity of a Newly Developed Measure of Memory: Feasibility Study of the Virtual Environment Grocery Store. %A Parsons, Thomas D %A Barnett, Michael %X

Virtual reality-based neuropsychological assessments proffer the potential to address the limited ecological validity of pen-and-paper measures of memory. To investigate the construct validity of a newly developed virtual reality measure of memory, the Virtual Environment Grocery Store (VEGS), traditional neuropsychological measures of memory and executive functioning were administered to 48 older adults and 55 young adults. Performances on the VEGS memory tasks and the traditional neuropsychological assessments of memory were positively correlated, indicating that memory for VEGS content was similar to memory for traditional paper-and-pencil measures. The older adults performed significantly worse than young adults on the VEGS and the California Verbal Learning Test, but the DKEFS Color-Word Interference failed to differentiate the groups. Furthermore, significant differences were found between groups for the VEGS memory and multitasking measures. The VEGS has the advantage over traditional measures of providing objective measurement of individual components of memory in simulations of everyday activities.

%B J Alzheimers Dis %V 59 %P 1227-1235 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28759971?dopt=Abstract %R 10.3233/JAD-170295 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Varying Degrees of Temporoparietal Hypometabolism on FDG-PET Reveal Amyloid-Positive Logopenic Primary Progressive Aphasia is not a Homogeneous Clinical Entity. %A Krishnan, Kamini %A Machulda, Mary M %A Whitwell, Jennifer L %A Butts, Alissa M %A Duffy, Joseph R %A Strand, Edythe A %A Senjem, Matthew L %A Spychalla, Anthony J %A Jack, Clifford R %A Lowe, Val J %A Josephs, Keith A %X

BACKGROUND: The logopenic variant of primary progressive aphasia (lvPPA) manifests due to a breakdown of the language network with prominent hypometabolism of the left temporoparietal region. LvPPA is strongly associated with amyloid deposition, yet there is question as to whether it is a homogeneous clinical entity.

OBJECTIVE: This study investigated whether differences in temporoparietal metabolic patterns on 18F fludeoxyglucose positron emission tomography (FDG-PET) could elucidate brain regions preferentially affected in lvPPA.

METHOD: We used differences in FDG-PET metabolic z-scores relative to controls for means of left lateral temporal, left inferior parietal, and left superior parietal regions to classify 53 amyloid-positive lvPPA patients into temporal, parietal, or temporoparietal predominate groups. Clinical features and FDG-PET regions of hypometabolism outside of the temporoparietal region were then compared across the three groups; the latter using statistical parametric mapping.

RESULTS: Of the 53 lvPPA patients, 15 were classified as temporal, 14 as temporoparietal, and 22 as parietal predominate. There were no significant differences between the groups on demographic measures, language evaluation, or apolipoprotein E genotype. Compared to the other two groups, individuals with the parietal predominate pattern had extensive hypometabolism in left frontal lobe and the precuneus. Furthermore, this group had greater behavioral dyscontrol and deficits in executive function, visuospatial skills, visual memory retention, working memory, and cognitive flexibility (Bonferronip < 0.05).

CONCLUSIONS: This study demonstrates that there is clinical heterogeneity within amyloid-positive lvPPA. Patients with lvPPA with predominant parietal hypometabolism, unlike those with temporal or temporoparietal predominant hypometabolism, demonstrated widespread cognitive and behavioral changes.

%B J Alzheimers Dis %V 55 %P 1019-1029 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802232?dopt=Abstract %R 10.3233/JAD-160614 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Visual Rating of Posterior Atrophy as a Marker of Progression to Dementia in Mild Cognitive Impairment Patients. %A Kim, Hang-Rai %A Park, Young Ho %A Jang, Jae-Won %A Park, So Young %A Wang, Min Jeong %A Baek, Min Jae %A Kim, Beom Joon %A Ahn, Soyeon %A Kim, SangYun %X

BACKGROUND: Although medial temporal atrophy (MTA) is a useful imaging marker of the progression to dementia in mild cognitive impairment (MCI), substantial numbers of MCI patients without MTA still progress to dementia.

OBJECTIVE: We investigated whether visual ratings of posterior atrophy (PA) on magnetic resonance imaging show independent predictive value for the progression to dementia in MCI patients.

METHODS: This was a retrospective cohort study of elderly patients who visited Seoul National University Bundang Hospital between 2004 and 2012. A total of 148 patients who were initially diagnosed with MCI were followed for up to 3 years (median 22 months) to determine whether they progressed to dementia. We used 4-point and 5-point visual rating scales to assess PA and MTA, respectively. PA and MTA scores were dichotomized into normal (no atrophy) or abnormal (atrophy) in each patient. We performed a Cox regression analysis to examine the hazard ratios (HRs) of PA and MTA for the progression to dementia with adjustment for age, APOEɛ4 allele status, and baseline Mini-Mental State Examination score.

RESULTS: Among the study population, 47 patients progressed to dementia. Visual assessment of the MRI scans revealed that 67 patients (45.3%) showed PA, whereas 85 patients (57.3%) showed MTA. The HRs with 95% confidence intervals for PA and MTA were 2.516 (1.244-5.091) and 4.238 (1.680-10.687), respectively. The predictive values of visually assessed PA and MTA remained significant, independent of the covariates.

CONCLUSION: Visual assessment of PA has independent predictive value for progression to dementia in MCI patients.

%B J Alzheimers Dis %V 55 %P 137-146 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636842?dopt=Abstract %R 10.3233/JAD-160339 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Visuospatial Functioning in Cerebral Amyloid Angiopathy: A Pilot Study. %A Valenti, Raffaella %A Charidimou, Andreas %A Xiong, Li %A Boulouis, Gregoire %A Fotiadis, Panagiotis %A Ayres, Alison %A Riley, Grace %A Kuijf, Hugo J %A Reijmer, Yael D %A Pantoni, Leonardo %A Gurol, M Edip %A Davidsdottir, Sigurros %A Greenberg, Steven M %A Viswanathan, Anand %X

Cerebral amyloid angiopathy (CAA) is a contributor to cognitive impairment in the elderly. We hypothesized that the posterior cortical predilection of CAA would cause visual-processing impairment. We systematically evaluated visuospatial abilities in 22 non-demented CAA patients. Neurocognitive evaluation demonstrated visuoperceptual impairment (23% on Benton Facial Recognition Test [BFRT] and 13.6% on Benton Judgment of Line Orientation Test [BJLO]). BFRT was inversely correlated with white matter hyperintensities volume and BJLO with parietal cerebral microbleeds. This pilot study highlights the presence of visual-processing deficits in CAA. The impairment could be related to global disease severity in addition to local brain injury.

%B J Alzheimers Dis %V 56 %P 1223-1227 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222510?dopt=Abstract %R 10.3233/JAD-160927 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Vitamin D Insufficiency and Cognitive Function Trajectories in Older Adults: The Rancho Bernardo Study. %A Laughlin, Gail A %A Kritz-Silverstein, Donna %A Bergstrom, Jaclyn %A Reas, Emilie T %A Jassal, Simerjot K %A Barrett-Connor, Elizabeth %A McEvoy, Linda K %X

BACKGROUND: Evidence of a role for vitamin D (VitD) in cognitive aging is mixed and based primarily on extreme VitD deficiency. We evaluated the association of VitD insufficiency with cognitive function in older, community-dwelling adults living in a temperate climate with year-round sunshine.

METHODS: A population-based longitudinal study of 1,058 adults (median age 75; 62% women) who had cognitive function assessed and serum levels of 25-hydroxyvitaminD (25OHD) measured in 1997-99 and were followed for up to three additional cognitive function assessments over a 12-year period.

RESULTS: Overall, 14% (n = 145) of participants had VitD insufficiency defined as 25OHD <30 ng/ml. Adjusting for age, sex, education, and season, VitD insufficiency was associated with poorer baseline performance on the Mini-Mental Status Exam (MMSE) (p = 0.013), Trails Making Test B (Trails B) (p = 0.015), Category Fluency (p = 0.006), and Long Term Retrieval (p = 0.019); differences were equivalent to 5 years of age. For those with VitD insufficiency, the odds of mildly impaired performance at baseline were 38% higher for MMSE (p = 0.08), 78% higher for Trails B (p = 0.017), and 2-fold higher for Category Fluency and Long Term Retrieval (both p = 0.001). VitD insufficiency was not related to the rate of cognitive decline on any test or the risk of developing impaired performance during follow-up.

CONCLUSION: In this population with little VitD deficiency, even moderately low VitD was associated with poorer performance on multiple domains of cognitive function. Low VitD did not predict 12-year cognitive decline. Clinical trials are essential to establish a causal link between VitD and cognitive well-being.

%B J Alzheimers Dis %V 58 %P 871-883 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28505973?dopt=Abstract %R 10.3233/JAD-161295 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Voluptuary Habits and Risk of Frontotemporal Dementia: A Case Control Retrospective Study. %A Tremolizzo, Lucio %A Bianchi, Elisa %A Susani, Emanuela %A Pupillo, Elisabetta %A Messina, Paolo %A Aliprandi, Angelo %A Salmaggi, Andrea %A Cosseddu, Maura %A Pilotto, Andrea %A Borroni, Barbara %A Padovani, Alessandro %A Bonomini, Cristina %A Zanetti, Orazio %A Appollonio, Ildebrando %A Beghi, Ettore %A Ferrarese, Carlo %X

Alcohol, coffee, and tobacco consumption was assessed on 151 FTD outpatients and 151 matched controls in a multicenter retrospective case-control design. No association was found for smoking and coffee intake. The risk of FTD was decreased by alcohol consumption (adj. OR 0.30, 95% CI 0.14-0.63); risk reduction was significant in current alcohol consumers (adj. OR 0.22, 95% CI 0.10-0.51). The risk of FTD inversely correlated with the duration of exposure (adj. OR 0.88, 95% CI 0.81-0.95, for every 5 years of exposure increase). Retrospective information and the unknown amount of consumed alcohol are limits of the present work.

%B J Alzheimers Dis %V 60 %P 335-340 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28946566?dopt=Abstract %R 10.3233/JAD-170260 %0 Journal Article %J J Alzheimers Dis %D 2017 %T What Drives Country Differences in Cost of Alzheimer's Disease? An Explanation from Resource Use in the GERAS Study. %A Reed, Catherine %A Happich, Michael %A Argimon, Josep Maria %A Haro, Josep Maria %A Wimo, Anders %A Bruno, Giuseppe %A Dodel, Richard %A Jones, Roy W %A Vellas, Bruno %A Belger, Mark %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Caregivers %K Cohort Studies %K Cost of Illness %K Europe %K Female %K Health Resources %K Humans %K International Cooperation %K Male %K Surveys and Questionnaires %X

BACKGROUND: Country differences in resource use and costs of Alzheimer's disease (AD) may be driven by differences in health care systems and resource availability.

OBJECTIVE: To compare country resource utilization drivers of societal costs for AD dementia over 18 months.

METHODS: GERAS is an observational study in France (n = 419), Germany (n = 550), and the UK (n = 526). Resource use of AD patients and caregivers contributing to >1% of total societal costs (year 2010) was assessed for country differences, adjusting for participant characteristics.

RESULTS: Mean 18-month societal costs per patient were France €33,339, Germany €38,197, and UK €37,899 (£32,501). Caregiver time spent on basic and instrumental activities of daily living (ADL) contributed the most to societal costs (54% France, 64% Germany, 65% UK). Caregivers in France spent less time on ADL than UK caregivers and missed fewer work days than in other countries. Compared with other countries, patients in France used more community care services overall and were more likely to use home aid. Patients in Germany were least likely to use temporary accommodation or to be institutionalized at 18 months. UK caregivers spent the most time on instrumental ADL, UK patients used fewest outpatient resources, and UK patients/caregivers were most likely to receive financial support.

CONCLUSION: Caregiver time on ADL contributed the most to societal costs and differed across countries, possibly due to use of community care services and institutionalization. Other resources had different patterns of use across countries, reflecting country-specific health and social care systems.

%B J Alzheimers Dis %V 57 %P 797-812 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304285?dopt=Abstract %R 10.3233/JAD-160449 %0 Journal Article %J J Alzheimers Dis %D 2017 %T White Matter Hyperintensities Potentiate Hippocampal Volume Reduction in Non-Demented Older Individuals with Abnormal Amyloid-β. %A Freeze, Whitney M %A Jacobs, Heidi I L %A Gronenschild, Ed H %A Jansen, Jacobus F A %A Burgmans, Saartje %A Aalten, Pauline %A Clerx, Lies %A Vos, Stephanie J %A van Buchem, Mark A %A Barkhof, Frederik %A van der Flier, Wiesje M %A Verbeek, Marcel M %A Rikkert, Marcel Olde %A Backes, Walter H %A Verhey, Frans R %X

Cerebral small vessel disease (cSVD) and amyloid-β (Aβ) deposition often co-exist in (prodromal) dementia, and both types of pathology have been associated with neurodegeneration. We examined whether cSVD and Aβ have independent or interactive effects on hippocampal volume (HV) in a memory clinic population. We included 87 individuals with clinical diagnoses of Alzheimer's disease (AD) (n = 24), mild cognitive impairment (MCI) (n = 26), and subjective cognitive complaints (SCC) (n = 37). cSVD magnetic resonance imaging markers included white matter hyperintensity (WMH) volume, lacunar infarct presence, and microbleed presence. Aβ pathology was assessed as cerebrospinal fluid-derived Aβ1 - 42 levels and dichotomized into normal or abnormal, and HV was determined by manual volumetric measurements. A linear hierarchical regression approach was applied for the detection of additive or interaction effects between cSVD and Aβ on HV in the total participant group (n = 87) and in the non-demented group (including SCC and MCI individuals only, n = 63). The results revealed that abnormal Aβ and lacunar infarct presence were independently associated with lower HV in the non-demented individuals. Interestingly, Aβ and WMH pathology interacted in the non-demented individuals, such that WMH had a negative effect on HV in individuals with abnormal CSF Aβ42 levels, but not in individuals with normal CSF Aβ42 levels. These associations were not present when individuals with AD were included in the analyses. Our observations suggest that relatively early on in the disease process older individuals with abnormal Aβ levels are at an increased risk of accelerated disease progression when concomitant cSVD is present.

%B J Alzheimers Dis %V 55 %P 333-342 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662299?dopt=Abstract %R 10.3233/JAD-160474 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Young to Middle-Aged Dogs with High Amyloid-β Levels in Cerebrospinal Fluid are Impaired on Learning in Standard Cognition tests. %A Borghys, Herman %A Van Broeck, Bianca %A Dhuyvetter, Deborah %A Jacobs, Tom %A de Waepenaert, Katja %A Erkens, Tim %A Brooks, Melissa %A Thevarkunnel, Sandy %A Araujo, Joseph A %X

Understanding differences in Alzheimer's disease biomarkers before the pathology becomes evident can contribute to an improved understanding of disease pathogenesis and treatment. A decrease in amyloid-β (Aβ)42 in cerebrospinal fluid (CSF) is suggested to be a biomarker for Aβ deposition in brain. However, the relevance of CSF Aβ levels prior to deposition is not entirely known. Dogs are similar to man with respect to amyloid-β protein precursor (AβPP)-processing, age-related amyloid plaque deposition, and cognitive dysfunction. In the current study, we evaluated the relation between CSF Aβ42 levels and cognitive performance in young to middle-aged dogs (1.5-7 years old). Additionally, CSF sAβPPα and sAβPPβ were measured to evaluate AβPP processing, and CSF cytokines were measured to determine the immune status of the brain. We identified two groups of dogs showing consistently low or high CSF Aβ42 levels. Based on prior studies, it was assumed that at this age no cerebral amyloid plaques were likely to be present. The cognitive performance was evaluated in standard cognition tests. Low or high Aβ concentrations coincided with low or high sAβPPα, sAβPPβ, and CXCL-1 levels, respectively. Dogs with high Aβ concentrations showed significant learning impairments on delayed non-match to position (DNMP), object discrimination, and reversal learning compared to dogs with low Aβ concentrations. Our data support the hypothesis that high levels of CSF Aβ in dogs coincide with lower cognitive performance prior to amyloid deposition. Further experiments are needed to investigate this link, as well as the relevance with respect to Alzheimer's disease pathology progression.

%B J Alzheimers Dis %V 56 %P 763-774 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035921?dopt=Abstract %R 10.3233/JAD-160434 %0 Journal Article %J J Alzheimers Dis %D 2016 %T ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies. %A Boehm-Cagan, Anat %A Bar, Roni %A Liraz, Ori %A Bielicki, John K %A Johansson, Jan O %A Michaelson, Daniel M %X

The allele ɛ4 of apolipoprotein E (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD) and is therefore a promising therapeutic target. Human and animal model studies suggest that apoE4 is hypolipidated; accordingly, we have previously shown that the retinoid X receptor (RXR) agonist bexarotene upregulates ABCA1, the main apoE-lipidating protein, resulting in increased lipidation of apoE4, and the subsequent reversal of the pathological effects of apoE4, namely: accumulation of Aβ42 and hyperphosphorylated tau, as well as reduction in the levels of synaptic markers and cognitive deficits. Since the RXR system has numerous other targets, it is important to devise the means of activating ABCA1 selectively. We presently utilized CS-6253, a peptide shown to directly activate ABCA1 in vitro, and examined the extent to which it can affect the degree of lipidation of apoE4 in vivo and counteract the associated brain and behavioral pathologies. This revealed that treatment of young apoE4-targeted replacement mice with CS-6253 increases the lipidation of apoE4. This was associated with a reversal of the apoE4-driven Aβ42 accumulation and tau hyperphosphorylation in hippocampal neurons, as well as of the synaptic impairments and cognitive deficits. These findings suggest that the pathological effects of apoE4 in vivo are associated with decreased activation of ABCA1 and impaired lipidation of apoE4 and that the downstream brain-related pathology and cognitive deficits can be counteracted by treatment with the ABCA1 agonist CS-6253. These findings have important clinical ramifications and put forward ABCA1 as a promising target for apoE4-related treatment of AD.

%B J Alzheimers Dis %V 54 %P 1219-1233 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567858?dopt=Abstract %R 10.3233/JAD-160467 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Accurate Prediction of Conversion to Alzheimer's Disease using Imaging, Genetic, and Neuropsychological Biomarkers. %A Dukart, Juergen %A Sambataro, Fabio %A Bertolino, Alessandro %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoproteins E %K Area Under Curve %K Brain %K Cognitive Dysfunction %K Disease Progression %K Female %K Fluorodeoxyglucose F18 %K Follow-Up Studies %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %K Prognosis %K Radiopharmaceuticals %K ROC Curve %K Sensitivity and Specificity %X

A variety of imaging, neuropsychological, and genetic biomarkers have been suggested as potential biomarkers for the identification of mild cognitive impairment (MCI) in patients who later develop Alzheimer's disease (AD). Here, we systematically evaluated the most promising combinations of these biomarkers regarding discrimination between stable and converter MCI and reflection of disease staging. Alzheimer's Disease Neuroimaging Initiative data of AD (n = 144), controls (n = 112), stable (n = 265) and converter (n = 177) MCI, for which apolipoprotein E status, neuropsychological evaluation, and structural, glucose, and amyloid imaging were available, were included in this study. Naïve Bayes classifiers were built on AD and controls data for all possible combinations of these biomarkers, with and without stratification by amyloid status. All classifiers were then applied to the MCI cohorts. We obtained an accuracy of 76% for discrimination between converter and stable MCI with glucose positron emission tomography as a single biomarker. This accuracy increased to about 87% when including further imaging modalities and genetic information. We also identified several biomarker combinations as strong predictors of time to conversion. Use of amyloid validated training data resulted in increased sensitivities and decreased specificities for differentiation between stable and converter MCI when amyloid was included as a biomarker but not for other classifier combinations. Our results indicate that fully independent classifiers built only on AD and controls data and combining imaging, genetic, and/or neuropsychological biomarkers can more reliably discriminate between stable and converter MCI than single modality classifiers. Several biomarker combinations are identified as strongly predictive for the time to conversion to AD.

%B J Alzheimers Dis %V 49 %P 1143-59 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599054?dopt=Abstract %R 10.3233/JAD-150570 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Activation of p53 in Down Syndrome and in the Ts65Dn Mouse Brain is Associated with a Pro-Apoptotic Phenotype. %A Tramutola, Antonella %A Pupo, Gilda %A Di Domenico, Fabio %A Barone, Eugenio %A Arena, Andrea %A Lanzillotta, Chiara %A Broekaart, Diede %A Blarzino, Carla %A Head, Elizabeth %A Butterfield, D Allan %A Perluigi, Marzia %K Acetylation %K Alzheimer Disease %K Animals %K Apoptosis %K Blotting, Western %K Disease Models, Animal %K Down Syndrome %K Female %K Frontal Lobe %K Humans %K Immunoprecipitation %K Male %K Mice, Inbred C3H %K Mice, Inbred C57BL %K Mice, Transgenic %K Middle Aged %K Phenotype %K Phosphorylation %K Tumor Suppressor Protein p53 %K Young Adult %X

Down syndrome (DS) is the most common genetic cause of intellectual disability, resulting from trisomy of chromosome 21. The main feature of DS neuropathology includes early onset of Alzheimer's disease (AD), with deposition of senile plaques and tangles. We hypothesized that apoptosis may be activated in the presence of AD neuropathology in DS, thus we measured proteins associated with upstream and downstream pathways of p53 in the frontal cortex from DS cases with and without AD pathology and from Ts65Dn mice, at different ages. We observed increased acetylation and phosphorylation of p53, coupled to reduced MDM2/p53 complex level and lower levels of SIRT1. Activation of p53 was associated with a number of targets (BAX, PARP1, caspase-3, p21, heat shock proteins, and PGC1α) that were modulated in both DS and DS/AD compared with age-matched controls. In particular, the most relevant changes (increased p-p53 and acetyl-p53 and reduced formation of MDM2/p53 complex) were found to be modified only in the presence of AD pathology in DS. In addition, a similar pattern of alterations in the p53 pathway was found in Ts65Dn mice. These results suggest that p53 may integrate different signals, which can result in a pro-apoptotic-phenotype contributing to AD neuropathology in people with DS.

%B J Alzheimers Dis %V 52 %P 359-71 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967221?dopt=Abstract %R 10.3233/JAD-151105 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory Clinic Patients in a Prospective Cohort. %A Handels, Ron L H %A Joore, Manuela A %A Vos, Stephanie J B %A Aalten, Pauline %A Ramakers, Inez H G B %A Rikkert, Marcel Olde %A Scheltens, Philip %A Jansen, Willemijn J %A Visser, Pieter-Jelle %A van Berckel, Bart M N %A van Domburg, Peter %A Smid, Machiel %A Hoff, Erik %A Hoogmoed, Jan %A Bouwman, Femke %A Claassen, Jurgen %A Leentjens, Albert F G %A Wolfs, Claire A G %A Severens, Johan L %A Verhey, Frans R J %X

BACKGROUND: Limited information is available on short-term prognosis of Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF) in addition to routine diagnostic workup.

OBJECTIVE: This study aims to investigate the added prognostic value of AD CSF biomarkers.

METHODS: In a prospective cohort study, clinical experts predicted cognitive and functional symptoms in 114 memory clinic patients by assessing comprehensive routine diagnostic test information (patient history, and physical, neurological, psychiatric, neuropsychological, and MRI examinations), without and with CSF biomarkers. The reference standard was the 'observed clinically relevant decline' using baseline and 1- and 2-year follow-up information.

RESULTS: Decline over a 2-year period was observed in 51% of all participants (3% in SMC, 48% in MCI, 90% in mild dementia). In the total sample, the accuracy of predicted decline did not differ significantly between routine assessment without (79% correctly predicted) and with (74% correctly predicted) CSF biomarkers. Subgroup analyses revealed 25 (83%) correct predictions in SMC, 30 (68%) in MCI, and 35 (88%) in dementia without the use of CSF; and 21 (70%), 27 (61%), and 36 (90%), respectively, with the use of CSF in addition to the routine assessment.

CONCLUSION: AD CSF biomarkers did not increase accuracy of 2-year prognosis of cognitive and functional decline when added to routine diagnostic workup. This suggests that the standard diagnostic workup without CSF biomarkers allows fairly accurate predictions for the short-term course of symptoms. Routine AD biomarkers in CSF have limited prognostic value over 2 years in persons with a suspected cognitive disorder.

%B J Alzheimers Dis %V 52 %P 875-85 %8 2016 Mar 31 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031483?dopt=Abstract %R 10.3233/JAD-151120 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Age-Dependent Regulation of the Blood-Brain Barrier Influx/Efflux Equilibrium of Amyloid-β Peptide in a Mouse Model of Alzheimer's Disease (3xTg-AD). %A Do, Tuan Minh %A Dodacki, Agnès %A Alata, Wael %A Calon, Frederic %A Nicolic, Sophie %A Scherrmann, Jean-Michel %A Farinotti, Robert %A Bourasset, Fanchon %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K ATP Binding Cassette Transporter, Sub-Family G, Member 1 %K ATP Binding Cassette Transporter, Sub-Family G, Member 2 %K ATP-Binding Cassette Transporters %K Biological Transport %K Blood-Brain Barrier %K Brain %K Carbon Isotopes %K Cholesterol %K Disease Models, Animal %K Humans %K Lipoproteins %K Mice %K Mice, Transgenic %K P-Glycoproteins %K Peptide Fragments %K Receptors, LDL %K Sucrose %K Tritium %K Tumor Suppressor Proteins %X

The involvement of transporters located at the blood-brain barrier (BBB) has been suggested in the control of cerebral Aβ levels, and thereby in Alzheimer's disease (AD). However, little is known about the regulation of these transporters at the BBB in animal models of AD. In this study, we investigated the BBB expression of Aβ influx (Rage) and efflux (Abcb1-Abcg2-Abcg4-Lrp-1) transporters and cholesterol transporter (Abca1) in 3-18-month-old 3xTg-AD and control mice. The age-dependent effect of BBB transporters regulation on the brain uptake clearance (Clup) of [3H]cholesterol and [3H]Aβ1 - 40 was then evaluated in these mice, using the in situ brain perfusion technique. Our data suggest that transgenes expression led to the BBB increase in Aβ influx receptor (Rage) and decrease in efflux receptor (Lrp-1). Our data also indicate that mice have mechanisms counteracting this increased net influx. Indeed, Abcg4 and Abca1 are up regulated in 3- and 3/6-month-old 3xTg-AD mice, respectively. Our data show that the balance between the BBB influx and efflux of Aβ is maintained in 3 and 6-month-old 3xTg-AD mice, suggesting that Abcg4 and Abca1 control the efflux of Aβ through the BBB by a direct (Abcg4) or indirect (Abca1) mechanism. At 18 months, the BBB Aβ efflux is significantly increased in 3xTg-AD mice compared to controls. This could result from the significant up-regulation of both Abcg2 and Abcb1 in 3xTg-AD mice compared to control mice. Thus, age-dependent regulation of several Aβ and cholesterol transporters at the BBB could ultimately limit the brain accumulation of Aβ.

%B J Alzheimers Dis %V 49 %P 287-300 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484906?dopt=Abstract %R 10.3233/JAD-150350 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Age-Related Effects of the Apolipoprotein E Gene on Brain Function. %A Matura, Silke %A Prvulovic, David %A Hartmann, Daniel %A Scheibe, Monika %A Sepanski, Beate %A Butz, Marius %A Oertel-Knöchel, Viola %A Knöchel, Christian %A Karakaya, Tarik %A Fußer, Fabian %A Hattingen, Elke %A Pantel, Johannes %X

The apolipoprotein E (ApoE) ɛ4 allele is a well-established genetic risk factor for sporadic Alzheimer's disease. Some evidence suggests a negative role of the ApoE ɛ4 allele for cognitive performance in late life, while beneficial effects on cognition have been shown in young age. We investigated age-related effects of the ApoE gene on brain function by assessing cognitive performance, as well as functional activation patterns during retrieval of Face-Name pairs in a group of young (n = 50; age 26.4±4.6 years, 25 ɛ4 carriers) and old (n = 40; age 66.1±7.0 years, 20 ɛ4 carriers) participants. A cross-sectional factorial design was used to examine the effects of age, ApoE genotype, and their interaction on both cognitive performance and the blood oxygenation level dependent (BOLD) brain response during retrieval of Face-Name pairs. While there were no genotype-related differences in cognitive performance, we found a significant interaction of age and ApoE genotype on task-related activation bilaterally in anterior cingulate gyrus and superior frontal gyrus, as well as left and right insula. Old age was associated with increased activity in ɛ4 carriers. The increased BOLD response in old ɛ4 carriers during retrieval could indicate a neurocognitive disadvantage associated with the ɛ4 allele with increasing age. Furthermore, recruitment of neuronal resources resulted in enhanced memory performance in young ɛ4 carriers, pointing to a better neurofunctional capacity associated with the ApoE4 genotype in young age.

%B J Alzheimers Dis %V 52 %P 317-31 %8 2016 03 16 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003211?dopt=Abstract %R 10.3233/JAD-150990 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Alcohol Consumption and Incident Dementia: Evidence from the Sydney Memory and Ageing Study. %A Heffernan, Megan %A Mather, Karen A %A Xu, Jing %A Assareh, Amelia A %A Kochan, Nicole A %A Reppermund, Simone %A Draper, Brian %A Trollor, Julian N %A Sachdev, Perminder %A Brodaty, Henry %X

Alcohol consumption is a potentially modifiable risk factor for dementia, but the literature is not completely consistent. This inconsistency may be partly due to an interaction with the apolipoprotein E (APOE) genotype, an established risk factor for Alzheimer's dementia. The aim of this study was to examine whether alcohol consumption is associated with incident dementia or decline in specific cognitive domains over 4 years, and if this effect is modified by APOEɛ4 status. Non-demented community dwelling older adults (70-90 years) from an ongoing longitudinal study were assessed for cognitive impairment in attention/processing speed, language, executive function, visuospatial ability, and memory. Incident dementia was diagnosed according to DSM-IV criteria. Compared to those who did not drink in the previous 12 months, neither low consumption (HR 0.64 95% CI 0.3-1.4) or risky consumption (HR 0.58 95% CI 0.2-1.5) was associated with incident dementia. Carriers of the APOEɛ4 allele were more likely to develop dementia, but there was no significant interaction with alcohol consumption.

%B J Alzheimers Dis %V 52 %P 529-38 %8 2016 Mar 29 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031466?dopt=Abstract %R 10.3233/JAD-150537 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Alterations in Phase-Related Prefrontal Activation During Cognitive Tasks and Nicotinic α4β2 Receptor Availability in Alzheimer's Disease. %A Oboshi, Yumi %A Kikuchi, Mitsuru %A Terada, Tatsuhiro %A Yoshikawa, Etsuji %A Bunai, Tomoyasu %A Ouchi, Yasuomi %X

BACKGROUND: Evidence shows that the cholinergic system plays an important role in regulating working memory and that working memory-related prefrontal activation decreases with age and neuronal degeneration, such as Alzheimer's disease (AD). However, the relation between attention-related α4β2 nicotinic cholinergic function and task-induced prefrontal activation especially time course-related activation remains to be explored.

OBJECTIVE: We aimed to elucidate the relationship between changes in task-induced oxy-hemoglobin concentration (cerebral blood flow, CBF) in the prefrontal cortex and the availability of α4β2 nicotinic receptors in the brain of AD patients in light of their task performance.

METHODS: Eleven mild-to-moderate AD patients and eleven normal elderly subjects underwent the near-infrared spectroscopy during easy and difficult working memory tasks for estimating prefrontal CBF changes and positron emission tomography with the α4β2 tracer [18F]2FA-85380 ([18F]2FA) for measuring the α4β2 nicotinic receptor binding.

RESULTS: Significant correlations between mean oxy-hemoglobin concentration in the channels with significant [group] main effects and prefrontal [18F]2FA binding were observed during the early easy task period in the normal group and during the late difficult task in the AD group. In addition, those prefrontal CBF responses were significantly correlated with not correct performance but the execution time to spend.

CONCLUSION: The α4β2 nicotinic acetylcholine receptors in the prefrontal cortex play an important role in increasing prefrontal activation when attending to novel stimuli, irrespective of the accuracy of the outcome. A delay in the cholinergic-induced increase in prefrontal activation in AD patients might explain their delayed responses in the cognitive task.

%B J Alzheimers Dis %V 53 %P 817-30 %8 2016 May 30 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258412?dopt=Abstract %R 10.3233/JAD-151165 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Altered Affective Evaluations of Smells in Alzheimer's Disease. %A Joussain, Pauline %A Bessy, Marion %A Fournel, Arnaud %A Ferdenzi, Camille %A Rouby, Catherine %A Delphin-Combe, Floriane %A Krolak-Salmon, Pierre %A Bensafi, Moustafa %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Case-Control Studies %K Emotions %K Female %K Humans %K Male %K Mood Disorders %K Odorants %K Olfaction Disorders %K Psychiatric Status Rating Scales %K Smell %K Surveys and Questionnaires %X

BACKGROUND: Studies of olfaction in Alzheimer's disease (AD) mainly focused on deficits in odor detection and identification, with very few investigations of olfactory emotional changes and their consequences for hedonics.

OBJECTIVE: The aim of the present study was to characterize affective evaluations of odors in AD patients.

METHODS: To this end, 20 AD patients and 20 matched controls were tested. Participants were screened for odor detection and identification ability and then asked to rate the intensity, pleasantness, and edibility of 20 odorants.

RESULTS: Results showed that, overall, AD patients had lower detection ability and perceived all odors as weaker than controls. As expected, they had lower identification ability on both cued and non-cued tasks. In addition, when smelling pleasant odors, patients had significantly lower hedonic ratings than controls (p <  0.02), whereas no group difference was found for neutral or unpleasant odors (p >  0.05 in both cases). Moreover, an analysis combining both intensity and pleasantness ratings showed that whereas intensity increased as a function of pleasantness and unpleasantness in controls, this quadratic relationship was not observed in AD patients.

CONCLUSIONS: The study suggests that the simplest categorization criteria of odors (intensity and hedonic valence) are impaired in AD patients (especially for pleasant odors).

%B J Alzheimers Dis %V 49 %P 433-41 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484905?dopt=Abstract %R 10.3233/JAD-150332 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Altered Brain Activities Associated with Neural Repetition Effects in Mild Cognitive Impairment Patients. %A Yu, Jing %A Li, Rui %A Jiang, Yang %A Broster, Lucas S %A Li, Juan %X

Older adults with mild cognitive impairment (MCI) manifest impaired explicit memory. However, studies on implicit memory such as repetition effects in persons with MCI have been limited. In the present study, 17 MCI patients and 16 healthy normal controls (NC) completed a modified delayed-match-to-sample task while undergoing functional magnetic resonance imaging. We aim to examine the neural basis of repetition; specifically, to elucidate whether and how repetition-related brain responses are altered in participants with MCI. When repeatedly rejecting distracters, both NC and MCI showed similar behavioral repetition effects; however, in both whole-brain and region-of-interest analyses of functional data, persons with MCI showed reduced repetition-driven suppression in the middle occipital and middle frontal gyrus. Further, individual difference analysis found that activation in the left middle occipital gyrus was positively correlated with rejecting reaction time and negatively correlated with accuracy rate, suggesting a predictor of repetition behavioral performance. These findings provide new evidence to support the view that neural mechanisms of repetition effect are altered in MCI who manifests compensatory repetition-related brain activities along with their neuropathology.

%B J Alzheimers Dis %V 53 %P 693-704 %8 2016 May 11 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27176074?dopt=Abstract %R 10.3233/JAD-160086 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Altered Energy Metabolism Pathways in the Posterior Cingulate in Young Adult Apolipoprotein E ɛ4 Carriers. %A Perkins, Michelle %A Wolf, Andrew B %A Chavira, Bernardo %A Shonebarger, Daniel %A Meckel, J P %A Leung, Lana %A Ballina, Lauren %A Ly, Sarah %A Saini, Aman %A Jones, T Bucky %A Vallejo, Johana %A Jentarra, Garilyn %A Valla, Jon %X

The APOE gene, encoding apolipoprotein E, is the primary genetic risk factor for late-onset Alzheimer's disease (AD). Apolipoprotein E ɛ4 allele (APOE4) carriers have alterations in brain structure and function (as measured by brain imaging) even as young adults. Examination of this population is valuable in further identifying details of these functional changes and their association with vulnerability to AD decades later. Previous work demonstrates functional declines in mitochondrial activity in the posterior cingulate cortex, a key region in the default mode network, which appears to be strongly associated with functional changes relevant to AD risk. Here, we demonstrate alterations in the pathways underlying glucose, ketone, and mitochondrial energy metabolism. Young adult APOE4 carriers displayed upregulation of specific glucose (GLUT1 & GLUT3) and monocarboxylate (MCT2) transporters, the glucose metabolism enzyme hexokinase, the SCOT & AACS enzymes involved in ketone metabolism, and complexes I, II, and IV of the mitochondrial electron transport chain. The monocarboxylate transporter (MCT4) was found to be downregulated in APOE4 carriers. These data suggest that widespread dysregulation of energy metabolism in this at-risk population, even decades before possible disease onset. Therefore, these findings support the idea that alterations in brain energy metabolism may contribute significantly to the risk that APOE4 confers for AD.

%B J Alzheimers Dis %V 53 %P 95-106 %8 2016 Apr 23 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27128370?dopt=Abstract %R 10.3233/JAD-151205 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Amyloid-β Increases Activity of Proteasomes Capped with 19S and 11S Regulators. %A Morozov, Alexey V %A Kulikova, Alexandra A %A Astakhova, Tatiana M %A Mitkevich, Vladimir A %A Burnysheva, Ksenia M %A Adzhubei, Alexei A %A Erokhov, Pavel A %A Evgen'ev, Michail B %A Sharova, Natalia P %A Karpov, Vadim L %A Makarov, Alexander A %X

Accumulation of amyloid-β (Aβ) in neurons accompanies Alzheimer's disease progression. In the cytoplasm Aβ influences activity of proteasomes, the multisubunit protein complexes that hydrolyze the majority of intracellular proteins. However, the manner in which Aβ affects the proteolytic activity of proteasomes has not been established. In this study the effect of Aβ42 and Aβ42 with isomerized Asp7 on activity of different forms of proteasomes has been analyzed. It has been shown that Aβ peptides efficiently reduce activity of the 20S proteasomes, but increase activity of the 20S proteasomes capped with the 19S and/or 11S regulators. Modulation of proteasome activity is mainly determined by the C-terminal segment of Aβ (amino acids 17-42). This study demonstrated an important role of proteasome regulators in the interplay between Aβ and the proteasomes.

%B J Alzheimers Dis %V 54 %P 763-76 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567864?dopt=Abstract %R 10.3233/JAD-160491 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Analysis of Cerebrospinal Fluid and [11C]PIB PET Biomarkers for Alzheimer's Disease with Updated Protocols. %A Wang, Min Jeong %A Yi, SangHak %A Han, Jee-Young %A Park, So Young %A Jang, Jae-Won %A Chun, In Kook %A Giau, Vo Van %A Bagyinszky, Eva %A Lim, Kun Taek %A Kang, Sung Min %A An, Seong Soo A %A Park, Young Ho %A Youn, Young Chul %A Kim, SangYun %X

BACKGROUND: Recently, a Korean research group suggested a consensus protocol, based on the Alzheimer's Disease Neuroimaging Initiative study protocol but with modifications for minimizing the confounding factors, for the evaluation of cerebrospinal fluid (CSF) biomarkers.

OBJECTIVE: Here, we analyzed fluid and imaging biomarkers of Alzheimer's disease (AD) in Korean population. We used the updated protocol to propose a more accurate CSF biomarker value for the diagnosis of AD.

METHODS: Twenty-seven patients with AD and 30 cognitively normal controls (NC) were enrolled. CSF was collected from 55 subjects (patients with AD = 26, NC = 29) following the Korea consensus protocol. CSF biomarkers were measured using the INNO-BIA AlzBio3 immunoassay, and Pittsburgh compound B (PIB) positron emission tomography (PET) scans were also performed.

RESULTS: The cutoff values of CSF amyloid beta 1-42 (Aβ42), total tau (t-Tau), and phosphorylated tau (p-Tau) proteins were 357.1 pg/ml, 83.35 pg/ml, and 38.00 pg/ml, respectively. The cutoff values of CSF t-Tau/Aβ42 and p-Tau/Aβ42 ratio- were 0.210 (sensitivity 100%, specificity 86.21%) and 0.1350 (sensitivity 88.46%, specificity of 92.86%). The concordance rate with PIB-PET was higher using the CSF t-Tau/Aβ42 ratio (κ= 0.849, CI 0.71-0.99) than CSF Aβ42 alone (κ= 0.703, CI 0.51-0.89).

CONCLUSIONS: Here, we improved controversial factors associated with the previous CSF study protocol and suggested a new cutoff value for the diagnosis of AD. Our results showed good diagnostic performance for differentiation of AD. Thus, we expect our findings could be a cornerstone in the establishment and clinical application of biomarkers for AD diagnosis.

%B J Alzheimers Dis %V 52 %P 1403-13 %8 2016 May 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163824?dopt=Abstract %R 10.3233/JAD-160143 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Analysis of the MIRIAD Data Shows Sex Differences in Hippocampal Atrophy Progression. %A Ardekani, Babak A %A Convit, Antonio %A Bachman, Alvin H %K Alzheimer Disease %K Atrophy %K Disease Progression %K Female %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %X

BACKGROUND: Hippocampus (HC) atrophy is a hallmark of early Alzheimer's disease (AD). Atrophy rates can be measured by high-resolution structural MRI. Longitudinal studies have previously shown sex differences in the progression of functional and cognitive deficits and rates of brain atrophy in early AD dementia. It is important to corroborate these findings on independent datasets.

OBJECTIVE: To study temporal rates of HC atrophy over a one-year period in probable AD patients and cognitively normal (CN) subjects by longitudinal MRI scans obtained from the Minimal Interval Resonance Imaging in AD (MIRIAD) database.

METHODS: We used a novel algorithm to compute an index of hippocampal (volumetric) integrity (HI) at baseline and one-year follow-up in 43 mild-moderate probable AD patients and 22 CN subjects in MIRIAD. The diagnostic power of longitudinal HI measurement was assessed using a support vector machines (SVM) classifier.

RESULTS: The HI was significantly reduced in the AD group (p <  10(-20)). In addition, the annualized percentage rate of reduction in HI was significantly greater in the AD group (p <  10(-13)). Within the AD group, the annual reduction of HI in women was significantly greater than in men (p = 0.008). The accuracy of SVM classification between AD and CN subjects was estimated to be 97% by 10-fold cross-validation.

CONCLUSION: In the MIRIAD patients with probable AD, the HC atrophies at a significantly faster rate in women as compared to men. Female sex is a risk factor for faster descent into AD. The HI measure has potential for AD diagnosis, as a biomarker of AD progression and a therapeutic target in clinical trials.

%B J Alzheimers Dis %V 50 %P 847-57 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836168?dopt=Abstract %R 10.3233/JAD-150780 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Anemia and Mild Cognitive Impairment in the German General Population. %A Dlugaj, Martha %A Winkler, Angela %A Weimar, Christian %A Dürig, Jan %A Broecker-Preuss, Martina %A Dragano, Nico %A Moebus, Susanne %A Jöckel, Karl-Heinz %A Erbel, Raimund %A Eisele, Lewin %K Aged %K Aged, 80 and over %K Anemia %K Cognitive Dysfunction %K Cohort Studies %K Executive Function %K Female %K Follow-Up Studies %K Germany %K Humans %K Male %K Memory %K Middle Aged %K Neuropsychological Tests %K Prevalence %K Speech Perception %X

There is increasing evidence that anemia is associated with cognitive impairment. Therefore, the aim of the study was to examine the cross-sectional association of anemia as well as the persistence of anemia over the last five years with mild cognitive impairment (MCI) and MCI subtypes (amnestic/non-amnestic MCI (aMCI/naMCI)). Out of 4,157 participants (50% men, 50-80 years) of the second examination (t1) of a cohort study (baseline (t0) 2000-2003), we included 4,033 participants with available hemoglobin information and complete cognitive assessment. Anemia was defined as hemoglobin <13 g/dl in men (n = 84) and <12 g/dl in women (n = 79). Group comparisons were used to compare the cognitive subtests. To determine the association of MCI with anemia at t1, with anemia five years prior to the cognitive assessment (t0) and anemia at both time points, we used logistic regression models and included 579 participants with MCI and 1,438 cognitively normal participants out of the total cohort. Anemic participants showed lower performances in verbal memory and executive functions. The fully adjusted odds ratios (OR) for MCI, aMCI, and naMCI in anemic versus non-anemic participants were 1.92 (95% -CI, 1.09-3.39), 1.96 (1.00-3.87), and 1.88 (0.91-3.87). Anemia at both times points showed a non-significant association with naMCI (OR 3.74, 0.94-14.81, fully adjusted). Our results suggest that anemia is associated with an increased risk of MCI independent of traditional cardiovascular risk factors. The association of anemia and MCI has important clinical relevance, because many causes of anemia can be treated effectively.

%B J Alzheimers Dis %V 49 %P 1031-42 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599053?dopt=Abstract %R 10.3233/JAD-150434 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Anthocyanins Protect SK-N-SH Cells Against Acrolein-Induced Toxicity by Preserving the Cellular Redox State. %A Belkacemi, Abdenour %A Ramassamy, Charles %K Acrolein %K Anthocyanins %K Antioxidants %K Cell Death %K Cell Line, Tumor %K Dose-Response Relationship, Drug %K Glutathione %K Humans %K Neuroprotective Agents %K NF-kappa B %K Oxidation-Reduction %K Oxidative Stress %K Reactive Oxygen Species %K Src Homology 2 Domain-Containing, Transforming Protein 1 %X

In Alzheimer's disease (AD) and in mild cognitive impairment (MCI) patients, by-products of lipid peroxidation such as acrolein accumulated in vulnerable regions of the brain. We have previously shown that acrolein is a highly reactive and neurotoxic aldehyde and its toxicity involves the alteration of several redox-sensitive pathways. Recently, protein-conjugated acrolein in cerebrospinal fluid has been proposed as a biomarker to distinguish between MCI and AD. With growing evidence of the early involvement of oxidative stress in AD etiology, one would expect that a successful therapy should prevent brain oxidative damage. In this regard, several studies have demonstrated that polyphenol-rich extracts exert beneficial effect on cognitive impairment and oxidative stress. We have recently demonstrated the efficacy of an anthocyanin formulation (MAF14001) against amyloid-β-induced oxidative stress. The aim of this study is to investigate the neuroprotective effect of MAF14001 as a mixture of anthocyanins, a particular class of polyphenols, against acrolein-induced oxidative damage in SK-N-SH neuronal cells. Our results demonstrated that MAF14001, from 5μM, was able to efficiently protect SK-N-SH cells against acrolein-induced cell death. MAF14001 was able to lower reactive oxygen species and protein carbonyl levels induced by acrolein. Moreover, MAF1401 prevented glutathione depletion and positively modulated, in the presence of acrolein, some oxidative stress-sensitive pathways including the transcription factors NF-κB and Nrf2, the proteins γ-GCS and GSK3β, and the protein adaptator p66Shc. Along with its proven protective effect against amyloid-β toxicity, these results demonstrate that MAF14001 could target multiple mechanisms and could be a promising agent for AD prevention.

%B J Alzheimers Dis %V 50 %P 981-98 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890747?dopt=Abstract %R 10.3233/JAD-150770 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Anti-Prion Antibody 15B3 Detects Toxic Amyloid-β Oligomers. %A Stravalaci, Matteo %A Tapella, Laura %A Beeg, Marten %A Rossi, Alessandro %A Joshi, Pooja %A Pizzi, Erika %A Mazzanti, Michele %A Balducci, Claudia %A Forloni, Gianluigi %A Biasini, Emiliano %A Salmona, Mario %A Diomede, Luisa %A Chiesa, Roberto %A Gobbi, Marco %X

15B3 is a monoclonal IgM antibody that selectively detects pathological aggregates of the prion protein (PrP). We report the unexpected finding that 15B3 also recognizes oligomeric but not monomeric forms of amyloid-β (Aβ)42, an aggregating peptide implicated in the pathogenesis of Alzheimer's disease (AD). The 15B3 antibody: i) inhibits the binding of synthetic Aβ42 oligomers to recombinant PrP and neuronal membranes; ii) prevents oligomer-induced membrane depolarization; iii) antagonizes the inhibitory effects of oligomers on the physiological pharyngeal contractions of the nematode Caenorhabditis elegans; and iv) counteracts the memory deficits induced by intracerebroventricular injection of Aβ42 oligomers in mice. Thus this antibody binds to pathologically relevant forms of Aβ, and offers a potential research, diagnostic, and therapeutic tool for AD.

%B J Alzheimers Dis %V 53 %P 1485-97 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392850?dopt=Abstract %R 10.3233/JAD-150882 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Anti-Viral Properties of Amyloid-β Peptides. %A Bourgade, Karine %A Dupuis, Gilles %A Frost, Eric H %A Fülöp, Tamás %X

Amyloid-β (Aβ) peptides generated by the amyloidogenic pathway of amyloid-β protein precursor processing contribute significantly to neurodegeneration characteristic of Alzheimer's disease (AD). The involvement of Aβ peptides in the etiology of AD remains a subject of debate. Data published in the last 6 years by three different groups have added a new twist by revealing that Aβ peptides could act as antimicrobial peptides (AMP) in in vitro assays against some common and clinically relevant microorganisms, inhibit replication of seasonal and pandemic strains of influenza A and HSV-1 virus. These observations are of significance with respect to the notion that pathogens may be important contributors to the development of AD, particularly in the case of herpes simplex virus (HSV) infection, which often resides in the same cerebral sites where AD arises. Here, we review the data that support the interpretation that Aβ peptides behave as AMP, with an emphasis on studies concerning HSV-1 and a putative molecular mechanism that suggests that interactions between Aβ peptides and the HSV-1 fusogenic protein gB lead to impairment of HSV-1 infectivity by preventing the virus from fusing with the plasma membrane. A number of avenues for future research are suggested.

%B J Alzheimers Dis %V 54 %P 859-878 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392871?dopt=Abstract %R 10.3233/JAD-160517 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association between Cerebrospinal Fluid Biomarkers for Alzheimer's Disease, APOE Genotypes and Auditory Verbal Learning Task in Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease. %A Mandecka, Monika %A Budziszewska, Magdalena %A Barczak, Anna %A Pepłońska, Beata %A Chodakowska-Żebrowska, Małgorzata %A Filipek-Gliszczyńska, Anna %A Nesteruk, Marta %A Styczyńska, Maria %A Barcikowska, Maria %A Gabryelewicz, Tomasz %X

In the course of Alzheimer's disease (AD), early pathological changes in the brain start decades before any clinical manifestation. The concentration levels of AD cerebrospinal fluid (CSF) biomarkers, such as amyloid-β1-42 (Aβ1-42), total tau (T-tau), and phosphorylated tau (P-tau), may reflect a cerebral pathology facilitating an early diagnosis of the disease and predicting a cognitive deterioration. The aim of this study was to estimate the prevalence of AD CSF biomarkers in those individuals with a subjective cognitive decline (SCD), a mild cognitive impairment (MCI), and Alzheimer's dementia (AD-D), together with the relationships between the biomarkers, an APOE ɛ4 presence, and a verbal episodic memory performance. We included 252 patients from the memory clinic with a diagnosis of SCD (n = 85), MCI (n = 87), and AD-D (n = 80). A verbal episodic memory performance level was assessed and was based on a delayed recall trial from the 10-word list of an auditory verbal learning task (AVLT). We found that the patients with more severe cognitive impairments had significantly lower levels of Aβ1-42 and higher levels of T-tau and P-tau. This pattern was also typical for the APOE ɛ4 carriers, who had lower levels of Aβ1-42 than the noncarriers in the AD-D and MCI groups. The levels of T-tau and P-tau were significantly higher in the APOE ɛ4 carriers than in the noncarriers, but only in the MCI patients. The AVLT performance in the whole study samples was predicted by age, Aβ1-42, and the T-tau CSF biomarkers, but not by the APOE genotyping.

%B J Alzheimers Dis %V 54 %P 157-68 %8 2016 Jul 29 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472875?dopt=Abstract %R 10.3233/JAD-160176 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Association Between Plasma Ceramides and Sphingomyelins and Risk of Alzheimer's Disease Differs by Sex and APOE in the Baltimore Longitudinal Study of Aging. %A Mielke, Michelle M %A Haughey, Norman J %A Han, Dingfen %A An, Yang %A Bandaru, Veera Venkata Ratnam %A Lyketsos, Constantine G %A Ferrucci, Luigi %A Resnick, Susan M %X

BACKGROUND: Cellular and animal studies demonstrated relationships between sphingolipid metabolism and Alzheimer's disease (AD) pathology. High blood ceramide levels have been shown to predict cognitive impairment and AD, but these studies had small sample sizes and did not assess differences in risk by sex or APOE genotype.

OBJECTIVE: To determine whether plasma ceramides and sphingomyelins were associated with risk of AD, and whether the association varied by sex and APOE genotype.

METHODS: Participants included 626 men and 366 women, aged 55 years and older, enrolled in the Baltimore Longitudinal Study of Aging. Plasma ceramides and sphingomyelins were determined using quantitative analyses performed on a high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometer. Cox proportional hazards models, stratified by sex, were used to examine the relationship of plasma ceramides and sphingomyelins with risk of AD over a mean (SD) follow-up of 15.0 (7.0) years for men and 13.1 (5.9) years for women.

RESULTS: Among men, the highest tertile of most ceramides and sphingomyelins were associated with an increased risk of AD. Among women, there were no associations between any of the ceramides and risk of AD. In contrast, women in the highest tertile of most sphingomyelins had a reduced risk of AD, which was most pronounced among APOE ɛ4 carriers.

CONCLUSION: These results provide further evidence for the role of sphingolipid metabolism in AD and highlight the importance of considering sex and APOE genotype in assessing this relationship.

%B J Alzheimers Dis %V 60 %P 819-828 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035934?dopt=Abstract %R 10.3233/JAD-160925 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association Between Serum Ceruloplasmin Specific Activity and Risk of Alzheimer's Disease. %A Siotto, Mariacristina %A Simonelli, Ilaria %A Pasqualetti, Patrizio %A Mariani, Stefania %A Caprara, Deborah %A Bucossi, Serena %A Ventriglia, Mariacarla %A Molinario, Rossana %A Antenucci, Mirca %A Rongioletti, Mauro %A Rossini, Paolo Maria %A Squitti, Rosanna %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Area Under Curve %K Biomarkers %K Blood Chemical Analysis %K Ceruloplasmin %K Copper %K Female %K Genotype %K Genotyping Techniques %K Humans %K Logistic Models %K Male %K Multivariate Analysis %K Prognosis %K Risk %K ROC Curve %K Sensitivity and Specificity %K Transferrin %X

Meta-analyses demonstrate copper involvement in Alzheimer's disease (AD), and the systemic ceruloplasmin status in relation to copper is an emerging issue. To deepen this matter, we evaluated levels of ceruloplasmin concentration, ceruloplasmin activity, ceruloplasmin specific activity (eCp/iCp), copper, non-ceruloplasmin copper iron, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype in a sample of 84 AD patients and 58 healthy volunteers. From the univariate logistic analyses we found that ceruloplasmin concentration, eCp/iCp, copper, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype were significantly associated with the probability of AD. In the multivariable logistic regression analysis, we selected the best subset of biological predictors by the forward stepwise procedure. The analysis showed a decrease of the risk of having AD for eCp/iCp (p = 0.001) and an increase of this risk for non-ceruloplasmin copper (p = 0.008), age (p = 0.001), and APOE-ɛ4 allele (p <  0.001). The estimated model showed a good power in discriminating AD patients from healthy controls (area under curve: 88% ; sensitivity: 66% ; specificity 93%). These data strength the breakdown of copper homeostasis and propose eCp/iCp as a reliable marker of ceruloplasmin status.

%B J Alzheimers Dis %V 50 %P 1181-9 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836154?dopt=Abstract %R 10.3233/JAD-150611 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Butyrylcholinesterase-K Allele and Apolipoprotein E ɛ4 Allele with Cognitive Decline in Dementia with Lewy Bodies and Alzheimer's Disease. %A Vijayaraghavan, Swetha %A Darreh-Shori, Taher %A Rongve, Arvid %A Berge, Guro %A Sando, Sigrid B %A White, Linda R %A Auestad, Bjørn H %A Witoelar, Aree %A Andreassen, Ole A %A Ulstein, Ingun D %A Aarsland, Dag %K Aged %K Aged, 80 and over %K Alleles %K Alzheimer Disease %K Apolipoprotein E4 %K Butyrylcholinesterase %K Cognition %K Disease Progression %K Female %K Gene Frequency %K Genotype %K Humans %K Lewy Body Disease %K Male %K Neuropsychological Tests %X

BACKGROUND: A common polymorphism of the butyrylcholinesterase gene, the K-variant (BCHE-K) is associated with reduced butyrylcholinesterase (BuChE) activity. Insufficient studies exist regarding the frequency and role of BCHE-K in dementias.

OBJECTIVE: To determine the association of BCHE-K and APOEɛ4 with diagnosis and rate of cognitive decline in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) patients.

METHODS: Genomic DNA from 368 subjects (108 AD, 174 DLB, and 86 controls) from two routine clinical cohort studies in Norway; DemVest and TrønderBrain, were genotyped for BCHE-K and APOEɛ4. The mild dementia DemVest subjects received annual Mini-Mental State Examination assessments for five years.

RESULTS: BCHE-K frequency was lower in DLB (33.9% ; p <  0.01) than in control subjects (51.2%), and was numerically lower in AD as well (38.9% ; p = 0.11). More rapid cognitive decline was associated with the APOEɛ4 genotype, but not with the BCHE-K genotype. In an exploratory analysis of patients who completed all five follow-up visits, there was greater cognitive decline in BCHE-K carriers in the presence of the APOEɛ4 allele than in the absence of these polymorphisms.

CONCLUSION: BCHE-K is associated with a reduced risk for AD and DLB whereas APOEɛ4 is associated with more rapid cognitive decline. The greater cognitive decline in individuals with both APOEɛ4 and BCHE-K alleles require prospective confirmation in well-controlled trials.

%B J Alzheimers Dis %V 50 %P 567-76 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757188?dopt=Abstract %R 10.3233/JAD-150750 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Coffee Consumption with MRI Markers and Cognitive Function: A Population-Based Study. %A Araújo, Larissa Fortunato %A Mirza, Saira Saeed %A Bos, Daniel %A Niessen, Wiro J %A Barreto, Sandhi Maria %A van der Lugt, Aad %A Vernooij, Meike W %A Hofman, Albert %A Tiemeier, Henning %A Ikram, M Arfan %X

BACKGROUND: Coffee is one of the most widely consumed beverages worldwide and has been of considerable interest in research on cognition and dementia.

OBJECTIVE: To investigate the effect of coffee on preclinical brain MRI markers of dementia and cognitive performance.

METHODS: In 2,914 participants from the population-based Rotterdam Study (mean age: 59.3±7.2 years, 55% females), we assessed coffee consumption, performed brain MRI, and assessed cognition at baseline. To study cognitive change, cognitive assessment was repeated after 5 years of follow-up. Coffee consumption was analyzed continuously (per cup increase) and in categories (0-1, >1-3, >3 cups/day). Using logistic and linear regression, associations of coffee consumption with lacunar infarcts and brain tissue volumes on MRI, and cognitive performance (cross-sectional and longitudinal) were investigated, adjusting for relevant confounders.

RESULTS: We found that higher coffee consumption was associated with a lower prevalence of lacunar infarcts [odds ratio per cup increase: 0.88 (95% CI:0.79;0.98)], and smaller hippocampal volume [difference: -0.01 (95% CI:-0.02;0.00)]. Also, we found that the highest category of coffee consumption was associated with better performance on the Letter Digit Substitution Task [difference: 1.13(95% CI:0.39;1.88)], Word Fluency test [0.74(95% CI:0.04,1.45)], Stroop interference task [1.82(95% CI:0.23;3.41)], and worse performance on the 15-Word Learning test delayed recall [-0.38(95% CI:-0.74;-0.02)]. These associations were not found when cognition was analyzed longitudinally.

CONCLUSION: We found complex associations between coffee consumption, brain structure, and cognition. Higher coffee consumption was cross-sectionally associated with a lower occurrence of lacunar infarcts and better executive function, but also with smaller hippocampal volume and worse memory function.

%B J Alzheimers Dis %V 53 %P 451-61 %8 2016 May 03 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163820?dopt=Abstract %R 10.3233/JAD-160116 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Physical Function with Clinical and Subclinical Brain Disease: The Framingham Offspring Study. %A Camargo, Erica C %A Weinstein, Galit %A Beiser, Alexa S %A Tan, Zaldy S %A DeCarli, Charles %A Kelly-Hayes, Margaret %A Kase, Carlos %A Murabito, Joanne M %A Seshadri, Sudha %X

BACKGROUND: Handgrip strength and gait speed are simple measures of physical capability and have been associated with current and future health outcomes. However, studies on their associations with brain structure and function in middle-aged adults are lacking.

OBJECTIVE: To assess the relationship of fast-paced walking speed and handgrip strength with risk of dementia, Alzheimer's disease (AD), and stroke, as well as the cross-sectional associations with cognitive and brain magnetic resonance imaging (MRI) measures in a middle-aged community sample.

METHODS: Framingham Offspring (n = 2,176; mean age 62, 54% female) had physical function, brain MRI, and cognitive evaluations between 1999 and 2005 and were followed-up for incident dementia AD and stroke until 11 years later. We related walking speed and handgrip strength to incident dementia, AD, and stroke using Cox models, and to brain and cognitive measures using multivariable linear and logistic regression. Models were adjusted for age, sex, education, and vascular risk factors.

RESULTS: Slow walking and weak handgrip were associated with more than 2.5-fold increase in risk of AD. Weaker handgrip was associated with an increased risk of incident stroke (HR 1.74, 95% CI: 1.12-2.70/SDU, p = 0.01) in persons ≥65 years. Both measures were associated with lower total brain volume and poorer performance on tests of visual memory, language, executive function, and visuoperceptual function. Slower gait was also related to poorer verbal memory, and weaker handgrip to poorer abstraction.

CONCLUSION: Tests of walking speed and handgrip strength may serve as clinical markers of brain structure and function and may improve dementia risk prediction.

%B J Alzheimers Dis %V 53 %P 1597-608 %8 2016 Jul 14 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27540965?dopt=Abstract %R 10.3233/JAD-160229 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Plasma Aβ40 Peptides, But Not Aβ42, with Coronary Artery Disease and Diabetes Mellitus. %A Roeben, Benjamin %A Maetzler, Walter %A Vanmechelen, Eugeen %A Schulte, Claudia %A Heinzel, Sebastian %A Stellos, Konstantinos %A Godau, Jana %A Huber, Heiko %A Brockmann, Kathrin %A Wurster, Isabel %A Gaenslen, Alexandra %A Grüner, Eva %A Niebler, Raphael %A Eschweiler, Gerhard W %A Berg, Daniela %X

BACKGROUND/OBJECTIVE: Plasma levels of amyloid-beta (Aβ) 1-40 peptide have been proposed to be associated with cardiovascular mortality in patients with coronary artery disease (CAD). Therefore, we aimed to investigate the association of plasma Aβ levels with CAD, cardiovascular risk factors (CVRF), and APOE genotype in non-demented elderly individuals.

METHODS: Plasma Aβ1 - 40 and Aβ1 - 42 levels of 526 individuals (mean age of 63.0±7.3 years) were quantified with the INNO-BIA plasma Aβ forms assay based on multiplextrademark technique. APOE genotype was determined with an established protocol. Presence of CAD and CVRFs were ascertained using a questionnaire and/or medical records.

RESULTS: Plasma Aβ1 - 40 levels were significantly higher in individuals with CAD (p = 0.043) and, independently, in individuals with diabetes mellitus (DM) type 2 (p = 0.001) while accounting for age- and gender-effects. Plasma Aβ1 - 42 levels were higher in APOEɛ4 carriers (p = 0.004), but were neither relevantly associated with CAD nor with any CVRF. Plasma Aβ1 - 40 showed no association with APOE genotype.

DISCUSSION: Our findings argue for an association of circulating plasma Aβ1 - 40 peptides with incident CAD and DM. Further investigations are needed to entangle the role of Aβ1 - 40 role in the pathophysiology of cardiovascular disease independent of its known role in Alzheimer's disease.

%B J Alzheimers Dis %V 52 %P 161-9 %8 2016 03 16 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003209?dopt=Abstract %R 10.3233/JAD-150575 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Platelet Serotonin Levels in Alzheimer's Disease with Clinical and Cerebrospinal Fluid Markers. %A Tajeddinn, Walid %A Fereshtehnejad, Seyed-Mohammad %A Seed Ahmed, Mohammed %A Yoshitake, Takashi %A Kehr, Jan %A Shahnaz, Tasmin %A Milovanovic, Micha %A Behbahani, Homira %A Höglund, Kina %A Winblad, Bengt %A Cedazo-Minguez, Angel %A Jelic, Vesna %A Järemo, Petter %A Aarsland, Dag %X

INTRODUCTION: Serotonin (5-HT) is involved in the pathology of Alzheimer's disease (AD).

OBJECTIVE: We aimed to measure 5-HT level in platelets in AD and explore its association with cerebrospinal fluid (CSF), AD biomarkers (amyloid-β 1-42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau)), and clinical symptoms.

METHODS: 15 patients with AD and 20 patients with subjective cognitive impairment (SCI) were included. 5-HT metabolites were measured, in a specific fraction, using high performance liquid chromatography with electrochemical detection (HPLC-ECD).

RESULTS: Significantly lower 5-HT concentrations were observed in AD patients compared to SCI patients both after normalization against total protein (p = 0.008) or platelet count (p = 0.019). SCI patients with lower 5-HT level have higher AD CSF biomarkers, total tau (p = 0.026) and tau/Aβ42 ratio (p = 0.001), compared to those with high 5-HT levels.

CONCLUSION: AD patients have reduced platelet 5-HT levels. In SCI, lower 5-HT content was associated with a higher AD-CSF biomarker burden.

%B J Alzheimers Dis %V 53 %P 621-30 %8 2016 May 04 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163811?dopt=Abstract %R 10.3233/JAD-160022 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Serum Vitamin D with the Risk of Incident Dementia and Subclinical Indices of Brain Aging: The Framingham Heart Study. %A Karakis, Ioannis %A Pase, Matthew P %A Beiser, Alexa %A Booth, Sarah L %A Jacques, Paul F %A Rogers, Gail %A DeCarli, Charles %A Vasan, Ramachandran S %A Wang, Thomas J %A Himali, Jayandra J %A Annweiler, Cedric %A Seshadri, Sudha %K Adult %K Aging %K Brain %K Cohort Studies %K Dementia %K Female %K Humans %K Incidence %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Multivariate Analysis %K Neuropsychological Tests %K Regression Analysis %K Risk %K Sensitivity and Specificity %K Vitamin D %X

BACKGROUND: Identifying nutrition- and lifestyle-based risk factors for cognitive impairment and dementia may aid future primary prevention efforts.

OBJECTIVE: We aimed to examine the association of serum vitamin D levels with incident all-cause dementia, clinically characterized Alzheimer's disease (AD), MRI markers of brain aging, and neuropsychological function.

METHODS: Framingham Heart Study participants had baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations measured between 1986 and 2001. Vitamin D status was considered both as a continuous variable and dichotomized as deficient (<10 ng/mL), or at the cohort-specific 20th and 80th percentiles. Vitamin D was related to the 9-year risk of incident dementia (n = 1663), multiple neuropsychological tests (n = 1291) and MRI markers of brain volume, white matter hyperintensities and silent cerebral infarcts (n = 1139).

RESULTS: In adjusted models, participants with vitamin D deficiency (n = 104, 8% of the cognitive sample) displayed poorer performance on Trail Making B-A (β= -0.03 to -0.05±0.02) and the Hooper Visual Organization Test (β= -0.09 to -0.12±0.05), indicating poorer executive function, processing speed, and visuo-perceptual skills. These associations remained when vitamin D was examined as a continuous variable or dichotomized at the cohort specific 20th percentile. Vitamin D deficiency was also associated with lower hippocampal volumes (β= -0.01±0.01) but not total brain volume, white matter hyperintensities, or silent brain infarcts. No association was found between vitamin D deficiency and incident all-cause dementia or clinically characterized AD.

CONCLUSIONS: In this large community-based sample, low 25(OH)D concentrations were associated with smaller hippocampal volume and poorer neuropsychological function.

%B J Alzheimers Dis %V 51 %P 451-61 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890771?dopt=Abstract %R 10.3233/JAD-150991 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Associations between Neuropsychiatric Symptoms and Cerebral Amyloid Deposition in Cognitively Impaired Elderly People. %A Bensamoun, David %A Guignard, Renaud %A Furst, Ansgar J %A Derreumaux, Alexandre %A Manera, Valeria %A Darcourt, Jacques %A Benoit, Michel %A Robert, Philippe H %A David, Renaud %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloidogenic Proteins %K Cerebral Cortex %K Cognition Disorders %K Cohort Studies %K Female %K Fluorodeoxyglucose F18 %K Humans %K Male %K Mental Status Schedule %K Mood Disorders %K Neuropsychological Tests %K Positron-Emission Tomography %X

BACKGROUND: Neuropsychiatric symptoms, also known as behavioral and psychological symptoms of dementia (BPSD), affect the majority of patients with dementia, and result in a greater cognitive and functional impairment.

OBJECTIVE: To investigate associations between BPSD and amyloid cerebral deposition as measured by 18F-Florbetapir-PET quantitative uptake in elderly subjects with and without cognitive impairment.

METHODS: Participants with cognitive impairment [mild cognitive impairment (MCI) or Alzheimer's disease (AD)] and healthy controls (HC) from the ADNI cohort (Alzheimer Disease Neuroimaging Initiative) who underwent an 18F-florbetapir PET scan between May 2010 and March 2014 were included. Clinical assessments included the Clinical Dementia Rating, the Mini-Mental State Examination (MMSE), and the Neuropsychiatric Inventory. Freesurfer software was used to extract PET counts based on T1-based structural ROI (frontal, cingulate, parietal, and temporal). Spearman's partial correlation scores between BPSD severity and regional amyloid uptake were calculated.

RESULTS: Data for 657 participants [age = 72.6 (7.19); MMSE = 27.4 (2.67)] were analyzed, including 230 HC [age = 73.1 (6.02); MMSE = 29 (1.21)], 308 MCI [age = 71.5 (7.44); MMSE = 28.0 (1.75)], and 119 AD subjects [age = 74.7 (8.05); MMSE = 23.1 (2.08)]. Considering all diagnostic groups together, positive significant correlations were found between anxiety and 18F-florbetapir uptake in the frontal (r = 0.102; p = 0.009), cingulate (r = 0.083; p = 0.034), and global cerebral uptake (r = 0.099; p = 0.011); between irritability and frontal (r = 0.089; p = 0.023), cingulate (r = 0.085; p = 0.030), parietal (r = 0.087; p = 0.025), and global cerebral uptake (r = 0.093; p = 0.017); in the MCI subgroup, between anxiety and frontal (r = 0.126; p = 0.03) and global uptake (r = 0.14; p = 0.013); in the AD subgroup, between irritability and parietal uptake (r = 0.201; p = 0.03).

CONCLUSION: Anxiety and irritability are associated with greater amyloid deposition in the neurodegenerative process leading to AD.

%B J Alzheimers Dis %V 49 %P 387-98 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484900?dopt=Abstract %R 10.3233/JAD-150181 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Associations between Performance on an Abbreviated CogState Battery, Other Measures of Cognitive Function, and Biomarkers in People at Risk for Alzheimer's Disease. %A Racine, Annie M %A Clark, Lindsay R %A Berman, Sara E %A Koscik, Rebecca L %A Mueller, Kimberly D %A Norton, Derek %A Nicholas, Christopher R %A Blennow, Kaj %A Zetterberg, Henrik %A Jedynak, Bruno %A Bilgel, Murat %A Carlsson, Cynthia M %A Christian, Bradley T %A Asthana, Sanjay %A Johnson, Sterling C %X

It is not known whether computerized cognitive assessments, like the CogState battery, are sensitive to preclinical cognitive changes or pathology in people at risk for Alzheimer's disease(AD). In 469 late middle-aged participants from the Wisconsin Registry for Alzheimer's Prevention(mean age 63.8±7 years at testing; 67% female; 39% APOE4+), we examined relationships between a CogState abbreviated battery(CAB) of seven tests and demographic characteristics, traditional paper-based neuropsychological tests as well as a composite cognitive impairment index, cognitive impairment status(determined by consensus review), and biomarkers for amyloid and tau(CSF phosphorylated-tau/Aβ42 and global PET-PiB burden) and neural injury(CSF neurofilament light protein). CSF and PET-PiB were collected in n = 71 and n = 91 participants, respectively, approximately four years prior to CAB testing. For comparison, we examined three traditional tests of delayed memory in parallel. Similar to studies in older samples, the CAB was less influenced by demographic factors than traditional tests. CAB tests were generally correlated with most paper-based cognitive tests examined and mapped onto the same cognitive domains. Greater composite cognitive impairment index was associated with worse performance on all CAB tests. Cognitively impaired participants performed significantly worse compared to normal controls on all but one CAB test. Poorer One Card Learning test performance was associated with higher levels of CSF phosphorylated-tau/Aβ42. These results support the use of the CogState battery as measures of early cognitive impairment in studies of people at risk for AD.

%B J Alzheimers Dis %V 54 %P 1395-1408 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589532?dopt=Abstract %R 10.3233/JAD-160528 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Atrophy in Alzheimer's Disease and Semantic Dementia: An ALE Meta-Analysis of Voxel-Based Morphometry Studies. %A Chapleau, Marianne %A Aldebert, Joséphine %A Montembeault, Maxime %A Brambati, Simona M %X

BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) and semantic dementia (SD) have distinct episodic memory profiles despite the hippocampal atrophy that characterizes both diseases. The aim of this study was to delineate the pattern of gray matter (GM) atrophy associated with AD and SD as well as any differences in these patterns by pooling together the results of previous voxel-based morphometry (VBM) studies.Methods/Overview: We conducted a meta-analysis of VBM studies that investigated GM atrophy in AD patients versus controls (CTRLs) and in SD patients versus CTRLs using the activation likelihood estimation (ALE) approach. Our systematic review allowed us to identify 63 VBM studies.

RESULTS: The results confirmed that in addition to the classical cortical pattern of atrophy involving posterior medial and lateral regions in AD and the anterior lateral temporal lobes in SD, both AD and SD patients are characterized by bilateral atrophy of the hippocampus. Furthermore, in SD, the hippocampal atrophy was limited to the anterior portion of the hippocampus, while in AD, both the anterior and posterior parts of the hippocampus exhibited atrophy. When we compared the foci identified in the studies that compared AD patients versus CTRLs with those identified in the studies that compared SD patients versus CTRLs, we observed that the atrophy in the posterior hippocampus and precuneus was more severe in AD.

CONCLUSION: These results support theories that propose that the deficits observed in AD result from damage to the episodic memory network, which involves the posterior hippocampus and posterior medial brain regions. However, sparing of the posterior hippocampus in SD could explain the absence of episodic memory deficits in this population.

%B J Alzheimers Dis %V 54 %P 941-955 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567843?dopt=Abstract %R 10.3233/JAD-160382 %0 Journal Article %J J Alzheimers Dis %D 2016 %T AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics. %A Eketjäll, Susanna %A Janson, Juliette %A Kaspersson, Karin %A Bogstedt, Anna %A Jeppsson, Fredrik %A Fälting, Johanna %A Haeberlein, Samantha Budd %A Kugler, Alan R %A Alexander, Robert C %A Cebers, Gvido %K Administration, Oral %K Amyloid beta-Peptides %K Amyloid Precursor Protein Secretases %K Animals %K Blood Chemical Analysis %K Blood-Brain Barrier %K Brain %K Dogs %K Dose-Response Relationship, Drug %K Drug Evaluation, Preclinical %K Enzyme Inhibitors %K Female %K Guinea Pigs %K Humans %K Imidazoles %K Kinetics %K Male %K Mice, Inbred C57BL %K Peptide Fragments %K Spiro Compounds %X

A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-β peptide (Aβ) concentrations, plays a key role in the pathogenesis of Alzheimer's disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-β protein precursor (AβPP) to Aβ peptides, with the soluble N terminal fragment of AβPP (sAβPPβ) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of Aβ. Here, we report the in vitro and in vivo pharmacological profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAβPPβ. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of Aβ. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.

%B J Alzheimers Dis %V 50 %P 1109-23 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890753?dopt=Abstract %R 10.3233/JAD-150834 %0 Journal Article %J J Alzheimers Dis %D 2016 %T AβPP/PS1 Transgenic Mice Show Sex Differences in the Cerebellum Associated with Aging. %A Ordoñez-Gutierrez, Lara %A Fernandez-Perez, Ivan %A Herrera, Jose Luis %A Anton, Marta %A Benito-Cuesta, Irene %A Wandosell, Francisco %X

Cerebellar pathology has been related to presenilin 1 mutations in certain pedigrees of familial Alzheimer's disease. However, cerebellum tissue has not been intensively analyzed in transgenic models of mutant presenilins. Furthermore, the effect of the sex of the mice was not systematically analyzed, despite the fact that important gender differences in the evolution of the disease in the human population have been described. We analyzed whether the progression of amyloidosis in a double transgenic mouse, AβPP/PS1, is susceptible to aging and differentially affects males and females. The accumulation of amyloid in the cerebellum differentially affects males and females of the AβPP/PS1 transgenic line, which was found to be ten-fold higher in 15-month-old females. Amyloid-β accumulation was more evident in the molecular layer of the cerebellum, but glia reaction was only observed in the granular layer of the older mice. The sex divergence was also observed in other neuronal, survival, and autophagic markers. The cerebellum plays an important role in the evolution of the pathology in this transgenic mouse model. Sex differences could be crucial for a complete understanding of this disease. We propose that the human population could be studied in this way. Sex-specific treatment strategies in human populations could show a differential response to the therapeutic approach.

%B J Alzheimers Dis %V 54 %P 645-56 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567877?dopt=Abstract %R 10.3233/JAD-160572 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Bacterial Component to Alzheimer's-Type Dementia Seen via a Systems Biology Approach that Links Iron Dysregulation and Inflammagen Shedding to Disease. %A Pretorius, Etheresia %A Bester, Janette %A Kell, Douglas B %X

The progression of Alzheimer's disease (AD) is accompanied by a great many observable changes, both molecular and physiological. These include oxidative stress, neuroinflammation, and (more proximal to cognitive decline) the death of neuronal and other cells. A systems biology approach seeks to organize these observed variables into pathways that discriminate those that are highly involved (i.e., causative) from those that are more usefully recognized as bystander effects. We review the evidence that iron dysregulation is one of the central causative pathway elements here, as this can cause each of the above effects. In addition, we review the evidence that dormant, non-growing bacteria are a crucial feature of AD, that their growth in vivo is normally limited by a lack of free iron, and that it is this iron dysregulation that is an important factor in their resuscitation. Indeed, bacterial cells can be observed by ultrastructural microscopy in the blood of AD patients. A consequence of this is that the growing cells can shed highly inflammatory components such as lipopolysaccharides (LPS). These too are known to be able to induce (apoptotic and pyroptotic) neuronal cell death. There is also evidence that these systems interact with elements of vitamin D metabolism. This integrative systems approach has strong predictive power, indicating (as has indeed been shown) that both natural and pharmaceutical iron chelators might have useful protective roles in arresting cognitive decline, and that a further assessment of the role of microbes in AD development is more than highly warranted.

