%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 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 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 Odor Identification Across Time in Mutation Carriers and Non-Carriers in Autosomal-Dominant Alzheimer's Disease. %A Almkvist, Ove %A Larsson, Maria %A Graff, Caroline %K Alzheimer Disease %K Cognition %K Cognitive Dysfunction %K Humans %K Mutation %K Odorants %K Presenilin-1 %X

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

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

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

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

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

%B J Alzheimers Dis %V 97 %P 587-598 %8 2024 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/38160354?dopt=Abstract %R 10.3233/JAD-230618 %0 Journal Article %J J Alzheimers Dis %D 2024 %T The Role of Impaired Receptor Trafficking in Mediating the Pathological Effects of APOE4 in Alzheimer's Disease. %A Safieh, Mirna %A Liraz, Ori %A Ovadia, Maayan %A Michaelson, Danny %K Alzheimer Disease %K Animals %K Apolipoprotein E3 %K Apolipoprotein E4 %K Apolipoproteins E %K Mice %K Mice, Transgenic %X

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

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

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

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

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

%B J Alzheimers Dis %V 97 %P 753-775 %8 2024 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/38217595?dopt=Abstract %R 10.3233/JAD-230514 %0 Journal Article %J J Alzheimers Dis %D 2023 %T A 19-Year-Old Adolescent with Probable Alzheimer's Disease. %A Jia, Jianping %A Zhang, Yue %A Shi, Yuqing %A Yin, Xuping %A Wang, Shiyuan %A Li, Yan %A Zhao, Tan %A Liu, Wenying %A Zhou, Aihong %A Jia, Longfei %K Adolescent %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Fluorodeoxyglucose F18 %K Humans %K Magnetic Resonance Imaging %K Male %K Positron-Emission Tomography %X

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

%B J Alzheimers Dis %V 91 %P 915-922 %8 2023 %G eng %N 3 %R 10.3233/JAD-221065 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Activation of TNF Receptor 2 Improves Synaptic Plasticity and Enhances Amyloid-β Clearance in an Alzheimer's Disease Mouse Model with Humanized TNF Receptor 2. %A Ortí-Casañ, Natalia %A Wajant, Harald %A Kuiperij, H Bea %A Hooijsma, Annelien %A Tromp, Leon %A Poortman, Isabelle L %A Tadema, Norick %A de Lange, Julia H E %A Verbeek, Marcel M %A De Deyn, Peter P %A Naudé, Petrus J W %A Eisel, Ulrich L M %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Humans %K Mice %K Mice, Transgenic %K Neuronal Plasticity %K Receptors, Tumor Necrosis Factor, Type II %K Tumor Necrosis Factor-alpha %X

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

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

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 96 %P 759-766 %8 2023 %G eng %N 2 %R 10.3233/JAD-230868 %0 Journal Article %J J Alzheimers Dis %D 2023 %T An Alternative View of Familial Alzheimer's Disease Genetics. %A Lardelli, Michael %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Humans %K Iron %K Mutation %K Presenilin-1 %X

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

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

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

%B J Alzheimers Dis %V 91 %P 43-70 %8 2023 %G eng %N 1 %R 10.3233/JAD-220720 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The Alzheimer's Disease Mitochondrial Cascade Hypothesis: A Current Overview. %A Swerdlow, Russell H %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Humans %K Mitochondria %K Signal Transduction %X

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

%B J Alzheimers Dis %V 92 %P 751-768 %8 2023 %G eng %N 3 %R 10.3233/JAD-221286 %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 Association Between Oral Bacteria and Alzheimer's Disease: A Systematic Review and Meta-Analysis. %A Liu, Sixin %A Dashper, Stuart G %A Zhao, Rui %K Alzheimer Disease %K Cognitive Dysfunction %K Humans %K Microbiota %K Porphyromonas gingivalis %K Risk Factors %X

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

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

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

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

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

%B J Alzheimers Dis %V 91 %P 129-150 %8 2023 %G eng %N 1 %R 10.3233/JAD-220627 %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 BACE2: A Promising Neuroprotective Candidate for Alzheimer's Disease. %A Yeap, Yee Jie %A Kandiah, Nagaendran %A Nizetic, Dean %A Lim, Kah-Leong %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Aspartic Acid Endopeptidases %K Humans %X

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 95 %P 829-845 %8 2023 %G eng %N 3 %R 10.3233/JAD-230473 %0 Journal Article %J J Alzheimers Dis %D 2023 %T CERAD (Consortium to Establish a Registry for Alzheimer's Disease) Neuropsychology Assessment Battery: 35 Years and Counting. %A Fillenbaum, Gerda G %A Mohs, Richard %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cross-Sectional Studies %K Humans %K Neuropsychological Tests %K Neuropsychology %K Psychometrics %K Registries %X

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

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

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

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

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

%B J Alzheimers Dis %V 93 %P 1-27 %8 2023 %G eng %N 1 %R 10.3233/JAD-230026 %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 Characterizing Performance Gaps of a Code-Based Dementia Algorithm in a Population-Based Cohort of Cognitive Aging. %A Vassilaki, Maria %A Fu, Sunyang %A Christenson, Luke R %A Garg, Muskan %A Petersen, Ronald C %A St Sauver, Jennifer %A Sohn, Sunghwan %K Alzheimer Disease %K Cognitive Aging %K Cognitive Dysfunction %K Dementia %K Disease Progression %K Female %K Humans %K Male %X

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

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

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 94 %P 291-301 %8 2023 %G eng %N 1 %R 10.3233/JAD-230142 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Coexistence of Amyotrophic Lateral Sclerosis and Alzheimer's Disease: Case Report and Review of the Literature. %A Verde, Federico %A Aiello, Edoardo Nicolò %A Adobbati, Laura %A Poletti, Barbara %A Solca, Federica %A Tiloca, Cinzia %A Sangalli, Davide %A Maranzano, Alessio %A Muscio, Cristina %A Ratti, Antonia %A Zago, Stefano %A Ticozzi, Nicola %A Frisoni, Giovanni Battista %A Silani, Vincenzo %K Alzheimer Disease %K Amyotrophic Lateral Sclerosis %K Brain %K Cognitive Dysfunction %K Female %K Frontotemporal Dementia %K Humans %K Male %X

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

%B J Alzheimers Dis %V 95 %P 1383-1399 %8 2023 %G eng %N 4 %R 10.3233/JAD-230562 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Cognitive and Neuropsychological Profiles in Alzheimer's Disease and Primary Age-Related Tauopathy and the Influence of Comorbid Neuropathologies. %A Walker, Jamie M %A Gonzales, Mitzi M %A Goette, William %A Farrell, Kurt %A White Iii, Charles L %A Crary, John F %A Richardson, Timothy E %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Cognition %K Executive Function %K Humans %K Tauopathies %X

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

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

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

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

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

%B J Alzheimers Dis %V 92 %P 1037-1049 %8 2023 %G eng %N 3 %R 10.3233/JAD-230022 %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 COVID-19 as a Risk Factor for Alzheimer's Disease. %A Golzari-Sorkheh, Mahdieh %A Weaver, Donald F %A Reed, Mark A %K Alzheimer Disease %K COVID-19 %K Humans %K Nervous System Diseases %K Neuroinflammatory Diseases %K Risk Factors %K SARS-CoV-2 %X

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

%B J Alzheimers Dis %V 91 %P 1-23 %8 2023 %G eng %N 1 %R 10.3233/JAD-220800 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Deep Reinforcement Learning-Based Retinal Imaging in Alzheimer's Disease: Potential and Perspectives. %A Hui, Herbert Y H %A Ran, An Ran %A Dai, Jia Jia %A Cheung, Carol Y %K Alzheimer Disease %K Artificial Intelligence %K Humans %K Machine Learning %K Magnetic Resonance Imaging %K Retina %X

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

%B J Alzheimers Dis %V 94 %P 39-50 %8 2023 %G eng %N 1 %R 10.3233/JAD-230055 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Detecting Anosognosia from the Prodromal Stage of Alzheimer's Disease. %A Guieysse, Thomas %A Lamothe, Roxane %A Houot, Marion %A Razafimahatratra, Solofo %A Medani, Takfarinas %A Lejeune, François-Xavier %A Dreyfus, Gérard %A Klarsfeld, André %A Pantazis, Dimitrios %A Koechlin, Etienne %A Andrade, Katia %K Agnosia %K Alzheimer Disease %K Brain %K Caregivers %K Humans %K Neuropsychological Tests %K Prodromal Symptoms %X

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

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

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

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

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

%B J Alzheimers Dis %V 95 %P 1723-1733 %8 2023 %G eng %N 4 %R 10.3233/JAD-230552 %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 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 Lecanemab in Early Alzheimer's Disease: Mechanistic Interpretation in the Amyloid Cascade Hypothesis 2.0 Perspective. %A Volloch, Vladimir %A Rits-Volloch, Sophia %K Alzheimer Disease %K Amyloid %K Amyloid beta-Peptides %K Amyloidogenic Proteins %K Humans %X

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

%B J Alzheimers Dis %V 93 %P 1277-1284 %8 2023 %G eng %N 4 %R 10.3233/JAD-230164 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Effects of Striatal Amyloidosis on the Dopaminergic System and Behavior: A Comparative Study in Male and Female 5XFAD Mice. %A Lansdell, Theresa A %A Xu, Hui %A Galligan, James J %A Dorrance, Anne M %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloidosis %K Animals %K Disease Models, Animal %K Dopamine %K Female %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Plaque, Amyloid %X

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

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

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

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

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

%B J Alzheimers Dis %V 94 %P 1361-1375 %8 2023 %G eng %N 4 %R 10.3233/JAD-220905 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Emerging Roles of Meningeal Lymphatic Vessels in Alzheimer's Disease. %A Guo, Xiaodi %A Zhang, Guoxin %A Peng, Qinyu %A Huang, Liqin %A Zhang, Zhaohui %A Zhang, Zhentao %K Alzheimer Disease %K Apolipoprotein E4 %K Glymphatic System %K Humans %K Lymphatic System %K Lymphatic Vessels %X

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 93 %P 521-532 %8 2023 %G eng %N 2 %R 10.3233/JAD-220948 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Etiology and Clinical Significance of Network Hyperexcitability in Alzheimer's Disease: Unanswered Questions and Next Steps. %A Samudra, Niyatee %A Ranasinghe, Kamalini %A Kirsch, Heidi %A Rankin, Katherine %A Miller, Bruce %K Alzheimer Disease %K Causality %K Clinical Relevance %K Electroencephalography %K Humans %K Levetiracetam %K Seizures %X

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 92 %P 95-107 %8 2023 %G eng %N 1 %R 10.3233/JAD-221118 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Exploring Reasons for Differential Vulnerability and Alzheimer's Disease Risk in Racial and Ethnic Minorities. %A Daniel, E Valerie %A Kleiman, Michael J %A Galvin, James E %K Aged %K Alzheimer Disease %K Cross-Sectional Studies %K Ethnic and Racial Minorities %K Ethnicity %K Humans %K White People %X

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

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

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

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

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 91 %P 779-794 %8 2023 %G eng %N 2 %R 10.3233/JAD-221046 %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 Impact of Computerized Cognitive Training on Default Mode Network Connectivity in Subjects at Risk for Alzheimer's Disease: A 78-week Randomized Controlled Trial. %A Petrella, Jeffrey R %A Michael, Andrew M %A Qian, Min %A Nwosu, Adaora %A Sneed, Joel %A Goldberg, Terry E %A Devanand, Davangere P %A Doraiswamy, P Murali %K Alzheimer Disease %K Brain %K Cognitive Dysfunction %K Cognitive Training %K Default Mode Network %K Humans %K Magnetic Resonance Imaging %K Nerve Net %X

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

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

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

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

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

%B J Alzheimers Dis %V 91 %P 483-494 %8 2023 %G eng %N 1 %R 10.3233/JAD-220946 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Impact of the MIND Diet on Cognition in Individuals with Dementia. %A Healy, Elizabeth %K Alzheimer Disease %K Cognition %K Cognition Disorders %K Cognitive Dysfunction %K Diet, Mediterranean %K Humans %X

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

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

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

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

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

%B J Alzheimers Dis %V 96 %P 967-977 %8 2023 %G eng %N 3 %R 10.3233/JAD-230651 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Insights into the Pathophysiology of Alzheimer's Disease and Potential Therapeutic Targets: A Current Perspective. %A Rajah Kumaran, Kesevan %A Yunusa, Suleiman %A Perimal, Enoch %A Wahab, Habibah %A Müller, Christian P %A Hassan, Zurina %K Aged %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Humans %K Neurofibrillary Tangles %K Oxidative Stress %K Plaque, Amyloid %K tau Proteins %X

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

%B J Alzheimers Dis %V 91 %P 507-530 %8 2023 %G eng %N 2 %R 10.3233/JAD-220666 %0 Journal Article %J J Alzheimers Dis %D 2023 %T JAD: A Forum for Philosophy in Science. %A Daly, Timothy %K Alzheimer Disease %K Humans %K Philosophy %X

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

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

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

%B J Alzheimers Dis %V 92 %P 1173-1198 %8 2023 %G eng %N 4 %R 10.3233/JAD-230002 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The Lipid Invasion Model: Growing Evidence for This New Explanation of Alzheimer's Disease. %A Rudge, Jonathan D'Arcy %K Alzheimer Disease %K Amyloid beta-Peptides %K Blood-Brain Barrier %K Brain %K Cholesterol %K Humans %X

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

%B J Alzheimers Dis %V 94 %P 457-470 %8 2023 %G eng %N 2 %R 10.3233/JAD-221175 %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 Malignant Brain Aging: The Formidable Link Between Dysregulated Signaling Through Mechanistic Target of Rapamycin Pathways and Alzheimer's Disease (Type 3 Diabetes). %A de la Monte, Suzanne M %K Alzheimer Disease %K Brain %K Diabetes Mellitus %K Humans %K Insulin %K Sirolimus %K TOR Serine-Threonine Kinases %X

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

%B J Alzheimers Dis %V 95 %P 1301-1337 %8 2023 %G eng %N 4 %R 10.3233/JAD-230555 %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 Microglia-Astrocyte Communication in Alzheimer's Disease. %A Wu, Yingying %A Eisel, Ulrich L M %K Alzheimer Disease %K Astrocytes %K Central Nervous System %K Communication %K Humans %K Microglia %X

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

%B J Alzheimers Dis %V 95 %P 785-803 %8 2023 %G eng %N 3 %R 10.3233/JAD-230199 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Microglia-Mediated Neurovascular Unit Dysfunction in Alzheimer's Disease. %A Huang, Wenhao %A Xia, Qing %A Zheng, Feifei %A Zhao, Xue %A Ge, Fangliang %A Xiao, Jiaying %A Liu, Zijie %A Shen, Yingying %A Ye, Ke %A Wang, Dayong %A Li, Yanze %K Alzheimer Disease %K Astrocytes %K Blood-Brain Barrier %K Humans %K Microglia %K Neurons %X

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

%B J Alzheimers Dis %V 94 %P S335-S354 %8 2023 %G eng %N s1 %R 10.3233/JAD-221064 %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 miRNAs and Stem Cells as Promising Diagnostic and Therapeutic Targets for Alzheimer's Disease. %A Elzayat, Emad M %A Shahien, Sherif A %A El-Sherif, Ahmed A %A Hosney, Mohamed %K Acitretin %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Disease Susceptibility %K Humans %K MicroRNAs %K Stem Cell Transplantation %K Stem Cells %X

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

%B J Alzheimers Dis %V 94 %P S203-S225 %8 2023 %G eng %N s1 %R 10.3233/JAD-221298 %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 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 Mortality Risks and Causes of Death by Dementia Types in a Japanese Cohort with Dementia: NCGG-STORIES. %A Ono, Rei %A Sakurai, Takashi %A Sugimoto, Taiki %A Uchida, Kazuaki %A Nakagawa, Takeshi %A Noguchi, Taiji %A Komatsu, Ayane %A Arai, Hidenori %A Saito, Tami %K Aged %K Alzheimer Disease %K Cause of Death %K Cognitive Dysfunction %K Dementia %K East Asian People %K Female %K Humans %K Lewy Body Disease %K Male %X

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

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

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

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

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

%B J Alzheimers Dis %V 92 %P 487-498 %8 2023 %G eng %N 2 %R 10.3233/JAD-221290 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Necroptosis and Alzheimer's Disease: Pathogenic Mechanisms and Therapeutic Opportunities. %A Zhang, Ruxin %A Song, Yanrong %A Su, Xuefeng %K Alzheimer Disease %K Amyloid beta-Peptides %K Apoptosis %K Humans %K Necrosis %K Neurodegenerative Diseases %X

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

%B J Alzheimers Dis %V 94 %P S367-S386 %8 2023 %G eng %N s1 %R 10.3233/JAD-220809 %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 Neuroinflammation: A Common Pathway in Alzheimer's Disease and Epilepsy. %A Liew, Yee %A Retinasamy, Thaarvena %A Arulsamy, Alina %A Ali, Idrish %A Jones, Nigel C %A O'Brien, Terence J %A Shaikh, Mohd Farooq %K Alzheimer Disease %K Biomarkers %K Brain %K Epilepsy %K Humans %K Neuroinflammatory Diseases %X

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

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

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

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

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

%B J Alzheimers Dis %V 94 %P S253-S265 %8 2023 %G eng %N s1 %R 10.3233/JAD-230059 %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 A Novel Strategy for Alzheimer's Disease Based on the Regulatory Effect of Amyloid-β on Gut Flora. %A Huang, Li %A Lu, Zhaogang %A Zhang, Hexin %A Wen, Hongyong %A Li, Zongji %A Liu, Qibing %A Wang, Rui %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloidogenic Proteins %K Brain %K Gastrointestinal Microbiome %K Humans %X

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

%B J Alzheimers Dis %V 94 %P S227-S239 %8 2023 %G eng %N s1 %R 10.3233/JAD-220651 %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 Odor Discrimination as a Marker of Early Alzheimer's Disease. %A Audronyte, Egle %A Pakulaite-Kazliene, Gyte %A Sutnikiene, Vaiva %A Kaubrys, Gintaras %K Alzheimer Disease %K Cognitive Dysfunction %K Humans %K Neuropsychological Tests %K Odorants %K Olfaction Disorders %K Smell %X

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

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

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

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

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

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

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

%B J Alzheimers Dis %V 94 %P 1265-1301 %8 2023 %G eng %N 4 %R 10.3233/JAD-230326 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Phonological and Semantic Fluency in Alzheimer's Disease: A Systematic Review and Meta-Analysis. %A Olmos-Villaseñor, Rocio %A Sepulveda-Silva, Consuelo %A Julio-Ramos, Teresa %A Fuentes-Lopez, Eduardo %A Toloza-Ramirez, David %A Santibañez, Rodrigo A %A Copland, David A %A Mendez-Orellana, Carolina %K Alzheimer Disease %K Humans %K Linguistics %K Neuropsychological Tests %K Semantics %K Verbal Behavior %X

BACKGROUND: Semantic and Phonological fluency (SF and PF) are routinely evaluated in patients with Alzheimer's disease (AD). There are disagreements in the literature regarding which fluency task is more affected while developing AD. Most studies focus on SF assessment, given its connection with the temporoparietal amnesic system. PF is less reported, it is related to working memory, which is also impaired in probable and diagnosed AD. Differentiating between performance on these tasks might be informative in early AD diagnosis, providing an accurate linguistic profile.

OBJECTIVE: Compare SF and PF performance in healthy volunteers, volunteers with probable AD, and patients with AD diagnosis, considering the heterogeneity of age, gender, and educational level variables.

METHODS: A total of 8 studies were included for meta-analysis, reaching a sample size of 1,270 individuals (568 patients diagnosed with AD, 340 with probable AD diagnosis, and 362 healthy volunteers).

RESULTS: The three groups consistently performed better on SF than PF. When progressing to a diagnosis of AD, we observed a significant difference in SF and PF performance across our 3 groups of interest (p = 0.04). The age variable explained a proportion of this difference in task performance across the groups, and as age increases, both tasks equally worsen.

CONCLUSION: The performance of SF and PF might play a differential role in early AD diagnosis. These tasks rely on partially different neural bases of language processing. They are thus worth exploring independently in diagnosing normal aging and its transition to pathological stages, including probable and diagnosed AD.

%B J Alzheimers Dis %V 95 %P 1-12 %8 2023 %G eng %N 1 %R 10.3233/JAD-221272 %0 Journal Article %J J Alzheimers Dis %D 2023 %T The PI3K/AKT Signaling Pathway and Caspase-3 in Alzheimer's Disease: Which One Is the Beginner? %A Khezri, Mohammad Rafi %A Ghasemnejad-Berenji, Morteza %A Moloodsouri, Donya %K Alzheimer Disease %K Apoptosis %K Caspase 3 %K Humans %K Phosphatidylinositol 3-Kinases %K Proto-Oncogene Proteins c-akt %K Signal Transduction %X

One of the main players in apoptosis during Alzheimer's disease progression are different members of caspase family of proteases. The most well-known member of this family is caspase-3, in which alterations of its levels have been detected in samples from Alzheimer's disease patients. There are numerous intracellular factors involved in regulation of cellular apoptosis through regulation of caspase-3 activity, the most important of which is the PI3K/AKT signaling pathway. This commentary tries to highlight the probable relations between PI3K/AKT signaling pathway and caspase-3 in Alzheimer's disease.

%B J Alzheimers Dis %V 92 %P 391-393 %8 2023 %G eng %N 2 %R 10.3233/JAD-221157 %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 Plasma Soluble ST2 Levels Are Higher in Neurodegenerative Disorders and Associated with Poorer Cognition. %A Tan, Yi Jayne %A Siow, Isabel %A Saffari, Seyed Ehsan %A Ting, Simon K S %A Li, Zeng %A Kandiah, Nagaendran %A Tan, Louis C S %A Tan, Eng King %A Ng, Adeline S L %K Alzheimer Disease %K Biomarkers %K Cognition %K Cross-Sectional Studies %K Frontotemporal Dementia %K Humans %K Interleukin-1 Receptor-Like 1 Protein %K Interleukin-33 %K Parkinson Disease %X

BACKGROUND: Suppressor of tumorgenicity 2 (ST2) is highly expressed in brain tissue and is a receptor for interleukin 33 (IL-33). ST2 exists in two forms, a transmembrane receptor (ST2L) and a soluble decoy receptor (sST2). IL-33 binds to ST2L, triggering downstream signaling pathways involved in amyloid plaque clearance. Conversely, sST2 binds competitively to IL-33, attenuating its neuroprotective effects. High sST2 levels have been reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD), suggesting that the IL-33/ST2 signaling pathway may be implicated in neurodegenerative diseases.

OBJECTIVE: To investigate plasma sST2 levels in controls and patients with MCI, AD, frontotemporal dementia (FTD), and Parkinson's disease (PD).

METHODS: Plasma sST2 levels were measured using ELISA in 397 subjects (91 HC, 46 MCI, 38 AD, 28 FTD, and 194 PD). Cerebrospinal fluid (CSF) levels of sST2 were measured in 22 subjects. Relationship between sST2 and clinical outcomes were analyzed.

RESULTS: Plasma sST2 levels were increased across all disease groups compared to controls, with highest levels seen in FTD followed by AD and PD. Dementia patients with higher sST2 had lower cross-sectional cognitive scores in Frontal Assessment Battery and Digit Span Backward. At baseline, PD-MCI patients had higher sST2, associated with worse attention. In the longitudinal PD cohort, higher sST2 significantly associated with decline in global cognition and visuospatial domains. Plasma sST2 levels correlated with CSF sST2 levels.

CONCLUSION: Plasma sST2 is raised across neurodegenerative diseases and is associated with poorer cognition. Higher baseline sST2 is a potential biomarker of disease severity in neurodegeneration.

%B J Alzheimers Dis %V 92 %P 573-580 %8 2023 %G eng %N 2 %R 10.3233/JAD-221072 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Playing Russian Roulette with Alzheimer's Disease Patients: Do the Cognitive Benefits of Lecanemab Outweigh the Risk of Edema, Stroke and Encephalitis? %A Atwood, Craig S %A Perry, George %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognition %K Edema %K Encephalitis %K Humans %K Russia %K Stroke %X

The questionable approval of aducanumab and the recent approval of lecanemab (Leqembi; Eisai and Biogen) by the FDA has raised the issue of safety (stroke, meningitis, and encephalitis) over efficacy (slowing of cognitive decline). This communication recounts the important physiological functions of amyloid-β as a barrier protein with unique sealant and anti-pathogenic activities important for maintaining vascular integrity coupled with innate immune functions that prevent encephalitis and meningitis. The approval of a drug that obviates both of these purposive functions increases the risk of hemorrhage, edema and downstream pathogenic outcomes and should be clearly outlined to patients.

%B J Alzheimers Dis %V 92 %P 799-801 %8 2023 %G eng %N 3 %R 10.3233/JAD-230040 %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 Preventing Neurocognitive Decline in Adults Aging with HIV: Implications for Practice and Research. %A Cody, Shameka L %A Miller, Gabe H %A Fazeli, Pariya L %A Wang, Ge %A Li, Wei %A Goodin, Burel R %A Vance, David E %K Aging %K Alzheimer Disease %K Comorbidity %K HIV Infections %K Humans %X

Mild to moderate forms of neurocognitive impairment persist among people living with HIV (PLWH), despite being virally suppressed on antiretroviral therapy. PLWH are disproportionally impacted by physiological and psychosocial comorbidities compared to those without HIV. As adults live longer with HIV, the neurocognitive burden of physiological and psychosocial stressors can impair everyday functioning and may contribute to the development of neurodegenerative diseases such as Alzheimer's disease. This article outlines neurocognitive consequences of everyday stressors in PLWH. While some lifestyle factors can exacerbate inflammatory processes and promote negative neurocognitive health, novel interventions including the use of cannabinoids may be neuroprotective for aging PLWH who are at risk for elevated levels of inflammation from comorbidities. Studies of integrated neurocognitive rehabilitation strategies targeting lifestyle factors are promising for improving neurocognitive health, and may over time, reduce the risk of Alzheimer's disease in PLWH.

%B J Alzheimers Dis %V 95 %P 753-768 %8 2023 %G eng %N 3 %R 10.3233/JAD-230203 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Psychopharmacological Medication Use in Frontotemporal Dementia at the Time of Diagnosis: Comparison with Alzheimer's Disease. %A Katisko, Kasper %A Krüger, Johanna %A Soppela, Helmi %A Hartikainen, Päivi %A Haapasalo, Annakaisa %A Remes, Anne M %A Solje, Eino %K Alzheimer Disease %K Delayed Diagnosis %K Female %K Frontotemporal Dementia %K Humans %K Memantine %K Neurodegenerative Diseases %X

BACKGROUND: Due to the significant presence of neuropsychiatric symptoms in patients with frontotemporal dementia (FTD) spectrum disorders, psychiatric misdiagnoses, diagnostic delay, and use of psychiatric treatments are common prior to the FTD diagnosis. Furthermore, treatment of diagnosed FTD patients mainly relies on off-label psychopharmacological approaches. Currently, limited real-world data are available regarding the actual use of psychopharmacological medications in FTD.

OBJECTIVE: To evaluate psychopharmacological medication use at the time of FTD diagnosis.

METHODS: Psychopharmacological medication use was evaluated in a Finnish FTD cohort containing 222 FTD patients, including the major clinical disease phenotypes (behavioral, language, and motor variants) and genetic patients carrying the C9orf72 repeat expansion. A cohort of 214 Alzheimer's disease (AD) patients was used as a neurodegenerative disease reference group.

RESULTS: Active use of psychopharmacological medications at the time of diagnosis was significantly more common in FTD compared to AD, especially in the case of antidepressants (26.1% versus 15.0%, OR = 2.01, p = 0.008), antipsychotics (23.9% versus 9.3%, OR = 3.15, p < 0.001), and mood-stabilizers (6.3% versus 1.9%, OR = 2.93, p = 0.085; not statistically significant), whereas the use of cholinesterase inhibitors or memantine was nearly nonexistent in FTD patients. Female gender and behavioral variant of FTD phenotype alongside with depressive and psychotic symptoms were the most prominent factors associating with the use of these medications among the FTD spectrum patients.

CONCLUSION: Use of off-label psychopharmacological medication and polypharmacy is substantially common at the time of FTD diagnosis. This likely reflects the challenges in using symptom-driven treatment approaches, especially prior to the eventual diagnosis.

%B J Alzheimers Dis %V 95 %P 677-685 %8 2023 %G eng %N 2 %R 10.3233/JAD-230494 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Re-Addressing Dementia by Network Medicine and Mechanism-Based Molecular Endotypes. %A Pacheco Pachado, Mayra %A Casas, Ana I %A Elbatreek, Mahmoud H %A Nogales, Cristian %A Guney, Emre %A Espay, Alberto J %A Schmidt, Harald H H W %K Aging %K Alzheimer Disease %K Amyloid %K Amyloid beta-Peptides %K Brain %K Humans %X

Alzheimer's disease (AD) and other forms of dementia are together a leading cause of disability and death in the aging global population, imposing a high personal, societal, and economic burden. They are also among the most prominent examples of failed drug developments. Indeed, after more than 40 AD trials of anti-amyloid interventions, reduction of amyloid-β (Aβ) has never translated into clinically relevant benefits, and in several cases yielded harm. The fundamental problem is the century-old, brain-centric phenotype-based definitions of diseases that ignore causal mechanisms and comorbidities. In this hypothesis article, we discuss how such current outdated nosology of dementia is a key roadblock to precision medicine and articulate how Network Medicine enables the substitution of clinicopathologic phenotypes with molecular endotypes and propose a new framework to achieve precision and curative medicine for patients with neurodegenerative disorders.

%B J Alzheimers Dis %V 96 %P 47-56 %8 2023 %G eng %N 1 %R 10.3233/JAD-230694 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Refining Risk for Alzheimer's Disease Among Heterozygous APOEɛ4 Carriers. %A Patel, Smita %A Wei, Jun %A Shi, Zhuqing %A Rifkin, Andrew S %A Zheng, S Lilly %A Gelfman, Elizabeth %A Duggan, David %A Helfand, Brian T %A Hulick, Peter J %A Xu, Jianfeng %K Alzheimer Disease %K Apolipoprotein E4 %K Apolipoproteins E %K Heterozygote %K Homozygote %K Humans %X

In a large population-based cohort, we show not all heterozygous APOEɛ4 carriers are at increased risk for Alzheimer's disease (AD); a significantly higher AD proportion was only found for ɛ3/ɛ4, not ɛ2/ɛ4. Among ɛ3/ɛ4 carriers (24% in the cohort), the AD proportion differed considerably by polygenic risk score (PRS). In particular, the AD proportion was lower than the entire cohort for subjects in the bottom 20-percentile PRS and was higher than that of homozygous ɛ4 carriers for subjects at the top 5th-percentile PRS. Family history was no longer a significant predictor of AD risk after adjusting APOE and PRS.

%B J Alzheimers Dis %V 94 %P 483-489 %8 2023 %G eng %N 2 %R 10.3233/JAD-230156 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Resveratrol Mediated Regulation of Hippocampal Neuroregenerative Plasticity via SIRT1 Pathway in Synergy with Wnt Signaling: Neurotherapeutic Implications to Mitigate Memory Loss in Alzheimer's Disease. %A Surya, Kumar %A Manickam, Nivethitha %A Jayachandran, Kesavan Swaminathan %A Kandasamy, Mahesh %A Anusuyadevi, Muthuswamy %K Alzheimer Disease %K Amnesia %K Hippocampus %K Humans %K Neurogenesis %K Resveratrol %K Sirtuin 1 %K Wnt Signaling Pathway %X

Alzheimer's disease (AD) is a major form of dementia. Abnormal amyloidogenic event-mediated degeneration of cholinergic neurons in the cognitive centers of the brain has been attributed to neuropathological sequelae and behavioral deficits in AD. Besides, impaired adult neurogenesis in the hippocampus has experimentally been realized as an underlying cause of dementia regardless of neurodegeneration. Therefore, nourishing the neurogenic process in the hippocampus has been considered an effective therapeutic strategy to mitigate memory loss. In the physiological state, the Wnt pathway has been identified as a potent mitogenic generator in the hippocampal stem cell niche. However, downstream components of Wnt signaling have been noticed to be downregulated in AD brains. Resveratrol (RSV) is a potent Sirtuin1 (SIRT1) enhancer that facilitates neuroprotection and promotes neurogenesis in the hippocampus of the adult brain. While SIRT1 is an important positive regulator of Wnt signaling, ample reports indicate that RSV treatment strongly mediates the fate determination of stem cells through Wnt signaling. However, the possible therapeutic roles of RSV-mediated SIRT1 enhancement on the regulation of hippocampal neurogenesis and reversal of memory loss through the Wnt signaling pathway have not been addressed yet. Taken together, this review describes RSV-mediated effects on the regulation of hippocampal neurogenesis via the activation of SIRT1 in synergy with the Wnt signaling. Further, the article emphasizes a hypothesis that RSV treatment can provoke the activation of quiescent neural stem cells and prime their neurogenic capacity in the hippocampus via Wnt signaling in AD.

%B J Alzheimers Dis %V 94 %P S125-S140 %8 2023 %G eng %N s1 %R 10.3233/JAD-220559 %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 Serotonin Degeneration and Amyloid-β Deposition in Mild Cognitive Impairment: Relationship to Cognitive Deficits. %A Smith, Gwenn S %A Kuwabara, Hiroto %A Yan, Haijuan %A Nassery, Najlla %A Yoon, Mark %A Kamath, Vidya %A Kraut, Michael %A Gould, Neda F %A Savonenko, Alena %A Coughlin, Jennifer M %A Lodge, Martin %A Pomper, Martin G %A Nandi, Ayon %A Holt, Daniel %A Dannals, Robert F %A Leoutsakos, Jeannie M %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Cognition %K Cognition Disorders %K Cognitive Dysfunction %K Humans %K Mice %K Positron-Emission Tomography %K Serotonin %X

BACKGROUND: Neuropathological and neuroimaging studies have demonstrated degeneration of the serotonin system in Alzheimer's disease (AD). Neuroimaging studies have extended these observations to the preclinical stages of AD, mild cognitive impairment (MCI). Serotonin degeneration has been observed also in transgenic amyloid mouse models, prior to widespread cortical distribution of amyloid-β (Aβ).

OBJECTIVE: The present study evaluated the regional distribution of the serotonin transporter (5-HTT) and of Aβ in individuals with MCI and healthy older controls, as well as the contribution of 5-HTT and Aβ to cognitive deficits.

METHODS: Forty-nine MCI participants and 45 healthy older controls underwent positron emission tomography (PET) imaging of 5-HTT and Aβ, structural magnetic resonance imaging and neuropsychological assessments.

RESULTS: Lower cortical, striatal, and limbic 5-HTT and higher cortical Aβ was observed in MCIs relative to healthy controls. Lower 5-HTT, mainly in limbic regions, was correlated with greater deficits in auditory-verbal and visual-spatial memory and semantic, not phonemic fluency. Higher cortical A β was associated with greater deficits in auditory-verbal and visual-spatial memory and in semantic, not phonemic fluency. When modeling the association between cognition, gray matter volumes and Aβ, inclusion of 5-HTT in limbic and in select cortical regions significantly improved model fit for auditory-verbal and visual-spatial memory and semantic, but not phonemic fluency.

CONCLUSIONS: These results support the role of serotonin degeneration in the memory and semantic fluency deficits observed in MCI.

%B J Alzheimers Dis %V 96 %P 215-227 %8 2023 %G eng %N 1 %R 10.3233/JAD-230570 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Soluble TREM2, Alzheimer's Disease Pathology, and Risk for Progression of Cerebral Small Vessel Disease: A Longitudinal Study. %A Wu, Chao %A Ma, Ya-Hui %A Hu, Hao %A Zhao, Bing %A Tan, Lan %K Alzheimer Disease %K Biomarkers %K Cerebral Small Vessel Diseases %K Humans %K Longitudinal Studies %K Membrane Glycoproteins %K Myeloid Cells %K Neuroinflammatory Diseases %K Receptors, Immunologic %X

BackgroundUntil recently, studies on associations between neuroinflammation in vivo and cerebral small vessel disease (CSVD) are scarce. Cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a candidate biomarker of microglial activation and neuroinflammation, were found elevated in Alzheimer's disease (AD), but they have not been fully explored in CSVD.ObjectiveTo determine whether CSF sTREM2 levels are associated with the increased risk of CSVD progression.MethodsA total of 426 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included in this study. All participants underwent measurements of CSF sTREM2 and AD pathology (Aβ1-42, P-tau181P). The progression of CSVD burden and imaging markers, including cerebral microbleeds (CMBs), white matter hyperintensities and lacunes, were estimated based on neuroimaging changes. Logistic regression and moderation effect models were applied to explore associations of sTREM2 with CSVD progression and AD pathology.Results Higher CSF sTREM2 levels at baseline were associated with increased CSVD burden (OR = 1.28 [95% CI, 1.01-1.62]) and CMBs counts (OR = 1.32 [95% CI, 1.03-1.68]). Similarly, increased change rates of CSF sTREM2 might predict elevated CMBs counts (OR = 1.44 [95% CI, 1.05-1.98]). Participants with AD pathology (Aβ1-42 and P-tau181P) showed a stronger association between CSF sTREM2 and CSVD progression.ConclusionThis longitudinal study found a positive association between CSF sTREM2 and CSVD progression, suggesting that neuroinflammation might promote CSVD. Furthermore, neuroinflammation could be a shared pathogenesis of CSVD and AD at the early stage. Targeting neuroinflammation to intervene the progression of CSVD and AD warrants further investigation.

%B J Alzheimers Dis %V 92 %P 311-322 %8 2023 %G eng %N 1 %R 10.3233/JAD-220731 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Unlocking Modifiable Risk Factors for Alzheimer's Disease: Does the Oral Microbiome Hold Some of the Keys? %A Loughman, Amy %A Adler, Christina J %A Macpherson, Helen %K Alzheimer Disease %K Amyloid beta-Peptides %K Gastrointestinal Microbiome %K Humans %K Microbiota %K Risk Factors %X

Advancing age is recognized as the primary risk factor for Alzheimer's disease (AD); however approximately one third of dementia cases are attributable to modifiable risk factors such as hypertension, diabetes, smoking, and obesity. Recent research also implicates oral health and the oral microbiome in AD risk and pathophysiology. The oral microbiome contributes to the cerebrovascular and neurodegenerative pathology of AD via the inflammatory, vascular, neurotoxic, and oxidative stress pathways of known modifiable risk factors. This review proposes a conceptual framework that integrates the emerging evidence regarding the oral microbiome with established modifiable risk factors. There are numerous mechanisms by which the oral microbiome may interact with AD pathophysiology. Microbiota have immunomodulatory functions, including the activation of systemic pro-inflammatory cytokines. This inflammation can affect the integrity of the blood-brain barrier, which in turn modulates translocation of bacteria and their metabolites to brain parenchyma. Amyloid-β is an antimicrobial peptide, a feature which may in part explain its accumulation. There are microbial interactions with cardiovascular health, glucose tolerance, physical activity, and sleep, suggesting that these modifiable lifestyle risk factors of dementia may have microbial contributors. There is mounting evidence to suggest the relevance of oral health practices and the microbiome to AD. The conceptual framework presented here additionally demonstrates the potential for the oral microbiome to comprise a mechanistic intermediary between some lifestyle risk factors and AD pathophysiology. Future clinical studies may identify specific oral microbial targets and the optimum oral health practices to reduce dementia risk.

%B J Alzheimers Dis %V 92 %P 1111-1129 %8 2023 %G eng %N 4 %R 10.3233/JAD-220760 %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 2023 %T Vacuolar Protein-Sorting Proteins Are Reduced Even Before Cognitive Decline in a Mouse Model of Alzheimer's Disease. %A Shinagawa, Hijiri %A Ohuchi, Kazuki %A Goto, Yuya %A Hashimoto, Kohei %A Kijima, Hideki %A Maekawa, Shogo %A Kurita, Hisaka %A Inden, Masatoshi %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Cognitive Dysfunction %K Humans %K Mice %K Protein Transport %K Vesicular Transport Proteins %X

Currently, interventions from the preclinical stage are considered necessary for the treatment of Alzheimer's disease (AD). Previous studies have reported that vacuolar protein-sorting protein (VPS), a retromer construct, is involved in the pathogenic mechanisms of AD and Parkinson's disease. This study evaluated VPS26, VPS29, and VPS35 before and after the onset of cognitive decline in an App knock-in mouse model of AD that more closely resembles the human pathology than previous AD models. The results showed that the expression of VPS26 and VPS35 decreased before the onset of cognitive decline, suggesting the possibility of anti-amyloid-β disease-modifying treatment targeting these proteins.

%B J Alzheimers Dis %V 96 %P 1011-1017 %8 2023 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/37980668?dopt=Abstract %R 10.3233/JAD-230686 %0 Journal Article %J J Alzheimers Dis %D 2022 %T 5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Diagnostic Biomarkers for Late-Onset Alzheimer's Disease. %A Chen, Lei %A Shen, Qianqian %A Xu, Shunliang %A Yu, Hongzhuan %A Pei, Shengjie %A Zhang, Yangting %A He, Xin %A Wang, QiuZhen %A Li, Duo %K 5-Methylcytosine %K Aged %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Cell-Free Nucleic Acids %K DNA Methylation %K DNA, Neoplasm %K Epigenesis, Genetic %K Female %K High-Throughput Nucleotide Sequencing %K Humans %K Male %K Middle Aged %X

BACKGROUND: 5-Hydroxymethylcytosine (5hmC) is an epigenetic DNA modification that is highly abundant in central nervous system. It has been reported that DNA 5hmC dysregulation play a critical role in Alzheimer's disease (AD) pathology. Changes in 5hmC signatures can be detected in circulating cell-free DNA (cfDNA), which has shown potential as a non-invasive liquid biopsy material.

OBJECTIVE: However, the genome-wide profiling of 5hmC in cfDNA and its potential for the diagnosis of AD has not been reported to date.

METHODS: We carried out a case-control study and used a genome-wide chemical capture followed by high-throughput sequencing to detect the genome-wide profiles of 5hmC in human cfDNA and identified differentially hydroxymethylated regions (DhMRs) in late-onset AD patients and the control.

RESULTS: We discovered significant differences of 5hmC enrichment in gene bodies which were linked to multiple AD pathogenesis-associated signaling pathways in AD patients compared with cognitively normal controls, indicating they can be well distinguished from normal controls by DhMRs in cfDNA. Specially, we identified 7 distinct genes (RABEP1, CPNE4, DNAJC15, REEP3, ROR1, CAMK1D, and RBFOX1) with predicting diagnostic potential based on their significant correlations with MMSE and MoCA scores of subjects.

CONCLUSION: The present results suggest that 5hmC markers derived from plasma cfDNA can served as an effective, minimally invasive biomarkers for clinical auxiliary diagnosis of late-onset AD.

%B J Alzheimers Dis %V 85 %P 573-585 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34864677?dopt=Abstract %R 10.3233/JAD-215217 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Alteration of Gut Microbiota in Alzheimer's Disease and Their Relation to the Cognitive Impairment. %A Khedr, Eman M %A Omeran, Nehad %A Karam-Allah Ramadan, Haidi %A Ahmed, Gellan K %A Abdelwarith, Ahmed M %K Alzheimer Disease %K Bacteria %K Cognitive Dysfunction %K Dysbiosis %K Gastrointestinal Microbiome %K Humans %K RNA, Ribosomal, 16S %X

BACKGROUND: Dysbiosis of gut microbiota has been reported to be enrolled in the pathogenesis of Alzheimer's disease (AD). However, there is a lack of relevant studies on this topic in Egyptian patients with AD.

OBJECTIVE: To investigate different species of gut microbiota in Egyptian patients with AD and correlate microbiota bacterial abundance with clinical data.

METHODS: The study included 25 patients with AD and 25 healthy volunteers as age and sex-matched controls. Clinical data was taken for each patient, including medical history and examination; Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were assessed for each participant. Bacterial DNA was extracted from stool, and abundance quantified via qPCR using 16S rRNA group-specific primers.

RESULTS: Akkermansia, Enterobacteria, Bacteroidetes, Bacillus cereus, Prevotella, and Clostridium cluster IV were more abundant in the AD group than in the control group, although there was significantly less abundance of Bifidobacterium spp., Firmicutes, and Actinobacteria in patients with AD than in controls, whereas no such significance was found for lactic acid bacteria between both groups. Lactic acid bacteria and Prevotella abundance was negatively correlated with cognitive impairment (p = 0.03 with MMSE, and p = 0.03 with MoCA). Prevotella abundance was positively correlated with age of onset and duration of illness and negatively correlated with smoking and coronary heart disease (p = 0.007, p = 0.03, p = 0.035, and p = 0.047, respectively).

CONCLUSION: The current work highlighted a significant relationship between AD and gut microbiota dysbiosis. A higher abundance of Prevotella species and lactic acid bacteria was correlated with cognition.

%B J Alzheimers Dis %V 88 %P 1103-1114 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35754271?dopt=Abstract %R 10.3233/JAD-220176 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Alzheimer's Disease: Key Insights from Two Decades of Clinical Trial Failures. %A Kim, C Kwon %A Lee, Yin Rui %A Ong, Lynnett %A Gold, Michael %A Kalali, Amir %A Sarkar, Joydeep %K Alzheimer Disease %K Humans %X

Given the acknowledged lack of success in Alzheimer's disease (AD) drug development over the past two decades, the objective of this review was to derive key insights from the myriad failures to inform future drug development. A systematic and exhaustive review was performed on all failed AD compounds for dementia (interventional phase II and III clinical trials from ClinicalTrials.gov) from 2004 to the present. Starting with the initial ∼2,700 AD clinical trials, ∼550 trials met our initial criteria, from which 98 unique phase II and III compounds with various mechanisms of action met our criteria of a failed compound. The two recent reported phase III successes of aducanumab and oligomannate are very encouraging; however, we are awaiting real-world validation of their effectiveness. These two successes against the 98 failures gives a 2.0% phase II and III success rate since 2003, when the previous novel compound was approved. Potential contributing methodological factors for the clinical trial failures were categorized into 1) insufficient evidence to initiate the pivotal trials, and 2) pivotal trial design shortcomings. Our evaluation found that rational drug development principles were not always followed for AD therapeutics development, and the question remains whether some of the failed compounds may have shown efficacy if the principles were better adhered to. Several recommendations are made for future AD therapeutic development. The whole database of the 98 failed compounds is presented in the Supplementary Material.

%B J Alzheimers Dis %V 87 %P 83-100 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35342092?dopt=Abstract %R 10.3233/JAD-215699 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Analysis and Identification Genetic Effect of SARS-CoV-2 Infections to Alzheimer's Disease Patients by Integrated Bioinformatics. %A Wang, Fang %A Xu, Jia %A Xu, Shu-Jun %A Guo, Jie-Jie %A Wang, Feiming %A Wang, Qin-Wen %K Alzheimer Disease %K Computational Biology %K COVID-19 %K Databases, Genetic %K Gene Expression Profiling %K Humans %K Protein Interaction Maps %K SARS-CoV-2 %X

BACKGROUND: COVID-19 pandemic is a global crisis which results in millions of deaths and causes long-term neurological sequelae, such as Alzheimer's disease (AD).

OBJECTIVE: We aimed to explore the interaction between COVID-19 and AD by integrating bioinformatics to find the biomarkers which lead to AD occurrence and development with COVID-19 and provide early intervention.

METHODS: The differential expressed genes (DEGs) were found by GSE147507 and GSE132903, respectively. The common genes between COVID-19 and AD were identified. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interactions (PPI) network analysis were carried out. Hub genes were found by cytoscape. A multivariate logistic regression model was constructed. NetworkAnalyst was used for the analysis of TF-gene interactions, TF-miRNA coregulatory network, and Protein-chemical Interactions.

RESULTS: Forty common DEGs for AD and COVID-19 were found. GO and KEGG analysis indicated that the DEGs were enriched in the calcium signal pathway and other pathways. A PPI network was constructed, and 5 hub genes were identified (ITPR1, ITPR3, ITPKB, RAPGEF3, MFGE8). Four hub genes (ITPR1, ITPR3, ITPKB, RAPGEF3) which were considered as important factors in the development of AD that were affected by COVID-19 were shown by nomogram. Utilizing NetworkAnalyst, the interaction network of 4 hub genes and TF, miRNA, common AD risk genes, and known compounds is displayed, respectively.

CONCLUSION: COVID-19 patients are at high risk of developing AD. Vaccination is required. Four hub genes can be considered as biomarkers for prediction and treatment of AD development caused by COVID-19. Compounds with neuroprotective effects can be used as adjuvant therapy for COVID-19 patients.

%B J Alzheimers Dis %V 85 %P 729-744 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34776447?dopt=Abstract %R 10.3233/JAD-215086 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Anti-Inflammatory Gene Therapy Improves Spatial Memory Performance in a Mouse Model of Alzheimer's Disease. %A Yoo, Tai June %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Anti-Inflammatory Agents %K Cognition %K Disease Models, Animal %K Female %K Genetic Therapy %K Immunity, Cellular %K Immunotherapy %K Injections, Intramuscular %K Interleukin-10 %K Interleukin-4 %K Male %K Mice %K Mice, Transgenic %K Spatial Memory %X

The immune system plays a critical role in neurodegenerative processes involved in Alzheimer's disease (AD). In this study, a gene-based immunotherapeutic method examined the effects of anti-inflammatory cellular immune response elements (CIREs) in the amyloid-β protein precursor (AβPP) mouse model. Bi-monthly intramuscular administration, beginning at either 4 or 6 months, and examined at 7.5 through 16 months, with plasmids encoding Interleukin (IL)-10, IL-4, TGF-β polynucleotides, or a combination thereof, into AβPP mice improved spatial memory performance. This work demonstrates an efficient gene therapy strategy to downregulate neuroinflammation, and possibly prevent or delay cognitive decline in AD.

%B J Alzheimers Dis %V 85 %P 1001-1008 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34897091?dopt=Abstract %R 10.3233/JAD-215270 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association Between Serum Vitamins and the Risk of Alzheimer's Disease in Chinese Population. %A Liu, Xi-Xi %A Wu, Peng-Fei %A Liu, Ying-Zi %A Jiang, Ya-Ling %A Wan, Mei-Dan %A Xiao, Xue-Wen %A Yang, Qi-Jie %A Jiao, Bin %A Liao, Xin-Xin %A Wang, Jun-Ling %A Liu, Shao-Hui %A Zhang, Xuewei %A Shen, Lu %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Case-Control Studies %K China %K Female %K Folic Acid %K Humans %K Logistic Models %K Male %K Mental Status and Dementia Tests %K Middle Aged %K Riboflavin %K Risk %K Vitamin B 12 %K Vitamin D %K Vitamin E %X

BACKGROUND: Alzheimer's disease (AD) is a chronic and fatal neurodegenerative disease; accumulating evidence suggests that vitamin deficiency is associated with the risk of AD. However, studies attempting to elucidate the relationship between vitamins and AD varied widely.

OBJECTIVE: This study aimed to investigate the relationship between serum vitamin levels and AD in a cohort of the Chinese population.

METHODS: A total of 368 AD patients and 574 healthy controls were recruited in this study; serum vitamin A, B1, B6, B9, B12, C, D, and E were measured in all participants.

RESULTS: Compared with the controls, vitamin B2, B9, B12, D, and E were significantly reduced in AD patients. Lower levels of vitamin B2, B9, B12, D, and E were associated with the risk of AD. After adjusting for age and gender, low levels of vitamin B2, B9, and B12 were still related to the risk of AD. In addition, a negative correlation was determined between vitamin E concentration and Activity of Daily Living Scale score while no significant association was found between serum vitamins and age at onset, disease duration, Mini-Mental State Examination, and Neuropsychiatric Inventory Questionnaire score.

CONCLUSION: We conclude that lower vitamin B2, B9, B12, D, and E might be associated with the risk of AD, especially vitamin B2, B9, and B12. And lower vitamin E might be related to severe ability impairment of daily activities.

%B J Alzheimers Dis %V 85 %P 829-836 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34864672?dopt=Abstract %R 10.3233/JAD-215104 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association of Alzheimer's Disease with COVID-19 Susceptibility and Severe Complications: A Nationwide Cohort Study. %A Chung, Seok Jong %A Chang, Yoonkyung %A Jeon, Jimin %A Shin, Jae Il %A Song, Tae-Jin %A Kim, Jinkwon %K Alzheimer Disease %K Cohort Studies %K COVID-19 %K Humans %K Pandemics %K Retrospective Studies %K SARS-CoV-2 %X

BACKGROUND: Identification of patients at high susceptibility and high risk of developing serious complications related to coronavirus disease 2019 (COVID-19) infection is clinically important in the face of the COVID-19 pandemic.

OBJECTIVE: To investigate whether patients with Alzheimer's disease (AD) are more susceptible to COVID-19 infection and whether they have a higher risk of developing serious complications.

METHODS: We retrospectively reviewed the Korean nationwide population-based COVID-19 dataset for participants who underwent real-time reverse transcription polymerase chain reaction assays for COVID-19 between January 1 and June 4, 2020. A 1 : 3 ratio propensity score matching and binary logistic regression analysis were performed to investigate the association between AD and the susceptibility or severe complications (i.e., mechanical ventilation, intensive care unit admission, or death) of COVID-19.

RESULTS: Among 195,643 study participants, 5,725 participants had AD and 7,334 participants were diagnosed with COVID-19. The prevalence of participants testing positive for COVID-19 did not differ according to the presence of AD (p = 0.234). Meanwhile, AD was associated with an increased risk of severe COVID-19 complications (OR 2.25 [95% CI 1.54-3.28]). Secondary outcome analyses showed that AD patients had an increased risk for mortality (OR 3.09 [95% CI 2.00-4.78]) but were less likely to receive mechanical ventilation (OR 0.42 [95% CI 0.20-0.87]).

CONCLUSION: AD was not associated with increased susceptibility to COVID-19 infection, but was associated with severe COVID-19 complications, especially with mortality. Early diagnosis and active intervention are necessary for patients with AD suspected COVID-19 infection.

%B J Alzheimers Dis %V 87 %P 701-710 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35275548?dopt=Abstract %R 10.3233/JAD-220031 %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 Avoiding Over-Reliance on Multi-Domain Interventions for Dementia Prevention. %A Daly, Timothy %A Mastroleo, Ignacio %A Migliaccio, Raffaella %K Alzheimer Disease %K Humans %K Risk Factors %K Risk Reduction Behavior %X

Given the unknown therapeutic value of targeting Alzheimer's disease pathology and the discovery of robust risk factors for dementia, non-pharmacological risk reduction (RR) is increasingly offered as an alternative to targeting Alzheimer's disease pathology. While RR will surely be a useful tool to make public health gains, we propose solutions to three possible issues with over-reliance on multi-domain interventions to achieve RR: limited individual impact, an exclusive focus on later life, and overlooking social determinants of dementia. We argue in favor of a broader debate within the research community and greater society about how different therapeutic avenues should be explored.

%B J Alzheimers Dis %V 90 %P 989-992 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35275544?dopt=Abstract %R 10.3233/JAD-215647 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Barriers to Effective Memory Assessments for Alzheimer's Disease. %A Parra, Mario A %K Alzheimer Disease %K Cognition %K Cognition Disorders %K Humans %K Longitudinal Studies %X

Recently, Alzheimer's Disease International (ADI) stressed that around 75% of people living with dementia globally are still not receiving a diagnosis. In this commentary, I reflect on how efforts towards better cognitive assessments, particularly of memory, can be aligned and harmonized to contribute to such needs. I highlight some barriers that ongoing collaborations and trials are facing and their potential drivers. I suggest some strategies that can help overcome them and in so doing, integrate research agendas. We need to ignite the debate towards strategies that can help level the playfield to tackle Alzheimer's disease with true global solutions.

%B J Alzheimers Dis %V 90 %P 981-988 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35147540?dopt=Abstract %R 10.3233/JAD-215445 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Behavioral and Psychological Symptoms of Dementia in Different Dementia Disorders: A Large-Scale Study of 10,000 Individuals. %A Schwertner, Emilia %A Pereira, Joana B %A Xu, Hong %A Secnik, Juraj %A Winblad, Bengt %A Eriksdotter, Maria %A Nägga, Katarina %A Religa, Dorota %K Alzheimer Disease %K Behavioral Symptoms %K Dementia, Vascular %K Frontotemporal Dementia %K Hallucinations %K Humans %K Parkinson Disease %X

BACKGROUND: The majority of individuals with dementia will suffer from behavioral and psychological symptoms of dementia (BPSD). These symptoms contribute to functional impairment and caregiver burden.

OBJECTIVE: To characterize BPSD in Alzheimer's disease (AD), vascular dementia (VaD), mixed (Mixed) dementia, Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and unspecified dementia in individuals residing in long-term care facilities.

METHODS: We included 10,405 individuals with dementia living in long-term care facilities from the Swedish registry for cognitive/dementia disorders (SveDem) and the Swedish BPSD registry. BPSD was assessed with the Neuropsychiatric Inventory - Nursing Home Version (NPI-NH). Multivariate logistic regression models were used to evaluate the associations between dementia diagnoses and different BPSDs.

RESULTS: The most common symptoms were aberrant motor behavior, agitation, and irritability. Compared to AD, we found a lower risk of delusions (in FTD, unspecified dementia), hallucinations (FTD), agitation (VaD, PDD, unspecified dementia), elation/euphoria (DLB), anxiety (Mixed, VaD, unspecified dementia), disinhibition (in PDD), irritability (in DLB, FTD, unspecified dementia), aberrant motor behavior (Mixed, VaD, unspecified dementia), and sleep and night-time behavior changes (unspecified dementia). Higher risk of delusions (DLB), hallucinations (DLB, PDD), apathy (VaD, FTD), disinhibition (FTD), and appetite and eating abnormalities (FTD) were also found in comparison to AD.

CONCLUSION: Although individuals in our sample were diagnosed with different dementia disorders, they all exhibited aberrant motor behavior, agitation, and irritability. This suggests common underlying psychosocial or biological mechanisms. We recommend prioritizing these symptoms while planning interventions in long-term care facilities.

%B J Alzheimers Dis %V 87 %P 1307-1318 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35491774?dopt=Abstract %R 10.3233/JAD-215198 %0 Journal Article %J J Alzheimers Dis %D 2022 %T A Blood Test for Alzheimer's Disease: It's about Time or Not Ready for Prime Time? %A Galasko, Douglas R %A Grill, Joshua D %A Lingler, Jennifer H %A Heidebrink, Judith L %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognitive Dysfunction %K Hematologic Tests %K Humans %K tau Proteins %X

A blood test for Alzheimer's disease is now available for clinical use in persons with cognitive impairment. This is an extraordinary milestone, though the amyloid-based PrecivityAD™ test is not without limitations. Pre and post-test counseling are essential. Phosphorylated tau blood tests are likely to follow soon. When used in conjunction with an appropriate clinical evaluation, blood tests provide the opportunity for an early, accurate, and accessible diagnosis of Alzheimer's disease. Standalone use, however, carries a significant risk of misinterpretation and is strongly discouraged. Now is the time to develop appropriate use criteria to guide the use of these promising assays.

%B J Alzheimers Dis %V 90 %P 963-966 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35147543?dopt=Abstract %R 10.3233/JAD-215490 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Blood Tests for Alzheimer's Disease: Increasing Efforts to Expand and Diversify Research Participation Is Critical for Widespread Validation and Acceptance. %A Karikari, Thomas K %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Hematologic Tests %K Humans %K tau Proteins %X

The recent academic and commercial development, and regulatory approvals, of blood-based Alzheimer's disease (AD) biomarkers are breakthrough developments of immense potential. However, clinical validation studies and therapeutic trial applications are limited almost exclusively to non-Hispanic White cohorts often including highly-educated, high-earning participants. This commentary argues that the true benefits of blood tests for AD will be realized by active inclusion of diverse groups including minoritized populations, people of socioeconomic status different from those included in existing cohorts, and residents of low- and middle-income countries. The article discusses key factors that are critical for a successful implementation of diversity programs.

%B J Alzheimers Dis %V 90 %P 967-974 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35491788?dopt=Abstract %R 10.3233/JAD-215730 %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 "Captive by the Uncertainty"-Experiences with Anticipatory Guidance for People Living with Dementia and Their Caregivers at a Specialty Dementia Clinic. %A Shafir, Adi %A Ritchie, Christine S %A Garrett, Sarah B %A Bernstein Sideman, Alissa %A Naasan, Georges %A Merrilees, Jennifer %A Widera, Eric %A Flint, Lynn %A Harrison, Krista L %K Aged %K Alzheimer Disease %K Caregivers %K Dementia %K Female %K Humans %K Male %K Qualitative Research %K Uncertainty %X

BACKGROUND: After a diagnosis of Alzheimer's disease and related disorders, people living with dementia (PWD) and caregivers wonder what disease trajectory to expect and how to plan for functional and cognitive decline. This qualitative study aimed to identify patient and caregiver experiences receiving anticipatory guidance about dementia from a specialty dementia clinic.

OBJECTIVE: To examine PWD and caregiver perspectives on receiving anticipatory guidance from a specialty dementia clinic.

METHODS: We conducted semi-structured interviews with PWD, and active and bereaved family caregivers, recruited from a specialty dementia clinic. Interviews were recorded, transcribed, and systematically summarized. Thematic analysis identified anticipatory guidance received from clinical or non-clinical sources and areas where respondents wanted additional guidance.

RESULTS: Of 40 participants, 9 were PWD, 16 were active caregivers, and 15 were bereaved caregivers. PWD had a mean age of 75 and were primarily male (n = 6/9); caregivers had a mean age of 67 and were primarily female (n = 21/31). Participants felt they received incomplete or "hesitant" guidance on prognosis and expected disease course via their clinicians and filled the gap with information they found via the internet, books, and support groups. They appreciated guidance on behavioral, safety, and communication issues from clinicians, but found more timely and advance guidance from other non-clinical sources. Guidance on legal and financial planning was primarily identified through non-clinical sources.

CONCLUSION: PWD and caregivers want more information about expected disease course, prognosis, and help planning after diagnosis. Clinicians have an opportunity to improve anticipatory guidance communication and subsequent care provision.

%B J Alzheimers Dis %V 86 %P 787-800 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35124641?dopt=Abstract %R 10.3233/JAD-215203 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Cerebral Volumetric Correlates of Apathy in Alzheimer's Disease and Cognitively Normal Older Adults: Meta-Analysis, Label-Based Review, and Study of an Independent Cohort. %A Chaudhary, Shefali %A Zhornitsky, Simon %A Chao, Herta H %A van Dyck, Christopher H %A Li, Chiang-Shan R %K Aged %K Alzheimer Disease %K Apathy %K Atrophy %K Basal Ganglia %K Brain %K Cognitive Dysfunction %K Cohort Studies %K Gray Matter %K Gyrus Cinguli %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Prefrontal Cortex %X

BACKGROUND: Affecting nearly half of the patients with Alzheimer's disease (AD), apathy is associated with higher morbidity and reduced quality of life. Basal ganglia and cortical atrophy have been implicated in apathy. However, the findings have varied across studies and left unclear whether subdomains of apathy may involve distinct neuroanatomical correlates.

OBJECTIVE: To identify neuroanatomical correlates of AD-associated apathy.

METHODS: We performed a meta-analysis and label-based review of the literature. Further, following published routines of voxel-based morphometry, we aimed to confirm the findings in an independent cohort of 19 patients with AD/mild cognitive impairment and 25 healthy controls assessed with the Apathy Evaluation Scale.

RESULTS: Meta-analysis of 167 AD and 56 healthy controls showed convergence toward smaller basal ganglia gray matter volume (GMV) in apathy. Label-based review showed anterior cingulate, putamen, insula, inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) atrophy in AD apathy. In the independent cohort, with small-volume-correction, right putamen and MTG showed GMVs in negative correlation with Apathy Evaluation Scale total, behavioral, and emotional scores, and right IFG with emotional score (p < 0.05 family-wise error (FWE)-corrected), controlling for age, education, intracranial volume, and depression. With the Mini-Mental State Examination scores included as an additional covariate, the correlation of right putamen GMV with behavioral and emotional score, right MTG GMV with total and emotional score, and right IFG GMV with emotional score were significant.

CONCLUSION: The findings implicate putamen, MTG and IFG atrophy in AD associated apathy, potentially independent of cognitive impairment and depression, and suggest potentially distinct volumetric correlates of apathy.

%B J Alzheimers Dis %V 85 %P 1251-1265 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34924392?dopt=Abstract %R 10.3233/JAD-215316 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Cognitive Function Associated with Gut Microbial Abundance in Sucrose and S-Adenosyl-L-Methionine (SAMe) Metabolic Pathways. %A Jeong, Sohyun %A Huang, Li-Kai %A Tsai, Ming-Ju %A Liao, Yi-Tyng %A Lin, Yow-Sien %A Hu, Chaur-Jong %A Hsu, Yi-Hsiang %K Alzheimer Disease %K Cognition %K Cognitive Dysfunction %K Gastrointestinal Microbiome %K Humans %K Metabolic Networks and Pathways %K RNA, Ribosomal, 16S %K S-Adenosylmethionine %K Sucrose %X

BACKGROUND: Differential abundance of gut microbiota has found to be associated with Alzheimer's disease (AD). However, the relative abundance of gut microbiota between dementia and mild cognitive impairment (MCI) in AD is not well studied.

OBJECTIVE: We attempted to identify differentially enriched gut microbes and their metabolic pathways in AD patients with dementia comparing to AD patients with MCI.

METHODS: Fecal samples were collected at Shuang Ho Hospital, Taipei Medical University, Taiwan and analyzed by whole metagenomic sequencing technique. For normal controls without AD (NC), 16S rRNA sequencing was obtained from the Taiwan Microbiome Database. A total of 48 AD (38 dementia and 10 MCI defined by cognitive function scores) and 50 NC were included. Microbiome alpha and beta diversities were estimated. Differentially enriched microbes were identified with HAllA, MaAsLin, DESeq2, and LEfSe statistical modeling approaches.

RESULTS: We found significantly increased abundance of Firmicutes but decreased abundance of Bacteroidetes at phylum level in AD compared to NC. In AD patients, cognitive function scores were negatively associated with abundance of Blautia hydrogenotrophica (Firmicutes), Anaerotruncus colihominis (Firmicutes), and Gordonibacter pamelaeae (Actinobacteria). In addition, microbial abundance in the sucrose and S-Adenosyl-L-methionine (SAMe) metabolic pathways was more enriched in AD with MCI than AD with dementia and significantly associated with higher cognitive function scores.

CONCLUSION: Gut microbe community diversity was similar in AD patients regardless of MCI or dementia status. However, differential analyses probed in lower-level taxa and metabolic pathways suggested that specific gut microbes in Firmicutes and Actinobacteria might involve in cognitive decline.

%B J Alzheimers Dis %V 87 %P 1115-1130 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35431236?dopt=Abstract %R 10.3233/JAD-215090 %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 The Correlation of Tau Levels with Blood Monocyte Count in Patients with Alzheimer's Disease. %A Sun, Hao-Lun %A Zhou, Fa-Ying %A Chen, Dong-Wan %A Tan, Cheng-Rong %A Zeng, Gui-Hua %A Liu, Yu-Hui %A Wang, Jun %A Bu, Xian-Le %A Wang, Yan-Jiang %A Li, Hui-Yun %A Jin, Wang-Sheng %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Brain %K Cognitive Dysfunction %K Cohort Studies %K Female %K Humans %K Male %K Monocytes %K tau Proteins %X

BACKGROUND: Recent studies have shown that monocytes can phagocytize the tau protein, which may ameliorate tau-type pathology in Alzheimer's disease (AD). However, there are few clinical studies on the relationship between monocytes and tau-type pathology in AD patients.

OBJECTIVE: We aimed to explore changes in peripheral monocytes and their association with tau protein in AD patients.

METHODS: A total of 127 clinically diagnosed AD patients and 100 age- and sex-matched cognitively normal controls were recruited for analysis of the correlation of plasma tau levels with the blood monocyte count. Cerebrospinal fluid (CSF) samples from 46 AD patients and 88 controls were further collected to analyze the correlation of CSF tau and amyloid-β (Aβ) levels with the blood monocyte count. 105 clinically diagnosed mild cognitive impairment (MCI) patients and 149 age- and sex-matched cognitively normal controls were recruited from another cohort for verification.

RESULTS: Compared to normal controls, AD patients showed a significant reduction in the blood monocyte count. In addition, the monocyte count of AD patients was negatively correlated with CSF t-tau and p-tau levels but not with plasma tau levels. In normal people, monocyte count lack correlation with tau levels both in plasma and CSF. Monocyte count were not correlated with CSF Aβ levels in either group but were negatively correlated with CSF tau/Aβ42 levels in the AD group. We had further verified the correlations of monocyte count with CSF tau levels in another cohort.

CONCLUSION: This study suggests that monocytes may play an important role in the clearance of tau protein in the brain.

%B J Alzheimers Dis %V 85 %P 1321-1328 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34924377?dopt=Abstract %R 10.3233/JAD-210692 %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 Detecting Alzheimer's Disease Using Natural Language Processing of Referential Communication Task Transcripts. %A Liu, Ziming %A Paek, Eun Jin %A Yoon, Si On %A Casenhiser, Devin %A Zhou, Wenjun %A Zhao, Xiaopeng %K Aged %K Alzheimer Disease %K Cognitive Dysfunction %K Communication %K Humans %K Natural Language Processing %K Speech %X

BACKGROUND: People with Alzheimer's disease (AD) often demonstrate difficulties in discourse production. Referential communication tasks (RCTs) are used to examine a speaker's capability to select and verbally code the characteristics of an object in interactive conversation.

OBJECTIVE: In this study, we used contextualized word representations from Natural language processing (NLP) to evaluate how well RCTs are able to distinguish between people with AD and cognitively healthy older adults.

METHODS: We adapted machine learning techniques to analyze manually transcribed speech transcripts in an RCT from 28 older adults, including 12 with AD and 16 cognitively healthy older adults. Two approaches were applied to classify these speech transcript samples: 1) using clinically relevant linguistic features, 2) using machine learned representations derived by a state-of-art pretrained NLP transfer learning model, Bidirectional Encoder Representation from Transformer (BERT) based classification model.

RESULTS: The results demonstrated the superior performance of AD detection using a designed transfer learning NLP algorithm. Moreover, the analysis showed that transcripts of a single image yielded high accuracies in AD detection.

CONCLUSION: The results indicated that RCT may be useful as a diagnostic tool for AD, and that the task can be simplified to a subset of images without significant sacrifice to diagnostic accuracy, which can make RCT an easier and more practical tool for AD diagnosis. The results also demonstrate the potential of RCT as a tool to better understand cognitive deficits from the perspective of discourse production in people with AD.

%B J Alzheimers Dis %V 86 %P 1385-1398 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35213368?dopt=Abstract %R 10.3233/JAD-215137 %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 Dimethyl Fumarate is a Potential Therapeutic Option for Alzheimer's Disease. %A Sun, Xiaodi %A Suo, Xinjun %A Xia, Xianyou %A Yu, Chunshui %A Dou, Yan %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Antioxidants %K Cell Survival %K Dimethyl Fumarate %K Disease Models, Animal %K Hippocampus %K Inflammation %K Male %K Memory Disorders %K Mice %K Mice, Inbred C57BL %K Neurons %K NF-E2-Related Factor 2 %K NF-kappa B %K Oxidative Stress %K Protective Agents %K Reactive Oxygen Species %X

BACKGROUND: Dimethyl fumarate (DMF) has been approved for clinical treatment of multiple sclerosis based on its antioxidant and anti-inflammatory effects by activating the Nrf2 pathway. Since both oxidative stress and inflammation are involved in Alzheimer's disease (AD), DMF is a potential therapeutic option for AD.

OBJECTIVE: This study aims to test the therapeutic effects of DMF on AD model mice and to reveal its underlying molecular mechanisms.

METHODS: Cell viability assay and in vitro immunofluorescence imaging were used to evaluate the antioxidant effect of DMF on embryonic mouse hippocampal neurons. Behavioral test and brain magnetic resonance imaging were used to assess the therapeutic effects of DMF on spatial learning and memory as well as hippocampal volume in AD model mice with and without Nrf2 knockdown. Western blotting was used to analyze the expression of antioxidant enzymes and molecules associated with AD-related pathological pathways.

RESULTS: DMF inhibits reactive oxygen species overproduction and protects neurons without Nrf2 knockdown from death. DMF reduces amyloid-β induced memory impairment and hippocampal atrophy in AD model mice rather than in Nrf2 knockdown AD mice. DMF delays the progression of AD by activating the Nrf2 pathway to enhance the expression of downstream antioxidant enzymes and inhibits lipid peroxidation, apoptosis, inflammation, mitochondrial dysfunction and amyloid-β deposition.

CONCLUSION: These results indicate that DMF is a potential therapeutic option for AD through its antioxidant, anti-inflammatory, anti-apoptotic, and other anti-AD effects by activating the Nrf2 pathway.

%B J Alzheimers Dis %V 85 %P 443-456 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34842188?dopt=Abstract %R 10.3233/JAD-215074 %0 Journal Article %J J Alzheimers Dis %D 2022 %T The Efficacy and Safety of Alzheimer's Disease Therapies: An Updated Umbrella Review. %A Fan, Fangcheng %A Liu, Hua %A Shi, Xiaojie %A Ai, Yangwen %A Liu, Qingshan %A Cheng, Yong %K Activities of Daily Living %K Alzheimer Disease %K Amino Acids %K Cholinesterase Inhibitors %K Cognition %K Donepezil %K Galantamine %K Ginkgo biloba %K Humans %K Nootropic Agents %K Patient Safety %K Plant Extracts %K Rivastigmine %X

BACKGROUND: Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer's disease (AD) are sparse.

OBJECTIVE: We aimed to perform an updated umbrella review to identify an efficacious and safe treatment for AD patients.

METHODS: We conducted a search for meta-analyses and systematic reviews on the Embase, PubMed, The Cochrane Library, and Web of Science to address this knowledge gap. We examined the cognitive functions, behavioral symptoms, global clinical assessment, and Activities of Daily Living as efficacy endpoints, and the incidence of adverse events as safety profiles.

RESULTS: Sixteen eligible papers including 149 studies were included in the umbrella review. The results showed that AChE inhibitors (donepezil, galantamine, rivastigmine, Huperzine A), Ginkgo biloba, and cerebrolysin appear to be beneficial for cognitive, global performances, and activities of daily living in patients with AD. Furthermore, anti-Aβ agents are unlikely to have an important effect on slowing cognitive or functional impairment in mild to moderate AD.

CONCLUSION: Our study demonstrated that AChE inhibitors, Ginkgo biloba, and cerebrolysin are the optimum cognitive and activities of daily living medication for patients with AD.

%B J Alzheimers Dis %V 85 %P 1195-1204 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34924395?dopt=Abstract %R 10.3233/JAD-215423 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Environmental Enrichment Effects on the Brain-Derived Neurotrophic Factor Expression in Healthy Condition, Alzheimer's Disease, and Other Neurodegenerative Disorders. %A Cutuli, Debora %A Landolfo, Eugenia %A Petrosini, Laura %A Gelfo, Francesca %K Alzheimer Disease %K Animals %K Brain %K Brain-Derived Neurotrophic Factor %K Cognition %K Disease Models, Animal %K Environment %K Humans %K Neurodegenerative Diseases %K Neuronal Plasticity %X

Brain-derived neurotrophic factor (BDNF), a protein belonging to the neurotrophin family, is known to be heavily involved in synaptic plasticity processes that support brain development, post-lesion regeneration, and cognitive performances, such as learning and memory. Evidence indicates that BDNF expression can be epigenetically regulated by environmental stimuli and thus can mediate the experience-dependent brain plasticity. Environmental enrichment (EE), an experimental paradigm based on the exposure to complex stimulations, constitutes an efficient means to investigate the effects of high-level experience on behavior, cognitive processes, and neurobiological correlates, as the BDNF expression. In fact, BDNF exerts a key role in mediating and promoting EE-induced plastic changes and functional improvements in healthy and pathological conditions. This review is specifically aimed at providing an updated framework of the available evidence on the EE effects on brain and serum BDNF levels, by taking into account both changes in protein expression and regulation of gene expression. A further purpose of the present review is analyzing the potential of BDNF regulation in coping with neurodegenerative processes characterizing Alzheimer's disease (AD), given BDNF expression alterations are described in AD patients. Moreover, attention is also paid to EE effects on BDNF expression in other neurodegenerative disease. To investigate such a topic, evidence provided by experimental studies is considered. A deeper understanding of environmental ability in modulating BDNF expression in the brain may be fundamental in designing more tuned and effective applications of complex environmental stimulations as managing approaches to AD.

%B J Alzheimers Dis %V 85 %P 975-992 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34897089?dopt=Abstract %R 10.3233/JAD-215193 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Evaluation of the Accuracy of Cognitive Screening Tests in Detecting Dementia Associated with Alzheimer's Disease: A Hierarchical Bayesian Latent Class Meta-Analysis. %A Wang, Xiaonan %A Li, Fengjie %A Gao, Qi %A Jiang, Zhen %A Abudusaimaiti, Xiayidanmu %A Yao, Jiangyue %A Zhu, Huiping %K Alzheimer Disease %K Bayes Theorem %K Cognition %K Cognitive Dysfunction %K Humans %K Mental Status and Dementia Tests %K Neuropsychological Tests %X

BACKGROUND: Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) are neuropsychological tests commonly used by physicians for screening cognitive dysfunction of Alzheimer's disease (AD). Due to different imperfect reference standards, the performance of MoCA and MMSE do not reach consensus. It is necessary to evaluate the consistence and differentiation of MoCA and MMSE in the absence of a gold standard for AD.

OBJECTIVE: We aimed to assess the accuracy of MoCA and MMSE in screening AD without a gold standard reference test.

METHODS: Studies were identified from PubMed, Web of Science, CNKI, Chinese Wanfang Database, China Science and Technology Journal Database, and Cochrane Library. Our search was limited to studies published in English and Chinese before August 2021. A hierarchical Bayesian latent class model was performed in meta-analysis when the gold standard was absent.

RESULTS: A total of 67 studies comprising 5,554 individuals evaluated for MoCA and 76,862 for MMSE were included in this meta-analysis. The pooled sensitivity was 0.934 (95% CI 0.905 to 0.954) for MoCA and 0.883 (95% CI 0.859 to 0.903) for MMSE, while the pooled specificity was 0.899 (95% CI 0.859 to 0.928) for MoCA and 0.903 (95% CI 0.879 to 0.923) for MMSE. MoCA was useful to rule out dementia associated with AD with lower negative likelihood ratio (LR-) (0.074, 95% CI 0.051 to 0.108). MoCA showed better performance with higher diagnostic odds ratio (DOR) (124.903, 95% CI 67.459 to 231.260).

CONCLUSION: MoCA had better performance than MMSE in screening dementia associated with AD from patients with mild cognitive impairment or healthy controls.

%B J Alzheimers Dis %V 87 %P 285-304 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35275533?dopt=Abstract %R 10.3233/JAD-215394 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Functional Neurophysiological Biomarkers of Early-Stage Alzheimer's Disease: A Perspective of Network Hyperexcitability in Disease Progression. %A Tok, Sean %A Ahnaou, Abdallah %A Drinkenburg, Wilhelmus %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Biomarkers %K Disease Progression %K Humans %K Nervous System Physiological Phenomena %K Neurophysiology %K tau Proteins %X

Network hyperexcitability (NH) has recently been suggested as a potential neurophysiological indicator of Alzheimer's disease (AD), as new, more accurate biomarkers of AD are sought. NH has generated interest as a potential indicator of certain stages in the disease trajectory and even as a disease mechanism by which network dysfunction could be modulated. NH has been demonstrated in several animal models of AD pathology and multiple lines of evidence point to the existence of NH in patients with AD, strongly supporting the physiological and clinical relevance of this readout. Several hypotheses have been put forward to explain the prevalence of NH in animal models through neurophysiological, biochemical, and imaging techniques. However, some of these hypotheses have been built on animal models with limitations and caveats that may have derived NH through other mechanisms or mechanisms without translational validity to sporadic AD patients, potentially leading to an erroneous conclusion of the underlying cause of NH occurring in patients with AD. In this review, we discuss the substantiation for NH in animal models of AD pathology and in human patients, as well as some of the hypotheses considering recently developed animal models that challenge existing hypotheses and mechanisms of NH. In addition, we provide a preclinical perspective on how the development of animal models incorporating AD-specific NH could provide physiologically relevant translational experimental data that may potentially aid the discovery and development of novel therapies for AD.

%B J Alzheimers Dis %V 88 %P 809-836 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34420957?dopt=Abstract %R 10.3233/JAD-210397 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Interaction Between Diet and Microbiota in the Pathophysiology of Alzheimer's Disease: Focus on Polyphenols and Dietary Fibers. %A Ticinesi, Andrea %A Mancabelli, Leonardo %A Carnevali, Luca %A Nouvenne, Antonio %A Meschi, Tiziana %A Del Rio, Daniele %A Ventura, Marco %A Sgoifo, Andrea %A Angelino, Donato %K Alzheimer Disease %K Animals %K Diet %K Diet, Mediterranean %K Dietary Fiber %K Humans %K Microbiota %K Polyphenols %X

Animal studies increasingly indicate that the gut microbiota composition and function can be involved in the pathophysiology and progression of Alzheimer's disease (AD) at multiple levels. However, few studies have investigated this putative gut-brain axis in human beings, and none of them considered diet as a determinant of intestinal microbiota composition. Epidemiological studies highlight that a high intake of fruit and vegetables, such as that typical of the Mediterranean diet, can modulate AD progression. Thus, nutritional interventions are being increasingly studied as a possible non-pharmacological strategy to slow down the progression of AD. In particular, polyphenols and fibers represent the nutritional compounds with the higher potential of counterbalancing the pathophysiological mechanisms of dementia due to their antioxidant, anti-inflammatory, and anti-apoptotic properties. These actions are mediated by the gut microbiota, that can transform polyphenols and fibers into biologically active compounds including, among others, phenyl-γ-valerolactones, urolithins, butyrate, and other short-chain fatty acids. In this review, the complex mechanisms linking nutrition, gut microbiota composition, and pathophysiology of cognitive decline in AD are discussed, with a particular focus on the role of polyphenols and fibers. The gaps between pre-clinical and clinical studies are particularly emphasized, as well as the urgent need for studies comprehensively evaluating the link between nutrition, microbiome, and clinical aspects of AD.

%B J Alzheimers Dis %V 86 %P 961-982 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35147544?dopt=Abstract %R 10.3233/JAD-215493 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Investigating Casual Associations Among Gut Microbiota, Metabolites, and Neurodegenerative Diseases: A Mendelian Randomization Study. %A Ning, Jing %A Huang, Shu-Yi %A Chen, Shi-Dong %A Zhang, Ya-Ru %A Huang, Yu-Yuan %A Yu, Jin-Tai %K Alzheimer Disease %K Amyotrophic Lateral Sclerosis %K Gastrointestinal Microbiome %K Genome-Wide Association Study %K Humans %K Mendelian Randomization Analysis %K Neurodegenerative Diseases %K Parkinson Disease %K Risk Factors %K Serotonin %X

BACKGROUND: Recent studies had explored that gut microbiota was associated with neurodegenerative diseases (including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)) through the gut-brain axis, among which metabolic pathways played an important role. However, the underlying causality remained unclear.

OBJECTIVE: Our study aimed to evaluate potential causal relationships between gut microbiota, metabolites, and neurodegenerative diseases through Mendelian randomization (MR) approach.

METHODS: We selected genetic variants associated with gut microbiota traits (N = 18,340) and gut microbiota-derived metabolites (N = 7,824) from genome-wide association studies. Summary statistics of neurodegenerative diseases were obtained from IGAP (AD, 17,008 cases; 37,154 controls), IPDGC (PD, 37,688 cases; 141,779 controls), and IALSC (ALS, 20,806 cases; 59,804 controls) respectively.

RESULTS: Greater abundance of Ruminococcus (OR, 1.245; 95% CI, 1.103-1.405; p = 0.0004) was found significantly related to higher risk of ALS. Besides, our study found suggestive associations of Actinobacteria, Lactobacillaceae, Faecalibacterium, Ruminiclostridium, and Lachnoclostridium with AD, of Lentisphaerae, Lentisphaeria, Oxalobacteraceae, Victivallales, Bacillales, Eubacteriumhalliigroup, Anaerostipes, and Clostridiumsensustricto1 with PD, and of Lachnospira, Fusicatenibacter, Catenibacterium, and Ruminococcusgnavusgroup with ALS. Our study also revealed suggestive associations between 12 gut microbiome-dependent metabolites and neurodegenerative diseases. Glutamine was related to lower risk of AD. For the serotonin pathway, serotonin was found as a protective factor of PD, while kynurenine as a risk factor for ALS.

CONCLUSION: Our study firstly applied a two-sample MR approach to detect causal relationships among gut microbiota, gut metabolites, and neurodegenerative diseases. Our findings may provide new targets for treatments and may offer valuable insights for further studies on the underlying mechanisms.

%B J Alzheimers Dis %V 87 %P 211-222 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35275534?dopt=Abstract %R 10.3233/JAD-215411 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Investigating Causal Relations Between Circulating Metabolites and Alzheimer's Disease: A Mendelian Randomization Study. %A Huang, Shu-Yi %A Yang, Yu-Xiang %A Zhang, Ya-Ru %A Kuo, Kevin %A Li, Hong-Qi %A Shen, Xue-Ning %A Chen, Shi-Dong %A Chen, Ke-Liang %A Dong, Qiang %A Tan, Lan %A Yu, Jin-Tai %K Alzheimer Disease %K Apolipoproteins B %K Cholesterol %K Genome-Wide Association Study %K Glutamine %K Humans %K Mendelian Randomization Analysis %K Polymorphism, Single Nucleotide %K Risk Factors %X

BACKGROUND: Metabolomics is a promising approach that can be used to understand pathophysiological pathways of Alzheimer's disease (AD). However, the causal relationships between metabolism and AD are poorly understood.

OBJECTIVE: We aimed to investigate the causal association between circulating metabolites and risk of AD through two-sample Mendelian randomization (MR) approach.

METHODS: Genetic associations with 123 circulating metabolic traits were utilized as exposures. Summary statistics data from International Genomics of Alzheimer's Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD, and 272,244 controls). We utilized inverse-variance weighted method as primary method.

RESULTS: We found significantly increased risks of developing AD per standard deviation increase in the levels of circulating ApoB (odd ratio[OR] = 3.18; 95% confidence interval[CI]: 1.52-6.66, p = 0.0022), glycoprotein acetyls (OR = 1.21; 95% CI: 1.05-1.39, p = 0.0093), total cholesterol (OR = 2.73; 95% CI: 1.41-5.30, p = 0.0030), and low-density lipoprotein (LDL) cholesterol (OR = 2.34; 95% CI: 1.53-3.57, p = 0.0001). Whereas glutamine (OR = 0.81; 95% CI: 0.71-0.92, p = 0.0011) were significantly associated with lower risk of AD. We also detected causal effects of several different composition of LDL fractions on increased AD risk, which has been verified in validation. However, we found no association between circulating high-density lipoprotein cholesterol and AD.

CONCLUSION: Our findings suggest causal effects of circulating glycoprotein acetyls, ApoB, LDL cholesterol, and serum total cholesterol on higher risk of AD, whereas glutamine showed the protective effect.

%B J Alzheimers Dis %V 87 %P 463-477 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35275550?dopt=Abstract %R 10.3233/JAD-220050 %0 Journal Article %J J Alzheimers Dis %D 2022 %T It's Groundhog Day! What Can the History of Science Say About the Crisis in Alzheimer's Disease Research? %A Jacobs, Noortje %A Theunissen, Bert %K Alzheimer Disease %K Amyloid %K Humans %X

For years now, Alzheimer's disease (AD) research has been stuck in a Groundhog-Day scenario: an endless time loop with no breakthrough in sight. Disagreement about the validity of the field's dominant approach, based on the Amyloid Cascade Hypothesis, has led to a seemingly unresolvable trench war between proponents and critics. Our paper evaluates the recent scientific literature on AD from a historical and philosophical perspective. We show that AD research is a classic example of the boundary work at play in a field in crisis: both parties deploy historical and philosophical references to illustrate what counts as good and bad science, as proper scientific method and appropriate scientific conduct. We also show that boundary work has proved unable to point a way out of the deadlock and argue that the science system's tools for establishing scientific quality, such as peer review and the grant system, are unlikely to resolve the crisis. Rather, they consolidate the dominant model's position even more. In conclusion, we suggest that some kind of reverse boundary-work is needed that reopens the discussion on the nature of AD, an issue that has never been settled scientifically. Drawing on historical and philosophical work, we make clear that the definition of AD as a biomedical disease for which a cure can be found has consequences, not only for funding opportunities, but also for patients and their lives. A reconsideration of the desirability of these consequences may lead to different choices with respect to research priorities and patient care.

%B J Alzheimers Dis %V 90 %P 1401-1415 %8 2022 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/36278350?dopt=Abstract %R 10.3233/JAD-220569 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Medial Temporal Atrophy in Posterior Cortical Atrophy and Its Relationship to the Cingulate Island Sign. %A Josephs, Kennedy A %A Pham, Nha Trang Thu %A Graff-Radford, Jonathan %A Machulda, Mary M %A Lowe, Val J %A Whitwell, Jennifer L %K Alzheimer Disease %K Atrophy %K Fluorodeoxyglucose F18 %K Humans %K Lewy Body Disease %K Magnetic Resonance Imaging %K Positron-Emission Tomography %X

BACKGROUND: It has been hypothesized that medial temporal sparing may be related to preserved posterior cingulate metabolism and the cingulate island sign (CIS) on [18F]fluorodeoxyglucose (FDG) PET in posterior cortical atrophy (PCA).

OBJECTIVE: To assess the severity of medial temporal atrophy in PCA and determine whether the presence of a CIS is related to medial temporal sparing.

METHODS: Fifty-five PCA patients underwent MRI and FDG-PET. The degree and symmetry of medial temporal atrophy on MRI was visually assessed using a five-point scale for both hemispheres. Visual assessments of FDG-PET coded the presence/absence of a CIS and whether the CIS was symmetric or asymmetric. Hippocampal volumes and a quantitative CIS were also measured.

RESULTS: Medial temporal atrophy was most commonly mild or moderate, was symmetric in 55% of patients, and when asymmetric was most commonly worse on the right (76%). Older age and worse memory performance were associated with greater medial temporal atrophy. The CIS was observed in 44% of the PCA patients and was asymmetric in 50% of these. The patients with a CIS showed greater medial temporal asymmetry, but did not show lower medial temporal atrophy scores, compared to those without a CIS. Hippocampal volumes were not associated with quantitative CIS.

CONCLUSION: Mild medial temporal atrophy is a common finding in PCA and is associated with memory impairment. However, medial temporal sparing was not related to the presence of a CIS in PCA.

%B J Alzheimers Dis %V 86 %P 491-498 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35068459?dopt=Abstract %R 10.3233/JAD-215263 %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 Peptidylarginine Deiminase and Alzheimer's Disease. %A Wang, Lai %A Chen, Hongyang %A Tang, Jing %A Guo, Zhengwei %A Wang, Yanming %K Alzheimer Disease %K Animals %K Cerebral Cortex %K Citrulline %K Hippocampus %K Humans %K Isoenzymes %K Protein Processing, Post-Translational %K Protein-Arginine Deiminases %X

Peptidylarginine deiminases (PADs) are indispensable enzymes for post-translational modification of proteins, which can convert Arg residues on the surface of proteins to citrulline residues. The PAD family has five isozymes, PAD1, 2, 3, 4, and 6, which have been found in multiple tissues and organs. PAD2 and PAD4 were detected in cerebral cortex and hippocampus from human and rodent brain. In the central nervous system, abnormal expression and activation of PADs are involved in the pathological changes and pathogenesis of Alzheimer's disease (AD). This article reviews the classification, distribution, and function of PADs, with an emphasis on the relationship between the abnormal activation of PADs and AD pathogenesis, diagnosis, and the therapeutic potential of PADs as drug targets for AD.

%B J Alzheimers Dis %V 85 %P 473-484 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34842193?dopt=Abstract %R 10.3233/JAD-215302 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Potential Mechanisms Underlying Resistance to Dementia in Non-Demented Individuals with Alzheimer's Disease Neuropathology. %A Kok, Frédérique K %A van Leerdam, Suzanne L %A de Lange, Elizabeth C M %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Hippocampus %K Humans %K Plaque, Amyloid %K Synapses %X

Alzheimer's disease (AD) is the most common form of dementia and typically characterized by the accumulation of amyloid-β plaques and tau tangles. Intriguingly, there also exists a group of elderly which do not develop dementia during their life, despite the AD neuropathology, the so-called non-demented individuals with AD neuropathology (NDAN). In this review, we provide extensive background on AD pathology and normal aging and discuss potential mechanisms that enable these NDAN individuals to remain cognitively intact. Studies presented in this review show that NDAN subjects are generally higher educated and have a larger cognitive reserve. Furthermore, enhanced neural hypertrophy could compensate for hippocampal and cingulate neural atrophy in NDAN individuals. On a cellular level, these individuals show increased levels of neural stem cells and 'von Economo neurons'. Furthermore, in NDAN brains, binding of Aβ oligomers to synapses is prevented, resulting in decreased glial activation and reduced neuroinflammation. Overall, the evidence stated here strengthens the idea that some individuals are more resistant to AD pathology, or at least show an elongation of the asymptomatic state of the disease compared to others. Insights into the mechanisms underlying this resistance could provide new insight in understanding normal aging and AD itself. Further research should focus on factors and mechanisms that govern the NDAN cognitive resilience in order to find clues on novel biomarkers, targets, and better treatments of AD.