%B J Alzheimers Dis %V 53 %P 1237-56 %8 2016 Jun 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340854?dopt=Abstract %R 10.3233/JAD-160318 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Behavioral and Electrophysiological Correlates of Memory Binding Deficits in Patients at Different Risk Levels for Alzheimer's Disease. %A Pietto, Marcos %A Parra, Mario A %A Trujillo, Natalia %A Flores, Facundo %A García, Adolfo M %A Bustin, Julian %A Richly, Pablo %A Manes, Facundo %A Lopera, Francisco %A Ibáñez, Agustín %A Baez, Sandra %X

Deficits in visual short-term memory (VSTM) binding have been proposed as an early and specific marker for Alzheimer's disease (AD). However, no studies have explored the neural correlates of this domain in clinical categories involving prodromal stages with different risk levels of conversion to AD. We assessed underlying electrophysiological modulations in patients with mild cognitive impairment (MCI), patients in the MCI stages of familial AD carrying the mutation E280A of the presenilin-1 gene (MCI-FAD), and healthy controls. Moreover, we compared the behavioral performance and neural correlates of both patient groups. Participants completed a change-detection VSTM task assessing recognition of changes between shapes or shape-color bindings, presented in two consecutive arrays (i.e., study and test) while event related potentials (ERPs) were recorded. Changes always occurred in the test array and consisted of new features replacing studied features (shape-only) or features swapping across items (shape-color binding). Both MCI and MCI-FAD patients performed worse than controls in the shape-color binding condition. Early electrophysiological activity (100-250 ms) was significantly reduced in both clinical groups, particularly over fronto-central and parieto-occipital regions. However, shape-color binding performance and their reduced neural correlates were similar between MCI and MCI-FAD. Our results support the validity of the VSTM binding test and their neural correlates in the early detection of AD and highlight the importance of studies comparing samples at different risk for AD conversion. The combined analysis of behavioral and ERP data gleaned with the VSTM binding task can offer a valuable memory biomarker for AD.

%B J Alzheimers Dis %V 53 %P 1325-40 %8 2016 Jun 30 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372640?dopt=Abstract %R 10.3233/JAD-160056 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Beneficial Effects of an Integrated Psychostimulation Program in Patients with Alzheimer's Disease. %A Ibarria, Marta %A Alegret, Montserrat %A Valero, Sergi %A Morera, Amèrica %A Guitart, Marina %A Cañabate, Pilar %A Moreno, Mariola %A Lara, Susana %A Diego, Susana %A Hernández, Joan %A Tantinyá, Natàlia %A Vera, Maribel %A Hernandez, Isabel %A Becker, James T %A Ruiz, Agustin %A Boada, Merce %A Tárraga, Lluís %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cholinesterase Inhibitors %K Cognition %K Combined Modality Therapy %K Disease Progression %K Female %K Humans %K Male %K Neuropsychological Tests %K Psychotherapy %K Severity of Illness Index %K Treatment Outcome %X

BACKGROUND: The existing pharmacological treatments for Alzheimer's disease (AD) can only slow the progression of symptoms or delay admission to long-term care facilities. The beneficial effects of non-drug treatments are poorly studied.

OBJECTIVE: To describe the effects of an Integrated Psychostimulation Program (IPP) in patients with mild-moderate AD treated with acetylcholinesterase inhibitors; and to identify factors related to greater benefit of the IPP.

METHODS: 206 patients (mean age = 75.9 years; MMSE = 19.6) were evaluated before starting the IPP and 3, 6, 9, and 12 months later. Measures included: Mini-Mental State Examination (MMSE), Cognitive Subscale of Alzheimer's Disease Assessment Scale (ADAS-Cog), Rapid Disability Rating Scale (RDRS-2), and Neuropsychiatric Inventory Questionnaire (NPI-Q).

RESULTS: Patients remained cognitively stable (MMSE/ADAS-Cog) for more than 6 months and significantly worsened at 9-month and 12-month follow-ups, without clinically significant functional changes (RDRS-2) or psychiatric symptoms(NPI-Q). The mean annual change on MMSE and ADAS-Cog were 2.06 and 3.56 points, respectively, lower than the annual decline demonstrated previously in similar patients (2.4 and 4.5, respectively). 42.7% of patients maintained or improved global cognitive scores between baseline and 12-month follow-up. The patients who maintained cognitive functions were older than those who did not (77.5 versus 74.7 years).

CONCLUSIONS: The IPP may be an effective treatment to maintain cognition, functionality, and psychiatric symptoms in AD patients pharmacologically treated, and older age seems to increase beneficial effects of IPP.

%B J Alzheimers Dis %V 50 %P 559-66 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757182?dopt=Abstract %R 10.3233/JAD-150455 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Better Objective Sleep Quality in Older Adults with High Subjective Memory Decline. %A Cavuoto, Marina G %A Ong, Ben %A Pike, Kerryn E %A Nicholas, Christian L %A Bei, Bei %A Kinsella, Glynda J %X

BACKGROUND: Sleep disturbance is implicated in memory function across normal aging and neurodegenerative disease. Furthermore, there is mounting evidence to suggest that high levels of subjective memory decline (SMD) may signal very early neurodegenerative changes associated with Alzheimer's disease (AD). This view prompts research examining the relationship between SMD and other risk factors for cognitive decline, including sleep disturbance.

OBJECTIVE: To determine whether objective and subjective indices of sleep predict SMD in older adults.

METHODS: 181 community-based older adults were divided into groups of high and low SMD based on their responses to the Memory Assessment Complaint Questionnaire (MAC-Q). They undertook two weeks of objective sleep monitoring (actigraphy), and completed a subjective sleep quality assessment using the Pittsburgh Sleep Quality Index.

RESULTS: Hierarchical logistic regression indicated that after controlling for demographics and mood, objective sleep quality predicted high SMD group status (ΔNagelkerke R2 = 0.07, χ2 = 9.80 (3), p = 0.020), while subjective sleep quality did not. Contrary to expectation, however, less sleep disruption predicted high SMD.

CONCLUSION: These unexpected results may suggest a non-linear trajectory between sleep and memory decline in aging. The findings are discussed in relation to previous research, which taken together, may indicate compensatory sleep patterns of reduced sleep disruption in people with high levels of SMD. These preliminary findings suggest the utility of including analysis of sleep behavior in further longitudinal research of this at-risk group of older people.

%B J Alzheimers Dis %V 53 %P 943-53 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340849?dopt=Abstract %R 10.3233/JAD-160187 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Biofunctionalized Silica Nanoparticles: Standards in Amyloid-β Oligomer-Based Diagnosis of Alzheimer's Disease. %A Hülsemann, Maren %A Zafiu, Christian %A Kühbach, Katja %A Lühmann, Nicole %A Herrmann, Yvonne %A Peters, Luriano %A Linnartz, Christina %A Willbold, Johannes %A Kravchenko, Kateryna %A Kulawik, Andreas %A Willbold, Sabine %A Bannach, Oliver %A Willbold, Dieter %X

Amyloid-β (Aβ) oligomers represent a promising biomarker for the early diagnosis of Alzheimer's disease (AD). However, state-of-the-art methods for immunodetection of Aβ oligomers in body fluids show a large variability and lack a reliable and stable standard that enables the reproducible quantitation of Aβ oligomers. At present, the only available standard applied in these assays is based on a random aggregation process of synthetic Aβ and has neither a defined size nor a known number of epitopes. In this report, we generated a highly stable standard in the size range of native Aβ oligomers that exposes a defined number of epitopes. The standard consists of a silica nanoparticle (SiNaP), which is functionalized with Aβ peptides on its surface (Aβ-SiNaP). The different steps of Aβ-SiNaP synthesis were followed by microscopic, spectroscopic and biochemical analyses. To investigate the performance of Aβ-SiNaPs as an appropriate standard in Aβ oligomer immunodetection, Aβ-SiNaPs were diluted in cerebrospinal fluid and quantified down to a concentration of 10 fM in the sFIDA (surface-based fluorescence intensity distribution analysis) assay. This detection limit corresponds to an Aβ concentration of 1.9 ng l-1 and lies in the sensitivity range of currently applied diagnostic tools based on Aβ oligomer quantitation. Thus, we developed a highly stable and well-characterized standard for the application in Aβ oligomer immunodetection assays that finally allows the reproducible quantitation of Aβ oligomers down to single molecule level and provides a fundamental improvement for the worldwide standardization process of diagnostic methods in AD research.

%B J Alzheimers Dis %V 54 %P 79-88 %8 2016 Jul 27 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472876?dopt=Abstract %R 10.3233/JAD-160253 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Biomarker Exposure-Response Analysis in Mild-To-Moderate Alzheimer's Disease Trials of Bapineuzumab. %A Russu, Alberto %A Samtani, Mahesh N %A Xu, Steven %A Adedokun, Omoniyi J %A Lu, Ming %A Ito, Kaori %A Corrigan, Brian %A Raje, Sangeeta %A Liu, Enchi %A Brashear, H Robert %A Styren, Scot %A Hu, Chuanpu %X

BACKGROUND: Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimer's disease (AD) patients.

OBJECTIVE: To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling.

METHODS: Biomarker data from two Phase III studies were combined to model the impact of bapineuzumab exposure on week-71 change from baseline in brain amyloid burden by 11C-labeled Pittsburgh compound B (PiB) PET imaging (global cortical average of the Standardized Uptake Value ratio values), cerebrospinal fluid (CSF) phosphorylated (p)-tau concentrations, and brain volumetrics (brain boundary shift integral) by magnetic resonance imaging. Bapineuzumab or placebo was administered as a 1-hour intravenous infusion every 13 weeks for 78 weeks. Pharmacokinetic/pharmacodynamic modeling helped determine the most appropriate exposure-response model and estimate the impact of disease-relevant covariates (baseline biomarker value, APOE*E4 allele copy number, and baseline disease status as measured by Mini-Mental State Examination score) on the three biomarkers.

RESULTS: Linear exposure-response relationships with negative and significant slope terms were observed for PiB PET and CSF p-tau concentration. Baseline biomarker value and APOE*E4 carrier status were significant covariates for both biomarkers. No exposure-response relationship on brain boundary shift integral was detected.

CONCLUSIONS: Bapineuzumab treatment induced exposure-dependent reductions in brain amyloid burden. Effects on CSF p-tau concentrations were significant only in APOE*E4 carriers. No apparent influence of bapineuzumab exposure on brain volume could be demonstrated.

%B J Alzheimers Dis %V 53 %P 535-46 %8 2016 May 03 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163805?dopt=Abstract %R 10.3233/JAD-151065 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly. %A Westwood, Sarah %A Leoni, Emanuela %A Hye, Abdul %A Lynham, Steven %A Khondoker, Mizanur R %A Ashton, Nicholas J %A Kiddle, Steven J %A Baird, Alison L %A Sainz-Fuertes, Ricardo %A Leung, Rufina %A Graf, John %A Hehir, Cristina Tan %A Baker, David %A Cereda, Cristina %A Bazenet, Chantal %A Ward, Malcolm %A Thambisetty, Madhav %A Lovestone, Simon %X

Increasingly, clinical trials for Alzheimer's disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aβ measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p <  0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q <  0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature.

%B J Alzheimers Dis %V 52 %P 561-72 %8 2016 Mar 29 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031486?dopt=Abstract %R 10.3233/JAD-151155 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Brain Metabolism Correlates of the Free and Cued Selective Reminding Test in Mild Cognitive Impairment. %A Caffarra, Paolo %A Ghetti, Caterina %A Ruffini, Livia %A Spallazzi, Marco %A Spotti, Annamaria %A Barocco, Federica %A Guzzo, Caterina %A Marchi, Massimo %A Gardini, Simona %K Aged %K Brain %K Cognitive Dysfunction %K Cues %K Female %K Fluorodeoxyglucose F18 %K Humans %K Male %K Memory Disorders %K Memory, Episodic %K Mental Recall %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %X

Free and Cued Selective Reminding Test (FCSRT) measures immediate and delayed episodic memory and cueing sensitivity and is suitable to detect prodromal Alzheimer's disease (AD). The present study aimed at investigating the segregation effect of FCSRT scores on brain metabolism of memory-related structures, usually affected by AD pathology, in the Mild Cognitive Impairment (MCI) stage. A cohort of forty-eight MCI patients underwent FCSRT and 18F-FDG-PET. Multiple regression analysis showed that Immediate Free Recall correlated with brain metabolism in the bilateral anterior cingulate and delayed free recall with the left anterior cingulate and medial frontal gyrus, whereas semantic cueing sensitivity with the left posterior cingulate. FCSRT in MCI is associated with neuro-functional activity of specific regions of memory-related structures connected to hippocampal formation, such as the cingulate cortex, usually damaged in AD.

%B J Alzheimers Dis %V 51 %P 27-31 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836012?dopt=Abstract %R 10.3233/JAD-150418 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebral Glucose Metabolism is Associated with Verbal but not Visual Memory Performance in Community-Dwelling Older Adults. %A Gardener, Samantha L %A Sohrabi, Hamid R %A Shen, Kai-Kai %A Rainey-Smith, Stephanie R %A Weinborn, Michael %A Bates, Kristyn A %A Shah, Tejal %A Foster, Jonathan K %A Lenzo, Nat %A Salvado, Olivier %A Laske, Christoph %A Laws, Simon M %A Taddei, Kevin %A Verdile, Giuseppe %A Martins, Ralph N %X

Increasing evidence suggests that Alzheimer's disease (AD) sufferers show region-specific reductions in cerebral glucose metabolism, as measured by [18F]-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET). We investigated preclinical disease stage by cross-sectionally examining the association between global cognition, verbal and visual memory, and 18F-FDG PET standardized uptake value ratio (SUVR) in 43 healthy control individuals, subsequently focusing on differences between subjective memory complainers and non-memory complainers. The 18F-FDG PET regions of interest investigated include the hippocampus, amygdala, posterior cingulate, superior parietal, entorhinal cortices, frontal cortex, temporal cortex, and inferior parietal region. In the cohort as a whole, verbal logical memory immediate recall was positively associated with 18F-FDG PET SUVR in both the left hippocampus and right amygdala. There were no associations observed between global cognition, delayed recall in logical memory, or visual reproduction and 18F-FDG PET SUVR. Following stratification of the cohort into subjective memory complainers and non-complainers, verbal logical memory immediate recall was positively associated with 18F-FDG PET SUVR in the right amygdala in those with subjective memory complaints. There were no significant associations observed in non-memory complainers between 18F-FDG PET SUVR in regions of interest and cognitive performance. We observed subjective memory complaint-specific associations between 18F-FDG PET SUVR and immediate verbal memory performance in our cohort, however found no associations between delayed recall of verbal memory performance or visual memory performance. It is here argued that the neural mechanisms underlying verbal and visual memory performance may in fact differ in their pathways, and the characteristic reduction of 18F-FDG PET SUVR observed in this and previous studies likely reflects the pathophysiological changes in specific brain regions that occur in preclinical AD.

%B J Alzheimers Dis %V 52 %P 661-72 %8 2016 Mar 31 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031482?dopt=Abstract %R 10.3233/JAD-151084 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebral Small Vessel Disease and Motoric Cognitive Risk Syndrome: Results from the Kerala-Einstein Study. %A Wang, Nan %A Allali, Gilles %A Kesavadas, Chandrasekharan %A Noone, Mohan L %A Pradeep, Vayyattu G %A Blumen, Helena M %A Verghese, Joe %K Aged %K Brain %K Cerebral Small Vessel Diseases %K Cognition Disorders %K Female %K Humans %K Image Processing, Computer-Assisted %K India %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Risk Factors %K Stroke, Lacunar %K White Matter %X

BACKGROUND: The contribution of cerebral small vessel disease to cognitive decline, especially in non-Caucasian populations, is not well established.

OBJECTIVE: We examined the relationship between cerebral small vessel disease and motoric cognitive risk syndrome (MCR), a recently described pre-dementia syndrome, in Indian seniors.

METHODS: 139 participants (mean age 66.6 ± 5.4 y, 33.1% female) participating in the Kerala-Einstein study in Southern India were examined in a cross-sectional study. The presence of cerebral small vessel disease (lacunar infarcts and cerebral microbleeds (CMB)) and white matter hyperintensities on MRI was ascertained by raters blinded to clinical information. MCR was defined by the presence of cognitive complaints and slow gait in older adults without dementia or mobility disability.

RESULTS: Thirty-eight (27.3%) participants met MCR criteria. The overall prevalence of lacunar infarcts and CMB was 49.6% and 9.4% , respectively. Lacunar infarcts in the frontal lobe, but no other brain regions, were associated with MCR even after adjusting for vascular risk factors and presence of white matter hyperintensities (adjusted Odds Ratio (aOR): 4.67, 95% CI: 1.69-12.94). Frontal lacunar infarcts were associated with slow gait (aOR: 3.98, 95% CI: 1.46-10.79) and poor performance on memory test (β: -1.24, 95% CI: -2.42 to -0.05), but not with cognitive complaints or non-memory tests. No association of CMB was found with MCR, individual MCR criterion or cognitive tests.

CONCLUSIONS: Frontal lacunar infarcts are associated with MCR in Indian seniors, perhaps, by contributing to slow gait and poor memory function.

%B J Alzheimers Dis %V 50 %P 699-707 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757037?dopt=Abstract %R 10.3233/JAD-150523 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Alzheimer's Disease Biomarkers Across the Spectrum of Lewy Body Diseases: Results from a Large Multicenter Cohort. %A van Steenoven, Inger %A Aarsland, Dag %A Weintraub, Daniel %A Londos, Elisabet %A Blanc, Frédéric %A van der Flier, Wiesje M %A Teunissen, Charlotte E %A Mollenhauer, Brit %A Fladby, Tormod %A Kramberger, Milica G %A Bonanni, Laura %A Lemstra, Afina W %X

BACKGROUND: Concomitant Alzheimer's disease (AD) pathology is observed in Lewy body diseases (LBD), but the clinical impact is unknown. Only a few biomarker studies in LBD exist and have included small cohorts from single centers.

OBJECTIVE: We aimed to evaluate the prevalence of abnormal cerebrospinal fluid (CSF) AD biomarkers across the spectrum of LBD in a large multicenter cohort and to assess whether an AD biomarker profile was associated with demographic and clinical differences in dementia with Lewy bodies (DLB).

METHODS: We included 375 DLB patients, 164 Parkinson's disease (PD) patients without dementia, and 55 PD patients with dementia (PDD) from 10 centers. CSF amyloid-beta42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) values were dichotomized as abnormal or normal according to locally available cut-off values. A CSF AD profile was defined as abnormal Aβ42 combined with abnormal t-tau and/or p-tau.

RESULTS: A substantial proportion of DLB patients had abnormal values for CSF Aβ42, t-tau, and p-tau, while abnormal values were uncommon in PD without dementia. Patients with PDD had values in between. A CSF AD profile was observed in 25% of DLB patients, compared with only 9% of PDD and 3% of PD without dementia. Within DLB, patients with a CSF AD profile were older, more often female, performed worse on the Mini-Mental State Examination, and had shorter disease duration compared with patients with normal CSF.

CONCLUSION: A CSF AD profile is more common in DLB compared with PDD and PD, and is associated with more severe cognitive impairment in DLB.

%B J Alzheimers Dis %V 54 %P 287-95 %8 2016 Aug 18 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567832?dopt=Abstract %R 10.3233/JAD-160322 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Cerebral Amyloid Angiopathy-Related Inflammation. %A Renard, Dimitri %A Wacongne, Anne %A Ayrignac, Xavier %A Charif, Mahmoud %A Fourcade, Genevieve %A Azakri, Souhayla %A Le Floch, Anne %A Bouly, Stephane %A Marelli, Cecilia %A Arquizan, Caroline %A Hirtz, Christophe %A Gabelle, Audrey %A Thouvenot, Eric %A Lehmann, Sylvain %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cerebral Amyloid Angiopathy %K Female %K Humans %K Inflammation %K Male %K Middle Aged %K Retrospective Studies %K tau Proteins %X

BACKGROUND: Decreased cerebrospinal fluid (CSF) amyloid-β 1-40 (Aβ40) and amyloid-β 1-42 (Aβ42) and increased total and phosphorylated tau (t-tau, p-tau) concentrations have been described in cerebral amyloid angiopathy (CAA).

OBJECTIVE: Our aim was to analyze these biomarkers in patients with CAA-related inflammation (CAA-I).

METHODS: We prospectively recruited nine patients with acute phase CAA-I fulfilling Chung criteria. CSF was analyzed for t-tau, p-tau, Aβ42, and Aβ40. Data were compared to controls (n = 14), patients with Alzheimer's disease (AD, n = 42), CAA (n = 10), and primary angiitis of the central nervous system (PACNS, n = 3).

RESULTS: For the CAA-I group, statistically significant differences were: lower Aβ42 (p = 0.00053) compared to the control group; lower t-tau (p = 0.018), p-tau (p <  0.001), and Aβ40 (p <  0.001) compared to AD; lower Aβ42 (p = 0.027) compared to CAA; lower Aβ42 (p = 0.012) compared to PACNS. Nearly significantly lower Aβ40 (p = 0.051) and higher t-tau (p = 0.051) were seen in CAA-I compared to controls.

CONCLUSION: CSF biomarkers profile similar to that of CAA was observed in CAA-I (with even lower levels of Aβ42 compared to CAA). Based on our findings, high p-tau seems more specific for AD, whereas low Aβ42 differentiates CAA-I from CAA, PACNS, and controls, and low Aβ40 differentiates CAA-I from AD.

%B J Alzheimers Dis %V 50 %P 759-64 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757185?dopt=Abstract %R 10.3233/JAD-150621 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Anti-Amyloid-β Autoantibodies and Amyloid PET in Cerebral Amyloid Angiopathy-Related Inflammation. %A Carmona-Iragui, María %A Fernández-Arcos, Ana %A Alcolea, Daniel %A Piazza, Fabrizio %A Morenas-Rodriguez, Estrella %A Antón-Aguirre, Sofía %A Sala, Isabel %A Clarimón, Jordi %A Dols-Icardo, Oriol %A Camacho, Valle %A Sampedro, Frederic %A Munuera, Josep %A Nuñez-Marin, Fidel %A Lleo, Alberto %A Fortea, Juan %A Gómez-Ansón, Beatriz %A Blesa, Rafael %K Aged %K Amyloid beta-Peptides %K Aniline Compounds %K Apolipoproteins E %K Autoantibodies %K Cerebral Amyloid Angiopathy %K Ethylene Glycols %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Meningoencephalitis %K Peptide Fragments %K Positron-Emission Tomography %K Statistics, Nonparametric %K tau Proteins %X

We report a biomarker and genetic evaluation of four patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) treated with corticosteroids. Patients presented with focal symptomatology and cognitive impairment. MRI revealed cortical microbleeds and asymmetrical hyperintense white matter lesions (WML). Cerebrospinal fluid (CSF) biomarker analyses showed increased anti-Aβ autoantibodies, t-Tau, and p-Tau and decreased Aβ40 and Aβ42. After treatment, focal symptomatology disappeared, and WML and anti-Aβ autoantibodies decreased. The APOEɛ4 allele was overrepresented. Florbetapir-PET showed cortical deposition with lower retention in swollen areas. In the case of suspected CAA-ri, both CSF anti-Aβ autoantibodies levels and Florbetapir-PET could provide highly useful data to guide the correct diagnosis.

%B J Alzheimers Dis %V 50 %P 1-7 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639966?dopt=Abstract %R 10.3233/JAD-150614 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Biomarkers and Reserve Variables as Predictors of Future "Non-Cognitive" Outcomes of Alzheimer's Disease. %A Ingber, Adam P %A Hassenstab, Jason %A Fagan, Anne M %A Benzinger, Tammie L S %A Grant, Elizabeth A %A Holtzman, David M %A Morris, John C %A Roe, Catherine M %X

BACKGROUND: The influence of reserve variables and Alzheimer's disease (AD) biomarkers on cognitive test performance has been fairly well-characterized. However, less is known about the influence of these factors on "non-cognitive" outcomes, including functional abilities and mood.

OBJECTIVE: We examined whether cognitive and brain reserve variables mediate how AD biomarker levels in cognitively normal persons predict future changes in function, mood, and neuropsychiatric behavior.

METHODS: Non-cognitive outcomes were examined in 328 individuals 50 years and older enrolled in ongoing studies of aging and dementia at the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal at baseline (Clinical Dementia Rating [CDR] 0), completed cerebrospinal fluid (CSF) and structural neuroimaging studies within one year of baseline, and were followed for an average of 4.6 annual visits. Linear mixed effects models explored how cognitive reserve and brain reserve variables mediate the relationships between AD biomarker levels and changes in function, mood, and neuropsychiatric behavior in cognitively normal participants.

RESULTS: Education levels did not have a significant effect on predicting non-cognitive decline. However, participants with smaller brain volumes exhibited the worst outcomes on measures of mood, functional abilities, and behavioral disturbance. This effect was most pronounced in individuals who also had abnormal CSF biomarkers.

CONCLUSIONS: The findings suggest that brain reserve plays a stronger, or earlier, role than cognitive reserve in protecting against non-cognitive impairment in AD.

%B J Alzheimers Dis %V 52 %P 1055-64 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104893?dopt=Abstract %R 10.3233/JAD-150478 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Fatty Acid-Binding Protein 3 is Related to Dementia Development in a Population-Based Sample of Older Adult Women Followed for 8 Years. %A Bjerke, Maria %A Kern, Silke %A Blennow, Kaj %A Zetterberg, Henrik %A Waern, Margda %A Börjesson-Hanson, Anne %A Östling, Svante %A Kern, Jürgen %A Skoog, Ingmar %K Aged %K Aged, 80 and over %K Albumins %K Amyloid beta-Peptides %K Community Health Planning %K Dementia %K Fatty Acid-Binding Proteins %K Female %K Humans %K Longitudinal Studies %K Peptide Fragments %K Sweden %K tau Proteins %X

BACKGROUND: Increased fatty acid-binding protein 3 (FABP-3) levels have been reported in neurodegenerative diseases, including Alzheimer's disease (AD). Cerebrospinal fluid (CSF) FABP-3 has therefore been proposed as a putative marker for dementia. Population-based studies examining whether CSF FABP-3 predicts later development of dementia are lacking.

OBJECTIVE: The aim of this study was to examine CSF levels of FABP-3 in relation to later development of dementia in elderly women and in relation to Aβ42, T-tau, P-tau181, and CSF: serum albumin ratio.

METHODS: 86 non-demented women aged 70-84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992-93. CSF-FABP-3, Aβ42, T-tau, P-tau181, and the CSF: serum albumin ratio were measured at baseline. Participants were examined with a neuropsychiatric exam at baseline and at follow-up in 2000. Dementia was diagnosed in accordance with DSM-III-R criteria.

RESULTS: Between 1992 and 2000, 8 women developed dementia (4 AD, 3 vascular dementia, 1 mixed vascular dementia and AD). Higher levels of CSF-FABP-3 at baseline were related to development of dementia (OR 1.36 CI [1.05-1.76] p = 0.022) and the subtype AD (OR 1.38 CI [1.06-1.82), p = 0.019) during follow-up. FABP-3 correlated with CSF T-tau (r = 0.88, p <  0.001), P-tau181 (r = 0.619, p <  0.001), and CSF:serum albumin ratio (r = 0.233, p = 0.031), but not with Aβ42 (r = -0.08, p = 0.444)CONCLUSION:CSF FABP-3 may be an early marker for later development of dementia, probably related to neuronal degeneration, but independent of Aβ metabolism.

%B J Alzheimers Dis %V 49 %P 733-41 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484922?dopt=Abstract %R 10.3233/JAD-150525 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Markers of Alzheimer's Disease Pathology and Microglial Activation are Associated with Altered White Matter Microstructure in Asymptomatic Adults at Risk for Alzheimer's Disease. %A Melah, Kelsey E %A Lu, Sharon Yuan-Fu %A Hoscheidt, Siobhan M %A Alexander, Andrew L %A Adluru, Nagesh %A Destiche, Daniel J %A Carlsson, Cynthia M %A Zetterberg, Henrik %A Blennow, Kaj %A Okonkwo, Ozioma C %A Gleason, Carey E %A Dowling, N Maritza %A Bratzke, Lisa C %A Rowley, Howard A %A Sager, Mark A %A Asthana, Sanjay %A Johnson, Sterling C %A Bendlin, Barbara B %K Adipokines %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Chemokine CCL2 %K Chitinase-3-Like Protein 1 %K Diffusion Tensor Imaging %K Female %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Lectins %K Male %K Microglia %K Middle Aged %K Peptide Fragments %K tau Proteins %K White Matter %X

BACKGROUND: The immune response in Alzheimer's disease (AD) involves activation of microglia which may remove amyloid-β (Aβ). However, overproduction of inflammatory compounds may exacerbate neural damage in AD. AD pathology accumulates years before diagnosis, yet the extent to which neuroinflammation is involved in the earliest disease stages is unknown.

OBJECTIVE: To determine whether neuroinflammation exacerbates neural damage in preclinical AD.

METHODS: We utilized cerebrospinal fluid (CSF) and magnetic resonance imaging collected in 192 asymptomatic late-middle-aged adults (mean age = 60.98 years). Neuroinflammatory markers chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1) in CSF were utilized as markers of neuroinflammation. Neural cell damage was assessed using CSF neurofilament light chain protein (NFL), CSF total tau (T-Tau), and neural microstructure assessed with diffusion tensor imaging (DTI). With regard to AD pathology, CSF Aβ42 and tau phosphorylated at threonine 181 (P-Tau181) were used as markers of amyloid and tau pathology, respectively. We hypothesized that higher YKL-40 and MCP-1 in the presence of AD pathology would be associated with higher NFL, T-Tau, and altered microstructure on DTI.

RESULTS: Neuroinflammation was associated with markers of neural damage. Higher CSF YKL-40 was associated with both higher CSF NFL and T-Tau. Inflammation interacted with AD pathology, such that greater MCP-1 and lower Aβ42 was associated with altered microstructure in bilateral frontal and right temporal lobe and that greater MCP-1 and greater P-Tau181 was associated with altered microstructure in precuneus.

CONCLUSION: Inflammation may play a role in neural damage in preclinical AD.

%B J Alzheimers Dis %V 50 %P 873-86 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836182?dopt=Abstract %R 10.3233/JAD-150897 %0 Journal Article %J J Alzheimers Dis %D 2016 %T CerefolinNAC Therapy of Hyperhomocysteinemia Delays Cortical and White Matter Atrophy in Alzheimer's Disease and Cerebrovascular Disease. %A Shankle, William R %A Hara, Junko %A Barrentine, Lori W %A Curole, Melanie V %X

We examined whether using a medical food therapy for hyperhomocysteinemia (HHcy) in patients with Alzheimer's disease (AD) or cognitive impairment due to cerebrovascular disease (CVD) with Cerefolin®/CerefolinNAC® (CFLN: L-methylfolate, methylcobalamin, and N-acetyl-cysteine) slowed regional brain atrophy. Thirty HHcy patients with AD and related disorders (ADRD) received CFLN (HHcy+CFLN: duration [μ ±  σ] = 18.6±16.1 months); a sub-sample of this group did not receive CFLN for varying periods of time (HHcy+NoCFLN: duration [μ ±  σ] = 12.6±5.6 months). Thirty-seven NoHHcy patients with ADRD did not receive CFLN (NoHHcy+NoCFLN: duration [μ ±  σ] = 13.3±17.7 months). No participant took supplemental B vitamins. Regional brain volumes were measured at baseline and end of study, and covariate-adjusted rates of hippocampal, cortical, and forebrain parenchymal (includes white matter) atrophy were predicted. The HHcy+CFLN group's hippocampal and cortical atrophy adjusted rates were 4.25 and 11.2 times slower than those of the NoHHcy+NoCFLN group (p < 0.024). The HHcy+CFLN group's forebrain parenchyma atrophy rate was significantly slower only for CVD; the rate of slowing was proportional to the degree of homocysteine lowering (p < 0.0001). CFLN was associated with significantly slowed hippocampal and cortical atrophy rates in ADRD patients with HHcy, and forebrain parenchymal atrophy rates in CVD patients with HHcy. The present results should be further validated.

%B J Alzheimers Dis %V 54 %P 1073-1084 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567825?dopt=Abstract %R 10.3233/JAD-160241 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Changes in Brain Volume with Bapineuzumab in Mild to Moderate Alzheimer's Disease. %A Novak, Gerald %A Fox, Nick %A Clegg, Shona %A Nielsen, Casper %A Einstein, Steven %A Lu, Yuan %A Tudor, Iulia Cristina %A Gregg, Keith %A Di, Jianing %A Collins, Peter %A Wyman, Bradley T %A Yuen, Eric %A Grundman, Michael %A Brashear, H Robert %A Liu, Enchi %K Aged %K Alzheimer Disease %K Antibodies, Monoclonal, Humanized %K Apolipoprotein E4 %K Brain %K Double-Blind Method %K Female %K Heterozygote %K Humans %K Least-Squares Analysis %K Magnetic Resonance Imaging %K Male %K Nootropic Agents %K Organ Size %K Severity of Illness Index %K Treatment Outcome %X

BACKGROUND: Bapineuzumab, an anti-amyloid-β monoclonal antibody, was evaluated in two placebo-controlled trials in APOE*ɛ4 carriers and noncarriers, respectively, with Alzheimer's disease.

OBJECTIVES: A volumetric magnetic resonance imaging substudy was performed to determine if bapineuzumab altered brain volume rate of change.

METHODS: Bapineuzumab dosages included 0.5 mg/kg in carriers and 0.5 or 1.0 mg/kg in noncarriers, every 13 weeks for 78 weeks. Volumetric outcomes included annualized brain, ventricular, and mean hippocampal boundary shift integrals (BBSI; VBSI; HBSI) up to Week 71. Treatment differences were estimated using mixed models for repeated measures.

RESULTS: For BBSI and HBSI, there were no significant treatment-related differences within either study, but, compared to pooled carriers and noncarriers receiving placebo, noncarriers receiving1.0 mg/kg bapineuzumab had greater increases in these measures. Bapineuzumab-treated patients showed significantly greater VBSI rates compared with placebo for 0.5 mg/kg in carriers and 1.0 mg/kg (but not 0.5 mg/kg) in noncarriers.

CONCLUSIONS: Bapineuzumab produced an increase in ventricular volume compared with placebo. Etiology for this increase is unclear but may be related to amyloid-β clearance or its consequences.

%B J Alzheimers Dis %V 49 %P 1123-34 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639957?dopt=Abstract %R 10.3233/JAD-150448 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Changes in Neural Connectivity and Memory Following a Yoga Intervention for Older Adults: A Pilot Study. %A Eyre, Harris A %A Acevedo, Bianca %A Yang, Hongyu %A Siddarth, Prabha %A Van Dyk, Kathleen %A Ercoli, Linda %A Leaver, Amber M %A Cyr, Natalie St %A Narr, Katherine %A Baune, Bernhard T %A Khalsa, Dharma S %A Lavretsky, Helen %X

BACKGROUND: No study has explored the effect of yoga on cognitive decline and resting-state functional connectivity.

OBJECTIVES: This study explored the relationship between performance on memory tests and resting-state functional connectivity before and after a yoga intervention versus active control for subjects with mild cognitive impairment (MCI).

METHODS: Participants ( ≥ 55 y) with MCI were randomized to receive a yoga intervention or active "gold-standard" control (i.e., memory enhancement training (MET)) for 12 weeks. Resting-state functional magnetic resonance imaging was used to map correlations between brain networks and memory performance changes over time. Default mode networks (DMN), language and superior parietal networks were chosen as networks of interest to analyze the association with changes in verbal and visuospatial memory performance.

RESULTS: Fourteen yoga and 11 MET participants completed the study. The yoga group demonstrated a statistically significant improvement in depression and visuospatial memory. We observed improved verbal memory performance correlated with increased connectivity between the DMN and frontal medial cortex, pregenual anterior cingulate cortex, right middle frontal cortex, posterior cingulate cortex, and left lateral occipital cortex. Improved verbal memory performance positively correlated with increased connectivity between the language processing network and the left inferior frontal gyrus. Improved visuospatial memory performance correlated inversely with connectivity between the superior parietal network and the medial parietal cortex.

CONCLUSION: Yoga may be as effective as MET in improving functional connectivity in relation to verbal memory performance. These findings should be confirmed in larger prospective studies.

%B J Alzheimers Dis %V 52 %P 673-84 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060939?dopt=Abstract %R 10.3233/JAD-150653 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Characteristics of Alzheimer's Disease Patients with Severe Executive Disorders. %A Godefroy, Olivier %A Bakchine, Serge %A Verny, Marc %A Delabrousse-Mayoux, Jean-Philippe %A Roussel, Martine %A Pere, Jean-Jacques %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Caregivers %K Cost of Illness %K Executive Function %K Female %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Prevalence %K Severity of Illness Index %K Treatment Outcome %X

BACKGROUND: Executive dysfunctions in Alzheimer's disease (AD) have been assessed using variable batteries and/or in selected populations.

OBJECTIVE: The primary objective of this observational study was to determine the prevalence and severity of executive dysfunction in AD patients using a previously validated battery. The secondary objective was to determine the characteristics including treatment outcomes of AD patients with severe executive dysfunction.

METHODS: The study included AD patients with mild-to-moderate dementia aged 60 or over, consulting in various clinical settings including memory clinics and requiring the introduction of an antidementia drug. Executive dysfunction was examined using a validated, shortened executive battery.

RESULTS: 381 patients were included. Executive dysfunctions were observed in 88.2% of the patients (95% CI: 84.9-91.4) and were severe (defined as ≥2/3 impaired scores) in 80.4% (95% CI: 76.9-84.8). Global hypoactivity with apathy was more frequent (p = 0.0001) than impairment in executive function tests. The 308 patients with severe executive dysfunction were older (p = 0.003) and had more severe dementia (p = 0.0001). Similarly, in the subset of 257 patients with mild dementia, individuals with severe executive dysfunction were older (p = 0.003) and had more severe dementia. Global hypoactivity was independently associated with difficulties in IADL and a higher caregiver burden (p = 0.0001 for both). The severity of executive dysfunction did not significantly influence the patients' outcomes at 6 months.

CONCLUSIONS: Executive dysfunction is a very common disorder in a representative population of patients with mild-to-moderate AD. It was independently correlated with impaired autonomy and increased caregiver burden but did not significantly influence treatment outcomes.

%B J Alzheimers Dis %V 51 %P 815-25 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890770?dopt=Abstract %R 10.3233/JAD-150971 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Characterization of Alzheimer's Disease and Mild Cognitive Impairment in Older Adults in Panama. %A Villarreal, Alcibiades E %A Grajales, Shantal %A O'Bryant, Sid E %A Edwards, Melissa %A López, Lineth %A Montalván, Astevia %A Britton, Gabrielle B %X

Research on age-related cognitive impairment is scarce in Central America. We report factors associated with cognitive impairment among a sample of older adults in Panama diagnosed with Alzheimer's disease (AD, n = 31), mild cognitive impairment (MCI, n = 43), or no cognitive impairment (controls, n = 185). Apolipoprotein E (ApoE) genotype was assessed in a subset of cases (n = 135). Age (OR = 2.53, 95% CI = 1.03-6.17) and ApoE ɛ4 (OR = 5.14, 95% CI = 2.11-12.52) were significantly related to cognitive impairment (AD/MCI combined). Results underscore the potential of genetic screening in Panama for identifying those at risk of dementia.

%B J Alzheimers Dis %V 54 %P 897-901 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567849?dopt=Abstract %R 10.3233/JAD-160402 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Characterization of Amyloid-β Deposits in Bovine Brains. %A Vallino Costassa, Elena %A Fiorini, Michele %A Zanusso, Gianluigi %A Peletto, Simone %A Acutis, Pierluigi %A Baioni, Elisa %A Maurella, Cristiana %A Tagliavini, Fabrizio %A Catania, Marcella %A Gallo, Marina %A Faro, Monica Lo %A Chieppa, Maria Novella %A Meloni, Daniela %A D'Angelo, Antonio %A Paciello, Orlando %A Ghidoni, Roberta %A Tonoli, Elisa %A Casalone, Cristina %A Corona, Cristiano %K Aging %K Amyloid beta-Peptides %K Animals %K Apolipoproteins E %K Blotting, Western %K Brain %K Cattle %K Extracellular Space %K Gene Frequency %K Genotyping Techniques %K Glial Fibrillary Acidic Protein %K Immunohistochemistry %K Intracellular Space %K Neuroglia %K Neurons %K Polymorphism, Genetic %K Presenilin-1 %K Presenilin-2 %K Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization %X

Amyloid-β (Aβ) deposits are seen in aged individuals of many mammalian species that possess the same aminoacid sequence as humans. This study describes Aβ deposition in 102 clinically characterized cattle brains from animals aged 0 to 20 years. Extracellular and intracellular Aβ deposition was detected with 4G8 antibody in the cortex, hippocampus, and cerebellum. X-34 staining failed to stain Aβ deposits, indicating the non β-pleated nature of these deposits. Western blot analysis and surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry revealed in Tris, Triton, and formic acid fractions the presence of different Aβ peptides, characterized mainly by C-terminally truncated forms. Exploration of the genetic variability of APOE, PSEN1, and PSEN2 genes involved in Alzheimer's disease pathogenesis revealed several previously unreported polymorphisms. This study demonstrates certain similarities between Aβ deposition patterns exhibited in cattle brains and those in the human brain in early stages of aging. Furthermore, the identification of the same Aβ peptides reported in humans, but unable to form aggregates, supports the hypothesis that cattle may be protected against amyloid plaque formation.

%B J Alzheimers Dis %V 51 %P 875-87 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890772?dopt=Abstract %R 10.3233/JAD-151007 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Characterizing Aging, Mild Cognitive Impairment, and Dementia with Blood-Based Biomarkers and Neuropsychology. %A Kleinschmidt, Martin %A Schoenfeld, Robby %A Göttlich, Claudia %A Bittner, Daniel %A Metzner, Jürgen Erich %A Leplow, Bernd %A Demuth, Hans-Ulrich %K Activities of Daily Living %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Aging %K Amyloid beta-Peptides %K Analysis of Variance %K Apolipoproteins E %K Biomarkers %K Case-Control Studies %K Cognitive Dysfunction %K Cross-Sectional Studies %K Cytokines %K Dementia %K Female %K Humans %K Male %K Memory Disorders %K Middle Aged %K Neuropsychological Tests %K Young Adult %X

BACKGROUND: Current treatment in Alzheimer's disease (AD) is initiated at a stage where the brain already has irreversible structural deteriorations. Therefore, the concept of treatment prior to obvious cognitive deficits has become widely accepted, and simple biochemical tests to discriminate normal aging from prodromal or demented stages are now common practice.

OBJECTIVE: The objective of the study was the differentiation of controls, mild cognitive impairment (MCI) and AD patients by novel blood-based assays in combination with neuropsychological tests.

METHODS: In a cross-sectional study, 143 subjects aged 18 to 85 years were recruited. All participants were classified by a comprehensive neuropsychological assessment. Blood samples were analyzed for several amyloid-β (Aβ) species, pro-inflammatory markers, anti-Aβ autoantibodies, and ApoE allele status, respectively.

RESULTS: Plasma Aβ1-42 was significantly decreased in MCI and AD compared to age-matched controls, whereas Aβ1-40 did not differ, but increases with age in healthy controls. The Aβ1-42 to Aβ1-40 ratio was stepwise decreased from age-matched controls via MCI to AD, and shows a clear correlation with memory scores. Reduced Aβ1-42 and Aβ1-42 to Aβ1-40 ratio have strongly correlated with carrying ApoE ɛ4 allele. Autoantibodies against pyroglutamate-modified Aβ, but only a certain subclass, were significantly decreased in AD compared to MCI and age-matched controls, whereas autoantibodies against the unmodified N-terminus of Aβ did not differ.

CONCLUSION: Comprehensive sample preparation and assay standardization enable reliable usage of plasma Aβ for diagnosis of MCI and AD. Anti-pGlu-Aβ autoantibodies correlate with cognition, but not with ApoE, supporting the associated plasma Aβ analysis with additional and independent information.

%B J Alzheimers Dis %V 50 %P 111-26 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639953?dopt=Abstract %R 10.3233/JAD-143189 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Chocolate Consumption is Associated with a Lower Risk of Cognitive Decline. %A Moreira, Afonso %A Diógenes, Maria José %A de Mendonça, Alexandre %A Lunet, Nuno %A Barros, Henrique %X

Cocoa-related products like chocolate have taken an important place in our food habits and culture. In this work, we aim to examine the relationship between chocolate consumption and cognitive decline in an elderly cognitively healthy population. In the present longitudinal prospective study, a cohort of 531 participants aged 65 and over with normal Mini-Mental State Examination (MMSE; median 28) was selected. The median follow-up was 48 months. Dietary habits were evaluated at baseline. The MMSE was used to assess global cognitive function at baseline and at follow-up. Cognitive decline was defined by a decrease ≥ 2 points in the MMSE score between evaluations. Relative risk (RR) and 95% confidence interval (95% CI) estimates were adjusted for age, education, smoking, alcohol drinking, body mass index, hypertension, and diabetes. Chocolate intake was associated with a lower risk of cognitive decline (RR = 0.59, 95% CI 0.38-0.92). This protective effect was observed only among subjects with an average daily consumption of caffeine lower than 75 mg (69% of the participants; RR = 0.50, 95% CI 0.31-0.82). To our knowledge, this is the first prospective cohort study to show an inverse association between regular long-term chocolate consumption and cognitive decline in humans.

%B J Alzheimers Dis %V 53 %P 85-93 %8 2016 May 06 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163823?dopt=Abstract %R 10.3233/JAD-160142 %0 Journal Article %J J Alzheimers Dis %D 2016 %T CHRNA7 Gene and Response to Cholinesterase Inhibitors in an Italian Cohort of Alzheimer's Disease Patients. %A Clarelli, Ferdinando %A Mascia, Elisabetta %A Santangelo, Roberto %A Mazzeo, Salvatore %A Giacalone, Giacomo %A Galimberti, Daniela %A Fusco, Federica %A Zuffi, Marta %A Fenoglio, Chiara %A Franceschi, Massimo %A Scarpini, Elio %A Forloni, Gianluigi %A Magnani, Giuseppe %A Comi, Giancarlo %A Albani, Diego %A Martinelli Boneschi, Filippo %X

Previous studies suggest that genetic variants in CHRNA7, which encodes for the major subunit of the acetylcholine receptor (α7-nAChR), are associated with the clinical response to cholinesterase inhibitors (ChEI) in Alzheimer's disease (AD) patients. We sought to replicate the association of two SNPs in the CHRNA7 gene, rs6494223 and rs8024987, with response to ChEI treatment in an Italian cohort of 169 AD patients, further extending the study to gene-level analysis. None of the tested variants was associated with clinical response. However, rs6494223 showed a consistent effect direction (OR = 1.4; p = 0.17), which after meta-analysis with previous study yielded a significant result (OR = 1.57, p = 0.02, I2 = 0%).

%B J Alzheimers Dis %V 52 %P 1203-8 %8 2016 Apr 16 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104904?dopt=Abstract %R 10.3233/JAD-160074 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Circadian Disruption Reveals a Correlation of an Oxidative GSH/GSSG Redox Shift with Learning and Impaired Memory in an Alzheimer's Disease Mouse Model. %A LeVault, Kelsey R %A Tischkau, Shelley A %A Brewer, Gregory J %K Age Factors %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Analysis of Variance %K Animals %K Brain %K Chromatography, High Pressure Liquid %K Chronobiology Disorders %K Disease Models, Animal %K Gene Expression Regulation %K Glutathione %K Glutathione Disulfide %K Humans %K Memory Disorders %K Mice %K Mice, Transgenic %K Mutation %K NADP %K Nitric Oxide Synthase Type II %K Oxidation-Reduction %X

It is unclear whether pre-symptomatic Alzheimer's disease (AD) causes circadian disruption or whether circadian disruption accelerates AD pathogenesis. In order to examine the sensitivity of learning and memory to circadian disruption, we altered normal lighting phases by an 8 h shortening of the dark period every 3 days (jet lag) in the APPSwDI NOS2-/- model of AD (AD-Tg) at a young age (4-5 months), when memory is not yet affected compared to non-transgenic (non-Tg) mice. Analysis of activity in 12-12 h lighting or constant darkness showed only minor differences between AD-Tg and non-Tg mice. Jet lag greatly reduced activity in both genotypes during the normal dark time. Learning on the Morris water maze was significantly impaired only in the AD-Tg mice exposed to jet lag. However, memory 3 days after training was impaired in both genotypes. Jet lag caused a decrease of glutathione (GSH) levels that tended to be more pronounced in AD-Tg than in non-Tg brains and an associated increase in NADH levels in both genotypes. Lower brain GSH levels after jet lag correlated with poor performance on the maze. These data indicate that the combination of the environmental stress of circadian disruption together with latent stress of the mutant amyloid and NOS2 knockout contributes to cognitive deficits that correlate with lower GSH levels.

%B J Alzheimers Dis %V 49 %P 301-16 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484899?dopt=Abstract %R 10.3233/JAD-150026 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Circulating microRNAs as Biomarkers of Alzheimer's Disease: A Systematic Review. %A Wu, Helen Zong Ying %A Ong, Kwok Leung %A Seeher, Katrin %A Armstrong, Nicola J %A Thalamuthu, Anbupalam %A Brodaty, Henry %A Sachdev, Perminder %A Mather, Karen %K Alzheimer Disease %K Biomarkers %K Databases, Bibliographic %K Humans %K MicroRNAs %X

BACKGROUND: In recent years, microRNAs (miRNA), a class of non-coding RNA known to regulate protein expression post-transcriptionally, have been recognized as novel biomarkers of diseases.

OBJECTIVE: In this systematic review, we identify miRNAs that are differentially expressed in Alzheimer's disease (AD) and/or mild cognitive impairment (MCI) and evaluate their accuracy as potential blood biomarkers.

METHODS: Eligible studies of miRNAs in peripheral blood distinguishing patients with AD or MCI from cognitively normal controls were identified through standardized search strategies in Medline, PubMed, and Embase. MiRNAs that were differentially expressed were identified and where available their sensitivity and specificity for AD or MCI extracted from the retrieved studies.

RESULTS: Eighteen studies investigated the diagnostic value of miRNAs as peripheral biomarkers of AD/MCI. Twenty miRNAs were significantly upregulated and 32 miRNAs downregulated in AD compared to controls in ten AD studies. Nine miRNAs were consistently dysregulated in more than one study. Of the 8 MCI studies, only one miRNA, miR-132, was consistently upregulated in three independent studies. Of the studies that reported diagnostic accuracy data, the majority of miRNA panels and individual miRNAs had a sensitivity and specificity greater than 0.75.

CONCLUSION: Individual studies suggest that miRNAs can differentiate patients with AD/MCI from cognitively normal controls with modest accuracy. However, the literature is constrained by methodological differences between studies, with few studies assessing the same miRNAs. To become potential biomarkers for AD, further studies with standardized study designs for replication and validation are required. Results from this review may help researchers select candidate miRNAs for further investigation.

%B J Alzheimers Dis %V 49 %P 755-66 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484928?dopt=Abstract %R 10.3233/JAD-150619 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Clearing Amyloid-β through PPARγ/ApoE Activation by Genistein is a Treatment of Experimental Alzheimer's Disease. %A Bonet-Costa, Vicent %A Herranz-Pérez, Vicente %A Blanco-Gandía, MariCarmen %A Mas-Bargues, Cristina %A Inglés, Marta %A Garcia-Tarraga, Patricia %A Rodriguez-Arias, Marta %A Miñarro, Jose %A Borras, Consuelo %A Garcia-Verdugo, Jose Manuel %A Viña, Jose %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Apolipoproteins E %K Astrocytes %K Avoidance Learning %K Brain %K Cells, Cultured %K Disease Models, Animal %K Female %K Genistein %K Habituation, Psychophysiologic %K Maze Learning %K Mice, Inbred C57BL %K Mice, Transgenic %K Neuroprotective Agents %K Nootropic Agents %K Olfactory Perception %K Plaque, Amyloid %K PPAR gamma %K Recognition (Psychology) %K Tetrahydronaphthalenes %X

Amyloid-β (Aβ) clearance from brain, which is decreased in Alzheimer's disease, is facilitated by apolipoprotein E (ApoE). ApoE is upregulated by activation of the retinoid X receptor moiety of the RXR/PPARγ dimeric receptor. Genistein, a non-toxic, well-tested, and inexpensive drug activates the other moiety of the receptor PPARγ. Treatment of an Alzheimer's disease mouse model with genistein results in a remarkable and rapid improvement in various parameters of cognition, such as hippocampal learning, recognition memory, implicit memory, and odor discrimination. This is associated with a lowering of Aβ levels in brain, in the number and the area of amyloid plaques (confirmed in vivo by positron emission tomography) as well as in microglial reactivity. Finally, incubation of primary astrocytes with genistein results in a PPARγ-mediated increased release of ApoE. Our results strongly suggest that controlled clinical trials should be performed to test the effect of genistein as treatment of human Alzheimer's disease.

%B J Alzheimers Dis %V 51 %P 701-11 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890773?dopt=Abstract %R 10.3233/JAD-151020 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Clinical Conversion or Reversion of Mild Cognitive Impairment in Community versus Hospital Based Studies: GDEMCIS (Gwangju Dementia and Mild Cognitive Impairment Study) and CREDOS (Clinical Research Center for Dementia of South Korea). %A Roh, Hyun Woong %A Hong, Chang Hyung %A Lee, Yunhwan %A Lee, Kang Soo %A Chang, Ki Jung %A Kang, Dae Ryong %A Lee, Jung-Dong %A Choi, Seong Hye %A Kim, Seong Yoon %A Na, Duk L %A Seo, Sang Won %A Kim, Doh Kwan %A Back, Joung Hwan %A Chung, Young Ki %A Lim, Ki Young %A Noh, Jai Sung %A Son, Sang Joon %X

BACKGROUND: In keeping with increasing interest in dementia, few recent studies suggest that clinical course of mild cognitive impairment vary across different studies with hospital-based subjects showing higher rates of conversion than community-based subjects.

OBJECTIVE: The main objective of the present study was to assess whether the clinical conversion or reversion rates differ according to recruitment source.

METHODS: The baseline study subjects comprised of patients who were diagnosed with mild cognitive impairment in community-based GDEMCIS or hospital-based CREDOS. The two studies had nearly the same protocol and were performed over a similar period. We used propensity score matching for baseline comparability. After that, Cox proportional hazards regression analyses were conducted to estimate the hazard ratios and 95% confidence intervals of clinical conversion or reversion.

RESULTS: Based on 89 GDEMCIS subjects, 1 : 4 propensity score matching was conducted and 356 CREDOS subjects were selected. After adjusting for covariates including baseline demographics, comorbidity, depression, disability, and neuropsychological result, Cox proportional hazard regression analysis for time to clinical conversion indicated that recruitment from hospital-based CREDOS exhibited hazard ratio of 2.13 (95% CI, 1.08-4.21), as compared to recruitment from community-based GDEMCIS. Similarly, Cox proportional hazard regression analysis for time to reversion indicated that recruitment from hospital-based CREDOS exhibited hazard ratio of 0.34 (95% CI, 0.20-0.59), as compared to recruitment from community-based GDEMCIS.

CONCLUSION: The present study demonstrated that even after the matching process and adjustments for baseline covariates, recruitment source greatly affected the course of mild cognitive impairment.

%B J Alzheimers Dis %V 53 %P 463-73 %8 2016 May 03 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163831?dopt=Abstract %R 10.3233/JAD-160341 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Clinical Impact of a Second FDG-PET in Atypical/Unclear Dementia Syndromes. %A Bergeron, David %A Beauregard, Jean-Mathieu %A Guimond, Jean %A Fortin, Marie-Pierre %A Houde, Michèle %A Poulin, Stéphane %A Verret, Louis %A Bouchard, Rémi W %A Laforce, Robert %K Adult %K Brain %K Dementia %K Diagnosis, Differential %K Female %K Fluorodeoxyglucose F18 %K Humans %K Male %K Middle Aged %K Positron-Emission Tomography %K Radiopharmaceuticals %K Retrospective Studies %X

Diagnosis of atypical/unclear dementia is often difficult and this delays treatment initiation. Several authors have shown that beyond standard dementia workup, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) reduces the number of unclear diagnoses, leads to earlier treatment, and has a beneficial impact on families. However, it is not uncommon that the FDG-PET findings are equivocal in this setting. For those cases, a repeat FDG-PET may clarify the diagnosis and prevent treatment delay. We retrospectively assessed the clinical impact of a repeat FDG-PET in 59 patients with atypical/unclear dementia syndromes and inconclusive initial FDG-PET. Changes in primary diagnosis, diagnostic confidence, and management following the second FDG-PET were examined. Conducting a second FDG-PET reduced the number of unclear diagnoses from 80% to 34% , led to diagnostic change in 24% of cases, and treatment modification in 22% of patients. Overall, the clinical impact was higher when initial diagnostic confidence was low and the second FDG-PET repeated ≥12 months after the first one. In tertiary care memory clinic settings, when diagnostic incertitude persists despite extensive evaluation and an equivocal FDG-PET, repeating the FDG-PET 12 months later can greatly clarify the diagnosis and improve management.

%B J Alzheimers Dis %V 49 %P 695-705 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484904?dopt=Abstract %R 10.3233/JAD-150302 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Clinical Utility of Amyloid PET Imaging in the Differential Diagnosis of Atypical Dementias and Its Impact on Caregivers. %A Bensaïdane, Mohamed Reda %A Beauregard, Jean-Mathieu %A Poulin, Stéphane %A Buteau, François-Alexandre %A Guimond, Jean %A Bergeron, David %A Verret, Louis %A Fortin, Marie-Pierre %A Houde, Michèle %A Bouchard, Rémi W %A Soucy, Jean-Paul %A Laforce, Robert %X

Recent studies have supported a role for amyloid positron emission tomography (PET) imaging in distinguishing Alzheimer's disease (AD) pathology from other pathological protein accumulations leading to dementia. We investigated the clinical utility of amyloid PET in the differential diagnosis of atypical dementia cases and its impact on caregivers. Using the amyloid tracer 18F-NAV4694, we prospectively scanned 28 patients (mean age 59.3 y, s.d. 5.8; mean MMSE 21.4, s.d. 6.0) with an atypical dementia syndrome. Following a comprehensive diagnostic workup (i.e., history taking, neurological examination, blood tests, neuropsychological evaluation, MRI, and FDG-PET), no certain diagnosis could be arrived at. Amyloid PET was then conducted and classified as positive or negative. Attending physicians were asked to evaluate whether this result led to a change in diagnosis or altered management. They also reported their degree of confidence in the diagnosis. Caregivers were met after disclosure of amyloid PET results and completed a questionnaire/interview to assess the impact of the scan. Our cohort was evenly divided between positive (14/28) and negative (14/28) 18F-NAV4694 cases. Amyloid PET resulted in a diagnostic change in 9/28 cases (32.1%: 17.8% changed from AD to non-AD, 14.3% from non-AD to AD). There was a 44% increase in diagnostic confidence. Altered management occurred in 71.4% (20/28) of cases. Knowledge of amyloid status improved caregivers' outcomes in all domains (anxiety, depression, disease perception, future anticipation, and quality of life). This study suggests a useful additive role for amyloid PET in atypical cases with an unclear diagnosis beyond the extensive workup of a tertiary memory clinic. Amyloid PET increased diagnostic confidence and led to clinically significant alterations in management. The information gained from that test was well received by caregivers and encouraged spending quality time with their loved ones.

%B J Alzheimers Dis %V 52 %P 1251-62 %8 2016 Apr 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104896?dopt=Abstract %R 10.3233/JAD-151180 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Cognitive Change Index as a Measure of Self and Informant Perception of Cognitive Decline: Relation to Neuropsychological Tests. %A Rattanabannakit, Chatchawan %A Risacher, Shannon L %A Gao, Sujuan %A Lane, Kathleen A %A Brown, Steven A %A McDonald, Brenna C %A Unverzagt, Frederick W %A Apostolova, Liana G %A Saykin, Andrew J %A Farlow, Martin R %K Adult %K Aged %K Aged, 80 and over %K Analysis of Variance %K Cognitive Dysfunction %K Cross-Sectional Studies %K Dementia %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Perception %K Self Report %X

BACKGROUND: The perception of cognitive decline by individuals and those who know them well ("informants") has been inconsistently associated with objective cognitive performance, but strongly associated with depressive symptoms.

OBJECTIVE: We investigated associations of self-report, informant-report, and discrepancy between self- and informant-report of cognitive decline obtained from the Cognitive Change Index (CCI) with cognitive test performance and self-reported depressive symptoms.

METHODS: 267 participants with normal cognition, mild cognitive impairment (MCI), or mild dementia were included from a cohort study and memory clinic. Association of test performance and self-rated depression (Geriatric Depression Scale, GDS) with CCI scores obtained from subjects (CCI-S), their informants (CCI-I), and discrepancy scores between subjects and informants (CCI-D; CCI-S minus CCI-I) were analyzed using correlation and analysis of covariance (ANCOVA) models.

RESULTS: CCI-S and CCI-I scores showed high internal consistency (Cronbach alpha 0.96 and 0.98, respectively). Higher scores on CCI-S and CCI-I, and lower scores on the CCI-D, were associated with lower performance on various cognitive tests in both univariate and in ANCOVA models adjusted for age, gender, and education. Adjustment for GDS slightly weakened the relationships between CCI and test performance but most remained significant.

CONCLUSION: Self- and informant-report of cognitive decline, as measured by the CCI, show moderately strong relationships with objective test performance independent of age, gender, education, and depressive symptoms. The CCI appears to be a valid cross-sectional measure of self and informant perception of cognitive decline across the continuum of functioning. Studies are needed to address the relationship of CCI scores to longitudinal outcome.

%B J Alzheimers Dis %V 51 %P 1145-55 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923008?dopt=Abstract %R 10.3233/JAD-150729 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cognitive Profile and its Association with Neuroimaging Markers of Non-Demented Cerebral Amyloid Angiopathy Patients in a Stroke Unit. %A Xiong, Li %A Davidsdottir, Sigurros %A Reijmer, Yael D %A Shoamanesh, Ashkan %A Roongpiboonsopit, Duangnapa %A Thanprasertsuk, Sekh %A Martinez-Ramirez, Sergi %A Charidimou, Andreas %A Ayres, Alison M %A Fotiadis, Panagiotis %A Gurol, Edip %A Blacker, Deborah L %A Greenberg, Steven M %A Viswanathan, Anand %K Aged %K Atrophy %K Brain %K Cerebral Amyloid Angiopathy %K Cognition %K Cognition Disorders %K Female %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Stroke %X

BACKGROUND: Cerebral amyloid angiopathy (CAA) is increasingly recognized as a cause of cognitive impairment in the elderly, but the cognitive profile in patients with the disease has not been well characterized.

OBJECTIVE: To characterize the neuropsychological profile of CAA patients without dementia and to determine the association between cognitive performance in different domains and neuroimaging lesions characteristic of CAA.

METHODS: Fifty-eight non-demented CAA patients were compared to 138 cognitively normal subjects using a standard neuropsychological test battery. Total brain volume (TBV), white matter hyperintensities, number of lobar cerebral microbleeds, hippocampal volume, and cortical superficial siderosis in all CAA patients were assessed. The association between these neuroimaging markers and neuropsychological performance in different cognitive domains in the CAA group were analyzed.

RESULTS: Patients with CAA had significantly worse performance on all individual neuropsychological domains tested, when compared to the cognitive normal group. The cognitive decline of CAA patients was most noticeable in tests for processing speed with a Z score of -1.92±1.56 (mean±SD), then followed by executive function (-0.93±1.01), episodic memory (-0.87±1.29), semantic fluency (-0.73±1.06), and attention (-0.42±0.98). TBV of the CAA patients was correlated with processing speed (β= 0.335, p = 0.03) and executive function (β= 0.394, p = 0.01).

CONCLUSIONS: Non-demented patients with CAA had cognitive deficits in multiple areas. Lower TBV was related to slower processing speed and worse executive function.

%B J Alzheimers Dis %V 52 %P 171-8 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060947?dopt=Abstract %R 10.3233/JAD-150890 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cognitive Stimulation for People with Dementia in Long-Term Care Facilities: Baseline Cognitive Level Predicts Cognitive Gains, Moderated by Depression. %A Middelstädt, Jennifer %A Folkerts, Ann-Kristin %A Blawath, Sabrina %A Kalbe, Elke %X

BACKGROUND: Increasing evidence demonstrates the efficacy of cognitive stimulation (CS) in individuals with dementia. However, conducting studies in nursing homes engenders specific challenges that have limited the data gathered on this topic so far.

OBJECTIVE: The aim of this randomized controlled trial was to investigate the effects of CS on cognition, quality of life (QoL), behavioral symptoms, and activities of daily life in persons with dementia living in nursing homes. We further aimed to identify predictors of the intervention's benefits.

METHODS: Seventy-one persons with mild to moderate dementia were randomly allocated to the experimental group (EG; n = 36) that visited a CS program twice weekly for eight weeks or to the control group (CG; n = 35) that was receiving usual care. Neuropsychological tests were conducted before and after the intervention period and at six-week follow-up.

RESULTS: There were no significant interaction effects Time×Group for the outcome measures. However, regression analysis revealed that a low cognitive baseline level predicted cognitive improvements. Furthermore, a low baseline level of QoL predicted a QoL benefit. For both findings, depression was a significant moderator, meaning that persons with fewer depressive symptoms had a higher probability of showing improvements.

CONCLUSION: This study provides data on profiles of patients who are most likely to profit from CS intervention in nursing-home settings and demonstrates that treatment of depression is of the utmost relevance for a positive outcome of CS. Living conditions will have to be considered more thoroughly in future research.

%B J Alzheimers Dis %V 54 %P 253-68 %8 2016 Aug 04 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497474?dopt=Abstract %R 10.3233/JAD-160181 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cognitive Stimulation Modulates Platelet Total Phospholipases A2 Activity in Subjects with Mild Cognitive Impairment. %A Balietti, Marta %A Giuli, Cinzia %A Fattoretti, Patrizia %A Fabbietti, Paolo %A Postacchini, Demetrio %A Conti, Fiorenzo %K Blood Platelets %K Cognition %K Cognitive Dysfunction %K Cognitive Therapy %K Cohort Studies %K Humans %K Mental Status Schedule %K Neuropsychological Tests %K Phospholipases A2 %K Treatment Outcome %X

We evaluated the effect of cognitive stimulation (CS) on platelet total phospholipases A2 activity (tPLA2A) in patients with mild cognitive impairment (MCI_P). At baseline, tPLA2A negatively correlated with Mini-Mental State Examination score (MMSE_s): patients with MMSE_s <26 (Subgroup 1) had significantly higher activity than those with MMSE_s ≥26 (Subgroup 2), who had values similar to the healthy elderly. Regarding CS effect, Subgroup 1 had a significant tPLA2A reduction, whereas Subgroup 2 did not significantly changes after training. Our results showed for the first time that tPLA2A correlates with the cognitive conditions of MCI_P, and that CS acts selectively on subjects with a dysregulated tPLA2A.

%B J Alzheimers Dis %V 50 %P 957-62 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836161?dopt=Abstract %R 10.3233/JAD-150714 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cohort Study on Predictors of Need for Nursing Care in Alzheimer's Disease: An Analysis of Healthcare Data. %A Brüggenjürgen, Bernd %A Andersohn, Frank %A Burkowitz, Jörg %A Ezzat, Nadja %A Gaudig, Maren %A Willich, Stefan N %X

BACKGROUND: The individual and societal burden of Alzheimer's disease (AD) is substantial. Identifying relevant factors deteriorating AD and inducing need for nursing care would be of high relevance for healthcare planning.

OBJECTIVE: The main objective of this study was the identification of predictors of first assignment of a level of long-term care in AD, used as an approximation for disease progression.

METHODS: In a retrospective cohort study using data from a large German statutory health and long-term care insurance (SHI) company, co-morbidities and drug exposure were evaluated with respect to their predictive value for disease progression (first day the amount of daily nursing care exceeded 1.5 hours). Time to disease progression was modeled using COX-proportional hazard regression with stepwise selection of predictor variables.

RESULTS: The risk of nursing care need increased substantially with increasing age. Number of hospitalizations and number of different drugs used were significant indicators for progression, whereas outpatient visits were associated with a reduced need for care. Gender did not indicate significant influence on progression. Malignant neoplasms of ill-defined, secondary, and unspecified sites, malnutrition, renal failure, and injuries increased the risk of need for nursing care most significantly. Among prescribed drugs, significant increased risks were associated with drugs used in diabetes, preparations for treatment of wounds and ulcers, antiseptics and disinfectants, and analgesics.

CONCLUSIONS: Physical comorbidities are relevant contributors to an increase in need for nursing care. Some medical predicting conditions may be linked to cognition, while others may be directly linked to demand for care. AD patients with these comorbidities should be monitored with special attention, as they may be under an increased risk of care dependency.

%B J Alzheimers Dis %V 54 %P 1365-1372 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662286?dopt=Abstract %R 10.3233/JAD-160137 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Combination of Structural MRI and FDG-PET of the Brain Improves Diagnostic Accuracy in Newly Manifested Cognitive Impairment in Geriatric Inpatients. %A Ritter, Kerstin %A Lange, Catharina %A Weygandt, Martin %A Mäurer, Anja %A Roberts, Anna %A Estrella, Melanie %A Suppa, Per %A Spies, Lothar %A Prasad, Vikas %A Steffen, Ingo %A Apostolova, Ivayla %A Bittner, Daniel %A Gövercin, Mehmet %A Brenner, Winfried %A Mende, Christine %A Peters, Oliver %A Seybold, Joachim %A Fiebach, Jochen B %A Steinhagen-Thiessen, Elisabeth %A Hampel, Harald %A Haynes, John-Dylan %A Buchert, Ralph %X

BACKGROUND: The cause of cognitive impairment in acutely hospitalized geriatric patients is often unclear. The diagnostic process is challenging but important in order to treat potentially life-threatening etiologies or identify underlying neurodegenerative disease.

OBJECTIVE: To evaluate the add-on diagnostic value of structural and metabolic neuroimaging in newly manifested cognitive impairment in elderly geriatric inpatients.

METHODS: Eighty-one inpatients (55 females, 81.6±5.5 y) without history of cognitive complaints prior to hospitalization were recruited in 10 acute geriatrics clinics. Primary inclusion criterion was a clinical hypothesis of Alzheimer's disease (AD), cerebrovascular disease (CVD), or mixed AD+CVD etiology (MD), which remained uncertain after standard diagnostic workup. Additional procedures performed after enrollment included detailed neuropsychological testing and structural MRI and FDG-PET of the brain. An interdisciplinary expert team established the most probable etiologic diagnosis (non-neurodegenerative, AD, CVD, or MD) integrating all available data. Automatic multimodal classification based on Random Undersampling Boosting was used for rater-independent assessment of the complementary contribution of the additional diagnostic procedures to the etiologic diagnosis.

RESULTS: Automatic 4-class classification based on all diagnostic routine standard procedures combined reproduced the etiologic expert diagnosis in 31% of the patients (p = 0.100, chance level 25%). Highest accuracy by a single modality was achieved by MRI or FDG-PET (both 45%, p≤0.001). Integration of all modalities resulted in 76% accuracy (p≤0.001).

CONCLUSION: These results indicate substantial improvement of diagnostic accuracy in uncertain de novo cognitive impairment in acutely hospitalized geriatric patients with the integration of structural MRI and brain FDG-PET into the diagnostic process.

%B J Alzheimers Dis %V 54 %P 1319-1331 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567842?dopt=Abstract %R 10.3233/JAD-160380 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Combining Cerebrospinal Fluid Biomarkers and Neuropsychological Assessment: A Simple and Cost-Effective Algorithm to Predict the Progression from Mild Cognitive Impairment to Alzheimer's Disease Dementia. %A Mazzeo, Salvatore %A Santangelo, Roberto %A Bernasconi, Maria Paola %A Cecchetti, Giordano %A Fiorino, Agnese %A Pinto, Patrizia %A Passerini, Gabriella %A Falautano, Monica %A Comi, Giancarlo %A Magnani, Giuseppe %X

BACKGROUND: Correctly diagnosing Alzheimer's disease (AD) in prodromal phases would allow the adoption of experimental therapeutic strategies that could selectively interrupt the pathogenetic process before neuronal damage becomes irreversible. Therefore, great efforts have been aimed at finding early reliable disease markers.

OBJECTIVE: The aim of this study was to identify a simple, cost effective, and reliable diagnostic algorithm to predict conversion from mild cognitive impairment (MCI) to AD.

METHODS: 96 consecutive MCI patients admitted to the Neurology department of San Raffaele Hospital in Milan between January 2009 and January 2015 were included. All patients underwent neuropsychological assessment and lumbar puncture with CSF analysis of amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels. Each patient underwent clinical and neuropsychological follow-up, in order to identify a possible progression from MCI to AD. The mean follow up time was 36.73 months.

RESULTS: 37 out of 96 MCI converted to AD during follow up. CSF analysis and neuropsychological assessment reliably detected MCI patients who developed AD. In a subsample of 43 subjects, a Composite Cognitive Score (CCS) was calculated including episodic memory, executive function, and verbal fluency tests. Combining together CSF biomarkers and CCS increased the accuracy of the single predictors, correctly classifying 86% of patients with a specificity of 96% and a Positive Predictive Value of 93%.

DISCUSSION: Even if preliminary, our data seem to suggest that CSF analysis and neuropsychological assessment could detect MCI patients who will convert to AD with high confidence. Their relative low cost and availability could make them worldwide essential tools in future clinical trials.

%B J Alzheimers Dis %V 54 %P 1495-1508 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589522?dopt=Abstract %R 10.3233/JAD-160360 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics. %A Lelental, Natalia %A Brandner, Sebastian %A Kofanova, Olga %A Blennow, Kaj %A Zetterberg, Henrik %A Andreasson, Ulf %A Engelborghs, Sebastiaan %A Mroczko, Barbara %A Gabryelewicz, Tomasz %A Teunissen, Charlotte %A Mollenhauer, Brit %A Parnetti, Lucilla %A Chiasserini, Davide %A Molinuevo, José Luis %A Perret-Liaudet, Armand %A Verbeek, Marcel M %A Andreasen, Niels %A Brosseron, Frederic %A Bahl, Justyna M C %A Herukka, Sanna-Kaisa %A Hausner, Lucrezia %A Frölich, Lutz %A Labonte, Anne %A Poirier, Judes %A Miller, Anne-Marie %A Zilka, Norbert %A Kovacech, Branislav %A Urbani, Andrea %A Suardi, Silvia %A Oliveira, Catarina %A Baldeiras, Ines %A Dubois, Bruno %A Rot, Uros %A Lehmann, Sylvain %A Skinningsrud, Anders %A Betsou, Fay %A Wiltfang, Jens %A Gkatzima, Olymbia %A Winblad, Bengt %A Buchfelder, Michael %A Kornhuber, Johannes %A Lewczuk, Piotr %K Amyloid beta-Peptides %K Animals %K Anti-Bacterial Agents %K Biomarkers %K Cattle %K Clinical Chemistry Tests %K Dementia %K Humans %K Peptide Fragments %K Quality Control %K Reference Standards %K Serum Albumin, Bovine %K Sodium Azide %K tau Proteins %K Time Factors %K Tissue Preservation %X

BACKGROUND: Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples.

OBJECTIVE: To prepare and test alternative matrices for QC samples that could facilitate intra- and inter-laboratory QC of the NDD biomarkers.

METHODS: Three matrices were validated in this study: (A) human pooled CSF, (B) Aβ peptides spiked into human prediluted plasma, and (C) Aβ peptides spiked into solution of bovine serum albumin in phosphate-buffered saline. All matrices were tested also after supplementation with an antibacterial agent (sodium azide). We analyzed short- and long-term stability of the biomarkers with ELISA and chemiluminescence (Fujirebio Europe, MSD, IBL International), and performed an inter-laboratory variability study.

RESULTS: NDD biomarkers turned out to be stable in almost all samples stored at the tested conditions for up to 14 days as well as in samples stored deep-frozen (at - 80°C) for up to one year. Sodium azide did not influence biomarker stability. Inter-center variability of the samples sent at room temperature (pooled CSF, freeze-dried CSF, and four artificial matrices) was comparable to the results obtained on deep-frozen samples in other large-scale projects.

CONCLUSION: Our results suggest that it is possible to replace self-made, CSF-based QC samples with large-scale volumes of QC materials prepared with artificial peptides and matrices. This would greatly facilitate intra- and inter-laboratory QC schedules for NDD measurements.

%B J Alzheimers Dis %V 52 %P 51-64 %8 2016 03 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967210?dopt=Abstract %R 10.3233/JAD-150883 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Comparison of Prefrontal Atrophy and Episodic Memory Performance in Dysexecutive Alzheimer's Disease and Behavioral-Variant Frontotemporal Dementia. %A Wong, Stephanie %A Bertoux, Maxime %A Savage, Greg %A Hodges, John R %A Piguet, Olivier %A Hornberger, Michael %K Aged %K Alzheimer Disease %K Atrophy %K Databases, Factual %K Diagnosis, Differential %K Executive Function %K Female %K Frontotemporal Dementia %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Memory, Episodic %K Middle Aged %K Neuropsychological Tests %K Prefrontal Cortex %X

Alzheimer's disease (AD) sometimes presents with prominent executive dysfunction and associated prefrontal cortex atrophy. The impact of such executive deficits on episodic memory performance as well as their neural correlates in AD, however, remains unclear. The aim of the current study was to investigate episodic memory and brain atrophy in AD patients with relatively spared executive functioning (SEF-AD; n = 12) and AD patients with relatively impaired executive functioning (IEF-AD; n = 23). We also compared the AD subgroups with a group of behavioral-variant frontotemporal dementia patients (bvFTD; n = 22), who typically exhibit significant executive deficits, and age-matched healthy controls (n = 38). On cognitive testing, the three patient groups showed comparable memory profiles on standard episodic memory tests, with significant impairment relative to controls. Voxel-based morphometry analyses revealed extensive prefrontal and medial temporal lobe atrophy in IEF-AD and bvFTD, whereas this was limited to the middle frontal gyrus and hippocampus in SEF-AD. Moreover, the additional prefrontal atrophy in IEF-AD and bvFTD correlated with memory performance, whereas this was not the case for SEF-AD. These findings indicate that IEF-AD patients show prefrontal atrophy in regions similar to bvFTD, and suggest that this contributes to episodic memory performance. This has implications for the differential diagnosis of bvFTD and subtypes of AD.

%B J Alzheimers Dis %V 51 %P 889-903 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923025?dopt=Abstract %R 10.3233/JAD-151016 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Complement Biomarkers as Predictors of Disease Progression in Alzheimer's Disease. %A Hakobyan, Svetlana %A Harding, Katharine %A Aiyaz, Mohammed %A Hye, Abdul %A Dobson, Richard %A Baird, Alison %A Liu, Benjamine %A Harris, Claire Louise %A Lovestone, Simon %A Morgan, Bryan Paul %X

There is a critical unmet need for reliable markers of disease and disease course in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). The growing appreciation of the importance of inflammation in early AD has focused attention on inflammatory biomarkers in cerebrospinal fluid or plasma; however, non-specific inflammation markers have disappointed to date. We have adopted a targeted approach, centered on an inflammatory pathway already implicated in the disease. Complement, a core system in innate immune defense and potent driver of inflammation, has been implicated in pathogenesis of AD based on a confluence of genetic, histochemical, and model data. Numerous studies have suggested that measurement of individual complement proteins or activation products in cerebrospinal fluid or plasma is useful in diagnosis, prediction, or stratification, but few have been replicated. Here we apply a novel multiplex assay to measure five complement proteins and four activation products in plasma from donors with MCI, AD, and controls. Only one complement analyte, clusterin, differed significantly between control and AD plasma (controls, 295 mg/l; AD, 388 mg/l: p < 10- 5). A model combining clusterin with relevant co-variables was highly predictive of disease. Three analytes (clusterin, factor I, terminal complement complex) were significantly different between MCI individuals who had converted to dementia one year later compared to non-converters; a model combining these three analytes with informative co-variables was highly predictive of conversion. The data confirm the relevance of complement biomarkers in MCI and AD and build the case for using multi-parameter models for disease prediction and stratification.