%B J Alzheimers Dis %V 87 %P 51-81 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35275527?dopt=Abstract %R 10.3233/JAD-210607 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Prions and Neurodegenerative Diseases: A Focus on Alzheimer's Disease. %A Crestini, Alessio %A Santilli, Francesca %A Martellucci, Stefano %A Carbone, Elena %A Sorice, Maurizio %A Piscopo, Paola %A Mattei, Vincenzo %K alpha-Synuclein %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Humans %K Neurofibrillary Tangles %K Neurons %K Prion Proteins %K Protein Aggregation, Pathological %K Randomized Controlled Trials as Topic %K Receptor, Metabotropic Glutamate 5 %K tau Proteins %X

Specific protein misfolding and aggregation are mechanisms underlying various neurodegenerative diseases such as prion disease and Alzheimer's disease (AD). The misfolded proteins are involved in prions, amyloid-β (Aβ), tau, and α-synuclein disorders; they share common structural, biological, and biochemical characteristics, as well as similar mechanisms of aggregation and self-propagation. Pathological features of AD include the appearance of plaques consisting of deposition of protein Aβ and neurofibrillary tangles formed by the hyperphosphorylated tau protein. Although it is not clear how protein aggregation leads to AD, we are learning that the cellular prion protein (PrPC) plays an important role in the pathogenesis of AD. Herein, we first examined the pathogenesis of prion and AD with a focus on the contribution of PrPC to the development of AD. We analyzed the mechanisms that lead to the formation of a high affinity bond between Aβ oligomers (AβOs) and PrPC. Also, we studied the role of PrPC as an AβO receptor that initiates an AβO-induced signal cascade involving mGluR5, Fyn, Pyk2, and eEF2K linking Aβ and tau pathologies, resulting in the death of neurons in the central nervous system. Finally, we have described how the PrPC-AβOs interaction can be used as a new potential therapeutic target for the treatment of PrPC-dependent AD.

%B J Alzheimers Dis %V 85 %P 503-518 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34864675?dopt=Abstract %R 10.3233/JAD-215171 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Relationship Between the Gut Microbiota and Alzheimer's Disease: A Systematic Review. %A González Cordero, Elisa Marina %A Cuevas-Budhart, Miguel Angel %A Pérez Morán, Diana %A Trejo Villeda, Miguel Angel %A Gomez-Del-Pulgar Gª-Madrid, Mercedes %K Alzheimer Disease %K Brain %K Brain-Gut Axis %K Cognitive Dysfunction %K Gastrointestinal Microbiome %K Humans %X

BACKGROUND: In recent years, scientific research on the gut microbiota and their relationship with some diseases, including neurological ones, has notably increased. As a result of these investigations, the so-called gut-brain axis arises. Despite its influence on the evolution and development of cognitive impairment, the gut-brain axis is little defined and demonstrated.

OBJECTIVE: To provide the best scientific evidence available on the relationship between the gut microbiota and Alzheimer's disease.

METHOD: Systematic and narrative review of the information generated in the last 5 years in national and international databases, in English and Spanish.

RESULTS: Eight observational studies were selected, carried out in humans and, therefore, suitable for inclusion in this review.

CONCLUSION: The results of these studies support the hypothesis that there is a relationship between the gut microbiota and cognitive disorders through the gut-brain axis. However, today, there is a substantial lack of human studies, especially clinical trials, which makes it difficult to formulate clinical recommendations on this topic.

%B J Alzheimers Dis %V 87 %P 519-528 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/35367961?dopt=Abstract %R 10.3233/JAD-215224 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Rheumatoid Arthritis, Cognitive Impairment, and Neuroimaging Biomarkers: Results from the Mayo Clinic Study of Aging. %A Vassilaki, Maria %A Crowson, Cynthia S %A Davis Iii, John M %A Duong, Stephanie Q %A Jones, David T %A Nguyen, Aivi %A Mielke, Michelle M %A Vemuri, Prashanthi %A Myasoedova, Elena %K Aged %K Aging %K Alzheimer Disease %K Amyloid %K Amyloid beta-Peptides %K Amyloidosis %K Arthritis, Rheumatoid %K Biomarkers %K Brain %K Cognitive Dysfunction %K Female %K Fluorodeoxyglucose F18 %K Humans %K Magnetic Resonance Imaging %K Male %K Neuroimaging %K Positron-Emission Tomography %X

BACKGROUND: Observational studies suggested that dementia risk in patients with rheumatoid arthritis (RA) is higher than in the general population.

OBJECTIVE: To examine the associations of RA with cognitive decline and dementia, and neuroimaging biomarkers of aging, Alzheimer's disease, and vascular pathology in adult participants in the Mayo Clinic Study of Aging (MCSA).

METHODS: Participants with RA were matched 1:3 on age, sex, education, and baseline cognitive diagnosis to participants without RA. RA cases with MRI were also matched with non-cases with available MRI. All available imaging studies (i.e., amyloid and FDG PET, sMRI, and FLAIR) were included. The study included 104 participants with RA and 312 without RA (mean age (standard deviation, SD) 75.0 (10.4) years, 33% male and average follow-up (SD) 4.2 (3.8) years).

RESULTS: Groups were similar in cognitive decline and risk of incident dementia. Among participants with neuroimaging, participants with RA (n = 33) and without RA (n = 98) had similar amyloid burden and neurodegeneration measures, including regions sensitive to aging and dementia, but greater mean white matter hyperintensity volume relative to the total intracranial volume (mean (SD)% : 1.12 (0.57)% versus 0.76 (0.69)% of TIV, p = 0.01), and had higher mean (SD) number of cortical infarctions (0.24 (0.44) versus 0.05 (0.33), p = 0.02).

CONCLUSION: Although cognitive decline and dementia risk were similar in participants with and without RA, participants with RA had more abnormal cerebrovascular pathology on neuroimaging. Future studies should examine the mechanisms underlying these changes and potential implications for prognostication and prevention of cognitive decline in RA.

%B J Alzheimers Dis %V 89 %P 943-954 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35964191?dopt=Abstract %R 10.3233/JAD-220368 %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 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 Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Positive Modulator of HGF/MET, Fosgonimeton, in Healthy Volunteers and Subjects with Alzheimer's Disease: Randomized, Placebo-Controlled, Double-Blind, Phase I Clinical Trial. %A Hua, Xue %A Church, Kevin %A Walker, William %A L'Hostis, Philippe %A Viardot, Geoffrey %A Danjou, Philippe %A Hendrix, Suzanne %A Moebius, Hans J %K Aged %K Alzheimer Disease %K Area Under Curve %K Dose-Response Relationship, Drug %K Double-Blind Method %K Healthy Volunteers %K Hepatocyte Growth Factor %K Humans %K Male %X

BACKGROUND: Fosgonimeton (ATH-1017) is being developed as a first-in-class regenerative therapy for people with Alzheimer's disease (AD) and dementia; potentially improving dementia symptoms and altering disease progression by reversing synaptic disconnection and neuronal loss.

OBJECTIVE: This randomized, double-blind, placebo-controlled phase I trial (NCT03298672) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of fosgonimeton.

METHODS: Fosgonimeton was administered once daily via subcutaneous injection to 88 subjects. The single ascending dose study enrolled healthy young male subjects (n = 48; age, 33.4±6.3 years; dose, 2, 6, 20, 40, 60, or 90 mg); the multiple ascending dose study enrolled healthy elderly subjects (n = 29; age, 63.8±4.0 years; dose, 20, 40, 60, or 80 mg; 9-day duration); and the fixed-dose study enrolled AD subjects (n = 11; age, 69.2±7.1 years; dose, 40 mg; 9-day duration). Quantitative electroencephalogram (qEEG) and event-related potential (ERP) P300 measured neurophysiological signals following fosgonimeton treatment, supporting brain penetration and target engagement.

RESULTS: Fosgonimeton and placebo were shown to be safe and well-tolerated across all doses. Pharmacokinetic results for fosgonimeton were dose-proportional, with no sex effect or accumulation over 9 days. The main effect of fosgonimeton on qEEG was acute and sustained gamma power induction. In AD subjects, there was a significant effect toward ERP P300 latency normalization compared with placebo (p = 0.027; n = 7 at 40 mg fosgonimeton versus n = 4 placebo).

CONCLUSION: These results support the continued development of fosgonimeton as a novel therapeutic for people with AD and dementia. The fast-onset normalization of ERP P300 latency in AD subjects suggests enhancement of synaptic function and potential procognitive effects.

%B J Alzheimers Dis %V 86 %P 1399-1413 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35180125?dopt=Abstract %R 10.3233/JAD-215511 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Sex Differences in Behavior and Molecular Pathology in the 5XFAD Model. %A Sil, Annesha %A Erfani, Arina %A Lamb, Nicola %A Copland, Rachel %A Riedel, Gernot %A Platt, Bettina %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Disease Models, Animal %K Female %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mutation %K Pathology, Molecular %K Presenilin-1 %K Sex Characteristics %X

BACKGROUND: The prevalence of Alzheimer's disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD.

OBJECTIVE: Here, we studied behavior and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, versus their wild-type littermate controls, to compare both sex- and genotype-dependent differences.

METHODS: A novel behavioral paradigm was utilized (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration (NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and western blotting.

RESULTS: Female 5XFAD mice had higher levels of human APP and amyloid-β and heightened inflammation versus males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with subtle deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with cognitive performance.

CONCLUSION: The impact of sex on AD-relevant phenotypes is in line with human data and emphasizes the necessity of appropriate study design and reporting. Differential molecular profiles observed in male versus female mice offer insights into possible protective mechanisms, and hence treatment strategies.

%B J Alzheimers Dis %V 85 %P 755-778 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34864660?dopt=Abstract %R 10.3233/JAD-210523 %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 A Tale of Two Diseases: Exploring Mechanisms Linking Diabetes Mellitus with Alzheimer's Disease. %A Lynn, Jessica %A Park, Mingi %A Ogunwale, Christiana %A Acquaah-Mensah, George K %K Alzheimer Disease %K Animals %K Biomarkers %K Brain Chemistry %K Cognitive Dysfunction %K Diabetes Mellitus, Type 2 %K Glucose %K Glycation End Products, Advanced %K Humans %K Inflammation %K Insulin Resistance %K Oxidative Stress %K Randomized Controlled Trials as Topic %X

Dementias, including the type associated with Alzheimer's disease (AD), are on the rise worldwide. Similarly, type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic diseases globally. Although mechanisms and treatments are well-established for T2DM, there remains much to be discovered. Recent research efforts have further investigated factors involved in the etiology of AD. Previously perceived to be unrelated diseases, commonalities between T2DM and AD have more recently been observed. As a result, AD has been labeled as "type 3 diabetes". In this review, we detail the shared processes that contribute to these two diseases. Insulin resistance, the main component of the pathogenesis of T2DM, is also present in AD, causing impaired brain glucose metabolism, neurodegeneration, and cognitive impairment. Dysregulation of insulin receptors and components of the insulin signaling pathway, including protein kinase B, glycogen synthase kinase 3β, and mammalian target of rapamycin are reported in both diseases. T2DM and AD also show evidence of inflammation, oxidative stress, mitochondrial dysfunction, advanced glycation end products, and amyloid deposition. The impact that changes in neurovascular structure and genetics have on the development of these conditions is also being examined. With the discovery of factors contributing to AD, innovative treatment approaches are being explored. Investigators are evaluating the efficacy of various T2DM medications for possible use in AD, including but not limited to glucagon-like peptide-1 receptor agonists and peroxisome proliferator-activated receptor-gamma agonists. Furthermore, there are 136 active trials involving 121 therapeutic agents targeting novel AD biomarkers. With these efforts, we are one step closer to alleviating the ravaging impact of AD on our communities.

%B J Alzheimers Dis %V 85 %P 485-501 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34842187?dopt=Abstract %R 10.3233/JAD-210612 %0 Journal Article %J J Alzheimers Dis %D 2022 %T α-Lipoic Acid Has the Potential to Normalize Copper Metabolism, Which Is Dysregulated in Alzheimer's Disease. %A Metsla, Kristel %A Kirss, Sigrid %A Laks, Katrina %A Sildnik, Gertrud %A Palgi, Mari %A Palumaa, Teele %A Tõugu, Vello %A Palumaa, Peep %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Aspartic Acid Endopeptidases %K Brain %K Cell Line %K Copper %K Disease Models, Animal %K Drosophila melanogaster %K Humans %K Neurons %K Thioctic Acid %X

BACKGROUND: Alzheimer's disease (AD) is an age-dependent progressive neurodegenerative disorder and the most common cause of dementia. The treatment and prevention of AD present immense yet unmet needs. One of the hallmarks of AD is the formation of extracellular amyloid plaques in the brain, composed of amyloid-β (Aβ) peptides. Besides major amyloid-targeting approach there is the necessity to focus also on alternative therapeutic strategies. One factor contributing to the development of AD is dysregulated copper metabolism, reflected in the intracellular copper deficit and excess of extracellular copper.

OBJECTIVE: In the current study, we follow the widely accepted hypothesis that the normalization of copper metabolism leads to the prevention or slowing of the disease and search for new copper-regulating ligands.

METHODS: We used cell culture, ICP MS, and Drosophila melanogaster models of AD.

RESULTS: We demonstrate that the natural intracellular copper chelator, α-lipoic acid (LA) translocates copper from extracellular to intracellular space in an SH-SY5Y-based neuronal cell model and is thus suitable to alleviate the intracellular copper deficit characteristic of AD neurons. Furthermore, we show that supplementation with LA protects the Drosophila melanogaster models of AD from developing AD phenotype by improving locomotor activity of fruit fly with overexpression of human Aβ with Iowa mutation in the fly brain. In addition, LA slightly weakens copper-induced smooth eye phenotype when amyloid-β protein precursor (AβPP) and beta-site AβPP cleaving enzyme 1 (BACE1) are overexpressed in eye photoreceptor cells.

CONCLUSION: Collectively, these results provide evidence that LA has the potential to normalize copper metabolism in AD.

%B J Alzheimers Dis %V 85 %P 715-728 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34864665?dopt=Abstract %R 10.3233/JAD-215026 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Alzheimer's Disease and Face Masks in Times of COVID-19. %A Gil, Roger %A Arroyo-Anlló, Eva M %K Alzheimer Disease %K Communicable Disease Control %K COVID-19 %K Emotions %K Facial Expression %K Humans %K Masks %X

Generalized lockdown caused by COVID-19, necessary yesterday, can no longer be that of tomorrow. It will no longer be possible to cram the humblest into cramped areas, but priority must be given to prevention (certainly with physical barriers, hydro-alcoholic gel, face masks), biological diagnosis, isolation, and also the care of any infected person. COVID-19 has hit the most vulnerable first in terms of biological inequality, such as Alzheimer's disease (AD) patients. Those with AD can have sensorial deficits and perception troubles, including visual difficulties and the inability to recognize faces and emotions. Face masks and physical distancing can disrupt facial familiarity and make it more difficult to recognize emotional facial expressions. It can provoke distress, which the visitor can perceive and feel obligated to take off the face mask. This gesture should not be considered as an act of indiscipline, but an act of empathy. Transparent face masks could improve the suffering of AD patients, distraught in the presence of their loved ones whose masks hide their faces. Wearing a mask should not be due to fear of punishment, but as an understanding of the responsibility of each individual in the control of the current pandemic. It may be necessary to convince more citizens of this civic duty, using clear and attractive messaging in order to standardize the wearing of face masks for the general public and to adapt them to the needs of patients.

%B J Alzheimers Dis %V 79 %P 9-14 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33252083?dopt=Abstract %R 10.3233/JAD-201233 %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 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 Bile Acids as Key Modulators of the Brain-Gut-Microbiota Axis in Alzheimer's Disease. %A Mulak, Agata %K Alzheimer Disease %K Bile Acids and Salts %K Brain-Gut Axis %K Humans %K Neuroprotection %K Signal Transduction %X

Recently, the concept of the brain-gut-microbiota (BGM) axis disturbances in the pathogenesis of Alzheimer's disease (AD) has been receiving growing attention. At the same time, accumulating data revealing complex interplay between bile acids (BAs), gut microbiota, and host metabolism have shed new light on a potential impact of BAs on the BGM axis. The crosstalk between BAs and gut microbiota is based on reciprocal interactions since microbiota determines BA metabolism, while BAs affect gut microbiota composition. Secondary BAs as microbe-derived neuroactive molecules may affect each of three main routes through which interactions within the BGM axis occur including neural, immune, and neuroendocrine pathways. BAs participate in the regulation of multiple gut-derived molecule release since their receptors are expressed on various cells. The presence of BAs and their receptors in the brain implies a direct effect of BAs on the regulation of neurological functions. Experimental and clinical data confirm that disturbances in BA signaling are present in the course of AD. Disturbed ratio of primary to secondary BAs as well as alterations in BA concertation in serum and brain samples have been reported. An age-related shift in the gut microbiota composition associated with its decreased diversity and stability observed in AD patients may significantly affect BA metabolism and signaling. Given recent evidence on BA neuroprotective and anti-inflammatory effects, new therapeutic targets have been explored including gut microbiota modulation by probiotics and dietary interventions, ursodeoxycholic acid supplementation, and use of BA receptor agonists.

%B J Alzheimers Dis %V 84 %P 461-477 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34569953?dopt=Abstract %R 10.3233/JAD-210608 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Blood-Based ATN Biomarkers of Alzheimer's Disease: A Meta-Analysis. %A Koychev, Ivan %A Jansen, Katrin %A Dette, Alina %A Shi, Liu %A Holling, Heinz %K Alzheimer Disease %K Amyloid beta-Peptides %K Humans %K Neurodegenerative Diseases %K Neurofibrillary Tangles %K Neurofilament Proteins %K Peptide Fragments %K Phosphorylation %K Plaque, Amyloid %K tau Proteins %X

BACKGROUND: The Amyloid Tau Neurodegeneration (ATN) framework was proposed to define the biological state underpinning Alzheimer's disease (AD). Blood-based biomarkers offer a scalable alternative to the costly and invasive currently available biomarkers.

OBJECTIVE: In this meta-analysis we sought to assess the diagnostic performance of plasma amyloid (Aβ40, Aβ42, Aβ42/40 ratio), tangle (p-tau181), and neurodegeneration (total tau [t-tau], neurofilament light [NfL]) biomarkers.

METHODS: Electronic databases were screened for studies reporting biomarker concentrations for AD and control cohorts. Biomarker performance was examined by random-effect meta-analyses based on the ratio between biomarker concentrations in patients and controls.

RESULTS: 83 studies published between 1996 and 2020 were included in the analyses. Aβ42/40 ratio as well as Aβ42 discriminated AD patients from controls when using novel platforms such as immunomagnetic reduction (IMR). We found significant differences in ptau-181 concentration for studies based on single molecule array (Simoa), but not for studies based on IMR or ELISA. T-tau was significantly different between AD patients and control in IMR and Simoa but not in ELISA-based studies. In contrast, NfL differentiated between groups across platforms. Exosome studies showed strong separation between patients and controls for Aβ42, t-tau, and p-tau181.

CONCLUSION: Currently available assays for sampling plasma ATN biomarkers appear to differentiate between AD patients and controls. Novel assay methodologies have given the field a significant boost for testing these biomarkers, such as IMR for Aβ, Simoa for p-tau181. Enriching samples through extracellular vesicles shows promise but requires further validation.

%B J Alzheimers Dis %V 79 %P 177-195 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33252080?dopt=Abstract %R 10.3233/JAD-200900 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Broader Insights into Understanding Tumor Necrosis Factor and Neurodegenerative Disease Pathogenesis Infer New Therapeutic Approaches. %A Clark, I A %A Vissel, B %K Alzheimer Disease %K Anti-Inflammatory Agents, Non-Steroidal %K Brain %K Brain Injuries %K COVID-19 %K Disease Progression %K Etanercept %K Heart Arrest %K Humans %K Locus Coeruleus %K Neurodegenerative Diseases %K Norepinephrine %K Parkinson Disease %K Risk Factors %K SARS-CoV-2 %K Stroke %K Survivors %K Tumor Necrosis Factor-alpha %X

Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post-traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer's disease and Parkinson's disease sufferers. In contrast, Alzheimer's disease and Parkinson's disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this.

%B J Alzheimers Dis %V 79 %P 931-948 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33459706?dopt=Abstract %R 10.3233/JAD-201186 %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 Clinical Approach of Low-Dose Whole-Brain Ionizing Radiation Treatment in Alzheimer's Disease Dementia Patients. %A Chung, Mijoo %A Rhee, Hak Young %A Chung, Weon Kuu %K Alzheimer Disease %K Animals %K Brain %K Cranial Irradiation %K Humans %X

Our research team recently published two relevant papers. In one study, we have seen the acute effect of low-dose ionizing irradiation (LDIR) did not reduce the amyloid-β (Aβ) protein concentration in brain tissue, yet significantly improved synaptic degeneration and neuronal loss in the hippocampus and cerebral cortex. Surprisingly, in another study, we could see late effect that the LDIR-treated mice showed significantly improved learning and memory skills compared with those in the sham group. In addition, Aβ concentrations were significantly decreased in brain tissue. Furthermore, the pro-inflammatory cytokine tumor necrosis factor-α was decreased and the anti-inflammatory cytokine transforming growth factor-β was increased in the brain tissue of 5xFAD mice treated with LDIR. Definitive clinical results for the safety and efficacy of LDIR have not yet been published and, despite the promising outcomes reported during preclinical studies, LDIR can only be applied to patients with Alzheimer's disease dementia when clinical results are made available. In addition, in the case of LDIR, additional large-scale clinical studies are necessary to determine the severity of Alzheimer's disease dementia, indications for LDIR, the total dose to be irradiated, fraction size, and intervals of LDIR treatment. The purpose of this review is to summarize the mechanism of LDIR based on existing preclinical results in a way that is useful for conducting subsequent clinical research.

%B J Alzheimers Dis %V 80 %P 941-947 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33612549?dopt=Abstract %R 10.3233/JAD-210042 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cognition at Each Stage of Lewy Body Disease with Co-occurring Alzheimer's Disease Pathology. %A Ryman, Sephira G %A Yutsis, Maya %A Tian, Lu %A Henderson, Victor W %A Montine, Thomas J %A Salmon, David P %A Galasko, Douglas %A Poston, Kathleen L %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Cognitive Dysfunction %K Female %K Humans %K Lewy Body Disease %K Male %X

BACKGROUND: Alzheimer's disease neuropathologic change (ADNC) may contribute to dementia in patients with Lewy body disease (LBD) pathology.

OBJECTIVE: To examine how co-occurring ADNC impacts domain specific cognitive impairments at each pathologic stage (brainstem, limbic, cerebral cortical) of LBD.

METHODS: 2,433 participants with antemortem longitudinal neuropsychological assessment and postmortem neuropathological assessment from the National Alzheimer's Coordinating Center's Uniform Data Set were characterized based on the evaluation of ADNC and LBD. Longitudinal mixed-models were used to derive measures of cumulative cognitive deficit for each cognitive domain at each pathologic stage of LBD (brainstem, limbic, and cerebral cortical).

RESULTS: 111 participants with a pathologic diagnosis of LBD, 741 participants with combined LBD and ADNC, 1,357 participants with ADNC only, and 224 with no pathology (healthy controls) were included in the analyses. In the executive/visuospatial domain, combined LBD and ADNC showed worse deficits than LBD only when Lewy bodies were confined to the brainstem, but no difference when Lewy bodies extended to the limbic or cerebral cortical regions. The cerebral cortical LBD only group exhibited greater executive/visuospatial deficits than the ADNC only group. By contrast, the ADNC only group and the combined pathology group both demonstrated significantly greater cumulative memory deficits relative to Lewy body disease only, regardless of stage.

CONCLUSION: The impact of co-occurring ADNC on antemortem cumulative cognitive deficits varies not only by domain but also on the pathological stage of Lewy bodies. Our findings stress the cognitive impact of different patterns of neuropathological progression in Lewy body diseases.

%B J Alzheimers Dis %V 80 %P 1243-1256 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646154?dopt=Abstract %R 10.3233/JAD-201187 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Combining Multimodal Behavioral Data of Gait, Speech, and Drawing for Classification of Alzheimer's Disease and Mild Cognitive Impairment. %A Yamada, Yasunori %A Shinkawa, Kaoru %A Kobayashi, Masatomo %A Caggiano, Vittorio %A Nemoto, Miyuki %A Nemoto, Kiyotaka %A Arai, Tetsuaki %K Aged %K Alzheimer Disease %K Cognitive Dysfunction %K Female %K Gait %K Humans %K Male %K Neuropsychological Tests %K Speech %X

BACKGROUND: Gait, speech, and drawing behaviors have been shown to be sensitive to the diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, previous studies focused on only analyzing individual behavioral modalities, although these studies suggested that each of these modalities may capture different profiles of cognitive impairments associated with AD.

OBJECTIVE: We aimed to investigate if combining behavioral data of gait, speech, and drawing can improve classification performance compared with the use of individual modality and if each of these behavioral data can be associated with different cognitive and clinical measures for the diagnosis of AD and MCI.

METHODS: Behavioral data of gait, speech, and drawing were acquired from 118 AD, MCI, and cognitively normal (CN) participants.

RESULTS: Combining all three behavioral modalities achieved 93.0% accuracy for classifying AD, MCI, and CN, and only 81.9% when using the best individual behavioral modality. Each of these behavioral modalities was statistically significantly associated with different cognitive and clinical measures for diagnosing AD and MCI.

CONCLUSION: Our findings indicate that these behaviors provide different and complementary information about cognitive impairments such that classification of AD and MCI is superior to using either in isolation.

%B J Alzheimers Dis %V 84 %P 315-327 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34542076?dopt=Abstract %R 10.3233/JAD-210684 %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 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 Current Status and Challenges of Stem Cell Treatment for Alzheimer's Disease. %A Pacheco-Herrero, Mar %A Soto-Rojas, Luis O %A Reyes-Sabater, Heidy %A Garcés-Ramirez, Linda %A de la Cruz López, Fidel %A Villanueva-Fierro, Ignacio %A Luna-Muñoz, José %K Alzheimer Disease %K Amyloid %K Government Regulation %K Hippocampus %K Humans %K Neocortex %K Neurofibrillary Tangles %K Plaque, Amyloid %K Stem Cells %K tau Proteins %X

Neurodegenerative diseases called tauopathies, such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, and Parkinson's disease, among others, are characterized by the pathological processing and accumulation of tau protein. AD is the most prevalent neurodegenerative disease and is characterized by two lesions: neurofibrillary tangles (NFTs) and neuritic plaques. The presence of NFTs in the hippocampus and neocortex in early and advanced stages, respectively, correlates with the patient's cognitive deterioration. So far, no drugs can prevent, decrease, or limit neuronal death due to abnormal pathological tau accumulation. Among potential non-pharmacological treatments, physical exercise has been shown to stimulate the development of stem cells (SCs) and may be useful in early stages. However, this does not prevent neuronal death from the massive accumulation of NFTs. In recent years, SCs therapies have emerged as a promising tool to repopulate areas involved in cognition in neurodegenerative diseases. Unfortunately, protocols for SCs therapy are still being developed and the mechanism of action of such therapy remains unclear. In this review, we show the advances and limitations of SCs therapy. Finally, we provide a critical analysis of its clinical use for AD.

%B J Alzheimers Dis %V 84 %P 917-935 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34633316?dopt=Abstract %R 10.3233/JAD-200863 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Dementia and COVID-19, a Bidirectional Liaison: Risk Factors, Biomarkers, and Optimal Health Care. %A Toniolo, Sofia %A Scarioni, Marta %A Di Lorenzo, Francesco %A Hort, Jakub %A Georges, Jean %A Tomic, Svetlana %A Nobili, Flavio %A Frederiksen, Kristian Steen %K Alzheimer Disease %K Biomarkers %K Brain %K Cognitive Dysfunction %K Comorbidity %K COVID-19 %K Humans %K Neuroimaging %K Neuroimmunomodulation %K Patient Care %K SARS-CoV-2 %X

Cognitive impairment following SARS-CoV-2 infection is being increasingly recognized as an acute and possibly also long-term sequela of the disease. Direct viral entry as well as systemic mechanisms such as cytokine storm are thought to contribute to neuroinflammation in these patients. Biomarkers of COVID-19-induced cognitive impairment are currently lacking, but there is some limited evidence that SARS-CoV-2 could preferentially target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18F-FDG-PET. Possible confounders include cognitive impairment due to hypoxia and mechanical ventilation and post-traumatic stress disorder. Conversely, patients already suffering from dementia, as well as their caregivers, have been greatly impacted by the disruption of their care caused by COVID-19. Patients with dementia have experienced worsening of cognitive, behavioral, and psychological symptoms, and the rate of COVID-19-related deaths is disproportionately high among cognitively impaired people. Multiple factors, such as difficulties in remembering and executing safeguarding procedures, age, comorbidities, residing in care homes, and poorer access to hospital standard of care play a role in the increased morbidity and mortality. Non-pharmacological interventions and new technologies have shown a potential for the management of patients with dementia, and for the support of their caregivers.

%B J Alzheimers Dis %V 82 %P 883-898 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34092646?dopt=Abstract %R 10.3233/JAD-210335 %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 Economic Burden of Alzheimer's Disease Dementia in Japan. %A Ikeda, Shunya %A Mimura, Masaru %A Ikeda, Manabu %A Wada-Isoe, Kenji %A Azuma, Mie %A Inoue, Sachie %A Tomita, Kiyoyuki %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Caregivers %K Female %K Health Care Costs %K Humans %K Japan %K Long-Term Care %K Male %X

BACKGROUND: Alzheimer's disease dementia (ADD) is the leading cause of long-term care in Japan.

OBJECTIVE: This study estimates the annual healthcare and long-term care costs in fiscal year 2018 for adults over 65 years of age with ADD in Japan and the informal care costs and productivity loss for their families.

METHODS: Healthcare and long-term care costs for ADD were estimated according to the disease severity classified by the clinical dementia rating (CDR) score, using reports from a literature review. For the costs of time spent on caregiving activities, productivity loss for ADD family caregivers aged 20-69 and informal care costs for all ADD family caregivers were estimated.

RESULTS: The total healthcare cost of ADD was JPY 1,073 billion, of which 86% (JPY 923 billion) was attributed to healthcare costs other than ADD drug costs (JPY 151 billion). The healthcare costs other than ADD drug costs by severity were less than JPY 200 billion for CDR 0.5, CDR 1, and CDR 2, respectively, but increased to JPY 447 billion (48%) for CDR 3. The public long-term care costs were estimated to be JPY 4,783 billion, which increased according to the severity. Total productivity loss for ADD family caregivers aged 20-69 was JPY 1,547 billion and the informal care cost for all ADD family caregivers was JPY 6,772 billion.

CONCLUSION: ADD costs have a significant impact on public-funded healthcare, long-term care systems, and families in Japan. To minimize the economic burden of ADD, prolonging healthy life expectancy is the key factor to address.

%B J Alzheimers Dis %V 81 %P 309-319 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33780371?dopt=Abstract %R 10.3233/JAD-210075 %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 Egocentric and Allocentric Spatial Memory in Mild Cognitive Impairment with Real-World and Virtual Navigation Tasks: A Systematic Review. %A Tuena, Cosimo %A Mancuso, Valentina %A Stramba-Badiale, Chiara %A Pedroli, Elisa %A Stramba-Badiale, Marco %A Riva, Giuseppe %A Repetto, Claudia %K Alzheimer Disease %K Cognitive Dysfunction %K Humans %K Spatial Memory %K Spatial Navigation %X

BACKGROUND: Spatial navigation is the ability to estimate one's position on the basis of environmental and self-motion cues. Spatial memory is the cognitive substrate underlying navigation and relies on two different reference frames: egocentric and allocentric. These spatial frames are prone to decline with aging and impairment is even more pronounced in Alzheimer's disease (AD) or in mild cognitive impairment (MCI).

OBJECTIVE: To conduct a systematic review of experimental studies investigating which MCI population and tasks are used to evaluate spatial memory and how allocentric and egocentric deficits are impaired in MCI after navigation.

METHODS: PRISMA and PICO guidelines were applied to carry out the systematic search. Down and Black checklist was used to assess methodological quality.

RESULTS: Our results showed that amnestic MCI and AD pathology are the most investigated typologies; both egocentric and allocentric memory are impaired in MCI individuals, and MCI due to AD biomarkers has specific encoding and retrieval impairments; secondly, spatial navigation is principally investigated with the hidden goal task (virtual and real-world version), and among studies involving virtual reality, the privileged setting consists of non-immersive technology; thirdly, despite subtle differences, real-world and virtual versions showed good overlap for the assessment of MCI spatial memory.

CONCLUSION: Considering that MCI is a subclinical entity with potential risk for conversion to dementia, investigating spatial memory deficits with navigation tasks might be crucial to make accurate diagnosis and rehabilitation.

%B J Alzheimers Dis %V 79 %P 95-116 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33216034?dopt=Abstract %R 10.3233/JAD-201017 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Elevated Norepinephrine Metabolism Gauges Alzheimer's Disease-Related Pathology and Memory Decline. %A Riphagen, Joost M %A van Egroo, Maxime %A Jacobs, Heidi I L %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognitive Dysfunction %K Cohort Studies %K Disease Progression %K Female %K Humans %K Learning %K Locus Coeruleus %K Male %K Memory Disorders %K Methoxyhydroxyphenylglycol %K Middle Aged %K Neuropsychological Tests %K Norepinephrine %K Predictive Value of Tests %K tau Proteins %X

The noradrenergic (NE) locus coeruleus (LC) is vulnerable to hyperphosphorylated tau, and dysregulated NE-metabolism is linked to greater tau and disease progression. We investigated whether elevated NE-metabolism alone predicts memory decline or whether concomitant presence of tau and amyloid-β is required. Among 114 memory clinic participants, time trends (max. six years) showed dose-response declines in learning across groups with elevated NE-metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) with no, one, or two Alzheimer's disease biomarkers; and no decline in the low MHPG group. Elevated MHPG is required and sufficient to detect learning declines, supporting a pathophysiologic model including the LC-NE system contributing to initial Alzheimer's disease-related processes.

%B J Alzheimers Dis %V 80 %P 521-526 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554915?dopt=Abstract %R 10.3233/JAD-201411 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Gut Microbiome Features of Chinese Patients Newly Diagnosed with Alzheimer's Disease or Mild Cognitive Impairment. %A Guo, Mingyan %A Peng, Jun %A Huang, Xiaoyan %A Xiao, Lingjun %A Huang, Fenyan %A Zuo, Zhiyi %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Asians %K Biodiversity %K China %K Cognition %K Cognitive Dysfunction %K Disease Progression %K Feces %K Female %K Gastrointestinal Microbiome %K Humans %K Male %K Middle Aged %K RNA, Ribosomal, 16S %X

BACKGROUND: Patients with Alzheimer's disease (AD) have gut microbiome alterations compared with healthy controls. However, previous studies often assess AD patients who have been on medications or other interventions for the disease. Also, simultaneous determination of gut microbiome in patients with mild cognitive impairment (MCI) or AD in a study is rare.

OBJECTIVE: To determine whether there was a gut microbiome alteration in patients newly diagnosed with AD or MCI and whether the degree of gut microbiome alteration was more severe in patients with AD than patients with MCI.

METHODS: Fecal samples of 18 patients with AD, 20 patients with MCI, and 18 age-matched healthy controls were collected in the morning for 16S ribosomal RNA sequencing. No patient had medications or interventions for AD or MCI before the samples were collected.

RESULTS: Although there was no difference in the microbial α-diversity among the three groups, patients with AD or MCI had increased β-diversity compared with healthy controls. Patients with AD had decreased Bacteroides, Lachnospira, and Ruminiclostridium_9 and increased Prevotella at the genus level compared with healthy controls. The changing direction of these genera in patients with MCI was the same as patients with AD. However, Lachnospira was the only genus whose abundance in patients with MCI was statistically significantly lower than healthy controls. Bacteroides, Lachnospira, and Ruminiclostridium_9 were positively associated with better cognitive functions whereas Prevotella was on the contrary when subjects of all three groups were considered. The negative correlation of Prevotella with cognitive functions remained among patients with MCI.

CONCLUSION: Patients newly diagnosed with AD or MCI have gut dysbiosis that includes the decrease of potentially protective microbiome, such as Bacteroides, and the increase of microbiome that can promote inflammation, such as Prevotella. Our results support a novel idea that the degree of gut dysbiosis is worsened with the disease stage from MCI to AD.

%B J Alzheimers Dis %V 80 %P 299-310 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33523001?dopt=Abstract %R 10.3233/JAD-201040 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Gut Microbiota Alterations and Cognitive Impairment Are Sexually Dissociated in a Transgenic Mice Model of Alzheimer's Disease. %A Cuervo-Zanatta, Daniel %A Garcia-Mena, Jaime %A Perez-Cruz, Claudia %K Alzheimer Disease %K Animals %K Cognitive Dysfunction %K Female %K Gastrointestinal Microbiome %K Humans %K Male %K Mice %K Mice, Transgenic %K Sex Characteristics %K Spatial Memory %X

BACKGROUND: Normal aging is accompanied by cognitive deficiencies, affecting women and men equally. Aging is the main risk factor for Alzheimer's disease (AD), with women having a higher risk. The higher prevalence of AD in women is associated with the abrupt hormonal decline seen after menopause. However, other factors may be involved in this sex-related cognitive decline. Alterations in gut microbiota (GM) and its bioproducts have been reported in AD subjects and transgenic (Tg) mice, having a direct impact on brain amyloid-β pathology in male (M), but not in female (F) mice.

OBJECTIVE: The aim of this work was to determine GM composition and cognitive dysfunction in M and F wildtype (WT) and Tg mice, in a sex/genotype segregation design.

METHODS: Anxiety, short term working-memory, spatial learning, and long-term spatial memory were evaluated in 6-month-old WT and Tg male mice. Fecal short chain fatty acids were determined by chromatography, and DNA sequencing and bioinformatic analyses were used to determine GM differences.

RESULTS: We observed sex-dependent differences in cognitive skills in WT mice, favoring F mice. However, the cognitive advantage of females was lost in Tg mice. GM composition showed few sex-related differences in WT mice. Contrary, Tg-M mice presented a more severe dysbiosis than Tg-F mice. A decreased abundance of Ruminococcaceae was associated with cognitive deficits in Tg-F mice, while butyrate levels were positively associated with better working- and object recognition-memory in WT-F mice.

CONCLUSION: This report describes a sex-dependent association between GM alterations and cognitive impairment in a mice model of AD.

%B J Alzheimers Dis %V 82 %P S195-S214 %8 2021 %G eng %N s1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33492296?dopt=Abstract %R 10.3233/JAD-201367 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Impact of a Global Pandemic on People Living with Dementia and Their Care Partners: Analysis of 417 Lived Experience Reports. %A Tam, Mallorie T %A Dosso, Jill A %A Robillard, Julie M %K Adaptation, Psychological %K Aged %K Alzheimer Disease %K British Columbia %K Caregivers %K COVID-19 %K Disabled Persons %K Female %K Humans %K Loneliness %K Male %K Needs Assessment %K Psychosocial Support Systems %K Social Isolation %K Social Support %K Stress, Psychological %K Surveys and Questionnaires %X

BACKGROUND: The COVID-19 pandemic is impacting the physical and emotional health of older adults living with dementia and their care partners.

OBJECTIVE: Using a patient-centered approach, we explored the experiences and needs of people living with dementia and their care partners during the COVID-19 pandemic as part of an ongoing evaluation of dementia support services in British Columbia, Canada.

METHODS: A survey instrument was developed around the priorities identified in the context of the COVID-19 and Dementia Task Force convened by the Alzheimer Society of Canada.

RESULTS: A total of 417 surveys were analyzed. Overall, respondents were able to access information that was helpful for maintaining their own health and managing a period of social distancing. Care partners reported a number of serious concerns, including the inability to visit the person that they care for in long-term or palliative care. Participants also reported that the pandemic increased their levels of stress overall and that they felt lonelier and more isolated than they did before the pandemic. The use of technology was reported as a way to connect socially with their loved ones, with the majority of participants connecting with others at least twice per week.

CONCLUSION: Looking at the complex effects of a global pandemic through the experiences of people living with dementia and their care partners is vital to inform healthcare priorities to restore their quality of life and health and better prepare for the future.

%B J Alzheimers Dis %V 80 %P 865-875 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554905?dopt=Abstract %R 10.3233/JAD-201114 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Implementing Delirium Prevention in the Era of COVID-19. %A Radhakrishnan, Nila S %A Mufti, Mariam %A Ortiz, Daniel %A Maye, Suzanne T %A Melara, Jennifer %A Lim, Duke %A Rosenberg, Eric I %A Price, Catherine C %K Aged %K Alzheimer Disease %K COVID-19 %K Delirium %K Humans %K Male %X

Patients admitted with COVID-19 can develop delirium due to predisposing factors, isolation, and the illness itself. Standard delirium prevention methods focus on interaction and stimulation. It can be challenging to deliver these methods of care in COVID settings where it is necessary to increase patient isolation. This paper presents a typical clinical vignette of representative patients in a tertiary care hospital and how a medical team modified an evidence-based delirium prevention model to deliver high-quality care to COVID-19 patients. The implemented model focuses on four areas of delirium-prevention: Mobility, Sleep, Cognitive Stimulation, and Nutrition. Future studies will be needed to track quantitative outcome measures.

%B J Alzheimers Dis %V 79 %P 31-36 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33252073?dopt=Abstract %R 10.3233/JAD-200696 %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 Incremental Healthcare Utilization and Cost Burden of Comorbid Insomnia in Alzheimer's Disease Patients. %A Qureshi, Zaina P %A Thiel, Ellen %A Nelson, James %A Khandker, Rezaul %K Aged, 80 and over %K Alzheimer Disease %K Comorbidity %K Databases, Factual %K Female %K Health Care Costs %K Humans %K Male %K Medicare %K Patient Acceptance of Health Care %K Retrospective Studies %K Sleep Initiation and Maintenance Disorders %K United States %X

BACKGROUND: Insomnia is associated with worsened clinical outcomes among Alzheimer's disease dementia (AD) patients, increased caregiver burden, and healthcare utilization.

OBJECTIVE: This study aimed to characterize the incremental healthcare burden of insomnia in AD using real-world data.

METHODS: A retrospective observational study was conducted on AD patients selected from the IBM® MarketScan Commercial and Medicare Supplemental Databases. AD patients with claims-based evidence of insomnia were direct matched to a non-insomnia cohort based on demographic factors. Healthcare utilization and associated costs were assessed for a 12-month follow-up period.

RESULTS: A total of 3,500 insomnia AD patients and 9,884 non-insomnia AD patients were analyzed. The insomnia cohort had a higher comorbidity burden at baseline (mean score on Charlson Comorbidity Index 2.5 versus 2.2, p < 0.001) and higher proportions of patients with baseline diagnoses for other conditions including depression: 40%, insomnia cohort versus 25%, non-insomnia (p < 0.001). AD patients with insomnia were more likely to have a claim for inpatient hospitalizations (39.8%versus 32.3%), emergency room services (56.4%versus 48.0%), and skilled-nursing services (42.6%versus 31.9%) (all p < 0.05). Mean total annual healthcare costs during the 12-month follow-up period were significantly higher among AD patients with insomnia as compared to those without. (Mean costs: $37,356 versus $27,990, p < 0.001).

CONCLUSION: AD patients with comorbid insomnia are more likely to use higher-cost healthcare services such as inpatient hospitalization, and skilled nursing, and have higher total healthcare costs. This real-world analysis provides evidence that AD disease management should consider proper treatment of comorbid insomnia due to the incremental burden and cost implications.

%B J Alzheimers Dis %V 83 %P 1679-1690 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/34420974?dopt=Abstract %R 10.3233/JAD-210713 %0 Journal Article %J J Alzheimers Dis %D 2021 %T An Introduction to Ultrasensitive Assays for Plasma Tau Detection. %A Ding, Xu-Long %A Tuo, Qing-Zhang %A Lei, Peng %K Alzheimer Disease %K Biological Assay %K Biomarkers %K Enzyme-Linked Immunosorbent Assay %K Humans %K Phosphorylation %K tau Proteins %X

The detection of plasma tau and its phosphorylation is technically challenging due to the relatively low sensitivity. However, in Alzheimer's disease and other tauopathies, it is hypothesized that tau in the biofluid may serve as a biomarker. In recent years, several ultrasensitive assays have been developed, which can successfully detect tau and its phosphorylation in various biofluids, and collectively demonstrated the prognostic and diagnostic value of plasma tau/phosphorylated tau. Here we have summarized the principle of four ultrasensitive assays newly developed suitable for plasma tau detection, namely single-molecule array, immunomagnetic reduction assay, enhanced immunoassay using multi-arrayed fiber optics, and meso scale discovery assay, with their advantages and applications. We have also compared these assays with traditional enzyme-linked-immunosorbent serologic assay, hoping to facilitate future tau-based biomarker discovery for Alzheimer's disease and other neurodegenerative diseases.

%B J Alzheimers Dis %V 80 %P 1353-1362 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33682718?dopt=Abstract %R 10.3233/JAD-201499 %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 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 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 Needs of Dementia Family Caregivers in Spain During the COVID-19 Pandemic. %A Carcavilla, Nuria %A Pozo, Ana Sofía %A González, Belén %A Moral-Cuesta, Débora %A Roldán, José Joaquín %A Erice, Victoria %A Remírez, Ana de Ganuza %K Adaptation, Psychological %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Anxiety Disorders %K Caregivers %K COVID-19 %K Feeding and Eating Disorders %K Female %K Humans %K Male %K Middle Aged %K Mood Disorders %K Needs Assessment %K Sleep Wake Disorders %K Social Isolation %K Social Support %K Spain %X

We explored the experience from caregivers of people with dementia (PwD) during mandatory confinement due to the COVID-19 pandemic in Spain. An online survey, which studied the perceptions of the main problems and consequences experienced during confinement, was answered by 106 family caregivers of PwD. Results showed that family caregivers of PwD experienced psychological problems, like anxiety, mood, sleep, or eating disorders during confinement and felt less supported when they had to handle challenging behaviors or offer meaningful activities. An innovative multi-tiered supportive approach is needed which considers a post-pandemic reality and ensures the continuity of quality care for PwD and their family careers.