%B J Alzheimers Dis %V 54 %P 707-16 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567854?dopt=Abstract %R 10.3233/JAD-160420 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cortical Amyloid Burden Differences Across Empirically-Derived Mild Cognitive Impairment Subtypes and Interaction with APOE ɛ4 Genotype. %A Bangen, Katherine J %A Clark, Alexandra L %A Werhane, Madeline %A Edmonds, Emily C %A Nation, Daniel A %A Evangelista, Nicole %A Libon, David J %A Bondi, Mark W %A Delano-Wood, Lisa %X

We examined cortical amyloid-β (Aβ) levels and interactions with apolipoprotein (APOE) ɛ4 genotype status across empirically-derived mild cognitive impairment (MCI) subgroups and cognitively normal older adults. Participants were 583 ADNI participants (444 MCI, 139 normal controls [NC]) with baseline florbetapir positron emission tomography (PET) amyloid imaging and neuropsychological testing. Of those with ADNI-defined MCI, a previous cluster analysis [1] classified 51% (n = 227) of the current sample as amnestic MCI, 8% (n = 37) as dysexecutive/mixed MCI, and 41% (n = 180) as cluster-derived normal (cognitively normal). Results demonstrated that the dysexecutive/mixed and amnestic MCI groups showed significantly greater levels of amyloid relative to the cluster-derived normal and NC groups who did not differ from each other. Additionally, 78% of the dysexecutive/mixed, 63% of the amnestic MCI, 42% of the cluster-derived normal, and 34% of the NC group exceeded the amyloid positivity threshold. Finally, a group by APOE genotype interaction demonstrated that APOE ɛ4 carriers within the amnestic MCI, cluster-derived normal, and NC groups showed significantly greater amyloid accumulation compared to non-carriers of their respective group. Such an interaction was not revealed within the dysexecutive/mixed MCI group which was characterized by both greater cognitive impairment and amyloid accumulation compared to the other participant groups. Our results from the ADNI cohort show considerable heterogeneity in Aβ across all groups studied, even within a group of robust NC participants. Findings suggest that conventional criteria for MCI may be susceptible to false positive diagnostic errors, and that onset of Aβ accumulation may occur earlier in APOE ɛ4 carriers compared to non-carriers.

%B J Alzheimers Dis %V 52 %P 849-61 %8 2016 Mar 29 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031472?dopt=Abstract %R 10.3233/JAD-150900 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Daily Function as Predictor of Dementia in Cognitive Impairment, No Dementia (CIND) and Mild Cognitive Impairment (MCI): An 8-Year Follow-Up in the ILSA Study. %A Di Carlo, Antonio %A Baldereschi, Marzia %A Lamassa, Maria %A Bovis, Francesca %A Inzitari, Marco %A Solfrizzi, Vincenzo %A Panza, Francesco %A Galluzzo, Lucia %A Scafato, Emanuele %A Inzitari, Domenico %X

BACKGROUND: Preclinical cognitive changes may predict an increased risk of dementia, allowing selection of subgroups as possible targets for preventive or therapeutic interventions.

OBJECTIVE: To evaluate the predictive effect of daily functioning and motor performance (MP) on the progression to dementia in normal cognition, cognitive impairment, no dementia (CIND), and mild cognitive impairment (MCI).

METHODS: The Italian Longitudinal Study on Aging is a large population-based survey on age-related diseases of the cardiovascular and nervous systems. After the baseline assessment, to detect prevalent cases of cognitive impairment and dementia, participants were re-examined at 4-year and 8-year follow-ups. Functional independence was evaluated using the Index of Activities of Daily Living (ADL) and the Instrumental Activities of Daily Living (IADL) Scale. A six-test battery was used to assess MP.

RESULTS: Overall, 2,386 individuals were included, for a total of 16,545 person-years. Eight-year incidence of dementia (per 1,000 person-years) was 12.69 in total sample, 9.86 in subjects with normal cognition at baseline, 22.99 in CIND, and 21.43 in MCI. Progression to dementia was significantly higher with increasing baseline ADL and IADL impairment, and with a worse MP. In Cox regression analyses controlled for demographics and major age-related conditions, increased IADL impairment was the stronger predictor of progression to dementia (p < 0.001), with HR ranging from 2.16 (95% CI, 0.82-5.70) to 9.57 (95% CI, 3.40-26.91) in subjects with MCI at baseline.

CONCLUSIONS: Inclusion of IADL in the MCI construct significantly improves the prediction of dementia. Individuation of different transition rates is required to plan cost-effective interventions.

%B J Alzheimers Dis %V 53 %P 505-15 %8 2016 May 07 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163817?dopt=Abstract %R 10.3233/JAD-160087 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Decade of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease in Belgium. %A Somers, Charisse %A Struyfs, Hanne %A Goossens, Joery %A Niemantsverdriet, Ellis %A Luyckx, Jill %A De Roeck, Naomi %A De Roeck, Ellen %A De Vil, Bart %A Cras, Patrick %A Martin, Jean-Jacques %A De Deyn, Peter-Paul %A Bjerke, Maria %A Engelborghs, Sebastiaan %X

During the past ten years, over 5,000 cerebrospinal fluid (CSF) samples were analyzed at the Reference Center for Biological Markers of Dementia (BIODEM), UAntwerp, for core Alzheimer's disease (AD) CSF biomarkers: amyloid-β peptide of 42 amino acids (Aβ1-42), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181P). CSF biomarker analyses were performed using single-analyte ELISA kits. In-house validated cutoff values were applied: Aβ1-42 <638.5 pg/mL, T-tau >296.5 pg/mL, P-tau181P >56.5 pg/mL. A CSF biomarker profile was considered to be suggestive for AD if the CSF Aβ1-42 concentration was below the cutoff, in combination with T-tau and/or P-tau181P values above the cutoff (IWG2 criteria for AD). Biomarker analyses were requested for following clinical indications: 1) neurochemical confirmation of AD in case of clinical AD, 2) neurochemical confirmation of AD in case of doubt between AD and a non-AD dementia, 3) neurochemical diagnosis of prodromal AD in case of mild cognitive impairment, 4) neurochemical confirmation of AD in case of psychiatric symptoms (like depression, psychosis), or 5) other clinical indications. During these ten years, the number of yearly referred samples increased by 238% and clinical indications for referral showed a shift from neurochemical confirmation of AD in case of clinical AD to differential dementia diagnosis in case of doubt between AD and a non-AD dementia. Four percent of the patients also had a postmortem neuropathological examination. Together, these biomarker data were the basis for several research papers, and significantly contributed to the validation of these biomarkers in autopsy-confirmed subjects.

%B J Alzheimers Dis %V 54 %P 383-95 %8 2016 Aug 10 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567807?dopt=Abstract %R 10.3233/JAD-151097 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia. %A Vallortigara, Julie %A Whitfield, David %A Quelch, William %A Alghamdi, Amani %A Howlett, David %A Hortobágyi, Tibor %A Johnson, Mary %A Attems, Johannes %A O'Brien, John T %A Thomas, Alan %A Ballard, Clive G %A Aarsland, Dag %A Francis, Paul T %K Aged %K Aged, 80 and over %K alpha-Synuclein %K Amyloid beta-Peptides %K Analysis of Variance %K Cognition Disorders %K Dementia %K Female %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Regression Analysis %K Synaptophysin %K tau Proteins %K Vesicle-Associated Membrane Protein 2 %X

Alpha-synuclein (α-syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), but are also frequently present in Alzheimer's disease (AD). Much remains unknown about the role of α-syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key 'SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor' (SNARE) proteins as a consequence of alterations in the aggregation state of α-syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large cohort (n = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric α-syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p <  0.001). This correlated to the final MMSE score before death (p = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p = 0.0004) and monomeric α-syn (p = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological α-syn.

%B J Alzheimers Dis %V 50 %P 101-10 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639969?dopt=Abstract %R 10.3233/JAD-150707 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dementia Risk and Protective Factors Differ in the Context of Memory Trajectory Groups. %A Zahodne, Laura B %A Schupf, Nicole %A Brickman, Adam M %A Mayeux, Richard %A Wall, Melanie M %A Stern, Yaakov %A Manly, Jennifer J %X

BACKGROUND: Previous research has identified multiple risk and protective factors for late onset Alzheimer's disease (LOAD). However, it is not known whether these risk and protective factors differ for individuals who are cognitively stable versus those already experiencing declines.

OBJECTIVE: This study examined how dementia risk factors differ across subgroups of older adults defined by memory trajectory. This line of research may lead to more individualized risk profiles.

METHODS: Risk factors for incident LOAD were compared across previously-validated groups of older adults exhibiting different memory trajectories ("Stable-High," "Stable-Low," "Decliner," "Rapid Decliner") using stratified Cox regressions. Participants included 2,593 racially/ethnically diverse older adults (mean age of 76 at study entry) in the Washington Heights-Inwood Columbia Aging Project.

RESULTS: Predictors of incident dementia differed across trajectory groups: older age only incurred independent risk in stable groups, education did not incur independent protection in the rapidly declining group, depression only incurred independent risk in the stable-low group, stroke incurred independent risk in the two extreme groups, and APOE-ɛ4 only incurred independent risk in the rapidly declining group.

CONCLUSION: The finding that different risk factors for LOAD were associated with specific memory trajectories may reflect the existence of resilience or vulnerability factors that modify the individual influences of risk/protective factors. This study highlights the utility of considering interactions between dementia risk factors and a patient's unique cognitive history.

%B J Alzheimers Dis %V 52 %P 1013-20 %8 2016 Apr 12 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079709?dopt=Abstract %R 10.3233/JAD-151114 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Detection of Striatal Amyloid Plaques with [18F]flutemetamol: Validation with Postmortem Histopathology. %A Beach, Thomas G %A Thal, Dietmar Rudolf %A Zanette, Michelle %A Smith, Adrian %A Buckley, Christopher %X

Amyloid imaging is limited by an inconsistent relationship between cerebral cortex amyloid- β (Aβ) plaques and dementia. Autopsy studies suggest that Aβ plaques first appear in the cerebral cortex while subcortical plaques are present only later in the disease course. The presence of abundant plaques in both cortex and striatum is more strongly correlated with the presence of dementia than cortical Aβ plaques alone. Additionally, detection of striatal plaques may allow, for the first time, pathology-based clinical staging of AD. Striatal plaques are reportedly identifiable by amyloid imaging but the accuracy and reliability of striatal amyloid imaging has never been tested against postmortem histopathology. To determine this, we correlated the presence of histopathologically-demonstrated striatal Aβ deposits with a visually positive panel consensus decision of a positive [18F]flutemetamol striatal PET signal in 68 subjects that later came to autopsy. The sensitivity of [18F]flutemetamol PET striatal amyloid imaging, for several defined density levels of histological striatal Aβ deposits, ranged between 69% and 87% while the specificity ranged between 96% and 100%. Sensitivity increased with higher histological density thresholds while the reverse was found for specificity. In general, as compared with PET alone, PET with CT had slightly higher sensitivities but slightly lower specificities. In conclusion, amyloid imaging of the striatum with [18F]flutemetamol PET has reasonable accuracy for the detection of histologically-demonstrated striatal Aβ plaques when present at moderate or frequent densities. Amyloid imaging of the cerebral cortex and striatum together may allow for a more accurate clinicopathological diagnosis of AD and enable pathology-based clinical staging of AD.

%B J Alzheimers Dis %V 52 %P 863-73 %8 2016 Mar 31 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031469?dopt=Abstract %R 10.3233/JAD-150732 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Development of a Standardized Approach to Disclosing Amyloid Imaging Research Results in Mild Cognitive Impairment. %A Lingler, Jennifer H %A Butters, Meryl A %A Gentry, Amanda L %A Hu, Lu %A Hunsaker, Amanda E %A Klunk, William E %A Mattos, Meghan K %A Parker, Lisa A %A Roberts, J Scott %A Schulz, Richard %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid %K Brain %K Brain Chemistry %K Cognitive Dysfunction %K Disclosure %K Family %K Female %K Focus Groups %K Health Communication %K Humans %K Male %K Middle Aged %K Patient Satisfaction %K Pilot Projects %K Positron-Emission Tomography %X

The increased use of PET amyloid imaging in clinical research has sparked numerous concerns about whether and how to return such research test results to study participants. Chief among these is the question of how best to disclose amyloid imaging research results to individuals who have cognitive symptoms that could impede comprehension of the information conveyed. We systematically developed and evaluated informational materials for use in pre-test counseling and post-test disclosures of amyloid imaging research results in mild cognitive impairment (MCI). Using simulated sessions, persons with MCI and their family care partners (N = 10 dyads) received fictitious but realistic information regarding brain amyloid status, followed by an explanation of how results impact Alzheimer's disease risk. Satisfaction surveys, comprehension assessments, and focus group data were analyzed to evaluate the materials developed. The majority of persons with MCI and their care partners comprehended and were highly satisfied with the information presented. Focus group data reinforced findings of high satisfaction and included 6 recommendations for practice: 1) offer pre-test counseling, 2) use clear graphics, 3) review participants' own brain images during disclosures, 4) offer take-home materials, 5) call participants post-disclosure to address emerging questions, and 6) communicate seamlessly with primary care providers. Further analysis of focus group data revealed that participants understood the limitations of amyloid imaging, but nevertheless viewed the prospect of learning one's amyloid status as valuable and empowering.

%B J Alzheimers Dis %V 52 %P 17-24 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060950?dopt=Abstract %R 10.3233/JAD-150985 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diagnosing Dementia in the Clinical Setting: Can Amyloid PET Provide Additional Value Over Cerebrospinal Fluid? %A Weston, Philip S J %A Paterson, Ross W %A Dickson, John %A Barnes, Anna %A Bomanji, Jamshed B %A Kayani, Irfan %A Lunn, Michael P %A Mummery, Catherine J %A Warren, Jason D %A Rossor, Martin N %A Fox, Nick C %A Zetterberg, Henrik %A Schott, Jonathan M %X

Cerebrospinal fluid (CSF) measures of amyloid and tau are the first-line Alzheimer's disease biomarkers in many clinical centers. We assessed if and when the addition of amyloid PET following CSF measurements provides added diagnostic value. Twenty patients from a cognitive clinic, who had undergone detailed assessment including CSF measures, went on to have amyloid PET. The treating neurologist's working diagnosis, and degree of diagnostic certainty, was assessed both before and after the PET. Amyloid PET changed the diagnosis in 7/20 cases. Amyloid PET can provide added diagnostic value, particularly in young-onset, atypical dementias, where CSF results are borderline and diagnostic uncertainty remains.

%B J Alzheimers Dis %V 54 %P 1297-1302 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567830?dopt=Abstract %R 10.3233/JAD-160302 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diagnostic Accuracy of MRI and Additional [18F]FDG-PET for Behavioral Variant Frontotemporal Dementia in Patients with Late Onset Behavioral Changes. %A Vijverberg, Everard G B %A Wattjes, Mike P %A Dols, Annemiek %A Krudop, Welmoed A %A Möller, Christiane %A Peters, Anne %A Kerssens, Cora J %A Gossink, Flora %A Prins, Niels D %A Stek, Max L %A Scheltens, Philip %A van Berckel, Bart N M %A Barkhof, Frederik %A Pijnenburg, Yolande A L %X

BACKGROUND: Neuroimaging has a reasonable accuracy to differentiate behavioral variant frontotemporal dementia (bvFTD) from other neurodegenerative disorders, its value for the differentiation of bvFTD among subjects with acquired behavioral disturbances is unknown.

OBJECTIVE: To determine the diagnostic accuracy of MRI, additional [18F]FDG-PET, and their combination for bvFTD among subjects with late onset behavioral changes.

METHODS: Patients with late onset behavioral changes referred to a memory clinic or psychiatric services were included. At baseline, 111 patients had a brain MRI scan and 74 patients received an additional [18F]FDG-PET when the MRI was inconclusive. The consensus diagnosis after two-year-follow-up was used as the gold standard to calculate sensitivity and specificity for baseline neuroimaging.

RESULTS: 27 patients had probable/definite bvFTD and 84 patients had a non-bvFTD diagnosis (primary psychiatric diagnosis or other neurological disorders). MRI had a sensitivity of 70% (95% CI 52-85%) with a specificity of 93% (95% CI 86-97%). Additional [18F]FDG-PET had a sensitivity of 90% (95% CI 66-100%) with a specificity of 68% (95% CI 56-79%). The sensitivity of combined neuroimaging was 96% (95% CI 85-100%) with a specificity of 73% (95% CI 63-81%). In 66% of the genetic FTD cases, MRI lacked typical frontotemporal atrophy. 40% of cases with a false positive [18F]FDG-PET scan had a primary psychiatric diagnosis.

CONCLUSION: A good diagnostic accuracy was found for MRI and additional [18F]FDG-PET for bvFTD in patients with late onset behavioral changes. Caution with the interpretation of neuroimaging results should especially be taken in cases with a genetic background and in cases with a primary psychiatric differential diagnosis where [18F]FDG-PET is the only abnormal investigation.

%B J Alzheimers Dis %V 53 %P 1287-97 %8 2016 Jun 30 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372646?dopt=Abstract %R 10.3233/JAD-160285 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diagnostic Assessment and Management of Dysphagia in Patients with Alzheimer's Disease. %A Boccardi, Virginia %A Ruggiero, Carmelinda %A Patriti, Alberto %A Marano, Luigi %K Alzheimer Disease %K Deglutition Disorders %K Humans %X

A growing concern in patients affected by Alzheimer's disease (AD) is dysphagia, or swallowing impairment, which leads to malnutrition, dehydration, weight loss, functional decline and fear of eating and drinking, as well as a decrease in the quality of life. Thus the diagnostic assessment of dysphagia in patients with AD is imperative to ensure that they receive effective management, avoiding complications, and reducing comorbidity and mortality in such a growing population. Dysphagia management requires a multidisciplinary approach considering that no single strategy is appropriate for all patients. However, evidence for clinical diagnostic assessment, interventions, and medical management of dysphagia in these patients are still limited: few studies are reporting the evaluation and the management among this group of patients. Here we analyzed the most recent findings in diagnostic assessment and management of swallowing impairment in patients affected by AD.

%B J Alzheimers Dis %V 50 %P 947-55 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836016?dopt=Abstract %R 10.3233/JAD-150931 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diagnostic Distortions: A Case Report of Progressive Apraxia of Speech. %A Brodtmann, Amy %A Pemberton, Hugh %A Darby, David %A Vogel, Adam P %X

Apraxia of speech (AOS) can be the presenting symptom of neurodegenerative disease. The position of primary progressive AOS in the nosology of the dementias is still controversial. Despite seeing many specialists, patients are often misdiagnosed, in part due to a lack of quantitative measures of speech dysfunction. We present a single case report of a patient presenting with AOS, including acoustic analysis, language assessment, and brain imaging. A 52-year-old woman presenting with AOS had remained undiagnosed for 6 years despite seeing 8 specialists. Results of her MRI scans, genetic testing, and computerized speech analysis are provided. AOS is an underdiagnosed clinical syndrome causing great distress to patients and families. Using acoustic analysis of speech may lead to improved diagnostic accuracy. AOS is a complex entity with an expanding phenotype, and quantitative clinical measures will be critical for detection and to assess progression.

%B J Alzheimers Dis %V 53 %P 79-83 %8 2016 Apr 19 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104903?dopt=Abstract %R 10.3233/JAD-160069 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diagnostic Value of Cerebrospinal Fluid Biomarkers (Phospho-Tau181, total-Tau, Aβ42, and Aβ40) in Prodromal Stage of Alzheimer's Disease and Dementia with Lewy Bodies. %A Bousiges, Olivier %A Cretin, Benjamin %A Lavaux, Thomas %A Philippi, Nathalie %A Jung, Barbara %A Hezard, Sylvie %A Heitz, Camille %A Demuynck, Catherine %A Gabel, Aurelia %A Martin-Hunyadi, Catherine %A Blanc, Frédéric %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Enzyme-Linked Immunosorbent Assay %K Female %K Humans %K Lewy Body Disease %K Male %K Middle Aged %K Peptide Fragments %K Prodromal Symptoms %K Psychiatric Status Rating Scales %K Retrospective Studies %K Statistics, Nonparametric %K tau Proteins %X

BACKGROUND: Dementia with Lewy bodies (DLB) symptoms are close to those of Alzheimer's disease (AD), and the differential diagnosis is difficult especially early in the disease. Unfortunately, AD biomarkers in cerebrospinal fluid (CSF), and more particularly Aβ1 - 42, appear to be altered in dementia with Lewy bodies (DLB). However, the level of these biomarkers has never been studied in the prodromal stage of the disease.

OBJECTIVE: To compare these biomarkers between DLB and AD, with a particular focus on the prodromal stage.

METHODS: A total of 166 CSF samples were collected at the memory clinic of Strasbourg. They were obtained from prodromal DLB (pro-DLB), DLB dementia, prodromal AD (pro-AD), and AD dementia patients, and elderly controls. Phospho-Tau181, total-Tau, Aβ42, and Aβ40 were measured in the CSF.

RESULTS: At the prodromal stage, contrary to AD patients, DLB patients' biomarker levels in the CSF were not altered. At the demented stage of DLB, Aβ42 levels were reduced as well as Aβ40 levels. Thus, the Aβ42/Aβ40 ratio remained unchanged between the prodromal and demented stages, contrary to what was observed in AD. Tau and Phospho-Tau181 levels were unaltered in DLB patients.

CONCLUSIONS: We have shown that at the prodromal stage the DLB patients had no pathological profile. Consequently, CSF AD biomarkers are extremely useful for differentiating AD from DLB patients particularly at this stage when the clinical diagnosis is difficult. Thus, these results open up new perspectives on the interpretation of AD biomarkers in DLB.

%B J Alzheimers Dis %V 51 %P 1069-83 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923009?dopt=Abstract %R 10.3233/JAD-150731 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Different Patterns of Correlation between Grey and White Matter Integrity Account for Behavioral and Psychological Symptoms in Alzheimer's Disease. %A Makovac, Elena %A Serra, Laura %A Spanò, Barbara %A Giulietti, Giovanni %A Torso, Mario %A Cercignani, Mara %A Caltagirone, Carlo %A Bozzali, Marco %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Atrophy %K Brain %K Depression %K Female %K Gray Matter %K Hallucinations %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K White Matter %X

Behavioral disorders and psychological symptoms (BPSD) in Alzheimer's disease (AD) are known to correlate with grey matter (GM) atrophy and, as shown recently, also with white matter (WM) damage. WM damage and its relationship with GM atrophy are reported in AD, reinforcing the interpretation of the AD pathology in light of a disconnection syndrome. It remains uncertain whether this disconnection might account also for different BPSD observable in AD. Here, we tested the hypothesis of different patterns of association between WM damage of the corpus callosum (CC) and GM atrophy in AD patients exhibiting one of the following BPSD clusters: Mood (i.e., anxiety and depression; ADmood), Frontal (i.e., dishinibition and elation; ADfrontal), and Psychotic (delusions and hallucinations; ADpsychotic) related symptoms, as well as AD patients without BPSD. Overall, this study brings to light the strict relationship between WM alterations in different parts of the CC and GM atrophy in AD patients exhibiting BPSD, supporting the hypothesis that such symptoms are likely to be caused by characteristic patterns of neurodegeneration of WM and GM, rather than being a reactive response to accumulation of cognitive disabilities, and should therefore be regarded as potential markers of diagnostic and prognostic value in AD.

%B J Alzheimers Dis %V 50 %P 591-604 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836635?dopt=Abstract %R 10.3233/JAD-150612 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Diagnosis of Dementia with High Levels of Cerebrospinal Fluid Tau Protein. %A Grangeon, Lou %A Paquet, Claire %A Bombois, Stephanie %A Quillard-Muraine, Muriel %A Martinaud, Olivier %A Bourre, Bertrand %A Lefaucheur, Romain %A Nicolas, Gaël %A Dumurgier, Julien %A Gerardin, Emmanuel %A Jan, Mary %A Laplanche, Jean-Louis %A Peoc'h, Katell %A Hugon, Jacques %A Pasquier, Florence %A Maltête, David %A Hannequin, Didier %A Wallon, David %K Adult %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Creutzfeldt-Jakob Syndrome %K Dementia, Vascular %K Diagnosis, Differential %K Female %K France %K Frontotemporal Dementia %K Humans %K Lewy Body Disease %K Male %K Mental Status Schedule %K Middle Aged %K Phosphorylation %K Retrospective Studies %K Sex Factors %K tau Proteins %X

BACKGROUND: Total Tau concentration in cerebrospinal fluid (CSF) is widely used as a biomarker in the diagnosis of neurodegenerative process primarily in Alzheimer's disease (AD). A particularly high Tau level may indicate AD but may also be associated with Creutzfeldt-Jakob disease (CJD). In such situations little is known about the distribution of differential diagnoses.

OBJECTIVE: Our study aimed to describe the different diagnoses encountered in clinical practice for patients with dementia and CSF Tau levels over 1000 pg/ml. We studied the p-Tau/Tau ratio to specify its ability to distinguish AD from CJD.

METHODS: Patients (n = 202) with CSF Tau levels over 1000 pg/ml were recruited in three memory clinics in France. All diagnoses were made using the same diagnostic procedure and criteria.

RESULTS: Patients were diagnosed with AD (n = 148, 73.2%), mixed dementia (n = 38, 18.8%), CJD, vascular dementia (n = 4, 2.0% for each), Lewy body dementia, and frontotemporal dementia (n = 3, 1.5% for each). Dispersion of CSF Tau levels clearly showed an overlap between all diagnoses. Using the p-Tau/Tau ratio suggestive of CJD (<0.075), all CJD patients were correctly categorized and only two AD patients were miscategorized. This ratio was highly associated with CJD compared to AD (p < 0.0001).

CONCLUSION: Our study showed that in clinical practice, extremely high CSF Tau levels are mainly related to diagnosis of AD. CJD patients represent a minority. Our results support a sequential interpretation algorithm for CSF biomarkers in dementia. High CSF Tau levels should alert clinicians to check the p-Tau/Tau ratio to consider a probable diagnosis of CJD.

%B J Alzheimers Dis %V 51 %P 905-13 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890785?dopt=Abstract %R 10.3233/JAD-151111 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Mass Spectrometry Profiles of Tau Protein in the Cerebrospinal Fluid of Patients with Alzheimer's Disease, Progressive Supranuclear Palsy, and Dementia with Lewy Bodies. %A Barthélemy, Nicolas R %A Gabelle, Audrey %A Hirtz, Christophe %A Fenaille, François %A Sergeant, Nicolas %A Schraen-Maschke, Susanna %A Vialaret, Jérôme %A Buée, Luc %A Junot, Christophe %A Becher, François %A Lehmann, Sylvain %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Analysis of Variance %K Chromatography, Liquid %K Enzyme-Linked Immunosorbent Assay %K Female %K Humans %K Lewy Body Disease %K Male %K Mental Status Schedule %K Middle Aged %K Neuroimaging %K Neuropsychological Tests %K Peptide Fragments %K Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization %K Statistics as Topic %K Supranuclear Palsy, Progressive %K tau Proteins %X

Microtubule-associated Tau proteins are major actors in neurological disorders, the so-called tauopathies. In some of them, and specifically in Alzheimer's disease (AD), hyperphosphorylated forms of Tau aggregate into neurofibrillary tangles. Following and understanding the complexity of Tau's molecular profile with its multiple isoforms and post-translational modifications represent an important issue, and a major analytical challenge. Immunodetection methods are, in fact, limited by the number, specificity, sensitivity, and capturing property of the available antibodies. Mass spectrometry (MS) has recently allowed protein quantification in complex biological fluids using isotope-labeled recombinant standard for absolute quantification (PSAQ). To study Tau proteins, which are found at very low concentrations within the cerebrospinal fluid (CSF), we relied on an innovative two-step pre-fractionation strategy, which was not dependent on immuno-enrichment. We then developed a sensitive multiplex peptide detection capability using targeted high-resolution MS to quantify Tau-specific peptides covering its entire sequence. This approach was used on a clinical cohort of patients with AD, progressive supranuclear palsy (PSP), and dementia with Lewy body (DLB) and with control non-neurodegenerative disorders. We uncovered a common CSF Tau molecular profile characterized by a predominance of central core expression and 1N/3R isoform detection. While PSP and DLB tau profiles showed minimal changes, AD was characterized by a unique pattern with specific modifications of peptide distribution. Taken together these results provide important information on Tau biology for future therapeutic interventions, and improved molecular diagnosis of tauopathies.

%B J Alzheimers Dis %V 51 %P 1033-43 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923020?dopt=Abstract %R 10.3233/JAD-150962 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Membrane Toxicity of Amyloid-β Fragments by Pore Forming Mechanisms. %A Peters, Christian %A Bascuñán, Denisse %A Opazo, Carlos %A Aguayo, Luis G %K Amyloid beta-Peptides %K Animals %K Calcium %K Cell Membrane %K Cells, Cultured %K Fluorescent Antibody Technique %K HEK293 Cells %K Hippocampus %K Humans %K Microscopy, Electron, Transmission %K Neurons %K Patch-Clamp Techniques %K Peptide Fragments %K Porosity %K Rats, Sprague-Dawley %K Voltage-Sensitive Dye Imaging %X

A major characteristic of Alzheimer's disease (AD) is the presence of amyloid-β peptide (Aβ) oligomers and aggregates in the brain. It is known that Aβ oligomers interact with the neuronal membrane and induce perforations that cause an influx of calcium ions and enhance the release of synaptic vesicles leading to a delayed synaptic failure by vesicle depletion. To better understand the mechanism by which Aβ exerts its effect on the plasma membrane, we evaluated three Aβ fragments derived from different regions of Aβ(1-42); Aβ(1-28) from the N-terminal region, Aβ(25-35) from the central region, and Aβ(17-42) from the C-terminal region. The neuronal activities of these fragments were examined with patch clamp, immunofluorescence, transmission electron microscopy, aggregation assays, calcium imaging, and MTT reduction assays. The present results indicate that the fragment Aβ(1-28) contributes to aggregation, an increase in intracellular calcium and synaptotoxicity, but is not involved in membrane perforation; Aβ(25-35) is important for membrane perforation, calcium increase, and synaptotoxicity; and Aβ(17-42) induced mitochondrial toxicity similar to the full length Aβ(1-42), but was unable to induce membrane perforation and calcium increase, supporting the idea that it is less toxic in the non-amyloidogenic pathway.

%B J Alzheimers Dis %V 51 %P 689-99 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890761?dopt=Abstract %R 10.3233/JAD-150896 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Risk of Incident Alzheimer's Disease Dementia in Stable Versus Unstable Patterns of Subjective Cognitive Decline. %A Wolfsgruber, Steffen %A Kleineidam, Luca %A Wagner, Michael %A Mösch, Edelgard %A Bickel, Horst %A Lϋhmann, Dagmar %A Ernst, Annette %A Wiese, Birgitt %A Steinmann, Susanne %A König, Hans-Helmut %A Brettschneider, Christian %A Luck, Tobias %A Stein, Janine %A Weyerer, Siegfried %A Werle, Jochen %A Pentzek, Michael %A Fuchs, Angela %A Maier, Wolfgang %A Scherer, Martin %A Riedel-Heller, Steffi G %A Jessen, Frank %X

BACKGROUND: It is unknown whether longitudinal stability versus instability in subjective cognitive decline (SCD) is a modifying factor of the association between SCD and risk of incident Alzheimer's disease (AD) dementia.

OBJECTIVE: We tested the modifying role of temporal stability of the SCD report on AD dementia risk in cognitively normal elderly individuals.

METHODS: We analyzed data of 1,990 cognitively normal participants from the longitudinal AgeCoDe Study. We assessed SCD with/without associated worries both at baseline and first follow-up 18 months later. Participants were then classified either as (a) Controls (CO, with no SCD at both baseline and follow-up 1, n = 613), (b) inconsistent SCD (with SCD reported only at baseline or at follow-up 1, n = 637), (c) consistent SCD but without/or with inconsistent worries (n = 610) or (d) consistent SCD with worries (n = 130). We estimated incident AD dementia risk over up to 6 years for each group with Cox-Proportional Hazard Regression analyses adjusted for age, gender, education, ApoE4 status, and depression.

RESULTS: Compared to CO, inconsistent SCD was not associated with increased risk of incident AD dementia. In contrast, risk was doubled in the group of consistent SCD without/ with inconsistent worries, and almost 4-fold in the group of consistent SCD with worries. These results could be replicated when using follow-up 1 to follow-up 2 response patterns for group definition.

CONCLUSION: These findings suggest that longitudinal stability versus instability is an important modifying factor of the association between SCD and AD dementia risk. Worrisome SCD that is also consistently reported over time is associated with greatly increased risk of AD dementia.

%B J Alzheimers Dis %V 54 %P 1135-1146 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567852?dopt=Abstract %R 10.3233/JAD-160407 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dihydropyridine Derivatives Modulate Heat Shock Responses and have a Neuroprotective Effect in a Transgenic Mouse Model of Alzheimer's Disease. %A Kasza, Ágnes %A Hunya, Ákos %A Frank, Zsuzsa %A Fülöp, Ferenc %A Török, Zsolt %A Balogh, Gábor %A Sántha, Miklós %A Bálind, Árpád %A Bernáth, Sándor %A Blundell, Katie L I M %A Prodromou, Chrisostomos %A Horváth, Ibolya %A Zeiler, Hans-Joachim %A Hooper, Philip L %A Vigh, László %A Penke, Botond %X

Heat shock proteins (Hsps) have chaperone activity and play a pivotal role in the homeostasis of proteins by preventing misfolding, by clearing aggregated and damaged proteins from cells, and by maintaining proteins in an active state. Alzheimer's disease (AD) is thought to be caused by amyloid-β peptide that triggers tau hyperphosphorylation, which is neurotoxic. Although proteostasis capacity declines with age and facilitates the manifestation of neurodegenerative diseases such as AD, the upregulation of chaperones improves prognosis. Our research goal is to identify potent Hsp co-inducers that enhance protein homeostasis for the treatment of AD, especially 1,4-dihydropyridine derivatives optimized for their ability to modulate cellular stress responses. Based on favorable toxicological data and Hsp co-inducing activity, LA1011 was selected for the in vivo analysis of its neuroprotective effect in the APPxPS1 mouse model of AD. Here, we report that 6 months of LA1011 administration effectively improved the spatial learning and memory functions in wild type mice and eliminated neurodegeneration in double mutant mice. Furthermore, Hsp co-inducer therapy preserves the number of neurons, increases dendritic spine density, and reduces tau pathology and amyloid plaque formation in transgenic AD mice. In conclusion, the Hsp co-inducer LA1011 is neuroprotective and therefore is a potential pharmaceutical candidate for the therapy of neurodegenerative diseases, particularly AD.

%B J Alzheimers Dis %V 53 %P 557-71 %8 2016 May 07 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163800?dopt=Abstract %R 10.3233/JAD-150860 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diminished CRE-Induced Plasticity is Linked to Memory Deficits in Familial Alzheimer's Disease Mice. %A Bartolotti, Nancy %A Segura, Laura %A Lazarov, Orly %K Alzheimer Disease %K Animals %K Cyclic AMP Response Element-Binding Protein %K Disease Models, Animal %K Hippocampus %K Maze Learning %K Memory Disorders %K Mice %K Neuronal Plasticity %K Neurons %K Phosphorylation %X

The mechanism underlying impaired learning and memory in Alzheimer's disease is not fully elucidated. The phosphorylation of cyclic-AMP response element binding protein (pCREB) in the hippocampus is thought to be a critical initiating step in the formation of long-term memories. Here, we tested CRE-driven gene expression following learning in mice harboring the familial Alzheimer's disease-linked APPswe/PS1ΔE9 mutations using CRE-β galactosidase reporter. We show that young adult APPswe/PS1ΔE9 mice exhibit impaired recognition memory and reduced levels of pCREB, and its cofactors CREB binding protein (CBP) and p-300 following a learning task, compared to their wild type littermate counterparts. Impairments in learning-induced activation of CREB in these mice are manifested by reduced CRE-driven gene transcription. Importantly, expression of the CRE-driven immediate early gene, Egr-1 (Zif268) is decreased in the CA1 region of the hippocampus. These studies implicate defective CREB-dependent plasticity in the mechanism underlying learning and memory deficits in Alzheimer's disease.

%B J Alzheimers Dis %V 50 %P 477-89 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682682?dopt=Abstract %R 10.3233/JAD-150650 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Direct Evidence of Internalization of Tau by Microglia In Vitro and In Vivo. %A Bolós, Marta %A Llorens-Martín, María %A Jurado-Arjona, Jerónimo %A Hernández, Félix %A Rábano, Alberto %A Avila, Jesús %K Alzheimer Disease %K Analysis of Variance %K Animals %K Animals, Newborn %K Calcium-Binding Proteins %K Cells, Cultured %K Cerebral Cortex %K Glial Fibrillary Acidic Protein %K Hippocampus %K Humans %K Mice %K Mice, Inbred C57BL %K Microfilament Proteins %K Microglia %K Phosphorylation %K Protein Transport %K Rats %K tau Proteins %K Time Factors %X

The microtubule-associated protein (MAP) tau plays a critical role in the pathogenesis of tauopathies. Excess tau can be released into the extracellular medium in a physiological or pathological manner to be internalized by surrounding neurons-a process that contributes to the spread of this protein throughout the brain. Such spreading may correlate with the progression of the abovementioned diseases. In addition to neurons, tau can be internalized into other cells. Here we demonstrate that microglia take up tau in vitro and in vivo. In this regard, microglia from primary cultures internalized soluble (human recombinant tau42) and insoluble (homogenates derived from human AD brain) tau in vitro. Furthermore, using stereotaxic injection of tau in mice in vivo, we show that murine microglia internalize human tau. In addition, we demonstrate, for the first time, that microglia colocalize with various forms of tau in postmortem brain tissue of patients with Alzheimer's disease and non-demented control subjects. Our data reveal a potential role of microglia in the internalization of tau that might be relevant for the design of strategies to enhance the clearance of extracellular tau in neurodegenerative diseases characterized by the accumulation of this protein.

%B J Alzheimers Dis %V 50 %P 77-87 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26638867?dopt=Abstract %R 10.3233/JAD-150704 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Discovering New Genes in the Pathways of Common Sporadic Neurodegenerative Diseases: A Bioinformatics Approach. %A Kim, Yong Hwan %A Beak, Seung Han %A Charidimou, Andreas %A Song, Min %K Computational Biology %K Female %K Gene Regulatory Networks %K Genetic Predisposition to Disease %K Humans %K Male %K MEDLINE %K Neurodegenerative Diseases %X

Late onset Alzheimer's disease (AD) and Parkinson's disease (PD) are mostly "sporadic" age-related neurodegenerative disorders, but with a clear genetic component. However, their genetic architecture is complex and heterogeneous, largely remaining a conundrum, with only a handful of well-established genetic risk factors consistently associated with these diseases. It is possible that numerous, yet undiscovered, AD and PD related genes might exist. We focused on the 'gene' as a mediator to find new potential genes that might have a relationship with both disorders using bio-literature mining techniques. Based on Entrez Gene, we extracted the genes and directional gene-gene relation in the entire MEDLINE records and then constructed a directional gene-gene network. We identified common genes associated with two different but related diseases by performing shortest path analysis on the network. With our approach, we were able to identify and map already known genes that have a direct relationship with PD and AD. In addition, we identified 7 genes previously unknown to be a bridge between these two disorders. We confirmed 4 genes, ROS1, FMN1, ATP8A2, and SNORD12C, by biomedical literature and further checked 3 genes, ERVK-10, PRS, and C7orf49, that might have a high possibility to be related with both diseases. Additional experiments were performed to demonstrate the effectiveness of our proposed method. Comparing to the co-occurrence approach, our approach detected 25% more candidate genes and verified 10% more genes that have the relationship between both diseases than the co-occurrence approach did.

%B J Alzheimers Dis %V 51 %P 293-312 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836166?dopt=Abstract %R 10.3233/JAD-150769 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Discrepancy in Expression of β-Secretase and Amyloid-β Protein Precursor in Alzheimer-Related Genes in the Rat Medial Temporal Lobe Cortex Following Transient Global Brain Ischemia. %A Pluta, Ryszard %A Kocki, Janusz %A Ułamek-Kozioł, Marzena %A Petniak, Alicja %A Gil-Kulik, Paulina %A Januszewski, Sławomir %A Bogucki, Jacek %A Jabłoński, Mirosław %A Brzozowska, Judyta %A Furmaga-Jabłońska, Wanda %A Bogucka-Kocka, Anna %A Czuczwar, Stanisław J %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Brain Ischemia %K Disease Models, Animal %K Down-Regulation %K Female %K Rats %K Rats, Wistar %K Temporal Lobe %K Time Factors %X

Brain ischemia may be causally related with Alzheimer's disease. Presumably, β-secretase and amyloid-β protein precursor gene expression changes may be associated with Alzheimer's disease neuropathology. Consequently, we have examined quantitative changes in both β-secretase and amyloid-β protein precursor genes in the medial temporal lobe cortex with the use of quantitative rtPCR analysis following 10-min global brain ischemia in rats with survival of 2, 7, and 30 days. The greatest significant overexpression of β-secretase gene was noted on the 2nd day, while on days 7-30 the expression of this gene was only modestly downregulated. Amyloid-β protein precursor gene was downregulated on the 2nd day, but on days 7-30 postischemia, there was a significant reverse tendency. Thus, the demonstrated alterations indicate that the considerable changes of expression of β-secretase and amyloid-β protein precursor genes may be connected with a response of neurons in medial temporal lobe cortex to transient global brain ischemia. Finally, the ischemia-induced gene changes may play a key role in a late and slow onset of Alzheimer-type pathology.

%B J Alzheimers Dis %V 51 %P 1023-31 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890784?dopt=Abstract %R 10.3233/JAD-151102 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Does Microglial Activation Influence Hippocampal Volume and Neuronal Function in Alzheimer's Disease and Parkinson's Disease Dementia? %A Femminella, Grazia D %A Ninan, Siddharth %A Atkinson, Rebecca %A Fan, Zhen %A Brooks, David J %A Edison, Paul %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Antineoplastic Agents %K Brain Mapping %K Cognition %K Female %K Fluorodeoxyglucose F18 %K Hippocampus %K Humans %K Isoquinolines %K Magnetic Resonance Imaging %K Male %K Microglia %K Middle Aged %K Neurons %K Neuropsychological Tests %K Parkinson Disease %K Positron-Emission Tomography %K Psychiatric Status Rating Scales %K Supranuclear Palsy, Progressive %X

BACKGROUND: The influence of neuroinflammation on neuronal function and hippocampal atrophy in Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) is still unclear.

OBJECTIVES: Here we investigated whether microglial activation measured by [11C]PK11195 PET is associated with neuronal function measured by cerebral glucose metabolic rate (rCMRGlc) using FDG-PET and hippocampal volume measurements.

METHODS: We enrolled 25 subjects (9 PDD, 8 AD, and 8 controls) who underwent PET scans with [11C](R)PK11195, [18F]FDG, and volumetric MRI scanning.

RESULTS: SPM correlation analysis in AD and PDD showed a negative correlation between hippocampal volume and microglial activation within hippocampus or parahippocampus and with cortical and subcortical areas of projections from hippocampus, while there was a positive correlation between rCMRGlc in cortical and subcortical areas of projections from hippocampus and hippocampal volume. Hippocampal volume was significantly reduced in AD compared to controls but not in PDD.

CONCLUSIONS: These findings indicate that microglial activation inversely correlated with hippocampal volume and hippocampal rCMRGlc in neurodegenerative diseases with dementia, providing further evidence for the central role of microglial activation in neurodegenerative diseases.

%B J Alzheimers Dis %V 51 %P 1275-89 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060942?dopt=Abstract %R 10.3233/JAD-150827 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dogs with Cognitive Dysfunction as a Spontaneous Model for Early Alzheimer's Disease: A Translational Study of Neuropathological and Inflammatory Markers. %A Schütt, Trine %A Helboe, Lone %A Pedersen, Lars Østergaard %A Waldemar, Gunhild %A Berendt, Mette %A Pedersen, Jan Torleif %K Aging %K Alzheimer Disease %K Animals %K Brain %K Cognitive Dysfunction %K Cytokines %K Denmark %K Disease Models, Animal %K Disease Progression %K Dog Diseases %K Dogs %K Female %K Humans %K Immunohistochemistry %K Longitudinal Studies %K Male %K Plaque, Amyloid %K Severity of Illness Index %K Species Specificity %K tau Proteins %K Translational Medical Research %X

Aged companion dogs with canine cognitive dysfunction (CCD) spontaneously develop varying degrees of progressive cognitive decline and particular neuropathological features correspondent to the changes associated with Alzheimer's disease (AD) in humans. The aim of the present study was to characterize certain aspects of neuropathology and inflammatory markers related to aging and CCD in dogs in comparison with human AD. Fifteen brains from aged dogs with normal cognitive function, mild cognitive impairment, or CCD were investigated and compared with two control brains from young dogs and brain sections from human AD subjects. The neuropathological investigations included evaluation of amyloid-β (Aβ) plaque deposition (N-terminally truncated and pyroglutamyl-modified Aβ included), tau pathology, and inflammatory markers in prefrontal cortex. Cortical Aβ deposition was found to be only of the diffuse subtype as no dense-core or neuritic plaques were found. The Aβ deposition followed a progressive pattern in four maturation stages. Accumulation of the Aβ peptide was also observed in the vessel walls. Both immunohistochemically and biochemically measured levels of Aβ pathology in prefrontal cortex showed a consistent positive correlation to age but not to cognitive deficit severity. No evidence of neurofibrillary tau pathology was found. The level of pro-inflammatory cytokines was generally low and showed no significant association to cognitive status. The findings of the present study support the senescent dog with spontaneous cognitive dysfunction as a valuable non-transgenic model for further investigations of the molecular events involved in the neurodegenerative processes associated with aging and early stage AD, especially the Aβ-related pathology.

%B J Alzheimers Dis %V 52 %P 433-49 %8 2016 03 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003213?dopt=Abstract %R 10.3233/JAD-151085 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dysregulation of Autophagy, Mitophagy, and Apoptotic Genes in the Medial Temporal Lobe Cortex in an Ischemic Model of Alzheimer's Disease. %A Ułamek-Kozioł, Marzena %A Kocki, Janusz %A Bogucka-Kocka, Anna %A Petniak, Alicja %A Gil-Kulik, Paulina %A Januszewski, Sławomir %A Bogucki, Jacek %A Jabłoński, Mirosław %A Furmaga-Jabłońska, Wanda %A Brzozowska, Judyta %A Czuczwar, Stanisław J %A Pluta, Ryszard %X

Ischemic brain damage is a pathological incident that is often linked with medial temporal lobe cortex injury and finally its atrophy. Post-ischemic brain injury associates with poor prognosis since neurons of selectively vulnerable ischemic brain areas are disappearing by apoptotic program of neuronal death. Autophagy has been considered, after brain ischemia, as a guardian against neurodegeneration. Consequently, we have examined changes in autophagy (BECN 1), mitophagy (BNIP 3), and apoptotic (caspase 3) genes in the medial temporal lobe cortex with the use of quantitative reverse-transcriptase PCR following transient 10-min global brain ischemia in rats with survival 2, 7, and 30 days. The intense significant overexpression of BECN 1 gene was noted on the 2nd day, while on days 7-30 the expression of this gene was still upregulated. BNIP 3 gene was downregulated on the 2nd day, but on days 7-30 post-ischemia, there was a significant reverse tendency. Caspase 3 gene, associated with apoptotic neuronal death, was induced in the same way as BNIP 3 gene after brain ischemia. Thus, the demonstrated changes indicate that the considerable dysregulation of expression of BECN 1, BNIP 3, and caspase 3 genes may be connected with a response of neuronal cells in medial temporal lobe cortex to transient complete brain ischemia.

%B J Alzheimers Dis %V 54 %P 113-21 %8 2016 Jul 27 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472881?dopt=Abstract %R 10.3233/JAD-160387 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dysregulation of Elongation Factor 1A Expression is Correlated with Synaptic Plasticity Impairments in Alzheimer's Disease. %A Beckelman, Brenna C %A Day, Stephen %A Zhou, Xueyan %A Donohue, Maggie %A Gouras, Gunnar K %A Klann, Eric %A Keene, C Dirk %A Ma, Tao %X

Synaptic dysfunction may represent an early and crucial pathophysiology in Alzheimer's disease (AD). Recent studies implicate a connection between synaptic plasticity deficits and compromised capacity of de novo protein synthesis in AD. The mRNA translational factor eukaryotic elongation factor 1A (eEF1A) is critically involved in several forms of long-lasting synaptic plasticity. By examining postmortem human brain samples, a transgenic mouse model, and application of synthetic human Aβ42 on mouse hippocampal slices, we demonstrated that eEF1A protein levels were significantly decreased in AD, particularly in the hippocampus. In contrast, brain levels of eukaryotic elongation factor 2 were unaltered in AD. Further, upregulation of eEF1A expression by the adenylyl cyclase activator forskolin, which induces long-lasting synaptic plasticity, was blunted in hippocampal slices derived from Tg2576 AD model mice. Finally, Aβ-induced hippocampal long-term potentiation defects were alleviated by upregulation of eEF1A signaling via brain-specific knockdown of the gene encoding tuberous sclerosis 2. In summary, our findings suggest a strong correlation between the dysregulation of eEF1A synthesis and AD-associated synaptic failure. These findings provide insights into the understanding of molecular mechanisms underlying AD etiology and may aid in identification of novel biomarkers and therapeutic targets.

%B J Alzheimers Dis %V 54 %P 669-78 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567813?dopt=Abstract %R 10.3233/JAD-160036 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Early Cognitive Deficits in Type 2 Diabetes: A Population-Based Study. %A Marseglia, Anna %A Fratiglioni, Laura %A Laukka, Erika J %A Santoni, Giola %A Pedersen, Nancy L %A Bäckman, Lars %A Xu, Weili %X

Evidence links type 2 diabetes to dementia risk. However, our knowledge on the initial cognitive deficits in diabetic individuals and the factors that might promote such deficits is still limited. This study aimed to identify the cognitive domains initially impaired by diabetes and the factors that play a role in this first stage. Within the population-based Swedish National Study on Aging and Care-Kungsholmen, 2305 cognitively intact participants aged ≥60 y were identified. Attention/working memory, perceptual speed, category fluency, letter fluency, semantic memory, and episodic memory were assessed. Diabetes (controlled and uncontrolled) and prediabetes were ascertained by clinicians, who also collected information on vascular disorders (hypertension, heart diseases, and stroke) and vascular risk factors (VRFs, including smoking and overweight/obesity). Data were analyzed with linear regression models. Overall, 196 participants (8.5%) had diabetes, of which 144 (73.5%) had elevated glycaemia (uncontrolled diabetes); 571 (24.8%) persons had prediabetes. In addition, diabetes, mainly uncontrolled, was related to lower performance in perceptual speed (β - 1.10 [95% CI - 1.98, - 0.23]), category fluency (β - 1.27 [95% CI - 2.52, - 0.03]), and digit span forward (β - 0.35 [95% CI - 0.54, - 0.17]). Critically, these associations were present only among APOEɛ4 non-carriers. The associations of diabetes with perceptual speed and category fluency were present only among participants with VRFs or vascular disorders. Diabetes, especially uncontrolled diabetes, is associated with poorer performance in perceptual speed, category fluency, and attention/primary memory. VRFs, vascular disorders, and APOE status play a role in these associations.

%B J Alzheimers Dis %V 53 %P 1069-78 %8 2016 Jun 15 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27314527?dopt=Abstract %R 10.3233/JAD-160266 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Early Postmenopausal Transdermal 17β-Estradiol Therapy and Amyloid-β Deposition. %A Kantarci, Kejal %A Lowe, Val J %A Lesnick, Timothy G %A Tosakulwong, Nirubol %A Bailey, Kent R %A Fields, Julie A %A Shuster, Lynne T %A Zuk, Samantha M %A Senjem, Matthew L %A Mielke, Michelle M %A Gleason, Carey %A Jack, Clifford R %A Rocca, Walter A %A Miller, Virginia M %X

BACKGROUND: It remains controversial whether hormone therapy in recently postmenopausal women modifies the risk of Alzheimer's disease (AD).

OBJECTIVE: To investigate the effects of hormone therapy on amyloid-β deposition in recently postmenopausal women.

METHODS: Participants within 5-36 months past menopause in the Kronos Early Estrogen Prevention Study, a randomized, double blinded placebo-controlled clinical trial, were randomized to: 1) 0.45 mg/day oral conjugated equine estrogens (CEE); 2) 50μg/day transdermal 17β-estradiol; or 3) placebo pills and patch for four years. Oral progesterone (200 mg/day) was given to active treatment groups for 12 days each month. 11C Pittsburgh compound B (PiB) PET imaging was performed in 68 of the 118 participants at Mayo Clinic approximately seven years post randomization and three years after stopping randomized treatment. PiB Standard unit value ratio (SUVR) was calculated.

RESULTS: Women (age = 52-65) randomized to transdermal 17β-estradiol (n = 21) had lower PiB SUVR compared to placebo (n = 30) after adjusting for age [odds ratio (95% CI) = 0.31(0.11-0.83)]. In the APOEɛ4 carriers, transdermal 17β-estradiol treated women (n = 10) had lower PiB SUVR compared to either placebo (n = 5) [odds ratio (95% CI) = 0.04(0.004-0.44)], or the oral CEE treated group (n = 3) [odds ratio (95% CI) = 0.01(0.0006-0.23)] after adjusting for age. Hormone therapy was not associated with PiB SUVR in the APOEɛ4 non-carriers.

CONCLUSION: In this pilot study, transdermal 17β-estradiol therapy in recently postmenopausal women was associated with a reduced amyloid-β deposition, particularly in APOEɛ4 carriers. This finding may have important implications for the prevention of AD in postmenopausal women, and needs to be confirmed in a larger sample.

%B J Alzheimers Dis %V 53 %P 547-56 %8 2016 May 07 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163830?dopt=Abstract %R 10.3233/JAD-160258 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Early-Life Exposure to Lead (Pb) Alters the Expression of microRNA that Target Proteins Associated with Alzheimer's Disease. %A Masoud, Anwar M %A Bihaqi, Syed W %A Machan, Jason T %A Zawia, Nasser H %A Renehan, William E %K Age Factors %K Amyloid beta-Protein Precursor %K Animals %K Animals, Newborn %K Disease Models, Animal %K Dose-Response Relationship, Drug %K Female %K Gene Expression Regulation, Developmental %K Lead %K Male %K Mice %K Mice, Inbred C57BL %K MicroRNAs %K Pregnancy %K RNA, Messenger %K Sp1 Transcription Factor %X

There is a growing recognition of the impact of environmental toxins on the epigenetic regulation of gene expression, including the genes that play a critical role in neural development, neural function, and neurodegeneration. We have shown previously that exposure to the heavy metal lead (Pb) in early life results in a latent over-expression of AD-related proteins in rodents and primates. The present study provides evidence that early postnatal exposure to Pb also alters the expression of select miRNA. Mice were exposed to 0.2% Pb acetate from Postnatal Day 1 (PND 1, first 24 h after birth) to PND 20 via their mother's milk. Brain tissue was harvested at PND 20, 180, or 700, and miRNA were isolated and quantified by qPCR. This exposure produced a transient increase (relative to control) in the expression of miR-106b (binds to AβPP mRNA), miR-29b (targets the mRNA for the transcription factor SP1) and two miRNAs (miR-29b and miR-132) that have the ability to inhibit translation of proteins involved in promoter methylation. The expression of miR-106b decreased over time in the Pb-exposed animals and was significantly less than the levels exhibited by the control animals at PND700. The level of miR-124, which binds to SP1 mRNA, was also reduced (relative to controls) at PND700. In summary, we show that exposure to the heavy metal Pb in early life has a significant impact on the short- and long-term expression of miRNA that target epigenetic mediators and neurotoxic proteins.

%B J Alzheimers Dis %V 51 %P 1257-64 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923026?dopt=Abstract %R 10.3233/JAD-151018 %0 Journal Article %J J Alzheimers Dis %D 2016 %T EEG Markers of Dementia with Lewy Bodies: A Multicenter Cohort Study. %A Bonanni, Laura %A Franciotti, Raffaella %A Nobili, Flavio %A Kramberger, Milica G %A Taylor, John-Paul %A Garcia-Ptacek, Sara %A Falasca, N Walter %A Famá, Francesco %A Cromarty, Ruth %A Onofrj, Marco %A Aarsland, Dag %X

Quantitative EEG (QEEG) has demonstrated good discriminative capacity for dementia with Lewy bodies (DLB) diagnosis as compared to Alzheimer's disease (AD) with a predictive value of 100% in a single cohort study. EEG in DLB was characterized by a dominant frequency (DF) in pre-alpha (5.5-7.5 Hz), theta, or delta bands and DF variability (DFV) >1.2 Hz, frequency prevalence (FP) pre-alpha in >40% and FP alpha in <32% of the epochs. To validate the aforementioned QEEG findings in independent cohorts of clinically diagnosed DLB versus AD patients, we analyzed EEG traces of 79 DLB and 133 AD patients (MMSE >20) collected from four European Centers. EEG traces from 19 scalp derivations were acquired as at least 10 min continuous signals and epoched in off-setting as series of 2-second-long epochs, subsequently processed by Fast Fourier Transform (frequency resolution 0.5 Hz). DLB patients showed EEG specific abnormalities in posterior derivations characterized by DF <8 Hz FP pre-alpha >50%, FP alpha <25%. DFV was >0.5 Hz. AD patients displayed stable alpha DF, DFV <0.5 Hz, FP pre-alpha <30%, and FP alpha >55%. DLB and AD differed for DF (p < 10-6), DFV (p < 0.05), FP pre-alpha (p < 10-12) and FP alpha (p < 10-12). Discriminant analysis detected specific cut-offs for every EEG mathematical descriptor; DF = 8, DFV = 2.2 Hz, FP pre-alpha=33%, FP alpha = 41% for posterior derivations. If at least one of the cut-off values was met, the percentage of DLB and AD patients correctly classified was 90% and 64%, respectively. The findings in this multicenter study support the validity of QEEG analysis as a tool for diagnosis in DLB patients.

%B J Alzheimers Dis %V 54 %P 1649-1657 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589528?dopt=Abstract %R 10.3233/JAD-160435 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effect of Early Referral to Specialist in Dementia on Institutionalization and Functional Decline: Findings from a Population-Based Study. %A Pimouguet, Clément %A Le-Goff, Mélanie %A Rizzuto, Debora %A Berr, Claudine %A Leffondré, Karen %A Pérès, Karine %A Dartigues, Jean François %A Helmer, Catherine %K Activities of Daily Living %K Cognition Disorders %K Community Health Planning %K Dementia %K Disability Evaluation %K Female %K Finland %K Follow-Up Studies %K Humans %K Institutionalization %K Male %K Psychiatric Status Rating Scales %K Referral and Consultation %K Specialization %X

BACKGROUND: Although early diagnosis has been hypothesized to benefit both patients and caregivers, until now studies evaluating the effect of early dementia diagnosis are lacking.

OBJECTIVE: To investigate the influence of early specialist referral for dementia on the risk of institutionalization and functional decline in Activity of Daily Living (ADL).

METHODS: Incident dementia cases were screened in a prospective population-based cohort, the Three-City Study, and initial specialist consultation for cognitive complaint was assessed at dementia diagnosis. Proportional hazard regression and illness-death models were used to test the association between specialist referral and, respectively, institutionalization and functional decline.

RESULTS: Only one third of the incident individuals with dementia had consulted a specialist for cognitive problems early (36%). After adjustment on potential confounders (including cognitive and functional decline) and competing risk of death, participants who had consulted a specialist early in the disease course presented a higher rate of being institutionalized than those who did not (Hazard Ratio = 2.00, 95% Confidence Interval (CI): 1.09- 3.64). But early specialist referral was not associated with further functional decline (HR = 1.09, 95% CI: 0.71- 1.67).

CONCLUSIONS: Early specialist referral in dementia is associated with increased risk of institutionalization but not with functional decline in ADL. These findings suggest that early care referral in dementia may be a marker of concern for patients and/or caregivers; subsequent medical and social care could be suboptimal or inappropriate to allow patients to stay longer at home.

%B J Alzheimers Dis %V 49 %P 819-28 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484926?dopt=Abstract %R 10.3233/JAD-150574 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer's Disease: Results of a Randomized Trial. %A Berger, Miles %A Nadler, Jacob W %A Friedman, Allan %A McDonagh, David L %A Bennett, Ellen R %A Cooter, Mary %A Qi, Wenjing %A Laskowitz, Daniel T %A Ponnusamy, Vikram %A Newman, Mark F %A Shaw, Leslie M %A Warner, David S %A Mathew, Joseph P %A James, Michael L %X

BACKGROUND: Preclinical studies have found differential effects of isoflurane and propofol on the Alzheimer's disease (AD)-associated markers tau, phosphorylated tau (p-tau) and amyloid-β (Aβ).

OBJECTIVE: We asked whether isoflurane and propofol have differential effects on the tau/Aβ ratio (the primary outcome), and individual AD biomarkers. We also examined whether genetic/intraoperative factors influenced perioperative changes in AD biomarkers.

METHODS: Patients undergoing neurosurgical/otolaryngology procedures requiring lumbar cerebrospinal fluid (CSF) drain placement were prospectively randomized to receive isoflurane (n = 21) or propofol (n = 18) for anesthetic maintenance. We measured perioperative CSF sample AD markers, performed genotyping assays, and examined intraoperative data from the electronic anesthesia record. A repeated measures ANOVA was used to examine changes in AD markers by anesthetic type over time.

RESULTS: The CSF tau/Aβ ratio did not differ between isoflurane- versus propofol-treated patients (p = 1.000). CSF tau/Aβ ratio and tau levels increased 10 and 24 h after drain placement (p = 2.002×10-6 and p = 1.985×10-6, respectively), mean CSF p-tau levels decreased (p = 0.005), and Aβ levels did not change (p = 0.152). There was no interaction between anesthetic treatment and time for any of these biomarkers. None of the examined genetic polymorphisms, including ApoE4, were associated with tau increase (n = 9 polymorphisms, p > 0.05 for all associations).

CONCLUSION: Neurosurgery/otolaryngology procedures are associated with an increase in the CSF tau/Aβ ratio, and this increase was not influenced by anesthetic type. The increased CSF tau/Aβ ratio was largely driven by increases in tau levels. Future work should determine the functional/prognostic significance of these perioperative CSF tau elevations.

%B J Alzheimers Dis %V 52 %P 1299-310 %8 2016 Apr 15 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079717?dopt=Abstract %R 10.3233/JAD-151190 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effect of Tween-20 on Core Biomarkers Measured in Cerebrospinal Fluid from Patients with Alzheimer's Disease, Mild Cognitive Impairment, or Healthy Control Individuals. %A Berge, Guro %A Lauridsen, Camilla %A Sando, Sigrid Botne %A Holder, Daniel Joseph %A Møller, Ina %A Aasly, Jan Olav %A Bråthen, Geir %A Savage, Mary Josephine %A White, Linda Rosemary %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognitive Dysfunction %K Enzyme-Linked Immunosorbent Assay %K Female %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Peptide Fragments %K Phosphorylation %K Polysorbates %K ROC Curve %K Surface-Active Agents %K tau Proteins %X

BACKGROUND: There is substantial variation caused by preanalytical procedures in the measurement of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) reported in the literature.

OBJECTIVE: Determine whether the detergent Tween-20 improves diagnostic accuracy.

METHODS: CSF proteins (Aβ42, Aβ40, total tau, and phosphorylated tau) were measured by standard ELISA, in uncentrifuged CSF with or without 0.05% Tween-20 from patients with AD or amnestic mild cognitive impairment, and healthy elderly controls. In the main study, collection tubes containing Tween-20 (Sarstedt 15 mL) were filled with 5 mL CSF to ensure consistent detergent concentration across subsequent aliquots into Corning 2 mL tubes. These latter were also the primary collection vessel for samples without Tween-20. The effect of centrifugation, and extra tube transfer of samples with Tween-20 were also examined.

RESULTS: 0.05% Tween-20 significantly increased mean measured CSF concentration of Aβ42 (30% ), Aβ40 (23% ), and total tau (4% ), but not phosphorylated tau. Generally, these increases were similar in all groups, although for Aβ42, the mean percentage increase with Tween-20 was slightly larger for AD. Areas under receiver-operator characteristic curves were similar whether Tween-20 was present or not. Centrifuged CSF without Tween-20 significantly reduced the measured concentration of Aβ42 versus non-centrifuged samples, a difference not seen when detergent was added. Similar CSF Aβ42 levels were found whether Tween-20 was added at collection in an extra tube or directly to the main collection tube.

CONCLUSION: Addition of Tween-20 to CSF did not improve differentiation of patients from controls.

%B J Alzheimers Dis %V 49 %P 493-502 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484901?dopt=Abstract %R 10.3233/JAD-150234 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effectiveness of Exercise- and Cognitive-Based Treatments on Salivary Cortisol Levels and Sundowning Syndrome Symptoms in Patients with Alzheimer's Disease. %A Venturelli, Massimo %A Sollima, Alessio %A Cè, Emiliano %A Limonta, Eloisa %A Bisconti, Angela V %A Brasioli, Anna %A Muti, Ettore %A Esposito, Fabio %X

Sundowning syndrome (SDS) in patients with Alzheimer's disease (AD) is characterized by the intensification of behavioral disorders at sunset. Despite SDS etiology being unclear, a strong relationship between high cortisol levels and SDS has been reported. Aerobic exercise (AE) and cognitive training (CT) can reduce cortisol levels. However, whether SDS would benefit from AE and CT is still unknown. Therefore, the aim of this study was to investigate whether AE and CT treatments are effective in reducing SDS via downregulation of cortisol levels. The possible additive effects of combined AE+CT were also assessed. Eighty AD patients were randomly assigned to AE (n = 20), CT (n = 20), AE+CT (n = 20), and standard therapy (no treatment, NT; n = 20). Treatments were administered for 3 months, 5 days/week, 1 hour before sunset. Before and after treatments, salivary cortisol levels were sampled at 7, 11, 15, at sunset, and 20 (time of day). Blind assessment of behavioral disorders (neuropsychiatric inventory, NPI) and agitation (agitated behavior scale, ABS) were also performed. After interventions, cortisol levels were reduced in AE and AE+CT by ∼26%. In the same groups, NPI and ABS decreased by ∼50%. By contrast, cortisol and behavioral disorders were similar to baseline in CT and NT. Changes in NPI and ABS were significantly correlated with the reduction in cortisol levels. AE or AE+CT effects on SDS and cortisol levels and the lack of effect of CT alone indicate the effectiveness of an exercise-based treatment on SDS, suggesting a possible hypothalamic-pituitary-adrenal axis dysregulation underpinning SDS.

%B J Alzheimers Dis %V 53 %P 1631-40 %8 2016 Jul 14 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27540967?dopt=Abstract %R 10.3233/JAD-160392 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Effects of Latrepirdine on Amyloid-β Aggregation and Toxicity. %A Porter, Tenielle %A Bharadwaj, Prashant %A Groth, David %A Paxman, Adrian %A Laws, Simon M %A Martins, Ralph N %A Verdile, Giuseppe %K Amyloid beta-Peptides %K Analysis of Variance %K Antipsychotic Agents %K Cell Line, Tumor %K Dose-Response Relationship, Drug %K Drug Interactions %K Humans %K Indoles %K L-Lactate Dehydrogenase %K Microscopy, Atomic Force %K Neuroblastoma %K Peptide Fragments %K Protein Aggregates %X

Latrepirdine (Dimebon) has been demonstrated to be a neuroprotective and cognition improving agent in neurodegenerative diseases that feature protein aggregation and deposition, such as Alzheimer's disease (AD). The accumulation of amyloid-β (Aβ) protein aggregates is a key event in the neurodegenerative process in AD. This study explores if latrepirdine modulation of protein aggregation contributes to its neuroprotective mechanism of action. Assessment of neuronal cell death showed that there was a significant reduction in lactate dehydrogenase release at an equimolar ratio of Aβ:latrepirdine and with lower concentrations of latrepirdine. The ability of latrepirdine to alter the formation of Aβ42 aggregates was assessed by thioflavin-T fluorescence, western immunoblotting and atomic force microscopy (AFM). Despite showing a reduction in thioflavin-T fluorescence with latrepirdine treatment, indicating a decrease in aggregation, immunoblotting and AFM showed a modest increase in both the formation and size of Aβ aggregates. The discrepancies between thioflavin-T and the other assays are consistent with previous evidence that cyclic molecules can interfere with thioflavin-T binding of amyloid protein preparations. The ability of latrepirdine to modulate Aβ aggregation appears to be independent of its neuroprotective effects, and is unlikely to be a mechanism by which latrepirdine offers protection. This study investigates the effect of latrepirdine on Aβ aggregation, and presents evidence suggesting that caution should be applied in the use of thioflavin-T fluorescence based assays as a method for screening compounds for protein aggregation altering properties.

%B J Alzheimers Dis %V 50 %P 895-905 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836170?dopt=Abstract %R 10.3233/JAD-150790 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Epileptic Prodromal Alzheimer's Disease, a Retrospective Study of 13 New Cases: Expanding the Spectrum of Alzheimer's Disease to an Epileptic Variant? %A Cretin, Benjamin %A Sellal, François %A Philippi, Nathalie %A Bousiges, Olivier %A Di Bitonto, Laure %A Martin-Hunyadi, Catherine %A Blanc, Frédéric %X

BACKGROUND: Aside from rare case reports, only one study, with 12 patients, has addressed the phenotypic presentation of epilepsy in clinically defined amnestic mild cognitive impairment (aMCI, presumed to correspond to the AD prodromal stage): the authors highlighted a pharmacosensitive non-convulsive partial epileptic syndrome most probably related to the temporal or temporo-frontal cortices.

OBJECTIVE: The objective of this study was to verify the existence and the syndromic features of epileptic prodromal AD in a tertiary Memory Clinic.

METHODS: We conducted a retrospective, single-center study of the electro-radio-clinical features of 13 cases of epileptic prodromal AD patients (3.1% of a cohort of MCI, n = 430 subjects), selected on both clinical criteria and CSF biomarkers.

RESULTS: In our patients, a pharmacosensitive temporal lobe epilepsy syndrome, inaugurating prodromal AD, started at a mean age of 63 years (±12.8 years) and preceded MCI diagnosis by 4 to 7 years. At the stage of aMCI, median MMSE score was 26 and imaging showed mild hippocampal atrophy. After almost one year under treatment, cognitive complaints were not relieved but the MMSE score remained stable at 26 for 11 patients (2 patients were excluded from analysis because of the onset of aphasic or neurovisual symptoms altering MMSE scoring).

CONCLUSION: Our data, in conjunction with those of the 12 previously described subjects, suggest the existence of a currently unrecognized inaugural epilepsy syndrome of sporadic AD. Such a syndrome could be called the epileptic variant of AD because seizures are its sole feature for more than 2.5 years.

%B J Alzheimers Dis %V 52 %P 1125-33 %8 2016 Apr 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104892?dopt=Abstract %R 10.3233/JAD-150096 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease. %A Chouraki, Vincent %A Reitz, Christiane %A Maury, Fleur %A Bis, Joshua C %A Bellenguez, Celine %A Yu, Lei %A Jakobsdottir, Johanna %A Mukherjee, Shubhabrata %A Adams, Hieab H %A Choi, Seung Hoan %A Larson, Eric B %A Fitzpatrick, Annette %A Uitterlinden, Andre G %A De Jager, Philip L %A Hofman, Albert %A Gudnason, Vilmundur %A Vardarajan, Badri %A Ibrahim-Verbaas, Carla %A van der Lee, Sven J %A Lopez, Oscar %A Dartigues, Jean-François %A Berr, Claudine %A Amouyel, Philippe %A Bennett, David A %A van Duijn, Cornelia %A DeStefano, Anita L %A Launer, Lenore J %A Ikram, M Arfan %A Crane, Paul K %A Lambert, Jean-Charles %A Mayeux, Richard %A Seshadri, Sudha %X

Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI =   [1.13-1.21] per standard deviation increase in GRS; p-value =  2.86×10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95% CI =   [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI =   [1.08-1.18]; pinteraction = 3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex =  0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

%B J Alzheimers Dis %V 53 %P 921-32 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340842?dopt=Abstract %R 10.3233/JAD-150749 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evaluation of Neuropathological Effects of a High-Fat Diet in a Presymptomatic Alzheimer's Disease Stage in APP/PS1 Mice. %A Ettcheto, Miren %A Petrov, Dmitry %A Pedrós, Ignacio %A Alva, Norma %A Carbonell, Teresa %A Beas-Zarate, Carlos %A Pallas, Merce %A Auladell, Carme %A Folch, Jaume %A Camins, Antoni %X

Alzheimer's disease (AD) is currently an incurable aging-related neurodegenerative disorder. Recent studies give support to the hypotheses that AD should be considered as a metabolic disease. The present study aimed to explore the relationship between hippocampal neuropathological amyloid-β (Aβ) plaque formation and obesity at an early presymptomatic disease stage (3 months of age). For this purpose, we used APPswe/PS1dE9 (APP/PS1) transgenic mice, fed with a high-fat diet (HFD) in order to investigate the potential molecular mechanisms involved in both disorders. The results showed that the hippocampus from APP/PS1 mice fed with a HFD had an early significant decrease in Aβ signaling pathway specifically in the insulin degrading enzyme protein levels, an enzyme involved in (Aβ) metabolism, and α-secretase. These changes were accompanied by a significant increase in the occurrence of plaques in the hippocampus of these mice. Furthermore, APP/PS1 mice showed a significant hippocampal decrease in PGC-1α levels, a cofactor involved in mitochondrial biogenesis. However, HFD does not provoke changes in neither insulin receptors gene expression nor enzymes involved in the signaling pathway. Moreover, there are no changes in any enzymes (kinases) involved in tau phosphorylation, such as CDK5, and neither in brain oxidative stress production. These results suggest that early changes in brains of APP/PS1 mice fed with a HFD are mediated by an increase in Aβ1 ‒ 42, which induces a decrease in PKA levels and alterations in the p-CREB/ NMDA2B /PGC1-α pathway, favoring early AD neuropathology in mice.

%B J Alzheimers Dis %V 54 %P 233-51 %8 2016 Jul 14 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567882?dopt=Abstract %R 10.3233/JAD-160150 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evaluation of Underlying Causes of Death in Patients with Dementia to Support Targeted Advance Care Planning. %A van de Vorst, Irene E %A Koek, Huiberdina L %A Bots, Michiel L %A Vaartjes, Ilonca %X

BACKGROUND: Insight in causes of death in demented patients may help physicians in end-of-life care.

OBJECTIVES: To investigate underlying causes of death (UCD) in demented patients stratified by age, sex, dementia subtype [Alzheimer's disease (AD), vascular dementia (VaD)] and to compare them with UCD in the general population (GP).

METHODS: A nationwide cohort of 59,201 patients with dementia (admitted to a hospital or visiting a day clinic) was constructed [38.7% men, 81.4 years (SD 7.0)] from 2000 through 2010. UCDs were reported and compared to the GP by calculating relative risks (RRs).

RESULTS: During follow up [median follow up time 1.3 years (IQR 0.3- 3.0)], 64.2% of women and 69.3% of men died. Leading UCDs were dementia (17.5% in men and 23.7% in women) and cardiovascular disease (CVD) (18.7% and 19.2%, respectively). When compared to the GP, dementia was a more common UCD (RR in men 4.65, 95% CI 4.43-4.88), while CVD (RR in men 0.67, 95% CI 0.65-0.68) and cancer (RR 0.40, 95% CI 0.39-0.41) were less common. These differences were more pronounced in patients aged between 60-69 as compared to those aged≥90 years. Patients with AD died less often of cerebrovascular diseases as compared to VaD (RR in men 0.53, 95% CI 0.47-0.59).

CONCLUSION: UCDs in patients with dementia differs from that of the GP, as dementia is more often and cancer less often an UCD. Although less frequent compared to the GP, CVD also is one of the leading UCDs in patients with dementia. This information is valuable for targeted advance care planning.

%B J Alzheimers Dis %V 53 %P 117-25 %8 2016 May 06 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163802?dopt=Abstract %R 10.3233/JAD-150925 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Excess Costs Associated with Possible Misdiagnosis of Alzheimer's Disease Among Patients with Vascular Dementia in a UK CPRD Population. %A Happich, Michael %A Kirson, Noam Y %A Desai, Urvi %A King, Sarah %A Birnbaum, Howard G %A Reed, Catherine %A Belger, Mark %A Lenox-Smith, Alan %A Price, David %X

BACKGROUND: Prior diagnosis of Alzheimer's disease (AD) among patients later diagnosed with vascular dementia (VaD) has been associated with excess costs, suggesting potential benefits of earlier rule-out of AD diagnosis.

OBJECTIVE: To investigate whether prior diagnosis with AD among patients with VaD is associated with excess costs in the UK.

METHODS: Patients with a final VaD diagnosis, continuous data visibility for≥6 months prior to index date, and linkage to Hospital Episode Statistics data were retrospectively selected from de-identified Clinical Practice Research Datalink data. Patients with AD diagnosis before a final VaD diagnosis were matched to similar patients with no prior AD diagnosis using propensity score methods. Annual excess healthcare costs were calculated for 5 years post-index, stratified by time to final diagnosis.

RESULTS: Of 9,311 patients with VaD, 508 (6%) had prior AD diagnosis with a median time to VaD diagnosis exceeding 2 years from index date. Over the entire follow-up period, patients with prior AD diagnosis had accumulated healthcare costs that were approximately GBP2,000 higher than those for matched counterparts (mostly due to higher hospitalization costs). Cost differentials peaked particularly in the period including the final VaD diagnosis, with excess costs quickly declining thereafter.

CONCLUSION: Potential misdiagnosis of AD among UK patients with VaD resulted in substantial excess costs. The decline in excess costs following a final VaD diagnosis suggests potential benefits from earlier rule-out of AD.

%B J Alzheimers Dis %V 53 %P 171-83 %8 2016 May 06 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163798?dopt=Abstract %R 10.3233/JAD-150685 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Exercise Plus Cognitive Performance Over and Above Exercise Alone in Subjects with Mild Cognitive Impairment. %A Sacco, Guillaume %A Caillaud, Corinne %A Ben Sadoun, Gregory %A Robert, Philippe %A David, Renaud %A Brisswalter, Jeanick %K Aged %K Analysis of Variance %K Cognitive Dysfunction %K Cognitive Therapy %K Exercise %K Exercise Therapy %K Female %K Humans %K Inhibition (Psychology) %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Reaction Time %K Retrospective Studies %K Treatment Outcome %X

BACKGROUND: Epidemiological studies highlight the relevance of regular exercise interventions to enhance or maintain neurocognitive function in subjects with cognitive impairments.

OBJECTIVES: The aim of this study was to ascertain the effect of aerobic exercise associated with cognitive enrichment on cognitive performance in subjects with mild cognitive impairment (MCI).

METHOD: Eight participants with MCI (72 ± 2 years) were enrolled in a 9-month study that consisted of two 3-months experimental interventions separated by a training cessation period of 3 months. The interventions included either aerobic exercise alone or aerobic exercise combined with cognitive enrichment. The exercise program involved two 20-min cycling exercise bouts per week at an intensity corresponding to 60% of the heart rate reserve. Cognitive performance was assessed using a task of single reaction time (SRT) and an inhibition task (Go-no-Go) before, immediately after, and 1 month after each intervention.

RESULTS: The exercise intervention improved the speed of responses during the Go-no-Go task without any increase in errors. This improvement was enhanced by cognitive enrichment (6 ± 1% ; p >  0.05), when compared with exercise alone (4 ± 0.5% ,). Following exercise cessation, this positive effect disappeared. No effect was observed on SRT performance.

CONCLUSION: Regular aerobic exercise improved cognitive performance in MCI subjects and the addition of cognitive tasks during exercise potentiated this effect. However, the influence of aerobic exercise on cognitive performance did not persist after cessation of training. Studies involving a larger number of subjects are necessary to confirm these results.