%B J Alzheimers Dis %V 80 %P 533-537 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554916?dopt=Abstract %R 10.3233/JAD-201430 %0 Journal Article %J J Alzheimers Dis %D 2021 %T New Frontiers in the Prevention, Diagnosis, and Treatment of Alzheimer's Disease. %A Guzmán-Martínez, Leonardo %A Calfío, Camila %A Farías, Gonzalo A %A Vilches, Cristian %A Prieto, Raul %A Maccioni, Ricardo B %K Acupuncture Therapy %K Aging %K Alzheimer Disease %K Biomarkers %K Dietary Supplements %K Early Diagnosis %K Humans %K Medicine, Chinese Traditional %K Meditation %K Quality of Life %K Treatment Outcome %X

One of the major puzzles in medical research and public health systems worldwide is Alzheimer's disease (AD), reaching nowadays a prevalence near 50 million people. This is a multifactorial brain disorder characterized by progressive cognitive impairment, apathy, and mood and neuropsychiatric disorders. The main risk of AD is aging; a normal biological process associated with a continuum dynamic involving a gradual loss of people's physical capacities, but with a sound experienced view of life. Studies suggest that AD is a break from normal aging with changes in the powerful functional capacities of neurons as well as in the mechanisms of neuronal protection. In this context, an important path has been opened toward AD prevention considering that there are elements of nutrition, daily exercise, avoidance of toxic substances and drugs, an active social life, meditation, and control of stress, to achieve healthy aging. Here, we analyze the involvement of such factors and how to control environmental risk factors for a better quality of life. Prevention as well as innovative screening programs for early detection of the disease using reliable biomarkers are becoming critical to control the disease. In addition, the failure of traditional pharmacological treatments and search for new drugs has stimulated the emergence of nutraceutical compounds in the context of a "multitarget" therapy, as well as mindfulness approaches shown to be effective in the aging, and applied to the control of AD. An integrated approach involving all these preventive factors combined with novel pharmacological approaches should pave the way for the future control of the disease.

%B J Alzheimers Dis %V 82 %P S51-S63 %8 2021 %G eng %N s1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33523002?dopt=Abstract %R 10.3233/JAD-201059 %0 Journal Article %J J Alzheimers Dis %D 2021 %T NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer's Disease. %A Van Zeller, Mariana %A Dias, Diogo %A Sebastião, Ana M %A Valente, Cláudia A %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Astrocytes %K Humans %K Inflammasomes %K Inflammation %K Microglia %K NLR Family, Pyrin Domain-Containing 3 Protein %K Tauopathies %X

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease commonly diagnosed among the elderly population. AD is characterized by the loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to the extracellular accumulation of senile plaques, composed by insoluble aggregates of amyloid-β (Aβ) peptides, and to the intraneuronal formation of neurofibrillary tangles shaped by hyperphosphorylated filaments of the microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release of proinflammatory cytokines by reactive glial cells, contribute to the pathophysiology of the disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor of a wide range of stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review the most recent findings regarding the involvement of NLRP3 in the pathogenesis of AD. We address the mechanisms of NLRP3 priming and activation in glial cells by Aβ species and the potential role of neurofibrillary tangles and extracellular vesicles in disease progression. Neuronal death by NLRP3-mediated pyroptosis, driven by the interneuronal tau propagation, is also discussed. We present considerable evidence to claim that NLRP3 inhibition, is undoubtfully a potential therapeutic strategy for AD.

%B J Alzheimers Dis %V 83 %P 939-961 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34366341?dopt=Abstract %R 10.3233/JAD-210268 %0 Journal Article %J J Alzheimers Dis %D 2021 %T A Novel Approach to the Treatment and Prevention of Alzheimer's Disease Based on the Pathology and Microbiology. %A Allen, Herbert B %K Alzheimer Disease %K Biofilms %K Borrelia burgdorferi %K Brain %K Humans %K Inflammation %K Neurons %K Penicillins %K Plaque, Amyloid %K tau Proteins %K Treponema denticola %X

Utilizing the pathology and microbiology found in tissue from patients with documented Alzheimer's disease (AD), the pathogenesis of this fateful disorder has been made clear. Borrelia burgdorferi and Treponema denticola spirochetes enter the brain, mostly via neuronal pathways and the entorhinal circulation. These organisms easily pass through the blood-brain barrier and have an affinity for neural tissue. Once in the brain, the spirochetes make intra- and extracellular biofilms, and it is the biofilms that create the pathology. Specifically, it is the intracellular biofilms that are ultimately responsible for neurofibrillary tangles and dendritic disintegration. The extracellular biofilms are responsible for the inflammation that initially is generated by the first responder, Toll-like receptor 2. The hypothesis that arises from this work is two-pronged: one is related to prevention; the other to treatment. Regarding prevention, it is very likely possible that AD could be prevented by periodic administration of penicillin (PCN), which would kill the spirochetes before they made biofilms; this would prevent the disease and would not allow any of the above deleterious changes generated by the biofilms to occur. As regards treatment, it may be possible to slow or prevent further decline in early AD by administration of PCN together with a biofilm disperser. The disperser would disrupt the biofilm coating and enable the PCN to kill the spirochetes. This protocol could be administered in a trial with the control arm utilizing the current treatment. The progress of the treatment could be evaluated by one of the current blood tests that is semi-quantitative. The specific protocols are listed.

%B J Alzheimers Dis %V 84 %P 61-67 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34542071?dopt=Abstract %R 10.3233/JAD-210429 %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 Plasma Biomarkers of Alzheimer's Disease in African Americans. %A Deniz, Kaancan %A Ho, Charlotte C G %A Malphrus, Kimberly G %A Reddy, Joseph S %A Nguyen, Thuy %A Carnwath, Troy P %A Crook, Julia E %A Lucas, John A %A Graff-Radford, Neill R %A Carrasquillo, Minerva M %A Ertekin-Taner, Nilufer %K African Americans %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Case-Control Studies %K Female %K Humans %K Interleukin-10 %K Interleukin-6 %K Male %K Middle Aged %K Peptide Fragments %K tau Proteins %K Tumor Necrosis Factor-alpha %X

BACKGROUND/OBJECTIVE: The aim of this study was to determine if plasma concentrations of 5 surrogate markers of Alzheimer's disease (AD) pathology and neuroinflammation are associated with disease status in African Americans.

METHODS: We evaluated 321 African Americans (159 AD, 162 controls) from the Florida Consortium for African-American Alzheimer's Disease Studies (FCA3DS). Five plasma proteins reflecting AD neuropathology or inflammation (Aβ42, tau, IL6, IL10, TNFα) were tested for associations with AD, age, sex, APOE and MAPT genotypes, and for pairwise correlations.

RESULTS: Plasma tau levels were higher in AD when adjusted for biological and technical covariates. APOEɛ4 was associated with lower plasma Aβ42 and tau levels. Older age was associated with higher plasma Aβ42, tau, and TNFα. Females had lower IL10 levels. Inflammatory proteins had strong pairwise correlations amongst themselves and with Aβ42.

CONCLUSION: We identified effects of demographic and genetic variants on five potential plasma biomarkers in African Americans. Plasma inflammatory biomarkers and Aβ42 may reflect correlated pathologies and elevated plasma tau may be a biomarker of AD in this population.

%B J Alzheimers Dis %V 79 %P 323-334 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33252078?dopt=Abstract %R 10.3233/JAD-200828 %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 Outer Membrane Vesicles as the Major Driver of and Explanation for Neuropathogenesis, the Cholinergic Hypothesis, Iron Dyshomeostasis, and Salivary Lactoferrin in Alzheimer's Disease. %A Nara, Peter L %A Sindelar, Daniel %A Penn, Marc S %A Potempa, Jan %A Griffin, W Sue T %K Alzheimer Disease %K Anti-Infective Agents %K Bacterial Outer Membrane Proteins %K Bacteroidaceae Infections %K Brain %K Cholinergic Agents %K Extremophiles %K Humans %K Iron %K Lactoferrin %K Porphyromonas gingivalis %K Saliva %X

Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced "chronic" multi-systems inflammatory disease(s) including Alzheimer's disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria's direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the "infection hypothesis" of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of "Pg bacteria" residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the "Gingipains Hypothesis", AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention.

%B J Alzheimers Dis %V 82 %P 1417-1450 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/34275903?dopt=Abstract %R 10.3233/JAD-210448 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Potential Role of Ferroptosis in Alzheimer's Disease. %A Zhang, Guimei %A Zhang, Yaru %A Shen, Yanxin %A Wang, Yongchun %A Zhao, Meng %A Sun, Li %K Alzheimer Disease %K Animals %K Ferroptosis %K Humans %X

Alzheimer's disease (AD) is the most prevalent cause of dementia, accounting for approximately 60%-80%of all cases. Although much effort has been made over the years, the precise mechanism of AD has not been completely elucidated. Recently, great attention has shifted to the roles of iron metabolism, lipid peroxidation, and oxidative stress in AD pathogenesis. We also note that these pathological events are the vital regulators of a novel regulatory cell death, termed ferroptosis-an iron-dependent, oxidative, non-apoptotic cell death. Ferroptosis differs from apoptosis, necrosis, and autophagy with respect to morphology, biochemistry, and genetics. Mounting evidence suggests that ferroptosis may be involved in neurological disorders, including AD. Here, we review the underlying mechanisms of ferroptosis; discuss the potential interaction between AD and ferroptosis in terms of iron metabolism, lipid peroxidation, and the glutathione/glutathione peroxidase 4 axis; and describe some associated studies that have explored the implication of ferroptosis in AD.

%B J Alzheimers Dis %V 80 %P 907-925 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646161?dopt=Abstract %R 10.3233/JAD-201369 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Race-Related Association between APOE Genotype and Alzheimer's Disease: A Systematic Review and Meta-Analysis. %A Qin, Wei %A Li, Wenwen %A Wang, Qi %A Gong, Min %A Li, Tingting %A Shi, Yuqing %A Song, Yang %A Li, Ying %A Li, Fangyu %A Jia, Jianping %K Alleles %K Alzheimer Disease %K Apolipoprotein E2 %K Apolipoprotein E4 %K Apolipoproteins E %K Genotype %K Humans %K Racial Groups %X

BACKGROUND: The global race-dependent association of Alzheimer's disease (AD) and apolipoprotein E (APOE) genotype is not well understood. Transethnic analysis of APOE could clarify the role of genetics in AD risk across populations.

OBJECTIVE: This study aims to determine how race and APOE genotype affect the risks for AD.

METHODS: We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library since 1993 to Aug 25, 2020. A total of 10,395 reports were identified, and 133 were eligible for analysis with data on 77,402 participants. Studies contained AD clinical diagnostic and APOE genotype data. Homogeneous data sets were pooled in case-control analyses. Odds ratios and 95% confidence intervals for developing AD were calculated for populations of different races and APOE genotypes.

RESULTS: The proportion of APOE genotypes and alleles differed between populations of different races. Results showed that APOEɛ4 was a risk factor for AD, whereas APOEɛ2 protected against it. The effects of APOEɛ4 and ɛ2 on AD risk were distinct in various races, and they were substantially attenuated among Black people. Sub-group analysis found a higher frequency of APOEɛ4/ɛ4 and lower frequency of APOEɛ3/ɛ3 among early-onset AD than late-onset AD in a combined group and different races.

CONCLUSION: Our meta-analysis suggests that the association of APOE genotypes and AD differ among races. These results enhance our understanding of APOE-related risk for AD across race backgrounds and provide new insights into precision medicine for AD.

%B J Alzheimers Dis %V 83 %P 897-906 %8 2021 %G eng %N 2 %R 10.3233/JAD-210549 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Retinal Vessel Density Can Reflect Cognitive Function in Patients with Alzheimer's Disease: Evidence from Optical Coherence Tomography Angiography. %A Yan, Yibing %A Wu, Xingqi %A Wang, Xiaojing %A Geng, Zhi %A Wang, Lu %A Xiao, Guixian %A Wu, Yue %A Zhou, Shanshan %A Liao, Rongfeng %A Wei, Ling %A Tian, Yanghua %A Wang, Kai %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Cognition %K Female %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Retinal Vessels %K Tomography, Optical Coherence %X

BACKGROUND: There is increasing evidence that Alzheimer's disease (AD) patients may present decreased cerebral blood perfusion before pathological brain changes. Using the retina as a window to the brain, we can study disorders of the central nervous system through the eyes.

OBJECTIVE: This study aimed to investigate differences in retinal structure and vessel density (VD) between patients with mild AD and healthy controls (HCs). Furthermore, we explored the relationship between retinal VD and cognitive function.

METHODS: We enrolled 37 patients with AD and 29 age-matched HCs who underwent standard ophthalmic optical coherence tomography angiography (OCTA) for evaluation of the retinal layer thickness and VD parameters. Cognitive function was evaluated using a battery of neuropsychological assessments. Finally, the correlations among retinal layer thickness, VD parameters, and cognitive function were evaluated.

RESULTS: The retinal fiber layer thickness and retinal VD of patients with AD were significantly reduced compared with HCs. The retinal VD was significantly correlated with overall cognition, memory, executive, and visual-spatial perception functions. However, there was no significant between-group difference in the macular thickness.

CONCLUSION: Our findings indicate a positive correlation between retinal VD and some, but not all, cognitive function domains. Most importantly, we demonstrated the role of OCTA in detecting early capillary changes, which could be a noninvasive biomarker for early AD.

%B J Alzheimers Dis %V 79 %P 1307-1316 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33427738?dopt=Abstract %R 10.3233/JAD-200971 %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 Sleep Deprivation, a Link Between Post-Traumatic Stress Disorder and Alzheimer's Disease. %A Delic, Vedad %A Ratliff, Whitney A %A Citron, Bruce A %K Alzheimer Disease %K Animals %K Humans %K Sleep Deprivation %K Stress Disorders, Post-Traumatic %X

An estimated 5 million Americans are living with Alzheimer's disease (AD), and there is also a significant impact on caregivers, with an additional 16 million Americans providing unpaid care for individuals with AD and other dementias. These numbers are projected to increase in the coming years. While AD is still without a cure, continued research efforts have led to better understanding of pathology and potential risk factors that could be exploited to slow disease progression. A bidirectional relationship between sleep deprivation and AD has been suggested and is well supported by both human and animal studies. Even brief episodes of inadequate sleep have been shown to cause an increase in amyloidβ and tau proteins, both well-established contributors toAD pathology. Sleep deprivation is also the most common consequence of post-traumatic stress disorder (PTSD). Patients with PTSD frequently present with sleep disturbances and also develop dementia at twice the rate of the general population accounting for a disproportionate representation of AD among U.S. Veterans. The goal of this review is to highlight the relationship triad between sleep deprivation, AD, and PTSD as well as their impact on molecular mechanisms driving AD pathology.

%B J Alzheimers Dis %V 79 %P 1443-1449 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33459652?dopt=Abstract %R 10.3233/JAD-201378 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Spiritual Fitness: A New Dimension in Alzheimer's Disease Prevention. %A Khalsa, Dharma Singh %A Newberg, Andrew B %K Alzheimer Disease %K Humans %K Life Style %K Love %K Meditation %K Spirituality %X

BACKGROUND: Religious and spiritual interventions may have an effect on Alzheimer's disease prevention. Kirtan Kriya meditation has been shown to mitigate the deleterious effects of chronic stress on cognition, reverse memory loss, and create psychological and spiritual wellbeing, which may reduce multiple drivers of Alzheimer's disease risk.

OBJECTIVE: To detail a new concept in medicine called Spiritual Fitness, a merging of stress reduction, basic wellbeing, and psycho/spiritual wellbeing to prevent Alzheimer's disease.

METHODS: The literature on the topics mentioned above is described, including an in-depth discussion on why and how each are critical to advancing the future of Alzheimer's disease prevention. The many negative effects of chronic stress, and the benefits of Kirtan Kriya, are reviewed. The four pillars of basic wellbeing, six practical aspects of psychological wellbeing, and the four new non-sectarian features of spiritual fitness are then disclosed. Moreover, instructions on practicing Kirtan Kriya are offered in the Supplementary Material.

CONCLUSION: Religious and spiritual practices, including Kirtan Kriya, are crucial components in the development of enhanced cognition and well-being, which may help prevent and, in some cases, reverse cognitive decline. The key point of this review is that making a commitment to live a brain longevity lifestyle including spiritual fitness is a critically important way for aging Alzheimer's disease free. We hope that this article will inspire scientists, clinicians, and patients to embrace this new concept of spiritual fitness and make it a part of every multidomain program for the prevention of cognitive disability.

%B J Alzheimers Dis %V 80 %P 505-519 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554917?dopt=Abstract %R 10.3233/JAD-201433 %0 Journal Article %J J Alzheimers Dis %D 2021 %T A Super-Resolved View of the Alzheimer's Disease-Related Amyloidogenic Pathway in Hippocampal Neurons. %A Yu, Yang %A Gao, Yang %A Winblad, Bengt %A Tjernberg, Lars O %A Schedin-Weiss, Sophia %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Amyloidogenic Proteins %K Animals %K Cells, Cultured %K Hippocampus %K Humans %K Mice %K Mice, Inbred C57BL %K Microscopy %K Neurons %K Peptide Fragments %K Protein Transport %X

BACKGROUND: Processing of the amyloid-β protein precursor (AβPP) is neurophysiologically important due to the resulting fragments that regulate synapse biology, as well as potentially harmful due to generation of the 42 amino acid long amyloid β-peptide (Aβ42), which is a key player in Alzheimer's disease.

OBJECTIVE: Our aim was to clarify the subcellular locations of the fragments involved in the amyloidogenic pathway in primary neurons with a focus on Aβ42 and its immediate substrate AβPP C-terminal fragment (APP-CTF). To overcome the difficulties of resolving these compartments due to their small size, we used super-resolution microscopy.

METHODS: Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional three-channel imaging, and quantitative image analyses.

RESULTS: The first (β-secretase) and second (γ-secretase) cleavages of AβPP were localized to functionally and distally distinct compartments. The β-secretase cleavage was observed in early endosomes in soma, where we were able to show that the liberated N- and C-terminal fragments were sorted into distinct vesicles budding from the early endosomes. Lack of colocalization of Aβ42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aβ42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AβPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aβ42 were localized in different compartments.

CONCLUSION: These findings provide critical super-resolved insight into amyloidogenic AβPP processing in primary neurons.

%B J Alzheimers Dis %V 83 %P 833-852 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34366358?dopt=Abstract %R 10.3233/JAD-215008 %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 2020 %T Awareness of the COVID-19 Outbreak and Resultant Depressive Tendencies in Patients with Severe Alzheimer's Disease. %A Tsugawa, Akito %A Sakurai, Shu %A Inagawa, Yuta %A Hirose, Daisuke %A Kaneko, Yoshitsugu %A Ogawa, Yusuke %A Serisawa, Shuntaro %A Takenoshita, Naoto %A Sakurai, Hirofumi %A Kanetaka, Hidekazu %A Hirao, Kentaro %A Shimizu, Soichiro %K Aged %K Alzheimer Disease %K Awareness %K Betacoronavirus %K Caregivers %K Communicable Disease Control %K Coronavirus Infections %K COVID-19 %K Female %K Humans %K Japan %K Male %K Mental Competency %K Pandemics %K Patient Care %K Pneumonia, Viral %K Psychosocial Support Systems %K SARS-CoV-2 %K Severity of Illness Index %X

The ongoing coronavirus disease 2019 (COVID-19) pandemic has substantially affected patients with dementia and their caregivers. However, we found not all Alzheimer's disease (AD) patients were afraid of COVID-19 infection. Therefore, we investigated the association between rate of awareness of COVID-19 and depressive tendency in AD. 126 consecutive outpatients with AD were enrolled in this study from May 25, on the day when the declaration of emergency was lifted in Japan, through June 30, 2020. In addition to routine psychological tests, the participants were asked the following two questions: "Do you know COVID-19?" and "Why are you wearing a face mask?". Moderate to severe AD patients were found to have a low COVID-19 recognition rate and did not fully understand why they were wearing face masks. In addition, because they did not understand the seriousness of the COVID-19 outbreak, their Geriatric Depression Scale scores were also substantially lower. These results may appear to simply indicate that people with severe dementia are unaware of current events. However, these results provide insights into how to care for patients with dementia and how to allocate the time and support of our limited staff during the COVID-19 outbreak.

%B J Alzheimers Dis %V 77 %P 539-541 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32925073?dopt=Abstract %R 10.3233/JAD-200832 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Circulating Vitamin D Levels and Alzheimer's Disease: A Mendelian Randomization Study in the IGAP and UK Biobank. %A Wang, Longcai %A Qiao, Yanchun %A Zhang, Haihua %A Zhang, Yan %A Hua, Jiao %A Jin, Shuilin %A Liu, Guiyou %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biological Specimen Banks %K Cognition Disorders %K Databases, Factual %K Female %K Genome-Wide Association Study %K Humans %K Hydroxycholecalciferols %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Nutritional Status %K United Kingdom %K Vitamin D %K Vitamin D Deficiency %X

Observational studies strongly supported the association of low levels of circulating 25-hydroxyvitamin D (25OHD) and cognitive impairment or dementia in aging populations. However, randomized controlled trials have not shown clear evidence that vitamin D supplementation could improve cognitive outcomes. In fact, some studies reported the association between vitamin D and cognitive impairment based on individuals aged 60 years and over. However, it is still unclear that whether vitamin D levels are causally associated with Alzheimer's disease (AD) risk in individuals aged 60 years and over. Here, we performed a Mendelian randomization (MR) study to investigate the causal association between vitamin D levels and AD using a large-scale vitamin D genome-wide association study (GWAS) dataset and two large-scale AD GWAS datasets from the IGAP and UK Biobank with individuals aged 60 years and over. Our results showed that genetically increased 25OHD levels were significantly associated with reduced AD risk in individuals aged 60 years and over. Hence, our findings in combination with previous literature indicate that maintaining adequate vitamin D status in older people especially aged 60 years and over, may contribute to slow down cognitive decline and forestall AD. Long-term randomized controlled trials are required to test whether vitamin D supplementation may prevent AD in older people especially those aged 60 years and may be recommended as preventive agents.

%B J Alzheimers Dis %V 73 %P 609-618 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/31815694?dopt=Abstract %R 10.3233/JAD-190713 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Death Rate Due to COVID-19 in Alzheimer's Disease and Frontotemporal Dementia. %A Matías-Guiu, Jordi A %A Pytel, Vanesa %A Matías-Guiu, Jorge %K Age Factors %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Coronavirus Infections %K COVID-19 %K Female %K Frontotemporal Dementia %K Humans %K Hypertension %K Independent Living %K Male %K Nursing Homes %K Pandemics %K Pneumonia, Viral %K Prevalence %K Risk Factors %X

We aimed to evaluate the frequency and mortality of COVID-19 in patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD). We conducted an observational case series. We enrolled 204 patients, 15.2% of whom were diagnosed with COVID-19, and 41.9% of patients with the infection died. Patients with AD were older than patients with FTD (80.36±8.77 versus 72.00±8.35 years old) and had a higher prevalence of arterial hypertension (55.8% versus 26.3%). COVID-19 occurred in 7.3% of patients living at home, but 72.0% of those living at care homes. Living in care facilities and diagnosis of AD were independently associated with a higher probability of death. We found that living in care homes is the most relevant factor for an increased risk of COVID-19 infection and death, with AD patients exhibiting a higher risk than those with FTD.

%B J Alzheimers Dis %V 78 %P 537-541 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33074240?dopt=Abstract %R 10.3233/JAD-200940 %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 Potential Novel Role of COVID-19 in Alzheimer's Disease and Preventative Mitigation Strategies. %A Naughton, Sean X %A Raval, Urdhva %A Pasinetti, Giulio M %K Aged %K Alzheimer Disease %K Betacoronavirus %K Coronavirus Infections %K COVID-19 %K Diabetes Mellitus, Type 2 %K Humans %K Interferon Type I %K Pandemics %K Pneumonia, Viral %K SARS-CoV-2 %K Synapses %X

There are a number of potential implications for the field of Alzheimer's disease (AD) stemming from the global spread of SARS-CoV-2. Neuroinflammation is known to be a prominent feature of neurodegeneration and plays a major role in AD pathology. Immune response and excessive inflammation in COVID-19 may also accelerate the progression of brain inflammatory neurodegeneration, and elderly individuals are more susceptible to severe outcomes after SARS-CoV-2 infection. Individuals with type 2 diabetes (T2D) are at an increased risk for AD as well as severe outcomes after SARS-CoV-2 infection. Genetic and socioeconomic factors influencing the rates of T2D, AD, and COVID-19 severity may create an exceptionally high-risk profile for certain demographics such as African Americans and Hispanic Americans. Type I interferon response plays an important role in both host response to viral infection, as well as AD pathology and may be a sensible therapeutic target in both AD and COVID-19.

%B J Alzheimers Dis %V 76 %P 21-25 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32538855?dopt=Abstract %R 10.3233/JAD-200537 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Resilience of Alzheimer's Disease to COVID-19. %A Li, Jingwen %A Long, Xi %A Huang, Heqing %A Tang, Jine %A Zhu, Chunli %A Hu, Shaoping %A Wu, Jing %A Li, Jinghong %A Lin, Zhicheng %A Xiong, Nian %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cluster Analysis %K Cohort Studies %K Coronavirus Infections %K COVID-19 %K Disease Progression %K Fatigue %K Female %K Humans %K Length of Stay %K Male %K Middle Aged %K Pandemics %K Patient Discharge %K Pleural Effusion %K Pneumonia %K Pneumonia, Viral %K Prognosis %K Resilience, Psychological %X

BACKGROUND: Facing the novel coronavirus disease 2019 (COVID-19), most vulnerable individuals are seniors, especially those with comorbidities. More attention needs to been paid to the COVID-19 patients with Alzheimer's disease (AD), which is the top age-related neurodegenerative disease.

OBJECTIVE: Since it is unclear whether AD patients are prone to COVID-19 infection and progression to severe stages, we report for the first time a retrospective analysis of the clinical characteristics of AD patients with COVID-19 pneumonia.

METHODS: We conducted a retrospective cohort study of the clinical data of 19 AD patients with COVID-19 pneumonia, compared with 23 non-AD COVID-19 patients admitted at the same time to our hospital. Demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed.

RESULTS: Between AD patients and non-AD patients with COVID-19 pneumonia, the pneumonia severity was not significantly different. AD patients had a higher clustering onset than non-AD patients. The median duration from symptom onset to hospitalization were shorter in AD patients than non-AD patients, indicating the former were sent to the hospital by their family or from nursing home earlier than the later. The median duration from hospitalization to discharge seemed shorter in AD patients than non-AD patients. Dementia patients seemed less likely to report fatigue. It is noticed that more AD patients might have pericardial effusion than the non-AD patients.

CONCLUSION: AD patients with COVID-19 were in milder conditions with a better prognosis than non-AD patients. AD patients who had adequate access to healthcare showed resilience to COVID-19 with shorter hospital stays.

%B J Alzheimers Dis %V 77 %P 67-73 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32804094?dopt=Abstract %R 10.3233/JAD-200649 %0 Journal Article %J J Alzheimers Dis %D 2018 %T ABC Transporters Are Key Players in Alzheimer's Disease. %A Pereira, Cátia D %A Martins, Filipa %A Wiltfang, Jens %A da Cruz E Silva, Odete A B %A Rebelo, Sandra %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K ATP-Binding Cassette Transporters %K Blood-Brain Barrier %K Humans %X

Human ATP-binding cassette (ABC) transporters mediate a critical function in the cell, namely the transport of molecules across lipid membranes. Associated to their ubiquitous tissue distribution, they are key players in cellular homeostasis but also potential causative or contributing factors for many pathologies, including Alzheimer's disease (AD). In the central nervous system (CNS), numerous ABC transporters are present throughout the brain parenchyma and especially at the blood-brain barrier (BBB). AD is a neurodegenerative disorder mainly characterized by extracellular deposition of amyloid-β (Aβ) peptides and intracellular accumulation of hyperphosphorylated forms of tau protein. Besides being degraded via proteolytic and phagocytic processes mediated by brain parenchymal cells, a major mechanism for eliminating cerebral Aβ is through its transport across the BBB into the peripheral blood. In fact, many AD cases are associated with impaired Aβ clearance. Consistently, several studies have recently uncovered important roles for ABC transporters in AD pathophysiology. Hence, this review focuses on the relevance of ABC transporters in CNS homeostasis by highlighting AD as a strong example of the deleterious consequences that might result from the former's altered expression and/or activity in the brain. The potentiality of human ABC transporters as novel pharmacological targets for both the diagnosis and therapeutics of AD is emphasized.

%B J Alzheimers Dis %V 61 %P 463-485 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171999?dopt=Abstract %R 10.3233/JAD-170639 %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 Alterations in Acrolein Metabolism Contribute to Alzheimer's Disease. %A Tsou, Han-Hsing %A Hsu, Wen-Chin %A Fuh, Jong-Ling %A Chen, Shih-Pin %A Liu, Tsung-Yun %A Wang, Hsiang-Tsui %K Acetylcysteine %K Acrolein %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Creatinine %K Disease Progression %K Early Diagnosis %K Female %K Humans %K Male %K Middle Aged %X

Alzheimer's disease (AD) is a detrimental neurodegenerative disease, and early diagnosis appears to be the key to successful treatment. Acrolein, a byproduct of lipid peroxidation, has been shown to contribute to the pathological process of AD. This study recruited 118 elderly subjects consisting of 58 non-demented control subjects and 62 AD patients. We analyzed the acrolein-related metabolites in the plasma, cerebrospinal fluid (CSF), and urine of all subjects. We found that the levels of acrolein-conjugated protein (Acr-PC) in the plasma (p = 0.00012) and CSF (p = 0.00161) of AD patients were significantly higher than those of control subjects, whereas the levels of a urinary acrolein metabolite, 3-hydroxypropyl mercapturic acid (3-HPMA), were markedly decreased (p = 0.00882) in AD patients. These data suggest that deregulated acrolein metabolism may be correlated with neuronal damage in AD patients, which might provide further insights into the disease progression and early diagnosis of AD.

%B J Alzheimers Dis %V 61 %P 571-580 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226874?dopt=Abstract %R 10.3233/JAD-170736 %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 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 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: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines. %A Zádori, Dénes %A Veres, Gábor %A Szalárdy, Levente %A Klivenyi, Peter %A Vecsei, Laszlo %K Alzheimer Disease %K Animals %K Central Nervous System %K Disease Models, Animal %K Energy Metabolism %K Glutamic Acid %K Humans %K Immunity, Innate %K Inflammation %K Kynurenine %K Mitochondria %K Quinolinic Acid %K Reactive Oxygen Species %K Receptors, Glutamate %K Signal Transduction %X

The pathomechanism of Alzheimer's disease (AD) certainly involves mitochondrial disturbances, glutamate excitotoxicity, and neuroinflammation. The three main aspects of mitochondrial dysfunction in AD, i.e., the defects in dynamics, altered bioenergetics, and the deficient transport, act synergistically. In addition, glutamatergic neurotransmission is affected in several ways. The balance between synaptic and extrasynaptic glutamatergic transmission is shifted toward the extrasynaptic site contributing to glutamate excitotoxicity, a phenomenon augmented by increased glutamate release and decreased glutamate uptake. Neuroinflammation in AD is predominantly linked to central players of the innate immune system, with central nervous system (CNS)-resident microglia, astroglia, and perivascular macrophages having been implicated at the cellular level. Several abnormalities have been described regarding the activation of certain steps of the kynurenine (KYN) pathway of tryptophan metabolism in AD. First of all, the activation of indolamine 2,3-dioxygenase, the first and rate-limiting step of the pathway, is well-demonstrated. 3-Hydroxy-L-KYN and its metabolite, 3-hydroxy-anthranilic acid have pro-oxidant, antioxidant, and potent immunomodulatory features, giving relevance to their alterations in AD. Another metabolite, quinolinic acid, has been demonstrated to be neurotoxic, promoting glutamate excitotoxicity, reactive oxygen species production, lipid peroxidation, and microglial neuroinflammation, and its abundant presence in AD pathologies has been demonstrated. Finally, the neuroprotective metabolite, kynurenic acid, has been associated with antagonistic effects at glutamate receptors, free radical scavenging, and immunomodulation, giving rise to potential therapeutic implications. This review presents the multiple connections of KYN pathway-related alterations to three main domains of AD pathomechanism, such as mitochondrial dysfunction, excitotoxicity, and neuroinflammation, implicating possible therapeutic options.

%B J Alzheimers Dis %V 62 %P 523-547 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480191?dopt=Abstract %R 10.3233/JAD-170929 %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 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 Apparent Cognitive Decline as Revealed by an Executive Function Test within a Cohort of Elderly Individuals Self-Reporting Normal Cognitive Performance. %A Shea, Thomas B %A Remington, Ruth %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition %K Cognitive Dysfunction %K Cohort Studies %K Executive Function %K Female %K Humans %K Male %K Memory %K Neuropsychological Tests %K Self Report %X

Alzheimer's disease (AD) can be preceded by subtle memory decline that can last a decade or more before progressing to what would be diagnosed as the mild cognitive impairment stage. During this early stage of decline, individuals and even their caregivers can fail to perceive any serious difficulty or need to consult a physician. Herein, we present evidence in support of these concerns, and demonstrate how this can interfere not only with clinical trials of AD but also those involving cognitive performance of elderly individuals without intentional reference to AD.

%B J Alzheimers Dis %V 61 %P 913-915 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332053?dopt=Abstract %R 10.3233/JAD-170794 %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 Assay of Plasma Phosphorylated Tau Protein (Threonine 181) and Total Tau Protein in Early-Stage Alzheimer's Disease. %A Yang, Che-Chuan %A Chiu, Ming-Jang %A Chen, Ta-Fu %A Chang, Hui-Ling %A Liu, Bing-Hsien %A Yang, Shieh-Yueh %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Case-Control Studies %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Phosphorylation %K tau Proteins %X

The feasibility of assaying plasma phosphorylated tau protein (threonine 181), denoted p-tau181, using immunomagnetic reduction (IMR) is explored. The reagent for assaying p-tau181 with IMR was synthesized, and its analytic performances were characterized. Seventy-three subjects were recruited. Each participant was examined with neuropsychological tests, magnetic resonance imaging, and IMR assay for plasma p-tau181. Using commercially available IMR kits, the plasma total tau protein (T-tau) of each subject was assayed. The dynamic range for assaying p-tau181 using IMR was 1.96×10-2 pg/ml to 104 pg/ml. There was no significant interference from total tau protein in the assay of p-tau181. The measured concentrations of plasma p-tau181 were 2.46±1.09 pg/ml for healthy controls, 4.41±1.85 pg/ml for MCI due to AD, and 6.14±1.59 pg/ml for very mild AD. Meanwhile, the measured concentrations of plasma T-tau were 18.85±10.16 pg/ml for healthy controls, 32.98±10.18 pg/ml for MCI due to AD, and 37.54±12.29 pg/ml for very mild AD. A significant difference in plasma p-tau181 was observed between healthy controls and MCI due to AD (p < 0.001) and between MCI due to AD and very mild AD (p < 0.001). However, for the plasma T-tau concentration, a significant difference existed only between healthy controls and MCI due to AD (p < 0.001). This implies that the plasma p-tau181 level is correlated more to AD severity than plasma T-tau is. Additionally, p-tau181 was observed as approximately 14% of T-tau in human plasma.

%B J Alzheimers Dis %V 61 %P 1323-1332 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376870?dopt=Abstract %R 10.3233/JAD-170810 %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 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 Associations between Use of Specific Analgesics and Concentrations of Amyloid-β 42 or Phospho-Tau in Regions of Human Cerebral Cortex. %A Flanagan, Margaret E %A Larson, Eric B %A Walker, Rod L %A Keene, C Dirk %A Postupna, Nadia %A Cholerton, Brenna %A Sonnen, Joshua A %A Dublin, Sascha %A Crane, Paul K %A Montine, Thomas J %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Analgesics %K Analgesics, Opioid %K Anti-Inflammatory Agents, Non-Steroidal %K Autopsy %K Cerebral Cortex %K Female %K Humans %K Logistic Models %K Male %K Peptide Fragments %K Prospective Studies %K tau Proteins %X

Analgesics are commonly used by older adults, raising the question of whether their use might contribute to dementia risk and neuropathologic changes of Alzheimer's disease (AD). The Adult Changes in Thought (ACT) study is a population-based study of brain aging and incident dementia among people 65 years or older who are community dwelling and not demented at entry. Amyloid-β (Aβ)42 and phospho-tau were quantified using Histelide in regions of cerebral cortex from 420 brain autopsies. Total standard daily doses of prescription opioid and non-aspirin nonsteroidal anti-inflammatory drug (NSAID) exposure during a defined 10-year exposure window were identified using automated pharmacy dispensing data and used to classify people as having no/low, intermediate, or high exposure. People with high NSAID exposure had significantly greater Aβ42 concentration in middle frontal gyrus and superior and middle temporal gyri, but not inferior parietal lobule; no Aβ42 regional concentration was associated with prescription opioid usage. People with high opioid usage had significantly greater concentration of phospho-tau in middle frontal gyrus than people with little-to-no opioid usage. Consistent with our previous studies, findings suggest that high levels of NSAID use in older individuals may promote Aβ42 accumulation in cerebral cortex.

%B J Alzheimers Dis %V 61 %P 653-662 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226863?dopt=Abstract %R 10.3233/JAD-170414 %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 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 Cardiorespiratory Fitness and White Matter Neuronal Fiber Integrity in Mild Cognitive Impairment. %A Ding, Kan %A Tarumi, Takashi %A Zhu, David C %A Tseng, Benjamin Y %A Thomas, Binu P %A Turner, Marcel %A Repshas, Justin %A Kerwin, Diana R %A Womack, Kyle B %A Lu, Hanzhang %A Cullum, C Munro %A Zhang, Rong %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Anisotropy %K Cardiorespiratory Fitness %K Case-Control Studies %K Cognition %K Cognitive Dysfunction %K Diffusion Tensor Imaging %K Executive Function %K Female %K Humans %K Linear Models %K Male %K Memory %K Middle Aged %K Nerve Fibers, Myelinated %K Neuropsychological Tests %K Texas %K White Matter %X

BACKGROUND: Mounting evidence showed the self-reported levels of physical activity are positively associated with white matter (WM) integrity and cognitive performance in normal adults and patients with mild cognitive impairment (MCI). However, the objective measure of cardiorespiratory fitness (CRF) was not used in these studies.

OBJECTIVE: To determine the associations of CRF measured by maximal oxygen uptake (VO2max) with WM fiber integrity and neurocognitive performance in older adults with MCI.

METHODS: Eighty-one participants (age = 65±7 years, 43 women), including 26 cognitively normal older adults and 55 amnestic MCI patients, underwent VO2max test to measure CRF, diffusion tensor imaging (DTI) to assess WM fiber integrity, and neurocognitive assessment focused on memory and executive function. DTI data were analyzed by the tract-based spatial statistics and region-of-interest approach.

RESULTS: Cognitively normal older adults and MCI patients were not different in global WM fiber integrity and VO2max. VO2max was associated positively with DTI metrics of fractional anisotropy in ∼54% WM fiber tracts, and negatively with mean and radial diffusivities in ∼46% and ∼56% of the WM fiber tracts. The associations of VO2max with DTI metrics remained statistically significant after adjustment of age, sex, body mass index, WM lesion burden, and MCI status. The DTI metrics obtained from the area that correlated to VO2max were associated with executive function performance in MCI patients.

CONCLUSIONS: Higher levels of CRF are associated with better WM fiber integrity, which in turn is correlated with better executive function performance in MCI patients.

%B J Alzheimers Dis %V 61 %P 729-739 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226864?dopt=Abstract %R 10.3233/JAD-170415 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid Amyloid-β Levels are Increased in Patients with Insomnia. %A Chen, Dong-Wan %A Wang, Jun %A Zhang, Li-Li %A Wang, Yan-Jiang %A Gao, Chang-Yue %K Adult %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Female %K Humans %K Male %K Middle Aged %K Phosphorylation %K Sleep Initiation and Maintenance Disorders %K tau Proteins %X

Previous studies demonstrate that patients with sleep disorders are at risk of developing Alzheimer's disease (AD), with the mechanism unknown. It is suggested that acute sleep deprivation induces an increase of amyloid-β (Aβ), the major pathological agent in AD, in the cerebrospinal fluid (CSF). In the present study, we recruited 23 patients with chronic insomnia aged between 46 to 67 years and 23 healthy controls aged between 43 to 67 years. We investigated the CSF levels of Aβ and tau, another pathological hallmark in the AD pathogenesis. We found that CSF Aβ42 levels were significantly increased in insomnia patients. However, no significant difference was found in Aβ40, total tau (t-Tau), and phosphorylated tau (p-Tau) between the two groups. Furthermore, we found that CSF Aβ40 and Aβ42 levels are significantly correlated with the sleep quality, as reflected by the Pittsburgh Sleep Quality Index (PSQI) scores. But no significant correlation was found in CSF t-Tau and p-Tau levels with PSQI. Our results indicate that chronic sleep disorders may induce the disruption of Aβ metabolism in the brain, thus increase the risk for developing AD.

%B J Alzheimers Dis %V 61 %P 645-651 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29278891?dopt=Abstract %R 10.3233/JAD-170032 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid C-C Motif Chemokine Ligand 2 Correlates with Brain Atrophy and Cognitive Impairment in Alzheimer's Disease. %A Kimura, Akio %A Yoshikura, Nobuaki %A Hayashi, Yuichi %A Inuzuka, Takashi %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Atrophy %K Biomarkers %K Chemokine CCL2 %K Cognitive Dysfunction %K Disease Progression %K Female %K Gray Matter %K Humans %K Linear Models %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K tau Proteins %K Temporal Lobe %X

BACKGROUND: Chronic neuroinflammation has been implicated in Alzheimer's disease (AD) pathology.

OBJECTIVE: To investigate the association between cytokine and anti-amyloid-β (Aβ) autoantibody levels and the degree of brain atrophy and cognitive impairment in AD patients.

METHODS: Cerebrospinal fluid (CSF) levels of C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 8, C-X-C motif chemokine ligand 10, interleukin 6, and anti-Aβ autoantibody were evaluated in 69 AD patients. Serum levels of CCL2 and anti-Aβ autoantibody were also examined. The degree of brain atrophy was assessed using the voxel-based specific regional analysis system for AD, which targets the volumes of interest (VOI) in medial temporal structures. Cognitive function was evaluated by neuropsychological testing, including the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB).

RESULTS: CSF CCL2 levels correlated significantly with the severity (p = 0.023) and the extent (p = 0.022) of VOI atrophy, and with the extent of gray matter atrophy (p = 0.039) in AD patients. CSF anti-Aβ autoantibody levels were inversely correlated with the severity of VOI atrophy (p = 0.020), the extent of VOI atrophy (p = 0.015), and the ratio of VOI/GM atrophy (r = -0.358, p = 0.004). CSF CCL2 levels were also inversely correlated with MMSE (p = 0.0497) and FAB scores (p = 0.016).

CONCLUSIONS: CSF CCL2 levels are associated with the degree of medial temporal lobe and gray matter atrophy, and cognitive decline in AD.

%B J Alzheimers Dis %V 61 %P 581-588 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171996?dopt=Abstract %R 10.3233/JAD-170519 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Clinical Trials for Disease-Modifying Therapies in Alzheimer's Disease: A Primer, Lessons Learned, and a Blueprint for the Future. %A Cummings, Jeffrey %A Ritter, Aaron %A Zhong, Kate %K Alzheimer Disease %K Animals %K Clinical Trials as Topic %K Humans %X

Alzheimer's disease (AD) has no currently approved disease-modifying therapies (DMTs), and treatments to prevent, delay the onset, or slow the progression are urgently needed. A delay of 5 years if available by 2025 would decrease the total number of patients with AD by 50% in 2050. To meet the definition of DMT, an agent must produce an enduring change in the course of AD; clinical trials of DMTs have the goal of demonstrating this effect. AD drug discovery entails target identification followed by high throughput screening and lead optimization of drug-like compounds. Once an optimized agent is available and has been assessed for efficacy and toxicity in animals, it progresses through Phase I testing with healthy volunteers, Phase II learning trials to establish proof-of-mechanism and dose, and Phase III confirmatory trials to demonstrate efficacy and safety in larger populations. Phase III is followed by Food and Drug Administration review and, if appropriate, market access. Trial populations include cognitively normal at-risk participants in prevention trials, mildly impaired participants with biomarker evidence of AD in prodromal AD trials, and subjects with cognitive and functional impairment in AD dementia trials. Biomarkers are critical in trials of DMTs, assisting in participant characterization and diagnosis, target engagement and proof-of-pharmacology, demonstration of disease-modification, and monitoring side effects. Clinical trial designs include randomized, parallel group; delayed start; staggered withdrawal; and adaptive. Lessons learned from completed trials inform future trials and increase the likelihood of success.

%B J Alzheimers Dis %V 64 %P S3-S22 %8 2018 Jun 12 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad179901?id=journal-of-alzheimers-disease%2Fjad179901 %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562511?dopt=Abstract %R 10.3233/JAD-179901 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Clinically-Translatable Machine Learning Algorithm for the Prediction of Alzheimer's Disease Conversion in Individuals with Mild and Premild Cognitive Impairment. %A Grassi, Massimiliano %A Perna, Giampaolo %A Caldirola, Daniela %A Schruers, Koen %A Duara, Ranjan %A Loewenstein, David A %K Aged %K Aged, 80 and over %K Algorithms %K Alzheimer Disease %K Area Under Curve %K Atrophy %K Brain %K Cognitive Dysfunction %K Disease Progression %K Female %K Humans %K Logistic Models %K Machine Learning %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Predictive Value of Tests %K Prognosis %K Regression Analysis %K Sensitivity and Specificity %K Support Vector Machine %X

BACKGROUND: Available therapies for Alzheimer's disease (AD) can only alleviate and delay the advance of symptoms, with the greatest impact eventually achieved when provided at an early stage. Thus, early identification of which subjects at high risk, e.g., with MCI, will later develop AD is of key importance. Currently available machine learning algorithms achieve only limited predictive accuracy or they are based on expensive and hard-to-collect information.

OBJECTIVE: The current study aims to develop an algorithm for a 3-year prediction of conversion to AD in MCI and PreMCI subjects based only on non-invasively and effectively collectable predictors.

METHODS: A dataset of 123 MCI/PreMCI subjects was used to train different machine learning techniques. Baseline information regarding sociodemographic characteristics, clinical and neuropsychological test scores, cardiovascular risk indexes, and a visual rating scale for brain atrophy was used to extract 36 predictors. Leave-pair-out-cross-validation was employed as validation strategy and a recursive feature elimination procedure was applied to identify a relevant subset of predictors.

RESULTS: 16 predictors were selected from all domains excluding sociodemographic information. The best model resulted a support vector machine with radial-basis function kernel (whole sample: AUC = 0.962, best balanced accuracy = 0.913; MCI sub-group alone: AUC = 0.914, best balanced accuracy = 0.874).

CONCLUSIONS: Our algorithm shows very high cross-validated performances that outperform the vast majority of the currently available algorithms, and all those which use only non-invasive and effectively assessable predictors. Further testing and optimization in independent samples will warrant its application in both clinical practice and clinical trials.

%B J Alzheimers Dis %V 61 %P 1555-1573 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29355115?dopt=Abstract %R 10.3233/JAD-170547 %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 Decline in Preclinical Alzheimer's Disease: Amyloid-Beta versus Tauopathy. %A Huber, Colin M %A Yee, Connor %A May, Taylor %A Dhanala, Apoorva %A Mitchell, Cassie S %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Cognitive Dysfunction %K Disease Models, Animal %K Maze Learning %K Mice %K Reaction Time %K Recognition (Psychology) %K tau Proteins %X

 We perform a large-scale meta-analysis of 51 peer-reviewed 3xTg-AD mouse publications to compare Alzheimer's disease (AD) quantitative clinical outcome measures, including amyloid-β (Aβ), total tau, and phosphorylated tau (pTau), with cognitive performance in Morris water maze (MWM) and Novel Object Recognition (NOR). "High" levels of Aβ (Aβ40, Aβ42) showed significant but weak trends with cognitive decline (MWM: slope = 0.336, R2 = 0.149, n = 259, p < 0.001; NOR: slope = 0.156, R2 = 0.064, n = 116, p < 0.05); only soluble Aβ or directly measured Aβ meaningfully contribute. Tau expression in 3xTg-AD mice was within 10-20% of wild type and not associated with cognitive decline. In contrast, increased pTau is directly and significantly correlated with cognitive decline in MWM (slope = 0.408, R2 = 0.275, n = 371, p < < 0.01) and NOR (slope = 0.319, R2 = 0.176, n = 113, p < 0.05). While a variety of pTau epitopes (AT8, AT270, AT180, PHF-1) were examined, AT8 correlated most strongly with cognition (slope = 0.586, R2 = 0.521, n = 185, p < < 0.001). Multiple linear regression confirmed pTau is a stronger predictor of MWM performance than Aβ. Despite pTau's lower physical concentration than Aβ, pTau levels more directly and quantitatively correlate with 3xTg-AD cognitive decline. pTau's contribution to neurofibrillary tangles well after Aβ levels plateau makes pTau a viable treatment target even in late-stage clinical AD. Principal component analysis, which included hyperphosphorylation induced by kinases (pGSK3β, GSK3β, CDK5), identified phosphorylated ser9 GSK3β as the primary contributor to MWM variance. In summary, meta-analysis of cognitive decline in preclinical AD finds tauopathy more impactful than Aβ. Nonetheless, complex AD interactions dictate successful therapeutics harness synergy between Aβ and pTau, possibly through the GSK3 pathway.

%B J Alzheimers Dis %V 61 %P 265-281 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154274?dopt=Abstract %R 10.3233/JAD-170490 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cognitive Variability Predicts Incident Alzheimer's Disease and Mild Cognitive Impairment Comparable to a Cerebrospinal Fluid Biomarker. %A Gleason, Carey E %A Norton, Derek %A Anderson, Eric D %A Wahoske, Michelle %A Washington, Danielle T %A Umucu, Emre %A Koscik, Rebecca L %A Dowling, N Maritza %A Johnson, Sterling C %A Carlsson, Cynthia M %A Asthana, Sanjay %K Aged %K Aged, 80 and over %K Algorithms %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognitive Dysfunction %K Cross-Sectional Studies %K Female %K Humans %K Incidence %K Logistic Models %K Male %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Statistics, Nonparametric %K tau Proteins %X

BACKGROUND: Alzheimer's disease (AD) biomarkers are emerging as critically important for disease detection and monitoring. Most biomarkers are obtained through invasive, resource-intense procedures. A cognitive marker, intra-individual cognitive variability (IICV) may provide an alternative or adjunct marker of disease risk for individuals unable or disinclined to undergo lumbar puncture.

OBJECTIVE: To contrast risk of incident AD and mild cognitive impairment (MCI) associated with IICV to risk associated with well-established biomarkers: cerebrospinal fluid (CSF) phosphorylated tau protein (p-tau181) and amyloid-β 42 (Aβ42) peptide.

METHODS: Dispersion in cognitive performance, IICV, was estimated with a published algorithm, and included Trail Making Test A and B, Rey Auditory Verbal Learning Test (RAVLT), and the American National Adult Reading Test (ANART). CSF biomarkers were expressed as a ratio: p-tau181/Aβ42, wherein high values signified pathognomonic profiles. Logistic regression models included longitudinal data from 349 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who completed lumbar puncture. All subjects were cognitively healthy (n = 105) or diagnosed with MCI (n = 244) at baseline. We examined odds of conversion associated with baseline elevations in IICV and/or ratio of CSF p-tau181/Aβ42.

RESULTS: When included in models alone or in combination with CSF p-tau181/Aβ42, one standard IICV unit higher was associated with an estimated odds ratio for incident AD or MCI of 2.81 (95% CI: 1.83-4.33) in the most inclusive sample, and an odds ratio of 3.41 (95% CI: 2.03-5.73) when restricted to participants with MCI. Iterative analyses suggested that IICV independently improved model fit even when individual index components were included in comparative models.

CONCLUSIONS: These analyses provide preliminary support for IICV as a marker of incident AD and MCI. This easily-disseminated, non-invasive marker compared favorably to well-established CSF biomarkers.

%B J Alzheimers Dis %V 61 %P 79-89 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125485?dopt=Abstract %R 10.3233/JAD-170498 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Combined Socio-Behavioral Evaluation Improves the Differential Diagnosis Between the Behavioral Variant of Frontotemporal Dementia and Alzheimer's Disease: In Search of Neuropsychological Markers. %A Dodich, Alessandra %A Cerami, Chiara %A Cappa, Stefano F %A Marcone, Alessandra %A Golzi, Valeria %A Zamboni, Michele %A Giusti, Maria Cristina %A Iannaccone, Sandro %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Cognition %K Diagnosis, Differential %K Female %K Frontotemporal Dementia %K Humans %K Logistic Models %K Male %K Memory, Episodic %K Mental Recall %K Middle Aged %K Neuropsychological Tests %K Retrospective Studies %K Social Skills %X

BACKGROUND: Current diagnostic criteria for behavioral variant of frontotemporal dementia (bvFTD) and typical Alzheimer's disease (AD) include a differential pattern of neuropsychological impairments (episodic memory deficit in typical AD and dysexecutive syndrome in bvFTD). There is, however, large evidence of a frequent overlap in neuropsychological features, making the differential diagnosis extremely difficult.

OBJECTIVES: In this retrospective study, we evaluated the diagnostic value of different cognitive and neurobehavioral markers in bvFTD and AD patient groups.

METHODS: We included 95 dementia patients with a clinical and biomarker evidence of bvFTD (n = 48) or typical AD (n = 47) pathology. A clinical 2-year follow-up confirmed clinical classification. Performances at basic cognitive tasks (memory, executive functions, visuo-spatial, language) as well as social cognition skills and neurobehavioral profiles have been recorded. A stepwise logistic regression model compared the neuropsychological profiles between groups and assessed the accuracy of cognitive and neurobehavioral markers in discriminating bvFTD from AD.

RESULTS: Statistical comparison between patient groups proved social cognition and episodic memory impairments as main cognitive signatures of bvFTD and AD neuropsychological profiles, respectively. Only half of bvFTD patients showed attentive/executive deficits, questioning their role as cognitive marker of bvFTD. Notably, the large majority of bvFTD sample (i.e., 70%) poorly performed at delayed recall tasks. Logistic regression analysis identified social cognition performances, Frontal Behavioral Inventory and Mini-Mental State Examination scores as the best combination in distinguishing bvFTD from AD.

CONCLUSION: Social cognition tasks and socio-behavioral questionnaires are recommended in clinical settings to improve the accuracy of early diagnosis of bvFTD.

%B J Alzheimers Dis %V 61 %P 761-772 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254091?dopt=Abstract %R 10.3233/JAD-170650 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Comparison between FCSRT and LASSI-L to Detect Early Stage Alzheimer's Disease. %A Matías-Guiu, Jordi A %A Cabrera-Martín, María Nieves %A Curiel, Rosie E %A Valles-Salgado, María %A Rognoni, Teresa %A Moreno-Ramos, Teresa %A Carreras, José Luis %A Loewenstein, David A %A Matías-Guiu, Jorge %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cues %K Female %K Fluorodeoxyglucose F18 %K Humans %K Male %K Memory Disorders %K Mental Recall %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %K Psychiatric Status Rating Scales %K ROC Curve %K Semantics %X

BACKGROUND: The Free and Cued Selective Reminding Test (FCSRT) is the most accurate test for the diagnosis of prodromal Alzheimer's disease (AD). Recently, a novel cognitive test, the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L), has been developed in order to provide an early diagnosis.

OBJECTIVE: To compare the diagnostic accuracy of the FCSRT and the LASSI-L for the diagnosis of AD in its preclinical and prodromal stages using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) as a reference.

METHODS: Fifty patients consulting for subjective memory complaints without functional impairment and at risk for AD were enrolled and evaluated using FCSRT, LASSI-L, and FDG-PET. Participants were evaluated using a comprehensive neurological and neuropsychological protocol and were assessed with the FCSRT and LASSI-L. FDG-PET was acquired concomitantly and used for classification of patients as AD or non-AD according to brain metabolism using both visual and semi-quantitative methods.

RESULTS: LASSI-L scores allowed a better classification of patients as AD/non-AD in comparison to FCSRT. Logistic regression analysis showed delayed recall and failure to recovery from proactive semantic interference from LASSI-L as independent statistically significant predictors, obtaining an area under the curve of 0.894. This area under the curve provided a better discrimination than the best FCSRT score (total delayed recall, area under the curve 0.708, p = 0.029).

CONCLUSIONS: The LASSI-L, a cognitive stress test, was superior to FCSRT in the prediction of AD features on FDG-PET. This emphasizes the possibility to advance toward an earlier diagnosis of AD from a clinical perspective.

%B J Alzheimers Dis %V 61 %P 103-111 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125488?dopt=Abstract %R 10.3233/JAD-170604 %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 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 Deep Brain Stimulation of Frontal Lobe Networks to Treat Alzheimer's Disease. %A Scharre, Douglas W %A Weichart, Emily %A Nielson, Dylan %A Zhang, Jun %A Agrawal, Punit %A Sederberg, Per B %A Knopp, Michael V %A Rezai, Ali R %K Aged %K Alzheimer Disease %K Deep Brain Stimulation %K Female %K Frontal Lobe %K Humans %K Male %K Middle Aged %K Ohio %K Pilot Projects %K Positron-Emission Tomography %K Prospective Studies %X

The study objective was to evaluate the safety and efficacy of deep brain stimulation (DBS) at the ventral capsule/ventral striatum (VC/VS) region to specifically modulate frontal lobe behavioral and cognitive networks as a novel treatment approach for Alzheimer's disease (AD) patients. This is a non-randomized phase I prospective open label interventional trial of three subjects with matched comparison groups. AD participants given DBS for at least 18 months at the VC/VS target were compared on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), our primary outcome clinical measure, to matched groups without DBS from the AD Neuroimaging Initiative (ADNI) cohort. Serial 2-Deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET) images of AD participants were also compared longitudinally over time. Three AD DBS participants were matched to subjects from the ADNI cohort. All participants tolerated DBS well without significant adverse events. All three AD DBS participants had less performance decline and two of them meaningfully less decline over time on our primary outcome measure, CDR-SB, relative to matched comparison groups from the ADNI using score trajectory slopes. Minimal changes or increased metabolism on FDG-PET were seen in frontal cortical regions after chronic DBS at the VC/VS target. The first use of DBS in AD at a frontal lobe behavior regulation target (VC/VS) was well-tolerated and revealed less performance decline in CDR-SB. Frontal network modulation to improve executive and behavioral deficits should be furthered studied in AD.

%B J Alzheimers Dis %V 62 %P 621-633 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29400666?dopt=Abstract %R 10.3233/JAD-170082 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Development of a High-Sensitivity Method for the Measurement of Human Nasal Aβ42, Tau, and Phosphorylated Tau. %A Liu, Ziyi %A Kameshima, Naoko %A Nanjo, Toshifumi %A Shiino, Akihiko %A Kato, Tomoko %A Shimizu, Shino %A Shimizu, Takeshi %A Tanaka, Sachiko %A Miura, Katsuyuki %A Tooyama, Ikuo %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Case-Control Studies %K Female %K Humans %K Male %K Middle Aged %K Nasal Mucosa %K Peptide Fragments %K Phosphorylation %K Reproducibility of Results %K ROC Curve %K tau Proteins %X

Cost-effective and feasible methods for early diagnosis of Alzheimer's disease (AD) are needed. We present two methods to measure AD-related biomarkers simultaneously from one nasal smear for the purpose of diagnosing AD. Japanese men and women aged 63-85 years old were recruited in 2015-2016 for this case-control study. A total of 25 AD cases and 25 controls (22 men and 28 women) participated in this research. Nasal smears were collected from the common nasal meatus, inferior concha, middle nasal meatus, and olfactory cleft, and the proteins in the samples were analyzed by two methods, which we named PGD (Pre-treatment with guanidine- n-Dodecyl-beta-D-maltoside solution) method 1 (PGD-I) and 2 (PGD-II). The PGD-I method measured total tau and amyloid-β (Aβ)42, but no differences in median levels of total tau and Aβ42 between AD cases and controls were found in any of the nasal locations. The PGD-II method measured Aβ42, total tau, and phosphorylated tau, but levels of Aβ40 in all nasal locations of both groups were near zero. Median levels of phosphorylated tau to total tau (p-tau/t-tau) ratios in the middle nasal meatus and in the olfactory cleft were significantly higher in AD cases than in controls, and could significantly predict AD. To assess diagnostic reliability, areas under the ROC curve were 0.74 (95% CL = 0.52-0.95, p = 0.030) for the middle nasal meatus and 0.72 (95% CL = 0.52-0.92, p = 0.029) for the olfactory cleft. Thus, PGD-I and PGD-II can detect AD-related biomarkers in nasal smears and PGD-II may be a useful tool for diagnosing AD.

%B J Alzheimers Dis %V 62 %P 737-744 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480194?dopt=Abstract %R 10.3233/JAD-170962 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Diagnostic and Prognostic Value of a Dual-Tasking Paradigm in a Memory Clinic. %A Nielsen, Malene Schjnning %A Simonsen, Anja Hviid %A Siersma, Volkert %A Hasselbalch, Steen Gregers %A Hoegh, Peter %K Aged %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Cognitive Dysfunction %K Disease Progression %K Female %K Humans %K Logistic Models %K Male %K Memory %K Middle Aged %K Neuropsychological Tests %K Prognosis %K Prospective Studies %K ROC Curve %X

BACKGROUND: Daily living requires the ability to perform dual-tasking. As cognitive skills decrease in dementia, performing a cognitive and motor task simultaneously become increasingly challenging and subtle gait abnormalities may even be present in pre-dementia stages. Therefore, a dual-tasking paradigm, such as the Timed Up and Go-Dual Task (TUG-DT), may be useful in the diagnostic assessment of mild cognitive impairment (MCI).

OBJECTIVE: To investigate the diagnostic and prognostic ability of a dual-tasking paradigm in patients with MCI or mild Alzheimer's disease (AD) and to evaluate the association between the dual-tasking paradigm and cerebrospinal fluid (CSF) AD biomarkers.

METHODS: The study is a prospective cohort study conducted in a clinical setting in two memory clinics. Eighty-six patients were included (28 MCI, 17 AD, 41 healthy controls (HC)). The ability to perform dual-tasking was evaluated by the TUG-DT. Patients underwent a standardized diagnostic assessment and were evaluated to determine progression yearly.

RESULTS: ROC curve analysis illustrated a high discriminative ability of the dual-tasking paradigm in separating MCI patients from HC (AUC: 0.78, AUC: 0.82) and a moderate discriminative ability in separating MCI from AD (AUC: 0.73, AUC: 0.55). Performance discriminated clearly between all groups (p < 0.01). Logistic regression analyses revealed a low prognostic value of the dual-tasking paradigm for progression and rate of cognitive decline. A moderately strong correlation between the dual-tasking paradigm and CSF AD biomarkers was observed.

CONCLUSION: In our study, we found that patients with MCI and mild AD have increasing difficulties in dual-tasking compared to healthy elderly. Hence, the dual-tasking paradigm may be a potential complement in the diagnostic assessment in a typical clinical setting.

%B J Alzheimers Dis %V 61 %P 1189-1199 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29278887?dopt=Abstract %R 10.3233/JAD-161310 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Differences in Synaptic Dysfunction Between rTg4510 and APP/PS1 Mouse Models of Alzheimer's Disease. %A Gelman, Simon %A Palma, Jonathan %A Tombaugh, Geoffrey %A Ghavami, Afshin %K Age Factors %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Analysis of Variance %K Animals %K Biophysics %K Disease Models, Animal %K Electric Stimulation %K Excitatory Postsynaptic Potentials %K Hippocampus %K Humans %K Mice %K Mice, Transgenic %K Mutation %K Presenilin-1 %K Synapses %K Synaptic Transmission %K tau Proteins %X

Genetically modified mice have provided insights into the progression and pathology of Alzheimer's disease (AD). Here, we have examined two mouse models of AD: the rTg4510 mouse, which overexpresses mutant human Tau gene, and the APP/PS1 mouse, which overexpresses mutant human genes for amyloid precursor protein and presenilin 1. Both models exhibit deficits in hippocampal function, but comparative analyses of these deficits are sparse. We used extracellular field potential recordings in hippocampal slices to study basal synaptic transmission (BST), paired-pulse facilitation (PPF), and long-term potentiation (LTP) at the Schaffer collateral-CA1 pyramidal cell synapses in both models. We found that 6-7, but not 2-3-month-old rTg4510 mice exhibited reduced pre-synaptic activation (fiber volley (FV) amplitude, ∼50%) and field excitatory post-synaptic potential (fEPSP) slope (∼40%) compared to wild-type controls. In contrast to previous reports, BST, when controlled for FV amplitude, was not altered in rTg4510. APP/PS1 mice (2-3 mo and 8-10 mo) had unchanged FV amplitude compared to wild-type controls, while fEPSP slope was reduced by ∼34% in older mice, indicating a deficit in BST. PPF was unchanged in 8-10-month-old APP/PS1 mice, but was reduced in 6-7-month-old rTg4510 mice. LTP was reduced only in older rTg4510 and APP/PS1 mice. Our data suggest that BST deficits appear earlier in APP/PS1 than in rTg4510, which exhibited no BST deficits at the ages tested. However, FV and synaptic plasticity deficits developed earlier in rTg4510. These findings highlight fundamental differences in the progression of synaptic pathology in two genetically distinct models of AD.

%B J Alzheimers Dis %V 61 %P 195-208 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154272?dopt=Abstract %R 10.3233/JAD-170457 %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 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 Dysregulation and Dislocation of SFPQ Disturbed DNA Organization in Alzheimer's Disease and Frontotemporal Dementia. %A Lu, Jing %A Shu, Runzhe %A Zhu, Yan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Animals %K Brain %K Cell Line, Tumor %K DNA Damage %K Female %K Frontotemporal Dementia %K Gene Expression Regulation %K Humans %K Male %K Mice %K PTB-Associated Splicing Factor %K tau Proteins %K Translocation, Genetic %X

SFPQ (Splicing factor proline- and glutamine-rich) is a DNA and RNA binding protein involved in transcription, pre-mRNA splicing, and DNA damage repair. SFPQ was found dysregulated in a few tauopathies such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). In addition, knock-down of SFPQ induced FTD-like behavior in mouse. To confirm the role of SFPQ in AD and FTD, we analyzed the brain sections from the AD and FTD brain samples with SFPQ upregulation and dislocation. Specifically, we observed SFPQ dislocated to the cytoplasm and nuclear envelopes, and DNA structures and organizations were associated with these dislocation phenotypes in AD and FTD brains. Consistently, we also found decreased DAPI intensities and smaller chromocenters associated with SFPQ dislocation in nerural-2a (N2a) cells. As the upregulation and hyperphosphorylation of tau protein is a hallmark of AD and FTD, our study sought to investigate potential interactions between tau and SFPQ by co-transfection and co-immunoprecipitation assays in N2a cells. SFPQ dislocation was found enhanced with tau co-transfection and tau co-transfection further resulted in extended DNA disorganization in N2a cells. Overall, our results indicate that dysregulation and dislocation of SFPQ and subsequent DNA disorganization might be a novel pathway in the progression of AD and FTD.

%B J Alzheimers Dis %V 61 %P 1311-1321 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376859?dopt=Abstract %R 10.3233/JAD-170659 %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 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 The Effects and Meanings of Receiving a Diagnosis of Mild Cognitive Impairment or Alzheimer's Disease When One Lives Alone. %A Portacolone, Elena %A Johnson, Julene K %A Covinsky, Kenneth E %A Halpern, Jodi %A Rubinstein, Robert L %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Emotions %K Female %K Health Services %K Humans %K Interviews as Topic %K Male %K Residence Characteristics %K Single Person %X

BACKGROUND: One third of older adults with cognitive impairment live alone and are at high risk for poor health outcomes. Little is known about how older adults who live alone experience the process of receiving a diagnosis of mild cognitive impairment (MCI) or Alzheimer's disease (AD).

OBJECTIVE: The aim of this study was to understand the effects and meanings of receiving a diagnosis of MCI or AD on the lived experience of older adults living alone.

METHODS: This is a qualitative study of adults age 65 and over living alone with cognitive impairment. Participants' lived experiences were elicited through ethnographic interviews and participant observation in their homes. Using a qualitative content analysis approach, interview transcripts and fieldnotes were analyzed to identify codes and themes.

RESULTS: Twenty-nine older adults and 6 members of their social circles completed 114 ethnographic interviews. Core themes included: relief, distress, ambiguous recollections, and not knowing what to do. Participants sometimes felt uplifted and relieved by the diagnostic process. Some participants did not mention having received a diagnosis or had only partial recollections about it. Participants reported that, as time passed, they did not know what to do with regard to the treatment of their condition. Sometimes they also did not know how to prepare for a likely worsening of their condition, which they would experience while living alone.

CONCLUSION: Findings suggest the need for more tailored care and follow-up as soon as MCI or AD is diagnosed in persons living alone.

%B J Alzheimers Dis %V 61 %P 1517-1529 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376864?dopt=Abstract %R 10.3233/JAD-170723 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effects of Physical Exercise on Alzheimer's Disease Biomarkers: A Systematic Review of Intervention Studies. %A Frederiksen, Kristian Steen %A Gjerum, Le %A Waldemar, Gunhild %A Hasselbalch, Steen Gregers %K Alzheimer Disease %K Biomarkers %K Exercise %K Hippocampus %K Humans %K Outcome Assessment (Health Care) %K Physical Therapy Modalities %X

Physical exercise may be an important adjunct to pharmacological treatment of Alzheimer's disease (AD). Animal studies indicate that exercise may be disease modifying through several mechanisms including reduction of AD pathology. We carried out a systematic review of intervention studies of physical exercise with hippocampal volume (on MRI), amyloid-β, total tau, phosphorylated tau in cerebrospinal fluid (CSF), 18F-FDG-PET or amyloid PET as outcome measures in healthy subjects, patients with subjective memory complaints, mild cognitive impairment, or AD. We identified a total of 8 studies of which 6 investigated the effects of exercise on hippocampal volume in healthy subjects and 1 on CSF biomarkers and 1 on hippocampal volume in AD, and none investigating the remaining outcome measures or patient groups. Methodological quality of identified studies was generally low. One study found a detrimental effect on hippocampal volume and one found a positive effect, whereas the remaining studies did not find an effect of exercise on outcome measures. The present systematic study identified a relatively small number of studies, which did not support an effect of exercise on hippocampal volume. Methodological issues such small to moderate sample sizes and inadequate ramdomization procedures further limits conclusions. Our findings highlight the difficulties in conducting high quality studies of exercise and further studies are needed before definite conclusions may be reached.

%B J Alzheimers Dis %V 61 %P 359-372 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154278?dopt=Abstract %R 10.3233/JAD-170567 %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 Epigenetic Drug Repositioning for Alzheimer's Disease Based on Epigenetic Targets in Human Interactome. %A Chatterjee, Paulami %A Roy, Debjani %A Rathi, Nitin %K Alzheimer Disease %K Antipsychotic Agents %K Computational Biology %K Drug Repositioning %K Epigenesis, Genetic %K Epigenomics %K Humans %K MicroRNAs %K Protein Interaction Maps %K PubMed %X

BACKGROUND: Epigenetics has emerged as an important field in drug discovery. Alzheimer's disease (AD), the leading neurodegenerative disorder throughout the world, is shown to have an epigenetic basis. Currently, there are very few effective epigenetic drugs available for AD.

OBJECTIVE: In this work, for the first time we have proposed 14 AD repositioning epigenetic drugs and identified their targets from extensive human interactome.

METHODS: Interacting partners of the AD epigenetic proteins were identified from the extensive human interactome to construct Epigenetic Protein-Protein Interaction Network (EP-PPIN). Epigenetic Drug-Target Network (EP-DTN) was constructed with the drugs associated with the proteins of EP-PPIN. Regulation of non-coding RNAs associated with the target proteins of these drugs was also studied. AD related target proteins, epigenetic targets, enriched pathways, and functional categories of the proposed repositioning drugs were also studied.

RESULTS: The proposed 14 AD epigenetic repositioning drugs have overlapping targets and miRs with known AD epigenetic targets and miRs. Furthermore, several shared functional categories and enriched pathways were obtained for these drugs with FDA approved epigenetic drugs and known AD drugs.

CONCLUSIONS: The findings of our work might provide insight into future AD epigenetic-therapeutics.

%B J Alzheimers Dis %V 61 %P 53-65 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29199645?dopt=Abstract %R 10.3233/JAD-161104 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Erythromyeloid-Derived TREM2: A Major Determinant of Alzheimer's Disease Pathology in Down Syndrome. %A Raha-Chowdhury, Ruma %A Henderson, James W %A Raha, Animesh Alexander %A Stott, Simon R W %A Vuono, Romina %A Foscarin, Simona %A Wilson, Liam %A Annus, Tiina %A Fincham, Robert %A Allinson, Kieren %A Devalia, Vinod %A Friedland, Robert P %A Holland, Anthony %A Zaman, Shahid H %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Cell Line %K Disease Progression %K Down Syndrome %K Exosomes %K Female %K Humans %K Immunity, Innate %K Macrophages %K Male %K Membrane Glycoproteins %K Microglia %K Middle Aged %K Phagocytosis %K Polymorphism, Single Nucleotide %K Receptors, Immunologic %X

BACKGROUND: Down syndrome (DS; trisomy 21) individuals have a spectrum of hematopoietic and neuronal dysfunctions and by the time they reach the age of 40 years, almost all develop Alzheimer's disease (AD) neuropathology which includes senile plaques and neurofibrillary tangles. Inflammation and innate immunity are key players in AD and DS. Triggering receptor expressed in myeloid cells-2 (TREM2) variants have been identified as risk factors for AD and other neurodegenerative diseases.

OBJECTIVE: To investigate the effects of TREM2 and the AD-associated R47H mutation on brain pathology and hematopoietic state in AD and DS.

METHODS: We analyzed peripheral blood, bone marrow, and brain tissue from DS, AD, and age-matched control subjects by immunohistochemistry and western blotting. TREM2-related phagocytosis was investigated using a human myeloid cell line.

RESULTS: TREM2 protein levels in brain and sera declined with age and disease progression in DS. We observed soluble TREM2 in brain parenchyma that may be carried by a subset of microglia, macrophages, or exosomes. Two DS cases had the AD-associated TREM2-R47H mutation, which manifested a morphologically extreme phenotype of megakaryocytes and erythrocytes in addition to impaired trafficking of TREM2 to the erythroid membrane. TREM2 was shown to be involved in phagocytosis of red blood cells. TREM2 was seen in early and late endosomes. Silencing TREM2 using siRNA in THP1 cells resulted in significant cell death.

CONCLUSION: We provide evidence that peripheral TREM2 originating from erythromyeloid cells significantly determines AD neuropathology in DS subjects. Understanding the molecular signaling pathways mediated by TREM2 may reveal novel therapeutic targets.

%B J Alzheimers Dis %V 61 %P 1143-1162 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29278889?dopt=Abstract %R 10.3233/JAD-170814 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Establishing a New Screening System for Mild Cognitive Impairment and Alzheimer's Disease with Mental Rotation Tasks that Evaluate Visuospatial Function. %A Suzuki, Ayuko %A Shinozaki, Jun %A Yazawa, Shogo %A Ueki, Yoshino %A Matsukawa, Noriyuki %A Shimohama, Shun %A Nagamine, Takashi %K Aged %K Aged, 80 and over %K Agnosia %K Alzheimer Disease %K Case-Control Studies %K Cognition %K Cognitive Dysfunction %K Disease Progression %K Early Diagnosis %K Eye Movements %K Female %K Humans %K Male %K Mental Status Schedule %K Reaction Time %K ROC Curve %X

BACKGROUND: The mental rotation task is well-known for the assessment of visuospatial function; however, it has not been used for screening of dementia patients.

OBJECTIVE: The aim of this study was to create a simple screening test for patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) by focusing on non-amnestic symptoms.

METHODS: Age-matched healthy controls (age 75.3±6.8), patients with MCI (76.5±5.5), and AD (78.2±5.0) participated in this study. They carried out mental rotation tasks targeting geometric graphics or alphabetical characters with three rotating angles (0°, 90°, and 180°) and indicated the correct answer. Response accuracy and reaction time were recorded along with their eye movements using an eye tracker. To quantify their visual processing strategy, the run count ratio (RC ratio) was calculated by dividing the mean number of fixations in incorrect answers by that in correct answers.

RESULTS: AD patients showed lower accuracy and longer reaction time than controls. They also showed a significantly greater number of fixation and smaller saccade amplitude than controls, while fixation duration did not differ significantly. The RC ratio was higher for AD, followed by MCI and control groups. By setting the cut-off value to 0.47 in the 180° rotating angle task, we could differentiate MCI patients from controls with a probability of 80.0%.

CONCLUSIONS: We established a new screening system for dementia patients by evaluating visuospatial function. The RC ratio during a mental rotation task is useful for discriminating MCI patients from controls.

%B J Alzheimers Dis %V 61 %P 1653-1665 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376869?dopt=Abstract %R 10.3233/JAD-170801 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Examining the Relationship between Trace Lithium in Drinking Water and the Rising Rates of Age-Adjusted Alzheimer's Disease Mortality in Texas. %A Fajardo, Val Andrew %A Fajardo, Val Andrei %A LeBlanc, Paul J %A MacPherson, Rebecca E K %K Adult %K Age Factors %K Alzheimer Disease %K Drinking Water %K Female %K Humans %K Lithium %K Longitudinal Studies %K Male %K Obesity %K Prevalence %K Risk Factors %K Statistics as Topic %K Texas %K Young Adult %X

BACKGROUND: Alzheimer's disease (AD) mortality rates have steadily increased over time. Lithium, the current gold standard treatment for bipolar disorder, can exert neuroprotective effects against AD.

OBJECTIVE: We examined the relationship between trace levels of lithium in drinking water and changes in AD mortality across several Texas counties.

METHODS: 6,180 water samples from public wells since 2007 were obtained and averaged for 234 of 254 Texas counties. Changes in AD mortality rates were calculated by subtracting aggregated age-adjusted mortality rates obtained between 2000-2006 from those obtained between 2009-2015. Using aggregated rates maximized the number of counties with reliable mortality data. Correlational analyses between average lithium concentrations and changes in AD mortality were performed while also adjusting for gender, race, education, rural living, air pollution, physical inactivity, obesity, and type 2 diabetes.

RESULTS: Age-adjusted AD mortality rate was significantly increased over time (+27%, p < 0.001). Changes in AD mortality were negatively correlated with trace lithium levels (p = 0.01, r = -0.20), and statistical significance was maintained after controlling for most risk factors except for physical inactivity, obesity, and type 2 diabetes. Furthermore, the prevalence of obesity and type 2 diabetes positively correlated with changes in AD mortality (p = 0.01 and 0.03, respectively), but also negatively correlated with trace lithium in drinking water (p = 0.05 and <0.0001, respectively).

CONCLUSION: Trace lithium in water is negatively linked with changes in AD mortality, as well as obesity and type 2 diabetes, which are important risk factors for AD.

%B J Alzheimers Dis %V 61 %P 425-434 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103043?dopt=Abstract %R 10.3233/JAD-170744 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Executive and Language Subjective Cognitive Decline Complaints Discriminate Preclinical Alzheimer's Disease from Normal Aging. %A Valech, Natalia %A Tort-Merino, Adrià %A Coll-Padrós, Nina %A Olives, Jaume %A León, María %A Rami, Lorena %A Molinuevo, José Luis %K Aged %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognitive Dysfunction %K Executive Function %K Factor Analysis, Statistical %K Female %K Humans %K Language %K Male %K Middle Aged %K Neuropsychological Tests %K Self Report %X

BACKGROUND: There is a need to specify the profile of subjective cognitive decline in preclinical Alzheimer's disease (preAD).

OBJECTIVES: To explore specific items of the Subjective Cognitive Decline Questionnaire (SCD-Q) that discriminate preAD from normal aging.

METHODS: 68 cognitively normal older adults were classified as controls (n = 52) or preAD (n = 16) according to amyloid-β (Aβ) levels. An exploratory factor analysis and item analysis of the SCD-Q were performed. Informant reports of the SCD-Q were used to corroborate the findings of self-reports. One-year neuropsychological follow-up was available.

RESULTS: Four SCD-Q factors were extracted: EM-factor (episodic memory), A-factor (attention), O-factor (organization), and L-factor (language). PreAD reported a significantly higher decline in L-factor (F(1) = 6.49; p = 0.014) and A-factor (F(1) = 4.04; p = 0.049) compared to controls, and showed a higher frequency of perceived decline in SCD-Q items related with language and executive tasks (Sig-items.) Significant discriminative powers for Aβ-positivity were found for L-factor (AUC = 0.75; p = 0.003) and A-factor (AUC = 0.74; p = 0.004). Informants in the preAD group confirmed significantly higher scores in L-factor and Sig-items. A significant time×group interaction was found in the Semantic Fluency and Stroop tests, with the preAD group showing a decrease in performance at one-year.

CONCLUSIONS: Our results suggest that SCD-Q items related with language and executive decline may help in prediction algorithms to detect preAD. Validation in an independent population is needed.

%B J Alzheimers Dis %V 61 %P 689-703 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254090?dopt=Abstract %R 10.3233/JAD-170627 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Executive Dysfunction Detected with the Frontal Assessment Battery in Alzheimer's Disease Versus Vascular Dementia. %A D'Onofrio, Grazia %A Panza, Francesco %A Sancarlo, Daniele %A Addante, Filomena %A Solfrizzi, Vincenzo %A Cantarini, Chiara %A Mangiacotti, Antonio %A Lauriola, Michele %A Cascavilla, Leandro %A Paris, Francesco %A Lozupone, Madia %A Daniele, Antonio %A Greco, Antonio %A Seripa, Davide %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Comorbidity %K Dementia, Vascular %K Executive Function %K Female %K Frontal Lobe %K Geriatric Assessment %K Humans %K Logistic Models %K Male %K Polypharmacy %K Severity of Illness Index %X

Alzheimer's disease (AD) and vascular dementia (VaD) lead to progressive decline in executive function. We estimated the prevalence of executive dysfunction in AD and VaD patients, investigating cognitive, functional, and clinical correlates and also using a multidimensional approach based on a standardized comprehensive geriatric assessment (CGA). We included 215 patients (115 AD patients and 100 VaD patients) consecutively evaluated with a complete cognitive and affective assessment, a CGA, and the Frontal Assessment Battery (FAB) with six subtests investigating conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. The prevalence of dysexecutive syndrome screened with a FAB score <12 points was high in both AD (97 patients) and VaD (77 patients) (84.3% versus 77.0%, p = 0.171). AD patients were significantly younger, with higher grade of cognitive impairment and less severe comorbidity and polypharmacy than VaD patients. AD patients showed a significantly higher impairment in FAB total score and five FAB subtests (conceptualization, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy) than VaD patients. These findings were largely confirmed in a sub-analysis conducted subdividing the sample in mild and moderate-to-severe demented patients and suggesting that in moderate-to-severe AD there was higher impairment in FAB total score and four FAB subtests (conceptualization, sensitivity to interference, inhibitory control, and environmental autonomy). Executive dysfunction could be greater in AD patients with moderate-to-severe dementia compared to VaD patients, although our groups were also not matched for age, comorbidity or polypharmacy, which could also exert an effect.

%B J Alzheimers Dis %V 62 %P 699-711 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480171?dopt=Abstract %R 10.3233/JAD-170365 %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 Free Heme and Amyloid-β: A Fatal Liaison in Alzheimer's Disease. %A Chiziane, Elisabeth %A Telemann, Henriette %A Krueger, Martin %A Adler, Juliane %A Arnhold, Jürgen %A Alia, A %A Flemmig, Jörg %K Alzheimer Disease %K Amino Acid Sequence %K Amyloid %K Amyloid beta-Peptides %K Animals %K Brain %K Disease Models, Animal %K Heme %K Humans %K Hydrogen Peroxide %K Mice %K Mice, Transgenic %K Oxidation-Reduction %K Peptide Fragments %K Peroxidases %X

While the etiology of Alzheimer's disease (AD) is still unknown, an increased formation of amyloid-β (Aβ) peptide and oxidative processes are major pathological mechanism of the disease. The interaction of Aβ with free heme leads to the formation of peroxidase-active Aβ-heme complexes. However, enzyme-kinetic data and systematic mutational studies are still missing. These aspects were addressed in this study to evaluate the role of Aβ-heme complexes in AD. The enzyme-kinetic measurements showed peroxidase-specific pH- and H2O2-dependencies. In addition, the enzymatic activity of Aβ-heme complexes constantly increased at higher peptide excess. Moreover, the role of the Aβ sequence for the named enzymatic activity was tested, depicting human-specific R5, Y10, and H13 as essential amino acids. Also by studying Y10 as an endogenous peroxidase substrate for Aβ-heme complexes, ratio-specific effects were observed, showing an optimal dityrosine formation at an about 40-fold peptide excess. As dityrosine formation promotes Aβ fibrillation while free heme disturbs protein aggregation, we also investigated the effect of Aβ-heme complex-derived peroxidase activity on the formation of Aβ fibrils. The fluorescence measurements showed a different fibrillation behavior at strong peroxidase activity, leading also to altered fibril morphologies. The latter was detected by electron microscopy. As illustrated by selected in vivo measurements on a mouse model of AD, the disease is also characterized by Aβ-derived microvessel destructions and hemolytic processes. Thus, thrombo-hemorrhagic events are discussed as a source for free heme in brain tissue. In summary, we suggest the formation and enzymatic activity of Aβ-heme complexes as pathological key features of AD.

%B J Alzheimers Dis %V 61 %P 963-984 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332049?dopt=Abstract %R 10.3233/JAD-170711 %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 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 Geographical Distribution and Diversity of Gut Microbial NADH:Ubiquinone Oxidoreductase Sequence Associated with Alzheimer's Disease. %A Paley, Elena L %A Merkulova-Rainon, Tatiana %A Faynboym, Aleksandr %A Shestopalov, Valery I %A Aksenoff, Igor %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Anti-Bacterial Agents %K Biological Transport %K DNA Primers %K Electron Transport Complex I %K Feces %K Female %K Gastrointestinal Microbiome %K Geography %K Host-Pathogen Interactions %K Humans %K Male %K Middle Aged %K Sequence Analysis, DNA %K Young Adult %X

Earlier we reported induction of neurotoxicity and neurodegeneration by tryptophan metabolites that link the metabolic alterations to Alzheimer's disease (AD). Tryptophan is a product of Shikimate pathway (SP). Human cells lack SP, which is found in human gut bacteria exclusively using SP to produce aromatic amino acids (AAA). This study is a first attempt toward gene-targeted analysis of human gut microbiota in AD fecal samples. The oligonucleotide primers newly-designed for this work target SP-AAA in environmental bacteria associated with human activity. Using polymerase chain reaction (PCR), we found unique gut bacterial sequence in most AD patients (18 of 20), albeit rarely in controls (1 of 13). Cloning and sequencing AD-associated PCR products (ADPP) enables identification of Na(+)-transporting NADH: Ubiquinone reductase (NQR) in Clostridium sp. The ADPP of unrelated AD patients possess near identical sequences. NQR substrate, ubiquinone is a SP product and human neuroprotectant. A deficit in ubiquinone has been determined in a number of neuromuscular and neurodegenerative disorders. Antibacterial therapy prompted an ADPP reduction in an ADPP-positive control person who was later diagnosed with AD-dementia. We explored the gut microbiome databases and uncovered a sequence similarity (up to 97%) between ADPP and some healthy individuals from different geographical locations. Importantly, our main finding of the significant difference in the gut microbial genotypes between the AD and control human populations is a breakthrough.

%B J Alzheimers Dis %V 61 %P 1531-1540 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376868?dopt=Abstract %R 10.3233/JAD-170764 %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 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 Human Gut Microbiota in Health and Alzheimer's Disease. %A Szablewski, Leszek %K Alzheimer Disease %K Diet, High-Fat %K Dysbiosis %K Gastrointestinal Microbiome %K Gastrointestinal Tract %K Humans %K Risk Factors %X

Gut microbiota plays a crucial role in human health and disease. The alterations in the composition of gut microbiota may cause the onset of certain human pathologies. One of these is Alzheimer's disease (AD). High-fat diets, administration of antibiotics, lack of probiotics and/or prebiotics in diet increase the risk of AD. On the other hand, modulation of the composition of gut microbiota may decrease the risk of AD and be able to slow down the progression of AD.

%B J Alzheimers Dis %V 62 %P 549-560 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480188?dopt=Abstract %R 10.3233/JAD-170908 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Impact of APOE ɛ4 in Alzheimer's Disease Differs According to Age. %A Kim, Jaeho %A Park, Seongbeom %A Yoo, Heejin %A Jang, Hyemin %A Kim, Yeshin %A Kim, Ko Woon %A Jang, Young Kyoung %A Lee, Jin San %A Kim, Sung Tae %A Kim, Seonwoo %A Lee, Jong Min %A Ki, Chang-Seok %A Na, Duk L %A Seo, Sang Won %A Kim, Hee Jin %K Age Factors %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Atrophy %K Brain %K Case-Control Studies %K Cognition %K Female %K Heterozygote %K Humans %K Magnetic Resonance Imaging %K Male %K Memory %K Middle Aged %K Republic of Korea %X

We evaluated how the impact of apolipoprotein E4 (APOE4) differs according to age in Alzheimer's disease (AD) patients. We recruited 846 AD patients and 815 cognitively normal controls and categorized into three groups with respect to their age (<65, 65-74, and ≥75 years). We evaluated the risk of AD in APOE4 carriers and compared cortical thickness and cognitive function according to APOE4 status in each age group. At the point of this study, in young (<65 years) AD, APOE4 noncarriers had the most severe frontal and perisylvian atrophy, while in old (≥75 years) AD, APOE4 carriers had the most severe medial temporal atrophy. In AD under 75 years, APOE4 noncarriers and heterozygotes showed worse performance in language, visuospatial, and frontal function compared to homozygotes, while, in old (≥75 years) AD, APOE4 homozygotes showed worse performance in memory compared to noncarriers. As the detrimental effects of APOE4 seen in older AD patients were not found in younger AD patients, we suggest that some unrevealed factors are associated with cortical atrophy and non-amnestic cognitive dysfunction in young AD with APOE4 noncarriers.

%B J Alzheimers Dis %V 61 %P 1377-1385 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376853?dopt=Abstract %R 10.3233/JAD-170556 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impaired IL-17 Production in Gut-Residing Immune Cells of 5xFAD Mice with Alzheimer's Disease Pathology. %A Saksida, Tamara %A Koprivica, Ivan %A Vujičić, Milica %A Stošić-Grujičić, Stanislava %A Perović, Milka %A Kanazir, Selma %A Stojanović, Ivana %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K B-Lymphocytes %K Disease Models, Animal %K Female %K Interleukin-17 %K Lymph Nodes %K Male %K Mice %K Mice, Transgenic %K MicroRNAs %K Peyer's Patches %K Th17 Cells %X

Alzheimer's disease (AD) is characterized by accumulation of amyloid-β plaques that further promotes microglia-mediated neuroinflammatory responses and inflammation in the brain. Emerging data are revealing the relation between gut-associated lymphoid tissue (GALT) cells and CNS, as effector cells primed in the gut might home to the brain. This study aimed to determine cell composition of GALT in 5xFAD mice, an established model for AD. Immune cells isolated from Peyer's patches (PP) and mesenteric lymph nodes (MLN) were stained with surface and intracellular markers for T helper (Th) subpopulations, B lymphocytes and macrophages and analyzed cytofluorimetrically, while cytokine expression and production were determined by qPCR and ELISA, respectively. Inflammation was detected in GALT of 5xFAD mice with established AD pathology. Although the production of IFN-γ, IL-4, and IL-10 was comparable between the strains, lower IL-17 production was observed in PP and MLN cells. This phenomenon could not be attributed to a lower abundance of Th17 cells, or cytokines that initiate their formation or propagation (TGF-β, IL-6, and IL-23). Also, reduced IL-17 production was not a consequence of altered Il-17 mRNA transcription or deficiency of Rorγt, a key transcription factor for IL-17. However, the expression of miR-155 (a non-coding micro RNA that promotes the development of Th17 cells), was significantly lower in MLN cells of 5xFAD mice. In contrast, mice without AD neuropathology did not have inflammation in GALT or altered Th17 numbers, nor decreased IL-17 production. In conclusion, the observed changes in GALT of 5xFAD mice mirror the disease progression and might reflect inadequate immune surveillance in the gut and lead to enhanced AD pathology.