%B J Alzheimers Dis %V 50 %P 19-25 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639954?dopt=Abstract %R 10.3233/JAD-150194 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Expression of Tau Produces Aberrant Plasma Membrane Blebbing in Glial Cells Through RhoA-ROCK-Dependent F-Actin Remodeling. %A Torres-Cruz, Francisco M %A Rodríguez-Cruz, Fanny %A Escobar-Herrera, Jaime %A Barragán-Andrade, Norma %A Basurto-Islas, Gustavo %A Ripova, Daniela %A Avila, Jesús %A Garcia-Sierra, Francisco %X

Abnormal aggregation of Tau in glial cells has been reported in Alzheimer's disease (AD) and other tauopathies; however, the pathological significance of these aggregates remains unsolved to date. In this study, we evaluated whether full-length Tau (Tau441) and its aspartic acid421-truncated Tau variant (Tau421) produce alterations in the normal organization of the cytoskeleton and plasma membrane (PM) when transiently expressed in cultured C6-glial cells. Forty-eight hours post-transfection, abnormal microtubule bundling was observed in the majority of the cells, which expressed either Tau441 or Tau421. Moreover, both variants of Tau produced extensive PM blebbing associated with cortical redistribution of filamentous actin (F-Actin). These effects were reverted when Tau-expressing cells were incubated with drugs that depolymerize F-Actin. In addition, when glial cells showing Tau-induced PM blebbing were incubated with inhibitors of the Rho-associated protein kinase (ROCK) signaling pathway, both formation of abnormal PM blebs and F-Actin remodeling were avoided. All of these effects were initiated upstream by abnormal Tau-induced microtubule bundling, which may release the microtubule-bound guanine nucleotide exchange factor-H1 (GEF-H1) into the cytoplasm in order to activate its major effector RhoA-GTPase. These results may represent a new mechanism of Tau toxicity in which Tau-induced microtubule bundling produces activation of the Rho-GTPase-ROCK pathway that in turn mediates the remodeling of cortical Actin and PM blebbing. In AD and other tauopathies, these Tau-induced abnormalities may occur and contribute to the impairment of glial activity.

%B J Alzheimers Dis %V 52 %P 463-82 %8 2016 03 21 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003208?dopt=Abstract %R 10.3233/JAD-150396 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Expression of the Alzheimer's Disease Mutations AβPP695sw and PSEN1M146I in Double-Transgenic Göttingen Minipigs. %A Jakobsen, Jannik E %A Johansen, Marianne G %A Schmidt, Mette %A Liu, Ying %A Li, Rong %A Callesen, Henrik %A Melnikova, Margarita %A Habekost, Mette %A Matrone, Carmela %A Bouter, Yvonne %A Bayer, Thomas A %A Nielsen, Anders Lade %A Duthie, Monika %A Fraser, Paul E %A Holm, Ida E %A Jørgensen, Arne Lund %X

Mutations in the amyloid-β protein precursor gene (AβPP), the presenilin 1 gene (PSEN1) or the presenilin 2 gene (PSEN2) that increase production of the AβPP-derived peptide Aβ42 cause early-onset Alzheimer's disease. Rodent models of the disease show that further increase in Aβ42 production and earlier brain pathology can be obtained by coexpressing AβPP and PSEN1 mutations. To generate such elevated Aβ42 level in a large animal model, we produced Göttingen minipigs carrying in their genome one copy of a human PSEN1 cDNA with the Met146Ile (PSEN1M146I) mutation and three copies of a human AβPP695 cDNA with the Lys670Asn/Met671Leu (AβPPsw) double-mutation. Both transgenes were expressed in fibroblasts and in the brain, and their respective proteins were processed normally. Immunohistochemical staining with Aβ42-specific antibodies detected intraneuronal accumulation of Aβ42 in brains from a 10- and an 18-month-old pig. Such accumulation may represent an early event in the pathogenesis of Alzheimer's disease.

%B J Alzheimers Dis %V 53 %P 1617-30 %8 2016 Jul 14 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27540966?dopt=Abstract %R 10.3233/JAD-160408 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Extracellular Vesicles Containing P301L Mutant Tau Accelerate Pathological Tau Phosphorylation and Oligomer Formation but Do Not Seed Mature Neurofibrillary Tangles in ALZ17 Mice. %A Baker, Siân %A Polanco, Juan Carlos %A Götz, Jϋrgen %X

In Alzheimer's disease, the distribution of neurofibrillary tangles, a histological hallmark comprised of phosphorylated forms of the protein tau, follows a distinct pattern through anatomically connected brain regions. The well-documented correlation between the severity of tau pathology and disease progression implies a prion-like seeding and spreading mechanism for tau. Experimentally, this has been addressed in transgenic mice by the injection of protein lysates isolated from brains of transgenic mice or patients with tauopathies, including AD, that were shown to behave like seeds, accelerating tau pathology and tangle formation in predisposed mice. More specifically, in vivo data suggest that brain lysates from mice harboring the P301S mutation of tau can seed protein aggregation when injected into the hippocampi of human wild-type tau transgenic ALZ17 mice. Here, we compared the seeding potential of lysates and extracellular vesicles enriched for exosomes (EVs) from wild-type and human P301L tau transgenic rTg4510 mouse brains. We show that transgenic EVs cause increased tau phosphorylation and soluble oligomer formation in a manner comparable to that of freely available proteins in brain lysates, a prerequisite for the formation of mature protein aggregates.

%B J Alzheimers Dis %V 54 %P 1207-1217 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567840?dopt=Abstract %R 10.3233/JAD-160371 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Feasibility of a Memory Clinic-Based Physical Activity Prescription Program. %A Vidoni, Eric D %A Watts, Amber S %A Burns, Jeffrey M %A Greer, Colby S %A Graves, Rasinio S %A Van Sciver, Angela %A Black, Jessica R %A Cooper, Sarah K %A Nagely, Allison C %A Uphoff, Elaine %A Volmer, Jennifer M %A Bieberle, Natalie A %X

BACKGROUND: Effective programs for promoting physical activity are needed for those with cognitive impairment.

OBJECTIVE: To test the feasibility of mobile Health (mHealth) technology-supported physical activity prescription from a tertiary care memory clinic.

METHODS: This feasibility study was designed as a 16-week randomized, crossover trial of a physical activity prescription: 8 weeks of intervention, 8 weeks of baseline or maintenance phase data collection. We recruited 2 cohorts: 21 individuals with Alzheimer-related cognitive impairment (mean age 72.3 (5.2), 9 females), and 9 individuals with normal cognition (mean age 69.6 (5.8), 8 females). We gave each cohort an mHealth accelerometer-based physical activity prescription to double number of steps taken. Our primary outcomes were feasibility and safety. Our secondary outcomes were change in weekly steps taken, Dementia Quality of Life Scale, Self-efficacy Scale, 6-minute Walk, and mini-Physical Performance Test.

RESULTS: Set-up and use of the device was not a barrier to participation. However, only 62% of participants with cognitive impairment completed the intervention. The cohort with cognitive impairment did not change their weekly step count above Week 1. All participants in the cohort with normal cognition were able to set up and use their device and increased their weekly step count above Week 1. There were no differences between Week 1 and Week 8 for any secondary measures in either cohort.

CONCLUSIONS: Setup and daily use of mHealth technology appears to be feasible for a person with cognitive impairment with the help of a partner, but increasing daily step counts over 8 weeks was not achieved. Future work needs to assess alternative activity prescription goals or additional support for patients and their partners.

%B J Alzheimers Dis %V 53 %P 161-70 %8 2016 Apr 21 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104905?dopt=Abstract %R 10.3233/JAD-160158 %0 Journal Article %J J Alzheimers Dis %D 2016 %T First Symptoms and Neurocognitive Correlates of Behavioral Variant Frontotemporal Dementia. %A Santamaría-García, Hernando %A Reyes, Pablo %A García, Adolfo %A Baez, Sandra %A Martinez, Angela %A Santacruz, José Manuel %A Slachevsky, Andrea %A Sigman, Mariano %A Matallana, Diana %A Ibáñez, Agustín %X

BACKGROUND: Previous works highlight the neurocognitive differences between apathetic and disinhibited clinical presentations of the behavioral variant frontotemporal dementia (bvFTD). However, little is known regarding how the early presentation (i.e., first symptom) is associated to the neurocognitive correlates of the disease's clinical presentation at future stages of disease.

OBJECTIVES: We analyzed the neurocognitive correlates of patients with bvFTD who debuted with apathy or disinhibition as first symptom of disease.

METHODS: We evaluated the neuropsychological, clinical, and neuroanatomical (3T structural images) correlates in a group of healthy controls (n = 30) and two groups of bvFTD patients (presented with apathy [AbvFTD, n = 18] or disinhibition [DbvFTD, n = 16]). To differentiate groups according to first symptoms, we used multivariate analyses.

RESULTS: The first symptom in patients described the evolution of the disease. AbvFTD and DbvFTD patients showed increased brain atrophy and increased levels of disinhibition and apathy, respectively. Whole brain analyzes in AbvFTD revealed atrophy in the frontal, insular, and temporal areas. DbvFTD, in turn, presented atrophy in the prefrontal regions, temporoparietal junction, insula, and temporoparietal region. Increased atrophy in DbvFTD patients (compared to AbvFTD) was observed in frontotemporal regions. Multivariate analyses confirmed that a set of brain areas including right orbitofrontal, right dorsolateral prefrontal, and left caudate were enough to distinguish the patients' subgroups.∥Conclusion: First symptom in bvFTD patients described the neurocognitive impairments after around three years of disease, playing an important role in the early detection, disease tracking, and neuroanatomical specification of bvFTD, as well as in future research on potential disease-modifying treatments.

%B J Alzheimers Dis %V 54 %P 957-970 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567867?dopt=Abstract %R 10.3233/JAD-160501 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Functional Connectivity of Ventral and Dorsal Visual Streams in Posterior Cortical Atrophy. %A Migliaccio, Raffaella %A Gallea, Cécile %A Kas, Aurélie %A Perlbarg, Vincent %A Samri, Dalila %A Trotta, Laura %A Michon, Agnès %A Lacomblez, Lucette %A Dubois, Bruno %A Lehéricy, Stéphane %A Bartolomeo, Paolo %K Aged %K Alzheimer Disease %K Atrophy %K Case-Control Studies %K Cerebral Cortex %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Oxygen %K Visual Pathways %X

BACKGROUND: Posterior cortical atrophy (PCA) induces progressive dysfunction of ventral and dorsal visual networks. Little is known, however, about corresponding changes in functional connectivity (FC).

OBJECTIVES: To investigate FC changes in the visual networks, their relationship with cortical atrophy, and the association with Alzheimer's disease (AD) pathology.

METHODS: Ten PCA patients and 28 age-matched controls participated in the study. Using resting state fMRI, we measured FC in ventral and dorsal cortical visual networks, defined on the basis of a priori knowledge of long-range white matter connections. To assess the relationships with AD, we determined AD biomarkers in cerebrospinal fluid and FC in the default mode network (DMN), which is vulnerable to AD pathology. Voxel-based morphometry analysis assessed the pattern of grey matter (GM) atrophy.

RESULTS: PCA patients showed GM atrophy in bilateral occipital and inferior parietal regions. PCA patients had lower FC levels in a ventral network than controls, but higher FC in inferior components of the dorsal network. In particular, the increased connectivity correlated with greater GM atrophy in occipital regions. All PCA patients had positive cerebrospinal fluid biomarkers for AD; however, FC in global DMN did not differ from controls.

CONCLUSIONS: FC in PCA reflects brain structure in a non-univocal way. Hyperconnectivity of dorsal networks may indicate aberrant communication in response to posterior brain atrophy or processes of neural resilience during the initial stage of brain dysfunction. The lack of difference from controls in global DMN FC highlights the atypical nature of PCA with respect to typical AD.

%B J Alzheimers Dis %V 51 %P 1119-30 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923019?dopt=Abstract %R 10.3233/JAD-150934 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Gene Expression Profiling in the APP/PS1KI Mouse Model of Familial Alzheimer's Disease. %A Weissmann, Robert %A Hüttenrauch, Melanie %A Kacprowski, Tim %A Bouter, Yvonne %A Pradier, Laurent %A Bayer, Thomas A %A Kuss, Andreas W %A Wirths, Oliver %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Brain %K Disease Models, Animal %K Gene Expression Profiling %K Male %K Mice %K Mice, Transgenic %K Nerve Degeneration %K Presenilin-1 %K Transcriptome %X

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by early intraneuronal amyloid-β (Aβ) accumulation, extracellular deposition of Aβ peptides, and intracellular hyperphosphorylated tau aggregates. These lesions cause dendritic and synaptic alterations and induce an inflammatory response in the diseased brain. Although the neuropathological characteristics of AD have been known for decades, the molecular mechanisms causing the disease are still under investigation. Studying gene expression changes in postmortem AD brain tissue can yield new insights into the molecular disease mechanisms. To that end, one can employ transgenic AD mouse models and the next-generation sequencing technology. In this study, a whole-brain transcriptome analysis was carried out using the well-characterized APP/PS1KI mouse model for AD. These mice display a robust phenotype reflected by working memory deficits at 6 months of age, a significant neuron loss in a variety of brain areas including the CA1 region of the hippocampus and a severe amyloid pathology. Based on deep sequencing, differentially expressed genes (DEGs) between 6-month-old WT or PS1KI and APP/PS1KI were identified and verified by qRT-PCR. Compared to WT mice, 250 DEGs were found in APP/PS1KI mice, while 186 DEGs could be found compared to PS1KI control mice. Most of the DEGs were upregulated in APP/PS1KI mice and belong to either inflammation-associated pathways or lysosomal activation, which is likely due to the robust intraneuronal accumulation of Aβ in this mouse model. Our comprehensive brain transcriptome study further highlights APP/PS1KI mice as a valuable model for AD, covering molecular inflammatory and immune responses.

%B J Alzheimers Dis %V 50 %P 397-409 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639971?dopt=Abstract %R 10.3233/JAD-150745 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Genetic Counseling and Testing for Alzheimer's Disease and Frontotemporal Lobar Degeneration: An Italian Consensus Protocol. %A Bocchetta, Martina %A Mega, Anna %A Bernardi, Livia %A Di Maria, Emilio %A Benussi, Luisa %A Binetti, Giuliano %A Borroni, Barbara %A Colao, Rosanna %A Di Fede, Giuseppe %A Fostinelli, Silvia %A Galimberti, Daniela %A Gennarelli, Massimo %A Ghidoni, Roberta %A Piaceri, Irene %A Pievani, Michela %A Porteri, Corinna %A Redaelli, Veronica %A Rossi, Giacomina %A Suardi, Silvia %A Babiloni, Claudio %A Scarpini, Elio %A Tagliavini, Fabrizio %A Padovani, Alessandro %A Nacmias, Benedetta %A Sorbi, Sandro %A Frisoni, Giovanni B %A Bruni, Amalia C %K Alzheimer Disease %K Amyloid beta-Peptides %K Consensus %K Female %K Follow-Up Studies %K Frontotemporal Lobar Degeneration %K Genetic Counseling %K Genetic Testing %K Humans %K Italy %K Male %K Peptide Fragments %K Psychiatric Status Rating Scales %X

BACKGROUND: Genetic testing of familial Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) is attracting interest thanks to innovative primary prevention clinical trials and increased request for information by at-risk individuals. However, ethical, social, and psychological implications are paramount and genetic testing must be supported by structured genetic counseling. In Italy, practice parameters and guidelines for genetic counseling in dementia are not available.

OBJECTIVE: To develop a nationally harmonized protocol for genetic counseling and testing of familial AD and FTLD.

METHODS: Activities were carried out in the context of the Italian Dominantly Inherited Alzheimer's and Frontotemporal Network (IT-DIAfN) project, a national network of centers of excellence with expertise in managing patients with familial AD and FTLD. A survey of the literature on genetic counseling protocols and guidelines was conducted. Local protocols for genetic counseling were surveyed. Differences and commonalities among protocols were identified and discussed among project partners. Consensus was reached following implicit aggregation methods.

RESULTS: Consensus was reached on a protocol for patients with clinically diagnosed familial AD or FTLD and a distinct protocol for their at-risk relatives. Genetic counseling should be provided by a multidisciplinary team including a geneticist, a neurologist/geriatrician, and a psychologist/psychiatrist, according to the following schedule: (i) initial consultation with tailored information on the genetics of the dementias; (ii) clinical, psychological, and cognitive assessment; if deemed appropriate (iii) genetic testing following a structured decision tree for gene mutation search; (iv) genetic testing result disclosure; (v) psychological support follow-up.

CONCLUSION: This genetic counseling protocol provides Italian centers with a line of shared practice for dealing with the requests for genetic testing for familial AD and FTLD from patients and at-risk relatives, who may also be eligible participants for novel prevention clinical trials.

%B J Alzheimers Dis %V 51 %P 277-91 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26901402?dopt=Abstract %R 10.3233/JAD-150849 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians. %A Kim, Sungeun %A Nho, Kwangsik %A Ramanan, Vijay K %A Lai, Dongbing %A Foroud, Tatiana M %A Lane, Katie %A Murrell, Jill R %A Gao, Sujuan %A Hall, Kathleen S %A Unverzagt, Frederick W %A Baiyewu, Olusegun %A Ogunniyi, Adesola %A Gureje, Oye %A Kling, Mitchel A %A Doraiswamy, P Murali %A Kaddurah-Daouk, Rima %A Hendrie, Hugh C %A Saykin, Andrew J %K Adaptor Proteins, Signal Transducing %K African Americans %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Cohort Studies %K Cystathionine beta-Synthase %K Cytoskeletal Proteins %K Female %K Genetic Variation %K Genome-Wide Association Study %K Heterozygote %K Homocysteine %K Humans %K Indiana %K Longitudinal Studies %K Male %K Nigeria %K Prospective Studies %X

Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration.

%B J Alzheimers Dis %V 49 %P 991-1003 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519441?dopt=Abstract %R 10.3233/JAD-150651 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Genetic Variability of UCP4 Affects the Individual Susceptibility to Late-Onset Alzheimer's Disease and Modifies the Disease's Risk in APOE-ɛ4 Carriers. %A Montesanto, Alberto %A Crocco, Paolina %A Anfossi, Maria %A Smirne, Nicoletta %A Puccio, Gianfranco %A Colao, Rosanna %A Maletta, Raffaele %A Passarino, Giuseppe %A Bruni, Amalia C %A Rose, Giuseppina %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Female %K Genetic Association Studies %K Genotype %K Humans %K Male %K Mental Status Schedule %K Mitochondrial Uncoupling Proteins %K Neuroimaging %K Polymorphism, Single Nucleotide %X

Uncoupling proteins (UCPs) are a group of five mitochondrial inner membrane transporters with a tissue specific expression that uncouple biofuel oxidation from ATP synthesis and function as regulators of energy homeostasis and antioxidants. Previous data suggested that neuronal UCPs (UCP2, UCP4, and UCP5) can directly influence synaptic plasticity, neurotransmission, and neurodegenerative processes, and have a crucial role in the function and protection of the central nervous system. In fact, it has been observed that the expression of neuronal UCPs significantly decreases in Alzheimer's disease (AD) patients. Here we analyzed the variability of UCP2, -3, -4, and 5 genes in sporadic and familial cases (n = 465) of late-onset AD (LOAD) with respect to healthy controls (n = 442). We showed that a genetic variant in the human UCP4, rs9472817, not only significantly affects the individual susceptibility to LOAD, but also modulates the effect of APOE-ɛ4 on AD risk. In fact, rs9472817-C allele was significantly more frequent in both groups of patients with respect to the control group (p = 6.934*10-4 for familial and p = 1.033*10-3 for sporadic cases). In addition, gene-gene interaction analysis revealed that the effect of APOE-ɛ4 allele on LOAD risk was doubled in homozygote CC subjects; conversely, the risk conferred by the APOE-ɛ4 allele was annulled in subjects with two copies of the G allele. Our findings are further evidence that the efficiency in mitochondrial energy metabolism and oxidative stress are important factors in AD pathogenesis.

%B J Alzheimers Dis %V 51 %P 1265-74 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923023?dopt=Abstract %R 10.3233/JAD-150993 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Genetic Variant of the Sortilin 1 Gene is Associated with Reduced Risk of Alzheimer's Disease. %A Andersson, Carl-Henrik %A Hansson, Oskar %A Minthon, Lennart %A Andreasen, Niels %A Blennow, Kaj %A Zetterberg, Henrik %A Skoog, Ingmar %A Wallin, Anders %A Nilsson, Staffan %A Kettunen, Petronella %X

Alzheimer's disease (AD) is a neurodegenerative disorder represented by the accumulation of intracellular tau protein and extracellular deposits of amyloid-β (Aβ) in the brain. The gene sortilin 1 (SORT1) has previously been associated with cardiovascular disease in gene association studies. It has also been proposed to be involved in AD pathogenesis through facilitating Aβ clearance by binding apoE/Aβ complexes prior to cellular uptake. However, the neuropathological role of SORT1 in AD is not fully understood. To evaluate the associations between gene variants of SORT1 and risk of AD, we performed genetic analyses in a Swedish case-control cohort. Ten single nucleotide polymorphisms (SNPs), covering the whole SORT1 gene, were selected and genotyped in 620 AD patients and 1107 controls. The SNP rs17646665, located in a non-coding region of the SORT1 gene, remained significantly associated with decreased risk of AD after multiple testing (pc = 0.0061). In addition, other SNPs were found to be nominally associated with risk of AD, as well as altered cognitive function and the CSF biomarker Aβ42, but these associations did not survive correction for multiple testing. The fact that SORT1 has been strongly associated with risk of cardiovascular disease is intriguing as cardiovascular disease is also regarded as a risk factor for AD. Finally, increased knowledge about SORT1 function has a potential to increase our understanding of APOE, the strongest risk factor for AD.

%B J Alzheimers Dis %V 53 %P 1353-63 %8 2016 Jul 01 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392867?dopt=Abstract %R 10.3233/JAD-160319 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Genetic Variations in ABCA7 Can Increase Secreted Levels of Amyloid-β40 and Amyloid-β42 Peptides and ABCA7 Transcription in Cell Culture Models. %A Bamji-Mirza, Michelle %A Li, Yan %A Najem, Dema %A Liu, Qing Yan %A Walker, Douglas %A Lue, Lih-Fen %A Stupak, Jacek %A Chan, Kenneth %A Li, Jianjun %A Ghani, Mahdi %A Yang, Ze %A Rogaeva, Ekaterina %A Zhang, Wandong %X

Alzheimer's disease (AD) is characterized by extracellular deposits of amyloid-β (Aβ) in the brain. ABCA7 is highly expressed in the brain and a susceptibility gene for late-onset AD (LOAD). The minor alleles at two ABCA7 single-nucleotide polymorphisms (SNPs), rs3764650 (T>G; intron13) and rs3752246 at a predicted myristoylation site (C>G; exon33; p.Gly1527Ala), are significantly associated with LOAD risk; however, the mechanism of this association is unknown. Functional consequences of both SNPs were examined in HEK293 and CHO cells stably expressing AβPPSwe. Luciferase reporter assays in HEK293 cells suggested that intron13 carrying rs3764650 major T-allele (int13-T) possessed promoter-enhancing capabilities. Co-transfection experiments with hABCA7 and int13-T resulted in significantly increased ABCA7 protein level relative to that with int13-G. Expression of hABCA7 carrying rs3752246 risk allele led to increases in secreted Aβ40 and Aβ42 and β-secretase activity in CHO- and HEK-AβPPSwe cells. Hydroxymyristic acid treatment of cells expressing hABCA7 carrying the rs3752246 major G allele resulted in increased β-secretase activity and levels of Aβ, suggesting that lack of myristoylation contributes to the observed cell-phenotypes. Molecular weight determination, by gel-electrophoresis and mass spectrometry, of hABCA7 peptides spanning position 1527 showed loss of post-translational modification in the risk-allele peptide. These results suggest that decreased expression, or impaired function, of ABCA7 may contribute to AD pathology.

%B J Alzheimers Dis %V 53 %P 875-92 %8 2016 Jun 13 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27314524?dopt=Abstract %R 10.3233/JAD-150965 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Greater specificity for cerebrospinal fluid P-tau231 over P-tau181 in the differentiation of healthy controls from Alzheimer's disease. %A Spiegel, Jonathan %A Pirraglia, Elizabeth %A Osorio, Ricardo S %A Glodzik, Lidia %A Li, Yi %A Tsui, Wai %A Saint Louis, Leslie A %A Randall, Catherine %A Butler, Tracy %A Xu, Jinfeng %A Zinkowski, Raymond P %A Zetterberg, Henrik %A Fortea, Juan %A Fossati, Silvia %A Wisniewski, Thomas %A Davies, Peter %A Blennow, Kaj %A de Leon, Mony J %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Case-Control Studies %K Cross-Sectional Studies %K Female %K Humans %K Logistic Models %K Male %K Middle Aged %K Phosphorylation %K ROC Curve %K Sensitivity and Specificity %K tau Proteins %X

Cerebrospinal fluid (CSF) measures of phosphorylated-tau (P-tau) 231 and P-tau181 are two biomarkers for the identification of tau pathology as related to Alzheimer's disease (AD). While both are pathologically validated, their relative diagnostic performances are not well known. This cross-sectional diagnostic study of 87 normal (NL) subjects and 28 AD subjects compared CSF P-tau231 with CSF P-tau181. Logistic regression modeling demonstrated that the P-tau231 was superior to the P-tau181 in the diagnostic classifications. At a fixed 85% sensitivity cutoff, the ROC analysis shows that P-tau231 has greater overall specificity than P-tau181. While both P-tau analytes demonstrated equivalent negative predictive accuracies, P-tau231 yielded significantly fewer false positives. Moreover, P-tau231, but not P-tau181, demonstrated sensitivity to the E4 genotype. A postmortem validation with 9 AD subjects confirmed the superiority of the CSF P-tau231 specificity. This study suggests that P-tau231 has the potential to improve the CSF tau biomarker diagnosis of AD.

%B J Alzheimers Dis %V 49 %P 93-100 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444757?dopt=Abstract %R 10.3233/JAD-150167 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Gx-50 Inhibits Neuroinflammation via α7 nAChR Activation of the JAK2/STAT3 and PI3K/AKT Pathways. %A Shi, Shi %A Liang, Dongli %A Bao, Min %A Xie, Yilin %A Xu, Wangjie %A Wang, Lianyun %A Wang, Zhaoxia %A Qiao, Zhongdong %K Acrylamides %K alpha7 Nicotinic Acetylcholine Receptor %K Amyloid beta-Peptides %K Analysis of Variance %K Animals %K Anti-Inflammatory Agents %K Cell Line, Transformed %K Cytokines %K Enzyme Inhibitors %K Enzyme-Linked Immunosorbent Assay %K Gene Expression Regulation %K Janus Kinase 2 %K Mice %K Microglia %K Phosphatidylinositol 3-Kinases %K Protein Binding %K RNA, Messenger %K Signal Transduction %X

Recent studies have revealed that the α7 nicotinic acetylcholine receptor (α7 nAChR) is a critical link between inflammation and neurodegeneration, which is closely associated with Alzheimer's disease (AD). The JAK2/STAT3 and PI3K/AKT signaling pathways contribute to the neuroprotective and anti-inflammatory effects of α7nAChR. Our previous studies have shown that treatment with gx-50 improves cognitive function and is neuroprotective. Here, we investigated the effect of gx-50 on α7 nAChR and Aβ-induced inflammation in microglia. First, the binding affinity of gx-50 to α7 nAChR was examined using the fluorescence-based Octet RED system, and the expression of α7 nAChR was detected using real-time PCR and western blotting. We also investigated downstream events of α7 nAChR activity, including the translocation of p-STAT3 and the phosphorylation of JAK2, STAT3, PI3K, and AKT. Finally, the effect of gx-50 on Aβ-induced inflammation via α7 nAChR-mediated signaling pathways was investigated using cytokine assays. The results showed that gx-50 is able to act as a specific ligand to activate α7 nAChR, which then upregulates the JAK2/STAT3 and PI3K/AKT signaling pathways to inhibit the secretions of pro-inflammatory cytokines, such as IL-1β. In conclusion, the results suggest that gx-50 could inhibit the Aβ-induced inflammatory response in microglia via α7 nAChR activity, which might be a successful therapeutic target against AD.

%B J Alzheimers Dis %V 50 %P 859-71 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836188?dopt=Abstract %R 10.3233/JAD-150963 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Health-Related Quality of Life in Patients with Alzheimer's Disease in Different German Health Care Settings. %A Heßmann, Philipp %A Seeberg, Greta %A Reese, Jens Peter %A Dams, Judith %A Baum, Erika %A Müller, Matthias J %A Dodel, Richard %A Balzer-Geldsetzer, Monika %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Caregivers %K Depression %K Female %K Germany %K Humans %K Inpatients %K Male %K Multivariate Analysis %K Neuropsychological Tests %K Outpatients %K Psychiatric Status Rating Scales %K Quality of Life %K Residential Facilities %K Self Report %K Severity of Illness Index %X

The purpose of this study is to evaluate the health-related quality of life (HrQoL) of patients with Alzheimer's disease (AD) in different care settings (institutionalized versus community-dwelling) across all severity stages of dementia. Patients were consecutively recruited with their primary caregivers (123 inpatients and 272 outpatients), and the impact of patient-related parameters such as behavioral and psychological symptoms of dementia (BPSD) (Geriatric Depression Scale [GDS] and Neuropsychiatric Inventory [NPI]) and functional capacity (Alzheimer's Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]) on HrQoL was analyzed. Patients' HrQoL was assessed using self-reported and caregiver-rated generic (EuroQoL Instrument) and dementia-specific (Quality of Life-Alzheimer's Disease [Qol-AD]) scales. Patients reported a considerably higher HrQoL than their caregivers on the QoL-AD, EQ-5D, and EQ VAS (p <  0.001). Different dementia severity groups showed significantly worse results in HrQoL for patients with lower MMSE scores. The mean self-reported QoL-AD decreased from 32.3±5.7 in the group with the highest MMSE scores to 27.1±5.5 in patients with the lowest MMSE scores (p <  0.001). A considerably lower HrQoL was shown for institutionalized patients versus participants in outpatient settings (proxy-rated QoL-AD 19.7±4.6 versus 26.0±7.1, p <  0.001). Depressive symptoms (GDS), BPSD (NPI), and reduced functional capacity (ADCS-ADL) were evaluated for their impact on patients' HrQoL. Multivariate models explained between 22% and 54% of the variance in patients' HrQoL. To analyze the causative direction of the reported associations, further longitudinal studies should be conducted.

%B J Alzheimers Dis %V 51 %P 545-61 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890754?dopt=Abstract %R 10.3233/JAD-150835 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Heart Rate Spectra Confirm the Presence of Autonomic Dysfunction in Dementia Patients. %A Struhal, Walter %A Mahringer, Christoph %A Lahrmann, Heinz %A Mörtl, Christoph %A Buhl, Peter %A Huemer, Mario %A Ransmayr, Gerhard %X

Recent data suggest autonomic dysfunction in patients suffering dementia. This study evaluated autonomic modulation in dementia patients with and without autonomic involvement, employing ECG spectral analysis in the time-frequency domain (wavelet transform) in supine resting and head-up tilt (HUT) position. Thirty-six patients were prospectively evaluated at the Department of Neurology and Psychiatry, General Hospital of the City of Linz, between 2009 and 2014. A standard cardiovascular autonomic test series (Ewing battery) was performed to screen for autonomic dysfunction. The Ewing battery diagnoses were used as reference standard and compared to the diagnostic results obtained by spectral analysis (time-frequency domain) of ECG recordings. Based on the Ewing battery results, 14 patients suffered autonomic dysfunction, while 22 did not. Time frequency domain was accessed by using the continuous wavelet transformation (CWT) with an analytical Morlet mother wavelet in supine resting and HUT position. Within each cohort the modification of spectral components from supine resting to HUT was analyzed reflecting the autonomic modulation. For patients without autonomic dysfunction, a significant increase of autonomic modulation was detected by wavelet transformed ECG recordings (8%, p < 0.05; low frequency content) during HUT compared to supine resting. There was no significant modulation between HUT and supine resting in patients suffering autonomic dysfunction. In dementia patients suffering autonomic dysfunction, CWT identified blunted autonomic regulation only by analysis of ECG recordings without the need to assess other biosignals or tests depending on the patient's cooperation. Further studies are needed to evaluate whether CWT is a suitable method to support the standard Ewing battery in demented patients.

%B J Alzheimers Dis %V 54 %P 657-67 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567816?dopt=Abstract %R 10.3233/JAD-160084 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Higher Fasting Plasma Glucose Levels, within the Normal Range, are Associated with Decreased Processing Speed in High Functioning Young Elderly. %A Raizes, Meytal %A Elkana, Odelia %A Franko, Motty %A Ravona Springer, Ramit %A Segev, Shlomo %A Beeri, Michal Schnaider %K Aged %K Blood Glucose %K Cognition %K Diabetes Mellitus, Type 2 %K Fasting %K Female %K Humans %K Linear Models %K Male %K Middle Aged %K Neuropsychological Tests %K Psychomotor Performance %K Reaction Time %K Reference Values %X

We explored the association of plasma glucose levels within the normal range with processing speed in high functioning young elderly, free of type 2 diabetes mellitus (T2DM). A sample of 41 participants (mean age = 64.7, SD = 10; glucose 94.5 mg/dL, SD = 9.3), were examined with a computerized cognitive battery. Hierarchical linear regression analysis showed that higher plasma glucose levels, albeit within the normal range (<110 mg/dL), were associated with longer reaction times (p <  0.01). These findings suggest that even in the subclinical range and in the absence of T2DM, monitoring plasma glucose levels may have an impact on cognitive function.

%B J Alzheimers Dis %V 49 %P 589-92 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484908?dopt=Abstract %R 10.3233/JAD-150433 %0 Journal Article %J J Alzheimers Dis %D 2016 %T High-Throughput Screening for Identification of Blood-Brain Barrier Integrity Enhancers: A Drug Repurposing Opportunity to Rectify Vascular Amyloid Toxicity. %A Qosa, Hisham %A Mohamed, Loqman A %A Al Rihani, Sweilem B %A Batarseh, Yazan S %A Duong, Quoc-Viet %A Keller, Jeffrey N %A Kaddoumi, Amal %X

The blood-brain barrier (BBB) is a dynamic interface that maintains brain homeostasis and protects it from free entry of chemicals, toxins, and drugs. The barrier function of the BBB is maintained mainly by capillary endothelial cells that physically separate brain from blood. Several neurological diseases, such as Alzheimer's disease (AD), are known to disrupt BBB integrity. In this study, a high-throughput screening (HTS) was developed to identify drugs that rectify/protect BBB integrity from vascular amyloid toxicity associated with AD progression. Assessing Lucifer Yellow permeation across in-vitro BBB model composed from mouse brain endothelial cells (bEnd3) grown on 96-well plate inserts was used to screen 1280 compounds of Sigma LOPAC®1280 library for modulators of bEnd3 monolayer integrity. HTS identified 62 compounds as disruptors, and 50 compounds as enhancers of the endothelial barrier integrity. From these 50 enhancers, 7 FDA approved drugs were identified with EC50 values ranging from 0.76-4.56 μM. Of these 7 drugs, 5 were able to protect bEnd3-based BBB model integrity against amyloid toxicity. Furthermore, to test the translational potential to humans, the 7 drugs were tested for their ability to rectify the disruptive effect of Aβ in the human endothelial cell line hCMEC/D3. Only 3 (etodolac, granisetron, and beclomethasone) out of the 5 effective drugs in the bEnd3-based BBB model demonstrated a promising effect to protect the hCMEC/D3-based BBB model integrity. These drugs are compelling candidates for repurposing as therapeutic agents that could rectify dysfunctional BBB associated with AD.

%B J Alzheimers Dis %V 53 %P 1499-516 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392852?dopt=Abstract %R 10.3233/JAD-151179 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Human Truncated Tau Induces Mature Neurofibrillary Pathology in a Mouse Model of Human Tauopathy. %A Zimova, Ivana %A Brezovakova, Veronika %A Hromadka, Tomas %A Weisova, Petronela %A Cubinkova, Veronika %A Valachova, Bernadeta %A Filipcik, Peter %A Jadhav, Santosh %A Smolek, Tomas %A Novak, Michal %A Zilka, Norbert %X

Alzheimer's disease (AD) represents the most common neurodegenerative disorder. Several animal models have been developed in order to test pathophysiological mechanisms of the disease and to predict effects of pharmacological interventions. Here we examine the molecular and behavioral features of R3m/4 transgenic mice expressing human non-mutated truncated tau protein (3R tau, aa151-391) that were previously used for efficacy testing of passive tau vaccine. The mouse model reliably recapitulated crucial histopathological features of human AD, such as pre-tangles, neurofibrillary tangles, and neuropil threads. The pathology was predominantly located in the brain stem. Transgenic mice developed mature sarkosyl insoluble tau complexes consisting of mouse endogenous and human truncated and hyperphosphorylated forms of tau protein. The histopathological and biochemical features were accompanied by significant sensorimotor impairment and reduced lifespan. The sensorimotor impairment was monitored by a highly sensitive, fully-automated tool that allowed us to assess early deficit in gait and locomotion. We suggest that the novel transgenic mouse model can serve as a valuable tool for analysis of the therapeutic efficacy of tau vaccines for AD therapy.

%B J Alzheimers Dis %V 54 %P 831-43 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567836?dopt=Abstract %R 10.3233/JAD-160347 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Identification of Physician-Diagnosed Alzheimer's Disease and Related Dementias in Population-Based Administrative Data: A Validation Study Using Family Physicians' Electronic Medical Records. %A Jaakkimainen, R Liisa %A Bronskill, Susan E %A Tierney, Mary C %A Herrmann, Nathan %A Green, Diane %A Young, Jacqueline %A Ivers, Noah %A Butt, Debra %A Widdifield, Jessica %A Tu, Karen %X

BACKGROUND: Population-based surveillance of Alzheimer's and related dementias (AD-RD) incidence and prevalence is important for chronic disease management and health system capacity planning. Algorithms based on health administrative data have been successfully developed for many chronic conditions. The increasing use of electronic medical records (EMRs) by family physicians (FPs) provides a novel reference standard by which to evaluate these algorithms as FPs are the first point of contact and providers of ongoing medical care for persons with AD-RD.

OBJECTIVE: We used FP EMR data as the reference standard to evaluate the accuracy of population-based health administrative data in identifying older adults with AD-RD over time.

METHODS: This retrospective chart abstraction study used a random sample of EMRs for 3,404 adults over 65 years of age from 83 community-based FPs in Ontario, Canada. AD-RD patients identified in the EMR were used as the reference standard against which algorithms identifying cases of AD-RD in administrative databases were compared.

RESULTS: The highest performing algorithm was "one hospitalization code OR (three physician claims codes at least 30 days apart in a two year period) OR a prescription filled for an AD-RD specific medication" with sensitivity 79.3% (confidence interval (CI) 72.9-85.8%), specificity 99.1% (CI 98.8-99.4%), positive predictive value 80.4% (CI 74.0-86.8%), and negative predictive value 99.0% (CI 98.7-99.4%). This resulted in an age- and sex-adjusted incidence of 18.1 per 1,000 persons and adjusted prevalence of 72.0 per 1,000 persons in 2010/11.

CONCLUSION: Algorithms developed from health administrative data are sensitive and specific for identifying older adults with AD-RD.

%B J Alzheimers Dis %V 54 %P 337-49 %8 2016 Aug 10 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567819?dopt=Abstract %R 10.3233/JAD-160105 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Immunization Against Specific Fragments of Neurotrophin p75 Receptor Protects Forebrain Cholinergic Neurons in the Olfactory Bulbectomized Mice. %A Bobkova, Natalia %A Vorobyov, Vasily %A Medvinskaya, Natalia %A Nesterova, Inna %A Tatarnikova, Olga %A Nekrasov, Pavel %A Samokhin, Alexander %A Deev, Alexander %A Sengpiel, Frank %A Koroev, Dmitry %A Volpina, Olga %X

Alzheimer's disease (AD) is characterized by progressive cognitive impairment associated with marked cholinergic neuron loss and amyloid-β (Aβ) peptide accumulation in the brain. The cytotoxicity in AD is mediated, at least in part, by Aβ binding with the extracellular domain of the p75 neurotrophin receptor (p75NTR), localized predominantly in the membranes of acetylcholine-producing neurons in the basal forebrain. Hypothesizing that an open unstructured loop of p75NTR might be the effective site for Aβ binding, we have immunized both olfactory bulbectomized (OBX) and sham-operated (SO) mice (n = 82 and 49, respectively) with synthetic peptides, structurally similar to different parts of the loops, aiming to block them by specific antibodies. OBX-mice have been shown in previous studies, and confirmed in the present one, to be characterized by typical behavioral, morphological, and biochemical AD hallmarks, including cholinergic deficits in forebrain neurons. Immunization of OBX- or SO-mice with KLH conjugated fragments of p75NTR induced high titers of specific serum antibodies for each of nine chosen fragments. However, maximal protective effects on spatial memory, evaluated in a Morris water maze, and on activity of choline acetyltransferase in forebrain neurons, detected by immunoreactivity to specific antibodies, were revealed only for peptides with amino acid residue sequences of 155-164 and 167-176. We conclude that the approach based on immunological blockade of specific p75NTR sites, linked with the cytotoxicity, is a useful and effective tool for study of AD-associated mechanisms and for development of highly selective therapy of cholinergic malfunctioning in AD patients.

%B J Alzheimers Dis %V 53 %P 289-301 %8 2016 May 06 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163825?dopt=Abstract %R 10.3233/JAD-160146 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Immunization with Small Amyloid-β-derived Cyclopeptide Conjugates Diminishes Amyloid-β-Induced Neurodegeneration in Mice. %A Mulder, Cornelis K %A Dong, Yun %A Brugghe, Humphrey F %A Timmermans, Hans A M %A Tilstra, Wichard %A Westdijk, Janny %A van Riet, Elly %A van Steeg, Harry %A Hoogerhout, Peter %A Eisel, Ulrich L M %X

BACKGROUND: Soluble oligomeric (misfolded) species of amyloid-β (Aβ) are the main mediators of toxicity in Alzheimer's disease (AD). These oligomers subsequently form aggregates of insoluble fibrils that precipitate as extracellular and perivascular plaques in the brain. Active immunization against Aβ is a promising disease modifying strategy. However, eliciting an immune response against Aβ in general may interfere with its biological function and was shown to cause unwanted side-effects. Therefore, we have developed a novel experimental vaccine based on conformational neo-epitopes that are exposed in the misfolded oligomeric Aβ, inducing a specific antibody response.

OBJECTIVE: Here we investigate the protective effects of the experimental vaccine against oligomeric Aβ1-42-induced neuronal fiber loss in vivo.

METHODS: C57BL/6 mice were immunized or mock-immunized. Antibody responses were measured by enzyme-linked immunosorbent assay. Next, mice received a stereotactic injection of oligomeric Aβ1-42 into the nucleus basalis of Meynert (NBM) on one side of the brain (lesion side), and scrambled Aβ1-42 peptide in the contralateral NBM (control side). The densities of choline acetyltransferase-stained cholinergic fibers origination from the NBM were measured in the parietal neocortex postmortem. The percentage of fiber loss in the lesion side was determined relative to the control side of the brain.

RESULTS: Immunized responders (79%) showed 23% less cholinergic fiber loss (p = 0.01) relative to mock-immunized mice. Moreover, fiber loss in immunized responders correlated negatively with the measured antibody responses (R2 = 0.29, p = 0.02).

CONCLUSION: These results may provide a lead towards a (prophylactic) vaccine to prevent or at least attenuate (early onset) AD symptoms.

%B J Alzheimers Dis %V 52 %P 1111-23 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060957?dopt=Abstract %R 10.3233/JAD-151136 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Impact of Depressive Symptoms on Conversion from Mild Cognitive Impairment Subtypes to Alzheimer's Disease: A Community-Based Longitudinal Study. %A Kida, Jiro %A Nemoto, Kiyotaka %A Ikejima, Chiaki %A Bun, Shogyoku %A Kakuma, Tatsuyuki %A Mizukami, Katsuyoshi %A Asada, Takashi %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Cognitive Dysfunction %K Depression %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Prodromal Symptoms %K Prognosis %K Risk %X

BACKGROUND: While longitudinal studies have investigated the relationships between mild cognitive impairment (MCI) subtypes and dementia subtypes, the results have been contradictory. In addition, some research shows that depression accompanied by MCI might increase the risk of Alzheimer's disease (AD).

OBJECTIVE: The aim of this study is to longitudinally investigate the relationships between MCI subtypes and dementia subtypes, with special attention to the effect of comorbid depressive symptoms in a Japanese rural community.

METHODS: Non-demented participants (n = 802) completed a baseline and follow-up study. Outcomes were conversion to dementia especially AD, MCI, or no conversion. A complementary log-log analysis was conducted to investigate the risk of dementia and AD in amnestic MCI (aMCI) compared to nonamnestic MCI (naMCI) groups. The impact of depressive symptoms on the transition from MCI to AD and from cognitively normal to MCI or AD was also analyzed.

RESULTS: The risk of developing dementia, in particular AD, for the aMCI group was significantly higher than that for the naMCI group. In the aMCI group, the presence of depressive symptoms increased the risk of developing AD, but depressive symptoms in the naMCI group did not. In the cognitively normal group, the presence of depressive symptoms increased the risk of aMCI but not naMCI or AD.

CONCLUSION: MCI subtyping could be useful in finding a prodrome for dementia and in particular for AD. The differing impacts of depressive symptoms on the development of AD suggest that the relationship between depressive symptoms and cognitive impairment could differ in aMCI and naMCI patients.

%B J Alzheimers Dis %V 51 %P 405-15 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890740?dopt=Abstract %R 10.3233/JAD-150603 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Impaired Autophagy in APOE4 Astrocytes. %A Simonovitch, Shira %A Schmukler, Eran %A Bespalko, Alina %A Iram, Tal %A Frenkel, Dan %A Holtzman, David M %A Masliah, Eliezer %A Michaelson, Danny M %A Pinkas-Kramarski, Ronit %K Amyloid beta-Peptides %K Animals %K Apolipoprotein E3 %K Apolipoprotein E4 %K Astrocytes %K Autophagy %K Brain %K Cells, Cultured %K Central Nervous System Agents %K Chloroquine %K Disease Models, Animal %K Humans %K Mice, Transgenic %K Plaque, Amyloid %K Sirolimus %K Time Factors %X

Alzheimer's disease (AD) is the most prevalent form of dementia in elderly. Genetic studies revealed allelic segregation of the apolipoprotein E (ApoE) gene in sporadic AD and in families with higher risk of AD. The mechanisms underlying the pathological effects of ApoE4 are not yet entirely clear. Several studies indicate that autophagy, which plays an important role in degradation pathways of proteins, organelles and protein aggregates, may be impaired in AD. In the present study, we investigated the effects of ApoE4 versus the ApoE3 isoform on the process of autophagy in mouse-derived astrocytes. The results obtained reveal that under several autophagy-inducing conditions, astrocytes expressing ApoE4 exhibit lower autophagic flux compared to astrocytes expressing ApoE3. Using an in situ model, we examined the role of autophagy and the effects thereon of ApoE4 in the elimination of Aβ plaques from isolated brain sections of transgenic 5xFAD mice. This revealed that ApoE4 astrocytes eliminate Aβ plaques less effectively than the corresponding ApoE3 astrocytes. Additional experiments showed that the autophagy inducer, rapamycin, enhances Aβ plaque degradation by ApoE4 astrocytes whereas the autophagy inhibitor, chloroquine, blocks Aβ plaque degradation by ApoE3 astrocytes. Taken together, these findings show that ApoE4 impairs autophagy in astrocyte cultures and that this effect is associated with reduced capacity to clear Aβ plaques. This suggests that impaired autophagy may play a role in mediating the pathological effects of ApoE4 in AD.

%B J Alzheimers Dis %V 51 %P 915-27 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923027?dopt=Abstract %R 10.3233/JAD-151101 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Increased Electron Paramagnetic Resonance Signal Correlates with Mitochondrial Dysfunction and Oxidative Stress in an Alzheimer's disease Mouse Brain. %A Fang, Du %A Zhang, Zhihua %A Li, Hang %A Yu, Qing %A Douglas, Justin T %A Bratasz, Anna %A Kuppusamy, Periannan %A Yan, Shirley ShiDu %K Adenosine Triphosphate %K Age of Onset %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Brain %K Cognition %K Disease Models, Animal %K Electron Spin Resonance Spectroscopy %K Electron Transport Complex IV %K Female %K Humans %K Male %K Maze Learning %K Mice, Transgenic %K Mitochondria %K Oxidative Stress %K Reactive Oxygen Species %K Spatial Memory %X

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized clinically by cognitive decline and memory loss. The pathological features are amyloid-β peptide (Aβ) plaques and intracellular neurofibrillary tangles. Many studies have suggested that oxidative damage induced by reactive oxygen species (ROS) is an important mechanism for AD progression. Our recent study demonstrated that oxidative stress could further impair mitochondrial function. In the present study, we adopted a transgenic mouse model of AD (mAPP, overexpressing AβPP/Aβ in neurons) and performed redox measurements using in vivo electron paramagnetic resonance (EPR) imaging with methoxycarbamyl-proxyl (MCP) as a redox-sensitive probe for studying oxidative stress in an early stage of pathology in a transgenic AD mouse model. Through assessing oxidative stress, mitochondrial function and cognitive behaviors of mAPP mice at the age of 8-9 months, we found that oxidative stress and mitochondrial dysfunction appeared in the early onset of AD. Increased ROS levels were associated with defects of mitochondrial and cognitive dysfunction. Notably, the in vivo EPR method offers a unique way of assessing tissue oxidative stress in living animals under noninvasive conditions, and thus holds a potential for early diagnosis and monitoring the progression of AD.

%B J Alzheimers Dis %V 51 %P 571-80 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890765?dopt=Abstract %R 10.3233/JAD-150917 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Increased Levels of Extracellular Microvesicle Markers and Decreased Levels of Endocytic/Exocytic Proteins in the Alzheimer's Disease Brain. %A Musunuri, Sravani %A Khoonsari, Payam Emami %A Mikus, Maria %A Wetterhall, Magnus %A Häggmark-Mänberg, Anna %A Lannfelt, Lars %A Erlandsson, Anna %A Bergquist, Jonas %A Ingelsson, Martin %A Shevchenko, Ganna %A Nilsson, Peter %A Kultima, Kim %X

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder accounting for more than 50% of all dementia cases. AD neuropathology is characterized by the formation of extracellular plaques and intracellular neurofibrillary tangles consisting of aggregated amyloid-β and tau, respectively. The disease mechanism has only been partially elucidated and is believed to also involve many other proteins.

OBJECTIVE: This study intended to perform a proteomic profiling of post mortem AD brains and compare it with control brains as well as brains from other neurological diseases to gain insight into the disease pathology.

METHODS: Here we used label-free shotgun mass spectrometry to analyze temporal neocortex samples from AD, other neurological disorders, and non-demented controls, in order to identify additional proteins that are altered in AD. The mass spectrometry results were verified by antibody suspension bead arrays.

RESULTS: We found 50 proteins with altered levels between AD and control brains. The majority of these proteins were found at lower levels in AD. Pathway analyses revealed that several of the decreased proteins play a role in exocytic and endocytic pathways, whereas several of the increased proteins are related to extracellular vesicles. Using antibody-based analysis, we verified the mass spectrometry results for five representative proteins from this group of proteins (CD9, HSP72, PI42A, TALDO, and VAMP2) and GFAP, a marker for neuroinflammation.

CONCLUSIONS: Several proteins involved in exo-endocytic pathways and extracellular vesicle functions display altered levels in the AD brain. We hypothesize that such changes may result in disturbed cellular clearance and a perturbed cell-to-cell communication that may contribute to neuronal dysfunction and cell death in AD.

%B J Alzheimers Dis %V 54 %P 1671-1686 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636840?dopt=Abstract %R 10.3233/JAD-160271 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Inhibition of Histone Deacetylase 3 Restores Amyloid-β Oligomer-Induced Plasticity Deficit in Hippocampal CA1 Pyramidal Neurons. %A Krishna, Kumar %A Behnisch, Thomas %A Sajikumar, Sreedharan %K Acrylamides %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Excitatory Postsynaptic Potentials %K Hippocampus %K Histone Deacetylase Inhibitors %K Histone Deacetylases %K Long-Term Potentiation %K Male %K Patch-Clamp Techniques %K Peptide Fragments %K Phenylenediamines %K Pyramidal Cells %K Rats, Wistar %K Tissue Culture Techniques %X

Neurodegenerative diseases such as Alzheimer's disease (AD) are associated with alterations in epigenetic factors leading to cognitive decline. Histone deacetylase 3 (HDAC3) is a known critical epigenetic negative regulator of learning and memory. In this study, attenuation of long-term potentiation by amyloid-β oligomer, and its reversal by specific HDAC3 inhibitor RGFP966, was performed in rat CA1 pyramidal neurons using whole cell voltage-clamp and field recording techniques. Our findings provide the first evidence that amyloid-β oligomer-induced synaptic plasticity impairment can be prevented by inhibition of HDAC3 enzyme both at the single neuron as well as in a population of neurons, thus identifying HDAC3 as a potential target for ameliorating AD related plasticity impairments.

%B J Alzheimers Dis %V 51 %P 783-91 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890755?dopt=Abstract %R 10.3233/JAD-150838 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Instrumental Activity of Daily Living Profile in Aging: A Feasibility Study. %A Bier, Nathalie %A Belchior, Patricia da Cunha %A Paquette, Guillaume %A Beauchemin, Émilie %A Lacasse-Champagne, Ariane %A Messier, Chantal %A Pellerin, Marie-Line %A Petit, Marisol %A Mioshi, Eneida %A Bottari, Carolina %X

BACKGROUND: Dysfunctions in complex activities of daily living (ADLs) are a normal part of the aging process. However, differentiating functional decline associated with healthy aging from the subtle decline experienced by individuals with mild cognitive impairment and early dementia constitutes a challenge. Finding an appropriate tool that can capture these subtle but important functional changes represents a priority.

OBJECTIVES: The aims of this study were to evaluate the feasibility of using the Instrumental Activities of Daily Living Profile (IADL Profile) with elderly participants and to describe their level of difficulty encountered in each task.

METHODS: The tool was administered to a group of 40 elderly participants living in the community.

RESULTS: The IADL Profile was found to be feasible to use in older individuals; the tool also showed sensitivity to the difficulties experienced by this population in everyday functioning.

CONCLUSION: The IADL Profile is a promising ecological tool to evaluate independence in aging and may help to identify individuals with MCI. This tool may also contribute to the development of tailored interventions to enhance everyday functioning in the older population.

%B J Alzheimers Dis %V 52 %P 1361-71 %8 2016 Apr 12 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079703?dopt=Abstract %R 10.3233/JAD-150957 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Insulin Resistance is Associated with Increased Levels of Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Reduced Memory Function in At-Risk Healthy Middle-Aged Adults. %A Hoscheidt, Siobhan M %A Starks, Erika J %A Oh, Jennifer M %A Zetterberg, Henrik %A Blennow, Kaj %A Krause, Rachel A %A Gleason, Carey E %A Puglielli, Luigi %A Atwood, Craig S %A Carlsson, Cynthia M %A Asthana, Sanjay %A Johnson, Sterling C %A Bendlin, Barbara B %X

BACKGROUND: Type 2 diabetes is associated with an increased risk for Alzheimer's disease (AD). Regulation of normal insulin function may be important in reducing the prevalence of dementia due to AD, particularly in individuals who harbor genetic risk for or have a parental family history of AD. The relationship between insulin resistance (IR) and AD pathology remains poorly understood, particularly in midlife prior to the onset of clinical metabolic disease or cognitive decline.

OBJECTIVE: We examined associations between IR as indexed by HOMA-IR, cerebrospinal fluid (CSF) biomarkers of AD pathology, and memory in middle-aged adults enriched for AD. We postulated that higher HOMA-IR and APOEɛ4 carriage would be associated with greater CSF AD pathology and poor memory performance.

METHODS: Cognitively asymptomatic middle-aged adults (N = 70, mean age = 57.7 years) from the Wisconsin Alzheimer's Disease Research Center with a parental family history of dementia due to AD underwent lumbar puncture, blood draw, and neuropsychological testing. CSF AD biomarkers including soluble amyloid-β protein precursor β (sAβPPβ), amyloid-β42 (Aβ42), and phosphorylated tau (P-tau181) were examined with respect to HOMA-IR and APOEɛ4 status. Delayed memory performance was examined with respect to HOMA-IR, CSF AD biomarkers, and APOEɛ4 status.

RESULTS: Higher HOMA-IR was associated with higher sAβPPβ and Aβ42 . APOEɛ4 carriers had significantly higher levels of sAβPPα, sAβPPβ, and P-tau181/Aβ42 compared to noncarriers. The concurrent presence of higher HOMA-IR and CSF AD pathology predicted worse delayed memory performance.

CONCLUSION: Overall, the findings suggest that IR and APOEɛ4 are contributing factors to the development of AD pathology in midlife, and provide support for targeting insulin function as a potentially modifiable risk factor for AD.

%B J Alzheimers Dis %V 52 %P 1373-83 %8 2016 Apr 12 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079723?dopt=Abstract %R 10.3233/JAD-160110 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Integrating Biomarkers for Underlying Alzheimer's Disease in Mild Cognitive Impairment in Daily Practice: Comparison of a Clinical Decision Support System with Individual Biomarkers. %A Rhodius-Meester, Hanneke F M %A Koikkalainen, Juha %A Mattila, Jussi %A Teunissen, Charlotte E %A Barkhof, Frederik %A Lemstra, Afina W %A Scheltens, Philip %A Lötjönen, Jyrki %A van der Flier, Wiesje M %K Aged %K Aged, 80 and over %K Algorithms %K Alzheimer Disease %K Area Under Curve %K Biomarkers %K Cognitive Dysfunction %K Cohort Studies %K Decision Support Systems, Clinical %K Disease Progression %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Outcome Assessment (Health Care) %K Predictive Value of Tests %X

BACKGROUND: Recent criteria allow biomarkers to provide evidence of Alzheimer's disease (AD) pathophysiology. How they should be implemented in daily practice remains unclear, especially in mild cognitive impairment (MCI) patients.

OBJECTIVE: We evaluated how a clinical decision support system such as the PredictAD tool can aid clinicians to integrate biomarker evidence to support AD diagnosis.

METHODS: With available data on demographics, cerebrospinal fluid (CSF), and MRI, we trained the PredictAD tool on a reference population of 246 controls and 491 AD patients. We then applied the identified algorithm to 211 MCI patients. For comparison, we also classified patients based on individual biomarkers (MRI; CSF) and the NIA-AA criteria. Progression to dementia was used as outcome measure.

RESULTS: After a median follow up of 3 years, 72 (34%) MCI patients remained stable and 139 (66%) progressed to AD. The PredictAD tool assigned a likelihood of underlying AD to each patient (AUC 0.82). Excluding patients with missing data resulted in an AUC of 0.87. According to the NIA-AA criteria, half of the MCI patients had uninformative biomarkers, precluding an assignment of AD likelihood. A minority (41%) was assigned to high or low AD likelihood with good predictive value. The individual biomarkers showed best value for CSF total tau (AUC 0.86).

CONCLUSION: The ability of the PredictAD tool to identify AD pathophysiology was comparable to individual biomarkers. The PredictAD tool has the advantage that it assigns likelihood to all patients, regardless of missing or conflicting data, allowing clinicians to integrate biomarker data in daily practice.

%B J Alzheimers Dis %V 50 %P 261-70 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26577521?dopt=Abstract %R 10.3233/JAD-150548 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Interaction Between Midlife Blood Glucose and APOE Genotype Predicts Later Alzheimer's Disease Pathology. %A Bangen, Katherine J %A Himali, Jayandra J %A Beiser, Alexa S %A Nation, Daniel A %A Libon, David J %A Fox, Caroline S %A Seshadri, Sudha %A Wolf, Philip A %A McKee, Ann C %A Au, Rhoda %A Delano-Wood, Lisa %X

Elevated blood glucose and the apolipoprotein (APOE) ɛ4 allele have both been associated with increased dementia risk; however, the neuropathological mechanisms underlying these associations remain unclear. We examined the impact of APOE genotype and midlife blood glucose on post-mortem vascular and Alzheimer's disease (AD) neuropathology. Ninety-four participants from the Framingham Heart Study without diagnosed diabetes underwent health examination at midlife and brain autopsy at death. Histopathological measures of vascular and AD neuropathology were obtained and analyzed. Results demonstrated that, among APOE ɛ4 carriers, elevated blood glucose was associated with more severe AD pathology. There was no such relationship with vascular pathology. In a relatively healthy sample with low vascular risk burden, midlife elevated blood glucose was associated with greater AD pathology among APOE ɛ4 carriers. A better understanding of interactive effects of APOE genotype and vascular risk on neuropathology has implications for identification of individuals at risk for decline and long-term preventive treatment.

%B J Alzheimers Dis %V 53 %P 1553-62 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392855?dopt=Abstract %R 10.3233/JAD-160163 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Iron Regulates Apolipoprotein E Expression and Secretion in Neurons and Astrocytes. %A Xu, He %A Perreau, Victoria M %A Dent, Krista A %A Bush, Ashley I %A Finkelstein, David I %A Adlard, Paul A %K Amyloid beta-Peptides %K Animals %K Apolipoproteins E %K Astrocytes %K Blotting, Western %K Cell Survival %K Cells, Cultured %K Cerebral Cortex %K Copper %K Ferritins %K Immunohistochemistry %K Iron %K Mice, Inbred C57BL %K Neurons %K Polymerase Chain Reaction %K Reactive Oxygen Species %K Receptors, LDL %K RNA, Messenger %K Tumor Suppressor Proteins %K Zinc %X

BACKGROUND: There is strong evidence that iron homeostasis is impaired in the aging and Alzheimer's disease (AD) brain and that this contributes to neurodegeneration. Apolipoprotein E (APOE) has been identified as the strongest genetic risk factor for AD. However, the interaction between the two has yet to be fully explored.

OBJECTIVE: This study aimed to investigate the relationship between exogenous iron levels and ApoE in neurons and astrocytes.

METHODS: Our study used primary cultured cortical neurons and astrocytes to investigate the changes in ApoE caused by iron. Western blot and RT-PCR were used to measure ApoE.

RESULTS: We observed that iron upregulated intracellular ApoE levels in both neurons and astrocytes at the post-transcriptional and transcriptional level, respectively. However, there was less full-length ApoE secreted by neurons and astrocytes after iron treatment. We speculate that this might impair brain lipid metabolism and amyloid-β clearance. In terms of ApoE receptors, we observed that neuronal LRP-1 levels were increased by the addition of exogenous iron, which could contribute to AβPP endocytosis in neurons. However, there were no significant changes in neuronal LDLR, astrocyte LDLR, or astrocyte LRP-1.

CONCLUSION: Our study reveals that iron may contribute to the pathogenesis of AD by affecting ApoE and its receptors and supports the notion that iron chelation should be investigated as a therapeutic strategy for AD.

%B J Alzheimers Dis %V 51 %P 471-87 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890748?dopt=Abstract %R 10.3233/JAD-150797 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Lack of evidence for a role of HHV-6 in the pathogenesis of Alzheimer's disease. %A Agostini, Simone %A Mancuso, Roberta %A Baglio, Francesca %A Cabinio, Monia %A Hernis, Ambra %A Guerini, Franca Rosa %A Calabrese, Elena %A Nemni, Raffaello %A Clerici, Mario %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Antibodies %K Case-Control Studies %K Cognitive Dysfunction %K Female %K Herpesvirus 1, Human %K Herpesvirus 6, Human %K Humans %K Immunity, Humoral %K Magnetic Resonance Imaging %K Male %K Seroepidemiologic Studies %K Temporal Lobe %X

BACKGROUND: Alzheimer's disease (AD), the most common form of dementia worldwide, is associated with impairment in the mechanisms of the clearing of amyloid-β within a scenario of neuroinflammation. The etiopathogenesis of the AD is unclear, but a role for viral infection is suspected to play a role in initiating the disease. We recently described a positive correlation between high titers of HSV-1-specific antibodies (Ab) and the volumes of brain regions typically affected in disease.

OBJECTIVE: The exploration of a possible role for Herpesviridae in AD was extended by analyzing HHV-6-specific humoral immunity in individuals with AD or a diagnosis of amnestic mild cognitive impairment (aMCI), a condition that is often prodromic of the development of AD.

METHODS: 59 AD, 60 aMCI, and 61 age-matched healthy controls were enrolled in the study. Serum HHV-6 IgG antibody titers and avidity index were tested by ELISA. Two randomly selected subgroups of AD and aMCI in whom HHV-6 serum antibodies were detected underwent brain magnetic resonance imaging (MRI) by 1.5 T scanner.

RESULTS: HHV-6 seroprevalence, antibody titers, and avidity were similar in the three groups. No correlation was found between Ab titers or avidity and brain volumes, either overall or in the regions typically affected by disease.

CONCLUSIONS: The lack of any relation between humoral immune response against HHV-6 and AD and aMCI seems to rule out a role for this virus in the pathogenesis of AD.

%B J Alzheimers Dis %V 49 %P 229-35 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444787?dopt=Abstract %R 10.3233/JAD-150464 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Language Profile of Behavioral Variant Frontotemporal Dementia. %A Hardy, Chris J D %A Buckley, Aisling H %A Downey, Laura E %A Lehmann, Manja %A Zimmerer, Vitor C %A Varley, Rosemary A %A Crutch, Sebastian J %A Rohrer, Jonathan D %A Warrington, Elizabeth K %A Warren, Jason D %K Aged %K Aphasia, Primary Progressive %K Atrophy %K Brain %K Cognition %K Comprehension %K Female %K Frontotemporal Dementia %K Humans %K Language %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuroimaging %K Neuropsychological Tests %K Primary Progressive Nonfluent Aphasia %X

BACKGROUND: The language profile of behavioral variant frontotemporal dementia (bvFTD) remains to be fully defined.

OBJECTIVE: We aimed to quantify the extent of language deficits in this patient group.

METHODS: We assessed a cohort of patients with bvFTD (n = 24) in relation to patients with semantic variant primary progressive aphasia (svPPA; n = 14), nonfluent variant primary progressive aphasia (nfvPPA; n = 18), and healthy age-matched individuals (n = 24) cross-sectionally and longitudinally using a comprehensive battery of language and general neuropsychological tests. Neuroanatomical associations of language performance were assessed using voxel-based morphometry of patients' brain magnetic resonance images.

RESULTS: Relative to healthy controls, and after accounting for nonverbal executive performance, patients with bvFTD showed deficits of noun and verb naming and single word comprehension, diminished spontaneous propositional speech, and deterioration in naming performance over time. Within the bvFTD group, patients with MAPT mutations had more severe impairments of noun naming and single word comprehension than patients with C9orf72 mutations. Overall the bvFTD group had less severe language deficits than patients with PPA, but showed a language profile that was qualitatively similar to svPPA. Neuroanatomical correlates of naming and word comprehension performance in bvFTD were identified predominantly in inferior frontal and antero-inferior temporal cortices within the dominant hemispheric language network.

CONCLUSIONS: bvFTD is associated with a language profile including verbal semantic impairment that warrants further evaluation as a novel biomarker.

%B J Alzheimers Dis %V 50 %P 359-71 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682693?dopt=Abstract %R 10.3233/JAD-150806 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Late-Life Depressive Symptoms and Lifetime History of Major Depression: Cognitive Deficits are Largely Due to Incipient Dementia rather than Depression. %A Heser, Kathrin %A Bleckwenn, Markus %A Wiese, Birgitt %A Mamone, Silke %A Riedel-Heller, Steffi G %A Stein, Janine %A Lühmann, Dagmar %A Posselt, Tina %A Fuchs, Angela %A Pentzek, Michael %A Weyerer, Siegfried %A Werle, Jochen %A Weeg, Dagmar %A Bickel, Horst %A Brettschneider, Christian %A König, Hans-Helmut %A Maier, Wolfgang %A Scherer, Martin %A Wagner, Michael %X

BACKGROUND: Late-life depression is frequently accompanied by cognitive impairments.

OBJECTIVE: Whether these impairments indicate a prodromal state of dementia, or are a symptomatic expression of depression per se is not well-studied.

METHODS: In a cohort of very old initially non-demented primary care patients (n = 2,709, mean age = 81.1 y), cognitive performance was compared between groups of participants with or without elevated depressive symptoms and with or without subsequent dementia using ANCOVA (adjusted for age, sex, and education). Logistic regression analyses were computed to predict subsequent dementia over up to six years of follow-up. The same analytical approach was performed for lifetime major depression.

RESULTS: Participants with elevated depressive symptoms without subsequent dementia showed only small to medium cognitive deficits. In contrast, participants with depressive symptoms with subsequent dementia showed medium to very large cognitive deficits. In adjusted logistic regression models, learning and memory deficits predicted the risk for subsequent dementia in participants with depressive symptoms. Participants with a lifetime history of major depression without subsequent dementia showed no cognitive deficits. However, in adjusted logistic regression models, learning and orientation deficits predicted the risk for subsequent dementia also in participants with lifetime major depression.

CONCLUSION: Marked cognitive impairments in old age depression should not be dismissed as "depressive pseudodementia", but require clinical attention as a possible sign of incipient dementia. Non-depressed elderly with a lifetime history of major depression, who remained free of dementia during follow-up, had largely normal cognitive performance.

%B J Alzheimers Dis %V 54 %P 185-99 %8 2016 Aug 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497475?dopt=Abstract %R 10.3233/JAD-160209 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Lifelong Reading Disorder and Mild Cognitive Impairment: Implications for Diagnosis. %A Lebowitz, Brian K %A Weinstein, Cheryl %A Beiser, Alexa %A Seshadri, Sudha %A Wolf, Philip A %A Auerbach, Sandford %A Au, Rhoda %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Dyslexia %K Female %K Humans %K Independent Living %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Psychometrics %K Retrospective Studies %X

Although neuropsychological tests are commonly used in the evaluation of possible mild cognitive impairment (MCI), poor test scores may be indicative of factors other than neurological compromise. The current study assessed the role of lifelong reading disorder on MCI classification. Community dwelling older adults with a suspected developmental reading disorder were identified by inference based on reading test performance. Individuals with a suspected reading disorder were significantly more likely to perform at a level consistent with MCI on several commonly used neuropsychological tests. The findings suggest a relationship between a history of reading disorder and MCI classification.

%B J Alzheimers Dis %V 50 %P 41-5 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639959?dopt=Abstract %R 10.3233/JAD-150543 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Limiting Factors of Brain Donation in Neurodegenerative Diseases: The Example of French Memory Clinics. %A Le Bouc, Raphael %A Marelli, Cecilia %A Beaufils, Emilie %A Berr, Claudine %A Hommet, Caroline %A Touchon, Jacques %A Pasquier, Florence %A Deramecourt, Vincent %K Autopsy %K Brain %K France %K Health Knowledge, Attitudes, Practice %K Humans %K Neurodegenerative Diseases %K Physicians %K Retrospective Studies %X

Postmortem neuropathological examination of the brain is essential in neurodegenerative diseases, to ensure accurate diagnosis, to obtain an a posteriori critical assessment of the adequacy of clinical care, and to validate new biomarkers, but is only rarely performed. The purpose of this study was to assess factors limiting brain donation, such as reluctance of physicians to seek donation consent, opposition from patients and families, and organizational constraints. We conducted a survey across French memory clinics and major neuropathological centers. Few postmortem examinations were performed annually, as less than one third of the centers had performed at least five autopsies, and 41% had performed none. The main limiting factor was the lack of donation requests made by physicians, as half of them never approach patients for brain donation. Reasons for not seeking donation consent often include discomfort broaching the subject and lack of awareness of the medical and scientific benefit of postmortems (77%), organizational constraints (61%), and overestimation of families' negative reaction (51%). Family refusals represented a second major obstacle, and were often caused by misconceptions. Identifying and addressing these biases early could help improve physicians' rate of making requests and the public's awareness about the importance of brain donation.

%B J Alzheimers Dis %V 49 %P 1075-83 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26756326?dopt=Abstract %R 10.3233/JAD-150825 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Longitudinal Changes in Functional Brain Connectivity Predicts Conversion to Alzheimer's Disease. %A Serra, Laura %A Cercignani, Mara %A Mastropasqua, Chiara %A Torso, Mario %A Spanò, Barbara %A Makovac, Elena %A Viola, Vanda %A Giulietti, Giovanni %A Marra, Camillo %A Caltagirone, Carlo %A Bozzali, Marco %K Aged %K Alzheimer Disease %K Atrophy %K Brain %K Brain Mapping %K Cognitive Dysfunction %K Cross-Sectional Studies %K Discriminant Analysis %K Disease Progression %K Female %K Follow-Up Studies %K Gray Matter %K Humans %K Image Processing, Computer-Assisted %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Neural Pathways %K Neuropsychological Tests %K Prognosis %K Rest %X

This longitudinal study investigates the modifications in structure and function occurring to typical Alzheimer's disease (AD) brains over a 2-year follow-up, from pre-dementia stages of disease, with the aim of identifying biomarkers of prognostic value. Thirty-one patients with amnestic mild cognitive impairment were recruited and followed-up with clinical, neuropsychological, and MRI assessments. Patients were retrospectively classified as AD Converters or Non-Converters, and the data compared between groups. Cross-sectional MRI data at baseline, assessing volume and functional connectivity abnormalities, confirmed previous findings, showing a more severe pattern of regional grey matter atrophy and default-mode network disconnection in Converters than in Non-Converters. Longitudinally, Converters showed more grey matter atrophy in the frontotemporal areas, accompanied by increased connectivity in the precuneus. Discriminant analysis revealed that functional connectivity of the precuneus within the default mode network at baseline is the parameter able to correctly classify patients in Converters and Non-Converters with high sensitivity, specificity, and accuracy.

%B J Alzheimers Dis %V 51 %P 377-89 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890769?dopt=Abstract %R 10.3233/JAD-150961 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Longitudinal Relationships between Caloric Expenditure and Gray Matter in the Cardiovascular Health Study. %A Raji, Cyrus A %A Merrill, David A %A Eyre, Harris %A Mallam, Sravya %A Torosyan, Nare %A Erickson, Kirk I %A Lopez, Oscar L %A Becker, James T %A Carmichael, Owen T %A Gach, H Michael %A Thompson, Paul M %A Longstreth, W T %A Kuller, Lewis H %X

BACKGROUND: Physical activity (PA) can be neuroprotective and reduce the risk for Alzheimer's disease (AD). In assessing physical activity, caloric expenditure is a proxy marker reflecting the sum total of multiple physical activity types conducted by an individual.

OBJECTIVE: To assess caloric expenditure, as a proxy marker of PA, as a predictive measure of gray matter (GM) volumes in the normal and cognitively impaired elderly persons.

METHODS: All subjects in this study were recruited from the Institutional Review Board approved Cardiovascular Health Study (CHS), a multisite population-based longitudinal study in persons aged 65 and older. We analyzed a sub-sample of CHS participants 876 subjects (mean age 78.3, 57.5% F, 42.5% M) who had i) energy output assessed as kilocalories (kcal) per week using the standardized Minnesota Leisure-Time Activities questionnaire, ii) cognitive assessments for clinical classification of normal cognition, mild cognitive impairment (MCI), and AD, and iii) volumetric MR imaging of the brain. Voxel-based morphometry modeled the relationship between kcal/week and GM volumes while accounting for standard covariates including head size, age, sex, white matter hyperintensity lesions, MCI or AD status, and site. Multiple comparisons were controlled using a False Discovery Rate of 5 percent.

RESULTS: Higher energy output, from a variety of physical activity types, was associated with larger GM volumes in frontal, temporal, and parietal lobes, as well as hippocampus, thalamus, and basal ganglia. High levels of caloric expenditure moderated neurodegeneration-associated volume loss in the precuneus, posterior cingulate, and cerebellar vermis.

CONCLUSION: Increasing energy output from a variety of physical activities is related to larger gray matter volumes in the elderly, regardless of cognitive status.

%B J Alzheimers Dis %V 52 %P 719-29 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967227?dopt=Abstract %R 10.3233/JAD-160057 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Looking for Measures of Disease Severity in the Frontotemporal Dementia Continuum. %A Premi, Enrico %A Gualeni, Vera %A Costa, Paolo %A Cosseddu, Maura %A Gasparotti, Roberto %A Padovani, Alessandro %A Borroni, Barbara %X

Frontotemporal dementia (FTD) is characterized by executive dysfunctions, behavioral disturbances, language deficits and extrapyramidal symptoms. Frontotemporal lobar degeneration-modified Clinical Dementia Rating Scale (FTLD modified-CDR) has been proposed to measure disease severity in behavioral variant FTD (bvFTD). No tools of global disease severity are available in the other FTLD phenotypes [primary progressive aphasias (PPAs), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS)]. This would be strategic as outcome measures in clinical trials. To this aim, we evaluated the association between brain volume (voxel based morphometry) and available clinical scales in FTD. In 176 FTD patients (64 bvFTD, 40 PPAs, 32 PSP, 40 CBS), instrumental activities of daily living (ADLs), FTLD-modified CDR, Mini-Mental State Examination (MMSE), Frontal Behavioral Inventory (FBI), and Neuropsychiatry Inventory (NPI) were administered and MRI performed. Whole-brain linear correlation between each clinical rating scale and brain volume was performed. In bvFTD and PPAs, FTLD-modified CDR was associated with regional brain volume, thereby providing evidence for validity of the FTLD-modified CDR. In PSP, none of the clinical indicators were associated with regional brain volume. In CBS, ADLs and MMSE correlated with frontotemporal lower volume. Considering monogenic disease, FTLD-modified CDR was the best measure. In FTD continuum, different measures able to correlate with brain damage should be considered for the different clinical phenotypes or genetic traits.

%B J Alzheimers Dis %V 52 %P 1227-35 %8 2016 Apr 16 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104906?dopt=Abstract %R 10.3233/JAD-160178 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Looking for Neuroimaging Markers in Frontotemporal Lobar Degeneration Clinical Trials: A Multi-Voxel Pattern Analysis Study in Granulin Disease. %A Premi, Enrico %A Cauda, Franco %A Costa, Tommaso %A Diano, Matteo %A Gazzina, Stefano %A Gualeni, Vera %A Alberici, Antonella %A Archetti, Silvana %A Magoni, Mauro %A Gasparotti, Roberto %A Padovani, Alessandro %A Borroni, Barbara %K Adult %K Aged %K Brain %K Brain Mapping %K Cohort Studies %K Female %K Frontotemporal Lobar Degeneration %K Humans %K Image Processing, Computer-Assisted %K Intercellular Signaling Peptides and Proteins %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Mutation %K Neural Pathways %K Oxygen %K Phenylalanine %K Threonine %X

In light of future pharmacological interventions, neuroimaging markers able to assess the response to treatment would be crucial. In Granulin (GRN) disease, preclinical data will prompt pharmacological trials in the future. Two main points need to be assessed: (1) to identify target regions in different disease stages and (2) to determine the most accurate functional and structural neuroimaging index to be used. To this aim, we have taken advantage of the multivariate approach of multi-voxel pattern analysis (MVPA) to explore the information of brain activity patterns in a cohort of GRN Thr272fs carriers at different disease stages (14 frontotemporal dementia (FTD) patients and 17 asymptomatic carriers) and a group of 33 healthy controls. We studied structural changes by voxel-based morphometry (VBM), functional connectivity by assessing salience, default mode, fronto-parietal, dorsal attentional, executive networks, and local connectivity by regional homogeneity, amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), degree centrality, and voxel-mirrored homotopic connectivity. In FTD patients with GRN mutation, the most predictive measure was VBM structural analysis, while in asymptomatic carriers the best predictor marker was the local connectivity measure (fALFF). Altogether, all indexes demonstrated fronto-temporo-parietal damage in GRN pathology, with widespread structural damage of fronto-parietal and temporal regions when disease is overt. MVPA could be of aid in identifying the most accurate neuroimaging marker for clinical trials. This approach was able to identify both the target region and the best neuroimaging approach, which would be specific in the different disease stages. Further studies are needed to simultaneously integrate multimodal indexes in a classifier able to trace the disease progression moving from preclinical to clinical stage of the disease.

%B J Alzheimers Dis %V 51 %P 249-62 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836150?dopt=Abstract %R 10.3233/JAD-150340 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Low Prevalence of Mixed Dementia in a Cohort of 2,000 Elderly Patients in a Memory Clinic Setting. %A Claus, Jules J %A Staekenborg, Salka S %A Roorda, Jelmen J %A Stevens, Martijn %A Herderschee, Dirk %A van Maarschalkerweerd, Willy %A Schuurmans, Lilly %A Tielkes, Caroline E M %A Koster, Pieter %A Bavinck, Chris %A Scheltens, Philip %K Age Factors %K Aged %K Aged, 80 and over %K Analysis of Variance %K Cognitive Dysfunction %K Cohort Studies %K Dementia %K Female %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Prevalence %K Regression Analysis %K Risk Factors %K Tomography Scanners, X-Ray Computed %X

BACKGROUND: It is generally assumed that with increasing age, pathology in clinically diagnosed Alzheimer's disease (AD) becomes more mixed, i.e., co-existence of amyloid plaques and cerebrovascular pathology.

OBJECTIVE: To test the hypothesis of increasing prevalence of mixed dementia in late-onset clinically diagnosed Alzheimer's disease (AD) in a single-center memory clinic population.

METHODS: Patients included had diagnoses of AD (n = 832), subjective cognitive impairment (SCI, n = 333), mild cognitive impairment (MCI, n = 492), vascular dementia (VaD, n = 57), other dementia (n = 53), or other diagnosis (n = 233). Prevalence of severe white matter lesions (WML) was defined as a score of 2 or higher on the Fazekas-scale on brain computed tomography to classify AD patients as having mixed dementia. We examined the effect of age on WML using multiple linear regression analysis, and AD patients were compared to SCI to determine the effect of disease on WML.

RESULTS: Prevalence of severe WML was 33.6% in AD patients (mixed dementia), 11.4% in SCI, 22.7% in MCI, 75.4% in VaD, 3.8% in other dementia, and 15.5% in other diagnosis. With increasing age there was a significant and similar increase of WML scores in SCI, MCI, AD, other dementia, and other diagnosis, indicating no effect modification by AD. The difference between AD patients and SCI averaged 0.16 on the WML score and difference in percentage severe WML between AD and SCI patients was 15% across all ages.

CONCLUSION: We found a low prevalence of mixed dementia. Furthermore, severe WML in AD was largely explained by age rather than effect of disease.

%B J Alzheimers Dis %V 50 %P 797-806 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757192?dopt=Abstract %R 10.3233/JAD-150796 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Low Serum Insulin-Like Growth Factor-I Predicts Cognitive Decline in Alzheimer's Disease. %A Vidal, Jean-Sébastien %A Hanon, Olivier %A Funalot, Benoît %A Brunel, Nadège %A Viollet, Cécile %A Rigaud, Anne-Sophie %A Seux, Marie-Laure %A le-Bouc, Yves %A Epelbaum, Jacques %A Duron, Emmanuelle %X

BACKGROUND: The relationship between the insulin-like growth factor-I (IGF-I) system and Alzheimer's disease (AD) is mostly based on transversal studies. It remains, however, to demonstrate whether IGF-I is associated with cognitive decline over time in AD.

OBJECTIVE: The objective of the study was to analyze the course of cognitive decline of AD subjects over a 24-month period in relation to serum IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3) measured at baseline.

METHODS: Data are from the SIGAL follow-up study. IGF-I and IGFBP-3 were measured in AD subjects who performed a Mini-Mental State Examination (MMSE) every 6 months for 2 years. MMSE course was analyzed using a mixed model with random intercept and slope function.

RESULTS: Among the 200 AD participants, 146 (mean age = 81.1 (standard deviation (SD) = 5.9) years, 62.6% of women) had at least one follow-up visit. Mean IGF-I at baseline was 147.8 (74.2) ng/mL. Hundred forty-six participants (62.6%) had at least one follow-up visit. Mean MMSE was 21.7 (4.7)/30 and dropped on average by 2.28 points per year. MMSE decline was steeper among participants with lower IGF-I. For each decrease of 1 SD of IGF-I, subjects lost an additional 0.63 points per year in MMSE, e.g., participants with IGF-I level of 74 ng/mL lost 2.91 MMSE points per year whereas participants with IGF-I of 222 ng/mL lost 1.65 MMSE points per year. There was no association between IGFBP-3 and cognitive decline.

CONCLUSION: Lower baseline serum IGF-I was associated with faster cognitive decline in AD over a 2-year period.

%B J Alzheimers Dis %V 52 %P 641-9 %8 2016 Mar 29 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031487?dopt=Abstract %R 10.3233/JAD-151162 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Maintenance of Cognitive Performance and Mood for Individuals with Alzheimer's Disease Following Consumption of a Nutraceutical Formulation: A One-Year, Open-Label Study. %A Remington, Ruth %A Bechtel, Cynthia %A Larsen, David %A Samar, Annemarie %A Page, Robert %A Morrell, Christopher %A Shea, Thomas B %K Aged %K Aged, 80 and over %K alpha-Tocopherol %K Alzheimer Disease %K Cognition Disorders %K Dietary Supplements %K Disease Progression %K Female %K Folic Acid %K Follow-Up Studies %K Humans %K Male %K Mood Disorders %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Time Factors %K Vitamin B 12 %X

Nutritional interventions have shown varied efficacy on cognitive performance during Alzheimer's disease (AD). Twenty-four individuals diagnosed with AD received a nutraceutical formulation (NF: folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) under open-label conditions (ClinicalTrials.gov NCT01320527). Primary outcome was cognitive performance. Secondary outcomes were behavioral and psychological symptoms of dementia (BPSD) and activities of daily living. Participants maintained their baseline cognitive performance and BPSD over 12 months. These findings are consistent with improvement in cognitive performance and BPSD in prior placebo-controlled studies with NF, and contrast with the routine decline for participants receiving placebo.

%B J Alzheimers Dis %V 51 %P 991-5 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967219?dopt=Abstract %R 10.3233/JAD-151098 %0 Journal Article %J J Alzheimers Dis %D 2016 %T MAPT H1 Haplotype is Associated with Late-Onset Alzheimer's Disease Risk in APOEɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium. %A Pastor, Pau %A Moreno, Fermín %A Clarimón, Jordi %A Ruiz, Agustin %A Combarros, Onofre %A Calero, Miguel %A López de Munain, Adolfo %A Bullido, Maria J %A de Pancorbo, Marian M %A Carro, Eva %A Antonell, Anna %A Coto, Eliecer %A Ortega-Cubero, Sara %A Hernandez, Isabel %A Tárraga, Lluís %A Boada, Merce %A Lleo, Alberto %A Dols-Icardo, Oriol %A Kulisevsky, Jaime %A Vázquez-Higuera, José Luis %A Infante, Jon %A Rábano, Alberto %A Fernández-Blázquez, Miguel Ángel %A Valentí, Meritxell %A Indakoetxea, Begoña %A Barandiarán, Myriam %A Gorostidi, Ana %A Frank-García, Ana %A Sastre, Isabel %A Lorenzo, Elena %A Pastor, María A %A Elcoroaristizabal, Xabier %A Lennarz, Martina %A Maier, Wolfang %A Rámirez, Alfredo %A Serrano-Ríos, Manuel %A Lee, Suzee E %A Sánchez-Juan, Pascual %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Female %K Frontotemporal Dementia %K Genetic Predisposition to Disease %K Haplotypes %K Humans %K Logistic Models %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Spain %K tau Proteins %X

The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.

%B J Alzheimers Dis %V 49 %P 343-52 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444794?dopt=Abstract %R 10.3233/JAD-150555 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Memory Binding Test: Development of Two Alternate Forms into Spanish and Catalan. %A Gramunt, Nina %A Sánchez-Benavides, Gonzalo %A Buschke, Herman %A Diéguez-Vide, Faustino %A Peña-Casanova, Jordi %A Masramon, Xavier %A Fauria, Karine %A Gispert, Juan D %A Molinuevo, José L %X

BACKGROUND: The Memory Binding Test (MBT) is emerging as a promising tool for the detection of subtle memory impairment suggestive of Alzheimer's disease (AD). For such a test to be widely accessed and used, the availability of both alternate forms and language adaptations is required.

OBJECTIVES: To develop a thorough methodology for obtaining alternate forms (A and B) of the MBT in Spanish and Catalan and to assess their equivalence.

METHOD: According to the original development of the test, frequency was taken as the lexical variable of reference for the Spanish and Catalan adaptations. A crossed design protocol by form and language was used to compare the MBT results in a sample of 290 cognitively normal middle-aged participants. Pairwise Intraclass Correlation Coefficients (ICCs) were calculated among the six possible combinations.

RESULTS: The Spanish and Catalan lists of words for the MBT A and B resulting from the adaptation process as well as the original lists in English are presented. ICC indices for the comparisons between forms and languages ranged from 0.56 to 0.82.

CONCLUSION: The MBT A and B in Spanish and Catalan showed similar outcomes and can be considered equivalent. Moreover, the thorough methodology presented here for the transcultural adaptation and equivalence study, could serve as a model for future adaptations of the MBT and other verbal tests.

%B J Alzheimers Dis %V 52 %P 283-93 %8 2016 03 05 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060959?dopt=Abstract %R 10.3233/JAD-151175 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Memory Binding Test Predicts Incident Amnestic Mild Cognitive Impairment. %A Mowrey, Wenzhu B %A Lipton, Richard B %A Katz, Mindy J %A Ramratan, Wendy S %A Loewenstein, David A %A Zimmerman, Molly E %A Buschke, Herman %X

BACKGROUND: The Memory Binding Test (MBT), previously known as Memory Capacity Test, has demonstrated discriminative validity for distinguishing persons with amnestic mild cognitive impairment (aMCI) and dementia from cognitively normal elderly.

OBJECTIVE: We aimed to assess the predictive validity of the MBT for incident aMCI.

METHODS: In a longitudinal, community-based study of adults aged 70+, we administered the MBT to 246 cognitively normal elderly adults at baseline and followed them annually. Based on previous work, a subtle reduction in memory binding at baseline was defined by a Total Items in the Paired (TIP) condition score of ≤22 on the MBT. Cox proportional hazards models were used to assess the predictive validity of the MBT for incident aMCI accounting for the effects of covariates. The hazard ratio of incident aMCI was also assessed for different prediction time windows ranging from 4 to 7 years of follow-up, separately.

RESULTS: Among 246 controls who were cognitively normal at baseline, 48 developed incident aMCI during follow-up. A baseline MBT reduction was associated with an increased risk for developing incident aMCI (hazard ratio (HR) = 2.44, 95% confidence interval: 1.30-4.56, p = 0.005). When varying the prediction window from 4-7 years, the MBT reduction remained significant for predicting incident aMCI (HR range: 2.33-3.12, p: 0.0007-0.04).

CONCLUSION: Persons with poor performance on the MBT are at significantly greater risk for developing incident aMCI. High hazard ratios up to seven years of follow-up suggest that the MBT is sensitive to early disease.

%B J Alzheimers Dis %V 53 %P 1585-95 %8 2016 Jul 14 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27540964?dopt=Abstract %R 10.3233/JAD-160291 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Memory for Public Events in Mild Cognitive Impairment and Alzheimer's Disease: The Importance of Rehearsal. %A Langlois, Roxane %A Joubert, Sven %A Benoit, Sophie %A Dostie, Valérie %A Rouleau, Isabelle %K Aged %K Alzheimer Disease %K Cognitive Dysfunction %K Female %K Humans %K Learning %K Male %K Memory %K Psychological Tests %K Semantics %X

Ribot's law refers to the better preservation of remote memories compared with recent ones that presumably characterizes retrograde amnesia. Even if Ribot-type temporal gradient has been extensively studied in retrograde amnesia, particularly in Alzheimer's disease (AD), this pattern has not been consistently found. One explanation for these results may be that rehearsal frequency rather than remoteness accounts for the better preservation of these memories. Thus, the aim of present study was to address this question by studying retrograde semantic memory in subjects with amnestic mild cognitive impairment (aMCI) (n = 20), mild AD (n = 20) and in healthy older controls (HC; n = 19). In order to evaluate the impact of repetition as well as the impact of remoteness, we used a test assessing memory for enduring and transient public events that occurred in the recent and remote past. Results show no clear temporal gradient across time periods (1960-1975; 1976-1990; 1991-2005; 2006-2011), but a better performance was observed in all three groups for enduring compared with transient events. Moreover, although deficits were globally found in both patients groups compared with HC, more specific analyses revealed that aMCI patients were only impaired on transient events while AD patients were impaired on both transient and enduring events. Exploratory analyses also revealed a tendency suggesting preservation of remote transient events in aMCI. These findings are discussed with regards to memory consolidation models.

%B J Alzheimers Dis %V 50 %P 1023-33 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836162?dopt=Abstract %R 10.3233/JAD-150722 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Memory Impairment at Initial Clinical Presentation in Posterior Cortical Atrophy. %A Ahmed, Samrah %A Baker, Ian %A Husain, Masud %A Thompson, Sian %A Kipps, Christopher %A Hornberger, Michael %A Hodges, John R %A Butler, Christopher R %X

Posterior cortical atrophy (PCA) is characterized by core visuospatial and visuoperceptual deficits, and predominant atrophy in the parieto-occipital cortex. The most common underlying pathology is Alzheimer's disease (AD). Existing diagnostic criteria suggest that episodic memory is relatively preserved. The aim of this study was to examine memory performance at initial clinical presentation in PCA, compared to early-onset AD patients (EOAD). 15 PCA patients and 32 EOAD patients, and 34 healthy controls were entered into the study. Patients were tested on the Addenbrooke's Cognitive Examination (ACE-R), consisting of subscales in memory and visuospatial skills. PCA and EOAD patients were significantly impaired compared to controls on the ACE total score (p < 0.001), visuospatial skills (p < 0.001), and memory (p < 0.001). Consistent with the salient diagnostic deficits, PCA patients were significantly more impaired on visuospatial skills compared to EOAD patients (p < 0.001). However, there was no significant difference between patient groups in memory. Further analysis of learning, recall, and recognition components of the memory subscale showed that EOAD and PCA patients were significantly impaired compared to controls on all three components (p < 0.001), however, there was no significant difference between EOAD and PCA patients. The results of this study show that memory is impaired in the majority of PCA patients at clinical presentation. The findings suggest that memory impairment must be considered in assessment and management of PCA. Further study into memory in PCA is warranted, since the ACE-R is a brief screening tool and is likely to underestimate the presence of memory impairment.

%B J Alzheimers Dis %V 52 %P 1245-50 %8 2016 Apr 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27128371?dopt=Abstract %R 10.3233/JAD-160018 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Metallothioneins in Prion- and Amyloid-Related Diseases. %A Adam, Pavlína %A Křížková, Soňa %A Heger, Zbyněk %A Babula, Petr %A Pekařík, Vladimír %A Vaculovičoá, Markéta %A Gomes, Cláudio M %A Kizek, René %A Adam, Vojtěch %K Amyloidosis %K Animals %K Brain Diseases %K Humans %K Metallothionein %K Prion Diseases %X

Prion and other amyloid-forming diseases represent a group of neurodegenerative disorders that affect both animals and humans. The role of metal ions, especially copper and zinc is studied intensively in connection with these diseases. Their involvement in protein misfolding and aggregation and their role in creation of reactive oxygen species have been shown. Recent data also show that metal ions not only bind the proteins with high affinity, but also modify their biochemical properties, making them important players in prion-related diseases. In particular, the level of zinc ions is tightly regulated by several mechanisms, including transporter proteins and the low molecular mass thiol-rich metallothioneins. From four metallothionein isoforms, metallothionein-3, a unique brain-specific metalloprotein, plays a crucial role only in this regulation. This review critically evaluates the involvement of metallothioneins in prion- and amyloid-related diseases in connection with the relationship between metallothionein isoforms and metal ion regulation of their homeostasis.

%B J Alzheimers Dis %V 51 %P 637-56 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923022?dopt=Abstract %R 10.3233/JAD-150984 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Metformin Facilitates Amyloid-β Generation by β- and γ-Secretases via Autophagy Activation. %A Son, Sung Min %A Shin, Hong-Joon %A Byun, Jayoung %A Kook, Sun Young %A Moon, Minho %A Chang, Yu Jin %A Mook-Jung, Inhee %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Autophagy %K Cell Line, Tumor %K Disease Models, Animal %K Female %K Humans %K Hypoglycemic Agents %K Lysosomes %K Metformin %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Microscopy, Electron %K Mutation %K Neuroblastoma %K Signal Transduction %X

The evidence of strong pathological associations between type 2 diabetes and Alzheimer's disease (AD) has increased in recent years. Contrary to suggestions that anti-diabetes drugs may have potential for treating AD, we demonstrate here that the insulin sensitizing anti-diabetes drug metformin (Glucophage®) increased the generation of amyloid-β (Aβ), one of the major pathological hallmarks of AD, by promoting β- and γ-secretase-mediated cleavage of amyloid-β protein precursor (AβPP) in SH-SY5Y cells. In addition, we show that metformin caused autophagosome accumulation in Tg6799 AD model mice. Extremely high γ-secretase activity was also detected in autophagic vacuoles, apparently a novel site of Aβ peptide generation. Together, these data suggest that metformin-induced accumulation of autophagosomes resulted in increased γ-secretase activity and Aβ generation. Additional experiments indicated that metformin increased phosphorylation of AMP-activated protein kinase, which activates autophagy by suppressing mammalian target of rapamycin (mTOR). The suppression of mTOR then induces the abnormal accumulation of autophagosomes. We conclude that metformin, an anti-diabetes drug, may exacerbate AD pathogenesis by promoting amyloidogenic AβPP processing in autophagosomes.

%B J Alzheimers Dis %V 51 %P 1197-208 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967226?dopt=Abstract %R 10.3233/JAD-151200 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. %A Luchsinger, Jose A %A Perez, Thania %A Chang, Helena %A Mehta, Pankaj %A Steffener, Jason %A Pradabhan, Gnanavalli %A Ichise, Masanori %A Manly, Jennifer %A Devanand, Davangere P %A Bagiella, Emilia %K Aged %K Aged, 80 and over %K Amyloid beta-Peptides %K Brain %K Cognitive Dysfunction %K Double-Blind Method %K Female %K Follow-Up Studies %K Glucose %K Humans %K Male %K Metformin %K Middle Aged %K Nootropic Agents %K Overweight %K Peptide Fragments %K Pilot Projects %K Positron-Emission Tomography %K Psychological Tests %K Severity of Illness Index %K Treatment Outcome %X

Diabetes and hyperinsulinemia may be risk factors for Alzheimer's disease (AD). We conducted a pilot study of metformin, a medication efficacious in treating and preventing diabetes while reducing hyperinsulinemia, among persons with amnestic mild cognitive impairment (aMCI) with the goal of collecting preliminary data on feasibility, safety, and efficacy. Participants were 80 men and women aged 55 to 90 years with aMCI, overweight or obese, without treated diabetes. We randomized participants to metformin 1000 mg twice a day or matching placebo for 12 months. The co-primary clinical outcomes were changes from baseline to 12 months in total recall of the Selective Reminding Test (SRT) and the score of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcome was change in relative glucose uptake in the posterior cingulate-precuneus in brain fluorodeoxyglucose positron emission tomography. Change in plasma Aβ42 was an exploratory outcome. The mean age of participants was 65 years. Fifty percent of participants were women. The only baseline variable that was different between the arms was the ADAS-Cog. Metformin could not be tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose. There were no serious adverse events related to metformin. The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms. After adjusting for baseline ADAS-cog, changes in total recall of the SRT favored the metformin group (9.7±8.5 versus 5.3±8.5; p = 0.02). Differences for other outcomes were not significant. A larger trial seems warranted to evaluate the efficacy and cognitive safety of metformin in prodromal AD.

%B J Alzheimers Dis %V 51 %P 501-14 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890736?dopt=Abstract %R 10.3233/JAD-150493 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Mild Cognitive Impairment and Susceptibility to Scams in Old Age. %A Han, S Duke %A Boyle, Patricia A %A James, Bryan D %A Yu, Lei %A Bennett, David A %K Aged %K Aged, 80 and over %K Aging %K Cognitive Dysfunction %K Crime Victims %K Disease Susceptibility %K Female %K Humans %K Male %K Memory, Episodic %K Middle Aged %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Residence Characteristics %K Self Report %X

BACKGROUND: Falling victim to financial scams can have a significant impact upon social and financial wellbeing and independence. A large proportion of scam victims are older adults, but whether older victims with mild cognitive impairment (MCI) are at higher risk remains unknown.

OBJECTIVE: We tested the hypothesis that older persons with MCI exhibit greater susceptibility to scams compared to those without cognitive impairment.

METHODS: Seven hundred and thirty older adults without dementia were recruited from the Rush Memory and Aging Project, a community-based epidemiologic study of aging. Participants completed a five-item self-report measure of susceptibility to scams, a battery of cognitive measures, and clinical diagnostic evaluations.

RESULTS: In models adjusted for age, education, and gender, the presence of MCI was associated with greater susceptibility to scams (B = 0.125, SE = 0.063, p-value = 0.047). Further, in analyses of the role of specific cognitive systems in susceptibility to scams among persons with MCI (n = 144), the level of performance in two systems, episodic memory and perceptual speed abilities, were associated with susceptibility.

CONCLUSIONS: Adults with MCI may be more susceptible to scams in old age than older persons with normal cognition. Lower abilities in specific cognitive systems, particularly perceptual speed and episodic memory, may contribute to greater susceptibility to scams in those with MCI.

%B J Alzheimers Dis %V 49 %P 845-51 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519434?dopt=Abstract %R 10.3233/JAD-150442 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Mindfulness in the Maintenance of Cognitive Capacities in Alzheimer's Disease: A Randomized Clinical Trial. %A Quintana-Hernández, Domingo J %A Miró-Barrachina, María T %A Ibáñez-Fernández, Ignacio J %A Pino, Angelo Santana-Del %A Quintana-Montesdeoca, María P %A Rodríguez-de Vera, Bienvenida %A Morales-Casanova, David %A Pérez-Vieitez, María Del Carmen %A Rodríguez-García, Javier %A Bravo-Caraduje, Noelia %K Age Factors %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Cognition Disorders %K Double-Blind Method %K Female %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K Mindfulness %K Neuropsychological Tests %K Treatment Outcome %X

BACKGROUND: The Canary Islands longitudinal study on non-pharmacological treatments showed the overall effectiveness of mindfulness in Alzheimer's disease (AD). However, no specific data on the maintenance of cognitive capacities were presented.

OBJECTIVE: To determine whether the practice of mindfulness modifies the course of cognitive impairment in AD.

METHODS:

DESIGN: Longitudinal, non-inferiority and equivalence, randomized clinical trial, repeated-measures design, with three experimental groups and one control group.

PARTICIPANTS: Patients with AD who voluntarily attended the Lidia García Foundation (n = 502). Only those who were treated with donepezil and MMSE ≥18 were included (n = 120).

INTERVENTION: Over a two-year period, each group carried out three weekly sessions of stimulation based on mindfulness, cognitive stimulation therapy, and progressive muscle relaxation.

MEASURES: Cognitive assessment CAMDEX-R (MMSE and CAMCOG).

STATISTICAL ANALYSIS: Repeated-measures ANOVA (p <  0.05) and the effect size Cohen's d were performed.

RESULTS: The mindfulness group showed significant scores compared with the control and muscle relaxation groups (p <  0.05), while mindfulness and cognitive stimulation therapy were equivalent (p≥0.05). Group cognitive stimulation evolved better than the control (p <  0.05) group but not better than the muscle relaxation group (p≥0.05). The effect size compared over two years was large for the mindfulness group (p≥0.80), moderate for the relaxation group (p≥0.50), and low for the cognitive stimulation group (p≥0.20).

CONCLUSION: The practice of mindfulness maintained cognitive function over a period of two years. This longitudinal study suggests that mindfulness can be used as a non-pharmacological treatment to slow cognitive impairment in AD.

%B J Alzheimers Dis %V 50 %P 217-32 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639952?dopt=Abstract %R 10.3233/JAD-143009 %0 Journal Article %J J Alzheimers Dis %D 2016 %T "Missed" Mild Cognitive Impairment: High False-Negative Error Rate Based on Conventional Diagnostic Criteria. %A Edmonds, Emily C %A Delano-Wood, Lisa %A Jak, Amy J %A Galasko, Douglas R %A Salmon, David P %A Bondi, Mark W %X

Mild cognitive impairment (MCI) is typically diagnosed using subjective complaints, screening measures, clinical judgment, and a single memory score. Our prior work has shown that this method is highly susceptible to false-positive diagnostic errors. We examined whether the criteria also lead to "false-negative" errors by diagnostically reclassifying 520 participants using novel actuarial neuropsychological criteria. Results revealed a false-negative error rate of 7.1%. Participants' neuropsychological performance, cerebrospinal fluid biomarkers, and rate of decline provided evidence that an MCI diagnosis is warranted. The impact of "missed" cases of MCI has direct relevance to clinical practice, research studies, and clinical trials of prodromal Alzheimer's disease.

%B J Alzheimers Dis %V 52 %P 685-91 %8 2016 Mar 31 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031477?dopt=Abstract %R 10.3233/JAD-150986 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Mitochondrial Role of SV2a Protein in Aging and Alzheimer's Disease: Studies with Levetiracetam. %A Stockburger, Carola %A Miano, Davide %A Baeumlisberger, Marion %A Pallas, Thea %A Arrey, Tabiwang N %A Karas, Michael %A Friedland, Kristina %A Müller, Walter E %K Adenosine Triphosphate %K Aging %K Alzheimer Disease %K Animals %K Brain %K Cell Line %K Cognition Disorders %K Female %K GAP-43 Protein %K Gene Expression Regulation %K Humans %K Male %K Membrane Glycoproteins %K Mitochondria %K Mitochondrial Membrane Transport Proteins %K Nerve Tissue Proteins %K Nitroprusside %K Nootropic Agents %K Piracetam %K Proteomics %K Rats %K RNA, Small Interfering %X

Aberrant neuronal network activity associated with neuronal hyperexcitability seems to be an important cause of cognitive decline in aging and Alzheimer's disease (AD). Out of many antiepileptics, only levetiracetam improved cognitive dysfunction in AD patients and AD animal models by reducing hyperexcitability. As impaired inhibitory interneuronal function, rather than overactive neurons, seems to be the underlying cause, improving impaired neuronal function rather than quieting overactive neurons might be relevant in explaining the lack of activity of the other antiepileptics. Interestingly, improvement of cognitive deficits by levetiracetam caused by small levels of soluble Aβ was accompanied by improvement of synaptic function and plasticity. As the negative effects of Aβ on synaptic plasticity strongly correlate with mitochondrial dysfunction, wehypothesized that the effect of levetiracetam on synaptic activity might be raised by an improved mitochondrial function. Accordingly, we investigated possible effects of levetiracetam on neuronal deficits associated with mitochondrial dysfunction linked to aging and AD. Levetiracetam improved several aspects of mitochondrial dysfunction including alterations of fission and fusion balance in a cell model for aging and early late-onset AD. We demonstrate for the first time, using immunohistochemistry and proteomics, that the synaptic vesicle protein 2A (SV2a), the molecular target of levetiracetam, is expressed in mitochondria. In addition, levetiracetam shows significant effect on the opening of the mitochondrial permeability transition pore. Importantly, the effects of levetiracetam were significantly abolished when SV2a was knockdown using siRNA. In conclusion, interfering with the SV2a protein at the mitochondrial level and thereby improving mitochondrial function might represent an additional therapeutic effect of levetiracetam to improve symptoms of late-onset AD.

%B J Alzheimers Dis %V 50 %P 201-15 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639968?dopt=Abstract %R 10.3233/JAD-150687 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Moderate-to-High Intensity Physical Exercise in Patients with Alzheimer's Disease: A Randomized Controlled Trial. %A Hoffmann, Kristine %A Sobol, Nanna A %A Frederiksen, Kristian S %A Beyer, Nina %A Vogel, Asmus %A Vestergaard, Karsten %A Brændgaard, Hans %A Gottrup, Hanne %A Lolk, Annette %A Wermuth, Lene %A Jacobsen, Søren %A Laugesen, Lars P %A Gergelyffy, Robert G %A Høgh, Peter %A Bjerregaard, Eva %A Andersen, Birgitte B %A Siersma, Volkert %A Johannsen, Peter %A Cotman, Carl W %A Waldemar, Gunhild %A Hasselbalch, Steen G %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition %K Depression %K Exercise %K Exercise Therapy %K Female %K Humans %K Male %K Middle Aged %K Quality of Life %K Treatment Outcome %X

BACKGROUND: Studies of physical exercise in patients with Alzheimer's disease (AD) are few and results have been inconsistent.

OBJECTIVE: To assess the effects of a moderate-to-high intensity aerobic exercise program in patients with mild AD.

METHODS: In a randomized controlled trial, we recruited 200 patients with mild AD to a supervised exercise group (60-min sessions three times a week for 16 weeks) or to a control group. Primary outcome was changed from baseline in cognitive performance estimated by Symbol Digit Modalities Test (SDMT) in the intention-to-treat (ITT) group. Secondary outcomes included changes in quality of life, ability to perform activities of daily living, and in neuropsychiatric and depressive symptoms.

RESULTS: The ITT analysis showed no significant differences between intervention and control groups in change from baseline of SDMT, other cognitive tests, quality of life, or activities of daily living. The change from baseline in Neuropsychiatric Inventory differed significantly in favor of the intervention group (mean: -3.5, 95% confidence interval (CI) -5.8 to -1.3, p = 0.002). In subjects who adhered to the protocol, we found a significant effect on change from baseline in SDMT as compared with the control group (mean: 4.2, 95% CI 0.5 to 7.9, p = 0.028), suggesting a dose-response relationship between exercise and cognition.

CONCLUSIONS: This is the first randomized controlled trial with supervised moderate-to-high intensity exercise in patients with mild AD. Exercise reduced neuropsychiatric symptoms in patients with mild AD, with possible additional benefits of preserved cognition in a subgroup of patients exercising with high attendance and intensity.

%B J Alzheimers Dis %V 50 %P 443-53 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682695?dopt=Abstract %R 10.3233/JAD-150817 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Modulation of Amyloid-β1-40 Transport by ApoA1 and ApoJ Across an in vitro Model of the Blood-Brain Barrier. %A Merino-Zamorano, Cristina %A Fernández-de Retana, Sofía %A Montañola, Alex %A Batlle, Aina %A Saint-Pol, Julien %A Mysiorek, Caroline %A Gosselet, Fabien %A Montaner, Joan %A Hernández-Guillamon, Mar %X

Amyloid-β (Aβ) accumulation in Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) is likely caused by the impairment of its brain clearance that partly occurs through the blood-brain barrier (BBB). In this context, an in vitro BBB model is a valuable tool for studying the molecular mechanisms that regulate this process. This study assessed brain Aβ elimination across the BBB and its modulation by the natural chaperones Apolipoprotein A1 (ApoA1) and Apolipoprotein J/Clusterin (ApoJ). The model was based on primary cerebral endothelial cells that were cultured on Matrigel-coated Transwells and treated with fluorescently labeled-Aβ1-40 to track its efflux across the BBB, which corresponds to trafficking from the basolateral (brain) to apical (blood) compartments. We observed that the transport of basolateral Aβ1-40 was enhanced when it was complexed to rApoJ, whereas the complex formed with rApoA1 did not influence Aβ1-40 efflux. However, the presence of rApoA1 in the apical compartment was able to mobilize Aβ1-40 from the basolateral side. We also observed that both rApoA1 and rApoJ moderately crossed the monolayer (from blood to brain) through a mechanism involving the LDL receptor-related protein family. In contrast to the increased rApoJ efflux when complexed to Aβ1-40, rApoA1 trafficking was restricted when it was bound to the Aβ peptide. In summary, the present study highlights the role of ApoJ and ApoA1 in the in vitro modulation of Aβ elimination across the BBB.

%B J Alzheimers Dis %V 53 %P 677-91 %8 2016 May 25 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27232214?dopt=Abstract %R 10.3233/JAD-150976 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Monitoring Blood-Brain Barrier Integrity Following Amyloid-β Immunotherapy Using Gadolinium-Enhanced MRI in a PDAPP Mouse Model. %A Blockx, Ines %A Einstein, Steve %A Guns, Pieter-Jan %A Van Audekerke, Johan %A Guglielmetti, Caroline %A Zago, Wagner %A Roose, Dimitri %A Verhoye, Marleen %A Van der Linden, Annemie %A Bard, Frederique %X

BACKGROUND: Amyloid-related imaging abnormalities (ARIA) have been reported with some anti-amyloid-β (Aβ) immunotherapy trials. They are detected with magnetic resonance imaging (MRI) and thought to represent transient accumulation of fluid/edema (ARIA-E) or microhemorrhages (ARIA-H). Although the clinical significance and pathophysiology are unknown, it has been proposed that anti-Aβimmunotherapy may affect blood-brain barrier (BBB) integrity.

OBJECTIVE: To examine vascular integrity in aged (12-16 months) PDAPP and wild type mice (WT), we performed a series of longitudinal in vivo MRI studies.

METHODS: Mice were treated on a weekly basis using anti-Aβimmunotherapy (3D6) and follow up was done longitudinally from 1-12 weeks after treatment. BBB-integrity was assessed using both visual assessment of T1-weighted scans and repeated T1 mapping in combination with gadolinium (Gd-DOTA).

RESULTS: A subset of 3D6 treated PDAPP mice displayed numerous BBB disruptions, whereas WT and saline-treated PDAPP mice showed intact BBB integrity under the conditions tested. In addition, the contrast induced decrease in T1 value was observed in the meningeal and midline area. BBB disruption events occurred early during treatment (between 1 and 5 weeks), were transient, and resolved quickly. Finally, BBB-leakages associated with microhemorrhages were confirmed by Perls'Prussian blue histopathological analysis.

CONCLUSION: Our preclinical findings support the hypothesis that 3D6 leads to transient leakage from amyloid-positive vessels. The current study has provided valuable insights on the time course of vascular alterations during immunization treatment and supports further research in relation to the nature of ARIA and the utility of in vivo repeated T1 MRI as a translational tool.

%B J Alzheimers Dis %V 54 %P 723-35 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567811?dopt=Abstract %R 10.3233/JAD-160023 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Morroniside-Induced PP2A Activation Antagonizes Tau Hyperphosphorylation in a Cellular Model of Neurodegeneration. %A Yang, Cui-cui %A Kuai, Xue-xian %A Gao, Wen-bin %A Yu, Jian-chun %A Wang, Qi %A Li, Lin %A Zhang, Lan %K Analysis of Variance %K Cell Line %K Enzyme Inhibitors %K Gene Expression Regulation %K Glycogen Synthase Kinase 3 beta %K Glycosides %K HEK293 Cells %K Humans %K Neuroblastoma %K Okadaic Acid %K Phosphorylation %K Protein Phosphatase 2 %K RNA, Small Interfering %K tau Proteins %K Transfection %K Tyrosine %X

BACKGROUND: An accumulation of hyperphosphorylated tau in the brain is a hallmark of Alzheimer's disease (AD). Deficits in protein phosphatase 2A (PP2A) are associated with tau hyperphosphorylation in AD.

OBJECTIVE: To investigate the effects of morroniside (MOR), isolated from Cornus officinalis, on tau hyperphosphorylation and its underlying mechanisms related to PP2A.

METHODS: SK-N-SH cells were pretreated with 50-200 μM MOR for 24 h followed by 20 nM okadaic acid (OA) for 6 h. PP2Ac siRNA was transfected into HEK293 cells to determine the direct interaction of MOR with PP2A. Western blotting was used to measure the expression of proteins and enzymes. PP2A activity was measured by molybdenum blue spectrophotometry.

RESULTS: Pretreatment with MOR improved the cellular morphological damage and inhibited tau hyperphosphorylation in SK-N-SH cells induced by OA, a PP2A inhibitor. Moreover, MOR increased PP2A activity, concurrent with a decrease in the expression of demethylated PP2A at Leu309 and phosphorylated PP2A at Tyr307. MOR decreased protein phosphatase methylesterase 1 (PME-1) expression and the ratio of PME-1/leucine carboxyl methyltransferase 1 (LCMT-1). Furthermore, MOR treatment decreased the phosphorylation of Src at Tyr416, which regulates the phosphorylation of PP2A. MOR had no effect on PP2Ac expression and tau hyperphosphorylation in PP2Ac siRNA-transfected cells.

CONCLUSION: MOR attenuated OA-induced tau hyperphosphorylation via PP2A activation, and its mechanism might be related to the regulation of PP2Ac post-translational modification and upstream enzymes such as Src and PME-1.

%B J Alzheimers Dis %V 51 %P 33-44 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836014?dopt=Abstract %R 10.3233/JAD-150728 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Mortality in Mild Cognitive Impairment: A Longitudinal Study in Memory Clinics. %A Connors, Michael H %A Ames, David %A Boundy, Karyn %A Clarnette, Roger %A Kurrle, Sue %A Mander, Alastair %A Ward, John %A Woodward, Michael %A Brodaty, Henry %X

BACKGROUND: Patients with mild cognitive impairment (MCI) are at greater risk of mortality than the general population. Comparatively little research has examined predictors of mortality in MCI and no research has examined whether time-varying variables, such as change in cognition and function, predict survival.

OBJECTIVE: To identify predictors of mortality in patients with MCI.

METHODS: 185 patients with MCI were recruited from nine memory clinics around Australia. Patients completed measures of cognition, function, and neuropsychiatric symptoms over three years. Mortality data were obtained from state registries eight years after baseline.

RESULTS: 55 (30%) patients died within this period. Older age, lower cognitive and functional ability at baseline, and greater decline in functional ability over six months predicted mortality.

CONCLUSION: Easily measurable clinical data predict mortality in patients with MCI. Longitudinal assessment over time can provide additional information about patients' risk.

%B J Alzheimers Dis %V 54 %P 149-55 %8 2016 Jul 27 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472874?dopt=Abstract %R 10.3233/JAD-160148 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Motoric Cognitive Risk Syndrome and Falls Risk: A Multi-Center Study. %A Callisaya, Michele L %A Ayers, Emmeline %A Barzilai, Nir %A Ferrucci, Luigi %A Guralnik, Jack M %A Lipton, Richard B %A Otahal, Petr %A Srikanth, Velandai K %A Verghese, Joe %X

BACKGROUND: The Motoric Cognitive Risk Syndrome (MCR) is characterized by slow gait speed and cognitive complaints.

OBJECTIVES: The objective of this study was to determine if the presence of MCR increases the risk of falls in older people.

METHODS: Individual participant data (n = 6,204) from five longitudinal studies from three countries were used for this analysis. MCR diagnosis was defined as both the presence of objectively measured slow gait speed and subjective cognitive complaints in those without dementia or mobility disability. Falls were prospectively ascertained using phone calls or questionnaires. Log binomial regression was performed to determine if MCR increased the risk of falls separately in each cohort. Random effects meta-analysis was used to pool results from all cohorts.

RESULTS: The mean age of participants was 74.9 (SD 6.8) years and 44% (n = 2728) were male. Overall 33.9% (n = 2104) reported a fall over follow-up. Pooled relative risk of MCR with any falls was RR 1.44 95% CI 1.16, 1.79. The components of MCR, slow gait (RR 1.30 95% CI 1.14, 1.47) and cognitive complaint (RR 1.25, 95% CI 1.07, 1.46) were also associated with an increased risk of any falls. In sub-analyses MCR was associated with any fall independent of previous falls (RR 1.29 95% CI 1.09, 1.53) and with multiple falls (RR 1.77, 95% CI 1.25, 2.51).

CONCLUSION: MCR is associated with an increased risk of falls. The increase in risk was higher than for its individual components. The simplicity of the MCR makes it an attractive falls risk screening tool for the clinic.

%B J Alzheimers Dis %V 53 %P 1043-52 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340851?dopt=Abstract %R 10.3233/JAD-160230 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Multiple Object Test as a Performance Based Tool to Assess Cognitive Driven Activity of Daily Living Function in Parkinson's Disease. %A Glonnegger, Hannah %A Beyle, Aline %A Cerff, Bernhard %A Gräber, Susanne %A Csoti, Ilona %A Berg, Daniela %A Liepelt-Scarfone, Inga %X

BACKGROUND: There is need for multidimensional quantitative assessment of cognitive driven activities of daily living (ADL) functions in Parkinson's disease (PD).

OBJECTIVE: To determine whether there is an ADL profile related to cognitive impairment in PD assessed by the Multiple Object Test (MOT). We assumed MOT performance to be lower in PD patients versus controls and in PD patients with more severe cognitive impairment.

METHODS: 50 PD patients with no cognitive impairment (PD-NC), 54 patients with PD-mild cognitive impairment (PD-MCI), 29 with Parkinson's disease dementia (PDD), and 40 healthy controls (HC) were investigated. Besides comprehensive cognitive testing, the MOT, a performance based test consisting of five routine tasks (e.g., preparing a cup of coffee), was applied. Quantitative (total errors and time) and qualitative (error type) MOT parameters were analyzed.

RESULTS: Total time and number of MOT errors was increased in PD patients compared to controls (p < 0.001). These parameters also differentiated PDD patients from other cognitive groups (p < 0.05). No control subject had ≥ 4 errors in the MOT, but 30% of PD patients, especially PDD, scored above this cut-off. Omission (p < 0.001) and mislocation (p < 0.03) errors were more prominent in PDD than other cognitive groups. Perplexity errors did not differ between PD-MCI and PDD but between PD-NC and PDD (p = 0.01). MOT parameters discriminating between cognitive groups correlated mainly with lower test performance in psychomotor speed and executive function.

CONCLUSION: Performance based testing is promising to identify quantitative and qualitative ADL aspects differentiating between different cognitive groups which might be helpful for an early detection of PDD.

%B J Alzheimers Dis %V 53 %P 1475-84 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392856?dopt=Abstract %R 10.3233/JAD-160173 %0 Journal Article %J J Alzheimers Dis %D 2016 %T National Trends in Outpatient Antihypertensive Prescribing in People with Dementia in the United States. %A Tan, Edwin C K %A Bell, J Simon %A Lu, Christine Y %A Toh, Sengwee %X

OBJECTIVE: The objectives were to investigate national trends in outpatient antihypertensive prescribing in people with dementia in the United States between 2006 and 2012, and to investigate clinical and demographic factors associated with different antihypertensive prescribing patterns.

METHODS: This was an analysis of the National Ambulatory Medical Care Survey (NAMCS) and the outpatient department component of the National Hospital Ambulatory Medical Care Survey (NHAMCS). Outpatient visits by people aged ≥65 years with documented dementia were analyzed. Complex samples multivariate logistic regression was conducted to estimate temporal trends and adjusted odds ratios (AORs) with 95% confidence intervals (CIs) for factors associated with prescribing of antihypertensives, multiple antihypertensives and different antihypertensive classes.

RESULTS: There was a statistically significant increase in the proportion of physician visits by older people with dementia with a documented diagnosis of hypertension from 49.3% (95% CI: 41.3% -57.4%) in 2006 to 55.7% (95% CI: 50.2% -61.2%) in 2012. There were non-significant increases in overall antihypertensive use and the use of multiple antihypertensive classes. Male sex was associated with any antihypertensive use (AOR 1.37, 95% CI 1.02-1.84) and multiple antihypertensive class use (AOR 1.52, 95% CI 1.14-2.04). Black race (AOR 2.04, 95% CI 1.12-3.71) and Midwest residence (AOR 2.03, 95% CI 1.46-2.82) were associated with multiple antihypertensive use.

CONCLUSION: There was an increase in documented hypertension in physician visits by older people with dementia from 2006 to 2012, but minimal increases in overall antihypertensive use. Various demographic and clinical factors were associated with the prescribing of antihypertensives in people with dementia.

%B J Alzheimers Dis %V 54 %P 1425-1435 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589531?dopt=Abstract %R 10.3233/JAD-160470 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer's Disease. %A Spilman, Patricia R %A Corset, Veronique %A Gorostiza, Olivia %A Poksay, Karen S %A Galvan, Veronica %A Zhang, Junli %A Rao, Rammohan %A Peters-Libeu, Clare %A Vincelette, Jon %A McGeehan, Andrew %A Dvorak-Ewell, Melita %A Beyer, Janine %A Campagna, Jesus %A Bankiewicz, Krystof %A Mehlen, Patrick %A John, Varghese %A Bredesen, Dale E %X

Recent studies have shown that inoculation of susceptible mice with amyloid-β (Aβ) peptides accelerates Aβ deposition in the brain, supporting the idea that Aβ may be self-amplifying; however, the exact mechanism is not understood. Here we provide evidence that Aβ may self-amplify, in part, by inhibiting α-secretase ADAM10 (a disintegrin and metalloprotease) cleavage of full-length Aβ precursor protein (FL AβPP) and therefore allow greater β-secretase processing, and that Aβ itself is a substrate for ADAM10. Exposure of primary neuronal cultures from PDAβPP mice to exogenous rat Aβ1- 40 resulted in increased de novo human Aβ1-42 production and exposure of cells to Aβ decreased production of ADAM10 cleavage product soluble AβPPα (sAβPPα). In a cell-free assay, Aβ decreased ADAM10 cleavage of the chimeric substrate MBP-AβPPC125 and Aβ itself was apparently cleaved by the enzyme. The axonal guidance and trophic factor netrin-1, however, reduced the Aβ1- 40-induced Aβ1-42 increase, increased sAβPPα, and reversed the Aβ-induced sAβPPα decrease in vitro. In vivo, induction of netrin-1 expression in PDAβPPSwe/Ind transgenic mice resulted in reductions in both Aβ1-42 and Aβ1- 40, and ICV delivery of netrin-1 to PDAβPPSwe/Ind mice increased sAβPPα, decreased Aβ, and improved working memory. Finally, to support further study of netrin-1's potential as a therapeutic for Alzheimer's disease, pilot gene therapy studies were performed and a netrin mimetic peptide synthesized and tested that, like netrin, can increase sAβPPα and decrease Aβ1-42in vitro. Taken together, these data provide mechanistic insights into Aβ self-amplification and the ability of netrin-1 to disrupt it.

%B J Alzheimers Dis %V 52 %P 223-42 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060954?dopt=Abstract %R 10.3233/JAD-151046 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neurocognitive Deficits Distinguishing Mild Dementia with Lewy Bodies from Mild Alzheimer's Disease are Associated with Parkinsonism. %A Brønnick, Kolbørn %A Breitve, Monica H %A Rongve, Arvid %A Aarsland, Dag %X

BACKGROUND: The cognitive profile of mild dementia with Lewy bodies (DLB) versus mild Alzheimer's disease (AD) has not been extensively studied, and the relation of cognitive deficits to the core diagnostic criteria for DLB (fluctuations, visual hallucinations, and parkinsonism) remains poorly understood.

OBJECTIVE: To compare the cognitive profile in patients with mild DLB to patients with mild AD and investigate the relation between cognitive deficits distinguishing DLB from AD and the core diagnostic features in DLB.

METHODS: Patients with mild dementia were recruited from the southwestern part of Norway and patients diagnosed with probable AD (n = 113) or probable DLB (n = 77) were included. The DLB core diagnostic symptoms were assessed using standardized clinical measures, and standardized neurocognitive tests assessing attention, language, memory, and visuospatial functions were administered. Univariate and multivariate comparisons of cognitive tests were performed, and tests distinguishing between AD and DLB were subjected to correlational analyses with the core diagnostic symptoms.

RESULTS: DLB patients performed worse than AD patients on test of visuoconstruction, but not visual perception and on all tests involving attention and executive functions, except verbal fluency. The multivariate model distinguished between DLB and AD with a sensitivity of 74% and a specificity of 82%. Tests where DLB performed worse than AD were highly correlated with degree of parkinsonism, but not with cognitive fluctuations or visual hallucinations.

CONCLUSIONS: The cognitive profile in mild DLB can be useful in distinguishing AD from DLB. The strong relation between relative deficits in DLB and parkinsonism warrants further studies.

%B J Alzheimers Dis %V 53 %P 1277-85 %8 2016 Jun 30 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372647?dopt=Abstract %R 10.3233/JAD-160294 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations. %A Luis, Elkin %A Ortiz, Alexandra %A Eudave, Luis %A Ortega-Cubero, Sara %A Borroni, Barbara %A van der Zee, Julie %A Gazzina, Stefano %A Caroppo, Paola %A Rubino, Elisa %A D'Agata, Federico %A Le Ber, Isabelle %A Santana, Isabel %A Cunha, Gil %A Almeida, Maria R %A Boutoleau-Bretonnière, Claire %A Hannequin, Didier %A Wallon, David %A Rainero, Innocenzo %A Galimberti, Daniela %A Van Broeckhoven, Christine %A Pastor, María A %A Pastor, Pau %X

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1), among other genes. Rare SQSTM1 gene mutations have been associated with Paget's disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD).

OBJECTIVE: The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction.

METHODS: We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 pathogenic variants (FTD/SQSTM1 mutation carriers; n = 10), compared with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD; n = 20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n = 20). The groups were matched according to current age, disease duration, and gender.

RESULTS: After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres.

CONCLUSIONS: These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineatinga specific gene-linked atrophy pattern.

%B J Alzheimers Dis %V 53 %P 303-13 %8 2016 May 07 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163810?dopt=Abstract %R 10.3233/JAD-160006 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neurophysiological assessment of Alzheimer's disease individuals by a single electroencephalographic marker. %A Lizio, Roberta %A Del Percio, Claudio %A Marzano, Nicola %A Soricelli, Andrea %A Yener, Görsev G %A Başar, Erol %A Mundi, Ciro %A De Rosa, Salvatore %A Triggiani, Antonio Ivano %A Ferri, Raffaele %A Arnaldi, Dario %A Nobili, Flavio Mariano %A Cordone, Susanna %A Lopez, Susanna %A Carducci, Filippo %A Santi, Giulia %A Gesualdo, Loreto %A Rossini, Paolo M %A Cavedo, Enrica %A Mauri, Margherita %A Frisoni, Giovanni B %A Babiloni, Claudio %K Aged %K Alzheimer Disease %K Biomarkers %K Brain Mapping %K Case-Control Studies %K Cognition Disorders %K Electroencephalography %K Female %K Humans %K Italy %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Occipital Lobe %K Rest %K ROC Curve %K Turkey %X

Here we presented a single electroencephalographic (EEG) marker for a neurophysiological assessment of Alzheimer's disease (AD) patients already diagnosed by current guidelines. The ability of the EEG marker to classify 127 AD individuals and 121 matched cognitively intact normal elderly (Nold) individuals was tested. Furthermore, its relationship to AD patients' cognitive status and structural brain integrity was examined. Low-resolution brain electromagnetic tomography (LORETA) freeware estimated cortical sources of resting state eyes-closed EEG rhythms. The EEG marker was defined as the ratio between the activity of parieto-occipital cortical sources of delta (2-4 Hz) and low-frequency alpha (8-10.5 Hz) rhythms. Results showed 77.2% of sensitivity in the recognition of the AD individuals; 65% of specificity in the recognition of the Nold individuals; and 0.75 of area under the receiver-operating characteristic curve. Compared to the AD subgroup with the EEG maker within one standard deviation of the Nold mean (EEG-), the AD subgroup with EEG+ showed lower global cognitive status, as revealed by Mini-Mental State Evaluation score, and more abnormal values of white-matter and cerebrospinal fluid normalized volumes, as revealed by structural magnetic resonance imaging. We posit that cognitive and functional status being equal, AD patients with EEG+ should receive special clinical attention due to a neurophysiological "frailty". EEG+ label can be also used in clinical trials (i) to form homogeneous groups of AD patients diagnosed by current guidelines and (ii) as end-point to evaluate intervention effects.

%B J Alzheimers Dis %V 49 %P 159-77 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444753?dopt=Abstract %R 10.3233/JAD-143042 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neuropsychological Markers of Medial Perirhinal and Entorhinal Cortex Functioning are Impaired Twelve Years Preceding Diagnosis of Alzheimer's Dementia. %A Hirni, Daniela I %A Kivisaari, Sasa L %A Krumm, Sabine %A Monsch, Andreas U %A Berres, Manfred %A Oeksuez, Fatma %A Reinhardt, Julia %A Ulmer, Stephan %A Kressig, Reto W %A Stippich, Christoph %A Taylor, Kirsten I %X

Neurofibrillary pathology in Alzheimer's dementia (AD) is associated with cognitive impairments and cortical thinning, and begins in medial perirhinal cortex (mPRC) before entering entorhinal cortex (ERC). Thus, mPRC dysfunction (e.g., semantic object memory impairments) may predate or accompany ERC (i.e., episodic memory) dysfunction in the preclinical course of typical AD. We developed formulae estimating mPRC and ERC integrity (i.e., cortical thickness) using common neuropsychological tests in 31 healthy individuals and 58 early AD patients. These formulae estimated the longitudinal courses of mPRC and ERC functioning in independent groups of 28 optimally healthy individuals who developed AD (NC-AD) over 2.8-13.4 years and 28 pairwise-matched, stable, healthy individuals (NC-NC). Mixed models demonstrated significantly worse NC-AD than NC-NC estimated mPRC and ERC functioning at the earliest observation, 12 years preceding diagnosis, and a significant decline 4 years preceding the AD diagnosis. These findings demonstrate that specific neuropsychological impairments occur early in the course of preclinical AD and that tasks measuring mPRC functioning may serve as additional, powerful markers of preclinical AD.

%B J Alzheimers Dis %V 52 %P 573-80 %8 2016 Mar 26 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031465?dopt=Abstract %R 10.3233/JAD-150158 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Non Fluent Variant of Primary Progressive Aphasia Due to the Novel GRN g.9543delA(IVS3-2delA) Mutation. %A Cioffi, Sara M G %A Galimberti, Daniela %A Barocco, Federica %A Spallazzi, Marco %A Fenoglio, Chiara %A Serpente, Maria %A Arcaro, Marina %A Gardini, Simona %A Scarpini, Elio %A Caffarra, Paolo %X

Mutations in progranulin gene (GRN) are a common cause of autosomal dominant frontotemporal lobar degeneration syndromes and are associated with a wide phenotypic heterogeneity. The majority of genetic defects in GRN consists of loss-of-function mutations, causing haploinsufficiency, and is associated with extremely low plasma progranulin levels. Herein, we describe a patient who developed language dysfunctions and memory disturbances at 63 years of age. Considering the early onset and the positive family history (sister aged 50 with non-fluent/agrammatic variant of primary progressive aphasia, father with behavioral disturbances in his sixties), a genetic analysis was carried out, showing the presence of a novel mutation [g.9543delA (IVS3-2delA)] in a predicted splicing site of GRN. Her progranulin plasma levels were under the reference threshold, as in her sister, thus supporting the causative role of the new variant. The same genetic mutation was confirmed by sequencing in her sister. Results described enlarge current knowledge on genetic causes of the disease and clinical characteristics of carriers.

%B J Alzheimers Dis %V 54 %P 717-21 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567822?dopt=Abstract %R 10.3233/JAD-160185 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Novel Small Molecule Modulator of Amyloid Pathology. %A Lovell, Mark A %A Lynn, Bert C %A Fister, Shuling %A Bradley-Whitman, Melissa %A Murphy, M Paul %A Beckett, Tina L %A Norris, Christopher M %X

Because traditional approaches to drug development for Alzheimer's disease are becoming increasingly expensive and in many cases disappointingly unsuccessful, alternative approaches are required to shift the paradigm. Following leads from investigations of dihydropyridine calcium channel blockers, we observed unique properties from a class of functionalized naphthyridines and sought to develop these as novel therapeutics that minimize amyloid pathology without the adverse effects associated with current therapeutics. Our data show methyl 2,4-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-1-carboxylate (BNC-1) significantly decreases amyloid burden in a well-established mouse model of amyloid pathology through a unique mechanism mediated by Elk-1, a transcriptional repressor of presenilin-1. Additionally, BNC-1 treatment leads to increased levels of synaptophysin and synapsin, markers of synaptic integrity, but does not adversely impact presenilin-2 or processing of Notch-1, thus avoiding negative off target effects associated with pan-gamma secretase inhibition. Overall, our data show BNC-1 significantly decreases amyloid burden and improves markers of synaptic integrity in a well-established mouse model of amyloid deposition by promoting phosphorylation and activation of Elk-1, a transcriptional repressor of presenilin-1 but not presenilin-2. These data suggest BNC-1 might be a novel, disease-modifying therapeutic that will alter the pathogenesis of Alzheimer's disease.

%B J Alzheimers Dis %V 53 %P 273-87 %8 2016 May 04 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163808?dopt=Abstract %R 10.3233/JAD-151160 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy. %A Sassi, Celeste %A Capozzo, Rosa %A Gibbs, Raphael %A Crews, Cynthia %A Zecca, Chiara %A Arcuti, Simona %A Copetti, Massimiliano %A Barulli, Maria R %A Brescia, Vincenzo %A Singleton, Andrew B %A Logroscino, Giancarlo %X

Heterozygous loss of function mutations in granulin represent a significant cause of frontotemporal lobar degeneration with ubiquitin and TDP-43 inclusions (FTLD-TDP). We report a novel GRN splice site mutation (c.709-2 A>T), segregating with frontotemporal dementia spectrum in a large family from southern Italy. The GRN c.709-2 A>T is predicted to result in the skipping of exon 8, leading to non-sense mediated mRNA decay. Moreover, the PGRN plasma levels in the GRN c.709-2 A>T carriers were significantly lower (24 ng/ml) compared to controls (142.7 ng/ml) or family members non-carriers (82.0 ng/ml) (p-value = 0.005, Kruskal Wallis), suggesting progranulin haploinsufficiency. We do not report any potential pathogenic GRN mutation in a follow-up cohort composed of 6 FTD families and 43 sporadic FTD cases, from the same geographic area. Our study suggests that GRN (c.709-2 A>T) is a novel and likely very rare cause of FTD in this Italian cohort. Finally, in line with previous studies, we show that GRN haploinsufficiency leads to a heterogeneous clinical picture, and plasma progranulin levels may be a reliable tool to identify GRN loss of function mutations. However, given that a) genetic and environmental factors, gender, and age may regulate PGRN plasma levels and b) plasma progranulin levels may not reflect PGRN levels in the central nervous system, we suggest that the measurement of progranulin in the plasma should always be coupled with genetic screening of GRN for mutations.

%B J Alzheimers Dis %V 53 %P 475-85 %8 2016 May 30 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258413?dopt=Abstract %R 10.3233/JAD-151170 %0 Journal Article %J J Alzheimers Dis %D 2016 %T N-truncated Aβ2-X starting with position two in sporadic Alzheimer's disease cases and two Alzheimer mouse models. %A Savastano, Adriana %A Klafki, Hans %A Haußmann, Ute %A Oberstein, Timo Jan %A Muller, Petr %A Wirths, Oliver %A Wiltfang, Jens %A Bayer, Thomas A %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Blotting, Western %K Brain %K Cerebral Amyloid Angiopathy %K Disease Models, Animal %K Female %K Humans %K Male %K Mice %K Mice, Transgenic %K Plaque, Amyloid %X

According to the modified amyloid hypothesis, the key event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid β-peptides (Aβs) in plaques and cerebral blood vessels. Additionally to full-length peptides, a great diversity of N-truncated Aβ variants is derived from the larger amyloid-β protein precursor (AβPP). Vast evidence suggests that Aβx-42 isoforms play an important role in triggering neurodegeneration due to their high abundance, amyloidogenic propensity and toxicity. Although N-truncated Aβ peptides and Aβx-42 species appear to be the crucial players in AD etiology, the Aβ2-X isoforms did not receive much attention yet. The present study is the first to show immunohistochemical evidence of Aβ2-X in cases of AD and its distribution in AβPP/PS1KI and 5XFAD transgenic mouse models using a novel antibody pAB77 that has been developed using Aβ2-14 as antigen. Positive plaques and congophilic amyloid angiopathy (CAA) were observed in AD cases and in both mouse models. While in AD cases, abundant CAA and less pronounced plaque pathology was evident, the two mouse models showed predominantly extracellular Aβ deposits and minor CAA staining. Western blotting and a capillary isoelectric focusing immunoassay demonstrated the high specificity of the antibody pAb77 against Aβ-variants starting with the N-terminal Alanine-2.

%B J Alzheimers Dis %V 49 %P 101-10 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26529393?dopt=Abstract %R 10.3233/JAD-150394 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Nutritional Status is Associated with Faster Cognitive Decline and Worse Functional Impairment in the Progression of Dementia: The Cache County Dementia Progression Study1. %A Sanders, Chelsea %A Behrens, Stephanie %A Schwartz, Sarah %A Wengreen, Heidi %A Corcoran, Chris D %A Lyketsos, Constantine G %A Tschanz, JoAnn T %K Age of Onset %K Aged, 80 and over %K Alzheimer Disease %K Dementia, Vascular %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K Nutritional Status %K Severity of Illness Index %K Sex Factors %K Utah %X

Nutritional status may be a modifiable factor in the progression of dementia. We examined the association of nutritional status and rate of cognitive and functional decline in a U.S. population-based sample. Study design was an observational longitudinal study with annual follow-ups up to 6 years of 292 persons with dementia (72% Alzheimer's disease, 56% female) in Cache County, UT using the Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-sb), and modified Mini Nutritional Assessment (mMNA). mMNA scores declined by approximately 0.50 points/year, suggesting increasing risk for malnutrition. Lower mMNA score predicted faster rate of decline on the MMSE at earlier follow-up times, but slower decline at later follow-up times, whereas higher mMNA scores had the opposite pattern (mMNA by time β= 0.22, p = 0.017; mMNA by time2 β= -0.04, p = 0.04). Lower mMNA score was associated with greater impairment on the CDR-sb over the course of dementia (β= 0.35, p <  0.001). Assessment of malnutrition may be useful in predicting rates of progression in dementia and may provide a target for clinical intervention.

%B J Alzheimers Dis %V 52 %P 33-42 %8 2016 02 27 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967207?dopt=Abstract %R 10.3233/JAD-150528 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Optimization of Statistical Single Subject Analysis of Brain FDG PET for the Prognosis of Mild Cognitive Impairment-to-Alzheimer's Disease Conversion. %A Lange, Catharina %A Suppa, Per %A Frings, Lars %A Brenner, Winfried %A Spies, Lothar %A Buchert, Ralph %K Aged %K Alzheimer Disease %K Area Under Curve %K Brain %K Cognitive Dysfunction %K Disease Progression %K Female %K Fluorodeoxyglucose F18 %K Follow-Up Studies %K Glucose %K Humans %K Image Interpretation, Computer-Assisted %K Male %K Positron-Emission Tomography %K Prognosis %K Radiopharmaceuticals %K ROC Curve %X

BACKGROUND: Positron emission tomography (PET) with the glucose analog F-18-fluorodeoxyglucose (FDG) is widely used in the diagnosis of neurodegenerative diseases. Guidelines recommend voxel-based statistical testing to support visual evaluation of the PET images. However, the performance of voxel-based testing strongly depends on each single preprocessing step involved.

OBJECTIVE: To optimize the processing pipeline of voxel-based testing for the prognosis of dementia in subjects with amnestic mild cognitive impairment (MCI).

METHODS: The study included 108 ADNI MCI subjects grouped as 'stable MCI' (n = 77) or 'MCI-to-AD converter' according to their diagnostic trajectory over 3 years. Thirty-two ADNI normals served as controls. Voxel-based testing was performed with the statistical parametric mapping software (SPM8) starting with default settings. The following modifications were added step-by-step: (i) motion correction, (ii) custom-made FDG template, (iii) different reference regions for intensity scaling, and (iv) smoothing was varied between 8 and 18 mm. The t-sum score for hypometabolism within a predefined AD mask was compared between the different settings using receiver operating characteristic (ROC) analysis with respect to differentiation between 'stable MCI' and 'MCI-to-AD converter'. The area (AUC) under the ROC curve was used as performance measure.

RESULTS: The default setting provided an AUC of 0.728. The modifications of the processing pipeline improved the AUC up to 0.832 (p = 0.046). Improvement of the AUC was confirmed in an independent validation sample of 241 ADNI MCI subjects (p = 0.048).

CONCLUSION: The prognostic value of voxel-based single subject analysis of brain FDG PET in MCI subjects can be improved considerably by optimizing the processing pipeline.

%B J Alzheimers Dis %V 49 %P 945-59 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26577523?dopt=Abstract %R 10.3233/JAD-150814 %0 Journal Article %J J Alzheimers Dis %D 2016 %T An Optimized Combination of Ginger and Peony Root Effectively Inhibits Amyloid-β Accumulation and Amyloid-β-Mediated Pathology in AβPP/PS1 Double-Transgenic Mice. %A Lim, Soonmin %A Choi, Jin Gyu %A Moon, Minho %A Kim, Hyo Geun %A Lee, Wonil %A Bak, Hyoung-Rok %A Sung, Hachang %A Park, Chi Hye %A Kim, Sun Yeou %A Oh, Myung Sook %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Analysis of Variance %K Animals %K Cyclooxygenase 2 %K Disease Models, Animal %K Dose-Response Relationship, Drug %K Ginger %K Glial Fibrillary Acidic Protein %K Humans %K Male %K Mice %K Mice, Transgenic %K Mutation %K Paeonia %K Phytotherapy %K Plant Preparations %K Plaque, Amyloid %K Presenilin-1 %X

The progressive aggregation of amyloid-β protein (Aβ) into senile plaques is a major pathological factor of Alzheimer's disease (AD) and is believed to result in memory impairment. We aimed to investigate the effect of an optimized combination of ginger and peony root (OCGP), a standardized herbal mixture of ginger and peony root, on Aβ accumulation and memory impairment in amyloid-β protein precursor (AβPP)/presenilin 1 (PS1) double-transgenic mice. In an in vitro thioflavin T fluorescence assay, 100 μg/ml OCGP inhibited Aβ accumulation to the same extent as did 10 μM curcumin. Furthermore, AβPP/PS1 double-transgenic mice treated with OCGP (50 or 100 mg/kg/day given orally for 14 weeks) exhibited reduced Aβ plaque accumulation in the hippocampus and lower levels of glial fibrillary acid protein and cyclooxygease-2 expression compared with vehicle-treated controls. These results suggest that OCGP may prevent memory impairment in AD by inhibiting Aβ accumulation and inflammation in the brain.

%B J Alzheimers Dis %V 50 %P 189-200 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639976?dopt=Abstract %R 10.3233/JAD-150839 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Optimized Standard Operating Procedures for the Analysis of Cerebrospinal Fluid Aβ42 and the Ratios of Aβ Isoforms Using Low Protein Binding Tubes. %A Vanderstichele, Hugo Marcel Johan %A Janelidze, Shorena %A Demeyer, Leentje %A Coart, Els %A Stoops, Erik %A Herbst, Victor %A Mauroo, Kimberley %A Brix, Britta %A Hansson, Oskar %X

BACKGROUND: Reduced cerebrospinal fluid (CSF) concentration of amyloid-β1-42 (Aβ1-42) reflects the presence of amyloidopathy in brains of subjects with Alzheimer's disease (AD).

OBJECTIVE: To qualify the use of Aβ1-42/Aβ1-40 for improvement of standard operating procedures (SOP) for measurement of CSF Aβ with a focus on CSF collection, storage, and analysis.

METHODS: Euroimmun ELISAs for CSF Aβ isoforms were used to set up a SOP with respect to recipient properties (low binding, polypropylene), volume of tubes, freeze/thaw cycles, addition of detergents (Triton X-100, Tween-20) in collection or storage tubes or during CSF analysis. Data were analyzed with linear repeated measures and mixed effects models.

RESULTS: Optimization of CSF analysis included a pre-wash of recipients (e.g., tubes, 96-well plates) before sample analysis. Using the Aβ1-42/Aβ1-40 ratio, in contrast to Aβ1-42, eliminated effects of tube type, additional freeze/thaw cycles, or effect of CSF volumes for polypropylene storage tubes. 'Low binding' tubes reduced the loss of Aβ when aliquoting CSF or in function of additional freeze/thaw cycles. Addition of detergent in CSF collection tubes resulted in an almost complete absence of variation in function of collection procedures, but affected the concentration of Aβ isoforms in the immunoassay.

CONCLUSION: The ratio of Aβ1-42/Aβ1-40 is a more robust biomarker than Aβ1-42 toward (pre-) analytical interfering factors. Further, 'low binding' recipients and addition of detergent in collection tubes are able to remove effects of SOP-related confounding factors. Integration of the Aβ1-42/Aβ1-40 ratio and 'low-binding tubes' into guidance criteria may speed up worldwide standardization of CSF biomarker analysis.

%B J Alzheimers Dis %V 53 %P 1121-32 %8 2016 May 31 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258423?dopt=Abstract %R 10.3233/JAD-160286 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Oral Iron Chelator, Deferasirox, Reverses the Age-Dependent Alterations in Iron and Amyloid-β Homeostasis in Rat Brain: Implications in the Therapy of Alzheimer's Disease. %A Banerjee, Priyanjalee %A Sahoo, Arghyadip %A Anand, Shruti %A Bir, Aritri %A Chakrabarti, Sasanka %K Administration, Oral %K Aging %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Benzoates %K Brain %K Ferritins %K Gene Expression Regulation %K Iron %K Iron Chelating Agents %K Neprilysin %K NF-kappa B %K Oxidative Stress %K Peptide Fragments %K Protein Carbonylation %K Rats %K Rats, Wistar %K Receptors, Transferrin %K Spectrophotometry %K Triazoles %X

The altered metabolism of iron impacts the brain function in multiple deleterious ways during normal aging as well as in Alzheimer's disease. We have shown in this study that chelatable iron accumulates in the aged rat brain along with overexpression of transferrin receptor 1 (TfR1) and ferritin, accompanied by significant alterations in amyloid-β (Aβ) peptide homeostasis in the aging brain, such as an increased production of the amyloid-β protein precursor, a decreased level of neprilysin, and increased accumulation of Aβ42. When aged rats are given daily the iron chelator, deferasirox, over a period of more than 4 months starting from the 18th month, the age-related accumulation of iron and overexpression of TfR1 and ferritin in the brain are significantly prevented. More interestingly, the chelator treatment also considerably reverses the altered Aβ peptide metabolism in the aging brain implying a significant role of iron in the latter phenomenon. Further, other results indicate that iron accumulation results in oxidative stress and the activation of NF-κB in the aged rat brain, which are also reversed by the deferasirox treatment. The analysis of the results together suggests that iron accumulation and oxidative stress interact at multiple levels that include transcriptional and post-transcriptional mechanisms to bring about changes in the expression levels of TfR1 and ferritin and also alterations in Aβ peptide metabolism in the aging rat brain. The efficacy of deferasirox in preventing age-related changes in iron and Aβ peptide metabolism in the aging brain, as shown here, has obvious therapeutic implications for Alzheimer's disease.

%B J Alzheimers Dis %V 49 %P 681-93 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484920?dopt=Abstract %R 10.3233/JAD-150514 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Overexpression of Metallothionein-1 Modulates the Phenotype of the Tg2576 Mouse Model of Alzheimer's Disease. %A Manso, Yasmina %A Comes, Gemma %A López-Ramos, Juan C %A Belfiore, Mónica %A Molinero, Amalia %A Giralt, Mercedes %A Carrasco, Javier %A Adlard, Paul A %A Bush, Ashley I %A Delgado-García, José María %A Hidalgo, Juan %K Age Factors %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Anxiety %K Disease Models, Animal %K Exploratory Behavior %K Female %K Gene Expression Regulation %K Humans %K Male %K Matrix Metalloproteinase 16 %K Maze Learning %K Metallothionein %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Motor Activity %K Mutation %K Phenotype %K Psychomotor Disorders %X

Alzheimer's disease (AD) is the most commonly diagnosed dementia, where signs of neuroinflammation and oxidative stress are prominent. In this study we intend to further characterize the roles of the antioxidant, anti-inflammatory, and heavy metal binding protein, metallothionein-1 (MT-1), by crossing Mt1 overexpressing mice with a well-known mouse model of AD, Tg2576 mice, which express the human amyloid-β protein precursor (hAβPP) with the Swedish K670N/M671L mutations. Mt1 overexpression increased overall perinatal survival, but did not affect significantly hAβPP-induced mortality and weight loss in adult mice. Amyloid plaque burden in ∼14-month-old mice was increased by Mt1 overexpression in the hippocampus but not the cortex. Despite full length hAβPP levels and amyloid plaques being increased by Mt1 overexpression in the hippocampus of both sexes, oligomeric and monomeric forms of Aβ, which may contribute more to toxicity, were decreased in the hippocampus of females and increased in males. Several behavioral traits such as exploration, anxiety, and learning were altered in Tg2576 mice to various degrees depending on the age and the sex. Mt1 overexpression ameliorated the effects of hAβPP on exploration in young females, and potentiated those on anxiety in old males, and seemed to improve the rate of spatial learning (Morris water maze) and the learning elicited by a classical conditioning procedure (eye-blink test). These results clearly suggest that MT-1 may be involved in AD pathogenesis.

%B J Alzheimers Dis %V 51 %P 81-95 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836194?dopt=Abstract %R 10.3233/JAD-151025 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Pain Assessment in Elderly with Behavioral and Psychological Symptoms of Dementia. %A Malara, Alba %A De Biase, Giuseppe Andrea %A Bettarini, Francesco %A Ceravolo, Francesco %A Di Cello, Serena %A Garo, Michele %A Praino, Francesco %A Settembrini, Vincenzo %A Sgrò, Giovanni %A Spadea, Fausto %A Rispoli, Vincenzo %K Affect %K Aged, 80 and over %K Analgesics %K Anxiety %K Dementia %K Depression %K Female %K Humans %K Italy %K Logistic Models %K Long-Term Care %K Male %K Multivariate Analysis %K Nursing Homes %K Pain %K Pain Measurement %K Prevalence %K Prospective Studies %K Psychiatric Status Rating Scales %K Self Report %K Severity of Illness Index %X

BACKGROUND: Pain is under-detected and undertreated in people with dementia. The present study investigates the prevalence of pain in people with dementia hospitalized in nursing homes that are members of National Association of Third Age Residences (ANASTE) Calabria, and evaluates the association among pain, mood, and behavioral and psychological symptoms of dementia (BPSD).

OBJECTIVE: The aim of this study is to define the prevalence of pain in people with dementia in long term care facilities using scales of self-reporting and observational tools and, particularly, to study the relationship between pain and BPSD.

METHODS: A prospective observational study was carried out on 233 patients. Pain assessment was performed using self-reporting tools such as the Numeric Rating Scale (NRS) for patients with slight cognitive impairment or no cognitive impairment and observational tools such as Pain Assessment In Advanced Dementia Scale (PAINAD) for patients with moderate or severe cognitive impairment. Mood was evaluated through the Cornell Scale for Depression in Dementia (CSDD) while behavioral problems were assessed through the Cohen-Mansfield Agitation Inventory (CMAI) and Neuropsychiatric Inventory (NPI).

RESULTS: Only 42.5% of patients evaluated by NRS provided a reliable answer; of these, 20.4% reported no pain. The percentage of pain evaluated by PAINAD was 51.8% . Analysis of data showed a statistically significant correlation between diagnosis of pain and depressive symptoms, assessed with CSDD (p = 0.0113), as well as by single items of NPI, such as anxiety (p = 0.0362) and irritability (p = 0.0034), and F1 profile (Aggression) of CMAI (p = 0.01).

CONCLUSION: This study confirms that self-report alone is not sufficient to assess pain in elderly people with dementia; the observational tool is a necessary and suitable way of assessing pain in patients with cognitive impairment. If not adequately treated, chronic pain can cause depression, agitation, and aggression in patients with dementia.

%B J Alzheimers Dis %V 50 %P 1217-25 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757042?dopt=Abstract %R 10.3233/JAD-150808 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Palmomental Reflex a Relevant Sign in Early Alzheimer's Disease Diagnosis? %A Gabelle, Audrey %A Gutierrez, Laure-Anne %A Dartigues, Jean-François %A Ritchie, Karen %A Touchon, Jacques %A Berr, Claudine %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cohort Studies %K Early Diagnosis %K Female %K Follow-Up Studies %K France %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Reflex %X

BACKGROUND: Sophisticated and expensive biomarkers are proposed for the diagnostic of Alzheimer's disease (AD). The amyloid process seems to be early in AD, and brain amyloid load affects the frontal lobe.

OBJECTIVE: To determine if certain simple clinical signs, especially frontal-related signs, could help reach an earlier and better diagnosis.

METHODS: In the frame of the 3-City cohort, we conducted a nested case-control study comparing incident cases of AD to controls matched for age, gender, and education. The standardized neurological exam included extrapyramidal signs (akinesia, rigidity, rest tremor), pyramidal symptoms (spastic rigidity, Babinski reflex), primitive reflexes (snout, palmomental reflex grasping), and tremor (essential, intentional, head) at the time of diagnosis and two years before.

RESULTS: We compared 106 incident AD subjects (mean age at diagnosis 82.2 (SD = 5.9); median MMSE at diagnosis = 23) to 208 matched controls. In patients younger than 80, palmomental reflexes were more frequent in AD than controls, two years before diagnosis (25.0 versus 7.0% , p = 0.03) and at time of diagnosis (30.3 versus 12.3% , p = 0.02). No difference was observed for other signs two years before diagnosis or for patients older than 80.

CONCLUSION: Before diagnosis, the clinical examination of AD patients is not strictly normal; the primitive reflexes appear to be pathological. It might be in connection with the frontal amyloid load at an early stage of the disease. Clinical examination can reveal simple and interesting signs that deserve consideration as well as the other more invasive and expensive biomarkers.

%B J Alzheimers Dis %V 49 %P 1135-41 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639955?dopt=Abstract %R 10.3233/JAD-150436 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Pauses During Autobiographical Discourse Reflect Episodic Memory Processes in Early Alzheimer's Disease. %A Pistono, Aurélie %A Jucla, Mélanie %A Barbeau, Emmanuel J %A Saint-Aubert, Laure %A Lemesle, Béatrice %A Calvet, Benjamin %A Köpke, Barbara %A Puel, Michèle %A Pariente, Jérémie %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid %K Brain %K Female %K Humans %K Male %K Memory Disorders %K Memory, Episodic %K Mental Status Schedule %K Neuropsychological Tests %K Positron-Emission Tomography %K Statistics as Topic %X

There is a large body of research on discourse production in Alzheimer's disease (AD). Some studies have focused on pause production, revealing that patients make extensive use of pauses during speech. This has been attributed to lexical retrieval difficulties, but pausing may also reflect other forms of cognitive impairment as it increases with cognitive load. The aim of the present study was to analyze autobiographical discourse impairment in AD from a broad perspective, looking at pausing behavior (frequency, duration, and location). Our first objective was to characterize discourse changes in mild cognitive impairment (MCI) due to AD. Our second objective was to determine the cognitive and neuroanatomical correlates of these changes. Fifteen patients with MCI due to AD and 15 matched cognitively normal controls underwent an ecological episodic memory task, a full neuropsychological assessment, and a 3D T1-weighted MRI scans. Autobiographical discourse collected from the ecological episodic memory task was recorded, transcribed, and analyzed, focusing on pausing. Intergroup comparisons showed that although patients did not produce more pauses than controls overall, they did make more between-utterance pauses. The number of these specific pauses was positively correlated with patients' episodic memory performance. Furthermore, neuroimaging analysis showed that, in the patient group, their use was negatively correlated with frontopolar area (BA 10) grey matter density. This region may therefore play an important role in the planning of autobiographical discourse production. These findings demonstrate that pauses in early AD may reflect a compensatory mechanism for improving mental time travel and memory retrieval.