%B J Alzheimers Dis %V 61 %P 619-630 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254086?dopt=Abstract %R 10.3233/JAD-170538 %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 Foxo3a Nuclear Translocation and Activity is an Early Neuronal Response to βγ-Secretase-Mediated Processing of the Amyloid-β Protein Precursor: Utility of an AβPP-GAL4 Reporter Assay. %A Law, Bernard M %A Guest, Amy L %A Pullen, Matthew W J %A Perkinton, Michael S %A Williams, Robert J %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Disease Models, Animal %K Forkhead Box Protein O3 %K Mice %K Mutagenesis, Site-Directed %K Mutation %K Neurons %K Phosphorylation %K Protein Transport %K Signal Transduction %X

Sequential cleavage of the amyloid-β protein precursor (AβPP) by BACE1 (β-secretase) followed by theγ-secretase complex, is strongly implicated in Alzheimer's disease (AD) but the initial cellular responses to these cleavage events are not fully defined. β-secretase-mediated AβPP processing yields an extracellular domain (sAβPPβ) and a C-terminal fragment of AβPP of 99 amino acids (C99). Subsequent cleavage by γ-secretase produces amyloid-β (Aβ) and an AβPP intracellular domain (AICD). A cellular screen based on the generation of AICD from an AβPP-Gal4 fusion protein was adapted by introducing familial AD (FAD) mutations into the AβPP sequence and linking the assay to Gal4-UAS driven luciferase and GFP expression, to identify responses immediately downstream of AβPP processing in neurons with a focus on the transcription factor Foxo3a which has been implicated in neurodegeneration. The K670N/M671L, E682K, E693G, and V717I FAD mutations and the A673T protective mutation, were introduced into the AβPP sequence by site directed mutagenesis. When expressed in mouse cortical neurons, AβPP-Gal4-UAS driven luciferase and GFP expression was substantially reduced by γ-secretase inhibitors, lowered by β-secretase inhibitors, and enhanced by α-secretase inhibitors suggesting that AICD is a product of the βγ-secretase pathway. AβPP-Gal4-UAS driven GFP expression was exploited to identify individual neurons undergoing amyloidogenic AβPP processing, revealing increased nuclear localization of Foxo3a and enhanced Foxo3a-mediated transcription downstream of AICD production. Foxo3a translocation was not driven by AICD directly but correlated with reduced Akt phosphorylation. Collectively this suggests that βγ-secretase-mediated AβPP processing couples to Foxo3a which could be an early neuronal signaling response in AD.

%B J Alzheimers Dis %V 61 %P 673-688 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254083?dopt=Abstract %R 10.3233/JAD-170393 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Increased Serum Acylated Ghrelin Levels in Patients with Mild Cognitive Impairment. %A Cao, Xi %A Zhu, Min %A He, Yan %A Chu, Wenzheng %A Du, Yifeng %A Du, Heng %K Aged %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Cognitive Dysfunction %K Female %K Ghrelin %K Humans %K Male %K Middle Aged %K Risk Factors %X

Ghrelin is a stomach-derived circulating hormone. In addition to its function as an orexigenic stimulant, the role of ghrelin in the consolidation of learning and memory has been implicated in recent years. However, the status of circulating acylated ghrelin (AG, that is, the functional form of ghrelin) in the symptomatic predementia stage of Alzheimer's disease (AD) has rarely been investigated. In the current study, we examined the serum levels of acylated and total ghrelin in 22 patients with mild cognitive impairment (MCI) and 30 cognitively normal controls. We have found that patients with MCI had significantly increased serum AG levels, which were inversely associated with defected short- and long-term memory as well as language skills. Of note, the levels of total circulating ghrelin were similar between the two groups. Intriguingly, serum AG but not total ghrelin was associated with AD risk factors including the age, hypertension, and hyperlipidemia. Therefore, circulating AG may serve as a potential early systemic biomarker for AD-related cognitive impairments. Nevertheless, the simplest interpretation of the results is that the levels of circulating AG are associated with cognitive impairments in patients with MCI, thereby forming the groundwork for our future studies on the systemic mechanisms of AD pertaining to the ghrelin system.

%B J Alzheimers Dis %V 61 %P 545-552 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226871?dopt=Abstract %R 10.3233/JAD-170721 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Increased Vulnerability of the Hippocampus in Transgenic Mice Overexpressing APP and Triple Repeat Tau. %A Arner, Andrew %A Rockenstein, Edward %A Mante, Michael %A Florio, Jazmin %A Masliah, Deborah %A Salehi, Bahar %A Adame, Anthony %A Overk, Cassia %A Masliah, Eliezer %A Rissman, Robert A %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Disease Models, Animal %K Female %K Glycogen Synthase Kinase 3 %K Hippocampus %K Humans %K Male %K Mice %K Mice, Transgenic %K Neocortex %K tau Proteins %K Tauopathies %X

Alzheimer's disease (AD) is the most common tauopathy, characterized by progressive accumulation of amyloid-β (Aβ) and hyperphosphorylated tau. While pathology associated with the 4-repeat (4R) tau isoform is more abundant in corticobasal degeneration and progressive supranuclear palsy, both 3R and 4R tau isoforms accumulate in AD. Many studies have investigated interactions between Aβ and 4R tau in double transgenic mice, but few, if any, have examined the effects of Aβ with 3R tau. To examine this relationship, we crossed our APP751 mutant line with our recently characterized 3R tau mutant model to create a bigenic line (hAPP-3RTau) to model AD neuropathology. Mice were analyzed at 3 and 6 months of age for pathological and behavioral endpoints. While both the 3RTau and the hAPP-3RTau mice showed neuronal loss, increased tau aggregation, Aβ plaques and exhibited more behavioral deficits compared to the non-tg control, the bigenic mice often displaying relatively worsening levels. We found that even in young animals we found that the presence of APP/Aβ increased the accumulation of 3R tau in the neocortex and hippocampus. This observation was accompanied by activation of GSK3 and neurodegeneration in the neocortex and CA1 region. These results suggest that in addition to 4R tau, APP/Aβ may also enhance accumulation of 3R tau, a process which may be directly relevant to pathogenic pathways in AD. Our results demonstrate that this bigenic model closely parallels the pathological course of AD and may serve as a valuable model for testing new pharmacological interventions.

%B J Alzheimers Dis %V 61 %P 1201-1219 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332037?dopt=Abstract %R 10.3233/JAD-170388 %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 Interaction between Cytomegalovirus and Herpes Simplex Virus Type 1 Associated with the Risk of Alzheimer's Disease Development. %A Lövheim, Hugo %A Olsson, Jan %A Weidung, Bodil %A Johansson, Anders %A Eriksson, Sture %A Hallmans, Göran %A Elgh, Fredrik %K Aged %K Alzheimer Disease %K Antibodies, Viral %K Case-Control Studies %K Cytomegalovirus %K Cytomegalovirus Infections %K Enzyme-Linked Immunosorbent Assay %K Female %K Herpes Simplex %K Herpesvirus 1, Human %K Humans %K Immunoglobulin G %K Immunoglobulin M %K Logistic Models %K Male %K Middle Aged %X

BACKGROUND: Several environmental factors, including infectious agents, have been suggested to cause Alzheimer's disease (AD). Cytomegalovirus (CMV) has been associated with AD in several recent studies.

OBJECTIVE: To investigate whether carriage of CMV, alone or in combination with Herpes simplex virus (HSV), increased the risk of developing AD.

METHODS: Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years), taken an average of 9.6 years before AD diagnosis, and 360 age-, sex-, cohort-, and sampling date matched dementia-free controls were analyzed to detect anti-CMV (immunoglobulin [Ig] G and IgM), group-specific anti-HSV (IgG and IgM), and specific anti-HSV1 and HSV2 IgG antibodies by enzyme-linked immunosorbent assays. AD cases and dementia-free controls were compared using conditional logistic regression analyses.

RESULTS: The presence of anti-CMV IgG antibodies did not increase the risk of AD (odds ratio [OR], 0.857; p = 0.497). Among AD cases, an association between CMV and HSV1 carriage was detected (OR 7.145, p < 0.001); in a conditional logistic regression model, the interaction between CMV and HSV1 was associated with AD development (OR 5.662; p = 0.007).

CONCLUSION: The present findings do not support a direct relationship between CMV infection and the development of AD; however, an interaction between CMV and HSV1 was found to be associated significantly with AD development. These findings suggest that CMV infection facilitates the development of HSV1-associated AD, possibly via its effects on the immune system.

%B J Alzheimers Dis %V 61 %P 939-945 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254081?dopt=Abstract %R 10.3233/JAD-161305 %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 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 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 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 A Longitudinal Study of Total and Phosphorylated α-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer's Disease and Mild Cognitive Impairment. %A Wang, Hua %A Stewart, Tessandra %A Toledo, Jon B %A Ginghina, Carmen %A Tang, Lu %A Atik, Anzari %A Aro, Patrick %A Shaw, Leslie M %A Trojanowski, John Q %A Galasko, Douglas R %A Edland, Steven %A Jensen, Poul H %A Shi, Min %A Zhang, Jing %K Aged %K Aged, 80 and over %K alpha-Synuclein %K Alzheimer Disease %K Biomarkers %K Cognitive Dysfunction %K Cross-Sectional Studies %K Disease Progression %K Executive Function %K Female %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Memory Disorders %K Multivariate Analysis %K Neuropsychological Tests %K Phosphorylation %K tau Proteins %X

Alzheimer's disease (AD) features a dynamic sequence of amyloid deposition, neurodegeneration, and cognitive impairment. A significant fraction of AD brains also displays Lewy body pathology, suggesting that addition of classically Parkinson's disease-related proteins to the AD biomarker panel may be of value. To determine whether addition of cerebrospinal fluid (CSF) total α-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-β1-42 (Aβ42), tau, and phosphorylated tau (p-tau181)] improves its performance, we examined CSF samples collected longitudinally up to 7 years as part of the Alzheimer's Disease Neuroimaging Initiative. From 87 AD, 177 mild cognitive impairment (MCI), and 104 age-matched healthy controls, 792 baseline and longitudinal CSF samples were tested for total α-synuclein, pS129, Aβ42, tau, and p-tau181. pS129, but not total α-synuclein, was weakly associated with diagnosis at baseline when t-tau/Aβ42 was included in the statistical model (β= 0.0026, p = 0.041, 95% CI [(0.0001)-(0.005)]). CSF α-synuclein predicted Alzheimer's Disease Assessment Scale-Cognitive (β= -0.59, p = 0.0015, 95% CI [(-0.96)-(-0.23)]), memory (β= 0.4, p = 0.00025, 95% CI [(0.16)-(0.59)]), and executive (0.62,<0.0001, 95% CI [(0.31)-(0.93)]) function composite scores, and progression from MCI to AD (β= 0.019, p = 0.0011, 95% CI [(0.002)-(0.20)]). pS129 was associated with executive function (β= -2.55, p = 0.0085, 95% CI [(-4.45)-(-0.66)]). Lower values in the mismatch between α-synuclein and p-tau181 predicted faster cognitive decline (β= 0.64, p = 0.0012, 95% CI [(0.48)-(0.84)]). Longitudinal biomarker changes did not differ between groups, and may not reflect AD progression. The α-synuclein-p-tau181-Mismatch could better predict longitudinal cognitive changes than classical AD markers alone, and its pathological correlates should be investigated further.

%B J Alzheimers Dis %V 61 %P 1541-1553 %8 2018 Jan 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376878?dopt=Abstract %R 10.3233/JAD-171013 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Low Prevalence of Cancer in Patients with Frontotemporal Lobar Degeneration. %A Katisko, Kasper %A Haapasalo, Annakaisa %A Koivisto, Anne %A Krüger, Johanna %A Hartikainen, Päivi %A Korhonen, Ville %A Helisalmi, Seppo %A Herukka, Sanna-Kaisa %A Remes, Anne M %A Solje, Eino %K Aged %K Alzheimer Disease %K C9orf72 Protein %K DNA Repeat Expansion %K Female %K Finland %K Frontotemporal Lobar Degeneration %K Heterozygote %K Humans %K Male %K Middle Aged %K Neoplasms %K Prevalence %X

Several studies have reported reduced risk of cancer in patients with Alzheimer's disease (AD) or Parkinson's disease. The relationship between cancer and frontotemporal lobar degeneration (FTLD) has not been previously reported. Here, our aim was to evaluate the occurrence of cancer in Finnish FTLD patients with a high proportion of C9ORF72 repeat expansion carriers in comparison to age- and sex-matched group of AD patients and control subjects classified as not cognitively impaired (NCI). The prevalence of cancer was 9.7% in FTLD, 18.7% in AD, and 17.4% in NCI (FTLD versus AD p = 0.012, FTLD versus NCI p = 0.029) groups. No differences were observed between C9ORF72 repeat expansion carriers and non-carriers inside the FTLD group. To our knowledge, this is the first study showing significantly lower prevalence of cancer in FTLD patients compared to patients with AD or NCI subjects. Our data suggest an inverse association between neurodegeneration and cancer and that FTLD-specific mechanisms may underlie the especially strong inverse association observed in this study.

%B J Alzheimers Dis %V 62 %P 789-794 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480183?dopt=Abstract %R 10.3233/JAD-170854 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Mental States in Moving Shapes: Distinct Cortical and Subcortical Contributions to Theory of Mind Impairments in Dementia. %A Synn, Artemis %A Mothakunnel, Annu %A Kumfor, Fiona %A Chen, Yu %A Piguet, Olivier %A Hodges, John R %A Irish, Muireann %K Aged %K Alzheimer Disease %K Brain %K Case-Control Studies %K Female %K Frontotemporal Dementia %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Memory, Episodic %K Mentalization %K Middle Aged %K Neuropsychological Tests %K Task Performance and Analysis %K Theory of Mind %X

Impaired capacity for Theory of Mind (ToM) represents one of the hallmark features of the behavioral variant of frontotemporal dementia (bvFTD) and is suggested to underpin an array of socioemotional disturbances characteristic of this disorder. In contrast, while social processing typically remains intact in Alzheimer's disease (AD), the cognitive loading of socioemotional tasks may adversely impact mentalizing performance in AD. Here, we employed the Frith-Happé animations as a dynamic on-line assessment of mentalizing capacity with reduced incidental task demands in 18 bvFTD, 18 AD, and 25 age-matched Controls. Participants viewed silent animations in which geometric shapes interact in Random, Goal-Directed, and ToM conditions. An exclusive deficit in ToM classification was observed in bvFTD relative to Controls, while AD patients were impaired in the accurate classification of both Random and ToM trials. Correlation analyses revealed robust associations between ToM deficits and carer ratings of affective empathy disruption in bvFTD, and with episodic memory dysfunction in AD. Voxel-based morphometry analyses further identified dissociable neural correlates contingent on patient group. A distributed network of medial prefrontal, frontoinsular, striatal, lateral temporal, and parietal regions were implicated in the bvFTD group, whereas the right hippocampus correlated with task performance in AD. Notably, subregions of the cerebellum, including lobules I-IV and V, bilaterally were implicated in task performance irrespective of patient group. Our findings reveal new insights into the mechanisms potentially mediating ToM disruption in dementia syndromes, and suggest that the cerebellum may play a more prominent role in social cognition than previously appreciated.

%B J Alzheimers Dis %V 61 %P 521-535 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad170809?id=journal-of-alzheimers-disease%2Fjad170809 %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29172002?dopt=Abstract %R 10.3233/JAD-170809 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Mesenchymal Stem Cell-Derived Extracellular Vesicles Suppresses iNOS Expression and Ameliorates Neural Impairment in Alzheimer's Disease Mice. %A Wang, Shan-Shan %A Jia, Jianjun %A Wang, Zhenfu %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Cells, Cultured %K Disease Models, Animal %K Extracellular Vesicles %K Humans %K Male %K Mesenchymal Stem Cells %K Mice %K Mice, Transgenic %K Neuronal Plasticity %K Neurons %K Nitric Oxide Synthase Type II %K Synaptic Transmission %X

BACKGROUND: Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been reported to exhibit therapeutic effects in various animal models of neurological diseases, such as stroke and hypoxic-ischemic brain injury.

OBJECTIVE: The present study investigated the potential beneficial effect of MSC-derived EVs in an animal model of Alzheimer's disease (AD).

METHODS: APP/PS1 mice and their non-transgenic littermates (WT) received intracerebroventricle injection of MSC-derived EVs once per two days for two weeks. Then novel object recognition and water maze tasks were carried out to measure the cognitive behaviors. Electrophysiological tests were carried out to measure hippocampal synaptic plasticity. Inducible nitric oxide synthase (iNOS) mRNA and protein levels were measured by qRT-PCR and western blotting in primary cultured neurons treated with amyloid-β peptide (Aβ) or prepared from APP/PS1 mice.

RESULTS: Treatment with MSC-derived EVs alleviates exogenous Aβ-induced iNOS mRNA and protein expression. In cultured primary neurons prepared from APP/PS1 pups, iNOS mRNA and protein levels were significantly reduced when treated with MSC-derived EVs. MSC-derived EVs improved cognitive behavior, rescued impairment of CA1 synaptic transmission, and long-term potentiation in APP/PS1 mice.

CONCLUSION: MSC-derived EVs possessed beneficial effects in a mouse model of AD, probably by suppressing Aβ induced iNOS expression.

%B J Alzheimers Dis %V 61 %P 1005-1013 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254100?dopt=Abstract %R 10.3233/JAD-170848 %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 microRNA 221 Targets ADAM10 mRNA and is Downregulated in Alzheimer's Disease. %A Manzine, Patricia R %A Pelucchi, Silvia %A Horst, Maria A %A Vale, Francisco A C %A Pavarini, Sofia C I %A Audano, Matteo %A Mitro, Nico %A Di Luca, Monica %A Marcello, Elena %A Cominetti, Márcia R %K ADAM10 Protein %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cell Line, Tumor %K Cohort Studies %K Down-Regulation %K Female %K Humans %K Male %K MicroRNAs %K Middle Aged %K Neuroblastoma %K Psychiatric Status Rating Scales %K RNA, Messenger %K ROC Curve %K Transfection %X

ADAM10 is the α-secretase that cleaves amyloid-β protein precursor in the non-amyloidogenic pathway in Alzheimer's disease (AD) and is known to be regulated by different microRNAs (miRNAs), which are post-transcriptional regulators related to several biological and pathological processes, including AD. Here we proposed to explore and validate miRNAs that have direct or indirect relations to the AD pathophysiology and ADAM10 gene. Approximately 700 miRNAs were analyzed and 21 differentially expressed miRNAs were validated in a sample of 21 AD subjects and 17 cognitively healthy matched controls. SH-SY5Y cells were transfected with miR-144-5p, miR-221, and miR-374 mimics and inhibitors, and ADAM10 protein levels were evaluated. miR-144-5p, miR-221, and miR-374 were downregulated in AD. The overexpression of miR-221 in SH-SY5Y cells resulted in ADAM10 reduction and its inhibition in ADAM10 increased. These findings show that miR-221 can be a new potential therapeutic target for increasing ADAM10 levels in AD. In addition, these results can contribute to the better understanding of ADAM10 post-transcriptional regulation.

%B J Alzheimers Dis %V 61 %P 113-123 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036829?dopt=Abstract %R 10.3233/JAD-170592 %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 Mutation Screening of the CHCHD2 Gene for Alzheimer's Disease and Frontotemporal Dementia in Chinese Mainland Population. %A Che, Xiang-Qian %A Zhao, Qian-Hua %A Huang, Yue %A Li, Xia %A Ren, Ru-Jing %A Chen, Sheng-Di %A Guo, Qi-Hao %A Wang, Gang %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Asian Continental Ancestry Group %K Case-Control Studies %K China %K Female %K Frontotemporal Dementia %K Genetic Association Studies %K Humans %K Male %K Middle Aged %K Mitochondrial Proteins %K Mutation %K Transcription Factors %X

As an important multifunctional protein involved in regulation of mitochondrial metabolism, CHCHD2 was identified as a causative gene for Parkinson's disease (PD), yet the relationship between CHCHD2 and neurodegenerative dementia is not well understood. We directly sequenced the entire coding region of CHCHD2 gene in 150 AD patients, 84 FTD patients, and 417 controls. Four rare putative pathogenic variants of CHCHD2, including rs142444896 (c.5C>T, p.P2L), rs752705344 (c.15C>G, p.S5R), rs145190179 (c.94G>A, p.A32T), and rs182992574 (c.255T>A, p.S85R) were identified from a cohort composed of 150 AD and 84 FTD patients. These results suggest that CH CHD2 gene play an important role in other neurodegenerative disorders from our dementia study in China.

%B J Alzheimers Dis %V 61 %P 1283-1288 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376860?dopt=Abstract %R 10.3233/JAD-170692 %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 Negative Prospective Memory in Alzheimer's Disease: "Do Not Perform That Action". %A El Haj, Mohamad %A Coello, Yann %A Kapogiannis, Dimitrios %A Gallouj, Karim %A Antoine, Pascal %K Aged %K Alzheimer Disease %K Case-Control Studies %K Female %K Humans %K Inhibition (Psychology) %K Male %K Memory Disorders %K Memory, Episodic %K Mental Recall %K Neuropsychological Tests %X

Relatively to "standard" prospective memory, i.e., remembering to perform a future action, little is known about negative prospective memory, i.e., remembering not to perform a future action. This study investigated the latter ability in Alzheimer's disease (AD). AD participants and healthy older adults were asked to click on the keyboard or not to click on it when a cue word was encountered. Results showed more omissions (i.e., forgetting to click the keyboard when the instruction was to do so) in AD participants than in healthy older adults, suggesting a prospective memory deficit. Interestingly, more commissions (i.e., clicking the keyboard when the instruction was not to do so) were also observed in AD participants than in healthy older adults. Similar levels of commissions and omissions were observed in AD participants and in healthy older adults. Also, commissions and omissions were correlated with performance on an inhibition assessment task. Our findings reveal that AD is characterized by not only difficulty in the retrieval of recent information, but also difficulty to inhibit no-longer appropriate stimulus-response associations previously learned, suggesting a specific deficit of negative prospective memory in AD.

%B J Alzheimers Dis %V 61 %P 663-672 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226877?dopt=Abstract %R 10.3233/JAD-170807 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer's Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOEɛ4 Carriers. %A Sapkota, Shraddha %A Dixon, Roger A %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Brain-Derived Neurotrophic Factor %K Canada %K Catechol O-Methyltransferase %K Clusterin %K Cognitive Aging %K Cognitive Dysfunction %K Executive Function %K Female %K Genetic Predisposition to Disease %K Heterozygote %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Monomeric Clathrin Assembly Proteins %K Neuropsychological Tests %K Receptors, Complement 3b %X

BACKGROUND: Trajectories of complex neurocognitive phenotypes in preclinical aging may be produced differentially through selective and interactive combinations of genetic risk.

OBJECTIVE: We organize three possible combinations into a "network" of genetic risk indices derived from polymorphisms associated with normal and impaired cognitive aging, as well as Alzheimer's disease (AD). Specifically, we assemble and examine three genetic clusters relevant to non-demented cognitive trajectories: 1) Apolipoprotein E (APOE), 2) a Cognitive Aging Genetic Risk Score (CA-GRS; Catechol-O-methyltransferase + Brain-derived neurotrophic factor), and 3) an AD-Genetic Risk Score (AD-GRS; Clusterin + Complement receptor 1 + Phosphatidylinositol-binding clathrin assembly protein).

METHOD: We use an accelerated longitudinal design (n = 634; age range = 55-95 years) to test whether AD-GRS (low versus high) moderates the effect of increasing CA-GRS risk on executive function (EF) performance and change as stratified by APOE status (ɛ4+ versus ɛ4-).

RESULTS: APOEɛ4 carriers with high AD-GRS had poorer EF performance at the centering age (75 years) and steeper 9-year decline with increasing CA-GRS but this association was not present in APOEɛ4 carriers with low AD-GRS.

CONCLUSIONS: APOEɛ4 carriers with high AD-GRS are at elevated risk of cognitive decline when they also possess higher CA-GRS risk. Genetic risk from both common cognitive aging and AD-related indices may interact in intensification networks to differentially predict (1) level and trajectories of EF decline and (2) potential selective vulnerability for transitions into impairment and dementia.

%B J Alzheimers Dis %V 62 %P 887-900 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480189?dopt=Abstract %R 10.3233/JAD-170909 %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 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 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 Ozone Atmospheric Pollution and Alzheimer's Disease: From Epidemiological Facts to Molecular Mechanisms. %A Croze, Marine L %A Zimmer, Luc %K Air Pollution %K Alzheimer Disease %K Animals %K Central Nervous System %K Humans %K Incidence %K Inhalation Exposure %K Ozone %K Particulate Matter %X

Atmospheric pollution is a well-known environmental hazard, especially in developing countries where millions of people are exposed to airborne pollutant levels above safety standards. Accordingly, several epidemiological and animal studies confirmed its role in respiratory and cardiovascular pathologies and identified a strong link between ambient air pollution exposure and adverse health outcomes such as hospitalization and mortality. More recently, the potential deleterious effect of air pollution inhalation on the central nervous system was also investigated and mounting evidence supports a link between air pollution exposure and neurodegenerative pathologies, especially Alzheimer's disease (AD). The focus of this review is to highlight the possible link between ozone air pollution exposure and AD incidence. This review's approach will go from observational and epidemiological facts to the proposal of molecular mechanisms. First, epidemiological and postmortem human study data concerning residents of ozone-severely polluted megacities will be presented and discussed. Then, the more particular role of ozone air pollution in AD pathology will be described and evidenced by toxicological studies in rat or mouse with ozone pollution exposure only. The experimental paradigms used to reproduce in rodent the human exposure to ozone air pollution will be described. Finally, current insights into the molecular mechanisms through which ozone inhalation can affect the brain and play a role in AD development or progression will be recapitulated.

%B J Alzheimers Dis %V 62 %P 503-522 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480184?dopt=Abstract %R 10.3233/JAD-170857 %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 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 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 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 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 Profiling of Specific Gene Expression Pathways in Peripheral Cells from Prodromal Alzheimer's Disease Patients. %A Serpente, Maria %A Fenoglio, Chiara %A Cioffi, Sara Maria Giulia %A Oldoni, Emanuela %A Arcaro, Marina %A Arighi, Andrea %A Fumagalli, Giorgio Giulio %A Ghezzi, Laura %A Scarpini, Elio %A Galimberti, Daniela %K Aged %K Alzheimer Disease %K Antigens, CD %K Biomarkers %K Case-Control Studies %K Cognitive Dysfunction %K Female %K Gene Expression Profiling %K Humans %K Insulin %K Male %K Middle Aged %K Receptor, Insulin %X

Herein, we performed a gene expression profiling in a cohort of 10 mild cognitive impairment (MCI), subdivided, according to the analysis of cerebrospinal fluid biomarkers, in prodromal Alzheimer's disease (AD) and non-AD MCI, as compared with 27 AD patients and 24 controls, in order to detect early gene expression alterations. We observed a significant upregulation of insulin (INS) and INS Receptor (INSR) expression levels in AD both prodromal and fully symptomatic, as compared with controls, but not in MCI subjects. Our results suggest an early dysregulation of INS and INSR in AD pathogenesis and pave the way to a possible utility of these transcripts as peripheral biomarkers.

%B J Alzheimers Dis %V 61 %P 1289-1294 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376874?dopt=Abstract %R 10.3233/JAD-170861 %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 Progression of Alzheimer's Disease-Related Pathology and Cell Counts in a Patient with Idiopathic Normal Pressure Hydrocephalus. %A Libard, Sylwia %A Laurell, Katarina %A Cesarini, Kristina Giuliana %A Alafuzoff, Irina %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Biopsy %K Brain %K Cell Count %K Disease Progression %K Female %K Glial Fibrillary Acidic Protein %K Humans %K Hydrocephalus, Normal Pressure %K Microglia %K tau Proteins %X

We had an opportunity to assess the change observed in the brain regarding Alzheimer's disease (AD)-related alterations, cell count, and inflammation that took place during a period of 21 months in a subject with a definite diagnosis of AD and idiopathic Normal Pressure Hydrocephalus (iNPH). Four neuronal markers, i.e., synaptophysin, microtubule associated protein 2, non-phosphorylated neurofilament H (SMI32), and embryonic lethal abnormal visual system proteins 3/4 HuC/HuD (HuC/HuD); three microglial markers CD68, Human Leucocytic Antigen DR, ionized calcium-binding adaptor molecule 1, glial fibrillary acidic protein (GFAP); and AD-related markers, hyperphosphorylated τ (HPτ) and amyloid-β (Aβ, Aβ40, Aβ42) were assessed. Morphometrically assessed immunoreactivity of all neuronal and all microglial markers and Aβ42 decreased parallel with an increase in the HPτ in the frontal cortex. The expression of GFAP was stable with time. The first sample was obtained during the therapeutic shunting procedure for iNPH, and the second sample was obtained postmortem. Negligible reactive changes were observed surrounding the shunt channel. In conclusion, in the late stage of AD with time, a neuronal loss, increase in the HPτ, and decrease in Aβ42 and microglia was observed, whereas the expression of GFAP was rather stable. The observations described here suggest that when a brain biopsy has been obtained from an adult subject with iNPH, the assessment of postmortem brain is of major significance.

%B J Alzheimers Dis %V 61 %P 1451-1462 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376849?dopt=Abstract %R 10.3233/JAD-170446 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Progression of Neuropsychiatric Symptoms in Alzheimer's Disease During a Five-Year Follow-Up: Kuopio ALSOVA Study. %A Hallikainen, Ilona %A Hongisto, Kristiina %A Välimäki, Tarja %A Hänninen, Tuomo %A Martikainen, Janne %A Koivisto, Anne M %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Anxiety %K Caregivers %K Delusions %K Disease Progression %K Female %K Finland %K Hallucinations %K Humans %K Linear Models %K Male %K Motor Activity %K Multivariate Analysis %K Neuropsychological Tests %K Severity of Illness Index %X

BACKGROUND: An improved understanding of the role of neuropsychiatric symptoms (NPS) in the course of Alzheimer's disease (AD) has recently emerged. NPS lead to hospitalization and caregiver stress, but are more variable during the course of the disease than other symptoms. Knowledge about the role of specific NPS in disease progression and prognosis is especially limited.

OBJECTIVES: To examine the relationship between specific NPS and AD severity during a 5-year follow-up period, and to determine which baseline NPS predict AD progression.

METHODS: 236 persons with very mild (CDR 0.5) or mild (CDR 1) AD at baseline and their caregivers were followed up for five years as part of the ALSOVA study. The Neuropsychiatric Inventory was used to assess NPS, and AD severity progression was measured with the Clinical Dementia Rating Sum of Boxes. Data was analyzed with Generalized Estimated Equations and Linear Mixed Models.

RESULTS: The baseline NPS that best predicted AD progression were delusions, agitation, and aberrant motor behavior, while AD severity during follow-up was associated with hallucinations, delusions, agitation, apathy, aberrant motor behavior, and sleep and appetite disturbances.

CONCLUSIONS: Persons with mild AD presenting delusions, agitation, and aberrant motor behavior at the time of diagnosis could have a more rapidly progressing disease, and some NPS are associated with AD severity. These results highlight the importance of evaluating NPS at the time of AD diagnosis, and the need to offer additional support to persons presenting delusions, agitation and aberrant motor behavior, and their caregivers.

%B J Alzheimers Dis %V 61 %P 1367-1376 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376861?dopt=Abstract %R 10.3233/JAD-170697 %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 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 Relationships Between Lower Olfaction and Brain White Matter Lesions in Elderly Subjects with Mild Cognitive Impairment. %A Heinrich, Juliette %A Vidal, Jean-Sébastien %A Simon, Axelle %A Rigaud, Anne-Sophie %A Hanon, Olivier %A Epelbaum, Jacques %A Viollet, Cécile %A Duron, Emmanuelle %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Atrophy %K Cognitive Dysfunction %K Cross-Sectional Studies %K Disease Progression %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Multivariate Analysis %K Neuropsychological Tests %K Olfaction Disorders %K Severity of Illness Index %K White Matter %X

BACKGROUND: Olfactory impairment is reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD) and is associated with hippocampal atrophy. In elderly people, dementia with AD neuropathology and white matter lesions (WML) is common. In this context, olfactory impairment could also depend on the presence of WML.

OBJECTIVE: To assess the cross-sectional relationship between olfaction and WML in elderly subjects with MCI.

METHODS: Consecutive subjects, >65 years old, diagnosed as MCI after a comprehensive neuropsychological assessment in an expert memory center, with a brain MRI performed within a year and without major depressive state, were included. Olfaction was assessed by the Brief Smell Identification Test (BSIT). Two trained neuroradiologists, blind to cognitive and olfaction status, visually assessed hippocampal atrophy according to Scheltens' scale and WML according to Fazekas criteria.

RESULTS: Seventy-five MCI subjects (mean age (SD) = 77.1 (6.2) years, 74.7% of women) were included. After adjustment for age and sex, factors associated with low BSIT scores were older age (p = 0.007), lower BMI (p = 0.08), lower MMSE score (p = 0.05), lower FCRST (p = 0.008), hippocampal atrophy (p = 0.04), periventricular WML (p = 0.007), and deep WML burden (p = 0.005). In multivariate analysis, severe deep WML (OR (95% CI) = 6.29 (1.4-35.13), p = 0.02) remained associated with low BSIT score independently from hippocampal atrophy.

CONCLUSION: In elderly MCI subjects, low olfactory performances are associated with WML, whose progression may be slowed by vascular treatments. A longitudinal study to evaluate whether the progression of WML, hippocampal atrophy and low olfactory function, can predict accurately conversion from MCI to dementia is ongoing.

%B J Alzheimers Dis %V 61 %P 1133-1141 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332036?dopt=Abstract %R 10.3233/JAD-170378 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Retinoic Acid Enhances Apolipoprotein E Synthesis in Human Macrophages. %A Clemens, Vera %A Regen, Francesca %A Le Bret, Nathalie %A Heuser, Isabella %A Hellmann-Regen, Julian %K Alzheimer Disease %K Apolipoproteins E %K Cells, Cultured %K Humans %K Macrophages %K Signal Transduction %K Tretinoin %X

Apolipoprotein E (ApoE) represents a pivotal target in Alzheimer's disease (AD) and is modulated through retinoic acid (RA), an endogenous neuroprotective and anti-inflammatory compound. A major source of ApoE are microglia, which are pathologically activated in AD. Activated microglia are known to block RA signaling. This suggests a vicious cycle between inflammation, RA signaling, and ApoE homeostasis in AD pathogenesis. To test this hypothesis, we investigated effects of RA and proinflammatory activation on ApoE synthesis in primary human macrophage-derived microglial-like cells. Our results indicate that proinflammatory activation attenuates ApoE synthesis, an effect blocked by RA.

%B J Alzheimers Dis %V 61 %P 1295-1300 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376871?dopt=Abstract %R 10.3233/JAD-170823 %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 Role of ASK1/p38 Cascade in a Mouse Model of Alzheimer's Disease and Brain Aging. %A Hasegawa, Yu %A Toyama, Kensuke %A Uekawa, Ken %A Ichijo, Hidenori %A Kim-Mitsuyama, Shokei %K Aging %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Aspartic Acid Endopeptidases %K Avoidance Learning %K Disease Models, Animal %K Gene Expression Regulation %K MAP Kinase Kinase Kinase 5 %K MAP Kinase Signaling System %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Presenilin-1 %K Reaction Time %X

To examine the role of ASK1 in Alzheimer's disease (AD), we generated 5XFAD mice deficient in ASK1 and investigated the characteristics of old 5XFAD and wild-type mice with ASK1 deficiency. ASK1 deficiency improved cognitive function in 24-month-old 5XFAD mice, which was associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade seems to play some role in the pathogenesis of AD in mice. In 24-month-old wild-type mice, ASK1 deficiency increased cerebral vasoreactivity to acetazolamide and significantly reduced brain soluble Aβ, which were also associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade may contribute to brain aging of wild-type mice. Collectively, our present results provided the evidence suggesting the involvement of ASK1/p38 cascade in AD and brain aging.

%B J Alzheimers Dis %V 61 %P 259-263 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154282?dopt=Abstract %R 10.3233/JAD-170645 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Role of Genetics and Epigenetics in the Pathogenesis of Alzheimer's Disease and Frontotemporal Dementia. %A Fenoglio, Chiara %A Scarpini, Elio %A Serpente, Maria %A Galimberti, Daniela %K Alzheimer Disease %K Animals %K Epigenesis, Genetic %K Frontotemporal Dementia %K Genetic Predisposition to Disease %K Humans %X

Alzheimer's disease (AD) and frontotemporal dementia (FTD) represent the first cause of dementia in senile and pre-senile population, respectively. A percentage of cases have a genetic cause, inherited with an autosomal dominant pattern of transmission. The majority of cases, however, derive from complex interactions between a number of genetic and environmental factors. Gene variants may act as risk or protective factors. Their combination with a variety of environmental exposures may result in increased susceptibility to these diseases or may influence their course. The scenario is even more complicated considering the effect of epigenetics, which encompasses mechanisms able to alter the expression of genes without altering the DNA sequence. In this review, an overview of the current genetic and epigenetic progresses in AD and FTD will be provided, with particular focus on 1) causative genes, 2) genetic risk factors and disease modifiers, and 3) epigenetics, including methylation, non-coding RNAs and chromatin remodeling.

%B J Alzheimers Dis %V 62 %P 913-932 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad170702?id=journal-of-alzheimers-disease%2Fjad170702 %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562532?dopt=Abstract %R 10.3233/JAD-170702 %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 Roles of Mitochondrial 17β-Hydroxysteroid Dehydrogenase Type 10 in Alzheimer's Disease. %A He, Xue-Ying %A Isaacs, Charles %A Yang, Song-Yu %K 3-Hydroxyacyl CoA Dehydrogenases %K Alzheimer Disease %K Amyloid beta-Peptides %K Brain %K Endoplasmic Reticulum %K Humans %K Mitochondria %K Neurotransmitter Agents %K Oxidation-Reduction %X

17β-Hydroxysteroid dehydrogenase type 10 is a multifunctional, homotetrameric, mitochondrial protein encoded by the HSD17B10 gene at Xp 11.2. This protein, 17β-HSD10, is overexpressed in brain cells of Alzheimer's disease (AD) patients. It was reported to be involved in AD pathogenesis as the endoplasmic reticulum-associated amyloid-β binding protein (ERAB) and as amyloid-β binding alcohol dehydrogenase (ABAD). However, the exaggerated catalytic efficiencies for ERAB/ABAD in these reports necessitated the re-characterization of the catalytic functions of this brain enzyme. In addition to isoleucine metabolism, 17β-HSD10 is also responsible for the mitochondrial metabolism of neurosteroids such as 5α-androstane-3α,17β-diol and 17β-estradiol. These neurosteroids are inactivated by the oxidation catalyzed by 17β-HSD10. Since neurosteroid homeostasis is presumably essential for cognitive function, analysis of the impact of 17β-HSD10 and its inhibitor, amyloid-β peptide (Aβ), on the metabolism of neuroactive steroids offers a new approach to AD pathogenesis.

%B J Alzheimers Dis %V 62 %P 665-673 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480196?dopt=Abstract %R 10.3233/JAD-170974 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Sally-Anne Test in Patients with Alzheimer's Disease Dementia. %A Takenoshita, Shintaro %A Terada, Seishi %A Yokota, Osamu %A Kutoku, Yumiko %A Wakutani, Yosuke %A Nakashima, Makoto %A Maki, Yohko %A Hattori, Hideyuki %A Yamada, Norihito %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition Disorders %K Disease Progression %K Female %K Humans %K Logistic Models %K Male %K Neuropsychological Tests %K Social Behavior Disorders %K Theory of Mind %X

Social cognition has recently been recognized as one of the essential cognitive domains. Some reports suggested that patients with Alzheimer's disease dementia (ADD) presented significant theory of mind deficits even in the mild condition. However, most previous studies included only small numbers of patients with ADD. The present study administered the first-order false belief (Sally-Anne) test to 116 consecutive patients with ADD from the outpatient units of the Memory Clinic and compared the characteristics of the two groups with correct and incorrect answers on the test. Then various clinical characteristics were evaluated. Only 37.1% of patients with ADD correctly answered the Sally-Anne test with the right explanation. Comparison between the two groups of correct and incorrect answers revealed a significant association between the frontal assessment battery score and the result of the Sally-Anne test in the multiple logistic regression analyses. Thus, patients with ADD presented a significant deficit in social cognition even in the mild condition. Frontal dysfunction was thought to be related to the deficits in mild ADD.

%B J Alzheimers Dis %V 61 %P 1029-1036 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332047?dopt=Abstract %R 10.3233/JAD-170621 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Serum Non-Ceruloplasmin Non-Albumin Copper Elevation in Mild Cognitive Impairment and Dementia due to Alzheimer's Disease: A Case Control Study. %A Rozzini, Luca %A Lanfranchi, Francesco %A Pilotto, Andrea %A Catalani, Simona %A Gilberti, Maria Enrica %A Paganelli, Matteo %A Apostoli, Pietro %A Padovani, Alessandro %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Cognitive Dysfunction %K Copper %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Psychiatric Status Rating Scales %X

Several studies showed high serum copper levels in Alzheimer's disease (AD). The present study applied a newly developed method to detect serum copper free from proteins (free-Cu). Forty-four patients affected by dementia due to AD, thirty-six patients affected by mild cognitive impairment (MCI) due to AD, and twenty-eight healthy controls underwent clinical, cognitive, and MRI assessment. The new method showed higher free-Cu concentrations in MCI and dementia due to AD compared to controls (p < 0.0001). No correlation between copper levels, cognitive or MRI measures were found.

%B J Alzheimers Dis %V 61 %P 907-912 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332043?dopt=Abstract %R 10.3233/JAD-170552 %0 Journal Article %J J Alzheimers Dis %D 2018 %T SIRT1 Deacetylates SC35 and Suppresses Its Function in Tau Exon 10 Inclusion. %A Yin, Xiaomin %A Jiang, Xiaosu %A Wang, Jia %A Qian, Shuo %A Liu, Fei %A Qian, Wei %K Alternative Splicing %K Alzheimer Disease %K Exons %K HEK293 Cells %K HeLa Cells %K Humans %K Phosphorylation %K Ribonucleoproteins %K Serine-Arginine Splicing Factors %K Sirtuin 1 %K tau Proteins %K Tauopathies %X

Approximately equal amounts of 3R-tau and 4R-tau resulting from alternative splicing of tau exon 10 is necessary to maintain normal brain function. Dysregulation of alternative splicing of tau exon 10 and the imbalance of 3R-tau/4R-tau have been seen in inherited and sporadic tauopathies. Splicing factor SC35 (also name as SRSF2) plays an important role in promoting tau exon 10 inclusion. SC35 is post-translationally modified by phosphorylation and acetylation, but the role of acetylation in SC35-medicated tau exon 10 inclusion is unknown. Sirtuin type 1 (SIRT1) is an enzyme that deacetylates proteins and associates with age-related disease such as Alzheimer's disease. In the present study, we determined the role of SIRT1 in SC35 acetylation and in the alternative splicing of tau exon 10. We found that SIRT1 interacts with and deacetylates SC35, and inhibits SC35-promoted tau exon 10 inclusion. Substituting K52 residue of SC35 by arginine impairs the role of SC35 in tau exon 10 inclusion. These results suggest that SIRT1 may serve as a therapeutic target for tauopathy by regulating SC35-mediated tau exon 10 splicing.

%B J Alzheimers Dis %V 61 %P 561-570 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226865?dopt=Abstract %R 10.3233/JAD-170418 %0 Journal Article %J J Alzheimers Dis %D 2018 %T SORL1 Variants in Familial Alzheimer's Disease. %A Gómez-Tortosa, Estrella %A Ruggiero, María %A Sainz, Ma José %A Villarejo-Galende, Alberto %A Prieto-Jurczynska, Cristina %A Venegas Pérez, Begoña %A Ordás, Carlos %A Agüero, Pablo %A Guerrero-López, Rosa %A Pérez-Pérez, Julián %K Aged %K Alzheimer Disease %K Case-Control Studies %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Humans %K LDL-Receptor Related Proteins %K Male %K Membrane Transport Proteins %K Middle Aged %K Mutation %K Polymorphism, Single Nucleotide %K Siblings %K Spain %X

The SORL1 gene encodes a protein involved in the amyloidogenic process, and its variants have been associated with Alzheimer's disease (AD) physiopathology. We screened for SORL1 variants in 124 familial (44 early- and 80 late-onset) dementia of Alzheimer type (DAT) cases. Nine potentially pathogenic changes (three not previously reported and six rare variants) were found in nine probands (7%). After screening the control population and siblings (presence in at least 1/200 controls and/or absence of segregation pattern), a causal relationship with the disease was considered unlikely in six variants and uncertain in one. The change Trp848Ter and a splice-site variant remained likely correlated with the disease. SORL1 mutations are present in 7% of our familial DAT cohort, though in most cases cannot be considered the direct cause of the disease.

%B J Alzheimers Dis %V 61 %P 1275-1281 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376855?dopt=Abstract %R 10.3233/JAD-170590 %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 Structural Connectivity Alterations Along the Alzheimer's Disease Continuum: Reproducibility Across Two Independent Samples and Correlation with Cerebrospinal Fluid Amyloid-β and Tau. %A Tucholka, Alan %A Grau-Rivera, Oriol %A Falcon, Carles %A Rami, Lorena %A Sánchez-Valle, Raquel %A Lladó, Albert %A Gispert, Juan Domingo %A Molinuevo, José Luis %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Atrophy %K Biomarkers %K Case-Control Studies %K Cognitive Dysfunction %K Cohort Studies %K Disease Progression %K Female %K Gray Matter %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Reproducibility of Results %K Spain %K tau Proteins %K White Matter %X

BACKGROUND: Gray matter changes associated with the progression of Alzheimer's disease (AD) have been thoroughly studied. However, alterations in white matter tracts have received less attention, particularly during early or preclinical stages of the disease.

OBJECTIVE: To identify the structural connectivity changes across the AD continuum.

METHODS: We performed probabilistic tractography in a total of 183 subjects on two independent samples that include control (n = 68) and preclinical AD individuals (n = 28), patients diagnosed with mild cognitive impairment (MCI) due to AD (n = 44), and AD patients (n = 43). We compared the connectivity between groups, and with CSF Aβ42 and tau biomarkers.

RESULTS: We observed disconnections in preclinical individuals, mainly located in the temporal lobe. This pattern of disconnection spread to the parietal and frontal lobes at the MCI stage and involved almost all the brain in AD. These findings were not driven by gray matter atrophy.

DISCUSSION: Using tractography, we were able to identify white matter changes between subsequent disease stages and, notably, also in preclinical AD. Therefore, this method may be useful for detecting early and specific brain structural changes during preclinical AD stage.

%B J Alzheimers Dis %V 61 %P 1575-1587 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376852?dopt=Abstract %R 10.3233/JAD-170553 %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 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 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 Validation of the Delayed Matching-to-Sample Task 48 (DMS48) in Elderly Chinese. %A Feng, Xueyan %A Zhou, Aihong %A Liu, Zhixin %A Li, Fangyu %A Wei, Cuibai %A Zhang, Guili %A Jia, Jianping %K Aged %K Aged, 80 and over %K Alzheimer Disease %K China %K Cognitive Dysfunction %K Cross-Sectional Studies %K Female %K Humans %K Linear Models %K Male %K Memory Disorders %K Middle Aged %K Neuropsychological Tests %K ROC Curve %K Sensitivity and Specificity %K Severity of Illness Index %X

BACKGROUND: Delayed Matching-to-Sample Task 48 (DMS48), a brief tool measuring visual recognition memory, is valid to identify the early stage of Alzheimer's disease (AD) in Caucasians. However, little data is available in Chinese.