%B J Alzheimers Dis %V 50 %P 687-98 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757034?dopt=Abstract %R 10.3233/JAD-150408 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Performance Evaluation of an Automated ELISA System for Alzheimer's Disease Detection in Clinical Routine. %A Chiasserini, Davide %A Biscetti, Leonardo %A Farotti, Lucia %A Eusebi, Paolo %A Salvadori, Nicola %A Lisetti, Viviana %A Baschieri, Francesca %A Chipi, Elena %A Frattini, Giulia %A Stoops, Erik %A Vanderstichele, Hugo %A Calabresi, Paolo %A Parnetti, Lucilla %X

The variability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers undermines their full-fledged introduction into routine diagnostics and clinical trials. Automation may help to increase precision and decrease operator errors, eventually improving the diagnostic performance. Here we evaluated three new CSF immunoassays, EUROIMMUNtrademark amyloid-β 1-40 (Aβ1-40), amyloid-β 1-42 (Aβ1-42), and total tau (t-tau), in combination with automated analysis of the samples. The CSF biomarkers were measured in a cohort consisting of AD patients (n = 28), mild cognitive impairment (MCI, n = 77), and neurological controls (OND, n = 35). MCI patients were evaluated yearly and cognitive functions were assessed by Mini-Mental State Examination. The patients clinically diagnosed with AD and MCI were classified according to the CSF biomarkers profile following NIA-AA criteria and the Erlangen score. Technical evaluation of the immunoassays was performed together with the calculation of their diagnostic performance. Furthermore, the results for EUROIMMUN Aβ1-42 and t-tau were compared to standard immunoassay methods (INNOTESTtrademark). EUROIMMUN assays for Aβ1-42 and t-tau correlated with INNOTEST (r = 0.83, p < 0.001 for both) and allowed a similar interpretation of the CSF profiles. The Aβ1-42/Aβ1-40 ratio measured with EUROIMMUN was the best parameter for AD detection and improved the diagnostic accuracy of Aβ1-42 (area under the curve = 0.93). In MCI patients, the Aβ1-42/Aβ1-40 ratio was associated with cognitive decline and clinical progression to AD.The diagnostic performance of the EUROIMMUN assays with automation is comparable to other currently used methods. The variability of the method and the value of the Aβ1-42/Aβ1-40 ratio in AD diagnosis need to be validated in large multi-center studies.

%B J Alzheimers Dis %V 54 %P 55-67 %8 2016 Jul 22 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27447425?dopt=Abstract %R 10.3233/JAD-160298 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Performance of Hippocampus Volumetry with FSL-FIRST for Prediction of Alzheimer's Disease Dementia in at Risk Subjects with Amnestic Mild Cognitive Impairment. %A Suppa, Per %A Hampel, Harald %A Kepp, Timo %A Lange, Catharina %A Spies, Lothar %A Fiebach, Jochen B %A Dubois, Bruno %A Buchert, Ralph %K Aged %K Aging %K Alzheimer Disease %K Area Under Curve %K Cognitive Dysfunction %K Databases, Factual %K Disease Progression %K Hippocampus %K Humans %K Image Interpretation, Computer-Assisted %K Magnetic Resonance Imaging %K Neuropsychological Tests %K Organ Size %K Pattern Recognition, Automated %K Prognosis %K Reproducibility of Results %K Risk %K ROC Curve %K Sensitivity and Specificity %K Time Factors %X

MRI-based hippocampus volume, a core feasible biomarker of Alzheimer's disease (AD), is not yet widely used in clinical patient care, partly due to lack of validation of software tools for hippocampal volumetry that are compatible with routine workflow. Here, we evaluate fully-automated and computationally efficient hippocampal volumetry with FSL-FIRST for prediction of AD dementia (ADD) in subjects with amnestic mild cognitive impairment (aMCI) from phase 1 of the Alzheimer's Disease Neuroimaging Initiative. Receiver operating characteristic analysis of FSL-FIRST hippocampal volume (corrected for head size and age) revealed an area under the curve of 0.79, 0.70, and 0.70 for prediction of aMCI-to-ADD conversion within 12, 24, or 36 months, respectively. Thus, FSL-FIRST provides about the same power for prediction of progression to ADD in aMCI as other volumetry methods.

%B J Alzheimers Dis %V 51 %P 867-73 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923010?dopt=Abstract %R 10.3233/JAD-150804 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Performance on Specific Cognitive Domains and Cause of Death: A Prospective Population-Based Study in Non-Demented Older Adults (NEDICES). %A Benito-León, Julián %A Contador, Israel %A Mitchell, Alex J %A Domingo-Santos, Ángela %A Bermejo-Pareja, Félix %K Aged %K Cause of Death %K Cerebrovascular Disorders %K Cognitive Aging %K Dementia %K Educational Status %K Female %K Follow-Up Studies %K Humans %K Intelligence %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Prospective Studies %K Risk %K Spain %X

Evidence regarding the relationship between performance on specific cognitive domains and cause of death is scarce. We assessed whether specific cognitive domains predicted mortality and the presence of any association with specific causes of death in a population-dwelling sample of non-demented older adults. In this population-based, prospective study (NEDICES), 2,390 non-demented subjects ≥65 years completed a brief neuropsychological battery. Cox's proportional hazards models, adjusted by sociodemographic and comorbidity factors, global cognitive performance, educational level, and premorbid intelligence were used to assess the risk of death. Participants were followed for a median of 9.2 years (range 0.01-10.7), after which the death certificates of those who died were examined. 880 (36.8%) of 2,390 participants died over a median follow-up of 5.5 years (range 0.01-10.5). Using adjusted Cox regression models, we found that hazard ratios for mortality in participants within the lowest tertiles (worse performance) were 1.31 (speed of cognitive processing, p = 0.03); 1.22 (semantic fluency, p = 0.04), 1.32 (delayed free recall, p = 0.003), and 1.23 (delayed logical memory, p = 0.03). Poor performance on delayed recall and speed of cognitive processing tests were associated with dementia and cerebrovascular disease mortality, respectively. Further, poor performance on semantic fluency was associated with decreased cancer mortality. In this study of community dwelling non-demented older adults, worse neuropsychological performance was associated with increased risk of mortality. Performance on specific cognitive domains were related to different causes of death. Of particular note there appears to be an inverse association between poor semantic fluency and cancer mortality.

%B J Alzheimers Dis %V 51 %P 533-44 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890757?dopt=Abstract %R 10.3233/JAD-150875 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Perlecan Domain V Inhibits Amyloid-β Induced Activation of the α2β1 Integrin-Mediated Neurotoxic Signaling Cascade. %A Parham, Christi L %A Shaw, Courtney %A Auckland, Lisa D %A Dickeson, S Kent %A Griswold-Prenner, Irene %A Bix, Gregory %X

Alzheimer's disease (AD) is characterized by neuronal death, neurofibrillary tangles, and senile plaques. Amyloid-beta (Aβ) is the major component of plaques and consists of two prominent isoforms, Aβ40 and Aβ42. As many risk factors for AD are vascular in origin and blood vessel defects in clearing Aβ from the brain are a potential key component of AD pathology, we have focused on the neuron-blood vessel interface, and in particular, the vascular basement membrane, which coats blood vessels and physically separates them from neurons. A prominent component of the vascular basement membrane is the extracellular matrix proteoglycan perlecan. Domain V (DV) is the C-terminal domain and is generated by perlecan proteolysis. DV interacts with the α2 integrin and Aβ is a ligand for both α2β1 and αvβ1. Due to the known interaction of DV with α2β1 and α2β1's requirement for Aβ deposition and neurotoxicity, we hypothesized that DV and/or its C-terminal domain, LG3, might alter neurotoxic signaling pathways by directly blocking or otherwise interfering with α2β1 binding by Aβ. Our study suggests that α2β1 mediates Aβ-induced activation of c-Jun and caspase-3, key components of the neurotoxic pathway, in primary cortical and hippocampal neurons. We further demonstrate that DV and/or LG3 may therapeutically modulate these α2β1 mediated neurotoxic effects suggesting that they or other α2β1 integrin modulators could represent a novel approach to treat AD. Finally, our results suggest different neurotoxicity susceptibilities between cortical and hippocampal neurons to Aβ40 and Aβ42 as further underscored by differing neuroprotective potencies of LG3 in each cell type.

%B J Alzheimers Dis %V 54 %P 1629-1647 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636841?dopt=Abstract %R 10.3233/JAD-160290 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Pharmacological Agents Targeting γ-Secretase Increase Risk of Cancer and Cognitive Decline in Alzheimer's Disease Patients: A Systematic Review and Meta-Analysis. %A Penninkilampi, Ross %A Brothers, Holly M %A Eslick, Guy D %X

BACKGROUND: Drugs targeting γ-secretase in Alzheimer's disease (AD) have failed to demonstrate efficacy in clinical trials.

OBJECTIVE: To perform a meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of drugs targeting γ-secretase in AD.

METHODS: Ten trials were identified involving 5,227 patients using electronic databases and manual review of reference lists. RCTs of at least two weeks duration involving a drug targeting γ-secretase were eligible. The main outcomes examined were adverse events and cognitive measures (ADAS-cog, MMSE, ADCS-ADL, and CDR-sb). A sub-group analysis was performed, excluding the γ-secretase modulator tarenflurbil, to evaluate the safety and efficacy of γ-secretase inhibitors only.

RESULTS: There was an increased risk of adverse events (Odds Ratio (OR) 1.38, 95% CI 1.09-1.73; p = 0.01), serious adverse events (OR 1.50, 95% CI 1.22-1.84; p < 0.001), and skin cancers (OR 4.77, 95% CI 2.83-8.06; p < 0.001). There was significantly increased risk of infections (OR 1.36, 95% CI 1.13-1.63; p < 0.001) in the subgroup analysis excluding tarenflurbil. Pooled results also revealed a worsening in ADAS-cog (difference in means 1.33, 95% CI 0.58-2.08; p < 0.001) and MMSE (difference in means -0.66, 95% CI -0.96 to 0.35; p < 0.001), but not ADCS-ADL or CDR-sb.

CONCLUSION: The use of γ-secretase inhibitors is associated with significantly increased risk of serious adverse events including skin cancers, and worsening in cognitive indicators. This evidence indicates that γ-secretase may not be an appropriate target for clinical treatment of AD.

%B J Alzheimers Dis %V 53 %P 1395-404 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392862?dopt=Abstract %R 10.3233/JAD-160275 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Safety, Pharmacokinetics, and Biomarker Results of Subcutaneous Bapineuzumab in Patients with mild to moderate Alzheimer's disease. %A Brody, Mark %A Liu, Enchi %A Di, Jianing %A Lu, Ming %A Margolin, Richard A %A Werth, John L %A Booth, Kevin %A Shadman, Anna %A Brashear, H Robert %A Novak, Gerald %X

BACKGROUND: Bapineuzumab, a humanized monoclonal antibody, targets amyloid-β (Aβ1-40/1 -42) that is believed to play a key role in the pathogenesis of Alzheimer disease (AD).

OBJECTIVES: To assess the effects of monthly subcutaneous (SC) bapineuzumab versus placebo on cerebral amyloid signal in amyloid-positive patients with mild to moderate AD. The incidence of amyloid-related imaging abnormalities-edema/effusion (ARIA-E), pharmacokinetics, pharmacodynamics, immunogenicity, and other safety aspects of bapineuzumab were also evaluated.

METHODS: In this multicenter, double-blind study, 146 patients were randomized (1 : 1:1 : 1) to SC bapineuzumab 2, 7, or 20 mg/month or placebo. Lack of efficacy of intravenous (IV) bapineuzumab in Phase III studies led to truncation of the treatment duration from 24 months to 12 months. Primary endpoint: change from baseline to month 12 in brain amyloid signal as measured by standardized uptake value ratio (SUVR) using florbetapir positron emission tomography (PET).

RESULTS: Florbetapir PET SUVR decreased significantly (p = 0.038) from baseline to month 12 for the bapineuzumab 7 mg/month group only; reductions versus placebo were not significant for any dosage. One patient each in bapineuzumab 2 mg/month and 20 mg/month groups had ARIA-E. The percentages of patients with treatment-emergent adverse events were similar in placebo (77.8%) and bapineuzumab 2 mg/month (78.4%) group, but higher in 7 mg/month (94.4%) and 20 mg/month (89.2%) groups.

CONCLUSION: Bapineuzumab SC once-monthly did not demonstrate significant treatment difference over placebo on cerebral amyloid signal at one year but was well-tolerated. There was less ARIA-E than had been expected based on prior experience with comparable exposure on IV bapineuzumab.

%B J Alzheimers Dis %V 54 %P 1509-1519 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589523?dopt=Abstract %R 10.3233/JAD-160369 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease. %A Lozano, Andres M %A Fosdick, Lisa %A Chakravarty, M Mallar %A Leoutsakos, Jeannie-Marie %A Munro, Cynthia %A Oh, Esther %A Drake, Kristen E %A Lyman, Christopher H %A Rosenberg, Paul B %A Anderson, William S %A Tang-Wai, David F %A Pendergrass, Jo Cara %A Salloway, Stephen %A Asaad, Wael F %A Ponce, Francisco A %A Burke, Anna %A Sabbagh, Marwan %A Wolk, David A %A Baltuch, Gordon %A Okun, Michael S %A Foote, Kelly D %A McAndrews, Mary Pat %A Giacobbe, Peter %A Targum, Steven D %A Lyketsos, Constantine G %A Smith, Gwenn S %X

BACKGROUND: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown.

OBJECTIVE: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer's disease (AD).

METHODS: We evaluated active "on" versus sham "off" bilateral DBS directed at the fornix-a major fiber bundle in the brain's memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation.

RESULTS: Surgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the "on" versus "off" stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients 

CONCLUSION: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation.

%B J Alzheimers Dis %V 54 %P 777-87 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567810?dopt=Abstract %R 10.3233/JAD-160017 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Phase IIa Randomized Control Trial of VEL015 (Sodium Selenate) in Mild-Moderate Alzheimer's Disease. %A Malpas, Charles B %A Vivash, Lucy %A Genc, Sila %A Saling, Michael M %A Desmond, Patricia %A Steward, Christopher %A Hicks, Rodney J %A Callahan, Jason %A Brodtmann, Amy %A Collins, Steven %A Macfarlane, Stephen %A Corcoran, Niall M %A Hovens, Christopher M %A Velakoulis, Dennis %A O'Brien, Terence J %X

BACKGROUND: There is increasing interest in targeting hyperphosphorylated tau (h-tau) as a disease modifying approach for Alzheimer's disease (AD). Sodium selenate directly stimulates the activity of PP2A, the main enzyme responsible for h-tau dephosphorylation in the brain.

OBJECTIVE: This study assessed the safety and tolerability of 24-week treatment with VEL015 (sodium selenate) in AD. Investigating the effects of VEL015 on cognitive, CSF, and neuroimaging biomarkers of AD were secondary, exploratory objectives. Data were used to identify biomarkers showing most promise for use in subsequent efficacy trials.

METHODS: A 24-week, multicenter, Phase IIa, double-blinded randomized controlled trial. Forty patients aged ≥55 y with mild-moderate AD (MMSE 14-26) were randomized to supranutritional (VEL015 10 mg tds [n = 20]) and control (VEL015 320μg tds [n = 10] or placebo [n = 10]) groups. Patients were regularly monitored for safety, adverse events (AEs), and protocol compliance. Exploratory biomarkers included cognitive tests, neuroimaging (diffusion MR), and CSF (p-tau, t-tau, and Aβ1-42).

RESULTS: Thirty-six (90%; [supranutritional n = 18, control/placebo n = 18]) patients completed the trial. There were no differences in the incidence of specific AEs between groups. Only one secondary biomarker, diffusion MR measures, showed group differences, with less deterioration in the supranutritional group (p < 0.05).

CONCLUSION: Treatment with VEL015 at doses up to 30 mg per day for 24 weeks was safe and well-tolerated in patients with AD. Diffusion MR measures appear to be the most sensitive biomarkers to assess disease progression over 24 weeks.

%B J Alzheimers Dis %V 54 %P 223-32 %8 2016 Jul 22 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27447428?dopt=Abstract %R 10.3233/JAD-160544 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Physical and Cognitive Stimulation Using an Exergame in Subjects with Normal Aging, Mild and Moderate Cognitive Impairment. %A Ben-Sadoun, Grégory %A Sacco, Guillaume %A Manera, Valeria %A Bourgeois, Jérémy %A König, Alexandra %A Foulon, Pierre %A Fosty, Baptiste %A Bremond, François %A d'Arripe-Longueville, Fabienne %A Robert, Philippe %X

BACKGROUND: The use of Serious exerGames (SeG) as enriched environments (EE), which promotes cognitive simulation with physical activity in a positive emotional context, has been proposed to represent a powerful method to slow down the decline due to neurodegenerative diseases (ND), such as Alzheimer's disease (AD). However, so far, no SeG targeting EE has been tested in ND subjects.

OBJECTIVE: This study aimed at evaluating the usability and short-term training effects of X-Torp, an action SeG designed for elderly ND subjects with mild cognitive impairment (MCI) and AD.

METHODS: X-Torp is a SeG played using the Microsoft® Kinect™. 10 ND subjects and 8 healthy elderly controls (HEC) were enrolled in a 1-month program with three training sessions per week. Usability was evaluated through game time, game performance, the aerobic intensity level reached, perceived emotions, and perceived usability.

RESULTS: All participants successfully completed the training program. ND subjects played less and had a lower game performance compared to HEC. During the sessions, ND subjects maintained a light intensity of aerobic activity, while HEC maintained a moderate intensity. Both groups experienced only positive emotions, and reported a 'moderate' to 'high' perceived competence, a 'moderate' game difficulty, and a 'high' interest in the game.

CONCLUSION: Usability results suggest that X-Torp represents a usable EE for healthy subjects and persons with MCI and AD. However, in order to reach moderate or high intensity of aerobic activity, X-Torp control modes should be adapted to become more physically stimulating.

%B J Alzheimers Dis %V 53 %P 1299-314 %8 2016 Jun 30 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372645?dopt=Abstract %R 10.3233/JAD-160268 %0 Journal Article %J J Alzheimers Dis %D 2016 %T PiB-PET Imaging-Based Serum Proteome Profiles Predict Mild Cognitive Impairment and Alzheimer's Disease. %A Kang, Seokjo %A Jeong, Hyobin %A Baek, Je-Hyun %A Lee, Seung-Jin %A Han, Sun-Ho %A Cho, Hyun Jin %A Kim, Hee %A Hong, Hyun Seok %A Kim, Young Ho %A Yi, Eugene C %A Seo, Sang Won %A Na, Duk L %A Hwang, Daehee %A Mook-Jung, Inhee %X

Development of a simple, non-invasive early diagnosis platform of Alzheimer's disease (AD) using blood is urgently required. Recently, PiB-PET imaging has been shown to be powerful to quantify amyloid-β plaque loads leading to pathophysiological alterations in AD brains. Thus, there has been a need for serum biomarkers reflecting PiB-PET imaging data as an early diagnosis platform of AD. Here, using LC-MS/MS analysis coupled with isobaric tagging, we performed comprehensive proteome profiling of serum samples from cognitively normal controls, mild cognitive impairment (MCI), and AD patients, who were selected using PiB-PET imaging. Comparative analysis of the proteomes revealed 79 and 72 differentially expressed proteins in MCI and AD, respectively, compared to controls. Integrated analysis of these proteins with genomic and proteomic data of AD brain tissues, together with network analysis, identified three biomarker candidates representing the altered proteolysis-related process in MCI or AD: proprotein convertase subtilisin/kexin type 9 (PCSK9), coagulation factor XIII, A1 polypeptide (F13A1), and dermcidin (DCD). In independent serum samples of MCI and AD, we confirmed the elevation of the candidates using western blotting and ELISA. Our results suggest that these biomarker candidates can serve as a potential non-invasive early diagnosis platform reflecting PiB-PET imaging for MCI and AD.

%B J Alzheimers Dis %V 53 %P 1563-76 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392853?dopt=Abstract %R 10.3233/JAD-160025 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Pilot Study Measuring Aluminum in Bone in Alzheimer's Disease and control Subjects Using in vivo Neutron Activation Analysis. %A Mohseni, Hedieh K %A Cowan, David %A Chettle, David R %A Milić, Ana Pejović %A Priest, Nicholas %A Matysiak, Witold %A Atanackovic, Jovica %A Byun, Soo Hyun %A Prestwich, William V %X

Aluminum, being the most abundant metal in the earth's crust, is widely distributed in the environment, and is routinely taken up by the human body through ingestion and inhalation. Aluminum is not considered an essential element and it can be toxic in high concentrations. Most of the body burden of aluminum is stored in the bones. Aluminum has been postulated to be involved in the causality of Alzheimer's disease. A system for non-invasive measurement of bone aluminum using the in vivo neutron activation analysis technique has been developed and previously reported in the literature by our group. The results are reported as ratio of Al to Ca in order to eliminate the variations in beam parameters and geometry as well as the physical variations among the subjects such as size of the hand and bone structure. This pilot study included 30 subjects, 15 diagnosed with Alzheimer's disease in mild and moderate stages and 15 control subjects, all of whom were 60 years of age or older. The mean value of aluminum for the control group was 2.7±8.2μg Al/g Ca (inverse-variance weighted mean 3.5±0.9μg Al/g Ca) and for the Alzheimer's disease subjects was 12.5±13.1μg Al/g Ca (inverse-variance weighted mean 7.6±0.6μg Al/g Ca). The difference between the mean of the Alzheimer's disease group and the mean of the control group was 9.8±15.9μg Al/g Ca, with a p-value of 0.02. An age-dependent linear increase in bone aluminum concentration was observed for all subjects. The difference in serum aluminum levels between the two groups did not reach significance.

%B J Alzheimers Dis %V 53 %P 933-42 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340850?dopt=Abstract %R 10.3233/JAD-160194 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Plasma Phospholipid and Sphingolipid Alterations in Presenilin1 Mutation Carriers: A Pilot Study. %A Chatterjee, Pratishtha %A Lim, Wei L F %A Shui, Guanghou %A Gupta, Veer B %A James, Ian %A Fagan, Anne M %A Xiong, Chengjie %A Sohrabi, Hamid R %A Taddei, Kevin %A Brown, Belinda M %A Benzinger, Tammie %A Masters, Colin %A Snowden, Stuart G %A Wenk, Marcus R %A Bateman, Randall J %A Morris, John C %A Martins, Ralph N %K Adult %K Alzheimer Disease %K Apolipoproteins E %K Female %K Humans %K Linear Models %K Male %K Middle Aged %K Mutation %K Phospholipids %K Pilot Projects %K Presenilin-1 %K Sphingolipids %X

BACKGROUND AND OBJECTIVE: Aberrant lipid metabolism has been implicated in sporadic Alzheimer's disease (AD). The current study investigated plasma phospholipid and sphingolipid profiles in individuals carrying PSEN1 mutations responsible for autosomal dominant AD (ADAD).

METHODS: Study participants evaluated were from the Perth and Melbourne sites of the Dominantly Inherited Alzheimer Network (DIAN) study. Plasma phospholipid and sphingolipid profiles were measured using liquid chromatography coupled with mass spectrometry in 20 PSEN1 mutation carriers (MC; eight of whom were symptomatic and twelve asymptomatic, based on Clinical Dementia Rating scores) and compared with six non carriers (NC) using linear mixed models. Further, AD gold standard biomarker data obtained from the DIAN database were correlated with lipid species significantly altered between MC and NC, using Spearman's correlation coefficient.

RESULTS: One-hundred and thirty-nine plasma phospholipid and sphingolipid species were measured. Significantly altered species in MC compared to NC primarily belonged to choline and ethanolamine containing phospholipid classes and ceramides. Further phosphatidylcholine species (34:6, 36:5, 40:6) correlated with cerebrospinal fluid tau (p <  0.05), and plasmalogen ethanolamine species (34:2, 36:,4) correlated with both cerebrospinal fluid tau and brain amyloid load within the MC group (p <  0.05).

CONCLUSION: These findings indicate altered phospholipid and sphingolipid metabolism in ADAD and provide insight into the pathomolecular changes occurring with ADAD pathogenesis. Further, findings reported in this study allow comparison of lipid alterations in ADAD with those reported previously in sporadic AD. The findings observed in the current pilot study warrant validation in the larger DIAN cohort.

%B J Alzheimers Dis %V 50 %P 887-94 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836186?dopt=Abstract %R 10.3233/JAD-150948 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Plasma Screening for Progranulin Mutations in Patients with Progressive Supranuclear Palsy and Corticobasal Syndromes. %A Galimberti, Daniela %A Bertram, Kelly %A Formica, Alessandra %A Fenoglio, Chiara %A Cioffi, Sara M G %A Arighi, Andrea %A Scarpini, Elio %A Colosimo, Carlo %X

Progranulin gene (GRN) mutations are characterized by heterogeneous presentations. Corticobasal syndrome (CBS) is often associated with GRN mutations, whereas association with progressive supranuclear palsy syndrome (PSPS) is rare. Plasma progranulin levels were evaluated in 34 patients, including 19 with PSPS, 12 with CBS, and 3 with mixed signs, with the purpose to screen for the presence of causal mutations, associated with low levels. We found undetectable levels in a patient with CBS. Sequencing confirmed the presence of the Thr272fs deletion. Progranulin mutation screening is suggested in cases of CBS, even in the absence of positive family history for dementia and/or movement disorders.

%B J Alzheimers Dis %V 53 %P 445-9 %8 2016 May 04 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163816?dopt=Abstract %R 10.3233/JAD-160073 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Platelet Membrane β-Secretase Activity in Mild Cognitive Impairment and Conversion to Dementia: a Longitudinal Study. %A McGuinness, Bernadette %A Fuchs, Marc %A Barrett, Suzanne L %A Passmore, A Peter %A Johnston, Janet A %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid Precursor Protein Secretases %K Biomarkers %K Blood Platelets %K Cholesterol %K Cognitive Dysfunction %K Cross-Sectional Studies %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Neuropsychological Tests %K Sensitivity and Specificity %X

A blood-based biomarker to complement the clinical and neuropsychological assessments used to evaluate the risk of individuals with mild cognitive impairment (MCI) developing Alzheimer's disease (AD) would be invaluable. Previous pilot studies by our group identified elevated platelet membrane β-secretase activity in patients with AD and MCI, as compared to controls, and this activity was influenced by membrane cholesterol levels. The present study investigated baseline platelet membrane β-secretase activity and cholesterol levels in 97 MCI participants and 85 controls and explored whether these parameters differed in individuals with stable MCI, as compared to those who subsequently developed AD. To evaluate signal specificity, β-secretase activity assays were conducted in the presence and absence of beta-site amyloid-β protein precursor-cleaving enzyme (BACE) inhibitors. Baseline platelet membrane β-secretase activity did not differ significantly in MCI participants, as compared to controls, and platelet membrane cholesterol levels were significantly lower in the MCI group. The longitudinal study indicated that the activities inhibited by two different BACE inhibitors did not predict conversion to AD; however, the activity that was not affected by BACE inhibitors was significantly (40%) higher in individuals with stable MCI, as compared with those who subsequently developed AD. These findings indicated that further research into the source of this activity could contribute to a measure facilitating prediction of the risk of conversion from MCI to AD.

%B J Alzheimers Dis %V 49 %P 1095-103 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639974?dopt=Abstract %R 10.3233/JAD-150795 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Polyphenol Oleuropein Aglycone Modulates the PARP1-SIRT1 Interplay: An In Vitro and In Vivo Study. %A Luccarini, Ilaria %A Pantano, Daniela %A Nardiello, Pamela %A Cavone, Leonardo %A Lapucci, Andrea %A Miceli, Caterina %A Nediani, Chiara %A Berti, Andrea %A Stefani, Massimo %A Casamenti, Fiorella %X

Poly(ADP-ribose) polymerase-1 (PARP1) activation contributes to the cascade of events initiated by amyloid-β (Aβ) peptide eventually leading to cell death in Alzheimer's disease brain. A significant accumulation of PAR polymers and increase of PARP1 expression were detected in the cortex at the early (3.5 months) and intermediate (6 months) stage of Aβ deposition in the TgCRND8 mouse model. Our previous data highlighted the beneficial effects of oleuropein aglycone (OLE), the main polyphenol found in the olive oil, against neurodegeneration both in cultured cells and in model organisms. Here we found that 8-week OLE treatment (50 mg/kg of diet) to 6-month-old TgCRND8 mice rescued to control values PARP1 activation and the levels of its product, PAR. In N2a neuroblastoma cells, PARP1 activation and PAR formation upon exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were abolished by pretreatment for 24 h with either OLE (100μM) or PARP inhibitors. A significant reduction of the NAD+ content, compared to controls, was found in N2a cells exposed to MNNG (100μM) for 90 min; the latter was slightly attenuated by cell treatment for 24 h with PJ-34 or with OLE. In vitro and in vivo, the OLE-induced reduction of PARP1 activation was paralleled by the overexpression of Sirtuin1 (SIRT1), and, in vivo, by a decrease of NF-κB and the pro-apoptotic marker p53. In N2a cells, we also found that OLE potentiates the MNNG-induced increase of Beclin1 levels. In conclusion, our data show that OLE treatment counteracts neuronal damage through modulation of the PARP1-SIRT1 interplay.

%B J Alzheimers Dis %V 54 %P 737-50 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567859?dopt=Abstract %R 10.3233/JAD-160471 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Postmortem Adult Human Microglia Proliferate in Culture to High Passage and Maintain Their Response to Amyloid-β. %A Guo, Ling %A Rezvanian, Aras %A Kukreja, Lokesh %A Hoveydai, Ramez %A Bigio, Eileen H %A Mesulam, M-Marsel %A El Khoury, Joseph %A Geula, Changiz %X

Microglia are immune cells of the brain that display a range of functions. Most of our knowledge about microglia biology and function is based on cells from the rodent brain. Species variation in the complexity of the brain and differences in microglia response in the primate when compared with the rodent, require use of adult human microglia in studies of microglia biology. While methods exist for isolation of microglia from postmortem human brains, none allow culturing cells to high passage. Thus cells from the same case could not be used in parallel studies and multiple conditions. Here we report a method, which includes use of growth factors such as granulocyte macrophage colony stimulating factor, for successful culturing of adult human microglia from postmortem human brains up to 28 passages without significant loss of proliferation. Such cultures maintained their phenotype, including uptake of the scavenger receptor ligand acetylated low density lipoprotein and response to the amyloid-β peptide, and were used to extend in vivo studies in the primate brain demonstrating that inhibition of microglia activation protects neurons from amyloid-β toxicity. Significantly, microglia cultured from brains with pathologically confirmed Alzheimer's disease displayed the same characteristics as microglia cultured from normal aged brains. The method described here provides the scientific community with a new and reliable tool for mechanistic studies of human microglia function in health from childhood to old age, and in disease, enhancing the relevance of the findings to the human brain and neurodegenerative conditions.

%B J Alzheimers Dis %V 54 %P 1157-1167 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567845?dopt=Abstract %R 10.3233/JAD-160394 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Potentially Inappropriate Prescribing Among People with Dementia in Primary Care: A Retrospective Cross-Sectional Study Using the Enhanced Prescribing Database. %A Barry, Heather E %A Cooper, Janine A %A Ryan, Cristín %A Passmore, A Peter %A Robinson, A Louise %A Molloy, Gerard J %A Darcy, Carmel M %A Buchanan, Hilary %A Hughes, Carmel M %X

BACKGROUND: Little is known about prescribing appropriateness for community-dwelling people with dementia (PWD).

OBJECTIVE: To estimate potentially inappropriate prescribing (PIP) prevalence among PWD in primary care in Northern Ireland, and to investigate associations between PIP, polypharmacy, age, and gender.

METHODS: A retrospective cross-sectional study was conducted, using data from the Enhanced Prescribing Database. Patients were eligible if a medicine indicated for dementia management was dispensed to them during 1 January 2013-31 December 2013. Polypharmacy was indicated by use of ≥4 repeat medications from different drug groups. A subset of the Screening Tool of Older Persons Potentially Inappropriate Prescriptions (STOPP) criteria, comprising 36 indicators, was applied to the dataset. Overall prevalence of PIP and the prevalence per each STOPP criterion was calculated as a proportion of all eligible persons in the dataset. Logistic regression was used to investigate associations between PIP, polypharmacy, age, and gender.

RESULTS: The study population comprised 6826 patients. Polypharmacy was observed in 81.5% (n = 5564) of patients. PIP prevalence during the study period was 64.4% (95% CI 63.2- 65.5; n = 4393). The most common instance of PIP was the use of anticholinergic/antimuscarinic medications (25.2%; 95% CI 24.2-26.2; n = 1718). In multivariable analyses, both polypharmacy and gender (being female) were associated with PIP, with odds ratios of 7.6 (95% CI 6.6-8.7) and 1.3 (95% CI 1.2-1.4), respectively. No association was observed between PIP and age, after adjustments for gender and polypharmacy.

CONCLUSION: This study identified a high prevalence of PIP in community-dwelling PWD. Future interventions may need to focus on certain therapeutic categories and polypharmacy.

%B J Alzheimers Dis %V 52 %P 1503-13 %8 2016 Apr 11 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079714?dopt=Abstract %R 10.3233/JAD-151177 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Predictive Value of Cerebrospinal Fluid Visinin-Like Protein-1 Levels for Alzheimer's Disease Early Detection and Differential Diagnosis in Patients with Mild Cognitive Impairment. %A Babić Leko, Mirjana %A Borovečki, Fran %A Dejanović, Nenad %A Hof, Patrick R %A Šimić, Goran %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognitive Dysfunction %K Diagnosis, Differential %K Disease Progression %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neurocalcin %K Peptide Fragments %K Predictive Value of Tests %K ROC Curve %K Statistics as Topic %K tau Proteins %X

Visinin-like protein 1 (VILIP-1) recently emerged as a potential biomarker of Alzheimer's disease (AD). This neuronal calcium sensor protein previously used as a marker of acute ischemic stroke is elevated in the cerebrospinal fluid (CSF) of AD patients. The goal of this study was to assess CSF VILIP-1 potential in early AD diagnosis and in differentiating mild cognitive impairment (MCI) patients with and without risk of AD. Additionally, we tested VILIP-1 ability to differentiate AD from other primary causes of dementia, and predict the progression of AD-related cognitive decline. VILIP-1 levels were compared with five CSF AD biomarkers (t-tau, Aβ1-42, p-tau181, p-tau199, and p-tau231). VILIP-1 successfully differentiated two MCI patient groups characterized by absence or presence of pathological levels of these CSF biomarkers, except for t-tau. VILIP-1/Aβ(1-42) and VILIP-1/p-tau181 ratios also differentiated MCI patients with pathological CSF biomarker levels. However, there was no difference in VILIP-1 levels between AD and MCI patients. VILIP-1/Aβ(1-42) and VILIP-1/p-tau231 ratios reached high sensitivities (above 70%) and very high specificities (above 85%) in differentiating AD patients from HC. Additionally, VILIP-1 differentiated AD from patients with Lewy body disease with 77.1% sensitivity and 100% specificity. VILIP-1 potential as a prognostic biomarker of cognitive decline in AD was also proved since VILIP-1/t-tau, VILIP-1/p-tau181, and VILIP-1/p-tau231 ratios correlated with MMSE scores. These data indicate that VILIP-1 alone or in combination with other AD CSF biomarkers represent a valuable marker for the early diagnosis of AD, recognition of MCI patients at higher risk to develop dementia, and in differentiating AD from LBD.

%B J Alzheimers Dis %V 50 %P 765-78 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836160?dopt=Abstract %R 10.3233/JAD-150705 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Predictors of Mortality in Dementia: The PRIME Study. %A Connors, Michael H %A Ames, David %A Boundy, Karyn %A Clarnette, Roger %A Kurrle, Sue %A Mander, Alastair %A Ward, John %A Woodward, Michael %A Brodaty, Henry %X

BACKGROUND: Dementia is a terminal illness. While various baseline characteristics of patients, such as age, sex, and dementia severity, are known to predict mortality, little research has examined how changes in patients' symptoms over time predict survival. There are also limited data on patients seen in memory clinics, as opposed to other health care settings, and whether antipsychotic medications are associated with mortality in dementia once patients' demographic and clinical features are controlled for.

OBJECTIVE: To identify predictors of mortality in patients with dementia.

METHOD: Of 970 patients recruited from nine memory clinics around Australia, 779 patients had dementia at baseline. Patients completed measures of dementia severity, cognition, functional ability, neuropsychiatric symptoms, caregiver burden, and medication use at baseline and at regular intervals over a three-year period. Mortality data were obtained from state registries eight years after baseline.

RESULTS: Overall, 447 (57.4%) of the patients with dementia died within the eight years. Older age, male sex, more severe dementia and functional impairment at baseline, greater decline in dementia severity and functional impairment over six months, taking a larger number of medications, and use of atypical antipsychotic medication predicted earlier mortality.

CONCLUSIONS: The findings confirm that demographic and diagnostic features predict the survival of patients with dementia. Importantly, the findings indicate that changes in dementia severity and functional impairment over time predict mortality independently of baseline levels, and provide further evidence for the higher mortality risk of patients taking antipsychotic medications.

%B J Alzheimers Dis %V 52 %P 967-74 %8 2016 Apr 12 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079702?dopt=Abstract %R 10.3233/JAD-150946 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy. %A Stern, Robert A %A Tripodis, Yorghos %A Baugh, Christine M %A Fritts, Nathan G %A Martin, Brett M %A Chaisson, Christine %A Cantu, Robert C %A Joyce, James A %A Shah, Sahil %A Ikezu, Tsuneya %A Zhang, Jing %A Gercel-Taylor, Cicek %A Taylor, Douglas D %K Adult %K Aged %K Analysis of Variance %K Case-Control Studies %K Chronic Traumatic Encephalopathy %K Extracellular Vesicles %K Humans %K Male %K Middle Aged %K Plasma %K tau Proteins %X

BACKGROUND: Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer's disease, there is a need for methods to diagnose CTE during life through objective biomarkers.

OBJECTIVE: The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker.

METHODS: Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau.

RESULTS: The NFL group had higher exosomal tau than the control group (p <  0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p = 0.0126) and psychomotor speed (p = 0.0093).

CONCLUSION: These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.

%B J Alzheimers Dis %V 51 %P 1099-109 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890775?dopt=Abstract %R 10.3233/JAD-151028 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Presence of Select Tau Species in Human Peripheral Tissues and Their Relation to Alzheimer's Disease. %A Dugger, Brittany N %A Whiteside, Charisse M %A Maarouf, Chera L %A Walker, Douglas G %A Beach, Thomas G %A Sue, Lucia I %A Garcia, Angelica %A Dunckley, Travis %A Meechoovet, Bessie %A Reiman, Eric M %A Roher, Alex E %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Blotting, Western %K Colon %K Enzyme-Linked Immunosorbent Assay %K Female %K Frontal Lobe %K Gray Matter %K Humans %K Immunohistochemistry %K Liver %K Male %K Neurofibrillary Tangles %K Phosphorylation %K Severity of Illness Index %K Sex Characteristics %K Skin %K Submandibular Gland %K tau Proteins %X

Tau becomes excessively phosphorylated in Alzheimer's disease (AD) and is widely studied within the brain. Further examination of the extent and types of tau present in peripheral tissues and their relation to AD is warranted given recent publications on pathologic spreading. Cases were selected based on the presence of pathological tau spinal cord deposits (n = 18). Tissue samples from sigmoid colon, scalp, abdominal skin, liver, and submandibular gland were analyzed by western blot and enzyme-linked immunosorbent assays (ELISAs) for certain tau species; frontal cortex gray matter was used for comparison. ELISAs revealed brain to have the highest total tau levels, followed by submandibular gland, sigmoid colon, liver, scalp, and abdominal skin. Western blots with antibodies recognizing tau phosphorylated at threonine 231(pT231), serine 396 and 404 (PHF-1), and an unmodified total human tau between residues 159 and 163 (HT7) revealed multiple banding patterns, some of which predominated in peripheral tissues. As submandibular gland had the highest levels of peripheral tau, a second set of submandibular gland samples were analyzed (n = 36; 19 AD, 17 non-demented controls). ELISAs revealed significantly lower levels of pS396 (p = 0.009) and pT231 (p = 0.005) in AD cases but not total tau (p = 0.18). Furthermore, pT231 levels in submandibular gland inversely correlated with Braak neurofibrillary tangle stage (p = 0.04), after adjusting for age at death, gender, and postmortem interval. These results provide evidence that certain tau species are present in peripheral tissues. Of potential importance, submandibular gland pT231 is progressively less abundant with increasing Braak neurofibrillary tangle stage.

%B J Alzheimers Dis %V 51 %P 345-56 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890756?dopt=Abstract %R 10.3233/JAD-150859 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Primary Progressive Aphasia in the Network of French Alzheimer Plan Memory Centers. %A Magnin, Eloi %A Démonet, Jean-François %A Wallon, David %A Dumurgier, Julien %A Troussière, Anne-Cécile %A Jager, Alain %A Duron, Emmanuelle %A Gabelle, Audrey %A de la Sayette, Vincent %A Volpe-Gillot, Lisette %A Tio, Gregory %A Evain, Sarah %A Boutoleau-Bretonnière, Claire %A Enderle, Adeline %A Mouton-Liger, François %A Robert, Philippe %A Hannequin, Didier %A Pasquier, Florence %A Hugon, Jacques %A Paquet, Claire %X

BACKGROUND: Few demographical data about primary progressive aphasia (PPA) are available, and most knowledge regarding PPA is based on tertiary centers' results.

OBJECTIVE: Our aims were to describe demographical characteristics of the PPA population in a large sample of PPA patients from the network of French Alzheimer plan memory centers (Sample 1), and to describe the stratification of cerebrospinal fluid (CSF) biomarkers in two different samples of PPA patients (Samples 2 and 3).

METHODS: All registered PPA patients in the French Alzheimer's disease (AD) databank (Sample 1: n = 2,035) and a subsample (Sample 2: n = 65) derived from a multicentric prospective cohort with CSF biomarker analysis were analyzed. A multicentric retrospective cohort from language expert tertiary centers (Sample 3: n = 97) with CSF biomarker analysis was added. Sample 3 was added to replicate the CSF results of the Sample 2 and to evaluate repartition of AD pathology in the three variant of PPA according to the latest classification.

RESULTS: Non-Fluent/Agrammatic, Logopenic, and Unclassifiable PPA patients (NF/A-Logo-Unclass PPA) were older and more frequent than Semantic PPA patients (2.2 versus 0.8/100,000 inhabitants; p < 0.00001). Male predominance occurred after the age of 80 (p < 0.00001). A higher level of education was observed in the PPA population compared to a typical amnesic AD group. No demographical significant difference between PPA due to AD and not due to AD was observed. The Logopenic variant was most frequent with 85% of AD CSF biomarker profiles (35% in NF/A PPA; 20% in Semantic PPA).

CONCLUSION: PPA occurs also in an elderly population, especially in male patients over 80. CSF biomarkers are useful to stratify PPA. The epidemiology of PPA should be further investigated to confirm gender and cognitive reserve role in PPA to better understand the factors and mechanisms leading to this language-predominant deficit during neurodegenerative diseases.

%B J Alzheimers Dis %V 54 %P 1459-1471 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589533?dopt=Abstract %R 10.3233/JAD-160536 %0 Journal Article %J J Alzheimers Dis %D 2016 %T PRNP P39L Variant is a Rare Cause of Frontotemporal Dementia in Italian Population. %A Oldoni, Emanuela %A Fumagalli, Giorgio G %A Serpente, Maria %A Fenoglio, Chiara %A Scarioni, Marta %A Arighi, Andrea %A Bruno, Giuseppe %A Talarico, Giuseppina %A Confaloni, Annamaria %A Piscopo, Paola %A Nacmias, Benedetta %A Sorbi, Sandro %A Rainero, Innocenzo %A Rubino, Elisa %A Pinessi, Lorenzo %A Binetti, Giuliano %A Ghidoni, Roberta %A Benussi, Luisa %A Grande, Giulia %A Arosio, Beatrice %A Bursey, Devan %A Kauwe, John S %A Cioffi, Sara Mg %A Arcaro, Marina %A Mari, Daniela %A Mariani, Claudio %A Scarpini, Elio %A Galimberti, Daniela %K Aged %K Atrophy %K Frontal Lobe %K Frontotemporal Dementia %K Genetic Predisposition to Disease %K Humans %K Italy %K Language %K Magnetic Resonance Imaging %K Male %K Memory Disorders %K Memory, Short-Term %K Neuropsychological Tests %K Prion Proteins %K Prions %K Temporal Lobe %X

The missense P39L variant in the prion protein gene (PRNP) has recently been associated with frontotemporal dementia (FTD). Here, we analyzed the presence of the P39L variant in 761 patients with FTD and 719 controls and found a single carrier among patients. The patient was a 67-year-old male, with a positive family history for dementia, who developed apathy, short term memory deficit, and postural instability at 66. Clinical and instrumental workup excluded prion disease. At MRI, bilateral frontal lobe atrophy was present. A diagnosis of FTD was made, with a mainly apathetic phenotype. The PRNP P39L mutation may be an extremely rare cause of FTD (0.13%).

%B J Alzheimers Dis %V 50 %P 353-7 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757195?dopt=Abstract %R 10.3233/JAD-150863 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Profiling of p5, a 24 Amino Acid Inhibitory Peptide Derived from the CDK5 Activator, p35 CDKR1 Against 70 Protein Kinases. %A Binukumar, B K %A Pelech, Steven L %A Sutter, Catherine %A Shukla, Varsha %A Amin, Niranjana D %A Grant, Philip %A Bhaskar, Manju %A Skuntz, Suzanne %A Steiner, Joseph %A Pant, Harish C %X

Cyclin-dependent kinase 5 (CDK5) is a multifunctional serine/threonine kinase that regulates a large number of neuronal processes essential for nervous system development and function with its activator p35 CDK5R1. Upon neuronal insults, p35 is proteolyzed and cleaved to p25 producing deregulation and hyperactivation of CDK5 (CDK5/p25), implicated in tau hyperphosphorylation, a pathology in some neurodegenerative diseases. A truncated, 24 amino acid peptide, p5, derived from p35 inhibits the deregulated CDK5 phosphotransferase activity and ameliorates Alzheimer's disease (AD) phenotypes in AD model mice. In the present study, we have screened a diverse panel of 70 human protein kinases for their sensitivities to p5, and a subset of these to p35. At least 16 of the tested protein kinases exhibited IC50 values that were 250 μM or less, with CAMK4, ZAP70, SGK1, and PIM1 showing greater sensitivity to inhibition by p5 than CDK5/p35 and CDK5/p25. In contrast, the p5 peptide modestly activated LKB1 and GSK3β. A sub set of kinases screened against p35 showed that activity of CAMK4 in the absence of calcium and calmodulin was also markedly inhibited by p35. The Cyclin Y-dependent kinases PFTK1 (CDK14) and PCTK1 (CDK16) were activated by p35 at least 10-fold in the absence of Cyclin Y and by approximately 50% in its presence. These findings provide additional insights into the mechanisms of action for p5 and p35 in the regulation of protein phosphorylation in the nervous system.

%B J Alzheimers Dis %V 54 %P 525-33 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567857?dopt=Abstract %R 10.3233/JAD-160458 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Prognostic Significance of Mild Cognitive Impairment Subtypes for Dementia and Mortality: Data from the NEDICES Cohort. %A Bermejo-Pareja, Félix %A Contador, Israel %A Trincado, Rocío %A Lora, David %A Sánchez-Ferro, Álvaro %A Mitchell, Alex J %A Boycheva, Elina %A Herrero, Alejandro %A Hernández-Gallego, Jesús %A Llamas, Sara %A Villarejo Galende, Alberto %A Benito-León, Julián %K Aged %K Aged, 80 and over %K Algorithms %K Cognitive Dysfunction %K Cohort Studies %K Dementia %K Female %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Predictive Value of Tests %K Prognosis %K Proportional Hazards Models %K Spain %X

BACKGROUND: The predictive value of diverse subtypes of mild cognitive impairment (MCI) for dementia and death is highly variable.

OBJECTIVE: To compare the predictive value of several MCI subtypes in progression to dementia and/or mortality in the NEDICES (Neurological Disorders in Central Spain) elderly cohort.

METHODS: Retrospect algorithmic MCI subgroups were established in a non-dementia baseline NEDICES cohort using Spanish adaptations of the original Mini-Mental State Examination (MMSE-37) and Pfeffer's Functional Activities Questionnaire (Pfeffer-11). The presence of MCI was defined according two cognitive criteria: using two cut-offs points on the total MMSE-37 score. Five cognitive domains were used to establish the MCI subtypes. Functional capacity (Pfeffer-11) was preserved or minimally impaired in all MCI participants. The incident dementia diagnoses were established by specialists and the mortality data obtained from Spanish official registries.

RESULTS: 3,411 participants without dementia were assessed in 1994-5. The baseline prevalence of MCI varied according to the MCI definition (4.3%-31.8%). The follow-up was a mean of 3.2 years (1997-8). The dementia incidence varied between 14.9 and 71.8 per 1,000/person-years. The dementia conversion rate was increased in almost all MCI subgroups (p >  0.01), and mortality rate was raised only in four MCI subtypes. The amnestic-multi-domain MCI (aMd-MCI) had the best dementia predictive accuracy (highest positive likelihood ratio and highest clinical utility when negative).

CONCLUSIONS: Those with aMd-MCI were at greatest risk of progression to dementia, as in other surveys and might be explored with increased attention in MCI research and in dementia preventive trials.

%B J Alzheimers Dis %V 50 %P 719-31 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757038?dopt=Abstract %R 10.3233/JAD-150625 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Progranulin Protein Levels in Cerebrospinal Fluid in Primary Neurodegenerative Dementias. %A Morenas-Rodriguez, Estrella %A Cervera-Carles, Laura %A Vilaplana, Eduard %A Alcolea, Daniel %A Carmona-Iragui, María %A Dols-Icardo, Oriol %A Ribosa-Nogué, Roser %A Muñoz-Llahuna, Laia %A Sala, Isabel %A Belén Sánchez-Saudinós, M %A Blesa, Rafael %A Clarimón, Jordi %A Fortea, Juan %A Lleo, Alberto %K Aged %K Aged, 80 and over %K Amyloid beta-Peptides %K Biomarkers %K Dementia %K Female %K Humans %K Intercellular Signaling Peptides and Proteins %K Male %K Middle Aged %K Neurodegenerative Diseases %K Polymorphism, Single Nucleotide %K tau Proteins %X

BACKGROUND: Progranulin is implicated in frontotemporal dementia (FTD), but its role in other neurodegenerative disorders is unknown.

OBJECTIVE: To investigate the levels of progranulin (PGRN) in cerebrospinal fluid (CSF) in different neurodegenerative dementias and their correlation with levels in plasma in cognitively normal subjects.

METHODS: We measured PGRN in CSF in 229 patients with amnestic mild cognitive impairment, Alzheimer's disease dementia, sporadic FTD, dementia with Lewy bodies, corticobasal syndrome, or progressive supranuclear palsy. We also measured PGRN in CSF and plasma in 74 cognitively normal individuals. We examined the correlation between PGRN levels in CSF and diagnosis, cortical thickness, genetic factors and other CSF biomarkers. We also investigated the correlation between plasma and CSF levels of PGRN in cognitively normal individuals.

RESULTS: CSF levels did not differ across diagnoses or correlate with cortical thickness. Polymorphism rs5848 in GRN influenced CSF PGRN levels, but APOEɛ4 allele did not. Amyloid-β42, t-tau, p-tau, and YKL-40 levels correlated weakly with PGRN in CSF. We found a weak correlation (r = 0.362) between plasma and CSF PGRN levels in cognitively normal individuals.

CONCLUSIONS: Our findings do not support a diagnostic value of CSF PGRN in neurodegenerative diseases. Our data confirm that levels of PGRN in plasma do not reflect accurately levels in CSF in cognitively normal controls. These data should be considered in clinical trials aiming to increase PGRN.

%B J Alzheimers Dis %V 50 %P 539-46 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682689?dopt=Abstract %R 10.3233/JAD-150746 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Progression of Extrapyramidal Signs in Alzheimer's Disease: Clinical and Neuropathological Correlates. %A Tosto, Giuseppe %A Monsell, Sarah E %A Hawes, Stephen E %A Bruno, Giuseppe %A Mayeux, Richard %K Aged %K Algorithms %K Alzheimer Disease %K Cluster Analysis %K Databases, Factual %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Severity of Illness Index %X

BACKGROUND: Extrapyramidal signs (EPS) are frequent in Alzheimer's disease (AD) and core manifestation of related diseases, i.e., dementia with Lewy bodies and Parkinson's disease; furthermore, Lewy bodies and AD-type pathology occur in all three conditions.

OBJECTIVE: To identify clusters of EPS progression over time and their clinical and neuropathological correlates.

METHODS: 3,502 AD patients with longitudinal assessment from the National Alzheimer's Coordinating Center database were included; 394 provided neuropathological data. k-means algorithm was employed to identify clusters of EPS progression and those were compared in terms of cognitive profile, neuropsychiatric features and neuropathological findings.

RESULTS: Three clusters of EPS progression were identified: no/low (n = 1,583), medium (n = 1,259), and high (n = 660) EPS burden. Compared to those with no/low and medium EPS, those with high EPS had greater cognitive and neuropsychiatric impairment, specifically hallucinations. Despite similar AD-pathology across the three clusters, the high EPS cluster had a significantly number of subjects diagnosed with dementia with Lewy bodies.

CONCLUSIONS: Cluster analysis of EPS progression over time identified different subgroups of AD patients with distinct clinical and neuropathological features.

%B J Alzheimers Dis %V 49 %P 1085-93 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599050?dopt=Abstract %R 10.3233/JAD-150244 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Prolonged Visual Facial Grasp in Frontotemporal Dementia. %A Paholpak, Pongsatorn %A Li-Jung, Liang %A Carr, Drew R %A Jimenez, Elvira %A Barrows, Robin J %A Sabodash, Valeiry %A Mendez, Mario F %X

BACKGROUND: Gaze and eye contact is a critical aspect of social interaction. Patients with behavioral variant frontotemporal dementia (bvFTD) may exhibit abnormally prolonged stare toward human faces.

OBJECTIVE: To study characteristics of social gaze in patients with bvFTD compared to age and education matched-patients with early-onset Alzheimer's disease (eAD) and healthy controls (HC).

METHOD: Fifty picture stimuli were presented to each participant (bvFTD = 12, eAD = 18, HC = 13). Each stimuli contained two properties: face (facial versus non-facial) and valence (positive, negative, and neutral). The "facial" stimuli contained human faces. The participants Visual Fixation Time (VFT) was measured for each picture stimuli of interest (per facial expressions on the Facial Action Coding System). A linear mixed-effects regression model with participant-level of random effects was used to compare VFTs between groups.

RESULTS: The patients with bvFTD showed significantly prolonged VFTs to faces than the patients with eAD and the HC, regardless of valence (all p < 0.01). There were no differences in VFTs for non-facial stimuli between patients with bvFTD and eAD. However, patients with bvFTD and eAD had significantly prolonged VFTs to negative non-facial stimuli than the HC (p = 0.006 and 0.019, respectively).

CONCLUSION: Patients with bvFTD exhibited a prolonged stare toward human faces. This prolonged visual facial grasp may contribute to the disturbed social interactions of patients with bvFTD and can help distinguish them from those with Alzheimer's disease and other conditions. Additionally, both dementia groups tended to stare at negative stimuli whether faces or non-faces.

%B J Alzheimers Dis %V 53 %P 327-35 %8 2016 May 07 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163801?dopt=Abstract %R 10.3233/JAD-150864 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Promising Role of Neuromodulation in Predicting the Progression of Mild Cognitive Impairment to Dementia. %A Naro, Antonino %A Corallo, Francesco %A De Salvo, Simona %A Marra, Angela %A Di Lorenzo, Giuseppe %A Muscarà, Nunzio %A Russo, Margherita %A Marino, Silvia %A De Luca, Rosaria %A Bramanti, Placido %A Calabrò, Rocco Salvatore %X

The differential diagnosis of mild cognitive impairment (MCI) and Alzheimer's disease (AD) is not always straightforward, and the rate of progression of MCI to dementia is not negligible. Thus, there is a need for para-clinical approaches that can improve the differential diagnosis and identify patients that are at risk of progression. There is a growing interest, at present, in the role of the deterioration of brain oscillations as a predictor of MCI-to-AD conversion. For this reason, we experimentally modulated γ-band oscillations (GBO) in a sample of MCI and AD patients and an age-matched healthy elderly group, using a transcranial alternating current stimulation (tACS) protocol that was applied to different cortical sites. We correlated the after-effects of tACS on the GBO and the neuropsychological data, in an attempt to differentiate MCI from AD patients and identify, among the MCI patients, those that could be at potential risk of MCI-to-dementia conversion. MCI patients showed a partial GBO increase and improvement in some neuropsychological tests whereas AD individuals did not show significant tACS after-effects. Notably, some MCI subjects lacked significant neuropsychological and electrophysiological after-effects, similar to AD individuals. In a two-year follow-up, such MCI individuals had converted into AD. Therefore, our data suggest that tACS may support the clinical differential diagnosis of MCI and AD and identify MCI patients who could be at risk of developing dementia. This prediction index may help the clinician to adopt a better prevention/follow-up strategy in such a disabling neurodegenerative disease.

%B J Alzheimers Dis %V 53 %P 1375-88 %8 2016 Jul 01 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392866?dopt=Abstract %R 10.3233/JAD-160305 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Protective Effect of Amyloid-β Peptides Against Herpes Simplex Virus-1 Infection in a Neuronal Cell Culture Model. %A Bourgade, Karine %A Le Page, Aurélie %A Bocti, Christian %A Witkowski, Jacek M %A Dupuis, Gilles %A Frost, Eric H %A Fülöp, Tamás %K Amyloid beta-Peptides %K Amyloid Precursor Protein Secretases %K Cell Line, Tumor %K Coculture Techniques %K Culture Media, Conditioned %K Herpes Simplex %K Herpesvirus 1, Human %K Humans %K Interferon-alpha %K Interleukin-1beta %K Neuroglia %K Neurons %K Peptide Fragments %K Tumor Necrosis Factor-alpha %K Virus Replication %X

Senile amyloid plaques are one of the main hallmarks of Alzheimer's disease (AD). They correspond to insoluble deposits of amyloid-β peptides (Aβ) and are responsible for the inflammatory response and neurodegeneration that lead to loss of memory. Recent data suggest that Aβ possess antimicrobial and anti-viral activity in vitro. Here, we have used cocultures of neuroglioma (H4) and glioblastoma (U118-MG) cells as a minimal in vitro model to investigate whether Aβ is produced by neuroglioma cells and whether this could result in protective anti-viral activity against HSV-1 infection. Results showed that H4 cells secreted Aβ42 in response to HSV-1 challenge and that U118-MG cells could rapidly internalize Aβ42. Production of pro-inflammatory cytokines TNFα and IL-1β by H4 and U118-MG cells occurred under basal conditions but infection of the cells with HSV-1 did not significantly upregulate production. Both cell lines produced low levels of IFNα. However, extraneous Aβ42 induced strong production of these cytokines. A combination of Aβ42 and HSV-1 induced production of pro-inflammatory cytokines TNFα and IL-1β, and IFNα in the cell lines. The reported anti-viral protection of Aβ42 was revealed in transfer experiments involving conditioned medium (CM) of HSV-1-infected H4 cells. CM conferred Aβ-dependent protection against HSV-1 replication in de novo cultures of H4 cells challenged with HSV-1. Type 1 interferons did not play a role in these assays. Our data established that H4 neuroglioma cells produced Aβ42 in response to HSV-1 infection thus inhibiting secondary replication. This mechanism may play a role in the etiology of AD.

%B J Alzheimers Dis %V 50 %P 1227-41 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836158?dopt=Abstract %R 10.3233/JAD-150652 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Protein Kinase Activity Decreases with Higher Braak Stages of Alzheimer's Disease Pathology. %A Rosenberger, Andrea F N %A Hilhorst, Riet %A Coart, Elisabeth %A García Barrado, Leandro %A Naji, Faris %A Rozemuller, Annemieke J M %A van der Flier, Wiesje M %A Scheltens, Philip %A Hoozemans, Jeroen J M %A van der Vies, Saskia M %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cohort Studies %K Female %K Hippocampus %K Humans %K Male %K Middle Aged %K Phosphorylation %K Protein Kinases %K Protein-Serine-Threonine Kinases %K Severity of Illness Index %X

Alzheimer's disease (AD) is characterized by a long pre-clinical phase (20-30 years), during which significant brain pathology manifests itself. Disease mechanisms associated with pathological hallmarks remain elusive. Most processes associated with AD pathogenesis, such as inflammation, synaptic dysfunction, and hyper-phosphorylation of tau are dependent on protein kinase activity. The objective of this study was to determine the involvement of protein kinases in AD pathogenesis. Protein kinase activity was determined in postmortem hippocampal brain tissue of 60 patients at various stages of AD and 40 non-demented controls (Braak stages 0-VI) using a peptide-based microarray platform. We observed an overall decrease of protein kinase activity that correlated with disease progression. The phosphorylation of 96.7% of the serine/threonine peptides and 37.5% of the tyrosine peptides on the microarray decreased significantly with increased Braak stage (p-value <0.01). Decreased activity was evident at pre-clinical stages of AD pathology (Braak I-II). Increased phosphorylation was not observed for any peptide. STRING analysis in combination with pathway analysis and identification of kinases responsible for peptide phosphorylation showed the interactions between well-known proteins in AD pathology, including the Ephrin-receptor A1 (EphA1), a risk gene for AD, and sarcoma tyrosine kinase (Src), which is involved in memory formation. Additionally, kinases that have not previously been associated with AD were identified, e.g., protein tyrosine kinase 6 (PTK6/BRK), feline sarcoma oncogene kinase (FES), and fyn-associated tyrosine kinase (FRK). The identified protein kinases are new biomarkers and potential drug targets for early (pre-clinical) intervention.

%B J Alzheimers Dis %V 49 %P 927-43 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519433?dopt=Abstract %R 10.3233/JAD-150429 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Psychometric Properties of the Memory Binding Test: Test-Retest Reliability and Convergent Validity. %A Gramunt, Nina %A Sánchez-Benavides, Gonzalo %A Buschke, Herman %A Lipton, Richard B %A Masramon, Xavier %A Gispert, Juan D %A Peña-Casanova, Jordi %A Fauria, Karine %A Molinuevo, José L %K Aged %K Alzheimer Disease %K Female %K Humans %K Male %K Memory %K Middle Aged %K Psychological Tests %K Psychometrics %K Reproducibility of Results %X

BACKGROUND: Episodic memory testing is fundamental for the diagnosis of Alzheimer's disease (AD). Although the Free and Cued Selective Reminding Test (FCSRT) is widely used for this purpose, it may not be sensitive enough for early detection of subtle decline in preclinical AD. The Memory Binding Test (MBT) intends to overcome this limitation.

OBJECTIVES: To analyze the test-retest reliability of the MBT and its convergent validity with the FCRST.

METHODS: 36 cognitively healthy participants of the ALFA Study, aged 45 to 65, were included for the test-retest study and 69 for the convergent analysis. They were visited twice in a period of 6 ± 2 weeks. Test-retest reliability was determined by the calculation of the intra-class correlation coefficient (ICC). Score differences were studied by computing the mean percentage of score variation between visits and visualized by Bland-Altman plots. Convergent validity was determined by Pearson's correlations.

RESULTS: ICC values in the test-retest reliability analysis of the MBT direct scores ranged from 0.64 to 0.76. Subjects showed consistent practice effects, with mean amounts of score increasing between 10% and 26%. Pearson correlation between MBT and FCSRT direct scores showed r values between 0.40 and 0.53. The FCSRT displayed ceiling effects not observed in the MBT.

CONCLUSIONS: The MBT shows adequate test-retest reliability and overall moderate convergent validity with the FCSRT. Unlike the FCSRT, the MBT does not have ceiling effects and it may therefore be especially useful in longitudinal studies, facilitating the measurement of subtle memory performance decline and the detection of very early AD.

%B J Alzheimers Dis %V 50 %P 999-1010 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836167?dopt=Abstract %R 10.3233/JAD-150776 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Psychotropic Drug Prescription in Patients with Dementia: Nursing Home Residents Versus Patients Living at Home. %A Jacquin-Piques, Agnès %A Sacco, Guillaume %A Tavassoli, Neda %A Rouaud, Olivier %A Bejot, Yannick %A Giroud, Maurice %A Robert, Philippe %A Vellas, Bruno %A Bonin-Guillaume, Sylvie %K Aged %K Aged, 80 and over %K Chi-Square Distribution %K Cross-Sectional Studies %K Databases, Factual %K Dementia %K Drug Prescriptions %K Female %K Humans %K Male %K Nursing Homes %K Psychotropic Drugs %K Residence Characteristics %X

BACKGROUND: Psychotropic drugs are frequently prescribed in nursing homes (NH). Nonetheless, we hoped that institutionalization decreases the number of psychotropic drug classes prescribed, because NH residents may have more psychosocial interventions than patients living at home.

OBJECTIVE: The aim was to compare the type and number of psychotropic drugs prescribed in elderly NH residents with dementia with those in community-living patients.

METHODS: This cross-sectional study included elderly patients (at least 75 years old) with dementia recorded in the National Alzheimer's data Bank ("Banque Nationale Alzheimer") during the year 2012 and who were taking at least one psychotropic drug. Psychotropic drugs were classified as follows: antidepressant, anxiolytic, hypnotic, and antipsychotic drugs. Patients were classified into three categories of dementia severity according to the MMSE score.

RESULTS: Among the 50,932 patients with dementia recorded in the BNA, 40.1% had at least one psychotropic drug prescribed. Most of the patients who were treated by at least one psychotropic drug class had antidepressant therapy (69.0%), whatever their residence type, and 16.1% were treated with antipsychotics. Among the study population, 51.9% of the NH residents and 67.4% of the patients living at home had only one psychotropic drug class prescribed. Living in a NH was significantly associated with the more frequent prescription of anxiolytic, hypnotic, and antipsychotic drugs, and with a greater number of psychotropic drug classes prescribed, whatever the severity of the dementia.

CONCLUSION: We underlined the more frequent prescription of psychotropic drugs in NH residents regardless of MMSE scores.

%B J Alzheimers Dis %V 49 %P 671-80 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484903?dopt=Abstract %R 10.3233/JAD-150280 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Puerarin Ameliorates D-Galactose Induced Enhanced Hippocampal Neurogenesis and Tau Hyperphosphorylation in Rat Brain. %A Hong, Xiao-Ping %A Chen, Tao %A Yin, Ni-Na %A Han, Yong-Ming %A Yuan, Fang %A Duan, Yan-Jun %A Shen, Feng %A Zhang, Yan-Hong %A Chen, Ze-Bin %K Animals %K Cognition Disorders %K Disease Models, Animal %K Fibroblast Growth Factor 2 %K Galactose %K Glycogen Synthase Kinase 3 %K Hippocampus %K Isoflavones %K Male %K Maze Learning %K Neurogenesis %K Neurons %K Neuroprotective Agents %K Phosphorylation %K Random Allocation %K Rats, Sprague-Dawley %K Signal Transduction %K Spatial Memory %K tau Proteins %X

Enhanced neurogenesis has been reported in the hippocampus of patients with Alzheimer's disease (AD), the most common neurodegenerative disorder characterized with amyloid-β (Aβ) aggregation, tau hyperphosphorylation, and progressive neuronal loss. Previously we reported that tau phosphorylation played an essential role in adult hippocampal neurogenesis, and activation of glycogen synthase kinase (GSK-3), a crucial tau kinase, could induce increased hippocampal neurogenesis. In the present study, we found that treatment of D-galactose rats with Puerarin could significantly improve behavioral performance and ameliorate the enhanced neurogenesis and microtubule-associated protein tau hyperphosphorylation in the hippocampus of D-galactose rat brains. FGF-2/GSK-3 signaling pathway might be involved in the effects of Puerarin on hippocampal neurogenesis and tau hyperphosphorylation. Our finding provides primary in vivo evidence that Puerarin can attenuate AD-like enhanced hippocampal neurogenesis and tau hyperphosphorylation. Our finding also suggests Puerarin can be served as a treatment for age-related neurodegenerative disorders, such as AD.

%B J Alzheimers Dis %V 51 %P 605-17 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890737?dopt=Abstract %R 10.3233/JAD-150566 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Purported Interactions of Amyloid-β and Glucocorticoids in Cytotoxicity and Genotoxicity: Implications in Alzheimer's Disease. %A Bengoetxea, Xabier %A de Cerain, Adela López %A Azqueta, Amaya %A Ramirez, Maria J %X

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the presence of aggregates of the amyloid-β peptide (Aβ) that are believed to be neurotoxic. One of the purposed damaging mechanisms of Aβ is oxidative insult, which eventually could damage the cellular genome. Stress and associated increases in glucocorticoids (GCs) have been described as a risk factor for the development of AD, although the purported genotoxic effects of GCs have not been fully characterized. Therefore, it is possible to speculate about purported synergistic effects of GCs on the Aβ-driven genotoxic damage. This in vitro study addresses the single and combined cyto/genotoxic effects of Aβ and GCs in SH-SY5Y cells. Cytotoxicity was determined by the MTT assay, and the genotoxic effects were studied using the comet assay. A comet assay derivation allows for measuring the presence of the FPG-sensitive sites (mainly 8-oxoguanines) in the DNA, apart from the DNA strand breaks. Treatment with Aβ (10 μM, 72 h) induced cytotoxicity (35% decrease in cell viability) and DNA strand breaks, but had no significant effect on oxidative DNA damage (FPG sites). Corticosterone showed no effect on cell viability, genotoxicity, or reparation processes. Corticosterone was unable to neither reverse nor potentiate Aβ driven effects. The present results suggest the existence of alternative mechanisms for the Aβ driven damage, not involving oxidative damage of DNA. In addition, could be suggested that the interaction between Aβ and GCs in AD does not seem to involve DNA damage.

%B J Alzheimers Dis %V 54 %P 1085-1094 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589535?dopt=Abstract %R 10.3233/JAD-160636 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Qualitative Impairment in Face Perception in Alzheimer's Disease: Evidence from a Reduced Face Inversion Effect. %A Lavallée, Marie Maxime %A Gandini, Delphine %A Rouleau, Isabelle %A Vallet, Guillaume T %A Joannette, Maude %A Kergoat, Marie-Jeanne %A Busigny, Thomas %A Rossion, Bruno %A Joubert, Sven %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Face %K Facial Recognition %K Female %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Orientation %K Pattern Recognition, Visual %K Perceptual Disorders %K Photic Stimulation %K Psychiatric Status Rating Scales %K Reaction Time %K Statistics as Topic %X

Prevalent face recognition difficulties in Alzheimer's disease (AD) have typically been attributed to the underlying episodic and semantic memory impairment. The aim of the current study was to determine if AD patients are also impaired at the perceptual level for faces, more specifically at extracting a visual representation of an individual face. To address this question, we investigated the matching of simultaneously presented individual faces and of other nonface familiar shapes (cars), at both upright and inverted orientation, in a group of mild AD patients and in a group of healthy older controls matched for age and education. AD patients showed a reduced inversion effect (i.e., larger performance for upright than inverted stimuli) for faces, but not for cars, both in terms of error rates and response times. While healthy participants showed a much larger decrease in performance for faces than for cars with inversion, the inversion effect did not differ significantly for faces and cars in AD. This abnormal inversion effect for faces was observed in a large subset of individual patients with AD. These results suggest that AD patients have deficits in higher-level visual processes, more specifically at perceiving individual faces, a function that relies on holistic representations specific to upright face stimuli. These deficits, combined with their memory impairment, may contribute to the difficulties in recognizing familiar people that are often reported in patients suffering from the disease and by their caregivers.

%B J Alzheimers Dis %V 51 %P 1225-36 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967217?dopt=Abstract %R 10.3233/JAD-151027 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Quantitative Neuroimaging Software for Clinical Assessment of Hippocampal Volumes on MR Imaging. %A Ahdidan, Jamila %A Raji, Cyrus A %A DeYoe, Edgar A %A Mathis, Jedidiah %A Noe, Karsten Ø %A Rimestad, Jens %A Kjeldsen, Thomas K %A Mosegaard, Jesper %A Becker, James T %A Lopez, Oscar %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Female %K Hippocampus %K Humans %K Image Interpretation, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Software %X

BACKGROUND: Multiple neurological disorders including Alzheimer's disease (AD), mesial temporal sclerosis, and mild traumatic brain injury manifest with volume loss on brain MRI. Subtle volume loss is particularly seen early in AD. While prior research has demonstrated the value of this additional information from quantitative neuroimaging, very few applications have been approved for clinical use. Here we describe a US FDA cleared software program, NeuroreaderTM, for assessment of clinical hippocampal volume on brain MRI.

OBJECTIVE: To present the validation of hippocampal volumetrics on a clinical software program.

METHOD: Subjects were drawn (n = 99) from the Alzheimer Disease Neuroimaging Initiative study. Volumetric brain MR imaging was acquired in both 1.5 T (n = 59) and 3.0 T (n = 40) scanners in participants with manual hippocampal segmentation. Fully automated hippocampal segmentation and measurement was done using a multiple atlas approach. The Dice Similarity Coefficient (DSC) measured the level of spatial overlap between NeuroreaderTM and gold standard manual segmentation from 0 to 1 with 0 denoting no overlap and 1 representing complete agreement. DSC comparisons between 1.5 T and 3.0 T scanners were done using standard independent samples T-tests.

RESULTS: In the bilateral hippocampus, mean DSC was 0.87 with a range of 0.78-0.91 (right hippocampus) and 0.76-0.91 (left hippocampus). Automated segmentation agreement with manual segmentation was essentially equivalent at 1.5 T (DSC = 0.879) versus 3.0 T (DSC = 0.872).

CONCLUSION: This work provides a description and validation of a software program that can be applied in measuring hippocampal volume, a biomarker that is frequently abnormal in AD and other neurological disorders.

%B J Alzheimers Dis %V 49 %P 723-32 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484924?dopt=Abstract %R 10.3233/JAD-150559 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Quantitative phosphoproteomic analyses of the inferior parietal lobule from three different pathological stages of Alzheimer's disease. %A Triplett, Judy C %A Swomley, Aaron M %A Cai, Jian %A Klein, Jon B %A Butterfield, D Allan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognitive Dysfunction %K Disease Progression %K Female %K Humans %K Male %K Memory %K Neurofibrillary Tangles %K Oxidative Stress %K Parietal Lobe %K Phosphorylation %K Plaque, Amyloid %K Proteome %X

Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is clinically characterized by progressive neuronal loss resulting in loss of memory and dementia. AD is histopathologically characterized by the extensive distribution of senile plaques and neurofibrillary tangles, and synapse loss. Amnestic mild cognitive impairment (MCI) is generally accepted to be an early stage of AD. MCI subjects have pathology and symptoms that fall on the scale intermediately between 'normal' cognition with little or no pathology and AD. A rare number of individuals, who exhibit normal cognition on psychometric tests but whose brains show widespread postmortem AD pathology, are classified as 'asymptomatic' or 'preclinical' AD (PCAD). In this study, we evaluated changes in protein phosphorylation states in the inferior parietal lobule of subjects with AD, MCI, PCAD, and control brain using a 2-D PAGE proteomics approach in conjunction with Pro-Q Diamond phosphoprotein staining. Statistically significant changes in phosphorylation levels were found in 19 proteins involved in energy metabolism, neuronal plasticity, signal transduction, and oxidative stress response. Changes in the disease state phosphoproteome may provide insights into underlying mechanisms for the preservation of memory with expansive AD pathology in PCAD and the progressive memory loss in amnestic MCI that escalates to the dementia and the characteristic pathology of AD brain.

%B J Alzheimers Dis %V 49 %P 45-62 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444780?dopt=Abstract %R 10.3233/JAD-150417 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Redefining Amnestic Mild Cognitive Impairment as an Early Form of Alzheimer's Disease Based on Assessment of Memory Systems. %A Bolívar, Juan Carlos Cejudo %A Saladie, Domènec Gil %X

BACKGROUND: It has been suggested that mild cognitive impairment (MCI) can be used to identify patients at risk of developing clinical stages of Alzheimer's disease (AD).

OBJECTIVE: The aim of this study was to describe the characteristics of amnesic syndrome of dementia of the Alzheimer's type (DAT) as a continuous degenerative process from normality to amnesic syndrome and provide a classification of the degrees of amnesia.

METHODS: Of 3,800 new incidental cases at the Memory Clinic, 747 were classified as non-demented patients. A 96-month follow-up study was conducted. We described and compared longitudinal outcomes from normality to amnesic syndrome based on immediate memory, verbal learning, free recall, and recognition using the memory scale from the Basic Neuropsychological Battery, version D (BNB-D) and created a new classification of memory impairment.

RESULTS: Based on differences observed in this longitudinal study, we classified patients in four memory stages: M1, Normal episodic memory; M2, mild impairment in learning and/or free recall; M3, clear impairment in learning and/or free recall; and M4, complete amnesic syndrome. With this new amnesia classification, we studied the chronological progression of all patients diagnosed without dementia from baseline to DAT conversion using the Kaplan-Meier estimator of survival probability (Log Rank/Mantel Cox comparison. χ2  = 171.84, p = 0.001).

CONCLUSION: This new classification of memory impairment can help increase the prediction certainty of conversion from amnestic MCI to AD and improve research on AD biomarkers and their relationship with memory as the principal manifestation of AD.

%B J Alzheimers Dis %V 53 %P 705-12 %8 2016 May 04 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163821?dopt=Abstract %R 10.3233/JAD-160117 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reduction of Amyloid-β Plasma Levels by Hemodialysis: An Anti-Amyloid Treatment Strategy? %A Tholen, Susanne %A Schmaderer, Christoph %A Chmielewski, Stefan %A Förstl, Hans %A Heemann, Uwe %A Baumann, Marcus %A Steubl, Dominik %A Grimmer, Timo %K Adult %K Aged %K Aged, 80 and over %K Amyloid beta-Peptides %K Cognition Disorders %K Enzyme-Linked Immunosorbent Assay %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Renal Dialysis %X

BACKGROUND: Cognitive impairment in hemodialysis patients is common, but the underlying pathogenesis remains unclear. Alzheimer's disease is the most common cause of dementia in the general elderly population. Histopathological hallmarks are, among others, senile plaques, which consist of amyloid-β (Aβ).

OBJECTIVE: To measure plasma levels of Aβ42 and Aβ40 during hemodialysis and to examine potential associations with cognitive performance in cognitively impaired hemodialysis patients.

METHODS: Plasma samples of 26 hemodialysis patients were collected shortly before, after 50% of dialysis time, and at the end of a dialysis session. Aβ42 and Aβ40 levels were measured by a high-sensitivity ELISA for human amyloid-β. Cognition was tested under standardized conditions using the Montreal Cognitive Assessment (MoCA) as proposed previously.

RESULTS: Clearance rates of both peptides during one dialysis session were 22% and 35% for Aβ42 and Aβ40, respectively. Aβ42 but not Aβ40 baseline levels were significantly associated with MoCA test results (r = 0.654, p = 0.001).

CONCLUSION: In cognitively impaired hemodialysis patients plasma Aβ42 levels were associated with cognitive performance and both Aβ42 and Aβ40 plasma levels could be effectively reduced by dialysis. By inducing peripheral Aβ sink, hemodialysis may be considered as an anti-amyloid treatment strategy.

%B J Alzheimers Dis %V 50 %P 791-6 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682683?dopt=Abstract %R 10.3233/JAD-150662 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reelin in Alzheimer's Disease, Increased Levels but Impaired Signaling: When More is Less. %A Cuchillo-Ibañez, Inmaculada %A Balmaceda, Valeria %A Mata-Balaguer, Trinidad %A Lopez-Font, Inmaculada %A Sáez-Valero, Javier %X

In the continuing search for proteins that play a role in Alzheimer's disease (AD) and that are related to the pathological hallmarks, those that influence cognitive function and that constitute potential therapeutic targets deserve special interest. Reelin is a signaling protein that is involved in a cascade of cytoplasmic events that control tau phosphorylation and that regulate synaptic neurotransmission, plasticity, and memory. Both Reelin expression and glycosylation are modulated by amyloid-β (Aβ), suggesting that the activity of Reelin could be affected in AD and hence, its possible influence on this pathology should be taken into consideration. The levels of Reelin in the brain of AD patients appear to be altered and interestingly, disrupted Reelin signaling is associated with increased tau phosphorylation as well as with amyloid-β protein precursor processing. We discuss here the somewhat contradictory data regarding Reelin levels in AD and we evaluate the processing of the Reelin receptor, ApoER2, and other downstream events, such as the phosphorylation of the intracellular adapter Dab1. Together with brain Reelin levels, these changes may represent a relevant read-out of Reelin signaling in the human brain.

%B J Alzheimers Dis %V 52 %P 403-16 %8 2016 Mar 26 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031488?dopt=Abstract %R 10.3233/JAD-151193 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Regular Benzodiazepine and Z-Substance Use and Risk of Dementia: An Analysis of German Claims Data. %A Gomm, Willy %A von Holt, Klaus %A Thomé, Friederike %A Broich, Karl %A Maier, Wolfgang %A Weckbecker, Klaus %A Fink, Anne %A Doblhammer, Gabriele %A Haenisch, Britta %X

BACKGROUND: While acute detrimental effects of benzodiazepine (BDZ), and BDZ and related z-substance (BDZR) use on cognition and memory are known, the association of BDZR use and risk of dementia in the elderly is controversially discussed. Previous studies on cohort or claims data mostly show an increased risk for dementia with the use of BDZs or BDZRs. For Germany, analyses on large population-based data sets are missing.

OBJECTIVE: To evaluate the association between regular BDZR use and incident any dementia in a large German claims data set.

METHODS: Using longitudinal German public health insurance data from 2004 to 2011 we analyzed the association between regular BDZR use (versus no BDZR use) and incident dementia in a case-control design. We examined patient samples aged≥60 years that were free of dementia at baseline. To address potential protopathic bias we introduced a lag time between BDZR prescription and dementia diagnosis. Odds ratios were calculated applying conditional logistic regression, adjusted for potential confounding factors such as comorbidities and polypharmacy.

RESULTS: The regular use of BDZRs was associated with a significant increased risk of incident dementia for patients aged≥60 years (adjusted odds ratio [OR] 1.21, 95% confidence interval [CI] 1.13-1.29). The association was slightly stronger for long-acting substances than for short-acting ones. A trend for increased risk for dementia with higher exposure was observed.

CONCLUSION: The restricted use of BDZRs may contribute to dementia prevention in the elderly.

%B J Alzheimers Dis %V 54 %P 801-8 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567804?dopt=Abstract %R 10.3233/JAD-151006 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reliability and Validity of a Novel Internet-Based Battery to Assess Mood and Cognitive Function in the Elderly. %A Myers, Candice A %A Keller, Jeffrey N %A Allen, H Raymond %A Brouillette, Robert M %A Foil, Heather %A Davis, Allison B %A Greenway, Frank L %A Johnson, William D %A Martin, Corby K %X

Dementia is a chronic condition in the elderly and depression is often a concurrent symptom. As populations continue to age, accessible and useful tools to screen for cognitive function and its associated symptoms in elderly populations are needed. The aim of this study was to test the reliability and validity of a new internet-based assessment battery for screening mood and cognitive function in an elderly population. Specifically, the Helping Hand Technology (HHT) assessments for depression (HHT-D) and global cognitive function (HHT-G) were evaluated in a sample of 57 elderly participants (22 male, 35 female) aged 59-85 years. The study sample was categorized into three groups: 1) dementia (n = 8; Mini-Mental State Exam (MMSE) score 10-24), 2) mild cognitive impairment (n = 24; MMSE score 25-28), and 3) control (n = 25; MMSE score 29-30). Test-retest reliability (Pearson correlation coefficient, r) and internal consistency reliability (Cronbach's alpha, α) of the HHT-D and HHT-G were assessed. Validity of the HHT-D and HHT-G was tested via comparison (Pearson r) to commonly used pencil-and-paper based assessments: HHT-D versus the Geriatric Depression Scale (GDS) and HHT-G versus the MMSE. Good test-retest (r = 0.80; p < 0.0001) and acceptable internal consistency reliability (α= 0.73) of the HHT-D were established. Moderate support for the validity of the HHT-D was obtained (r = 0.60 between the HHT-D and GDS; p < 0.0001). Results indicated good test-retest (r = 0.87; p < 0.0001) and acceptable internal consistency reliability (α= 0.70) of the HHT-G. Validity of the HHT-G was supported (r = 0.71 between the HHT-G and MMSE; p < 0.0001). In summary, the HHT-D and HHT-G were found to be reliable and valid computerized assessments to screen for depression and cognitive status, respectively, in an elderly sample.

%B J Alzheimers Dis %V 54 %P 1359-1364 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589529?dopt=Abstract %R 10.3233/JAD-160441 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Retinal oximetry imaging in Alzheimer's disease. %A Einarsdottir, Anna Bryndis %A Hardarson, Sveinn Hakon %A Kristjansdottir, Jona Valgerdur %A Bragason, David Thor %A Snaedal, Jon %A Stefánsson, Einar %K Aged %K Alzheimer Disease %K Case-Control Studies %K Female %K Hemoglobins %K Humans %K Male %K Middle Aged %K Oximetry %K Oxygen %K Oxygen Consumption %K Regional Blood Flow %K Retina %K Retinal Vessels %X

BACKGROUND: Structural and physiological abnormalities have been reported in the retina in Alzheimer's disease (AD). Retinal oximetry detects changes in retinal oxygen metabolism in many eye diseases, where structural changes are seen.

OBJECTIVE: To compare oxygen saturation in retinal blood vessels in patients with AD and a healthy cohort.

METHODS: Oxygen saturation of hemoglobin was measured in retinal blood vessels, using imaging with spectrophotometric noninvasive retinal oximeter. 18 individuals with mild to moderate dementia of the Alzheimer-type (stage 3-5 according to the Global Deterioration Scale) and 18 healthy subjects underwent retinal oximetry in a case control study.

RESULTS: Retinal oxygen saturation in arterioles and venules in patients with moderate AD was significantly elevated compared to healthy individuals. Retinal arterioles have 94.2 ± 5.4% oxygen saturation in moderate AD compared with 90.5 ± 3.1% in healthy subjects (mean ± SD, n = 10, p = 0.028). Retinal venules were 51.9 ± 6.0% saturated in moderate AD compared with 49.7 ± 7.0% in healthy subjects (mean ± SD, n = 10, p = 0.02).

CONCLUSION: This is the first study of retinal oxygen metabolism in any central nervous system disease. It discovers abnormalities in retinal oxygen metabolism in AD. The findings are similar to those seen in age-related macular degeneration and diabetic retinopathy. Noninvasive retinal oximetry may offer new insights into pathophysiology of AD. Further studies are needed to confirm and expand these findings.

%B J Alzheimers Dis %V 49 %P 79-83 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444785?dopt=Abstract %R 10.3233/JAD-150457 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reversal of ApoE4-Driven Brain Pathology by Vascular Endothelial Growth Factor Treatment. %A Salomon-Zimri, Shiran %A Glat, Micaela Johanna %A Barhum, Yael %A Luz, Ishai %A Boehm-Cagan, Anat %A Liraz, Ori %A Ben-Zur, Tali %A Offen, Daniel %A Michaelson, Daniel M %X

Apolipoprotein E4 (ApoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is associated with increased neurodegeneration and vascular impairments. Vascular endothelial growth factor (VEGF), originally described as a key angiogenic factor, has recently been shown to play a crucial role in the nervous system. The objective of this research is to examine the role of VEGF in mediating the apoE4-driven pathologies. We show that hippocampal VEGF levels are lower in apoE4 targeted replacement mice compared to the corresponding apoE3 mice. This effect was accompanied by a specific decrease in both VEGF receptor-2 and HIF1-α. We next set to examine whether upregulation of VEGF can reverse apoE4-driven pathologies, namely the accumulation of hyperphosphorylated tau (AT8) and Aβ42, and reduced levels of the pre-synaptic marker, VGluT1, and of the ApoE receptor, ApoER2. This was first performed utilizing intra-hippocampal injection of VEGF-expressing-lentivirus (LV-VEGF). This revealed that LV-VEGF treatment reversed the apoE4-driven cognitive deficits and synaptic pathologies. The levels of Aβ42 and AT8, however, were increased in apoE3 mice, masking any potential effects of this treatment on the apoE4 mice. Follow-up experiments utilizing VEGF-expressing adeno-associated-virus (AAV-VEGF), which expresses VEGF specifically under the GFAP astrocytic promoter, prevented this effects on apoE3 mice, and reversed the apoE4-related increase in Aβ42 and AT8. Taken together, these results suggest that apoE4-driven pathologies are mediated by a VEGF-dependent pathway, resulting in cognitive impairments and brain pathology. These animal model findings suggest that the VEGF system is a promising target for the treatment of apoE4 carriers in AD.

%B J Alzheimers Dis %V 53 %P 1443-58 %8 2016 Jun 30 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372644?dopt=Abstract %R 10.3233/JAD-160182 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reversal of LTP-Like Cortical Plasticity in Alzheimer's Disease Patients with Tau-Related Faster Clinical Progression. %A Koch, Giacomo %A Di Lorenzo, Francesco %A Del Olmo, Miguel Fernandez %A Bonní, Sonia %A Ponzo, Viviana %A Caltagirone, Carlo %A Bozzali, Marco %A Martorana, Alessandro %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognition %K Disease Progression %K Evoked Potentials, Motor %K Female %K Humans %K Male %K Motor Cortex %K Neuronal Plasticity %K Neuropsychological Tests %K Phosphorylation %K tau Proteins %K Transcranial Magnetic Stimulation %X

Cerebrospinal fluid (CSF) concentrations of amyloid-β (Aβ), total tau (t-tau), and phosphorylated tau proteins are associated with different clinical progression in Alzheimer's disease (AD). We enrolled forty newly diagnosed AD patients, who underwent lumbar puncture, and carried out a K-means cluster analysis based on CSF biomarkers levels, resulting in two AD patient groups: Cluster 1 showed relatively high levels of Aβ and low levels of tau; Cluster 2 showed relatively low levels of Aβ and high levels of tau. Cortical plasticity was tested using the intermittent and continuous theta burst stimulation (iTBS and cTBS) protocols evoking respectively long-term potentiation (LTP) and depression (LTD). Cholinergic transmission was tested by the short-latency afferent inhibition protocol. Neurophysiological evaluation showed that the two AD groups differed in terms of cortical plasticity: after iTBS, Cluster 2 patients showed a remarkable reversal of LTP toward LTD that was not observed in Cluster 1. LTD and central cholinergic transmission did not differ between groups. Patients were assessed longitudinally with Mini-Mental State Examination at 6, 12, and 18 month follow-ups. Cluster 2 AD had a faster cognitive decline already evident at the 12 month follow-up. High tau CSF levels were associated with LTD-like cortical plasticity and faster clinical progression. These results suggest that more aggressive tau pathology is associated with prominent LTD-like mechanisms of cortical plasticity and faster cognitive decline.

%B J Alzheimers Dis %V 50 %P 605-16 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757193?dopt=Abstract %R 10.3233/JAD-150813 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings. %A Baiardi, Simone %A Capellari, Sabina %A Ladogana, Anna %A Strumia, Silvia %A Santangelo, Mario %A Pocchiari, Maurizio %A Parchi, Piero %K Aged %K Aged, 80 and over %K Brain %K Creutzfeldt-Jakob Syndrome %K Female %K Genotype %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Phenotype %K Prions %X

The Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex. Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients (4.9%) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall clinical disease, a high prevalence of periodic sharp-wave complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG findings, and cerebrospinal fluid concentration below threshold for the diagnosis of "probable" CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups. While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene, our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings between cases according to the dominant PrPSc type (type 1 versus type 2).

%B J Alzheimers Dis %V 50 %P 465-76 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682685?dopt=Abstract %R 10.3233/JAD-150668 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Risk Assessment of Alzheimer's Disease using the Information Diffusion Model from Structural Magnetic Resonance Imaging. %A Beheshti, Iman %A Olya, Hossain G T %A Demirel, Hasan %X

BACKGROUND: Recently, automatic risk assessment methods have been a target for the detection of Alzheimer's disease (AD) risk.

OBJECTIVE: This study aims to develop an automatic computer-aided AD diagnosis technique for risk assessment of AD using information diffusion theory.

METHODS: Information diffusion is a fuzzy mathematics logic of set-value that is used for risk assessment of natural phenomena, which attaches fuzziness (uncertainty) and incompleteness. Data were obtained from voxel-based morphometry analysis of structural magnetic resonance imaging.

RESULTS AND CONCLUSION: The information diffusion model results revealed that the risk of AD increases with a reduction of the normalized gray matter ratio (p > 0.5, normalized gray matter ratio <40%). The information diffusion model results were evaluated by calculation of the correlation of two traditional risk assessments of AD, the Mini-Mental State Examination and the Clinical Dementia Rating. The correlation results revealed that the information diffusion model findings were in line with Mini-Mental State Examination and Clinical Dementia Rating results. Application of information diffusion model contributes to the computerization of risk assessment of AD, which has a practical implication for the early detection of AD.

%B J Alzheimers Dis %V 52 %P 1335-42 %8 2016 Apr 05 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060960?dopt=Abstract %R 10.3233/JAD-151176 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Role of Alzheimer's and Cerebrovascular Pathology in Mediating the Effects of Age, Race, and Apolipoprotein E Genotype on Dementia Severity in Pathologically-Confirmed Alzheimer's Disease. %A Gavett, Brandon E %A John, Samantha E %A Gurnani, Ashita S %A Bussell, Cara A %A Saurman, Jessica L %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Apolipoproteins E %K Cerebrovascular Disorders %K Continental Population Groups %K Dementia %K Educational Status %K Female %K Genotype %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Models, Theoretical %X

BACKGROUND: Dementia severity can be modeled as the construct δ, representing the "cognitive correlates of functional status."

OBJECTIVE: We recently validated a model for estimating δ in the National Alzheimer's Coordinating Center's Uniform Data Set; however, the association of δ with neuropathology remains untested.

METHODS: We used data from 727 decedents evaluated at Alzheimer's Disease (AD) Centers nationwide. Participants spoke English, had no genetic abnormalities, and were pathologically diagnosed with AD as a primary or contributing etiology. Clinical data from participants' last visit prior to death were used to estimate dementia severity (δ).

RESULTS: A structural equation model using age, education, race, and apolipoprotein E (APOE) genotype (number of ɛ2 and ɛ4 alleles) as predictors and latent AD pathology and cerebrovascular disease (CVD) pathology as mediators fit the data well (RMSEA = 0.031; CFI = 0.957). AD pathology mediated the effects of age and APOE genotype on dementia severity. An older age at death and more ɛ2 alleles were associated with less AD pathology and, in turn, with less severe dementia. In contrast, more ɛ4 alleles were associated with more pathology and more severe dementia. Although age and race contributed to differences in CVD pathology, CVD pathology was not related to dementia severity in this sample of decedents with pathologically-confirmed AD.

CONCLUSIONS: Using δ as an estimate of dementia severity fits well within a structural model in which AD pathology directly affects dementia severity and mediates the relationship between age and APOE genotype on dementia severity.

%B J Alzheimers Dis %V 49 %P 531-45 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444761?dopt=Abstract %R 10.3233/JAD-150252 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Safety and Efficacy of Medical Cannabis Oil for Behavioral and Psychological Symptoms of Dementia: An-Open Label, Add-On, Pilot Study. %A Shelef, Assaf %A Barak, Yoram %A Berger, Uri %A Paleacu, Diana %A Tadger, Shelly %A Plopsky, Igor %A Baruch, Yehuda %K Aged %K Aged, 80 and over %K Antipsychotic Agents %K Behavioral Symptoms %K Cognition Disorders %K Dementia %K Female %K Humans %K Male %K Medical Marijuana %K Neuropsychological Tests %K Outcome Assessment (Health Care) %K Physical Examination %K Pilot Projects %K Prospective Studies %K Psychiatric Status Rating Scales %X

BACKGROUND: Tetrahydrocannabinol (THC) is a potential treatment for Alzheimer's disease (AD).

OBJECTIVE: To measure efficacy and safety of medical cannabis oil (MCO) containing THC as an add-on to pharmacotherapy, in relieving behavioral and psychological symptoms of dementia (BPSD).

METHODS: Eleven AD patients were recruited to an open label, 4 weeks, prospective trial.

RESULTS: Ten patients completed the trial. Significant reduction in CGI severity score (6.5 to 5.7; p <  0.01) and NPI score were recorded (44.4 to 12.8; p <  0.01). NPI domains of significant decrease were: Delusions, agitation/aggression, irritability, apathy, sleep and caregiver distress.

CONCLUSION: Adding MCO to AD patients' pharmacotherapy is safe and a promising treatment option.

%B J Alzheimers Dis %V 51 %P 15-9 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757043?dopt=Abstract %R 10.3233/JAD-150915 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Safety and Tolerability of R(+) Pramipexole in Mild-to-Moderate Alzheimer's Disease. %A Bennett, James %A Burns, Jeffrey %A Welch, Paul %A Bothwell, Rebecca %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Benzothiazoles %K Biomarkers %K Brain %K Female %K Glucose %K Humans %K Male %K Neuropsychological Tests %K Nootropic Agents %K Peptide Fragments %K Positron-Emission Tomography %K Severity of Illness Index %K tau Proteins %K Treatment Outcome %X

Alzheimer's disease (AD) is an aging-related, degenerative brain disease of adults. Most (∼95%) of AD occurs sporadically and is associated with early-appearing deficits in brain regional glucose uptake, changes in cerebrospinal fluid (CSF) AD-related proteins, regional brain atrophy, and oxidative stress damage. We treated mild-moderate AD individuals with R(+)-pramipexole-dihydrochloride (R(+)PPX), a neuroprotective, lipophilic-cation, free-radical scavenger that accumulates into brain and mitochondria. 19 subjects took R(+)PPX twice a day in increasing daily doses up to 300 mg/day under a physician-sponsor IND (60,948, JPB), IRB-approved protocol and quarterly external safety committee monitoring. 15 persons finished and contributed baseline and post-treatment serum, lumbar spinal fluid, brain 18F-2DG PET scans, and ADAS-Cog scores. ADAS-Cog scores did not change (n = 1), improved (n = 2), declined 1-3 points (n = 5), or declined 4-13 points (n = 8) over 6 months of R(+)PPX treatment. Serum PPX levels were not related to changes in ADAS-Cog scores. Fasting AM serum PPX levels at 6 months varied considerably across subjects and correlated strongly with CSF [PPX] (r = 0.97, p <  0.0001). CSF [PPX] was not related to CSF [Aβ(42)], [Tau], or [P-Tau]. Regional 18F-2DG measures of brain glucose uptake demonstrated a 3-6% decline during R(+)PPX treatment. 56 mild-moderate adverse events occurred, 26 probably/definitely related to R(+)PPX use, with 4 withdrawals. R(+)PPX was generally well-tolerated and entered brain extracellular space linearly. Further studies of R(+)PPX in AD should include a detailed pharmacokinetic study of peak and trough serum [PPX] variations among subjects prior to planning any larger studies that would be needed to determine efficacy in altering disease progression.

%B J Alzheimers Dis %V 49 %P 1179-87 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682692?dopt=Abstract %R 10.3233/JAD-150788 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Savvy Caregiver Program: A Probe Multicenter Randomized Controlled Pilot Trial in Caregivers of Patients Affected by Alzheimer's Disease. %A Sepe-Monti, Micaela %A Vanacore, Nicola %A Bartorelli, Luisa %A Tognetti, Alessandra %A Giubilei, Franco %X

Alzheimer's disease (AD) is a major cause of disability in the elderly, leading to a considerable burden on caregivers and high costs to society. Psycho-education programs such as the Savvy Caregiver Program (SCP) are reported to be a successful means of reducing caregivers' distress through various intervention strategies. The aim of the present study was to assess the efficacy of the SCP in reducing the burden and psychological symptoms in caregivers of AD patients and to analyze the coping strategies adopted by the caregivers. The study was designed as a multicenter, randomized, controlled, pilot clinical trial. One hundred and sixty-four caregivers of patients with probable AD were randomized. The SCP was structured in six, weekly, two-hour sessions. All the clinical scales were administered before treatment, two weeks and six months after treatment. Caregivers in the SCP group displayed better coping strategies adopted to positive attitudes, and they tended to be less anxious and less depressed than those in the control group. However, caregiver burden levels were not reduced in SCP caregivers. The patients of SCP caregivers received a lower number of new prescriptions of neuroleptics during the 6 months of follow-up than the patients of control caregivers and apathy was the neuropsychiatric symptom that improved most as a result of the SCP. The results of this study suggest that the SCP may improve coping strategies of caregivers of people affected by AD, influencing their psychological symptoms and those of their patients.

%B J Alzheimers Dis %V 54 %P 1235-1246 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567824?dopt=Abstract %R 10.3233/JAD-160235 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Searching for Primary Predictors of Conversion from Mild Cognitive Impairment to Alzheimer's Disease: A Multivariate Follow-Up Study. %A López, María Eugenia %A Turrero, Agustín %A Cuesta, Pablo %A López-Sanz, David %A Bruña, Ricardo %A Marcos, Alberto %A Gil, Pedro %A Yus, Miguel %A Barabash, Ana %A Cabranes, José Antonio %A Maestú, Fernando %A Fernández, Alberto %X

Recent proposals of diagnostic criteria within the healthy aging-Alzheimer's disease (AD) continuum stressed the role of biomarker information. More importantly, such information might be critical to predict those mild cognitive impairment (MCI) patients at a higher risk of conversion to AD. Usually, follow-up studies utilize a reduced number of potential markers although the conversion phenomenon may be deemed as multifactorial in essence. In addition, not only biological but also cognitive markers may play an important role. Considering this background, we investigated the role of cognitive reserve, cognitive performance in neuropsychological testing, hippocampal volumes, APOE genotype, and magnetoencephalography power sources to predict the conversion to AD in a sample of 33 MCI patients. MCIs were followed up during a 2-year period and divided into two subgroups according to their outcome: The "stable" MCI group (sMCI, 21 subjects) and the "progressive" MCI group (pMCI, 12 subjects). Baseline multifactorial information was submitted to a hierarchical logistic regression analysis to build a predictive model of conversion to AD. Results indicated that the combination of left hippocampal volume, occipital cortex theta power, and clock drawing copy subtest scores predicted conversion to AD with a 100% of sensitivity and 94.7% of specificity. According to these results it might be suggested that anatomical, cognitive, and neurophysiological markers may be considered as "first order" predictors of progression to AD, while APOE or cognitive reserve proxies might play a more secondary role.

%B J Alzheimers Dis %V 52 %P 133-43 %8 2016 03 05 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060953?dopt=Abstract %R 10.3233/JAD-151034 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Self-Consciousness in Patients with Behavioral Variant Frontotemporal Dementia. %A Arroyo-Anlló, Eva M %A Bouston, Adèle Turpin %A Fargeau, Marie-Noëlle %A Orgaz Baz, Begõna %A Gil, Roger %K Aged %K Brain %K Educational Status %K Female %K Frontotemporal Dementia %K Humans %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Positron-Emission Tomography %K Psychological Tests %K Self Concept %X

Self-consciousness (SC) is multifaceted and considered to be the consciousness of one's own mental states. The medial prefrontal cortex may play a critical role in SC. The main aim of this paper was to examine SC in patients with behavioral variant frontotemporal dementia, who are characterized more by changes in personal, social, and emotional conduct and loss of insight than by cognitive disturbances. Control and patient groups of 21 subjects each, matched by age, educational level, gender, and nationality were assessed using a SC questionnaire. It measures several aspects: Personal identity, Anosognosia, Affective state, Body representation, Prospective memory, Introspection, and Moral judgments. The most disturbed ones in patients were Anosognosia, Affective state, and Moral judgments, and the least disturbed aspects were awareness of identity and of body representation. No significant correlations were found between the SC score and any clinical or demographical characteristics. The core deficiency of SC in patients was related to behavioral SC aspects, which are more dependent on orbito-frontal functioning.

%B J Alzheimers Dis %V 49 %P 1021-9 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599058?dopt=Abstract %R 10.3233/JAD-150821 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Sensitivity of Neuropsychological Tests to Identify Cognitive Decline in Highly Educated Elderly Individuals: 12 Months Follow up. %A Elkana, Odelia %A Eisikovits, Osnat Reichman %A Oren, Noga %A Betzale, Vered %A Giladi, Nir %A Ash, Elissa L %K Aged %K Aged, 80 and over %K Aging %K Brain %K Cognition Disorders %K Educational Status %K Female %K Follow-Up Studies %K Humans %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Sensitivity and Specificity %K Statistics as Topic %X

Highly educated individuals have a lower risk of developing dementia and Alzheimer's disease (AD). A common assumption is that their "cognitive reserve" protects them from cognitive decline and postpones the clinical manifestation of dementia. These highly educated individuals usually obtain normal scores on cognitive screening tests, although at the same time they can experience subjective cognitive decline and difficulty in multiple cognitive domains. Although comprehensive neuropsychological evaluations usually identify subtle changes in cognition, they demand extensive resources and thus are expensive and difficult to obtain. Therefore, lack of sensitivity of screening tests on the one hand, along with difficulty to acquire a comprehensive neuropsychological evaluation on the other hand, impede identification of cognitive decline at its earliest stages in this special population. Accordingly, this study aims to identify which neuropsychological tests have the highest sensitivity to detect the earliest stages of cognitive decline among highly educated elderly [n = 27, ages 66-80 (mean = 72.6 SD = 4.54), mean education level = 17.14 (SD = 3.21 range: 12-24 years)]. Baseline scores and scores at one-year follow up were obtained. We also conducted MRI scans to characterize the relation between brain volume and cognitive performance. Results show significant reductions in RVALT, Semantic verbal Fluency, ROCF copy, and MoCA scores whereas PF, TMT, ROCF delay, digit span, and knowledge tests were not significant. The study stresses the importance of using sensitive neuropsychological tests to examine this special population and the need to create norms that combine an individual's education with age.

%B J Alzheimers Dis %V 49 %P 607-16 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484925?dopt=Abstract %R 10.3233/JAD-150562 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Serum Uric Acid and Its Association with Longitudinal Cognitive Change Among Urban Adults. %A Beydoun, May A %A Canas, Jose-Atilio %A Dore, Gregory A %A Beydoun, Hind A %A Rostant, Ola S %A Fanelli-Kuczmarski, Marie T %A Evans, Michele K %A Zonderman, Alan B %X

Uric acid, a waste metabolite among humans, was linked to various cognitive outcomes. We describe sex and age-group specific associations of baseline serum uric acid (SUAbase) and significant change in SUA (ΔSUA: 1 versus 0 = decrease versus no change; 2 versus 0 = increase versus no change) with longitudinal annual rate of cognitive change among a large sample of urban adults. Data from the Healthy Aging in Neighborhoods of Diversity across the Life Span study, 2004-2009 (visit 1) and 2009-2013 (visit 2) were used. Of 3,720 adults selected at baseline (age range: 30-64 y), complete data were available for N = 1,487-1,602 with a mean repeat of 1.5-1.7 visits/participant. Cognitive test domains spanned attention, processing speed, learning/memory, executive function, visuo-spatial/visuo-construction ability, language/verbal, and global cognitive function. SUA was measured at both visits. Multiple mixed-effects regression analyses were conducted. In the total population, a higher SUAbase was associated with a faster annual rate of decline on a measure of visual memory/visuo-construction ability (the Benton Visual Retention Test) by γ= 0.07 with a standard error of 0.02, p < 0.001. Among older men, a significant increase in SUA was associated with slower decline on a test of attention/processing speed, namely Trailmaking test, Part A, measured in seconds to completion (γ= -6.91 ± 1.73, p < 0.001). In sum, a higher SUAbase was associated with faster cognitive decline over-time in a visual memory/visuo-construction ability test. ΔSUA had particular beneficial effects of an increasing ΔSUA on the domain of attention/processing speed among older men. More longitudinal studies are needed to examine cognitive domain-specific effects of over-time change in SUA within sex and age groups.

%B J Alzheimers Dis %V 52 %P 1415-30 %8 2016 Apr 21 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104899?dopt=Abstract %R 10.3233/JAD-160028 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Shared Genetic Risk Factors for Late-Life Depression and Alzheimer's Disease. %A Ye, Qing %A Bai, Feng %A Zhang, Zhijun %K Age of Onset %K Alzheimer Disease %K Animals %K Depressive Disorder %K Genetic Predisposition to Disease %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %X

BACKGROUND: Considerable evidence has been reported for the comorbidity between late-life depression (LLD) and Alzheimer's disease (AD), both of which are very common in the general elderly population and represent a large burden on the health of the elderly. The pathophysiological mechanisms underlying the link between LLD and AD are poorly understood. Because both LLD and AD can be heritable and are influenced by multiple risk genes, shared genetic risk factors between LLD and AD may exist.

OBJECTIVE: The objective is to review the existing evidence for genetic risk factors that are common to LLD and AD and to outline the biological substrates proposed to mediate this association.

METHODS: A literature review was performed.

RESULTS: Genetic polymorphisms of brain-derived neurotrophic factor, apolipoprotein E, interleukin 1-beta, and methylenetetrahydrofolate reductase have been demonstrated to confer increased risk to both LLD and AD by studies examining either LLD or AD patients. These results contribute to the understanding of pathophysiological mechanisms that are common to both of these disorders, including deficits in nerve growth factors, inflammatory changes, and dysregulation mechanisms involving lipoprotein and folate. Other conflicting results have also been reviewed, and few studies have investigated the effects of the described polymorphisms on both LLD and AD.

CONCLUSION: The findings suggest that common genetic pathways may underlie LLD and AD comorbidity. Studies to evaluate the genetic relationship between LLD and AD may provide insights into the molecular mechanisms that trigger disease progression as the population ages.

%B J Alzheimers Dis %V 52 %P 1-15 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060956?dopt=Abstract %R 10.3233/JAD-151129 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Short-Term Effects of Rhythmic Sensory Stimulation in Alzheimer's Disease: An Exploratory Pilot Study. %A Clements-Cortes, Amy %A Ahonen, Heidi %A Evans, Michael %A Freedman, Morris %A Bartel, Lee %X

This study assessed the effect of stimulating the somatosensory system of Alzheimer's disease (AD) patients at three stages of their illness with 40 Hz sound. In this AB cross-over study design, 18 participants (6 mild, 6 moderate, 6 severe) each participated in 13 sessions: one intake and 12 treatment. Treatment A consisted of 40 Hz sound stimulation and Treatment B consisted of visual stimulation using DVDs, each provided twice a week over 6 weeks for a total of 6 times per treatment. Outcome measures included: St. Louis University Mental Status Test (SLUMS), Observed Emotion Rating Scale, and behavioral observation by the researcher. Data were submitted to regression analysis for the series of 6 SLUMS scores in treatment A and 6 scores in B with comparison by group. The slopes for the full sample and subgroups in the 40 Hz treatment were all significant beyond alpha = 0.05, while those for the DVD were not. A thematic analysis of qualitative observations supported the statistical findings. 40 Hz treatment appeared to have the strongest impact on persons with mild and moderate AD. Results are promising in terms of a potential new treatment for persons with AD, and further research is needed.

%B J Alzheimers Dis %V 52 %P 651-60 %8 2016 Mar 25 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031491?dopt=Abstract %R 10.3233/JAD-160081 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Sirtuin 2 Inhibition Improves Cognitive Performance and Acts on Amyloid-β Protein Precursor Processing in Two Alzheimer's Disease Mouse Models. %A Biella, Gloria %A Fusco, Federica %A Nardo, Emanuele %A Bernocchi, Ottavia %A Colombo, Alessio %A Lichtenthaler, Stefan F %A Forloni, Gianluigi %A Albani, Diego %X

The neuropathological hallmarks of Alzheimer's disease (AD) are extracellular plaques built up by the accumulation of the amyloid-β protein precursor (AβPP)-derived peptide β (Aβ), and intracellular tangles of hyperphosphorylated tau protein. Sirtuin 2 (SIRT2) is a member of the sirtuin family, featuring conserved enzymes with deacetylase activity and involved in several cell molecular pathways. We investigated the importance of SIRT2 inhibition in AD. We inhibited SIRT2 by small molecules (AGK-2, AK-7) and examined AβPP metabolism in H4-SW neuroglioma cells overexpressing AβPP and two AD transgenic mouse models (3xTg-AD and APP23). The in vitro studies suggested that the inhibition of SIRT2 reduced Aβ production; in vivo data showed an improvement of cognitive performance in the novel object recognition test, and an effect on AβPP proteolytic processing leading to a reduction of soluble β-AβPP and an increase of soluble α-AβPP protein. In 3xTg-AD mice, we noticed that total tau protein level rose. Overall, our pre-clinical data support a role for SIRT2 inhibition in the improvement of cognitive performance and the modulation of molecular mechanisms relevant for AD, thus deserving attention as possible therapeutic strategy.

%B J Alzheimers Dis %V 53 %P 1193-207 %8 2016 Jun 30 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372638?dopt=Abstract %R 10.3233/JAD-151135 %0 Journal Article %J J Alzheimers Dis %D 2016 %T So Close Yet So Far: Executive Contribution to Memory Processing in Behavioral Variant Frontotemporal Dementia. %A Bertoux, Maxime %A Ramanan, Siddharth %A Slachevsky, Andrea %A Wong, Stephanie %A Henriquez, Fernando %A Musa, Gada %A Delgado, Carolina %A Flanagan, Emma %A Bottlaender, Michel %A Sarazin, Marie %A Hornberger, Michael %A Dubois, Bruno %X

BACKGROUND: Memory impairment in behavioral variant frontotemporal dementia (bvFTD) is traditionally considered to be mild and attributed to prefrontal cortex dysfunction. Recent studies, however, indicated that some patients can present with a memory impairment of the hippocampal type, showing storage and consolidation deficits in addition to the more executive/prefrontal related encoding and strategic difficulties.

OBJECTIVE: This study aimed to study the relationship between executive functions (EF) and memory processes in bvFTD via a data-driven approach.

METHOD: Participants consisted of 71 bvFTD (among which 60.6% had a lumbar puncture showing non-Alzheimer biomarker profile) and 60 controls (among which 45% had amyloid imaging showing a normal profile). EF were assessed by the Frontal Assessment Battery, semantic/lexical verbal fluency tests, and forward/backward digit spans. Patients were split into amnestic (n = 33) and non-amnestic (n = 38) subgroups based on normative data (total recall score) from the Free and Cued Selective Reminding Test (FCSRT). Relationships between FCSRT subscores and EF measures were explored through hierarchical clustering analysis, partial correlation analysis with an EF component, and automated linear modeling.

RESULTS: Convergent findings across the statistical approaches show that, overall, memory performance was independent from EF in bvFTD whereas the relationship was stronger in controls. Indeed, in bvFTD, memory performance did not cluster with EF, was not correlated with the EF component, and was only partially (4% - 12.7%) predicted by EF.

DISCUSSION: These findings show that executive dysfunctions cannot solely explain the memory deficits occurring in bvFTD. Indeed, some patients present with a genuine amnesia affecting storage and consolidation abilities, which are independent from executive dysfunctions. On the clinical level, this study highlights the importance of revising the neuropsychological diagnosis criteria for bvFTD.

%B J Alzheimers Dis %V 54 %P 1005-1014 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567869?dopt=Abstract %R 10.3233/JAD-160522 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Social Cognition Deficits: The Key to Discriminate Behavioral Variant Frontotemporal Dementia from Alzheimer's Disease Regardless of Amnesia? %A Bertoux, Maxime %A de Souza, Leonardo Cruz %A O'Callaghan, Claire %A Greve, Andrea %A Sarazin, Marie %A Dubois, Bruno %A Hornberger, Michael %K Aged %K Alzheimer Disease %K Amnesia %K Cognition %K Diagnosis, Differential %K Emotions %K Female %K Frontotemporal Dementia %K Humans %K Male %K Memory, Episodic %K Neuropsychological Tests %K Social Perception %X

Relative sparing of episodic memory is a diagnostic criterion of behavioral variant frontotemporal dementia (bvFTD). However, increasing evidence suggests that bvFTD patients can show episodic memory deficits at a similar level as Alzheimer's disease (AD). Social cognition tasks have been proposed to distinguish bvFTD, but no study to date has explored the utility of such tasks for the diagnosis of amnestic bvFTD. Here, we contrasted social cognition performance of amnestic and non-amnestic bvFTD from AD, with a subgroup having confirmed in vivo pathology markers. Ninety-six participants (38 bvFTD and 28 AD patients as well as 30 controls) performed the short Social-cognition and Emotional Assessment (mini-SEA). BvFTD patients were divided into amnestic versus non-amnestic presentation using the validated Free and Cued Selective Reminding Test (FCSRT) assessing episodic memory. As expected, the accuracy of the FCSRT to distinguish the overall bvFTD group from AD was low (69.7% ) with ∼50% of bvFTD patients being amnestic. By contrast, the diagnostic accuracy of the mini-SEA was high (87.9% ). When bvFTD patients were split on the level of amnesia, mini-SEA diagnostic accuracy remained high (85.1% ) for amnestic bvFTD versus AD and increased to very high (93.9% ) for non-amnestic bvFTD versus AD. Social cognition deficits can distinguish bvFTD and AD regardless of amnesia to a high degree and provide a simple way to distinguish both diseases at presentation. These findings have clear implications for the diagnostic criteria of bvFTD. They suggest that the emphasis should be on social cognition deficits with episodic memory deficits not being a helpful diagnostic criterion in bvFTD.

%B J Alzheimers Dis %V 49 %P 1065-74 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26756325?dopt=Abstract %R 10.3233/JAD-150686 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Spatial Memory Impairment is Associated with Intraneural Amyloid-β Immunoreactivity and Dysfunctional Arc Expression in the Hippocampal-CA3 Region of a Transgenic Mouse Model of Alzheimer's Disease. %A Morin, Jean-Pascal %A Cerón-Solano, Giovanni %A Velázquez-Campos, Giovanna %A Pacheco-López, Gustavo %A Bermúdez-Rattoni, Federico %A Díaz-Cintra, Sofía %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Benzeneacetamides %K CA3 Region, Hippocampal %K Cytoskeletal Proteins %K Disease Models, Animal %K Gene Expression Regulation %K Humans %K Maze Learning %K Memory Disorders %K Mice %K Mice, Transgenic %K Mutation %K Nerve Tissue Proteins %K Neurons %K Presenilin-1 %K Pyridines %K tau Proteins %X

Dysfunction of synaptic communication in cortical and hippocampal networks has been suggested as one of the neuropathological hallmarks of the early stages of Alzheimer's disease (AD). Also, several lines of evidence have linked disrupted levels of activity-regulated cytoskeletal associated protein (Arc), an immediate early gene product that plays a central role in synaptic plasticity, with AD "synaptopathy". The mapping of Arc expression patterns in brain networks has been extensively used as a marker of memory-relevant neuronal activity history. Here we evaluated basal and behavior-induced Arc expression in hippocampal networks of the 3xTg-AD mouse model of AD. The basal percentage of Arc-expressing cells in 10-month-old 3xTg-AD mice was higher than wild type in CA3 (4.88% versus 1.77% , respectively) but similar in CA1 (1.75% versus 2.75% ). Noteworthy, this difference was not observed at 3 months of age. Furthermore, although a Morris water maze test probe induced a steep (∼4-fold) increment in the percentage of Arc+ cells in the CA3 region of the 10-month-old wild-type group, no such increment was observed in age-matched 3xTg-AD, whereas the amount of Arc+ cells in CA1 increased in both groups. Further, we detected that CA3 neurons with amyloid-β were much more likely to express Arc protein under basal conditions. We propose that in 3xTg-AD mice, intraneuronal amyloid-β expression in CA3 could increase unspecific neuronal activation and subsequent Arc protein expression, which might impair further memory-stabilizing processes.

%B J Alzheimers Dis %V 51 %P 69-79 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836189?dopt=Abstract %R 10.3233/JAD-150975 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Specific Triazine Herbicides Induce Amyloid-β42 Production. %A Portelius, Erik %A Durieu, Emilie %A Bodin, Marion %A Cam, Morgane %A Pannee, Josef %A Leuxe, Charlotte %A Mabondzo, Aloϊse %A Oumata, Nassima %A Galons, Hervé %A Lee, Jung Yeol %A Chang, Young-Tae %A Stϋber, Kathrin %A Koch, Philipp %A Fontaine, Gaëlle %A Potier, Marie-Claude %A Manousopoulou, Antigoni %A Garbis, Spiros D %A Covaci, Adrian %A Van Dam, Debby %A De Deyn, Peter %A Karg, Frank %A Flajolet, Marc %A Omori, Chiori %A Hata, Saori %A Suzuki, Toshiharu %A Blennow, Kaj %A Zetterberg, Henrik %A Meijer, Laurent %X

Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by secretases leads to extracellular release of amyloid-β (Aβ) peptides. Increased production of Aβ42 over Aβ40 and aggregation into oligomers and plaques constitute an Alzheimer's disease (AD) hallmark. Identifying products of the 'human chemical exposome' (HCE) able to induce Aβ42 production may be a key to understanding some of the initiating causes of AD and to generate non-genetic, chemically-induced AD animal models. A cell model was used to screen HCE libraries for Aβ42 inducers. Out of 3500+ compounds, six triazine herbicides were found that induced a β- and γ-secretases-dependent, 2-10 fold increase in the production of extracellular Aβ42 in various cell lines, primary neuronal cells, and neurons differentiated from human-induced pluripotent stem cells (iPSCs). Immunoprecipitation/mass spectrometry analyses show enhanced production of Aβ peptides cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and lower, a characteristic of AD. Neurons derived from iPSCs obtained from a familial AD (FAD) patient (AβPP K724N) produced more Aβ42 versus Aβ40 than neurons derived from healthy controls iPSCs (AβPP WT). Triazines enhanced Aβ42 production in both control and AD iPSCs-derived neurons. Triazines also shifted the cleavage pattern of alcadeinα, another γ-secretase substrate, suggesting a direct effect of triazines on γ-secretase activity. In conclusion, several widely used triazines enhance the production of toxic, aggregation prone Aβ42/Aβ43 amyloids, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in late-onset AD.

%B J Alzheimers Dis %V 54 %P 1593-1605 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589520?dopt=Abstract %R 10.3233/JAD-160310 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Standardized Uptake Value Ratio-Independent Evaluation of Brain Amyloidosis. %A Chincarini, Andrea %A Sensi, Francesco %A Rei, Luca %A Bossert, Irene %A Morbelli, Silvia %A Guerra, Ugo Paolo %A Frisoni, Giovanni %A Padovani, Alessandro %A Nobili, Flavio %X

The assessment of in vivo18F images targeting amyloid deposition is currently carried on by visual rating with an optional quantification based on standardized uptake value ratio (SUVr) measurements. We target the difficulties of image reading and possible shortcomings of the SUVr methods by validating a new semi-quantitative approach named ELBA. ELBA involves a minimal image preprocessing and does not rely on small, specific regions of interest (ROIs). It evaluates the whole brain and delivers a geometrical/intensity score to be used for ranking and dichotomic assessment. The method was applied to adniimages 18F-florbetapir images from the ADNI database. Five expert readers provided visual assessment in blind and open sessions. The longitudinal trend and the comparison to SUVr measurements were also evaluated. ELBA performed with area under the roc curve (AUC) = 0.997 versus the visual assessment. The score was significantly correlated to the SUVr values (r = 0.86, p < 10-4). The longitudinal analysis estimated a test/retest error of ≃2.3%. Cohort and longitudinal analysis suggests that the ELBA method accurately ranks the brain amyloid burden. The expert readers confirmed its relevance in aiding the visual assessment in a significant number (85) of difficult cases. Despite the good performance, poor and uneven image quality constitutes the major limitation.

%B J Alzheimers Dis %V 54 %P 1437-1457 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662288?dopt=Abstract %R 10.3233/JAD-160232 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Subjective Memory Complaints in APOEɛ4 Carriers are Associated with High Amyloid-β Burden. %A Zwan, Marissa D %A Villemagne, Victor L %A Doré, Vincent %A Buckley, Rachel %A Bourgeat, Pierrick %A Veljanoski, Robyn %A Salvado, Olivier %A Williams, Rob %A Margison, Laura %A Rembach, Alan %A Macaulay, S Lance %A Martins, Ralph %A Ames, David %A van der Flier, Wiesje M %A Ellis, Kathryn A %A Scheltens, Philip %A Masters, Colin L %A Rowe, Christopher C %K Aged %K Aging %K Amyloid beta-Peptides %K Aniline Compounds %K Apolipoprotein E4 %K Benzothiazoles %K Brain %K Cognition Disorders %K Female %K Genotyping Techniques %K Heterozygote %K Humans %K Logistic Models %K Male %K Neuropsychological Tests %K Positron-Emission Tomography %K Radiopharmaceuticals %K Thiazoles %X

BACKGROUND: APOEɛ4 genotype and aging have been identified as risk factors for Alzheimer's disease (AD). In addition, subjective memory complaints (SMC) might be a first clinical expression of the effect of AD pathology on cognitive functioning.

OBJECTIVE: To assess whether APOEɛ4 genotype, age, SMC, and episodic memory are risk factors for high amyloid-β (Aβ) burden in cognitively normal elderly.

METHODS: 307 cognitively normal participants (72.7 ± 6.8 years, 53% female, 55% SMC) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent amyloid PET and APOE genotyping. Logistic regression analyses were performed to determine the association of APOEɛ4 genotype, age, SMC, and episodic memory with Aβ pathology.

RESULTS: Odds of high Aβ burden were greater at an older age (OR = 3.21; 95% CI = 1.68-6.14), when SMC were present (OR = 1.90; 95% CI = 1.03-3.48), and for APOEɛ4 carriers (OR = 7.49; 95% CI = 3.96-14.15), while episodic memory was not associated with odds of high Aβ burden. Stratified analyses showed that odds of SMC for high Aβ burden were increased in specifically APOEɛ4 carriers (OR = 4.58, 95% CI = 1.83-11.49) and younger participants (OR = 3.73, 95% CI = 1.39-10.01).

CONCLUSION: Aging, APOEɛ4 genotype, and SMC were associated with high Aβ burden. SMC were especially indicative of high Aβ burden in younger participants and in APOEɛ4 carriers. These findings suggest that selection based on the presence of SMC, APOEɛ4 genotype and age may help identify healthy elderly participants with high Aβ burden eligible for secondary prevention trials.

%B J Alzheimers Dis %V 49 %P 1115-22 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639956?dopt=Abstract %R 10.3233/JAD-150446 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Tau in Late-Life Depression: A Systematic Review and Meta-Analysis. %A Brown, Eric E %A Iwata, Yusuke %A Chung, Jun Ku %A Gerretsen, Philip %A Graff-Guerrero, Ariel %X

A lifetime history of major depressive disorder (MDD) increases the risk of developing Alzheimer's disease, of which neurofibrillary tangles due to abnormal tau proteins are a hallmark. We systematically reviewed the literature on tau in MDD and identified 49 relevant articles spanning a number of modalities, including cerebrospinal fluid (CSF) analysis, positron emission tomography, and clinicopathological correlation. We compared CSF total and phosphorylated tau proteins in MDD and controls using a meta-analytic approach. We found no difference in total or phosphorylated tau in MDD. We also found no difference in a comparison of a subgroup excluding studies with significant age differences. Positron emission tomography studies lacked specificity. Clinicopathological studies failed to associate neurofibrillary tangles with MDD. The available data on tau in MDD is limited. The involvement of tau in a subset of MDD cannot be ruled out and requires prospective exploration.

%B J Alzheimers Dis %V 54 %P 615-33 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497481?dopt=Abstract %R 10.3233/JAD-160401 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A TgCRND8 Mouse Model of Alzheimer's Disease Exhibits Sexual Dimorphisms in Behavioral Indices of Cognitive Reserve. %A Granger, Matthew W %A Franko, Bettina %A Taylor, Matthew W %A Messier, Claude %A George-Hyslop, Peter St %A Bennett, Steffany A L %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Brain %K Cognitive Reserve %K Cyclic Nucleotide Phosphodiesterases, Type 6 %K Disease Models, Animal %K Female %K Humans %K Male %K Maze Learning %K Mice, Inbred C3H %K Mice, Inbred C57BL %K Mice, Transgenic %K Plaque, Amyloid %K Psychomotor Performance %K Sex Characteristics %K Spatial Memory %K Spatial Navigation %K Survival Analysis %X

Cognitive decline is sexually dimorphic in Alzheimer's disease (AD). Men show higher incidences of amnestic mild cognitive impairment yet women disproportionally phenoconvert to AD. It is hypothesized that men maintain greater cognitive reserve than women under comparable amyloid-β (Aβ) challenge. One behavioral aspect of cognitive reserve in mice is the capacity to cope with Aβ-associated stereotypies by switching to increasingly effective navigational search strategies in the Morris water maze. To explore inherent sex differences in this paradigm, however, we require an AβPP mouse model wherein behavioral flexibility is impaired earlier in females than males despite equivalent Aβ load. Here, we show that when F1 C57Bl/6×C3H/HeJ TgCRND8 mice are placed on C57Bl/6 background, N5 Tg males and females exhibit equivalent Aβ pathologies at 2, 4, 6, and 8 months of age yet females display learning and memory deficits earlier than males. We further show that this N5 line does not carry the autosomal recessive pde6brd1 mutation that impairs visual acuity and that the estrous cycle is not disrupted on this genetic background. At 5.5 months of age, Tg males, but not females, compensate for Aβ-associated stereotypic behaviors (i.e., hyperactive tight circling) by alternating navigational search strategies and adopting increasingly productive spatial search strategies. Females fail to overcome Aβ-associated stereotypies and do not efficiently switch from systematic to spatial learning strategies. Together, these data identify a novel AβPP mouse model that can be used for preclinical testing of interventions targeting sexual dimorphisms in behavioral indices of cognitive reserve.

%B J Alzheimers Dis %V 51 %P 757-73 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890738?dopt=Abstract %R 10.3233/JAD-150587 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Thyroid-Stimulating Hormone and Mild Cognitive Impairment: Results of the Heinz Nixdorf Recall Study. %A Winkler, Angela %A Weimar, Christian %A Jöckel, Karl-Heinz %A Erbel, Raimund %A Dragano, Nico %A Broecker-Preuss, Martina %A Moebus, Susanne %A Führer-Sakel, Dagmar %A Dlugaj, Martha %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Case-Control Studies %K Cognitive Dysfunction %K Female %K Follow-Up Studies %K Humans %K Logistic Models %K Male %K Middle Aged %K Neuropsychological Tests %K Risk Factors %K Sex Characteristics %K Statistics, Nonparametric %K Thyrotropin %X

BACKGROUND: Although some studies reported on the association of serum thyroid-stimulating hormone (TSH) concentration and cognition, only one population-based study investigated the association of TSH concentration and mild cognitive impairment (MCI).

OBJECTIVE: To investigate the gender-specific association of low- and high-normal TSH concentrations with MCI in euthyroid participants.

METHODS: Analysis sample 1 included 2,563 euthyroid participants (aged 50-80 years) from the second examination of the population-based Heinz Nixdorf Recall study. Gender-specific TSH quintiles (Q1 low, Q2-Q4 middle, Q5 high TSH concentration) were determined and group comparisons of age- and education-adjusted mean scores were performed for all cognitive subtests. Analysis sample 2 included 378 participants with MCI and 931 cognitively normal participants. MCI was diagnosed according to previously published MCI criteria. Multivariate logistic regression models were performed using TSH quintiles (Q2-Q4 as reference) to assess the association of low- and high-normal TSH concentration with MCI. Models were performed unadjusted and adjusted for sociodemographic and cardiovascular risk factors.

RESULTS: Group comparisons showed significant differences only in the immediate recall of the verbal memory task in women. Only women showed a strong association of high-normal TSH concentration with MCI (unadjusted: odds ratio 2.09, 95% confidence interval 1.29-3.37, full adjusted: 1.86, 1.06-3.27). There was no association with low-normal TSH concentration in women and no association of either low- or high-normal TSH concentration with MCI in men.

CONCLUSIONS: These results suggest that women with high-normal TSH concentration might be at higher risk of cognitive decline. This needs to be confirmed in the longitudinal analysis.

%B J Alzheimers Dis %V 49 %P 797-807 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519440?dopt=Abstract %R 10.3233/JAD-150561 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Transferring cut-off values between assays for cerebrospinal fluid Alzheimer's disease biomarkers. %A García Barrado, Leandro %A Coart, Els %A Vanderstichele, Hugo M J %A Burzykowski, Tomasz %K Alzheimer Disease %K Amyloid beta-Peptides %K Bayes Theorem %K Biomarkers %K Cognitive Dysfunction %K Datasets as Topic %K Humans %K Linear Models %K Multivariate Analysis %K Peptide Fragments %K tau Proteins %X

Current technologies quantifying cerebrospinal fluid biomarkers to identify subjects with Alzheimer's disease pathology report different concentrations in function of technology and suffer from between-laboratory variability. Hence, lab- and technology-specific cut-off values are required. It is common practice to establish cut-off values on small datasets and, in the absence of well-characterized samples, to transfer the cut-offs to another assay format using 'side-by-side' testing of samples with both assays. We evaluated the uncertainty in cut-off estimation and the performance of two methods of cut-off transfer by using two clinical datasets and simulated data. The cut-off for the new assay was transferred by applying the commonly-used linear regression approach and a new Bayesian method, which consists of using prior information about the current assay for estimation of the biomarker's distributions for the new assay. Simulations show that cut-offs established with current sample sizes are insufficiently precise and also show the effect of increasing sample sizes on the cut-offs' precision. The Bayesian method results in unbiased and less variable cut-offs with substantially narrower 95% confidence intervals compared to the linear-regression transfer. For the BIODEM datasets, the transferred cut-offs for INNO-BIA Aβ1-42 are 167.5 pg/mL (95% credible interval [156.1, 178.0] and 172.8 pg/mL (95% CI [147.6, 179.6]) with Bayesian and linear regression methods, respectively. For the EUROIMMUN assay, the estimated cut-offs are 402.8 pg/mL (95% credible interval [348.0, 473.9]) and 364.4 pg/mL (95% CI [269.7, 426.8]). Sample sizes and statistical methods used to establish and transfer cut-off values have to be carefully considered to guarantee optimal diagnostic performance of biomarkers.

%B J Alzheimers Dis %V 49 %P 187-99 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484919?dopt=Abstract %R 10.3233/JAD-150511 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Transthyretin Suppresses Amyloid-β Secretion by Interfering with Processing of the Amyloid-β Protein Precursor. %A Li, Xinyi %A Song, Yuanli %A Sanders, Charles R %A Buxbaum, Joel N %X

In Alzheimer's disease (AD), most hippocampal and cortical neurons show increased staining with anti-transthyretin (TTR) antibodies. Genetically programmed overexpression of wild type human TTR suppressed the neuropathologic and behavioral abnormalities in APP23 AD model mice and TTR-Aβ complexes have been isolated from some human AD brains and those of APP23 transgenic mice. In the present study, in vitro NMR analysis showed interaction between the hydrophobic thyroxine binding pocket of TTR and the cytoplasmic loop of the C99 fragment released by β-secretase cleavage of AβPP, with Kd = 86±9 μM. In cultured cells expressing both proteins, the interaction reduced phosphorylation of C99 (at T668) and suppressed its cleavage by γ-secretase, significantly decreasing Aβ secretion. Coupled with its previously demonstrated capacity to inhibit Aβ aggregation (with the resultant cytotoxicity in tissue culture) and its regulation by HSF1, these findings indicate that TTR can behave as a stress responsive multimodal suppressor of AD pathogenesis.

%B J Alzheimers Dis %V 52 %P 1263-75 %8 2016 Apr 08 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079720?dopt=Abstract %R 10.3233/JAD-160033 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Validation of a Commercial Chemiluminescence Immunoassay for the Simultaneous Measurement of Three Different Amyloid-β Peptides in Human Cerebrospinal Fluid and Application to a Clinical Cohort. %A Klafki, Hans-W %A Hafermann, Henning %A Bauer, Chris %A Haussmann, Ute %A Kraus, Inga %A Schuchhardt, Johannes %A Muck, Stephan %A Scherbaum, Norbert %A Wiltfang, Jens %X

A comprehensive assay validation campaign of a commercially available chemiluminescence multiplex immunoassay for the simultaneous measurement of the amyloid-β peptides Aβ38, Aβ40, and Aβ42 in human cerebrospinal fluid (CSF) is presented. The assay quality parameters we addressed included impact of sample dilution, parallelism, lower limits of detection, lower limits of quantification, intra- and inter-assay repeatability, analytical spike recoveries, and between laboratory reproducibility of the measurements. The assay performed well in our hands and fulfilled a number of predefined acceptance criteria. The CSF levels of Aβ40 and Aβ42 determined in a clinical cohort (n = 203) were statistically significantly correlated with available ELISA data of Aβ1-40 (n = 158) and Aβ1-42 (n = 179) from a different laboratory. However, Bland-Altman method comparison indicated systematic differences between the assays. The data presented here furthermore indicate that the CSF concentration of Aβ40 can surrogate total CSF Aβ and support the hypothesis that the Aβ42/Aβ40 ratio outperforms CSF Aβ42 alone as a biomarker for Alzheimer's disease due to a normalization to total Aβ levels.

%B J Alzheimers Dis %V 54 %P 691-705 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567847?dopt=Abstract %R 10.3233/JAD-160398 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Validation of microRNAs in Cerebrospinal Fluid as Biomarkers for Different Forms of Dementia in a Multicenter Study. %A Müller, Mareike %A Kuiperij, H Bea %A Versleijen, Alexandra A M %A Chiasserini, Davide %A Farotti, Lucia %A Baschieri, Francesca %A Parnetti, Lucilla %A Struyfs, Hanne %A De Roeck, Naomi %A Luyckx, Jill %A Engelborghs, Sebastiaan %A Claassen, Jurgen A %A Verbeek, Marcel M %X

MicroRNAs (miRNAs) regulate translational inhibition of proteins, but are also detected in body fluids, including cerebrospinal fluid (CSF), where they may serve as disease-specific biomarkers. Previously, we showed differential expression of miR-146a, miR-29a, and miR-125b in the CSF of Alzheimer's disease (AD) patients versus controls. In this study, we aim to confirm these findings by using larger, independent sample cohorts of AD patients and controls from three different centers. Furthermore, we aim to identify confounding factors that possibly arise using such a multicenter approach. The study was extended by including patients diagnosed with mild cognitive impairment due to AD, frontotemporal dementia and dementia with Lewy bodies. Previous results of decreased miR-146a levels in AD patients compared to controls were confirmed in one center. When samples from all three centers were combined, several confounding factors were identified. After controlling for these factors, we did not identify differences in miRNA levels between the different groups. However, we provide suggestions to circumvent various pitfalls when measuring miRNAs in CSF to improve future studies.

%B J Alzheimers Dis %V 52 %P 1321-33 %8 2016 Apr 16 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104900?dopt=Abstract %R 10.3233/JAD-160038 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview. %A Jefferson, Angela L %A Gifford, Katherine A %A Acosta, Lealani Mae Y %A Bell, Susan P %A Donahue, Manus J %A Davis, L Taylor %A Gottlieb, JoAnn %A Gupta, Deepak K %A Hohman, Timothy J %A Lane, Elizabeth M %A Libon, David J %A Mendes, Lisa A %A Niswender, Kevin %A Pechman, Kimberly R %A Rane, Swati %A Ruberg, Frederick L %A Su, Yan Ru %A Zetterberg, Henrik %A Liu, Dandan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Blood Pressure Monitoring, Ambulatory %K Brain %K Case-Control Studies %K Cerebral Angiography %K Cognitive Dysfunction %K Echocardiography %K Epidemiologic Research Design %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Research Design %X

BACKGROUND: Vascular health factors frequently co-occur with Alzheimer's disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities.

OBJECTIVE: To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics.

METHODS: From September 2012 to November 2014, 335 participants age 60- 92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73±8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72±7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection.

RESULTS: As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values < 0.001), were more likely to be APOEɛ4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower Aβ42 (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants.

CONCLUSION: Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline.

%B J Alzheimers Dis %V 52 %P 539-59 %8 2016 03 08 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967211?dopt=Abstract %R 10.3233/JAD-150914 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Vascular Risk Factors and Cognition in Parkinson's Disease. %A Pilotto, Andrea %A Turrone, Rosanna %A Liepelt-Scarfone, Inga %A Bianchi, Marta %A Poli, Loris %A Borroni, Barbara %A Alberici, Antonella %A Premi, Enrico %A Formenti, Anna %A Bigni, Barbara %A Cosseddu, Maura %A Cottini, Elisabetta %A Berg, Daniela %A Padovani, Alessandro %K Age of Onset %K Aged %K Attention %K Disability Evaluation %K Educational Status %K Executive Function %K Female %K Humans %K Male %K Motor Activity %K Neuropsychological Tests %K Parkinson Disease %K Prevalence %K Risk Factors %K Sex Factors %K Time Factors %K Vascular Diseases %X

Vascular risk factors have been associated with cognitive deficits and incident dementia in the general population, but their role on cognitive dysfunction in Parkinson's disease (PD) is still unclear. The present study addresses the single and cumulative effect of vascular risk factors on cognition in PD patients, taking clinical confounders into account. Standardized neuropsychological assessment was performed in 238 consecutive PD patients. We evaluated the association of single and cumulative vascular risk factors (smoking, diabetes, hypercholesterolemia, hypertension, and heart disease), with the diagnosis of PD normal cognition (PDNC, n = 94), mild cognitive impairment (PD-MCI, n = 111), and dementia (PDD, n = 33). The association between single neuropsychological tests and vascular risk factors was evaluated with covariance analyses adjusted for age at onset, educational levels, gender, disease duration, and motor performance. Age, educational levels, disease duration, and motor function were significantly different between PDNC, PD-MCI, and PDD. Heart disease was the only vascular factor significantly more prevalent in PDD compared with PDNC in adjusted analyses. Performance of tests assessing executive and attention functions were significantly worse in patients with hypertension, heart disease, and/or diabetes (p <  0.05). Heart disease is associated with dementia in PD, suggesting a potential window of intervention. Vascular risk factors act especially on attention and executive functions in PD. Vascular risk stratification may be useful in order to identify PD patients with a greater risk of developing dementia. These findings need to be verified in longitudinal studies.

%B J Alzheimers Dis %V 51 %P 563-70 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890741?dopt=Abstract %R 10.3233/JAD-150610 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Vitamin D and Memory Decline: Two Population-Based Prospective Studies. %A Kuźma, Elżbieta %A Soni, Maya %A Littlejohns, Thomas J %A Ranson, Janice M %A van Schoor, Natasja M %A Deeg, Dorly J H %A Comijs, Hannie %A Chaves, Paulo H M %A Kestenbaum, Bryan R %A Kuller, Lewis H %A Lopez, Oscar L %A Becker, James T %A Langa, Kenneth M %A Henley, William E %A Lang, Iain A %A Ukoumunne, Obioha C %A Llewellyn, David J %K Humans %K Memory Disorders %K Netherlands %K Prospective Studies %K United States %K Vitamin D %K Vitamin D Deficiency %X

BACKGROUND: Vitamin D deficiency has been linked with dementia risk, cognitive decline, and executive dysfunction. However, the association with memory remains largely unknown.

OBJECTIVE: To investigate whether low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with memory decline.

METHODS: We used data on 1,291 participants from the US Cardiovascular Health Study (CHS) and 915 participants from the Dutch Longitudinal Aging Study Amsterdam (LASA) who were dementia-free at baseline, had valid vitamin D measurements, and follow-up memory assessments. The Benton Visual Retention Test (in the CHS) and Rey's Auditory Verbal Learning Test (in the LASA) were used to assess visual and verbal memory, respectively.

RESULTS: In the CHS, those moderately and severely deficient in serum 25(OH)D changed -0.03 SD (95% CI: -0.06 to 0.01) and -0.10 SD (95% CI: -0.19 to -0.02) per year respectively in visual memory compared to those sufficient (p = 0.02). In the LASA, moderate and severe deficiency in serum 25(OH)D was associated with a mean change of 0.01 SD (95% CI: -0.01 to 0.02) and -0.01 SD (95% CI: -0.04 to 0.02) per year respectively in verbal memory compared to sufficiency (p = 0.34).

CONCLUSIONS: Our findings suggest an association between severe vitamin D deficiency and visual memory decline but no association with verbal memory decline. They warrant further investigation in prospective studies assessing different memory subtypes.

%B J Alzheimers Dis %V 50 %P 1099-108 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836174?dopt=Abstract %R 10.3233/JAD-150811 %0 Journal Article %J J Alzheimers Dis %D 2016 %T White Matter Abnormalities Track Disease Progression in PSEN1 Autosomal Dominant Alzheimer's Disease. %A Sánchez-Valle, Raquel %A Monté, Gemma C %A Sala-Llonch, Roser %A Bosch, Beatriz %A Fortea, Juan %A Lladó, Albert %A Antonell, Anna %A Balasa, Mircea %A Bargalló, Nuria %A Molinuevo, José Luis %K Adult %K Aging %K Alzheimer Disease %K Brain %K Cohort Studies %K Diffusion Tensor Imaging %K Disease Progression %K Family %K Female %K Heterozygote %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Mutation %K Neuropsychological Tests %K Organ Size %K Presenilin-1 %K White Matter %X

PSEN1 mutations are the most frequent cause of autosomal dominant Alzheimer's disease (ADAD), and show nearly full penetrance. There is presently increasing interest in the study of biomarkers that track disease progression in order to test therapeutic interventions in ADAD. We used white mater (WM) volumetric characteristics and diffusion tensor imaging (DTI) metrics to investigate correlations with the normalized time to expected symptoms onset (relative age ratio) and group differences in a cohort of 36 subjects from PSEN1 ADAD families: 22 mutation carriers, 10 symptomatic (SMC) and 12 asymptomatic (AMC), and 14 non-carriers (NC). Subjects underwent a 3T MRI. WM morphometric data and DTI metrics were analyzed. We found that PSEN1 MC showed significant negative correlation between fractional anisotropy (FA) and the relative age ratio in the genus and body of corpus callosum and corona radiate (p <  0.05 Family-wise error correction (FWE) at cluster level) and positive correlation with mean diffusivity (MD), axial diffusivity (AxD), and radial diffusivity (RD) in the splenium of corpus callosum. SMC presented WM volume loss, reduced FA and increased MD, AxD, and RD in the anterior and posterior corona radiate, corpus callosum (p <  0.05 FWE) compared with NC. No significant differences were observed between AMC and NC in WM volume or DTI measures. These findings suggest that the integrity of the WM deteriorates linearly in PSEN1 ADAD from the early phases of the disease; thus DTI metrics might be useful to monitor the disease progression. However, the lack of significant alterations at the preclinical stages suggests that these indexes might not be good candidates for early markers of the disease.

%B J Alzheimers Dis %V 51 %P 827-35 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923015?dopt=Abstract %R 10.3233/JAD-150899 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Analysis of the Inhibitory Elements in the p5 Peptide Fragment of the CDK5 Activator, p35, CDKR1 Protein. %A Binukumar, B K %A Shukla, Varsha %A Amin, Niranjana D %A Bhaskar, Manju %A Skuntz, Suzanne %A Steiner, Joseph %A Winkler, Dirk %A Pelech, Steven L %A Pant, Harish C %X

Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles, it is well documented that cyclin-dependent kinase 5 (CDK5), a critical neuronal protein kinase in nervous system development, function, and survival, when deregulated and hyperactivated induces Alzheimer's disease (AD) and amyotrophic lateral sclerosis and Parkinson's disease-like phenotypes in mice. In a recent study, we demonstrated that p5, a small, truncated fragment of 24 amino acid residues derived from the CDK5 activator protein 35 (NCK5A, p35), selectively inhibited deregulated CDK5 hyperactivity and ameliorated AD phenotypes in model mice. In this study, we identified the most inhibitory elements in the p5 peptide fragment. Each amino acid residue in p5 was systematically replaced with its homologous residues that may still be able to functionally substitute. The effects of these p5 peptide analogs were studied on the phosphotransferase activities of CDK5/p35, CDK5/p25, ERK1, and GSK3β. The mimetic p5 peptide (A/V substitution at the C-terminus of the peptide) in the sequence, KNAFYERALSIINLMTSKMVQINV (p5-MT) was the most effective inhibitor of CDK5 kinase activity of 79 tested mimetic peptides including the original p5 peptide, KEAFWDRCLSVINLMSSKMLQINA (p5-WT). Replacement of the residues in C-terminus end of the peptide affected CDK5 phosphotransferase activity most significantly. These peptides were strong inhibitors of CDK5, but not the related proline-directed kinases, ERK1 and GSK3β.

%B J Alzheimers Dis %8 2015 Oct 8 %G ENG %1 http://www.ncbi.nlm.nih.gov/pubmed/26444778?dopt=Abstract %R 10.3233/JAD-150412 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Ankle-Brachial Index but Neither Intima Media Thickness Nor Coronary Artery Calcification is Associated With Mild Cognitive Impairment. %A Weimar, Christian %A Winkler, Angela %A Dlugaj, Martha %A Lehmann, Nils %A Hennig, Frauke %A Bauer, Marcus %A Kröger, Knut %A Kälsch, Hagen %A Mahabadi, Amir-Abass %A Dragano, Nico %A Moebus, Susanne %A Hoffmann, Barbara %A Jöckel, Karl-Heinz %A Erbel, Raimund %X

BACKGROUND: Several studies have reported an association of atherosclerosis with mild cognitive impairment (MCI) and dementia independent of cardiovascular risk factors.

OBJECTIVE: To compare the cross-sectional association of the ankle-brachial index (ABI), intima media thickness (IMT), and coronary artery calcification (CAC) with MCI and its subtypes, amnestic MCI (aMCI) and non-amnestic MCI (naMCI) in the population-based Heinz Nixdorf Recall cohort study.

METHODS: 4,086 participants performed a validated brief cognitive assessment at the first follow-up examination (2006-2008). MCI was diagnosed according to previously published criteria. Prevalence ratio (PR) regression models adjusted for age, gender, education, cardiovascular risk factors, and APOE genotype were used to compare the association of the ABI, the CAC-Agatston score and the IMT with MCI and its subtypes.

RESULTS: We identified 490 participants with MCI (mean age 66.1 ± 7.8, 46.9 % male, aMCI n = 249, naMCI n = 241) and 1,242 cognitively normal participants. A decreasing ABI (per 0.1) was significantly associated with a higher MCI prevalence in fully adjusted models (PR 1.06; 95% confidence interval (CI) 1.01-1.11), whereas an increasing CAC (log(CAC+1)) or IMT (per 0.1 mm) were not associated after adjustment. A decreasing ABI was also significantly associated with naMCI in fully adjusted models (PR 1.12; CI 1.03-1.21) but not with aMCI.

CONCLUSIONS: Our data show that the degree of generalized atherosclerosis as measured by the ABI is associated with MCI and with naMCI in a population-based cohort.

%B J Alzheimers Dis %V 47 %P 433-42 %8 2015 Jul 24 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401565?dopt=Abstract %R 10.3233/JAD-150218 %0 Journal Article %J J Alzheimers Dis %D 2015 %T The APOE Gene is Differentially Methylated in Alzheimer's Disease. %A Foraker, Jessica %A Millard, Steven P %A Leong, Lesley %A Thomson, Zachary %A Chen, Sunny %A Keene, C Dirk %A Bekris, Lynn M %A Yu, Chang-En %X

The ɛ4 allele of the human apolipoprotein E gene (APOE) is a well-proven genetic risk factor for the late onset form of Alzheimer's disease (AD). However, the biological mechanisms through which the ɛ4 allele contributes to disease pathophysiology are incompletely understood. The three common alleles of APOE, ɛ2, ɛ3 and ɛ4, are defined by two single nucleotide polymorphisms (SNPs) that reside in the coding region of exon 4, which overlaps with a well-defined CpG island (CGI). Both SNPs change not only the protein codon but also the quantity of CpG dinucleotides, primary sites for DNA methylation. Thus, we hypothesize that the presence of an ɛ4 allele changes the DNA methylation landscape of the APOE CGI and that such epigenetic alteration contributes to AD susceptibility. To explore the relationship between APOE genotype, AD risk, and DNA methylation of the APOE CGI, we applied bisulfite pyrosequencing and evaluated methylation profiles of postmortem brain from 15 AD and 10 control subjects. We observed a tissue-specific decrease in DNA methylation with AD and identified two AD-specific differentially methylated regions (DMRs), which were also associated with APOE genotype. We further demonstrated that one DMR was completely un-methylated in a sub-population of genomes, possibly due to a subset of brain cells carrying deviated APOE methylation profiles. These data suggest that the APOE CGI is differentially methylated in AD brain in a tissue- and APOE-genotype-specific manner. Such epigenetic alteration might contribute to neural cell dysfunction in AD brain.

%B J Alzheimers Dis %8 2015 Sep 4 %G eng %R 10.3233/JAD-143060 %0 Journal Article %J J Alzheimers Dis %D 2015 %T AβPP-Transgenic 2576 Mice Mimic Cell Type-Specific Aspects of Acetyl-CoA-Linked Metabolic Deficits in Alzheimer's Disease. %A Bielarczyk, Hanna %A Jankowska-Kulawy, Agnieszka %A Hofling, Corinna %A Ronowska, Anna %A Gul-Hinc, Sylwia %A Rossner, Steffen %A Schliebs, Reinhard %A Pawelczyk, Tadeusz %A Szutowicz, Andrzej %X

The pyruvate-derived acetyl-CoA is a principal direct precursor substrate for bulk energy synthesis in the brain. Deficits of pyruvate dehydrogenase in the neocortex are common features of Alzheimer's disease and other age-related encephalopathies in humans. Therefore, amyloid-β overload in brains of diverse transgenic Alzheimer's disease model animals was investigated as one of neurotoxic compounds responsible for pyruvate dehydrogenase inhibition yielding deficits of cholinergic neurotransmission and cognitive functions. Brains of aged, 14-16-month-old Tg2576 mice contained 0.6 μmol/kg levels of amyloid-β 1-42. Activities of pyruvate dehydrogenase complex, choline acetyltransferase, and several enzymes of acetyl-CoA and energy metabolism were found to be unchanged in both forebrain mitochondria and synaptosomes of Tg2576 mice, indicating preservation of structural integrity at least cholinergic neuronal cells. However, in transgenic brain synaptosomes, pyruvate utilization, mitochondrial levels, and cytoplasmic acetyl-CoA levels, as well as acetylcholine content and its quantal release, were all found to be decreased by 25-40% . On the contrary, activation of pyruvate utilization was detected and no alterations in acetyl-CoA content and citrate or α-ketoglutarate accumulation were observed in transgenic whole brain mitochondria. These data indicate that amyloid-β evoked deficits in acetyl-CoA are confined to mitochondrial and cytoplasmic compartments of Tg2576 nerve terminals, becoming early primary signals paving path for further stages of neurodegeneration. On the other hand, acetyl-CoA synthesis in mitochondrial compartments of glial cells seems to be activated despite amyloid-β accumulated in transgenic brains.

%B J Alzheimers Dis %8 2015 Sep 19 %G eng %R 10.3233/JAD-150327 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Blood Protein Markers of Neocortical Amyloid-β Burden: A Candidate Study Using SOMAscan Technology. %A Voyle, Nicola %A Baker, David %A Burnham, Samantha C %A Covin, Antonia %A Zhang, Zhanpan %A Sangurdekar, Dipen P %A Tan Hehir, Cristina A %A Bazenet, Chantal %A Lovestone, Simon %A Kiddle, Steven %A Dobson, Richard J B %X

BACKGROUND: Four previously reported studies have tested for association of blood proteins with neocortical amyloid-β burden (NAB). If shown to be robust, these proteins could have utility as a blood test for enrichment in clinical trials of Alzheimer's disease (AD) therapeutics.

OBJECTIVE: This study aimed to investigate whether previously identified blood proteins also show evidence for association with NAB in serum samples from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL). The study considers candidate proteins seen in cohorts other than AIBL and candidates previously discovered in the AIBL cohort.

METHODS: Our study used the SOMAscan platform for protein quantification in blood serum. Linear and logistic regressions were used to model continuous NAB and dichotomized NAB respectively using single proteins as a predictor. Multiple protein models were built using stepwise regression techniques and support vectors machines. Age and APOE ε4 carriage were used as covariates for all analysis.

RESULTS: Of the 41 proteins previously reported, 15 AIBL candidates and 20 non-AIBL candidates were available for testing. Of these candidates, pancreatic polypeptide (PPY) and IgM showed a significant association with NAB. Notably, IgM was found to associate with continuous NAB across cognitively normal control subjects.

CONCLUSIONS: We have further demonstrated the association of PPY and IgM with NAB, despite technical differences between studies. There are several reasons for a lack of significance for the other candidates including platform differences and the use of serum rather than plasma samples. To investigate the possibility of technical differences causing lack of further replication, further studies are required.

%B J Alzheimers Dis %8 2015 Apr 16 %G eng %R 10.3233/JAD-150020 %0 Journal Article %J J Alzheimers Dis %D 2015 %T A Blood-Based, 7-Metabolite Signature for the Early Diagnosis of Alzheimer's Disease. %A Olazarán, Javier %A Gil-de-Gómez, Luis %A Rodríguez-Martín, Andrés %A Valentí-Soler, Meritxell %A Frades-Payo, Belén %A Marín-Muñoz, Juan %A Antúnez, Carmen %A Frank-García, Ana %A Jiménez, Carmen Acedo %A Gracia, Lorenzo Morlén %A Torregrossa, Roberto Petidier %A Guisasola, María Concepción %A Bermejo-Pareja, Félix %A Sánchez-Ferro, Álvaro %A Pérez-Martínez, David A %A Palomo, Sagrario Manzano %A Farquhar, Ruth %A Rábano, Alberto %A Calero, Miguel %X

Accurate blood-based biomarkers of Alzheimer's disease (AD) could constitute simple, inexpensive, and non-invasive tools for the early diagnosis and treatment of this devastating neurodegenerative disease. We sought to develop a robust AD biomarker panel by identifying alterations in plasma metabolites that persist throughout the continuum of AD pathophysiology. Using a multicenter, cross-sectional study design, we based our analysis on metabolites whose levels were altered both in AD patients and in patients with amnestic mild cognitive impairment (aMCI), the earliest identifiable stage of AD. UPLC coupled to mass spectrometry was used to independently compare the levels of 495 plasma metabolites in aMCI (n = 58) and AD (n = 100) patients with those of normal cognition controls (NC, n = 93). Metabolite alterations common to both aMCI and AD patients were used to generate a logistic regression model that accurately distinguished AD from NC patients. The final panel consisted of seven metabolites: three amino acids (glutamic acid, alanine, and aspartic acid), one non-esterified fatty acid (22:6n-3, DHA), one bile acid (deoxycholic acid), one phosphatidylethanolamine [PE(36:4)], and one sphingomyelin [SM(39:1)]. Detailed analysis ruled out the influence of potential confounding variables, including comorbidities and treatments, on each of the seven biomarkers. The final model accurately distinguished AD from NC patients (AUC, 0.918). Importantly, the model also distinguished aMCI from NC patients (AUC, 0.826), indicating its potential diagnostic utility in early disease stages. These findings describe a sensitive biomarker panel that may facilitate the specific detection of early-stage AD through the analysis of plasma samples.

%B J Alzheimers Dis %8 2015 Feb 3 %G ENG %1 http://www.ncbi.nlm.nih.gov/pubmed/25649659?dopt=Abstract %R 10.3233/JAD-142925 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Cognitive Function and Its Relationship with Macular Pigment Optical Density and Serum Concentrations of its Constituent Carotenoids. %A Kelly, David %A Coen, Robert F %A Akuffo, Kwadwo Owusu %A Beatty, Stephen %A Dennison, Jessica %A Moran, Rachel %A Stack, Jim %A Howard, Alan N %A Mulcahy, Riona %A Nolan, John M %X

BACKGROUND: Macular pigment (MP) levels correlate with brain concentrations of lutein (L) and zeaxanthin (Z), and have also been shown to correlate with cognitive performance in the young and elderly.

OBJECTIVE: To investigate the relationship between MP, serum concentrations of L and Z, and cognitive function in subjects free of retinal disease with low MP (Group 1, n = 105) and in subjects with AMD (Group 2, n = 121).

METHODS: MP was measured using customized heterochromatic flicker photometry and dual-wavelength autofluorescence; cognitive function was assessed using a battery of validated cognition tests; serum L and Z concentrations were determined by HPLC.

RESULTS: Significant correlations were evident between MP and various measures of cognitive function in both groups (r = -0.273 to 0.261, p≤0.05, for all). Both serum L and Z concentrations correlated significantly (r = 0.187, p≤0.05 and r = 0.197, p≤0.05, respectively) with semantic (animal) fluency cognitive scores in Group 2 (the AMD study group), while serum L concentrations also correlated significantly with Verbal Recognition Memory learning slope scores in the AMD study group (r = 0.200, p = 0.031). Most of the correlations with MP, but not serum L or Z, remained significant after controlling for age, gender, diet, and education level.