OBJECTIVE: To develop norms and optimal cutoff points for the DMS48 in Chinese elders.

METHODS: A cross-sectional study was conducted in seven memory clinics from five cities across China. DMS48 was applied to 369 Chinese aged 50 or older (138 cognitively normal [CN], 112 mild cognitive impairment due to AD (MCI-A), and 119 mild AD dementia). The demographic factors which influence DMS48 scores were investigated and the norms were established considering those factors. Receiver operating characteristic (ROC) analysis was used to determine the optimal cutoff points.

RESULTS: Age was shown to influence DMS48 scores (r = -0.36, p < 0.05), and we presented the age-stratified normative data for the DMS48. The optimal cutoff point is 42/43 for identifying cognitive impairment (MCI-A and AD dementia) against CN (sensitivity 97.80% and specificity 89.13%) and MCI-A against CN (sensitivity 86.60% and specificity 94.20%). A cutoff of 39/40 obtained good sensitivity (100.00%) and specificity (94.90%) in discriminating AD dementia from CN. The age-stratified optimal cutoff points for identifying MCI-A were 43/44 for individuals aged 50 to 59 years old, 42/43 for 60 to 69 years old, 41/42 for 70 to 79 years old, and 40/41 for 80 or older, respectively (sensitivity 84.80% and specificity 95.70%).

CONCLUSION: This study proved that DMS48 is of good validation in screening MCI-A in elderly Chinese.

%B J Alzheimers Dis %V 61 %P 1611-1618 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376851?dopt=Abstract %R 10.3233/JAD-170530 %0 Journal Article %J J Alzheimers Dis %D 2018 %T VEGFR1 and VEGFR2 in Alzheimer's Disease. %A Harris, Rachel %A Miners, James Scott %A Allen, Shelley %A Love, Seth %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Case-Control Studies %K Endothelial Cells %K Female %K Gene Expression Regulation %K Humans %K Male %K Middle Aged %K Neovascularization, Pathologic %K RNA, Messenger %K Signal Transduction %K Vascular Endothelial Growth Factor A %K Vascular Endothelial Growth Factor Receptor-1 %K Vascular Endothelial Growth Factor Receptor-2 %X

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. Despite upregulation of VEGF in the brain in Alzheimer's disease (AD), probably in response to amyloid-β, vasoconstriction, and tissue hypoxia, there is no consequent increase in microvessel density. VEGF binds to and activates VEGF receptor 2 (VEGFR2), but also binds to VEGF receptor 1 (VEGFR1), which exists in less-active membrane-bound and inactive soluble (sVEGFR1) forms and inhibits pro-angiogenic signaling. We have investigated whether altered expression of VEGF receptors might account for the lack of angiogenic response to VEGF in AD. We assessed the cellular distribution and protein level of VEGFR1 and VEGFR2 in parietal cortex from 50 AD and 36 age-matched control brains, and related the findings to measurements of VEGF and von Willebrand factor level (a marker of microvessel density) in the same tissue samples. VEGFR2 was expressed by neurons, astrocytes and endothelial cells. VEGFR1 was expressed predominantly neuronally and was significantly reduced in AD (p = 0.02). Western blot analysis on a subset of brains showed reduction in VEGFR1:sVEGFR1 in AD (p = 0.046). The lack of angiogenesis despite cerebral hypoperfusion in AD is not explained by altered expression of VEGFR2 or total VEGFR1; indeed, the downregulation of VEGFR1 may represent a pro-angiogenic response to the hypoperfusion. However, the relative increase in sVEGFR1 would be expected to have an anti-angiogenic effect which may be a factor in AD.

%B J Alzheimers Dis %V 61 %P 741-752 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226875?dopt=Abstract %R 10.3233/JAD-170745 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Vestibular Loss Predicts Poorer Spatial Cognition in Patients with Alzheimer's Disease. %A Wei, Eric X %A Oh, Esther S %A Harun, Aisha %A Ehrenburg, Matthew %A Agrawal, Yuri %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Bilateral Vestibulopathy %K Cognitive Dysfunction %K Cross-Sectional Studies %K Female %K Humans %K Linear Models %K Male %K Multivariate Analysis %K Neuropsychological Tests %K Prospective Studies %K Spatial Navigation %K Vestibular Function Tests %X

The vestibular system is an important contributor to balance control, spatial orientation, and falls risk. Recent evidence has shown that Alzheimer's disease (AD) patients have a higher prevalence of vestibular impairment relative to healthy controls. We sought to evaluate whether vestibular loss is specifically associated with poor spatial cognitive skills among patients with mild cognitive impairment (MCI) and AD. We enrolled 50 patients (22 MCI and 28 AD) from an interdisciplinary Memory Clinic and measured vestibular physiologic function in all patients. Spatial cognitive function was assessed using the Money Road Map Test (MRMT) and the Trail Making Test Part B (TMT-B). General cognitive function was assessed with the Mini-Mental Status Examination (MMSE). In multivariable linear regression analyses adjusted for age, gender, education level, and MMSE, MCI and AD patients with vestibular loss made significantly more errors on the MRMT relative to patients with normal vestibular function (β= 7.3, 95% CI 2.4, 12.1 for unilateral vestibular loss and β= 6.4, 95% CI 1.9, 10.9 for bilateral vestibular loss). We further stratified AD patients into "spatially normal" and "spatially impaired" groups based on MRMT performance, and found that the prevalence of vestibular loss was significantly higher in the spatially impaired AD group relative to the spatially normal AD group. These findings support the hypothesis that vestibular loss contributes specifically to a decline in spatial cognitive ability in MCI and AD patients, independently of general cognitive decline, and may predict a "spatially impaired" subtype of AD.

%B J Alzheimers Dis %V 61 %P 995-1003 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254098?dopt=Abstract %R 10.3233/JAD-170751 %0 Journal Article %J J Alzheimers Dis %D 2018 %T When Art Meets Gardens: Does It Enhance the Benefits? The Nancy Hypothesis of Care for Persons with Alzheimer's Disease. %A Jonveaux, Thérèse Rivasseau %A Fescharek, Reinhard %K Alzheimer Disease %K Art Therapy %K Cognition %K Cognitive Behavioral Therapy %K France %K Gardening %K Humans %X

The creation of healing gardens for persons with Alzheimer's disease and related diseases (ADRD) offers vast potential. They can play a role in the scaffolding of cognitive disorders, emotional stress, sensory processing, sense of harmony, and appeasement. These effects are achieved through a distributed interplay of psychological functions with the immediate environment and local culture on the one hand, and dialogue on the other. The garden, a natural canvas created by man, shares with art the ability to foster an esthetic sense for which the perception can be measured by functional neurological imaging exploration. Art represents a mediator for the collaborative realization of distributed psychological functions between different individuals. Based on the hypothesis of an optimization of the therapeutic potential of a garden by a design adapted to the neuro-psycho-social and cultural specificities of its users combined with the thoughtful introduction of an artistic dimension, the "art, memory and life" healing garden was created at the University Hospital of Nancy as a prototype for persons with ADRD. The design concept was based on two hypotheses that we formulate herein, discuss their theoretical foundation, and suggest enhanced design for therapeutic gardens based upon our experience.

%B J Alzheimers Dis %V 61 %P 885-898 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332052?dopt=Abstract %R 10.3233/JAD-170781 %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 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 Amyloid-β Deposition and Long-Term Progression in Mild Cognitive Impairment due to Alzheimer's Disease Defined with Amyloid PET Imaging. %A Hatashita, Shizuo %A Wakebe, Daichi %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid %K Aniline Compounds %K Cognitive Dysfunction %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Positron-Emission Tomography %K Thiazoles %X

The aim was to evaluate brain amyloid-β (Aβ) deposition in patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) using amyloid PET imaging and clarify the relationship between the annual change in Aβ deposition and disease progression. Forty-eight MCI patients underwent neuropsychological assessment and amyloid PET imaging using [11C]-PIB over a follow-up of 5.7±1.5 years. Thirty-nine MCI patients who had an amyloid-positive scan were defined as MCI due to AD, and 9 MCI patients who had an amyloid-negative scan were included. Regions of interest were defined on co-registered MRI, and the PIB standardized uptake value ratio (SUVR) on the same regions was used over follow-up. Annual change in PIB SUVR was calculated. Patients with MCI due to AD had higher baseline PIB SUVR (1.81±0.32, n = 39, p < 0.01) and a greater annual rate of change in PIB SUVR (0.044±0.027, n = 39, p < 0.01) compared to amyloid-negative MCI patients. Twenty-eight (71.8%) progressed to AD. In patients who progressed during a short duration of 1.7±0.8 years, the annual rate of increase in PIB SUVR was 0.101±0.094 (n = 16, p < 0.05), which was greater compared to patients with long conversion or stable patients. There was a negative correlation between the annual rate of increase in PIB SUVR and duration of progression to AD among individual MCI converters (r = -0.47, n = 28, p < 0.05). The patients defined as MCI due to AD could progress to AD with a shorter period if they have a greater increased annual rate in brain Aβ deposition.

%B J Alzheimers Dis %V 57 %P 765-773 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304292?dopt=Abstract %R 10.3233/JAD-161074 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cholinesterase Inhibitor Therapy in Alzheimer's Disease: The Limits and Tolerability of Irreversible CNS-Selective Acetylcholinesterase Inhibition in Primates. %A Moss, Donald E %A Perez, Ruth G %A Kobayashi, Haruo %K Acetylcholinesterase %K Alzheimer Disease %K Animals %K Brain %K Cholinesterase Inhibitors %K Dose-Response Relationship, Drug %K Drug Evaluation, Preclinical %K Erythrocytes %K Injections, Intramuscular %K Macaca fascicularis %K Male %K Nootropic Agents %K Time Factors %X

Irreversible acetylcholinesterase (AChE) inhibition accumulates to high levels in the central nervous system (CNS) because AChE turnover in the brain is much slower than in peripheral tissues. As expected from this CNS selectivity, the irreversible AChE inhibitor methanesulfonyl fluoride (MSF) produces significant cognitive improvement in Alzheimer's disease patients without the gastrointestinal toxicity that plagues other AChE inhibitors. However, without dose-limiting gastrointestinal toxicity, one shortcoming of the prior human studies of MSF is that the upper limits of CNS AChE inhibition that might be tolerated could not be tested. Therefore, in this study, monkeys were treated with escalating intramuscular (IM) doses of MSF that culminated with several weeks of 1.5 mg/kg dosing, more than eight times the prior human clinical dose, still without signs of toxicity. Brain biopsies showed that ∼80% AChE inhibition had been produced and that the new synthesis of cortical AChE had a half-time (t1/2) of ∼12 days. A single IM dose of 1.5 mg/kg MSF produced ∼59% inhibition in cerebrospinal fluid (CSF) AChE as measured one day later. This corresponds to a peak of ∼80% inhibition in CSF AChE at the time of the injection, recovering with a t1/2 of 2.4 days. Computational analyses suggest that MSF at clinically relevant doses could theoretically produce a steady-state AChE inhibition between 65% and 85% in the CNS. These data suggest that the full therapeutic advantage of AChE inhibition therapy can be realized without interference from dose-limiting gastrointestinal toxicity if an irreversible inhibitor is employed.

%B J Alzheimers Dis %V 55 %P 1285-1294 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27858711?dopt=Abstract %R 10.3233/JAD-160733 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Coordinate-Based Meta-Analysis of the Default Mode and Salience Network for Target Identification in Non-Invasive Brain Stimulation of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Networks. %A Pievani, Michela %A Pini, Lorenzo %A Ferrari, Clarissa %A Pizzini, Francesca B %A Boscolo Galazzo, Ilaria %A Cobelli, Chiara %A Cotelli, Maria %A Manenti, Rosa %A Frisoni, Giovanni B %K Alzheimer Disease %K Brain %K Databases, Bibliographic %K Deep Brain Stimulation %K Electroencephalography %K Frontotemporal Dementia %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Models, Neurological %X

BACKGROUND: The accurate choice of the site of non-invasive brain stimulation (NIBS) is an important factor in trial design.

OBJECTIVE: Based on the observation that Alzheimer's disease (AD) and behavioral frontotemporal dementia (bvFTD) affect specific large-scale networks, i.e., the default mode network (DMN) and the salience network (SN), respectively, we aimed to identify population-average coordinates of these networks that could be used as potential targets in NIBS trials aiming to modulate these circuits.

METHODS: A systematic literature search of resting-state functional MRI studies reporting DMN and SN stereotactic coordinates was performed according to PRISMA guidelines. Coordinate-based meta-analyses were conducted to identify consistent nodes of the DMN and SN using GingerALE BrainMap software and the activation likelihood estimation method.

RESULTS: DMN coordinates mapped primarily to mesial areas (posterior cingulate cortex/precuneus [Brodmann Area - BA 23/31] and medial prefrontal cortex [BA 9/10/32]). More superficial areas mapped to the bilateral parietal (angular gyrus [BA 39]), temporal (middle gyrus [BA 21]) and dorsolateral prefrontal (superior gyrus [BA 8]) cortex. SN coordinates mapped primarily to mesial and deep frontal areas (anterior insula, anterior cingulate cortex [BA 24/32]), but more superficial areas mapped to the bilateral parietal (supramarginal gyrus [BA 40]) and the right dorsolateral prefrontal (middle gyrus [BA 9/10]) cortex.

CONCLUSIONS: NIBS should target the bilateral angular, the middle temporal cortex, or superior frontal gyri in AD for DMN modulation, and the right middle frontal or supramarginal gyri in bvFTD for SN modulation.

%B J Alzheimers Dis %V 57 %P 825-843 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304293?dopt=Abstract %R 10.3233/JAD-161105 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Efficacy of Emotion Recognition Rehabilitation for People with Alzheimer's Disease. %A García-Casal, J Antonio %A Goñi-Imizcoz, Miguel %A Perea-Bartolomé, M Victoria %A Soto-Pérez, Felipe %A Smith, Sarah Jane %A Calvo-Simal, Sara %A Franco-Martín, Manuel %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Therapy %K Depression %K Emotions %K Female %K Follow-Up Studies %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Outcome Assessment (Health Care) %K Recognition (Psychology) %K Single-Blind Method %K Statistics, Nonparametric %X

BACKGROUND: The ability to recognize emotional expression is essential for social interactions, adapting to the environment, and quality of life. Emotion recognition is impaired in people with Alzheimer's disease (AD), thus rehabilitation of these skills has the potential to elicit significant benefits.

OBJECTIVE: This study sought to establish whether emotion recognition capacity could be rehabilitated in people with AD.

METHODS: Thirty-six participants with AD were assigned to one of three conditions: an experimental group (EG) that received 20 sessions of rehabilitation of emotion recognition and 20 sessions of cognitive stimulation therapy (CST), a control group (CG) that received 40 sessions of CST, and a treatment as usual group (TAU).

RESULTS: A positive treatment effect favoring the EG was found; participants were better able to correctly identify emotions (p = 0.021), made fewer errors of commission (p = 0.002), had greater precision of processing (p = 0.021), and faster processing speed (p = 0.001). Specifically, the EG were better able to identify sadness (p = 0.016), disgust (p = 0.005), and the neutral expression (p = 0.014), with quicker processing speed for disgust (p = 0.002). These gains were maintained at one month follow-up with the exception of processing speed for surprise, which improved.

CONCLUSION: Capacity to recognize facial expressions of emotions can be improved through specific rehabilitation in people with AD, and gains are still present at a one month follow up. These findings have implications for the design of rehabilitation techniques for people with AD that may lead to improved quality of life and social interactions for this population.

%B J Alzheimers Dis %V 57 %P 937-951 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304290?dopt=Abstract %R 10.3233/JAD-160940 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Family History of Alzheimer's Disease is Associated with Impaired Perceptual Discrimination of Novel Objects. %A Mason, Emily J %A Hussey, Erin P %A Molitor, Robert J %A Ko, Philip C %A Donahue, Manus J %A Ally, Brandon A %K Adult %K Alzheimer Disease %K Cerebral Cortex %K Discrimination (Psychology) %K Family Health %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Perceptual Disorders %K Photic Stimulation %K Recognition (Psychology) %K Signal Detection, Psychological %X

Early detection may be the key to developing therapies that will combat Alzheimer's disease (AD). It has been consistently demonstrated that one of the main pathologies of AD, tau, is present in the brain decades before a clinical diagnosis. Tau pathology follows a stereotypical route through the medial temporal lobe beginning in the entorhinal and perirhinal cortices. If early pathology leads to very subtle changes in behavior, it may be possible to detect these changes in subjects years before a clinical diagnosis can currently be made. We aimed to discover if cognitively normal middle-aged adults (40-60 years old) at increased risk for AD due to family history would have impaired performance on a cognitive task known to challenge the perirhinal cortex. Using an oddity detection task, we found that subjects with a family history of AD had lowered accuracy without demonstrating differences in rate of acquisition. There were no differences between subjects' medial temporal lobe volume or cortical thickness, indicating that the changes in behavior were not due to significant atrophy. These results demonstrate that subtle changes in perceptual processing are detectable years before a typical diagnosis even when there are no differences detectable in structural imaging data. Anatomically-targeted cognitive testing may be useful in identifying subjects in the earliest stages of AD.

%B J Alzheimers Dis %V 57 %P 735-745 %8 2017 %G eng %N 3 %R 10.3233/JAD-160772 %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 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 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 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 Role of Suppressor of Cytokine Signaling 3 (SOCS3) in Altering Activated Microglia Phenotype in APPswe/PS1dE9 Mice. %A Iwahara, Naotoshi %A Hisahara, Shin %A Kawamata, Jun %A Matsumura, Akihiro %A Yokokawa, Kazuki %A Saito, Taro %A Fujikura, Mai %A Manabe, Tatsuo %A Suzuki, Hiromi %A Matsushita, Takashi %A Suzuki, Syuuichirou %A Shimohama, Shun %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Brain %K Cells, Cultured %K Disease Models, Animal %K Female %K Humans %K Interleukin-6 %K Lipopolysaccharides %K Male %K Mice, Inbred C57BL %K Mice, Transgenic %K Microglia %K Neurons %K Presenilin-1 %K Suppressor of Cytokine Signaling 3 Protein %K Tumor Necrosis Factor-alpha %X

In response to changes of the central nervous system environment, microglia are capable of acquiring diverse phenotypes for cytotoxic or immune regulation and resolution of injury. Alzheimer's disease (AD) pathology also induces several microglial activations, resulting in production of pro-inflammatory cytokines and reactive oxygen species or clearance of amyloid-β (Aβ) through phagocytosis. We previously demonstrated that microglial activation and increase in oxidative stress started from the middle age in APPswe/PS1dE9 mice, and hypothesized that M1 activation occurs in middle-aged AD mice by Aβ stimulation. In the present study, we analyzed in vivo expressions of pro-inflammatory cytokines (M1 microglial markers), M2 microglial markers, and suppressor of cytokine signaling (SOCS) family, and examined the microglial phenotypic profile in APPswe/PS1dE9 mice. Then we compared the in vitro gene expression patterns of Aβ- and lipopolysaccharide (LPS)-stimulated primary-cultured microglia. Microglia in APPswe/PS1dE9 mice exhibited an M1-like phenotype, expressing tumor necrosis factor α (TNFα) but not interleukin 6 (IL6). Aβ-stimulated primary-cultured microglia also expressed TNFα but not IL6, whereas LPS-stimulated primary-cultured microglia expressed both pro-inflammatory cytokines. Furthermore, both microglia in APPswe/PS1dE9 mice and Aβ-stimulated primary-cultured microglia expressed SOCS3. Reduction of SOCS3 expression in Aβ-challenged primary-cultured microglia resulted in upregulation of IL6 expression. Our findings indicate that SOCS3 suppresses complete polarization to M1 phenotype through blocking IL6 production, and Aβ-challenged primary-cultured microglia replicate the in vivo gene expression pattern of microglia in APPswe/PS1dE9 mice. Aβ may induce the M1-like phenotype through blocking of IL6 by SOCS3.

%B J Alzheimers Dis %V 55 %P 1235-1247 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27814300?dopt=Abstract %R 10.3233/JAD-160887 %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 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 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 Activities of Daily Living and Depressive Symptoms in Patients with Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease. %A Stogmann, Elisabeth %A Moser, Doris %A Klug, Stefanie %A Gleiss, Andreas %A Auff, Eduard %A Dal-Bianco, Peter %A Pusswald, Gisela %A Lehrner, Johann %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Cognitive Dysfunction %K Depression %K Female %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Odds Ratio %K Perception %K Prospective Studies %X

BACKGROUND: Subjective cognitive decline (SCD) may be an early indicator for an increased risk of dementia. The exact definition of SCD remains unclear and has recently become a major research interest.

OBJECTIVES: To determine impairments in activities of daily living (ADL) and depressive symptoms in elderly individuals with SCD, mild cognitive impairment (MCI), and Alzheimer's disease (AD).

METHODS: We included 752 consecutive patients suffering from SCD, non-amnestic (naMCI) or amnestic MCI (aMCI), AD, and 343 healthy controls into this prospective cohort study. A neuropsychological test battery, B-ADL and BDI-II was performed.

RESULTS: SCD patients showed a decreased performance in ADL compared to controls. Performance in ADL declined concurrently with cognitive abilities along the controls-SCD-naMCI-aMCI-AD continuum. Individuals with cognitive complains, no matter if SCD, MCI, or AD patients, reported more often depressive symptoms compared to healthy controls without complaints. Within all five cognitive subgroups, patients with depressive symptoms reported more difficulties in ADL in comparison to patients without depressive symptoms. Adjusting for depressive symptoms, there was no significant group difference between the control versus the SCD group (OR 1.1, CI 0.6-1.7).

CONCLUSIONS: SCD is a heterogeneous clinical condition. Specific features such as slightly impaired ADL and depressive symptoms are associated with SCD. Clinical markers may serve as an indicator for preclinical AD and in combination with biomarkers guide to an early diagnosis of a progressive neurodegenerative disease.

%B J Alzheimers Dis %V 49 %P 1043-50 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26577522?dopt=Abstract %R 10.3233/JAD-150785 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Age and its association with low insulin and high amyloid-β peptides in blood. %A Li, Huajie %A Zhu, Haihao %A Wallack, Max %A Mwamburi, Mkaya %A Abdul-Hay, Samer O %A Leissring, Malcolm A %A Qiu, Wei Qiao %K Age Distribution %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Biomarkers %K Cognition Disorders %K Cross-Sectional Studies %K Female %K Humans %K Insulin %K Islet Amyloid Polypeptide %K Linear Models %K Male %K Middle Aged %K Multivariate Analysis %K Peptide Fragments %X

Age is the major risk factor for developing Alzheimer's disease (AD), and modifying age-related factors may help to delay the onset of the disease. The goal of this study was to investigate the relationship between age and the metabolic factors related to the risk of developing AD. The concentrations of insulin, amylin, and amyloid-β peptide (Aβ) in plasma were measured. We further measured the activity of serum Aβ degradation by using fluorescein- and biotin-labeled Aβ40. Apolipoprotein E4 allele (ApoE4) and cognitive impairment were characterized. Subjects were divided into three age groups: 60-70, 70-80, and ≥80 years old. We found that the older the subjects, the lower the concentration of insulin (p = 0.001) and the higher the concentration of Aβ1-40 (p = 0.004) in plasma. However, age was not associated with the concentration of another pancreatic peptide, amylin, and only marginally with Aβ1-42. These relationships remained in the absence of diabetes, cardiovascular disease, and stroke, and regardless of the presence of ApoE4 and cognitive impairment. Both age and ApoE4 were inversely associated with, while insulin was positively associated with, the activities of Aβ degradation in serum. Our study suggested that low concentration of insulin and high concentration of Aβ40 are aging factors related to the risk of AD.

%B J Alzheimers Dis %V 49 %P 129-37 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444783?dopt=Abstract %R 10.3233/JAD-150428 %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 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 sense of humor in dementia. %A Clark, Camilla N %A Nicholas, Jennifer M %A Gordon, Elizabeth %A Golden, Hannah L %A Cohen, Miriam H %A Woodward, Felix J %A Macpherson, Kirsty %A Slattery, Catherine F %A Mummery, Catherine J %A Schott, Jonathan M %A Rohrer, Jonathan D %A Warren, Jason D %K Aged %K Alzheimer Disease %K Case-Control Studies %K Cognition Disorders %K Emotions %K Female %K Frontotemporal Dementia %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Primary Progressive Nonfluent Aphasia %K Psychiatric Status Rating Scales %K Surveys and Questionnaires %X

Sense of humor is potentially relevant to social functioning in dementias, but has been little studied in these diseases. We designed a semi-structured informant questionnaire to assess humor behavior and preferences in patients with behavioral variant frontotemporal dementia (bvFTD; n = 15), semantic dementia (SD; n = 7), progressive nonfluent aphasia (PNFA; n = 10), and Alzheimer's disease (AD; n = 16) versus healthy age-matched individuals (n = 21). Altered (including frankly inappropriate) humor responses were significantly more frequent in bvFTD and SD (all patients) than PNFA or AD (around 40% of patients). All patient groups liked satirical and absurdist comedy significantly less than did healthy controls. This pattern was reported premorbidly for satirical comedy in bvFTD, PNFA, and AD. Liking for slapstick comedy did not differ between groups. Altered sense of humor is particularly salient in bvFTD and SD, but also frequent in AD and PNFA. Humor may be a sensitive probe of social cognitive impairment in dementia, with diagnostic, biomarker and social implications.

%B J Alzheimers Dis %V 49 %P 111-9 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444779?dopt=Abstract %R 10.3233/JAD-150413 %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 The Anti-Amyloid-β Monoclonal Antibody 4G8 Recognizes a Generic Sequence-Independent Epitope Associated with α-Synuclein and Islet Amyloid Polypeptide Amyloid Fibrils. %A Hatami, Asa %A Monjazeb, Sanaz %A Glabe, Charles %K alpha-Synuclein %K Alzheimer Disease %K Amyloid beta-Peptides %K Antibodies, Monoclonal %K Brain %K Epitopes %K Humans %K Islet Amyloid Polypeptide %X

Recently we reported that several monoclonal antibodies that recognize linear segments of amyloid-β (Aβ) also recognize amyloid fibrils, but not monomers of unrelated sequences, indicating that recognition of a linear sequence segment is not a reliable indicator of sequence specificity. We asked whether any of the commonly used commercially available Aβ antibodies also recognize fibrils of unrelated sequence. Here we report that 4G8, which recognizes residues 18-23 of the Aβ sequence and is widely believed to be sequence-specific, also recognizes fibrils formed from α-synuclein and islet amyloid polypeptide (IAPP). The recognition of amyloid fibrils is aggregation-dependent because 4G8 does not recognize α-synuclein or IAPP monomer. 4G8 also stains fibrillar α-synuclein aggregates in human multiple system atrophy brain where it colocalizes with anti-α-synuclein monoclonal antibody LB509 immunoreactivity. We also found that LB509 recognizes Aβ fibrils, but not monomer, indicating that generic epitope-reactive antibodies are also produced in response to α-synuclein immunization. Taken together, our results indicate that generic fibril conformational epitope specificity may be a pervasive property among monoclonal antibodies raised against amyloid-forming antigens and that the specificity of their immunoreactivity should be rigorously established and otherwise interpreted with caution.

%B J Alzheimers Dis %V 50 %P 517-25 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682688?dopt=Abstract %R 10.3233/JAD-150696 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer's Disease. %A Gomar, Jesus J %A Conejero-Goldberg, Concepcion %A Davies, Peter %A Goldberg, Terry E %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Atrophy %K Brain %K Disease Progression %K Female %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Prodromal Symptoms %K Regression Analysis %K Statistics, Nonparametric %K tau Proteins %X

BACKGROUND: The earliest stage of preclinical Alzheimer's disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood.

OBJECTIVE: To examine dynamic interrelationships between Aβ42 and tau in preclinical AD.

METHODS: We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n = 14); and 3) Aβ42 levels consistently abnormal (n = 18).

RESULTS: In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = -0.60; p = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p <  0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p-tau.

CONCLUSIONS: The evolution of Aβ42 and p-tau CSF biomarkers in CI subjects follows an anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.

%B J Alzheimers Dis %V 51 %P 1085-97 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967213?dopt=Abstract %R 10.3233/JAD-150937 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Apathy and Attentional Biases in Alzheimer's Disease. %A Chau, Sarah A %A Chung, Jonathan %A Herrmann, Nathan %A Eizenman, Moshe %A Lanctôt, Krista L %K Aged %K Alzheimer Disease %K Apathy %K Attentional Bias %K Cognition %K Cross-Sectional Studies %K Emotions %K Eye Movement Measurements %K Eye Movements %K Female %K Humans %K Linear Models %K Male %K Neuropsychological Tests %K Photic Stimulation %K Severity of Illness Index %K Social Perception %X

BACKGROUND: Apathy, one of the most prevalent neuropsychiatric symptoms in Alzheimer's disease (AD), can be difficult to assess as cognition deteriorates. There is a need for more objective assessments that do not rely on patient insight, communicative capacities, or caregiver observation.

OBJECTIVE: We measured visual scanning behavior, using an eye-tracker, to explore attentional bias in the presence of competing stimuli to assess apathy in AD patients.

METHODS: Mild-to-moderate AD patients (Standardized Mini-Mental Status Examination, sMMSE >10) were assessed for apathy (Neuropsychiatric Inventory [NPI] apathy, Apathy Evaluation Scale [AES]). Participants were presented with 16 slides, each containing 4 images of different emotional themes (2 neutral, 1 social, 1 dysphoric). The duration of time spent, and fixation frequency on images were measured.

RESULTS: Of the 36 AD patients (14 females, age = 78.2±7.8, sMMSE = 22.4±3.5) included, 17 had significant apathy (based on NPI apathy ≥4) and 19 did not. These groups had comparable age and sMMSE. Repeated-measures analysis of covariance models, controlling for total NPI, showed group (apathetic versus non-apathetic) by image (social versus dysphoric) interactions for duration (F(1,32) = 4.31, p = 0.046) and fixation frequency (F(1,32) = 11.34, p = 0.002). Apathetic patients demonstrated reduced duration and fixation frequency on social images compared with non-apathetic patients. Additionally, linear regression models suggest that more severe apathy predicted decreasing fixation frequency on social images (R2 = 0.26, Adjusted R2 = 0.19, F(3,32) = 3.65, p = 0.023).

CONCLUSION: These results suggest that diminished attentional bias toward social-themed stimuli is a marker of apathy in AD. Measurements of visual scanning behavior may have the potential to predict and monitor treatment response in apathy.

%B J Alzheimers Dis %V 51 %P 837-46 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890774?dopt=Abstract %R 10.3233/JAD-151026 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Apolipoprotein E Related Co-Morbidities and Alzheimer's Disease. %A Singhrao, Sim K %A Harding, Alice %A Chukkapalli, Sasanka %A Olsen, Ingar %A Kesavalu, Lakshmyya %A Crean, StJohn %K Aging %K Alzheimer Disease %K Animals %K Apolipoprotein E4 %K Cardiovascular Diseases %K Comorbidity %K Diabetes Mellitus, Type 2 %K Humans %K Mice %K Periodontal Diseases %X

The primary goal of advancement in clinical services is to provide a health care system that enhances an individual's quality of life. Incidence of diabetes mellitus, cardiovascular disease, and associated dementia coupled with the advancing age of the population, have led to an increase in the worldwide challenge to the healthcare system. In order to overcome these challenges, prior knowledge of common, reliable risk factors and their effectors is essential. Oral health constitutes one such relatively unexplored but indispensable risk factor for aforementioned co-morbidities, in the form of poor oral hygiene and tooth loss during aging. Behavioral traits such as low education, smoking, poor diet, neglect of oral health, lack of exercise, and hypertension are few of the risk factors that are shared commonly among these conditions. In addition, common genetic susceptibility traits such as the apolipoprotein E gene, together with an individual's lifestyle can also influence the development of co-morbidities such as periodontitis, atherosclerosis/stroke, diabetes, and Alzheimer's disease. This review specifically addresses the susceptibility of apolipoprotein E gene allele 4 as the plausible commonality for the etiology of co-morbidities that eventually result from periodontal diseases and ultimately progress to dementia.

%B J Alzheimers Dis %V 51 %P 935-48 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923007?dopt=Abstract %R 10.3233/JAD150690 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Apolipoprotein ɛ4 is Associated with Dementia and Cognitive Impairment Predominantly Due to Alzheimer's Disease and Not with Vascular Cognitive Impairment: A Singapore-Based Cohort. %A Chai, Yuek Ling %A Yeo, Hazel Kai-Hui %A Wang, Jiehao %A Hilal, Saima %A Ikram, Mohammad Kamran %A Venketasubramanian, Narayanaswamy %A Wong, Boon-Seng %A Chen, Christopher Li-Hsian %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Apolipoprotein E4 %K Cognition Disorders %K Cohort Studies %K Dementia %K Female %K Genetic Association Studies %K Genotype %K Humans %K Male %K Middle Aged %K Neuroimaging %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Singapore %K Vascular Diseases %X

BACKGROUND AND OBJECTIVE: While the association for apolipoprotein ɛ4 allele (APOE4) with Alzheimer's disease (AD) has been consistently confirmed, the association with vascular cognitive impairment (VCI) is unclear. We therefore explored the relationship of APOE with both AD and cerebrovascular disease (CeVD) by examining the prevalence of APOE4 in AD, AD with CeVD and vascular dementia (VaD), as well as in cognitive impairment no dementia (CIND) with and without CeVD.

METHODS: We performed a case-control study with subjects recruited from memory clinics and the community. All subjects underwent standardized brain neuroimaging, clinical and neuropsychological assessments, following which they were classified using research criteria.

RESULTS: A total of 411 subjects; 92 controls with no cognitive impairment (NCI), 77 CIND without CeVD, 87 CIND with CeVD, 55 AD without CeVD, 68 AD with CeVD, and 32 VaD patients were recruited. Compared to NCI (16.3%), the prevalence of APOE4 carriers was significantly higher only in CIND (37.7%) and AD in the absence of CeVD (45.5%), but not in the three subgroups of VCI, namely CIND with CeVD (20.7%), AD with CeVD (27.9%) and VaD (25.0%). Logistic regression analyses also showed that APOE4 carriers were more likely to have CIND without CeVD (Odds Ratio [OR]: 3.34; 95% Confidence Interval [CI]: 1.59-7.03) and AD without CeVD (OR: 7.21; 95% CI: 2.74-18.98), but no such association was observed in the VCI subgroups.

CONCLUSION: APOE4 is significantly associated with dementia and CIND due to AD pathology, but not with VCI.

%B J Alzheimers Dis %V 51 %P 1111-8 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923016?dopt=Abstract %R 10.3233/JAD-150902 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Application of the IWG-2 Diagnostic Criteria for Alzheimer's Disease to the ADNI. %A Wang, Hui-Fu %A Tan, Lan %A Cao, Lei %A Zhu, Xi-Chen %A Jiang, Teng %A Tan, Meng-Shan %A Liu, Ying %A Wang, Chong %A Tsai, Richard M %A Jia, Jian-Ping %A Yu, Jin-Tai %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid Precursor Protein Secretases %K Aspartic Acid Endopeptidases %K Cognitive Dysfunction %K Databases, Factual %K Disease Progression %K Female %K Humans %K Longitudinal Studies %K Male %K Multicenter Studies as Topic %K Neuroimaging %K Psychiatric Status Rating Scales %K tau Proteins %X

BACKGROUND: The International Working Group (IWG) recently proposed the revised diagnostic criteria for Alzheimer's disease (AD) to define and refine several types of AD, and to reclassify AD-related biomarkers into diagnostic and progression markers, but its performance is not known.

OBJECTIVE: This study was designed to describe the application of the revised IWG criteria in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, and to ascertain whether diagnostic and progression markers show significant differences in their relationships to AD severity and progression.

METHODS: Based on the requirements of the refined criteria, 857 ADNI subjects with memory evaluation and at least one pathophysiological marker (CSF or amyloid imaging biomarkers) were eligible and reclassified in this study, and we calculated the associations of diagnostic (CSF and amyloid PET) and progression markers (MRI and fluorodeoxyglucose-PET) with AD severity and progression respectively.

RESULTS: The majority (84.2% ) of ADNI AD group (n = 117) and 173 MCI (37.4% ) subjects in ADNI met the definition of typical AD; and 105 cognitively normal (41.0% ) individuals were diagnosed as asymptomatic AD. Furthermore, diagnostic and progression markers showed significant differences when correlated to AD severity and progression.

CONCLUSION: A large proportion of AD dementia subjects were categorized as typical AD, and the revised criteria could identify typical AD from MCI status as well as asymptomatic AD at the asymptomatic stage. Moreover, the significant differences between diagnostic and progression markers further supported the new biomarkers categorization in the refined criteria.

%B J Alzheimers Dis %V 51 %P 227-36 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836176?dopt=Abstract %R 10.3233/JAD-150824 %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 Frontotemporal Dementia GWAS Loci with Late-Onset Alzheimer's Disease in a Northern Han Chinese Population. %A Tan, Chen-Chen %A Wan, Yu %A Tan, Meng-Shan %A Zhang, Wei %A Wang, Zi-Xuan %A Sun, Fu-Rong %A Miao, Dan %A Tan, Lan %A Yu, Jin-Tai %K Age of Onset %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Asian Continental Ancestry Group %K Case-Control Studies %K China %K Female %K Frontotemporal Dementia %K Gene Frequency %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Genotyping Techniques %K Humans %K Linkage Disequilibrium %K Male %K Mental Status Schedule %K Polymorphism, Single Nucleotide %X

BACKGROUND: Both Alzheimer's disease (AD) and frontotemporal dementia (FTD) are a class of neurodegenerative diseases. Strong similarities in cerebrospinal fluid biomarker, imaging markers, and disease progression profiles suggest that some or most of the pathophysiology is shared between AD and FTD. A recent large genome-wide association study reported several single nucleotide polymorphisms (SNPs) at the RAB38, RAB38/CTSC, HLA-DRA/HLA-DRB5, and BTNL2 in association with FTD.

OBJECTIVE: To explore whether these SNPs are associated with AD risk.

METHODS: We conducted a case-control study to investigate the association of FTD-associated loci in 2338 Han Chinese subjects.

RESULTS: We observed significant differences in genotype distributions of rs302668 (pc = 0.025), rs9268877 (pc = 0.025), rs9268856 (p <  0.001), and rs1980493 (pc = 0.045) between cases and controls. The SNPs rs16913634 for RAB38/CTSC was unrelated to LOAD risk (p = 0.088).

CONCLUSION: The SNPs rs302668 in RAB38, rs9268877 and rs9268856 polymorphism in HLA-DRA/HLA-DRB5, and rs1980493 polymorphism in BTNL2 might play a role in the susceptibility to late-onset AD in the Han Chinese population.

%B J Alzheimers Dis %V 52 %P 43-50 %8 2016 02 26 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967218?dopt=Abstract %R 10.3233/JAD-151073 %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 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 Biochemical and Radiological Markers of Alzheimer's Disease Progression. %A Dziedzic, Tomasz %A Pera, Joanna %A Klimkowicz-Mrowiec, Aleksandra %A Mroczko, Barbara %A Slowik, Agnieszka %K Alzheimer Disease %K Biomarkers %K Disease Progression %K Humans %K Neuroimaging %K Radionuclide Imaging %X

Alzheimer's disease (AD) is a neurodegenerative, inevitably progressive disease with a rate of cognitive, functional, and behavioral decline that varies highly from patient to patient. Although several clinical predictors of AD progression have been identified, to our mind in clinical practice there is a lack of a reliable biomarker that enables one to stratify the risk of deterioration. Identification of biomarkers that allow the monitoring of AD progression could change the way physicians and caregivers make treatment decisions. This review summarizes the results of studies on potential biochemical and radiological markers related to AD progression.

%B J Alzheimers Dis %V 50 %P 623-44 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757184?dopt=Abstract %R 10.3233/IFS-150578 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Blood-Borne Activity-Dependent Neuroprotective Protein (ADNP) is Correlated with Premorbid Intelligence, Clinical Stage, and Alzheimer's Disease Biomarkers. %A Malishkevich, Anna %A Marshall, Gad A %A Schultz, Aaron P %A Sperling, Reisa A %A Aharon-Peretz, Judith %A Gozes, Illana %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Chi-Square Distribution %K Cognitive Dysfunction %K Cohort Studies %K Female %K Homeodomain Proteins %K Humans %K Independent Living %K Intelligence %K Male %K Mental Status Schedule %K Middle Aged %K Nerve Tissue Proteins %K Peptide Fragments %K RNA, Messenger %K tau Proteins %X

Biomarkers for Alzheimer's disease (AD) are vital for disease detection in the clinical setting. Discovered in our laboratory, activity-dependent neuroprotective protein (ADNP) is essential for brain formation and linked to cognitive functions. Here, we revealed that blood borne expression of ADNP and its paralog ADNP2 is correlated with premorbid intelligence, AD pathology, and clinical stage. Age adjustment showed significant associations between: 1) higher premorbid intelligence and greater serum ADNP, and 2) greater cortical amyloid and lower ADNP and ADNP2 mRNAs. Significant increases in ADNP mRNA levels were observed in patients ranging from mild cognitive impairment (MCI) to AD dementia. ADNP2 transcripts showed high correlation with ADNP transcripts, especially in AD dementia lymphocytes. ADNP plasma/serum and lymphocyte mRNA levels discriminated well between cognitively normal elderly, MCI, and AD dementia participants. Measuring ADNP blood-borne levels could bring us a step closer to effectively screening and tracking AD.

%B J Alzheimers Dis %V 50 %P 249-60 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639975?dopt=Abstract %R 10.3233/JAD-150799 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Brain-Specific Basal and Novelty-Induced Alternations in PI3K-Akt and MAPK/ERK Signaling in a Middle-Aged AβPP/PS1 Mouse Model of Alzheimer's Disease. %A Guillot, Florence %A Kemppainen, Susanna %A Lavasseur, Gregoire %A Miettinen, Pasi O %A Laroche, Serge %A Tanila, Heikki %A Davis, Sabrina %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Disease Models, Animal %K Gene Expression Regulation %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mitogen-Activated Protein Kinase Kinases %K Mutation %K Oncogene Protein v-akt %K Phosphatidylinositol 3-Kinases %K Presenilin-1 %K Signal Transduction %X

Although it is well established that insulin/IGF and BDNF signaling are dysfunctionally regulated in Alzheimer's disease, there are very few studies documenting changes in major target proteins in different murine models of the disease. We investigated a panel of proteins in the PI3K-Akt and MAPK/ERK cascades in parietal cortex, dentate gyrus and CA1 in 13-month-old AβPP/PS1 transgenic mice to determine whether amyloid pathology is associated with basal dysregulation of these proteins or following exposure to novelty. The most striking effect we found was that there was little common regulation of proteins either by pathology alone or exposure to novelty across the three structures, suggesting dysfunctional mechanisms that occur simultaneously have important structure specificity. CA1 shared certain dysfunctional regulation of proteins in the MAPK/ERK cascade, but shared dysfunctional regulation of the PI3K/Akt cascade with the dentate gyrus. Changes in ERK/CREB in transgenic mice did not result in coordinated dysfunction of the downstream transcription factor, Egr1, as it was overexpressed in a normal manner following exposure to novelty. In the PI3K-Akt cascade, there was a flagrant increase in the levels of proteins associated with inflammation, such as NFκB, and structure specific regulation of proteins associated with autophagy, such as mTOR and FOXO1 and lack of regulation of Beclin-1. Finally, Beclin-1 was increased by novelty in wild-type mice but deficient in transgenic mice. Results are interpreted in terms of structure-specific dysfunctional regulation of signaling mechanisms associated with Alzheimer's disease.

%B J Alzheimers Dis %V 51 %P 1157-73 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923018?dopt=Abstract %R 10.3233/JAD-150926 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Bridging Integrator 1 (BIN1) Genotypes Mediate Alzheimer's Disease Risk by Altering Neuronal Degeneration. %A Wang, Hui-Fu %A Wan, Yu %A Hao, Xiao-Ke %A Cao, Lei %A Zhu, Xi-Chen %A Jiang, Teng %A Tan, Meng-Shan %A Tan, Lin %A Zhang, Dao-Qiang %A Tan, Lan %A Yu, Jin-Tai %K Adaptor Proteins, Signal Transducing %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Brain %K Databases, Factual %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Genetic Predisposition to Disease %K Glucose %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Nerve Degeneration %K Nuclear Proteins %K Polymorphism, Single Nucleotide %K Positron-Emission Tomography %K Risk %K tau Proteins %K Tumor Suppressor Proteins %X

BACKGROUND: Bridging integrator 1 (BIN1) has been identified as one of the most associated loci for Alzheimer's disease (AD), and recently was reported to modulate tau pathology to mediate AD in vitro. However, the effects of BIN1 on the AD related biomarkers in AD continuum were not specifically assessed.

OBJECTIVE: We explored the effects of BIN1 loci on AD specific biomarkers (CSF proteins, brain structures, glucose and amyloid-β (Aβ) metabolisms) to investigate the role BIN1 in AD pathogenesis.

METHODS: We calculated the associations of BIN1 loci with these markers at baseline and follow-up in multiple linear models in 812 ADNI subjects.

RESULTS: BIN1 loci were significantly associated with the levels of T-tau (rs744373: pc = 0.047, rs13031703: pc = 0.042) and P-tau (rs744373: pc = 0.044, rs13031703: pc = 0.019), but not with Aβ in CSF test. BIN1 genotypes were strongly related to atrophy of hippocampus (rs7561528: pc = 0.011), CA1 (rs1469980: pc = 0.029) and parahippocampus (rs72838284, pc = 0.017) on MRI, and to glucose metabolism on FDG-PET, but not to Aβ deposition on AV45-PET imaging. Furthermore, haplotype and subgroup analysis confirmed these significant findings. In addition, the loci associated with these markers were also identified to influence the risk for AD in the meta-analysis of 74 046 European individuals.

CONCLUSION: This study supported that BIN1 contributes to the risk of AD by altering neural degeneration (abnormal tau, brain atrophy and glucose metabolism) but not Aβ pathology.