CONCLUSION: MP offers potential as a non-invasive clinical biomarker of cognitive health, and appears more successful in this role than serum concentrations of L or Z.

%B J Alzheimers Dis %V 48 %P 261-77 %8 2015 Aug 28 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401946?dopt=Abstract %R 10.3233/JAD-150199 %0 Journal Article %J J Alzheimers Dis %D 2015 %T The Continuing Failure of Bexarotene in Alzheimer's Disease Mice. %A Balducci, Claudia %A Paladini, Alessandra %A Micotti, Edoardo %A Tolomeo, Daniele %A La Vitola, Pietro %A Grigoli, Emanuele %A Richardson, Jill C %A Forloni, Gianluigi %X

Alzheimer's disease (AD) is the most common form of dementia characterized by synaptic dysfunction, memory loss, neuroinflammation, and neuronal cell death. Amyloid-β (Aβ), recognized as the main culprit of AD, aggregates and accumulates in the extracellular compartment as neuritic plaques, after deregulation of its production or clearance. Apolipoprotein E (ApoE) plays a major role in Aβ clearance and its expression is transcriptionally regulated by the liver X receptor and retinoid X receptors (RXRs) system. Bexarotene (BEXA), an RXR agonist, that increases ApoE expression and microglia phagocytosis and has been proposed as a promising therapy for AD, resolving both the amyloid pathology and memory loss. Despite the first compelling report, however, multiple failures have been documented, raising concern about whether BEXA could in fact become a novel disease-modifying strategy for AD. To help clarify this, we investigated the effect of BEXA in vivo at multiple levels in TASTPM transgenic mice. Seven-day oral administration of BEXA to these mice did not achieve any significant memory improvement, plaque reduction, or enhancement of microglial cell activation. No differences were found when specifically investigating the microglial phagocytic state in vivo. In addition, a brain structural analysis with magnetic resonance did not detect any BEXA-mediated change in the volume reduction of the main affected brain areas in our mice. These results suggest that BEXA has no beneficial effect on the multi-factorial pathologic phenotype of AD mice.

%B J Alzheimers Dis %8 2015 Mar 16 %G eng %R 10.3233/JAD-150029 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Correcting for the Absence of a Gold Standard Improves Diagnostic Accuracy of Biomarkers in Alzheimer's Disease. %A Coart, Els %A Barrado, Leandro García %A Duits, Flora H %A Scheltens, Philip %A van der Flier, Wiesje M %A Teunissen, Charlotte E %A van der Vies, Saskia M %A Burzykowski, Tomasz %X

BACKGROUND: Studies investigating the diagnostic accuracy of biomarkers for Alzheimer's disease (AD) are typically performed using the clinical diagnosis or amyloid-β positron emission tomography as the reference test. However, neither can be considered a gold standard or a perfect reference test for AD. Not accounting for errors in the reference test is known to cause bias in the diagnostic accuracy of biomarkers.

OBJECTIVE: To determine the diagnostic accuracy of AD biomarkers while taking the imperfectness of the reference test into account.

METHODS: To determine the diagnostic accuracy of AD biomarkers and taking the imperfectness of the reference test into account, we have developed a Bayesian method. This method establishes the biomarkers' true value in predicting the AD-pathology status by combining the reference test and the biomarker data with available information on the reliability of the reference test. The new methodology was applied to two clinical datasets to establish the joint accuracy of three cerebrospinal fluid biomarkers (amyloid-β1-42, Total tau, and P-tau181) by including the clinical diagnosis as imperfect reference test into the analysis.

RESULTS: The area under the receiver-operating-characteristics curve to discriminate between AD and controls, increases from 0.949 (with 95% credible interval [0.935,0.960]) to 0.990 ([0.985,0.995]) and from 0.870 ([0.817,0.912]) to 0.975 ([0.943,0.990]) for the cohorts, respectively.

CONCLUSIONS: Use of the Bayesian methodology enables an improved estimate of the exact diagnostic value of AD biomarkers and overcomes the lack of a gold standard for AD. Using the new method will increase the diagnostic confidence for early stages of AD.

%B J Alzheimers Dis %8 2015 Apr 13 %G eng %R 10.3233/JAD-142886 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Diabetes is Associated with Worse Executive Function in Both Eastern and Western Populations: Shanghai Aging Study and Mayo Clinic Study of Aging. %A Zhao, Qianhua %A Roberts, Rosebud O %A Ding, Ding %A Cha, Ruth %A Guo, Qihao %A Meng, Haijiao %A Luo, Jianfeng %A Machulda, Mary M %A Shane Pankratz, V %A Wang, Bei %A Christianson, Teresa J H %A Aakre, Jeremiah A %A Knopman, David S %A Boeve, Bradley F %A Hong, Zhen %A Petersen, Ronald C %X

BACKGROUND AND OBJECTIVES: It remains unknown whether the association between diabetes mellitus (DM) and cognitive function differs in Eastern and Western populations. This study aimed to elucidate whether DM is associated with worse cognitive performance in both populations.

METHODS: The Shanghai Aging Study (SAS) and the Mayo Clinic Study of Aging (MCSA) are two population-based studies with similar design and methodology in Shanghai, China and Rochester, MN, USA. Non-demented participants underwent cognitive testing, and DM was assessed from the medical record. Separate analyses were performed in SAS and MCSA regarding the association between DM and cognitive performance.

RESULTS: A total of 3,348 Chinese participants in the SAS and 3,734 American subjects in the MCSA were included. Compared with MCSA subjects, SAS participants were younger, less educated, and had lower frequency of vascular disease, APOE ɛ4 carriers and obesity. Participants with DM (compared to non-DM participants) performed significantly worse on all the cognitive domains in both the SAS and MCSA. After adjustment for age, gender, education, and vascular covariates, DM was associated with worse performance in executive function (β=-0.15, p = 0.001 for SAS, and β=-0.10, p = 0.008 for MCSA) in the total sample and in the cognitively normal sub-sample. Furthermore, DM was associated with poor performance in visuospatial skills, language, and memory in the SAS, but not in the MCSA.

CONCLUSIONS: Diabetes is associated with cognitive dysfunction and, in particular, exerts a negative impact on executive function regardless of race, age, and prevalence of vascular risk factors.

%B J Alzheimers Dis %V 47 %P 167-76 %8 2015 Jul 9 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26402765?dopt=Abstract %R 10.3233/JAD-150073 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Differential Effects of Meal Challenges on Cognition, Metabolism, and Biomarkers for Apolipoprotein E ɛ4 Carriers and Adults with Mild Cognitive Impairment. %A Hanson, Angela J %A Bayer, Jennifer L %A Baker, Laura D %A Cholerton, Brenna %A VanFossen, Brian %A Trittschuh, Emily %A Rissman, Robert A %A Donohue, Michael C %A Moghadam, Setareh H %A Plymate, Stephen R %A Craft, Suzanne %X

BACKGROUND: High intake of saturated fat (SF) and glycemic index (GI) foods is a risk factor for sporadic Alzheimer's disease. Meal challenges may elucidate mechanisms that contribute to this risk, enabling development of targeted interventions.

OBJECTIVE: To assess cognitive and metabolic changes after a meal high in SF and GI calories (HIGH) versus a meal low in these macronutrients (LOW) in older adults with and without cognitive impairment, and with and without the apolipoprotein E4 risk factor.

METHODS: 46 adults with either cognitive impairment (CI) or normal cognition (NC) ingested a LOW (25% total fat, 7% SF, GI <55) and a HIGH meal (50% total fat, 25% SF, GI >70) in a blinded random fashion. Participants then underwent cognitive testing and blood sampling for metabolic and Alzheimer's disease biomarkers. Data were analyzed using repeated measures ANOVA and Spearman correlations.

RESULTS: E4-adults with NC demonstrated lower delayed memory scores after the HIGH compared to the LOW meal, whereas normal E4+ and CI E4- groups had higher scores after the HIGH meal (ANOVA p = 0.03). These findings were associated with meal-induced changes in glucose (p = 0.05), insulin (p = 0.004), triglycerides (p <  0.01), and plasma Aβ42 (p = 0.05).

CONCLUSIONS: These preliminary data suggest that cognitive performance of adults without CI may worsen following high SF and sugar meals, whereas adults with CI or those at risk for CI due to E4 status may benefit acutely from such meals. Furthermore, plasma Aβ was affected by meal type, suggesting a relationship between metabolic response and amyloid regulation.

%B J Alzheimers Dis %V 48 %P 205-18 %8 2015 Aug 28 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401941?dopt=Abstract %R 10.3233/JAD-150273 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Divalent Copper as a Major Triggering Agent in Alzheimer's Disease. %A Brewer, George J %X

Alzheimer's disease (AD) is at epidemic proportions in developed countries, with a steady increase in the early 1900 s, and then exploding over the last 50 years. This epidemiology points to something causative in the environment of developed countries. This paper will review the considerable evidence that that something could be inorganic copper ingestion. The epidemic parallels closely the spread of copper plumbing, with copper leached from the plumbing into drinking water being a main causal feature, aided by the increasingly common use of supplement pills containing copper. Inorganic copper is divalent copper, or copper-2, while we now know that organic copper, or copper in foods, is primarily monovalent copper, or copper-1. The intestinal transport system, Ctr1, absorbs copper-1 and the copper moves to the liver, where it is put into safe channels. Copper-2 is not absorbed by Ctr1, and some of it bypasses the liver and goes directly into the blood, where it appears to be exquisitely toxic to brain cognition. Thus, while aggregation of amyloid-β has been postulated to be the cause of AD under current dogma, the great increase in prevalence over the last century appears to be due to ingestion of copper-2, which may be causing the aggregation, and/or increasing the oxidant toxicity of the aggregates. An alternative hypothesis proposes that oxidant stress is the primary injuring agent, and under this hypothesis, copper-2 accumulation in the brain may be a causal factor of the oxidant injury. Thus, irrespective of which hypothesis is correct, AD can be classified, at least in part, as a copper-2 toxicity disease. It is relatively easy to avoid copper-2 ingestion, as discussed in this review. If most people begin avoiding copper-2 ingestion, perhaps the epidemic of this serious disease can be aborted.

%B J Alzheimers Dis %8 2015 Apr 8 %G eng %R 10.3233/JAD-143123 %0 Journal Article %J J Alzheimers Dis %D 2015 %T The GLP-1 Receptor Agonist Liraglutide Improves Memory Function and Increases Hippocampal CA1 Neuronal Numbers in a Senescence-Accelerated Mouse Model of Alzheimer's Disease. %A Hansen, Henrik H %A Fabricius, Katrine %A Barkholt, Pernille %A Niehoff, Michael L %A Morley, John E %A Jelsing, Jacob %A Pyke, Charles %A Bjerre Knudsen, Lotte %A Farr, Susan A %A Vrang, Niels %X

Recent studies indicate that glucagon-like peptide 1 (GLP-1) receptor agonists, currently used in the management of type 2 diabetes, exhibit neurotrophic and neuroprotective effects in amyloid-β (Aβ) toxicity models of Alzheimer's disease (AD). We investigated the potential pro-cognitive and neuroprotective effects of the once-daily GLP-1 receptor agonist liraglutide in senescence-accelerated mouse prone 8 (SAMP8) mice, a model of age-related sporadic AD not dominated by Aβ plaques. Six-month-old SAMP8 mice received liraglutide (100 or 500 μg/kg/day, s.c.) or vehicle once daily for 4 months. Vehicle-dosed age-matched 50% back-crossed as well as untreated young (4-month-old) SAMP8 mice were used as control groups for normal memory function. Vehicle-dosed 10-month-old SAMP8 mice showed significant learning and memory retention deficits in an active-avoidance T-maze, as compared to both control groups. Also, 10-month-old SAMP8 mice displayed no immunohistological signatures of Aβ plaques or hyperphosphorylated tau, indicating the onset of cognitive deficits prior to deposition of amyloid plaques and neurofibrillary tangles in this AD model. Liraglutide significantly increased memory retention and total hippocampal CA1 pyramidal neuron numbers in SAMP8 mice, as compared to age-matched vehicle-dosed SAMP8 mice. In conclusion, liraglutide delayed or partially halted the progressive decline in memory function associated with hippocampal neuronal loss in a mouse model of pathological aging with characteristics of neurobehavioral and neuropathological impairments observed in early-stage sporadic AD.

%B J Alzheimers Dis %8 2015 Apr 13 %G eng %R 10.3233/JAD-143090 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Identification of Novel Tau Interactions with Endoplasmic Reticulum Proteins in Alzheimer's Disease Brain. %A Meier, Shelby %A Bell, Michelle %A Lyons, Danielle N %A Ingram, Alexandria %A Chen, Jing %A Gensel, John C %A Zhu, Haining %A Nelson, Peter T %A Abisambra, Jose F %X

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is pathologically characterized by the formation of extracellular amyloid plaques and intraneuronal tau tangles. We recently identified that tau associates with proteins known to participate in endoplasmic reticulum (ER)-associated degradation (ERAD); consequently, ERAD becomes dysfunctional and causes neurotoxicity. We hypothesized that tau associates with other ER proteins, and that this association could also lead to cellular dysfunction in AD. Portions of human AD and non-demented age matched control brains were fractionated to obtain microsomes, from which tau was co-immunoprecipitated. Samples from both conditions containing tau and its associated proteins were analyzed by mass spectrometry. In total, we identified 91 ER proteins that co-immunoprecipitated with tau; 15.4% were common between AD and control brains, and 42.9% only in the AD samples. The remainder, 41.8% of the proteins, was only seen in the control brain samples. We identified a variety of previously unreported interactions between tau and ER proteins. These proteins participate in over sixteen functional categories, the most abundant being involved in RNA translation. We then determined that association of tau with these ER proteins was different between the AD and control samples. We found that tau associated equally with the ribosomal protein L28 but more robustly with the ribosomal protein P0. These data suggest that the differential association between tau and ER proteins in disease could reveal the pathogenic processes by which tau induces cellular dysfunction.

%B J Alzheimers Dis %8 2015 Sep 3 %G eng %R 10.3233/JAD-150298 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Impairment of Age Estimation from Faces in Alzheimer's Disease. %A Moyse, Evelyne %A Bastin, Christine %A Salmon, Eric %A Brédart, Serge %X

A prerequisite for any function in social cognition is the perception and processing of social cues. Age estimation is a skill that is used in everyday life and is fundamental in social interactions. This study evaluated whether facial age estimation is impaired in patients with mild to moderate Alzheimer's disease (AD). The current age of faces is known to have an impact on age estimation, and therefore stimuli belonging to different age groups (young, middle-aged, and older adults' faces) were used. As expected, an impairment of age estimation from faces was observed in mild to moderate AD patients. However, the profile of impairment depended on the age of faces and stage of the disease. Mild AD patients presented difficulties mainly in assessing the age of middle-aged adults. In moderate disease stage, these difficulties also affected the age estimation of young adult faces. Interestingly, AD patients remained relatively good at estimating the age of older adults' faces, compared to healthy controls.

%B J Alzheimers Dis %8 2015 Jan 13 %G ENG %1 http://www.ncbi.nlm.nih.gov/pubmed/25589725?dopt=Abstract %R 10.3233/JAD-142253 %0 Journal Article %J J Alzheimers Dis %D 2015 %T A Novel Plasma Based Biomarker of Alzheimer's Disease. %A Bradley-Whitman, Melissa A %A Abner, Erin %A Lynn, Bert C %A Lovell, Mark A %X

Specific biomarkers in a readily accessible biological fluid, such as blood, could aid in the identification, characterization, validation, and routine monitoring of Alzheimer's disease (AD) progression. In the current study, levels of the previously described novel cerebrospinal fluid aberrant protein complex composed of prostaglandin-D-synthase (PDS) and transthyretin (TTR) were quantified in plasma by a custom two-probe sandwich ELISA and compared to amyloid-β (Aβ)1-42 as a standard plasma biomarker of AD. Plasma was analyzed from 140 probable AD subjects, 135 subjects with mild cognitive impairment (MCI), 74 normal control subjects (NC) prior to MCI transition, 23 diseased control (DC) subjects with either frontotemporal dementia or dementia with Lewy bodies, and 182 normal control (NC) subjects who did not progress to MCI or dementia. Levels of Aβ 1-42 were significantly elevated in NC subjects prior to MCI conversion but significantly reduced in probable AD subjects compared to NC subjects. Similarly, levels of the PDS-TTR complex were significantly reduced in both MCI and probable AD subjects compared to NC subjects. Furthermore, levels of Aβ 1-42 and the PDS-TTR complex were not significantly different in DC subjects compared to NC subjects. MMSE scores were weakly but significantly correlated with plasma levels of the PDS-TTR complex and Aβ 1-42. Trail B scores were weakly but significantly correlated with plasma levels of Aβ 1-42. Comparison of receiver operating curves shows the PDS-TTR complex is comparable to Aβ 1-42 in both MCI and probable AD subjects.

%B J Alzheimers Dis %V 47 %P 761-71 %8 2015 Aug 3 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401710?dopt=Abstract %R 10.3233/JAD-150183 %0 Journal Article %J J Alzheimers Dis %D 2015 %T A Phase II Randomized Clinical Trial of a Nutritional Formulation for Cognition and Mood in Alzheimer's Disease. %A Remington, Ruth %A Bechtel, Cynthia %A Larsen, David %A Samar, Annemarie %A Doshanjh, Laura %A Fishman, Paul %A Luo, Yuan %A Smyers, Kathleen %A Page, Robert %A Morrell, Christopher %A Shea, Thomas B %X

Background: Increasing evidence points toward the efficacy of nutritional modifications in delaying cognitive decline and mood/behavioral difficulties in Alzheimer's disease (AD). Nutritional supplementation with individual agents has shown varied results suggesting the need for combinatorial intervention. Objective: We set out to determine whether nutritional intervention could positively impact cognitive performance and behavioral difficulties for individuals diagnosed with AD. Methods: A double-blind, multi-site, phase II study (ClinicalTrials.gov NCT01320527; Alzheimer's Association Trialmatch) was conducted in which 106 individuals with AD were randomized to a nutraceutical formulation (NF; folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) or placebo for 3 or 6 months, followed by an open-label extension where participants received NF for 6 additional months. Results: The NF cohort improved versus the placebo cohort within 3 months (Clox-1 p = 0.0083, 95%CI [0.4481, 2.9343]; Dementia Rating Scale p = 0.0266, 95%CI [0.1722, 2.7171]). Caregivers reported non-significant improvements in Neuropsychiatric Inventory. Both cohorts improved or maintained baseline performance during open-label extensions. Activities of Daily Living did not change for either cohort. Conclusions: These findings extend phase I studies where NF maintained or improved cognitive performance and mood/behavior.

%B J Alzheimers Dis %8 2015 Jan 7 %G ENG %1 http://www.ncbi.nlm.nih.gov/pubmed/25589719?dopt=Abstract %R 10.3233/JAD-142499 %0 Journal Article %J J Alzheimers Dis %D 2015 %T sAβPPα is a Potent Endogenous Inhibitor of BACE1. %A Peters-Libeu, Clare %A Campagna, Jesus %A Mitsumori, Michael %A Poksay, Karen S %A Spilman, Patricia %A Sabogal, Alex %A Bredesen, Dale E %A John, Varghese %X

Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by the enzyme BACE1 (BACE) is the initial step in production of amyloid-β peptide (Aβ), and as such has been a major target of Alzheimer's disease (AD) drug discovery efforts. Overproduction of Aβ results in neuronal cell death and accumulation of amyloid plaques in AD and in traumatic brain injury, and is also associated with stroke due to cerebral amyloid angiopathy. Herein we report for the first time that sAβPPα, the product of the cleavage of AβPP by α-secretase, is a potent endogenous direct inhibitor of the BACE enzyme, and that its inhibition is likely by an allosteric mechanism. Furthermore, using small-angle X-ray scattering, we show that sAβPPβ, which is identical to sAβPPα except for a 16-amino acid truncation at the carboxy terminus, adopts a completely different structure than sAβPPα and does not inhibit BACE. Our data thus reveal a novel mechanistic role played by sAβPPα in regulating overproduction of Aβ and restoring neuronal homeostasis and neuroprotection. Identification of sAβPPα as a direct BACE inhibitor may lead to design of new therapeutics targeting pathologies associated with overproduction of Aβ.

%B J Alzheimers Dis %V 47 %P 545-55 %8 2015 Aug 3 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401691?dopt=Abstract %R 10.3233/JAD-150282 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Subtle Cognitive Decline and Biomarker Staging in Preclinical Alzheimer's Disease. %A Edmonds, Emily C %A Delano-Wood, Lisa %A Galasko, Douglas R %A Salmon, David P %A Bondi, Mark W %X

The NIA-AA criteria for "preclinical" Alzheimer's disease (AD) propose a staging method in which AD biomarkers follow an invariable temporal sequence in accordance with the amyloid cascade hypothesis. However, recent findings do not align with the proposed temporal sequence and "subtle cognitive decline," which has not been definitively operationalized, may occur earlier than suggested in preclinical AD. We aimed to define "subtle cognitive decline" using sensitive and reliable neuropsychological tests, and to examine the number and sequence of biomarker abnormalities in the Alzheimer's Disease Neuroimaging Initiative (ADNI). 570 cognitively normal ADNI participants were classified based on NIA-AA criteria and separately based on the number of abnormal biomarkers/cognitive markers associated with preclinical AD that each individual possessed. Results revealed that neurodegeneration alone was 2.5 times more common than amyloidosis alone at baseline. For those who demonstrated only one abnormal biomarker at baseline and later progressed to mild cognitive impairment/AD, neurodegeneration alone was most common, followed by amyloidosis alone or subtle cognitive decline alone, which were equally common. Findings suggest that most individuals do not follow the temporal order proposed by NIA-AA criteria. We provide an operational definition of subtle cognitive decline that captures both cognitive and functional decline. Additionally, we offer a new approach for staging preclinical AD based on number of abnormal biomarkers, without regard to their temporal order of occurrence. This method of characterizing preclinical AD is more parsimonious than the NIA-AA staging system and does not presume that all patients follow a singular invariant expression of the disease.

%B J Alzheimers Dis %V 47 %P 231-42 %8 2015 Jul 9 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26402771?dopt=Abstract %R 10.3233/JAD-150128 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Tracking Discourse Complexity Preceding Alzheimer's Disease Diagnosis: A Case Study Comparing the Press Conferences of Presidents Ronald Reagan and George Herbert Walker Bush. %A Berisha, Visar %A Wang, Shuai %A LaCross, Amy %A Liss, Julie %X

Changes in some lexical features of language have been associated with the onset and progression of Alzheimer's disease. Here we describe a method to extract key features from discourse transcripts, which we evaluated on non-scripted news conferences from President Ronald Reagan, who was diagnosed with Alzheimer's disease in 1994, and President George Herbert Walker Bush, who has no known diagnosis of Alzheimer's disease. Key word counts previously associated with cognitive decline in Alzheimer's disease were extracted and regression analyses were conducted. President Reagan showed a significant reduction in the number of unique words over time and a significant increase in conversational fillers and non-specific nouns over time. There was no significant trend in these features for President Bush.

%B J Alzheimers Dis %8 2015 Jan 29 %G ENG %1 http://www.ncbi.nlm.nih.gov/pubmed/25633673?dopt=Abstract %R 10.3233/JAD-142763 %0 Journal Article %J Lancet Neurol %D 2014 %T Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. %A Dubois, Bruno %A Feldman, Howard H %A Jacova, Claudia %A Hampel, Harald %A Molinuevo, José Luis %A Blennow, Kaj %A DeKosky, Steven T %A Gauthier, Serge %A Selkoe, Dennis %A Bateman, Randall %A Cappa, Stefano %A Crutch, Sebastian %A Engelborghs, Sebastiaan %A Frisoni, Giovanni B %A Fox, Nick C %A Galasko, Douglas %A Habert, Marie-Odile %A Jicha, Gregory A %A Nordberg, Agneta %A Pasquier, Florence %A Rabinovici, Gil %A Robert, Philippe %A Rowe, Christopher %A Salloway, Stephen %A Sarazin, Marie %A Epelbaum, Stéphane %A de Souza, Leonardo C %A Vellas, Bruno %A Visser, Pieter J %A Schneider, Lon %A Stern, Yaakov %A Scheltens, Philip %A Cummings, Jeffrey L %K Alzheimer Disease %K Biomarkers %K Humans %K International Cooperation %K Phenotype %K Practice Guidelines as Topic %K Societies, Medical %X

In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.

%B Lancet Neurol %V 13 %P 614-29 %8 2014 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24849862?dopt=Abstract %R 10.1016/S1474-4422(14)70090-0 %0 Journal Article %J Nat Med %D 2014 %T Plasma phospholipids identify antecedent memory impairment in older adults. %A Mapstone, Mark %A Cheema, Amrita K %A Fiandaca, Massimo S %A Zhong, Xiaogang %A Mhyre, Timothy R %A MacArthur, Linda H %A Hall, William J %A Fisher, Susan G %A Peterson, Derick R %A Haley, James M %A Nazar, Michael D %A Rich, Steven A %A Berlau, Dan J %A Peltz, Carrie B %A Tan, Ming T %A Kawas, Claudia H %A Federoff, Howard J %K Aged %K Alzheimer Disease %K Asparagine %K Biomarkers %K Carnitine %K Cohort Studies %K Dipeptides %K Female %K Humans %K Longitudinal Studies %K Lysophosphatidylcholines %K Malates %K Male %K Memory Disorders %K Metabolome %K Mild Cognitive Impairment %K Neuropsychological Tests %K Phosphatidylcholines %K Phosphatidylinositols %K Phospholipids %K Proline %K Prospective Studies %K Sensitivity and Specificity %K Sphingomyelins %K Ursodeoxycholic Acid %X

Alzheimer's disease causes a progressive dementia that currently affects over 35 million individuals worldwide and is expected to affect 115 million by 2050 (ref. 1). There are no cures or disease-modifying therapies, and this may be due to our inability to detect the disease before it has progressed to produce evident memory loss and functional decline. Biomarkers of preclinical disease will be critical to the development of disease-modifying or even preventative therapies. Unfortunately, current biomarkers for early disease, including cerebrospinal fluid tau and amyloid-β levels, structural and functional magnetic resonance imaging and the recent use of brain amyloid imaging or inflammaging, are limited because they are either invasive, time-consuming or expensive. Blood-based biomarkers may be a more attractive option, but none can currently detect preclinical Alzheimer's disease with the required sensitivity and specificity. Herein, we describe our lipidomic approach to detecting preclinical Alzheimer's disease in a group of cognitively normal older adults. We discovered and validated a set of ten lipids from peripheral blood that predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimer's disease within a 2-3 year timeframe with over 90% accuracy. This biomarker panel, reflecting cell membrane integrity, may be sensitive to early neurodegeneration of preclinical Alzheimer's disease.

%B Nat Med %V 20 %P 415-8 %8 2014 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24608097?dopt=Abstract %R 10.1038/nm.3466 %0 Journal Article %J Nature %D 2014 %T REST and stress resistance in ageing and Alzheimer's disease. %A Lu, Tao %A Aron, Liviu %A Zullo, Joseph %A Pan, Ying %A Kim, Haeyoung %A Chen, Yiwen %A Yang, Tun-Hsiang %A Kim, Hyun-Min %A Drake, Derek %A Liu, X Shirley %A Bennett, David A %A Colaiácovo, Monica P %A Yankner, Bruce A %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Autophagy %K Brain %K Caenorhabditis elegans Proteins %K Cell Death %K Cell Nucleus %K Chromatin Immunoprecipitation %K Cognition %K DNA-Binding Proteins %K Down-Regulation %K Frontotemporal Dementia %K Gene Expression Regulation %K Humans %K Lewy Body Disease %K Longevity %K Mice %K Mild Cognitive Impairment %K Neurons %K Neuroprotective Agents %K Oxidative Stress %K Phagosomes %K Repressor Proteins %K Transcription Factors %K Up-Regulation %K Wnt Signaling Pathway %K Young Adult %X

Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer's disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

%B Nature %V 507 %P 448-54 %8 2014 Mar 27 %G eng %N 7493 %1 http://www.ncbi.nlm.nih.gov/pubmed/24670762?dopt=Abstract %R 10.1038/nature13163 %0 Journal Article %J J Am Geriatr Soc %D 2014 %T Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive training trial on cognition and everyday functioning in older adults. %A Rebok, George W %A Ball, Karlene %A Guey, Lin T %A Jones, Richard N %A Kim, Hae-Young %A King, Jonathan W %A Marsiske, Michael %A Morris, John N %A Tennstedt, Sharon L %A Unverzagt, Frederick W %A Willis, Sherry L %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Aging %K Cognition Disorders %K Cognitive Therapy %K Female %K Follow-Up Studies %K Humans %K Independent Living %K Male %K Memory Disorders %K Mental Processes %K Single-Blind Method %K United States %X

OBJECTIVES: To determine the effects of cognitive training on cognitive abilities and everyday function over 10 years.

DESIGN: Ten-year follow-up of a randomized, controlled single-blind trial (Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE)) with three intervention groups and a no-contact control group.

SETTING: Six U.S. cities.

PARTICIPANTS: A volunteer sample of 2,832 persons (mean baseline age 73.6; 26% African American) living independently.

INTERVENTION: Ten training sessions for memory, reasoning, or speed of processing; four sessions of booster training 11 and 35 months after initial training.

MEASUREMENTS: Objectively measured cognitive abilities and self-reported and performance-based measures of everyday function.

RESULTS: Participants in each intervention group reported less difficulty with instrumental activities of daily living (IADLs) (memory: effect size = 0.48, 99% confidence interval (CI) = 0.12-0.84; reasoning: effect size = 0.38, 99% CI = 0.02-0.74; speed of processing: effect size = 0.36, 99% CI = 0.01-0.72). At a mean age of 82, approximately 60% of trained participants, versus 50% of controls (P < .05), were at or above their baseline level of self-reported IADL function at 10 years. The reasoning and speed-of-processing interventions maintained their effects on their targeted cognitive abilities at 10 years (reasoning: effect size = 0.23, 99% CI = 0.09-0.38; speed of processing: effect size = 0.66, 99% CI = 0.43-0.88). Memory training effects were no longer maintained for memory performance. Booster training produced additional and durable improvement for the reasoning intervention for reasoning performance (effect size = 0.21, 99% CI = 0.01-0.41) and the speed-of-processing intervention for speed-of-processing performance (effect size = 0.62, 99% CI = 0.31-0.93).

CONCLUSION: Each Advanced Cognitive Training for Independent and Vital Elderly cognitive intervention resulted in less decline in self-reported IADL compared with the control group. Reasoning and speed, but not memory, training resulted in improved targeted cognitive abilities for 10 years.

%B J Am Geriatr Soc %V 62 %P 16-24 %8 2014 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24417410?dopt=Abstract %R 10.1111/jgs.12607 %0 Journal Article %J N Engl J Med %D 2014 %T Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. %A Salloway, Stephen %A Sperling, Reisa %A Fox, Nick C %A Blennow, Kaj %A Klunk, William %A Raskind, Murray %A Sabbagh, Marwan %A Honig, Lawrence S %A Porsteinsson, Anton P %A Ferris, Steven %A Reichert, Marcel %A Ketter, Nzeera %A Nejadnik, Bijan %A Guenzler, Volkmar %A Miloslavsky, Maja %A Wang, Daniel %A Lu, Yuan %A Lull, Julia %A Tudor, Iulia Cristina %A Liu, Enchi %A Grundman, Michael %A Yuen, Eric %A Black, Ronald %A Brashear, H Robert %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Antibodies, Monoclonal, Humanized %K Apolipoproteins E %K Biomarkers %K Brain %K Cognition %K Double-Blind Method %K Edema %K Female %K Humans %K Intention to Treat Analysis %K Male %K Middle Aged %K Neuropsychological Tests %K Phosphorylation %K Positron-Emission Tomography %K Severity of Illness Index %K tau Proteins %K Treatment Failure %X

BACKGROUND: Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease.

METHODS: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease--one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations.

RESULTS: There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were -0.2 (P=0.80) and -1.2 (P=0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were -0.3 (P=0.64) and 2.8 (P=0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P=0.62) and 0.9 (P=0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers.

CONCLUSIONS: Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.).

%B N Engl J Med %V 370 %P 322-33 %8 2014 Jan 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24450891?dopt=Abstract %R 10.1056/NEJMoa1304839 %0 Journal Article %J Nat Med %D 2014 %T Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. %A Villeda, Saul A %A Plambeck, Kristopher E %A Middeldorp, Jinte %A Castellano, Joseph M %A Mosher, Kira I %A Luo, Jian %A Smith, Lucas K %A Bieri, Gregor %A Lin, Karin %A Berdnik, Daniela %A Wabl, Rafael %A Udeochu, Joe %A Wheatley, Elizabeth G %A Zou, Bende %A Simmons, Danielle A %A Xie, Xinmin S %A Longo, Frank M %A Wyss-Coray, Tony %K Age Factors %K Aging %K Animals %K Blood Transfusion %K Blotting, Western %K Cell Line %K Cognition Disorders %K Cyclic AMP Response Element-Binding Protein %K DNA Primers %K Hippocampus %K Immunohistochemistry %K Mice %K Mice, Inbred C57BL %K Microarray Analysis %K Neuronal Plasticity %K Parabiosis %K Polymerase Chain Reaction %X

As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.

%B Nat Med %V 20 %P 659-63 %8 2014 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24793238?dopt=Abstract %R 10.1038/nm.3569 %0 Journal Article %J Ann Neurol %D 2013 %T Anti-amyloid β autoantibodies in cerebral amyloid angiopathy-related inflammation: implications for amyloid-modifying therapies. %A Piazza, Fabrizio %A Greenberg, Steven M %A Savoiardo, Mario %A Gardinetti, Margherita %A Chiapparini, Luisa %A Raicher, Irina %A Nitrini, Ricardo %A Sakaguchi, Hideya %A Brioschi, Monica %A Billo, Giuseppe %A Colombo, Antonio %A Lanzani, Francesca %A Piscosquito, Giuseppe %A Carriero, Maria Rita %A Giaccone, Giorgio %A Tagliavini, Fabrizio %A Ferrarese, Carlo %A DiFrancesco, Jacopo C %K Adult %K Aged %K Amyloid beta-Peptides %K Apolipoproteins E %K Autoantibodies %K Brain %K Case-Control Studies %K Cerebral Amyloid Angiopathy %K Female %K Humans %K Inflammation %K Male %K Middle Aged %K Peptide Fragments %K Phosphorylation %K Retrospective Studies %K Steroids %K tau Proteins %X

OBJECTIVE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined amyloid-related imaging abnormalities (ARIA) reported in Alzheimer's disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid β (Aβ) autoantibodies in the acute and remission phases of CAA-ri.

METHODS: We used a novel ultrasensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aβ autoantibody concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis, and 25 control subjects. Levels of soluble Aβ40, Aβ42, tau, P-181 tau, and APOE genotype were also investigated.

RESULTS: During the acute phase of CAA-ri, anti-Aβ autoantibodies were specifically increased and directly correlated with Aβ mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aβ and axonal degeneration markers decreased in parallel.

INTERPRETATION: Our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebrovascular Aβ, directly related to autoantibody concentration and soluble Aβ. The CSF dosage of anti-Aβ autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Aβ autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA.

%B Ann Neurol %V 73 %P 449-58 %8 2013 Apr %G eng %N 4 %R 10.1002/ana.23857 %0 Journal Article %J Cell %D 2013 %T Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. %A Zhang, Bin %A Gaiteri, Chris %A Bodea, Liviu-Gabriel %A Wang, Zhi %A McElwee, Joshua %A Podtelezhnikov, Alexei A %A Zhang, Chunsheng %A Xie, Tao %A Tran, Linh %A Dobrin, Radu %A Fluder, Eugene %A Clurman, Bruce %A Melquist, Stacey %A Narayanan, Manikandan %A Suver, Christine %A Shah, Hardik %A Mahajan, Milind %A Gillis, Tammy %A Mysore, Jayalakshmi %A MacDonald, Marcy E %A Lamb, John R %A Bennett, David A %A Molony, Cliona %A Stone, David J %A Gudnason, Vilmundur %A Myers, Amanda J %A Schadt, Eric E %A Neumann, Harald %A Zhu, Jun %A Emilsson, Valur %K Adaptor Proteins, Signal Transducing %K Alzheimer Disease %K Animals %K Bayes Theorem %K Brain %K Gene Regulatory Networks %K Humans %K Membrane Proteins %K Mice %K Microglia %X

The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer's disease (LOAD), we constructed gene-regulatory networks in 1,647 postmortem brain tissues from LOAD patients and nondemented subjects, and we demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune- and microglia-specific module that is dominated by genes involved in pathogen phagocytosis, contains TYROBP as a key regulator, and is upregulated in LOAD. Mouse microglia cells overexpressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a framework to test models of disease mechanisms underlying LOAD.

%B Cell %V 153 %P 707-20 %8 2013 Apr 25 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23622250?dopt=Abstract %R 10.1016/j.cell.2013.03.030 %0 Journal Article %J Nat Genet %D 2013 %T Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. %A Lambert, J C %A Ibrahim-Verbaas, C A %A Harold, D %A Naj, A C %A Sims, R %A Bellenguez, C %A DeStafano, A L %A Bis, J C %A Beecham, G W %A Grenier-Boley, B %A Russo, G %A Thorton-Wells, T A %A Jones, N %A Smith, A V %A Chouraki, V %A Thomas, C %A Ikram, M A %A Zelenika, D %A Vardarajan, B N %A Kamatani, Y %A Lin, C F %A Gerrish, A %A Schmidt, H %A Kunkle, B %A Dunstan, M L %A Ruiz, A %A Bihoreau, M T %A Choi, S H %A Reitz, C %A Pasquier, F %A Cruchaga, C %A Craig, D %A Amin, N %A Berr, C %A Lopez, O L %A De Jager, P L %A Deramecourt, V %A Johnston, J A %A Evans, D %A Lovestone, S %A Letenneur, L %A Morón, F J %A Rubinsztein, D C %A Eiriksdottir, G %A Sleegers, K %A Goate, A M %A Fiévet, N %A Huentelman, M W %A Gill, M %A Brown, K %A Kamboh, M I %A Keller, L %A Barberger-Gateau, P %A McGuiness, B %A Larson, E B %A Green, R %A Myers, A J %A Dufouil, C %A Todd, S %A Wallon, D %A Love, S %A Rogaeva, E %A Gallacher, J %A St George-Hyslop, P %A Clarimon, J %A Lleo, A %A Bayer, A %A Tsuang, D W %A Yu, L %A Tsolaki, M %A Bossù, P %A Spalletta, G %A Proitsi, P %A Collinge, J %A Sorbi, S %A Sanchez-Garcia, F %A Fox, N C %A Hardy, J %A Deniz Naranjo, M C %A Bosco, P %A Clarke, R %A Brayne, C %A Galimberti, D %A Mancuso, M %A Matthews, F %A Moebus, S %A Mecocci, P %A Del Zompo, M %A Maier, W %A Hampel, H %A Pilotto, A %A Bullido, M %A Panza, F %A Caffarra, P %A Nacmias, B %A Gilbert, J R %A Mayhaus, M %A Lannefelt, L %A Hakonarson, H %A Pichler, S %A Carrasquillo, M M %A Ingelsson, M %A Beekly, D %A Alvarez, V %A Zou, F %A Valladares, O %A Younkin, S G %A Coto, E %A Hamilton-Nelson, K L %A Gu, W %A Razquin, C %A Pastor, P %A Mateo, I %A Owen, M J %A Faber, K M %A Jonsson, P V %A Combarros, O %A O'Donovan, M C %A Cantwell, L B %A Soininen, H %A Blacker, D %A Mead, S %A Mosley, T H %A Bennett, D A %A Harris, T B %A Fratiglioni, L %A Holmes, C %A de Bruijn, R F %A Passmore, P %A Montine, T J %A Bettens, K %A Rotter, J I %A Brice, A %A Morgan, K %A Foroud, T M %A Kukull, W A %A Hannequin, D %A Powell, J F %A Nalls, M A %A Ritchie, K %A Lunetta, K L %A Kauwe, J S %A Boerwinkle, E %A Riemenschneider, M %A Boada, M %A Hiltuenen, M %A Martin, E R %A Schmidt, R %A Rujescu, D %A Wang, L S %A Dartigues, J F %A Mayeux, R %A Tzourio, C %A Hofman, A %A Nöthen, M M %A Graff, C %A Psaty, B M %A Jones, L %A Haines, J L %A Holmans, P A %A Lathrop, M %A Pericak-Vance, M A %A Launer, L J %A Farrer, L A %A van Duijn, C M %A Van Broeckhoven, C %A Moskvina, V %A Seshadri, S %A Williams, J %A Schellenberg, G D %A Amouyel, P %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Cohort Studies %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

%B Nat Genet %V 45 %P 1452-8 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24162737?dopt=Abstract %R 10.1038/ng.2802 %0 Journal Article %J N Engl J Med %D 2013 %T TREM2 variants in Alzheimer's disease. %A Guerreiro, Rita %A Wojtas, Aleksandra %A Bras, Jose %A Carrasquillo, Minerva %A Rogaeva, Ekaterina %A Majounie, Elisa %A Cruchaga, Carlos %A Sassi, Celeste %A Kauwe, John S K %A Younkin, Steven %A Hazrati, Lilinaz %A Collinge, John %A Pocock, Jennifer %A Lashley, Tammaryn %A Williams, Julie %A Lambert, Jean-Charles %A Amouyel, Philippe %A Goate, Alison %A Rademakers, Rosa %A Morgan, Kevin %A Powell, John %A St George-Hyslop, Peter %A Singleton, Andrew %A Hardy, John %K Aged %K Alzheimer Disease %K Animals %K Brain %K Exome %K Genetic Variation %K Genome-Wide Association Study %K Genotype %K Genotyping Techniques %K Heterozygote %K Humans %K Membrane Glycoproteins %K Mice %K Mice, Inbred A %K Mutation %K Receptors, Immunologic %K Risk Factors %K RNA, Messenger %K Sequence Analysis, DNA %X

BACKGROUND: Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia.

METHODS: We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice.

RESULTS: We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease.

CONCLUSIONS: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).

%B N Engl J Med %V 368 %P 117-27 %8 2013 Jan 10 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23150934?dopt=Abstract %R 10.1056/NEJMoa1211851 %0 Journal Article %J Arch Gen Psychiatry %D 2012 %T Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. %A Buchhave, Peder %A Minthon, Lennart %A Zetterberg, Henrik %A Wallin, Asa K %A Blennow, Kaj %A Hansson, Oskar %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Female %K Follow-Up Studies %K Humans %K Male %K Mild Cognitive Impairment %K Peptide Fragments %K Predictive Value of Tests %K tau Proteins %K Time Factors %X

CONTEXT: Early detection of prodromal Alzheimer disease (AD) is important because new disease-modifying therapies are most likely to be effective when initiated during the early stages of disease.

OBJECTIVES: To assess the ability of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), and β-amyloid 1-42 (Aβ42) to predict future development of AD dementia within 9.2 years in patients with mild cognitive impairment (MCI) and to compare CSF biomarkers between early and late converters to AD.

DESIGN: A clinical study with a median follow-up of 9.2 years (range, 4.1-11.8 years).

SETTING: Memory disorder clinic. Patients A total of 137 patients with MCI who underwent lumbar puncture at baseline. MAIN OUTCOME MEASURE Conversion to AD dementia.

RESULTS: During follow-up, 72 patients (53.7%) developed AD and 21 (15.7%) progressed to other forms of dementia. At baseline, CSF Aβ42 levels were reduced and T-tau and P-tau levels were elevated in patients who converted to AD during follow-up compared with nonconverters (P < .001). Baseline CSF Aβ42 levels were equally reduced in patients with MCI who converted to AD within 0 to 5 years (early converters) compared with those who converted between 5 and 10 years (late converters). However, CSF T-tau and P-tau levels were significantly higher in early converters vs late converters. A baseline Aβ42:P-tau ratio predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 86%.

CONCLUSIONS: Approximately 90% of patients with MCI and pathologic CSF biomarker levels at baseline develop AD within 9 to 10 years. Levels of Aβ42 are already fully decreased at least 5 to 10 years before conversion to AD dementia, whereas T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered Aβ metabolism precedes tau-related pathology and neuronal degeneration.

%B Arch Gen Psychiatry %V 69 %P 98-106 %8 2012 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22213792?dopt=Abstract %R 10.1001/archgenpsychiatry.2011.155 %0 Journal Article %J J Clin Invest %D 2012 %T Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. %A Talbot, Konrad %A Wang, Hoau-Yan %A Kazi, Hala %A Han, Li-Ying %A Bakshi, Kalindi P %A Stucky, Andres %A Fuino, Robert L %A Kawaguchi, Krista R %A Samoyedny, Andrew J %A Wilson, Robert S %A Arvanitakis, Zoe %A Schneider, Julie A %A Wolf, Bryan A %A Bennett, David A %A Trojanowski, John Q %A Arnold, Steven E %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Brain %K Cerebellar Cortex %K Cognition Disorders %K Diabetes Complications %K Drug Resistance %K Female %K Glucose %K Hippocampus %K Humans %K Insulin %K Insulin Receptor Substrate Proteins %K Insulin Resistance %K Insulin-Like Growth Factor I %K Male %K Middle Aged %K Phosphorylation %K Phosphoserine %K Protein Processing, Post-Translational %K Recombinant Proteins %K Signal Transduction %X

While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS⁶¹⁶) and IRS-1 pS⁶³⁶/⁶³⁹. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS⁶¹⁶ and IRS-1 pS⁶³⁶/⁶³⁹ and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.

%B J Clin Invest %V 122 %P 1316-38 %8 2012 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22476197?dopt=Abstract %R 10.1172/JCI59903 %0 Journal Article %J Arch Neurol %D 2012 %T Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition. %A Head, Denise %A Bugg, Julie M %A Goate, Alison M %A Fagan, Anne M %A Mintun, Mark A %A Benzinger, Tammie %A Holtzman, David M %A Morris, John C %K Aged %K Aged, 80 and over %K Amyloid beta-Peptides %K Aniline Compounds %K Apolipoprotein E4 %K Brain %K Cognition %K Cohort Studies %K Exercise %K Female %K Genetic Association Studies %K Genotype %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Positron-Emission Tomography %K Regression Analysis %K Surveys and Questionnaires %K Thiazoles %X

OBJECTIVE: APOE ε4 status has been associated with greater cortical amyloid deposition, whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults.

DESIGN: APOE genotyping data and answers to a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB) positron emission tomography. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association.

SETTING: Knight Alzheimer's Disease Research Center at Washington University, St Louis, Missouri.

PARTICIPANTS: A total of 201 cognitively normal adults (135 of whom were women) aged 45 to 88 years were recruited from the Knight Alzheimer's Disease Research Center. Samples of CSF were collected from 165 participants. Amyloid imaging was performed for 163 participants.

RESULTS: APOE ε4 carriers evidenced higher [(11)C]PiB binding (P<.001) and lower CSF Aβ42 levels (P<.001) than did noncarriers. Our previous findings of higher [(11)C]PiB binding (P=.005) and lower CSF Aβ42 levels (P=.009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for [(11)C]PiB binding (P=.008) such that a more sedentary lifestyle was significantly associated with higher [(11)C]PiB binding for ε4 carriers (P=.013) but not for noncarriers (P=.20). All findings remained significant after controlling for age; sex; educational level; body mass index; the presence or history of hypertension, diabetes mellitus, heart problems, or depression; and the interval between assessments.

CONCLUSION: Collectively, these results suggest that cognitively normal sedentary APOE ε4-positive individuals may be at augmented risk for cerebral amyloid deposition.

%B Arch Neurol %V 69 %P 636-43 %8 2012 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/22232206?dopt=Abstract %R 10.1001/archneurol.2011.845 %0 Journal Article %J Nature %D 2012 %T A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. %A Jonsson, Thorlakur %A Atwal, Jasvinder K %A Steinberg, Stacy %A Snaedal, Jon %A Jonsson, Palmi V %A Bjornsson, Sigurbjorn %A Stefansson, Hreinn %A Sulem, Patrick %A Gudbjartsson, Daniel %A Maloney, Janice %A Hoyte, Kwame %A Gustafson, Amy %A Liu, Yichin %A Lu, Yanmei %A Bhangale, Tushar %A Graham, Robert R %A Huttenlocher, Johanna %A Bjornsdottir, Gyda %A Andreassen, Ole A %A Jönsson, Erik G %A Palotie, Aarno %A Behrens, Timothy W %A Magnusson, Olafur T %A Kong, Augustine %A Thorsteinsdottir, Unnur %A Watts, Ryan J %A Stefansson, Kari %K Aging %K Alleles %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Aspartic Acid Endopeptidases %K Cognition %K Cognition Disorders %K Genetic Predisposition to Disease %K HEK293 Cells %K Humans %K Mutation %K Plaque, Amyloid %X

The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-β precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.

%B Nature %V 488 %P 96-9 %8 2012 Aug 2 %G eng %N 7409 %1 http://www.ncbi.nlm.nih.gov/pubmed/22801501?dopt=Abstract %R 10.1038/nature11283 %0 Journal Article %J Alzheimers Dement %D 2012 %T National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. %A Hyman, Bradley T %A Phelps, Creighton H %A Beach, Thomas G %A Bigio, Eileen H %A Cairns, Nigel J %A Carrillo, Maria C %A Dickson, Dennis W %A Duyckaerts, Charles %A Frosch, Matthew P %A Masliah, Eliezer %A Mirra, Suzanne S %A Nelson, Peter T %A Schneider, Julie A %A Thal, Dietmar Rudolf %A Thies, Bill %A Trojanowski, John Q %A Vinters, Harry V %A Montine, Thomas J %K Alzheimer Disease %K Brain %K Consensus Development Conferences, NIH as Topic %K Humans %K National Institute on Aging (U.S.) %K Practice Guidelines as Topic %K Societies, Medical %K United States %X

A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.

%B Alzheimers Dement %V 8 %P 1-13 %8 2012 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22265587?dopt=Abstract %R 10.1016/j.jalz.2011.10.007 %0 Journal Article %J J Alzheimers Dis %D 2012 %T Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults. %A Calderón-Garcidueñas, Lilian %A Kavanaugh, Michael %A Block, Michelle %A D'Angiulli, Amedeo %A Delgado-Chávez, Ricardo %A Torres-Jardón, Ricardo %A González-Maciel, Angelica %A Reynoso-Robles, Rafael %A Osnaya, Norma %A Villarreal-Calderon, Rodolfo %A Guo, Ruixin %A Hua, Zhaowei %A Zhu, Hongtu %A Perry, George %A Diaz, Philippe %K Adolescent %K Adult %K Age Factors %K Air Pollution %K Child %K Child, Preschool %K Cohort Studies %K Down-Regulation %K Encephalitis %K Female %K Frontal Lobe %K Gene Regulatory Networks %K Humans %K Infant %K Male %K Mexico %K Phosphorylation %K Plaque, Amyloid %K Prions %K tau Proteins %K Young Adult %X

Air pollution exposures have been linked to neuroinflammation and neuropathology. Autopsy samples of the frontal cortex from control (n = 8) and pollution-exposed (n = 35) children and young adults were analyzed by RT-PCR (n = 43) and microarray analysis (n = 12) for gene expression changes in oxidative stress, DNA damage signaling, NFκB signaling, inflammation, and neurodegeneration pathways. The effect of apolipoprotein E (APOE) genotype on the presence of protein aggregates associated with Alzheimer's disease (AD) pathology was also explored. Exposed urbanites displayed differential (>2-fold) regulation of 134 genes. Forty percent exhibited tau hyperphosphorylation with pre-tangle material and 51% had amyloid-β (Aβ) diffuse plaques compared with 0% in controls. APOE4 carriers had greater hyperphosphorylated tau and diffuse Aβ plaques versus E3 carriers (Q = 7.82, p = 0.005). Upregulated gene network clusters included IL1, NFκB, TNF, IFN, and TLRs. A 15-fold frontal down-regulation of the prion-related protein (PrP(C)) was seen in highly exposed subjects. The down-regulation of the PrP(C) is critical given its important roles for neuroprotection, neurodegeneration, and mood disorder states. Elevation of indices of neuroinflammation and oxidative stress, down-regulation of the PrP(C) and AD-associated pathology are present in young megacity residents. The inducible regulation of gene expression suggests they are evolving different mechanisms in an attempt to cope with the constant state of inflammation and oxidative stress related to their environmental exposures. Together, these data support a role for air pollution in CNS damage and its impact upon the developing brain and the potential etiology of AD and mood disorders.

%B J Alzheimers Dis %V 28 %P 93-107 %8 2012 %G eng %N 1 %R 10.3233/JAD-2011-110722 %0 Journal Article %J Ann Neurol %D 2012 %T An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer disease. %A Jack, Clifford R %A Knopman, David S %A Weigand, Stephen D %A Wiste, Heather J %A Vemuri, Prashanthi %A Lowe, Val %A Kantarci, Kejal %A Gunter, Jeffrey L %A Senjem, Matthew L %A Ivnik, Robert J %A Roberts, Rosebud O %A Rocca, Walter A %A Boeve, Bradley F %A Petersen, Ronald C %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Aniline Compounds %K Biomarkers %K Brain %K Cognition Disorders %K Disease Progression %K Female %K Fluorodeoxyglucose F18 %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K National Institute on Aging (U.S.) %K Neuropsychological Tests %K Positron-Emission Tomography %K Thiazoles %K United States %X

OBJECTIVE: A workgroup commissioned by the Alzheimer's Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer disease (AD). We performed a preliminary assessment of these guidelines.

METHODS: We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis, and (18) fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cutpoints. A group of 450 cognitively normal (CN) subjects from a population-based sample was used to develop cognitive cutpoints and to assess population frequencies of the different preclinical AD stages using different cutpoint criteria.

RESULTS: The new criteria subdivide the preclinical phase of AD into stages 1 to 3. To classify our CN subjects, 2 additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected non-AD pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cutpoints corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0, 16% stage 1, 12 % stage 2, 3% stage 3, and 23% SNAP.

INTERPRETATION: This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1-3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving only 3% unclassified. Future longitudinal validation of the criteria will be important.

%B Ann Neurol %V 71 %P 765-75 %8 2012 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22488240?dopt=Abstract %R 10.1002/ana.22628 %0 Journal Article %J Sci Transl Med %D 2012 %T A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. %A Iliff, Jeffrey J %A Wang, Minghuan %A Liao, Yonghong %A Plogg, Benjamin A %A Peng, Weiguo %A Gundersen, Georg A %A Benveniste, Helene %A Vates, G Edward %A Deane, Rashid %A Goldman, Steven A %A Nagelhus, Erlend A %A Nedergaard, Maiken %K Amyloid beta-Peptides %K Animals %K Aquaporin 4 %K Astrocytes %K Biological Transport %K Brain %K Cerebral Ventricles %K Cerebrospinal Fluid %K Extracellular Fluid %K Imaging, Three-Dimensional %K Male %K Mice %K Mice, Inbred C57BL %K Microscopy, Fluorescence, Multiphoton %K Water %X

Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.

%B Sci Transl Med %V 4 %P 147ra111 %8 2012 Aug 15 %G eng %N 147 %1 http://www.ncbi.nlm.nih.gov/pubmed/22896675?dopt=Abstract %R 10.1126/scitranslmed.3003748 %0 Journal Article %J Neuron %D 2012 %T Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. %A Bakker, Arnold %A Krauss, Gregory L %A Albert, Marilyn S %A Speck, Caroline L %A Jones, Lauren R %A Stark, Craig E %A Yassa, Michael A %A Bassett, Susan S %A Shelton, Amy L %A Gallagher, Michela %K Aged %K Aged, 80 and over %K Amnesia %K Brain Mapping %K Case-Control Studies %K Choice Behavior %K Double-Blind Method %K Female %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Mild Cognitive Impairment %K Neuropsychological Tests %K Nootropic Agents %K Oxygen %K Photic Stimulation %K Piracetam %K Statistics as Topic %X

Elevated hippocampal activation is observed in conditions that confer risk for Alzheimer's disease, including amnestic mild cognitive impairment (aMCI). Studies in relevant animal models have indicated that overactivity in selective hippocampal circuits contributes to cognitive impairment. Here, we tested the effect of reducing hippocampal activation in aMCI. Under placebo treatment, hippocampal activation in the dentate gyrus/CA3 was elevated in aMCI patients compared to a healthy control group. By using a low dose of the antiepileptic levetiracetam hippocampal activation in aMCI was reduced to a level that did not differ from the control group. Compared to aMCI memory performance under placebo, performance in the scanning task was significantly improved under drug treatment. Contrary to the view that greater hippocampal activation might serve a beneficial function, these results support the view that increased hippocampal activation in aMCI is a dysfunctional condition and that targeting excess hippocampal activity has therapeutic potential.

%B Neuron %V 74 %P 467-74 %8 2012 May 10 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22578498?dopt=Abstract %R 10.1016/j.neuron.2012.03.023 %0 Journal Article %J Brain %D 2011 %T 18F-THK523: a novel in vivo tau imaging ligand for Alzheimer's disease. %A Fodero-Tavoletti, Michelle T %A Okamura, Nobuyuki %A Furumoto, Shozo %A Mulligan, Rachel S %A Connor, Andrea R %A McLean, Catriona A %A Cao, Diana %A Rigopoulos, Angela %A Cartwright, Glenn A %A O'Keefe, Graeme %A Gong, Sylvia %A Adlard, Paul A %A Barnham, Kevin J %A Rowe, Christopher C %A Masters, Colin L %A Kudo, Yukitsuka %A Cappai, Roberto %A Yanai, Kazuhiko %A Villemagne, Victor L %K Alzheimer Disease %K Analysis of Variance %K Aniline Compounds %K Animals %K Autoradiography %K Binding Sites %K Brain %K Female %K Fluorodeoxyglucose F18 %K Humans %K Immunohistochemistry %K Male %K Mice %K Quinolines %K Radiopharmaceuticals %K tau Proteins %X

While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimer's disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of (18)F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that (18)F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid(1-42) fibrils. Autoradiographic and histofluorescence analysis of human hippocampal serial sections with Alzheimer's disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of (18)F-THK523 (48%; P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that (18)F-THK523 fulfils ligand criteria for human imaging trials.

%B Brain %V 134 %P 1089-100 %8 2011 Apr %G eng %N Pt 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21436112?dopt=Abstract %R 10.1093/brain/awr038 %0 Journal Article %J Cell %D 2011 %T Astrocyte-neuron lactate transport is required for long-term memory formation. %A Suzuki, Akinobu %A Stern, Sarah A %A Bozdagi, Ozlem %A Huntley, George W %A Walker, Ruth H %A Magistretti, Pierre J %A Alberini, Cristina M %K Animals %K Arabinose %K Astrocytes %K Glycogen %K Hippocampus %K Imino Furanoses %K Lactic Acid %K Memory, Long-Term %K Monocarboxylic Acid Transporters %K Muscle Proteins %K Neurons %K Rats %K Sugar Alcohols %K Symporters %X

We report that, in the rat hippocampus, learning leads to a significant increase in extracellular lactate levels that derive from glycogen, an energy reserve selectively localized in astrocytes. Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by L-lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc, and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation.

%B Cell %V 144 %P 810-23 %8 2011 Mar 4 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/21376239?dopt=Abstract %R 10.1016/j.cell.2011.02.018 %0 Journal Article %J Nature %D 2011 %T Caspase signalling controls microglia activation and neurotoxicity. %A Burguillos, Miguel A %A Deierborg, Tomas %A Kavanagh, Edel %A Persson, Annette %A Hajji, Nabil %A Garcia-Quintanilla, Albert %A Cano, Josefina %A Brundin, Patrik %A Englund, Elisabet %A Venero, Jose L %A Joseph, Bertrand %K Alzheimer Disease %K Animals %K Caspase 3 %K Caspase 7 %K Caspase 8 %K Caspase Inhibitors %K Caspases %K Cell Death %K Cells, Cultured %K Dopamine %K Enzyme Activation %K Frontal Lobe %K Gene Knockdown Techniques %K Humans %K Lipopolysaccharides %K Mice %K Microglia %K Neostriatum %K Neurotoxicity Syndromes %K Parkinson Disease %K Protein Kinase C-delta %K Rats %K Signal Transduction %K Substantia Nigra %K Toll-Like Receptor 4 %X

Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.

%B Nature %V 472 %P 319-24 %8 2011 Apr 21 %G eng %N 7343 %1 http://www.ncbi.nlm.nih.gov/pubmed/21389984?dopt=Abstract %R 10.1038/nature09788 %0 Journal Article %J Arch Neurol %D 2011 %T Evidence for ordering of Alzheimer disease biomarkers. %A Jack, Clifford R %A Vemuri, Prashanthi %A Wiste, Heather J %A Weigand, Stephen D %A Aisen, Paul S %A Trojanowski, John Q %A Shaw, Leslie M %A Bernstein, Matthew A %A Petersen, Ronald C %A Weiner, Michael W %A Knopman, David S %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Female %K Hippocampus %K Humans %K Longitudinal Studies %K Male %K Mild Cognitive Impairment %K tau Proteins %X

OBJECTIVE: To empirically assess the concept that Alzheimer disease (AD) biomarkers significantly depart from normality in a temporally ordered manner.

DESIGN: Validation sample.

SETTING: Multisite, referral centers.

PARTICIPANTS: A total of 401 elderly participants in the Alzheimer's Disease Neuroimaging Initiative who were cognitively normal, who had mild cognitive impairment, or who had AD dementia. We compared the proportions of 3 AD biomarker values (the Aβ42 level in cerebrospinal fluid [CSF], the total tau level in CSF, and the hippocampal volume adjusted for intracranial volume [hereafter referred to as the adjusted hippocampal volume]) that were abnormal as cognitive impairment worsened. Cut points demarcating normal vs abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples.

MAIN OUTCOME MEASURES: Three AD biomarkers (ie, the CSF Aβ42 level, the CSF total tau level, and the adjusted hippocampal volume).

RESULTS: Within each clinical group of the entire sample (n = 401), the CSF Aβ42 level was abnormal more often than was the CSF total tau level or the adjusted hippocampal volume. Among the 298 participants with both baseline and 12-month data, the proportion of participants with an abnormal Aβ42 level did not change from baseline to 12 months in any group. The proportion of participants with an abnormal total tau level increased from baseline to 12 months in cognitively normal participants (P = .05) but not in participants with mild cognitive impairment or AD dementia. For 209 participants with an abnormal CSF Aβ42 level at baseline, the percentage with an abnormal adjusted hippocampal volume but normal CSF total tau level increased from baseline to 12 months in participants with mild cognitive impairment. No change in the percentage of MCI participants with an abnormal total tau level was seen between baseline and 12 months.

CONCLUSIONS: A reduction in the CSF Aβ42 level denotes a pathophysiological process that significantly departs from normality (ie, becomes dynamic) early, whereas the CSF total tau level and the adjusted hippocampal volume are biomarkers of downstream pathophysiological processes. The CSF total tau level becomes dynamic before the adjusted hippocampal volume, but the hippocampal volume is more dynamic in the clinically symptomatic mild cognitive impairment and AD dementia phases of the disease than is the CSF total tau level.

%B Arch Neurol %V 68 %P 1526-35 %8 2011 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21825215?dopt=Abstract %R 10.1001/archneurol.2011.183 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2011 %T Exercise training increases size of hippocampus and improves memory. %A Erickson, Kirk I %A Voss, Michelle W %A Prakash, Ruchika Shaurya %A Basak, Chandramallika %A Szabo, Amanda %A Chaddock, Laura %A Kim, Jennifer S %A Heo, Susie %A Alves, Heloisa %A White, Siobhan M %A Wojcicki, Thomas R %A Mailey, Emily %A Vieira, Victoria J %A Martin, Stephen A %A Pence, Brandt D %A Woods, Jeffrey A %A McAuley, Edward %A Kramer, Arthur F %K Aged %K Aging %K Brain-Derived Neurotrophic Factor %K Enzyme-Linked Immunosorbent Assay %K Exercise %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Memory %K Middle Aged %K Organ Size %K Space Perception %X

The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.

%B Proc Natl Acad Sci U S A %V 108 %P 3017-22 %8 2011 Feb 15 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21282661?dopt=Abstract %R 10.1073/pnas.1015950108 %0 Journal Article %J Sci Transl Med %D 2011 %T Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. %A Castellano, Joseph M %A Kim, Jungsu %A Stewart, Floy R %A Jiang, Hong %A DeMattos, Ronald B %A Patterson, Bruce W %A Fagan, Anne M %A Morris, John C %A Mawuenyega, Kwasi G %A Cruchaga, Carlos %A Goate, Alison M %A Bales, Kelly R %A Paul, Steven M %A Bateman, Randall J %A Holtzman, David M %K Adult %K Aged %K Alleles %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Apolipoprotein E4 %K Biomarkers %K Brain %K Female %K Genotype %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Microdialysis %K Middle Aged %K Protein Isoforms %X

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE ε4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. In contrast, the APOE ε2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of Aβ(42) peptide. However, the mechanism by which APOE alleles differentially modulate Aβ accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral Aβ deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Aβ clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Aβ accumulation later in life. Performing in vivo microdialysis in a mouse model of Aβ-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Aβ in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Aβ deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble Aβ metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of Aβ deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and Aβ synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of Aβ from the brain, suggesting that Aβ clearance pathways may be useful therapeutic targets for AD prevention.

%B Sci Transl Med %V 3 %P 89ra57 %8 2011 Jun 29 %G eng %N 89 %1 http://www.ncbi.nlm.nih.gov/pubmed/21715678?dopt=Abstract %R 10.1126/scitranslmed.3002156 %0 Journal Article %J Nat Neurosci %D 2011 %T Neuronal activity regulates the regional vulnerability to amyloid-β deposition. %A Bero, Adam W %A Yan, Ping %A Roh, Jee Hoon %A Cirrito, John R %A Stewart, Floy R %A Raichle, Marcus E %A Lee, Jin-Moo %A Holtzman, David M %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Cerebral Cortex %K Disease Models, Animal %K Extracellular Fluid %K Female %K Lactic Acid %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Microdialysis %K Neurons %K Plaque, Amyloid %K Sensory Deprivation %K Somatosensory Cortex %X

Amyloid-β (Aβ) plaque deposition in specific brain regions is a pathological hallmark of Alzheimer's disease. However, the mechanism underlying the regional vulnerability to Aβ deposition in Alzheimer's disease is unknown. Herein, we provide evidence that endogenous neuronal activity regulates the regional concentration of interstitial fluid (ISF) Aβ, which drives local Aβ aggregation. Using in vivo microdialysis, we show that ISF Aβ concentrations in several brain regions of APP transgenic mice before plaque deposition were commensurate with the degree of subsequent plaque deposition and with the concentration of lactate, a marker of neuronal activity. Furthermore, unilateral vibrissal stimulation increased ISF Aβ, and unilateral vibrissal deprivation decreased ISF Aβ and lactate, in contralateral barrel cortex. Long-term unilateral vibrissal deprivation decreased amyloid plaque formation and growth. Our results suggest a mechanism to account for the vulnerability of specific brain regions to Aβ deposition in Alzheimer's disease.

%B Nat Neurosci %V 14 %P 750-6 %8 2011 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21532579?dopt=Abstract %R 10.1038/nn.2801 %0 Journal Article %J Neurology %D 2011 %T Report of the task force on designing clinical trials in early (predementia) AD. %A Aisen, P S %A Andrieu, S %A Sampaio, C %A Carrillo, M %A Khachaturian, Z S %A Dubois, B %A Feldman, H H %A Petersen, R C %A Siemers, E %A Doody, R S %A Hendrix, S B %A Grundman, M %A Schneider, L S %A Schindler, R J %A Salmon, E %A Potter, W Z %A Thomas, R G %A Salmon, D %A Donohue, M %A Bednar, M M %A Touchon, J %A Vellas, B %K Advisory Committees %K Alzheimer Disease %K Amyloidogenic Proteins %K Biomarkers %K Clinical Trials as Topic %K Cognition %K Consensus %K Disease Progression %K Drug Industry %K Early Diagnosis %K Europe %K Humans %K Indans %K International Cooperation %K Nootropic Agents %K Outcome Assessment (Health Care) %K Patient Selection %K Piperidines %K Positron-Emission Tomography %K Research Design %K Treatment Outcome %K United States %K United States Food and Drug Administration %K Vitamin E %X

BACKGROUND: A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia.

METHOD: An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD.

RESULTS: General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods.

CONCLUSION: A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.

%B Neurology %V 76 %P 280-6 %8 2011 Jan 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21178097?dopt=Abstract %R 10.1212/WNL.0b013e318207b1b9 %0 Journal Article %J J Neuropathol Exp Neurol %D 2011 %T Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. %A Braak, Heiko %A Thal, Dietmar R %A Ghebremedhin, Estifanos %A Del Tredici, Kelly %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Brain %K Child %K Child, Preschool %K Cohort Studies %K Disease Progression %K Female %K Humans %K Infant %K Male %K Middle Aged %K Neurofibrillary Tangles %K Neurons %K Silver Staining %K Statistics, Nonparametric %K tau Proteins %K Young Adult %X

Two thousand three hundred and thirty two nonselected brains from 1- to 100-year-old individuals were examined using immunocytochemistry (AT8) and Gallyas silver staining for abnormal tau; immunocytochemistry (4G8) and Campbell-Switzer staining were used for the detection ofβ-amyloid. A total of 342 cases was negative in the Gallyas stain but when restaged for AT8 only 10 were immunonegative. Fifty-eight cases had subcortical tau predominantly in the locus coeruleus, but there was no abnormal cortical tau (subcortical Stages a-c). Cortical involvement (abnormal tau in neurites) was identified first in the transentorhinal region (Stage 1a, 38 cases). Transentorhinal pyramidal cells displayed pretangle material (Stage 1b, 236 cases). Pretangles gradually became argyrophilic neurofibrillary tangles (NFTs) that progressed in parallel with NFT Stages I to VI. Pretangles restricted to subcortical sites were seen chiefly at younger ages. Of the total cases, 1,031 (44.2%) had β-amyloid plaques. The first plaques occurred in the neocortex after the onset of tauopathy in the brainstem. Plaques generally developed in the 40s in 4% of all cases, culminating in their tenth decade (75%). β-amyloid plaques and NFTs were significantly correlated (p < 0.0001). These data suggest that tauopathy associated with sporadic Alzheimer disease may begin earlier than previously thought and possibly in the lower brainstem rather than in the transentorhinal region.

%B J Neuropathol Exp Neurol %V 70 %P 960-9 %8 2011 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/22002422?dopt=Abstract %R 10.1097/NEN.0b013e318232a379 %0 Journal Article %J Alzheimers Dement %D 2011 %T Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. %A Sperling, Reisa A %A Aisen, Paul S %A Beckett, Laurel A %A Bennett, David A %A Craft, Suzanne %A Fagan, Anne M %A Iwatsubo, Takeshi %A Jack, Clifford R %A Kaye, Jeffrey %A Montine, Thomas J %A Park, Denise C %A Reiman, Eric M %A Rowe, Christopher C %A Siemers, Eric %A Stern, Yaakov %A Yaffe, Kristine %A Carrillo, Maria C %A Thies, Bill %A Morrison-Bogorad, Marcelle %A Wagster, Molly V %A Phelps, Creighton H %K Alzheimer Disease %K Biomarkers %K Cognition Disorders %K Humans %K National Institute on Aging (U.S.) %K Practice Guidelines as Topic %K United States %X

The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.

%B Alzheimers Dement %V 7 %P 280-92 %8 2011 May %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21514248?dopt=Abstract %R 10.1016/j.jalz.2011.03.003 %0 Journal Article %J Neurology %D 2010 %T Alzheimer's Disease Neuroimaging Initiative (ADNI): clinical characterization. %A Petersen, R C %A Aisen, P S %A Beckett, L A %A Donohue, M C %A Gamst, A C %A Harvey, D J %A Jack, C R %A Jagust, W J %A Shaw, L M %A Toga, A W %A Trojanowski, J Q %A Weiner, M W %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Cross-Sectional Studies %K Diagnostic Imaging %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Middle Aged %X

BACKGROUND: Neuroimaging measures and chemical biomarkers may be important indices of clinical progression in normal aging and mild cognitive impairment (MCI) and need to be evaluated longitudinally.

OBJECTIVE: To characterize cross-sectionally and longitudinally clinical measures in normal controls, subjects with MCI, and subjects with mild Alzheimer disease (AD) to enable the assessment of the utility of neuroimaging and chemical biomarker measures.

METHODS: A total of 819 subjects (229 cognitively normal, 398 with MCI, and 192 with AD) were enrolled at baseline and followed for 12 months using standard cognitive and functional measures typical of clinical trials.

RESULTS: The subjects with MCI were more memory impaired than the cognitively normal subjects but not as impaired as the subjects with AD. Nonmemory cognitive measures were only minimally impaired in the subjects with MCI. The subjects with MCI progressed to dementia in 12 months at a rate of 16.5% per year. Approximately 50% of the subjects with MCI were on antidementia therapies. There was minimal movement on the Alzheimer's Disease Assessment Scale-Cognitive Subscale for the normal control subjects, slight movement for the subjects with MCI of 1.1, and a modest change for the subjects with AD of 4.3. Baseline CSF measures of Abeta-42 separated the 3 groups as expected and successfully predicted the 12-month change in cognitive measures.

CONCLUSION: The Alzheimer's Disease Neuroimaging Initiative has successfully recruited cohorts of cognitively normal subjects, subjects with mild cognitive impairment (MCI), and subjects with Alzheimer disease with anticipated baseline characteristics. The 12-month progression rate of MCI was as predicted, and the CSF measures heralded progression of clinical measures over 12 months.

%B Neurology %V 74 %P 201-9 %8 2010 Jan 19 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20042704?dopt=Abstract %R 10.1212/WNL.0b013e3181cb3e25 %0 Journal Article %J Nature %D 2010 %T Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. %A He, Gen %A Luo, Wenjie %A Li, Peng %A Remmers, Christine %A Netzer, William J %A Hendrick, Joseph %A Bettayeb, Karima %A Flajolet, Marc %A Gorelick, Fred %A Wennogle, Lawrence P %A Greengard, Paul %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Benzamides %K Cell Line %K Disease Models, Animal %K Gene Knockdown Techniques %K Humans %K Imatinib Mesylate %K Mice %K Peptide Fragments %K Piperazines %K Proteins %K Pyrimidines %K Receptor, Notch1 %K RNA Interference %X

Accumulation of neurotoxic amyloid-beta is a major hallmark of Alzheimer's disease. Formation of amyloid-beta is catalysed by gamma-secretase, a protease with numerous substrates. Little is known about the molecular mechanisms that confer substrate specificity on this potentially promiscuous enzyme. Knowledge of the mechanisms underlying its selectivity is critical for the development of clinically effective gamma-secretase inhibitors that can reduce amyloid-beta formation without impairing cleavage of other gamma-secretase substrates, especially Notch, which is essential for normal biological functions. Here we report the discovery of a novel gamma-secretase activating protein (GSAP) that drastically and selectively increases amyloid-beta production through a mechanism involving its interactions with both gamma-secretase and its substrate, the amyloid precursor protein carboxy-terminal fragment (APP-CTF). GSAP does not interact with Notch, nor does it affect its cleavage. Recombinant GSAP stimulates amyloid-beta production in vitro. Reducing GSAP concentrations in cell lines decreases amyloid-beta concentrations. Knockdown of GSAP in a mouse model of Alzheimer's disease reduces levels of amyloid-beta and plaque development. GSAP represents a type of gamma-secretase regulator that directs enzyme specificity by interacting with a specific substrate. We demonstrate that imatinib, an anticancer drug previously found to inhibit amyloid-beta formation without affecting Notch cleavage, achieves its amyloid-beta-lowering effect by preventing GSAP interaction with the gamma-secretase substrate, APP-CTF. Thus, GSAP can serve as an amyloid-beta-lowering therapeutic target without affecting other key functions of gamma-secretase.

%B Nature %V 467 %P 95-8 %8 2010 Sep 2 %G eng %N 7311 %1 http://www.ncbi.nlm.nih.gov/pubmed/20811458?dopt=Abstract %R 10.1038/nature09325 %0 Journal Article %J PLoS One %D 2010 %T Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. %A Jones, Lesley %A Holmans, Peter A %A Hamshere, Marian L %A Harold, Denise %A Moskvina, Valentina %A Ivanov, Dobril %A Pocklington, Andrew %A Abraham, Richard %A Hollingworth, Paul %A Sims, Rebecca %A Gerrish, Amy %A Pahwa, Jaspreet Singh %A Jones, Nicola %A Stretton, Alexandra %A Morgan, Angharad R %A Lovestone, Simon %A Powell, John %A Proitsi, Petroula %A Lupton, Michelle K %A Brayne, Carol %A Rubinsztein, David C %A Gill, Michael %A Lawlor, Brian %A Lynch, Aoibhinn %A Morgan, Kevin %A Brown, Kristelle S %A Passmore, Peter A %A Craig, David %A McGuinness, Bernadette %A Todd, Stephen %A Holmes, Clive %A Mann, David %A Smith, A David %A Love, Seth %A Kehoe, Patrick G %A Mead, Simon %A Fox, Nick %A Rossor, Martin %A Collinge, John %A Maier, Wolfgang %A Jessen, Frank %A Schürmann, Britta %A Heun, Reinhard %A Kölsch, Heike %A van den Bussche, Hendrik %A Heuser, Isabella %A Peters, Oliver %A Kornhuber, Johannes %A Wiltfang, Jens %A Dichgans, Martin %A Frölich, Lutz %A Hampel, Harald %A Hüll, Michael %A Rujescu, Dan %A Goate, Alison M %A Kauwe, John S K %A Cruchaga, Carlos %A Nowotny, Petra %A Morris, John C %A Mayo, Kevin %A Livingston, Gill %A Bass, Nicholas J %A Gurling, Hugh %A McQuillin, Andrew %A Gwilliam, Rhian %A Deloukas, Panos %A Al-Chalabi, Ammar %A Shaw, Christopher E %A Singleton, Andrew B %A Guerreiro, Rita %A Mühleisen, Thomas W %A Nöthen, Markus M %A Moebus, Susanne %A Jöckel, Karl-Heinz %A Klopp, Norman %A Wichmann, H-Erich %A Rüther, Eckhard %A Carrasquillo, Minerva M %A Pankratz, V Shane %A Younkin, Steven G %A Hardy, John %A O'Donovan, Michael C %A Owen, Michael J %A Williams, Julie %K Alzheimer Disease %K Apolipoproteins E %K Cholesterol %K Chromosome Mapping %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Immune System %K Polymorphism, Single Nucleotide %X

BACKGROUND: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes.

METHODOLOGY: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.

PRINCIPAL FINDINGS: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD.

SIGNIFICANCE: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

%B PLoS One %V 5 %P e13950 %8 2010 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21085570?dopt=Abstract %R 10.1371/journal.pone.0013950 %0 Journal Article %J Ann Intern Med %D 2010 %T National Institutes of Health State-of-the-Science Conference statement: preventing alzheimer disease and cognitive decline. %A Daviglus, Martha L %A Bell, Carl C %A Berrettini, Wade %A Bowen, Phyllis E %A Connolly, E Sander %A Cox, Nancy Jean %A Dunbar-Jacob, Jacqueline M %A Granieri, Evelyn C %A Hunt, Gail %A McGarry, Kathleen %A Patel, Dinesh %A Potosky, Arnold L %A Sanders-Bush, Elaine %A Silberberg, Donald %A Trevisan, Maurizio %K Aged %K Alzheimer Disease %K Cognition Disorders %K Evidence-Based Medicine %K Humans %K Risk Factors %K Risk Reduction Behavior %X

The National Institute on Aging and the Office of Medical Applications of Research of the National Institutes of Health convened a State-of-the-Science Conference on 26-28 April 2010 to assess the available scientific evidence on prevention of cognitive decline and Alzheimer disease. This article provides the panel's assessment of the available evidence.

%B Ann Intern Med %V 153 %P 176-81 %8 2010 Aug 3 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20547888?dopt=Abstract %R 10.7326/0003-4819-153-3-201008030-00260