%B J Alzheimers Dis %V 52 %P 179-90 %8 2016 03 15 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003210?dopt=Abstract %R 10.3233/JAD-150972 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cannabinoid Receptor 2 Participates in Amyloid-β Processing in a Mouse Model of Alzheimer's Disease but Plays a Minor Role in the Therapeutic Properties of a Cannabis-Based Medicine. %A Aso, Ester %A Andrés-Benito, Pol %A Carmona, Margarita %A Maldonado, Rafael %A Ferrer, Isidre %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Cannabidiol %K Cognition %K Disease Models, Animal %K Dronabinol %K Humans %K Male %K Medical Marijuana %K Memory %K Mice, Inbred C57BL %K Mice, Transgenic %K Nootropic Agents %K Presenilin-1 %K Random Allocation %K Receptor, Cannabinoid, CB2 %K tau Proteins %K Treatment Outcome %X

The endogenous cannabinoid system represents a promising therapeutic target to modify neurodegenerative pathways linked to Alzheimer's disease (AD). The aim of the present study was to evaluate the specific contribution of CB2 receptor to the progression of AD-like pathology and its role in the positive effect of a cannabis-based medicine (1:1 combination of Δ9-tetrahidrocannabinol and cannabidiol) previously demonstrated to be beneficial in the AβPP/PS1 transgenic model of the disease. A new mouse strain was generated by crossing AβPP/PS1 transgenic mice with CB2 knockout mice. Results show that lack of CB2 exacerbates cortical Aβ deposition and increases the levels of soluble Aβ40. However, CB2 receptor deficiency does not affect the viability of AβPP/PS1 mice, does not accelerate their memory impairment, does not modify tau hyperphosphorylation in dystrophic neurites associated to Aβ plaques, and does not attenuate the positive cognitive effect induced by the cannabis-based medicine in these animals. These findings suggest a minor role for the CB2 receptor in the therapeutic effect of the cannabis-based medicine in AβPP/PS1 mice, but also constitute evidence of a link between CB2 receptor and Aβ processing.

%B J Alzheimers Dis %V 51 %P 489-500 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890764?dopt=Abstract %R 10.3233/JAD-150913 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Capillary amyloid-β protein deposition in a population-based study (Vantaa 85+). %A Mäkelä, Mira %A Paetau, Anders %A Polvikoski, Tuomo %A Myllykangas, Liisa %A Tanskanen, Maarit %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Autopsy %K Capillaries %K Cerebral Amyloid Angiopathy %K Female %K Finland %K Genotype %K Humans %K Immunohistochemistry %K Logistic Models %K Male %K Multivariate Analysis %K Occipital Lobe %K Prospective Studies %K Severity of Illness Index %X

BACKGROUND: Capillary amyloid-β (capAβ) deposition in the cerebral cortex is the neuropathological feature providing the basis for categorizing cerebral amyloid angiopathy (CAA) into two distinct types, CAA-Type1 with capAβ and CAA-Type2 without capAβ.

OBJECTIVE: We investigated the neuropathological and clinical characteristics of capAβ deposition in a prospective population-based study.

METHODS: Vantaa 85+ includes 601 individuals aged ≥85 years, of which 300 were studied clinically and neuropathologically. 278 subjects were analyzed for the apolipoprotein E (APOE) genotype. The diagnosis of capAβ was determined using immunohistochemistry against Aβ, and of CAA using Congo red confirmed by Aβ immunohistochemistry, both analyzed in six brain areas. The severity of capAβ was graded semi-quantitatively, and the severity of CAA was based on the percentage of affected vessels. Alzheimer's disease (AD)-type neuropathology (CERAD score and Braak stage) was analyzed using standard methods.

RESULTS: CAA-Type1 was present in 86/300, CAA-Type2 in 135/300, and 79/300 had no CAA. CapAβ was most frequent in the occipital lobe (79/86). CAA-Type1 was associated with the severity of CAA (p <  0.001), dementia (p <  0.001), severe AD-type neuropathology (p-value 0.09 for CERAD C and 0.017 for Braak stages V-VI), and APOE ɛ4 allele carrier status (p <  0.001).

CONCLUSIONS: This population-based study confirmed the presence of distinct CAA-Type1 and its association with the severity of CAA, severe AD-type neuropathology, and the APOE ɛ4 carrier status. Both the severity and localization of the deposition seemed to determine the clinical significance of capAβ.

%B J Alzheimers Dis %V 49 %P 149-57 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444758?dopt=Abstract %R 10.3233/JAD-150241 %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 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 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 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 Characterizing White Matter Tract Degeneration in Syndromic Variants of Alzheimer's Disease: A Diffusion Tensor Imaging Study. %A Madhavan, Ajay %A Schwarz, Christopher G %A Duffy, Joseph R %A Strand, Edythe A %A Machulda, Mary M %A Drubach, Daniel A %A Kantarci, Kejal %A Przybelski, Scott A %A Reid, Robert I %A Senjem, Matthew L %A Gunter, Jeffrey L %A Apostolova, Liana G %A Lowe, Val J %A Petersen, Ronald C %A Jack, Clifford R %A Josephs, Keith A %A Whitwell, Jennifer L %K Aged %K Alzheimer Disease %K Aniline Compounds %K Anisotropy %K Aphasia, Primary Progressive %K Case-Control Studies %K Diffusion Tensor Imaging %K Female %K Humans %K Image Processing, Computer-Assisted %K Male %K Middle Aged %K Nerve Fibers, Myelinated %K Neurodegenerative Diseases %K Neuropsychological Tests %K Positron-Emission Tomography %K Psychiatric Status Rating Scales %K Retrospective Studies %K Thiazoles %K White Matter %X

BACKGROUND: Different clinical syndromes can arise from Alzheimer's disease (AD) neuropathology, including dementia of the Alzheimer's type (DAT), logopenic primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA).

OBJECTIVE: To assess similarities and differences in patterns of white matter tract degeneration across these syndromic variants of AD.

METHODS: Sixty-four subjects (22 DAT, 24 lvPPA, and 18 PCA) that had diffusion tensor imaging and showed amyloid-β deposition on PET were assessed in this case-control study. A whole-brain voxel-based analysis was performed to assess differences in fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity across groups.

RESULTS: All three groups showed overlapping diffusion abnormalities in a network of tracts, including fornix, corpus callosum, posterior thalamic radiations, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and uncinate fasciculus. Subtle regional differences were also observed across groups, with DAT particularly associated with degeneration of fornix and cingulum, lvPPA with left inferior fronto-occipital fasciculus and uncinate fasciculus, and PCA with posterior thalamic radiations, superior longitudinal fasciculus, posterior cingulate, and splenium of the corpus callosum.

CONCLUSION: These findings show that while each AD phenotype is associated with degeneration of a specific structural network of white matter tracts, striking spatial overlap exists among the three network patterns that may be related to AD pathology.

%B J Alzheimers Dis %V 49 %P 633-43 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484918?dopt=Abstract %R 10.3233/JAD-150502 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cholesterol, 24-Hydroxycholesterol, and 27-Hydroxycholesterol as Surrogate Biomarkers in Cerebrospinal Fluid in Mild Cognitive Impairment and Alzheimer's Disease: A Meta-Analysis. %A Wang, Hua-Long %A Wang, Yan-Yong %A Liu, Xin-Gang %A Kuo, Sheng-Han %A Liu, Na %A Song, Qiao-Yun %A Wang, Ming-Wei %K Alzheimer Disease %K Cholesterol %K Cognitive Dysfunction %K Databases, Bibliographic %K Humans %K Hydroxycholesterols %X

Abnormal cholesterol metabolism is an established feature of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) is the fluid surrounding the central nervous system, and the protein and lipid content alterations in the CSF could be biomarkers for degenerative changes in the brain. The laboratory diagnosis of AD is limited to the analysis of three biomarkers in CSF: Aβ42, total tau, and phospho-tau. The purpose of this analysis is to systematically analyze the available data describing the biomarkers of cholesterol and its metabolites in the CSF of subjects with AD. MEDLINE, EMBASE, and the Cochrane Central database were systematically queried to collect studies that have evaluated the markers of cholesterol and its metabolites in the CSF of subjects with mild cognitive impairment (MCI) or AD and age-matched controls. Analysis of the published data shows that the levels of cholesterol are increased in MCI subjects; 24-hydroxycholesterol and 27-hydroxycholesterol are elevated in AD and MCI subjects compared to controls. There is a significant dysfunction of cholesterol metabolism in the CSF of AD subjects. This analysis indicates that in addition to the available biomarkers in the CSF, such as Aβ42, total tau, and phospho-tau, 24-hydroxycholesterol, 27-hydroxycholesterol, and cholesterol appear to be sensitive biomarkers for the evaluation of MCI and AD.

%B J Alzheimers Dis %V 51 %P 45-55 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836015?dopt=Abstract %R 10.3233/JAD-150734 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Chronic Sleep Deprivation Exacerbates Learning-Memory Disability and Alzheimer's Disease-Like Pathologies in AβPP(swe)/PS1(ΔE9) Mice. %A Qiu, Hongyan %A Zhong, Rujia %A Liu, Hui %A Zhang, Feng %A Li, Song %A Le, Weidong %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Apoptosis %K Brain %K Cognition Disorders %K Disease Models, Animal %K Humans %K In Situ Nick-End Labeling %K Learning Disorders %K Mice %K Mice, Transgenic %K Mitochondrial Diseases %K Mutation %K Phosphorylation %K Plaque, Amyloid %K Presenilin-1 %K Reversal Learning %K Sleep Deprivation %K tau Proteins %X

Recently, there is an increasing concern over the association between sleep disorders and Alzheimer's disease (AD). Clinical observations have reported that chronic sleep deprivation (SD) may serve as a risk factor for AD. However, the pathological evidence for this assumption is still lacking. In the present study, we examined the potential impacts of chronic SD on learning-memory and AD-related pathologies in AβPP(swe)/PS1(ΔE9) transgenic (TG) mice and their wild-type (WT) littermates. Results indicated that mice (both TG and WT) exposed to 2-month SD showed an altered amyloid-β protein precursor processing, an elevated level of phosphorylated tau protein, and impaired cognitive performance as compared to non-sleep deprivation (NSD) controls. Moreover, the SD-treated TG mice exhibited more amyloid-β(1-42) production and developed more senile plaques in the cortex and hippocampus than NSD-treated TG mice. In addition, SD caused a striking neuronal mitochondrial damage, caspase cascade activation, and neuronal apoptosis in the hippocampus of both TG and WT mice. More importantly, all these behavioral, neuropathological, and biochemical changes induced by chronic SD were long lasting and were irreversible during a 3-month normal housing condition. Collectively, these results indicate that chronic SD impairs learning and memory, exacerbates AD pathologies, and aggravates the mitochondria-mediated neuronal apoptosis in a long-lasting manner. Our findings provide important experimental evidence to prove that chronic SD is a risk factor for AD.

%B J Alzheimers Dis %V 50 %P 669-85 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757041?dopt=Abstract %R 10.3233/JAD-150774 %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 Classification of Neuropsychiatric Symptoms Requiring Antipsychotic Treatment in Patients with Alzheimer's Disease: Analysis of the CATIE-AD Study. %A Nagata, Tomoyuki %A Shinagawa, Shunichiro %A Nakajima, Shinichiro %A Plitman, Eric %A Mihashi, Yukiko %A Hayashi, Shogo %A Mimura, Masaru %A Nakayama, Kazuhiko %K Aged %K Aged, 80 and over %K Aggression %K Alzheimer Disease %K Antipsychotic Agents %K Apathy %K Cluster Analysis %K Female %K Humans %K Male %K Psychiatric Status Rating Scales %K Psychomotor Agitation %K Psychotic Disorders %K Retrospective Studies %K Severity of Illness Index %X

BACKGROUND: The Neuropsychiatric Inventory (NPI) comprises 12 items, which were conventionally determined by psychopathological symptoms of patients with dementia. The clinical rating scales with structured questionnaires have been useful to evaluate neuropsychiatric symptoms (NPSs) of patients with dementia over the past twenty year.

OBJECTIVE: The aim of this study was to classify the conventional NPSs in patients with Alzheimer's disease (AD) requiring antipsychotic treatment for their NPSs into distinct clusters to simplify assessment of these numerous symptoms.

METHODS: Twelve items scores (product of severity and frequency of each symptom) in the NPI taken from the baseline visit were classified into subgroups by principle component analysis using data from 421 outpatients with AD enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) Phase 1. Chi square tests were conducted to examine the co-occurrence of the subgroups.

RESULTS: We found four distinct clusters: aggressiveness (agitation and irritabilities), apathy and eating problems (apathy and appetite/eating disturbance), psychosis (delusions and hallucinations), and emotion and disinhibition (depression, euphoria, and disinhibition). Anxiety, aberrant motor behavior, and sleep disturbance were not included by these clusters. Apathy and eating problems, and emotion and disinhibition co-occurred (p = 0.002), whereas aggressiveness and psychosis occurred independent of the other clusters.

CONCLUSIONS: Four distinct category clusters were identified from NPSs in patients with AD requiring antipsychotic treatment. Future studies should investigate psychosocial backgrounds or risk factors of each distinct cluster, in addition to their longitudinal course over treatment intervention.

%B J Alzheimers Dis %V 50 %P 839-45 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836181?dopt=Abstract %R 10.3233/JAD-150869 %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 Dementia Rating Scale Detects White Matter Changes in Older Adults at Risk for Alzheimer's Disease. %A Chang, Yu-Ling %A Yen, Yu-Shiuan %A Chen, Ta-Fu %A Yan, Sui-Hing %A Tseng, Wen-Yih Isaac %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Cognition Disorders %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Memory %K Middle Aged %K Neuropsychological Tests %K Risk Factors %K White Matter %X

This study investigated the putative changes in regional gray matter and cingulum bundle segments in mild cognitive impairment (MCI) by using two diagnostic criteria. Participants comprised 50 older adults with MCI and 22 healthy older controls (HC). The older adults with MCI were further divided into two groups defined by a global Clinical Dementia Rating (CDR) score of 0.5 and with (the CDR/NPT MCI group) or without (the CDR MCI group) objective cognitive impairments determined using neuropsychological tests (NPTs). Comparable regional gray matter integrity was observed among the three groups. However, the integrity of the right inferior segment of the cingulum bundle in the two MCI groups was more reduced than that in the HC group, and the CDR/NPT MCI group exhibited additional disruption in the left inferior cingulum bundle. The results also demonstrated that neuropsychological measures have greater predictive value for changes in white matter beyond the contribution of an informant-based instrument alone. Overall, the findings confirm the utility of informant-based assessment in detecting microstructural brain changes in high-risk older adults, even before objective cognitive impairment is evident. The findings also suggest that combining the neuropsychological measures with the informant-based assessment provided the greatest predictive value in assessing white matter disruption. The essential role of the white matter measurement as a biomarker for detecting individuals at a high risk of developing dementia was highlighted.

%B J Alzheimers Dis %V 50 %P 411-23 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639963?dopt=Abstract %R 10.3233/JAD-150599 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Collapsin Response Mediator Protein-2 (CRMP2) is a Plausible Etiological Factor and Potential Therapeutic Target in Alzheimer's Disease: Comparison and Contrast with Microtubule-Associated Protein Tau. %A Hensley, Kenneth %A Kursula, Petri %K Alzheimer Disease %K Animals %K Humans %K Intercellular Signaling Peptides and Proteins %K Nerve Tissue Proteins %K tau Proteins %X

Alzheimer's disease (AD) has long been viewed as a pathology that must be caused either by aberrant amyloid-β protein precursor (AβPP) processing, dysfunctional tau protein processing, or a combination of these two factors. This is a reasonable assumption because amyloid-β peptide (Aβ) accumulation and tau hyperphosphorylation are the defining histological features in AD, and because AβPP and tau mutations can cause AD in humans or AD-like features in animal models. Nonetheless, other protein players are emerging that one can argue are significant etiological players in subsets of AD and potentially novel, druggable targets. In particular, the microtubule-associated protein CRMP2 (collapsin response mediator protein-2) bears striking analogies to tau and is similarly relevant to AD. Like tau, CRMP2 dynamically regulates microtubule stability; it is acted upon by the same kinases; collects similarly in neurofibrillary tangles (NFTs); and when sequestered in NFTs, complexes with critical synapse-stabilizing factors. Additionally, CRMP2 is becoming recognized as an important adaptor protein involved in vesicle trafficking, amyloidogenesis and autophagy, in ways that tau is not. This review systematically compares the biology of CRMP2 to that of tau in the context of AD and explores the hypothesis that CRMP2 is an etiologically significant protein in AD and participates in pathways that can be rationally engaged for therapeutic benefit.

%B J Alzheimers Dis %V 53 %P 1-14 %8 2016 04 15 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079722?dopt=Abstract %R 10.3233/JAD-160076 %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 Complementary and Alternative Medicine in the Context of Earlier Diagnoses of Alzheimer's Disease: Opening the Conversation to Prepare Ethical Responses. %A Racine, Eric %A Forlini, Cynthia %A Aspler, John %A Chandler, Jennifer %K Alzheimer Disease %K Complementary Therapies %K Early Diagnosis %K Ethical Analysis %K Humans %X

Preclinical Alzheimer's disease (AD), a newly proposed, actively researched, and hotly debated research-only diagnostic category, raises the prospect of an ethical dilemma: whether, and possibly how, to treat a disorder with no target symptoms. This proposed category rests on the detection of a number of biomarkers thought to provide evidence of AD pathophysiology years before any behavioral symptoms manifest. Faced with limited treatment options, patients and their relatives may come to consider complementary and alternative medicine (CAM) a viable option, albeit one with minimal supporting evidence. Accordingly, the hopes and needs of some preclinical patients and their relatives could further fuel market-oriented entrepreneurship for CAM. In this ethics review, we provide background and reflect on some ethical questions related to the roles of key stakeholders arising from the potential for CAM use in the context of a possible preclinical AD diagnosis.

%B J Alzheimers Dis %V 51 %P 1-9 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836152?dopt=Abstract %R 10.3233/JAD-150534 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Concanavalin agglutinin levels are decreased in peripheral blood of Alzheimer's disease patients. %A Sun, Xuying %A Ma, Ronghong %A Yao, Xiuqing %A Shang, Xiaoling %A Wang, Qun %A Wang, Jian-Zhi %A Liu, Gongping %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Concanavalin A %K Female %K Humans %K Lectins %K Male %K Plant Lectins %X

Alzheimer's disease (AD) seriously threatens patients' lives and causes severe burden to the families. Early prevention and treatment can alleviate the development of the disease; therefore it is important to find new effective and non-traumatic biomarkers for early diagnosis. In this study, peripheral blood samples were collected from 24 AD patients and the same number of age- and gender-matched control subjects. Lectin reactive glycosylation levels including beta-D-galactosyl ricinus communis agglutinin 120 (RCA), peanut agglutinin (PNA), concanavalin agglutinin (Con A), alpha-L-fucosyl ulex europeus agglutinin (UEA), dolichos biflorus agglutinin (DBA), and galanthus nivalis (GNL), in the red blood cells of peripheral blood were examined by western blotting. We found that lectin levels were altered with aging and gender; some lectin levels were different between AD patients and the control subjects. Only Con A levels were significantly decreased in AD patients compared to age-matched control subjects. These results suggest that Con A levels in peripheral blood may be a potent diagnostic marker for AD.

%B J Alzheimers Dis %V 49 %P 63-72 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444791?dopt=Abstract %R 10.3233/JAD-150539 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Course and Determinants of Anosognosia in Alzheimer's Disease: A 12-Month Follow-up. %A Turró-Garriga, Oriol %A Garre-Olmo, Josep %A Calvó-Perxas, Laia %A Reñé-Ramírez, Ramón %A Gascón-Bayarri, Jordi %A Conde-Sala, Josep Lluís %K Age Factors %K Aged %K Agnosia %K Alzheimer Disease %K Disability Evaluation %K Disease Progression %K Educational Status %K Female %K Follow-Up Studies %K Humans %K Incidence %K Logistic Models %K Longitudinal Studies %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Prevalence %K Prospective Studies %K Risk Factors %K Severity of Illness Index %X

Anosognosia in Alzheimer's disease (AD) has been associated with greater cognitive impairment and more behavioural and psychological symptoms of dementia (BPSD). This study examines the incidence, persistence, and remission rates of anosognosia over a 12-month period, as well as the related risk factors. This was an observational 12-month prospective study. The longitudinal sample comprised 177 patients with mild or moderate AD, and their respective caregivers. Anosognosia was assessed using the Anosognosia Questionnaire in Dementia, and we also evaluated cognitive status (Mini-Mental State Examination), functional disability (Disability Assessment in Dementia), and the presence of BPSD (Neuropsychiatric Inventory). Multinomial logistic regression was used to determine the variables associated with the incidence, persistence and remission of anosognosia. The prevalence of anosognosia was 39.5% (95% CI = 32.1-47.1) at baseline. At 12 months, incidence was 38.3% (95% CI = 28.6-48.0), persistence was 80.0% (95% CI = 69.9-90.1) and remission was 20.0% (95% CI = 9.9-30.1). The regression model identified lower age, more education, and the presence of delusions as variables associated with incidence, and more education, lower instrumental DAD score, and disinhibition as variables associated with persistence. No variables were associated with remission (n = 14). The presence of anosognosia in AD patients is high. Education and certain neuropsychiatric symptoms may explain a greater and earlier incidence of anosognosia. However, anosognosia also increases with greater cognitive impairment and disease severity.

%B J Alzheimers Dis %V 51 %P 357-66 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890611?dopt=Abstract %R 10.3233/JAD-150706 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Delusions in Patients with Alzheimer's Disease: A Multidimensional Approach. %A D'Onofrio, Grazia %A Panza, Francesco %A Sancarlo, Daniele %A Paris, Francesco F %A Cascavilla, Leandro %A Mangiacotti, Antonio %A Lauriola, Michele %A Paroni, Giulia H %A Seripa, Davide %A Greco, Antonio %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Delusions %K Female %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Prognosis %K Risk %K Severity of Illness Index %K Time Factors %X

In Alzheimer's disease (AD) patients with delusions, clinical outcomes and mortality result from a combination of psychological, biological, functional, and environmental factors. We determined the effect of delusions on mortality risk, clinical outcomes linked to comprehensive geriatric assessment (CGA), cognitive, depressive, and neuropsychiatric symptoms (NPS) in 380 consecutive AD patients with Mini-Mental State Examination, Clinical Dementia Rating scale, 15-item Geriatric Depression Scale, and Neuropsychiatric Inventory (NPI), assessing one-year mortality risk using the Multidimensional Prognostic Index (MPI). We included 121 AD patients with delusions (AD-D) and 259 AD patients without delusions (AD-noD). AD-D patients were significantly older, with higher age at onset and cognitive impairment, a more severe stage of dementia, and more depressive symptoms than AD-noD patients. Disease duration was slightly higher in AD-D patients than in those without delusions, although this difference was not statistically significant. At CGA, AD-D patients showed a higher grade of disability in basic and instrumental activities of daily living, and an increased risk of malnutrition and bedsores. The two groups of patients significantly differed in MPI score (AD-D: 0.65 versus AD-noD: 0.51, p <  0.0001) and MPI grade. AD-D patients showed also a significant higher score in NPI of the following NPS than AD-noD patients: hallucinations, agitation/aggression, depression mood, apathy, irritability/lability, aberrant motor activity, sleep disturbances, and eating disorders. Therefore, AD-D patients showed higher dementia severity, and higher impairment in cognitive and depressive symptoms, and several neuropsychiatric domains than AD-noD patients, and this appeared to be associated with higher multidimensional impairment and increased risk of mortality.

%B J Alzheimers Dis %V 51 %P 427-37 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890768?dopt=Abstract %R 10.3233/JAD-150944 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dementia Apraxia Test (DATE): A Brief Tool to Differentiate Behavioral Variant Frontotemporal Dementia from Alzheimer's Dementia Based on Apraxia Profiles. %A Johnen, Andreas %A Frommeyer, Jana %A Modes, Fenja %A Wiendl, Heinz %A Duning, Thomas %A Lohmann, Hubertus %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Apraxias %K Diagnosis, Differential %K Female %K Frontotemporal Dementia %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Psychometrics %K Reference Values %X

BACKGROUND: Standardized praxis assessments with modern, empirically validated screening tests have substantially improved clinical evaluation of apraxia in patients with stroke. Although apraxia may contribute to early differential diagnosis of Alzheimer's dementia (AD) and behavioral variant frontotemporal dementia (bvFTD), no comparable test is readily available to clinicians for this purpose to date.

OBJECTIVE: To design a clinically useful apraxia test for the differentiation of AD and bvFTD.

METHODS: 84 test items pertaining to twelve praxis subdomains were evaluated for their efficacy to discriminate between patients with bvFTD (n = 24), AD (n = 28), and elderly healthy controls (HC; n = 35). Items were then selected based on discriminative value and psychometric properties.

RESULTS: Items indicative of mild AD comprised spatially complex imitation of hand and finger postures and to a lesser degree, pantomime of common object-use. Buccofacial apraxia including imitation of face postures, emblematic face postures, and repetition of multisyllabic pseudowords differentiated bvFTD from HC and AD. The final test version consisting of 20 items proved highly efficient for the discrimination of biologically confirmed dementia patients from HC (sensitivity 91% , specificity 71%) but also for differential diagnosis of bvFTD and AD (sensitivity 74% , specificity 93%).

CONCLUSIONS: Assessment of praxis profiles effectively contributes to diagnosis and differential diagnosis of AD and bvFTD. The Dementia Apraxia Test (DATE) is a brief and easy to administer cognitive tool for dementia assessment, has a high inter-rater reliability (Cohen's κ= 0.885) and demonstrates content validity.

%B J Alzheimers Dis %V 49 %P 593-605 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484911?dopt=Abstract %R 10.3233/JAD-150447 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Detection of Alzheimer's Disease by Three-Dimensional Displacement Field Estimation in Structural Magnetic Resonance Imaging. %A Wang, Shuihua %A Zhang, Yudong %A Liu, Ge %A Phillips, Preetha %A Yuan, Ti-Fei %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Brain Mapping %K Datasets as Topic %K Female %K Humans %K Imaging, Three-Dimensional %K Machine Learning %K Magnetic Resonance Imaging %K Male %X

BACKGROUND: Within the past decade, computer scientists have developed many methods using computer vision and machine learning techniques to detect Alzheimer's disease (AD) in its early stages.

OBJECTIVE: However, some of these methods are unable to achieve excellent detection accuracy, and several other methods are unable to locate AD-related regions. Hence, our goal was to develop a novel AD brain detection method.

METHODS: In this study, our method was based on the three-dimensional (3D) displacement-field (DF) estimation between subjects in the healthy elder control group and AD group. The 3D-DF was treated with AD-related features. The three feature selection measures were used in the Bhattacharyya distance, Student's t-test, and Welch's t-test (WTT). Two non-parallel support vector machines, i.e., generalized eigenvalue proximal support vector machine and twin support vector machine (TSVM), were then used for classification. A 50 × 10-fold cross validation was implemented for statistical analysis.

RESULTS: The results showed that "3D-DF+WTT+TSVM" achieved the best performance, with an accuracy of 93.05 ± 2.18, a sensitivity of 92.57 ± 3.80, a specificity of 93.18 ± 3.35, and a precision of 79.51 ± 2.86. This method also exceled in 13 state-of-the-art approaches. Additionally, we were able to detect 17 regions related to AD by using the pure computer-vision technique. These regions include sub-gyral, inferior parietal lobule, precuneus, angular gyrus, lingual gyrus, supramarginal gyrus, postcentral gyrus, third ventricle, superior parietal lobule, thalamus, middle temporal gyrus, precentral gyrus, superior temporal gyrus, superior occipital gyrus, cingulate gyrus, culmen, and insula. These regions were reported in recent publications.

CONCLUSIONS: The 3D-DF is effective in AD subject and related region detection.

%B J Alzheimers Dis %V 50 %P 233-48 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682696?dopt=Abstract %R 10.3233/JAD-150848 %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 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 Impact of Cerebrospinal Fluid Biomarker (Pre-)Analytical Variability in Alzheimer's Disease. %A Niemantsverdriet, Ellis %A Goossens, Joery %A Struyfs, Hanne %A Martin, Jean-Jacques %A Goeman, Johan %A De Deyn, Peter Paul %A Vanderstichele, Hugo %A Engelborghs, Sebastiaan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Autopsy %K Cognitive Dysfunction %K Enzyme-Linked Immunosorbent Assay %K Exercise %K Female %K Follow-Up Studies %K Humans %K Male %K Middle Aged %K Peptide Fragments %K Psychiatric Status Rating Scales %K Retrospective Studies %K Statistics, Nonparametric %K tau Proteins %X

Intra- and inter-laboratory variability of cerebrospinal fluid (CSF) biomarker analyses remains an important issue. We investigated the clinical-diagnostic impact of CSF biomarker concentration shifts in mild cognitive impairment (MCI) and autopsy-confirmed Alzheimer's disease (AD) dementia patients. MCI patients (n = 85), autopsy-confirmed AD dementia patients (n = 72), and cognitively healthy controls (n = 100) were included in this prospective, longitudinal study. AD dementia patients were followed up until death, and controls were included from 1992 until 2003. In-house validated cutoff values of biomarkers were applied: Aβ1-42 <638.5 pg/mL, T-tau>296.5 pg/mL, P-tau(181P) >56.5 pg/mL. Both increments and decrements (from ± 5% to ± 40% ) were added to the true (=observed) CSF biomarker values, imitating the anticipated differences in biomarker concentrations. Within certain limits, the clinical diagnostic performance of AD CSF biomarkers remains largely unchanged and clinical diagnostic accuracy deviated less than 8.2% from the reference when concentration shifts ranging between -20% and +20% were added to one of the three CSF biomarkers in MCI and autopsy-confirmed AD patients. Notwithstanding the fact that (pre- and post-)analytical parameters can affect the clinical classification, the present exploratory study provides evidence that for a specific context of use, the impact on clinical accuracy of biomarker concentration shifts might be lower than originally expected. In conclusion, induced shifts of ±20% in only one of the three biomarkers has limited impact on the clinical accuracy of AD CSF biomarkers in MCI and autopsy-confirmed AD patients when using the IWG-2 criteria.

%B J Alzheimers Dis %V 51 %P 97-106 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836187?dopt=Abstract %R 10.3233/JAD-150953 %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 Diet and Inflammation in Alzheimer's Disease and Related Chronic Diseases: A Review. %A Gardener, Samantha L %A Rainey-Smith, Stephanie R %A Martins, Ralph N %K Alzheimer Disease %K Cardiovascular Diseases %K Chronic Disease %K Diet %K Humans %K Inflammation %K Neurodegenerative Diseases %X

Inflammation is one of the pathological features of the neurodegenerative disease, Alzheimer's disease (AD). A number of additional disorders are likewise associated with a state of chronic inflammation, including obesity, cardiovascular disease, and type-2 diabetes, which are themselves risk factors for AD. Dietary components have been shown to modify the inflammatory process at several steps of the inflammatory pathway. This review aims to evaluate the published literature on the effect of consumption of pro- or anti-inflammatory dietary constituents on the severity of both AD pathology and related chronic diseases, concentrating on the dietary constituents of flavonoids, spices, and fats. Diet-based anti-inflammatory components could lead to the development of potent novel anti-inflammatory compounds for a range of diseases. However, further work is required to fully characterize the therapeutic potential of such compounds, including gaining an understanding of dose-dependent relationships and limiting factors to effectiveness. Nutritional interventions utilizing anti-inflammatory foods may prove to be a valuable asset in not only delaying or preventing the development of age-related neurodegenerative diseases such as AD, but also treating pre-existing conditions including type-2 diabetes, cardiovascular disease, and obesity.

%B J Alzheimers Dis %V 50 %P 301-34 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682690?dopt=Abstract %R 10.3233/JAD-150765 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dietary high cholesterol and trace metals in the drinking water increase levels of ABCA1 in the rabbit hippocampus and temporal cortex. %A Schreurs, Bernard G %A Sparks, D Larry %K Aluminum %K Alzheimer Disease %K Animals %K ATP-Binding Cassette Transporters %K Brain Chemistry %K Cholesterol, Dietary %K Copper %K Drinking Water %K Hippocampus %K Male %K Neurons %K Rabbits %K Temporal Lobe %K Zinc %X

BACKGROUND: Cholesterol-fed rabbits have been documented to show increased amyloid-β (Aβ) deposits in the brain that can be exacerbated by the quality of drinking water especially if rabbits drink tap water or distilled water containing copper. One mechanism of cholesterol and Aβ clearance may be through the ATP-binding cassette transporter A1 (ABCA1).

OBJECTIVE AND METHODS: Using an ABCA1 antibody, we determined the number of ABCA1-immunopositive neurons in three areas of rabbit brain as a function of feeding 2% cholesterol and providing tap water, distilled water, or distilled water to which aluminum, copper, or zinc was added.

RESULTS: The number of neurons with ABCA1 immunoreactivity was increased significantly as a result of dietary cholesterol in the rabbit hippocampus and inferior and superior temporal cortex. The number of neurons with ABCA1 immunoreactivity was further increased in all three areas as a result of cholesterol-fed rabbits drinking tap water or distilled water with copper. Finally, cholesterol-fed rabbits that drank distilled water with aluminum also showed an increased number of ABCA1-immunopositive neurons in inferior and superior temporal cortex.

CONCLUSIONS: These data suggest that ABCA1 levels increase in parallel with previously documented increases in Aβ levels as a result of high dietary cholesterol and copper in the drinking water. Addition of aluminum to distilled water may have a similar effect in the temporal cortex. ABCA1 has been proposed as a means of clearing Aβ from the brain and manipulations that increase Aβ also result in an increase of clearance machinery.

%B J Alzheimers Dis %V 49 %P 201-9 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444796?dopt=Abstract %R 10.3233/JAD-150601 %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 Impairment of Cognitive and Affective Mentalizing Abilities in Neurodegenerative Dementias: Evidence from Behavioral Variant of Frontotemporal Dementia, Alzheimer's Disease, and Mild Cognitive Impairment. %A Dodich, Alessandra %A Cerami, Chiara %A Crespi, Chiara %A Canessa, Nicola %A Lettieri, Giada %A Iannaccone, Sandro %A Marcone, Alessandra %A Cappa, Stefano F %A Cacioppo, John T %K Aged %K Alzheimer Disease %K Cognition %K Cognitive Dysfunction %K Emotions %K Female %K Frontotemporal Dementia %K Humans %K Male %K Theory of Mind %X

Cognitive and affective theory of mind (ToM) can be impaired in the course of neurodegenerative dementias. Experimental tests based on different task conditions and/or complexity may fail to capture disease-specific patterns of impairments. In this study, we assessed with a single task both the affective and the cognitive facets of ToM ability in a sample of 47 patients (i.e., 12 AD, 20 bvFTD, and 15 aMCI fulfilling IWG criteria for AD in predementia phase) and 65 healthy controls. Subjects were administered the Story-based Empathy task (SET), a non-verbal task measuring the ability to infer others' intentions (IA) and emotions (EA) compared to a control condition (causal inferences, CI). Global and single sub-condition scores were evaluated with a vectorial method, analyzing the relationship between social abilities and basic cognitive functioning by means of two indices representing the basic ability to perform the task and the balance between basic functions and ToM skills.Dementia (AD and bvFTD) patients showed impaired performances on all SET sub-conditions, whereas aMCI subjects' performance was not different from healthy controls. Vectorial analysis revealed a specific change in the balance between EA and CI conditions only in the bvFTD group, supporting a disproportionate deficit in mental states attribution based on affective cues. The overall deficit in the task in AD appears to be more general and related to the severity of dementia. This latter finding is further supported by the normal performance of the prodromal AD group.

%B J Alzheimers Dis %V 50 %P 1011-22 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836153?dopt=Abstract %R 10.3233/JAD-150605 %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 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 The Disconnection Hypothesis in Alzheimer's Disease Studied Through Multimodal Magnetic Resonance Imaging: Structural, Perfusion, and Diffusion Tensor Imaging. %A Lacalle-Aurioles, María %A Navas-Sánchez, Francisco Javier %A Alemán-Gómez, Yasser %A Olazarán, Javier %A Guzmán-De-Villoria, Juan Adán %A Cruz-Orduña, Isabel %A Mateos-Pérez, José María %A Desco, Manuel %K Aged %K Alzheimer Disease %K Brain %K Brain Mapping %K Cerebral Angiography %K Cerebrovascular Circulation %K Cognitive Dysfunction %K Diffusion Tensor Imaging %K Female %K Functional Laterality %K Humans %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Models, Neurological %K Multimodal Imaging %K Organ Size %K Prospective Studies %X

According to the so-called disconnection hypothesis, the loss of synaptic inputs from the medial temporal lobes (MTL) in Alzheimer's disease (AD) may lead to reduced activity of target neurons in cortical areas and, consequently, to decreased cerebral blood flow (CBF) in those areas. The aim of this study was to assess whether hypoperfusion in parietotemporal and frontal cortices of patients with mild cognitive impairment who converted to AD (MCI-c) and patients with mild AD is associated with atrophy in the MTL and/or microstructural changes in the white matter (WM) tracts connecting these areas. We assessed these relationships by investigating correlations between CBF in hypoperfused areas, mean cortical thickness in atrophied regions of the MTL, and fractional anisotropy (FA) in WM tracts. In the MCI-c group, a strong correlation was observed between CBF of the superior parietal gyri and FA in the parahippocampal tracts (left: r = 0.90, p <  0.0001; right: r = 0.597, p = 0.024), and between FA in the right parahippocampal tract and the right precuneus (r = 0.551, p = 0.041). No significant correlations between CBF in hypoperfused regions and FA in the WM tract were observed in the AD group. These results suggest an association between perfusion deficits and altered WM tracts in prodromal AD, while microvasculature impairments may have a greater influence in more advanced stages. We did not find correlations between cortical thinning in the medial temporal lobes and decreased FA in the WM tracts of the limbic system in either group.

%B J Alzheimers Dis %V 50 %P 1051-64 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890735?dopt=Abstract %R 10.3233/JAD-150288 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Discovery and Subsequent Confirmation of Novel Serum Biomarkers Diagnosing Alzheimer's Disease. %A Shah, Dipti Jigar %A Rohlfing, Frederick %A Anand, Swati %A Johnson, W Evan %A Alvarez, MeiHwa Tanielle Bench %A Cobell, Jesse %A King, Jackson %A Young, Sydney A %A Kauwe, John S K %A Graves, Steven W %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Chromatography, Liquid %K Female %K Humans %K Male %K Psychiatric Status Rating Scales %K Reproducibility of Results %K ROC Curve %K Tandem Mass Spectrometry %X

BACKGROUND: Alzheimer's disease (AD) remains challenging to diagnose, especially early disease. Having serum AD biomarkers would be of significant interest both in the clinical setting and in drug development efforts.

OBJECTIVE: We applied a novel serum proteomic approach to interrogate the low-molecular weight proteome for serum AD biomarkers.

METHODS: A discovery study used sera from 58 any-stage AD cases and 55 matched controls analyzed by capillary liquid chromatography-electrospray ionization-tandem mass spectrometry. Candidate biomarkers were statistically modeled and promising biomarkers were retested in a second, blinded confirmatory study (AD cases = 68, controls = 57). Biomarkers that replicated in the second study were modeled for the diagnosis of any-stage and very early stage AD. Further, they were chemically identified by tandem MS.

RESULTS: The initial discovery study found 59 novel potential AD biomarkers. Thirteen recurred in more than one multi-marker panel. In a second, blinded, confirmatory study, these same biomarkers were retested in separate specimens. In that study, four markers validated comparing controls to patients with any-stage AD and also with very early AD. The four biomarkers with replicable ability to diagnose AD were then chemically identified.

CONCLUSION: These results suggest novel serum AD diagnostic biomarkers can be found using this approach.

%B J Alzheimers Dis %V 49 %P 317-27 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484917?dopt=Abstract %R 10.3233/JAD-150498 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Distinctive Resting State Network Disruptions Among Alzheimer's Disease, Subcortical Vascular Dementia, and Mixed Dementia Patients. %A Kim, Hee Jin %A Cha, Jungho %A Lee, Jong-Min %A Shin, Ji Soo %A Jung, Na-Yeon %A Kim, Yeo Jin %A Choe, Yearn Seong %A Lee, Kyung Han %A Kim, Sung Tae %A Kim, Jae Seung %A Lee, Jae Hong %A Na, Duk L %A Seo, Sang Won %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Aniline Compounds %K Cerebral Cortex %K Cross-Sectional Studies %K Dementia %K Dementia, Vascular %K Female %K Humans %K Image Processing, Computer-Assisted %K Male %K Middle Aged %K Models, Neurological %K Neural Pathways %K Neuropsychological Tests %K Oxygen %K Psychiatric Status Rating Scales %K Radionuclide Imaging %K Rest %K Thiazoles %X

BACKGROUND: Recent advances in resting-state functional MRI have revealed altered functional networks in Alzheimer's disease (AD), especially those of the default mode network (DMN) and central executive network (CEN). However, few studies have evaluated whether small vessel disease (SVD) or combined amyloid and SVD burdens affect the DMN or CEN.

OBJECTIVE: The aim of this study was to evaluate whether SVD or combined amyloid and SVD burdens affect the DMN or CEN.

METHODS: In this cross-sectional study, we investigated the resting-state functional connectivity within DMN and CEN in 37 Pittsburgh compound-B (PiB)(+) AD, 37 PiB(-) subcortical vascular dementia (SVaD), 13 mixed dementia patients, and 65 normal controls.

RESULTS: When the resting-state DMN of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(+) AD patients displayed lower functional connectivity in the inferior parietal lobule while the PiB(-) SVaD patients displayed lower functional connectivity in the medial frontal and superior frontal gyri. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the DMN in the posterior cingulate gyrus. When the resting-state CEN connectivity of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(-) SVaD patients displayed lower functional connectivity in the anterior insular region. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the CEN in the inferior frontal gyrus.

CONCLUSIONS: Our findings suggest that in PiB(+) AD and PiB(-) SVaD, there is divergent disruptions in resting-state DMN and CEN. Furthermore, patients with combined amyloid and SVD burdens exhibited more disrupted resting-state DMN and CEN than patients with only amyloid or SVD burden.

%B J Alzheimers Dis %V 50 %P 709-18 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757039?dopt=Abstract %R 10.3233/JAD-150637 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Do Microglia Default on Network Maintenance in Alzheimer's Disease? %A Southam, Katherine A %A Vincent, Adele J %A Small, David H %K Alzheimer Disease %K Animals %K Humans %K Microglia %K Synapses %X

Although the cause of Alzheimer's disease (AD) remains unknown, a number of new findings suggest that the immune system may play a critical role in the early stages of the disease. Genome-wide association studies have identified a wide array of risk-associated genes for AD, many of which are associated with abnormal functioning of immune cells. Microglia are the brain's immune cells. They play an important role in maintaining the brain's extracellular environment, including clearance of aggregated proteins such as amyloid-β (Aβ). Recent studies suggest that microglia play a more active role in the brain than initially considered. Specifically, microglia provide trophic support to neurons and also regulate synapses. Microglial regulation of neuronal activity may have important consequences for AD. In this article we review the function of microglia in AD and examine the possible relationship between microglial dysfunction and network abnormalities, which occur very early in disease pathogenesis.

%B J Alzheimers Dis %V 51 %P 657-69 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890782?dopt=Abstract %R 10.3233/JAD-151075 %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 and diagnostic potential of microRNA in Alzheimer's disease. %A Pan, Yaoqian %A Liu, Ruizhu %A Terpstra, Erin %A Wang, Yanqing %A Qiao, Fangfang %A Wang, Jin %A Tong, Yigang %A Pan, Bo %K Aged %K Alzheimer Disease %K Biomarkers %K Disease Progression %K Humans %K MicroRNAs %K Prognosis %X

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is considered to be the main cause of cognitive impairment in elderly people. The major symptom of AD is progressive dementia that eventually results in dysfunction of daily life. Due to the fact that AD has a long period of incubation before clinical symptoms emerge, the available therapeutic treatments can only improve the symptoms but not delay the progression of AD. Therefore, there is an urgent need to explore effective diagnostic approaches to catch and better treat the disease before clinical symptoms appear. Recent research revealed that abnormal expression of certain miRNA could have a crucial role in the pathological process of neurodegenerative disease including AD. Furthermore, given that AD patients show increased level of miRNAs in the blood and cerebrospinal fluid, miRNAs are considered promising non-invasive candidates for AD diagnosis and prognosis. Here, we reviewed the current research related to implications of miRNAs during the development of AD, summarized of actively used approaches to identifying potential miRNA biomarkers in body fluids, and discussed the diagnostic potential of microRNAs as biomarkers for AD.

%B J Alzheimers Dis %V 49 %P 1-12 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484912?dopt=Abstract %R 10.3233/JAD-150451 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Early in vivo Effects of the Human Mutant Amyloid-β Protein Precursor (hAβPPSwInd) on the Mouse Olfactory Bulb. %A Rusznák, Zoltán %A Kim, Woojin Scott %A Hsiao, Jen-Hsiang T %A Halliday, Glenda M %A Paxinos, George %A Fu, YuHong %K Age Factors %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Cell Proliferation %K Disease Models, Animal %K Gene Expression Regulation %K Humans %K Ki-67 Antigen %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mutation %K Nerve Tissue Proteins %K Neurogenesis %K Neurons %K Olfactory Bulb %K Piriform Cortex %X

The amyloid-β protein precursor (AβPP) has long been linked to Alzheimer's disease (AD). Using J20 mice, which express human AβPP with Swedish and Indiana mutations, we studied early pathological changes in the olfactory bulb. The presence of AβPP/amyloid-β (Aβ) was examined in mice aged 3 months (before the onset of hippocampal Aβ deposition) and over 5 months (when hippocampal Aβ deposits are present). The number of neurons, non-neurons, and proliferating cells was assessed using the isotropic fractionator method. Our results demonstrate that although AβPP is overexpressed in some of the mitral cells, widespread Aβ deposition and microglia aggregates are not prevalent in the olfactory bulb. The olfactory bulbs of the younger J20 group harbored significantly fewer neurons than those of the age-matched wild-type mice (5.57±0.13 million versus 6.59±0.36 million neurons; p = 0.011). In contrast, the number of proliferating cells was higher in the young J20 than in the wild-type group (i.e., 6617±425 versus 4455±623 cells; p = 0.011). A significant increase in neurogenic activity was also observed in the younger J20 olfactory bulb. In conclusion, our results indicate that (1) neurons participating in the mouse olfactory function overexpress AβPP; (2) the cellular composition of the young J20 olfactory bulb is different from that of wild-type littermates; (3) these differences may reflect altered neurogenic activity and/or delayed development of the J20 olfactory system; and (4) AβPP/Aβ-associated pathological changes that take place in the J20 hippocampus and olfactory bulb are not identical.

%B J Alzheimers Dis %V 49 %P 443-57 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484907?dopt=Abstract %R 10.3233/JAD-150368 %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 Efficacy and Safety of ABT-126 in Subjects with Mild-to-Moderate Alzheimer's Disease on Stable Doses of Acetylcholinesterase Inhibitors: A Randomized, Double-Blind, Placebo-Controlled Study. %A Florian, Hana %A Meier, Andreas %A Gauthier, Serge %A Lipschitz, Stanley %A Lin, Yunzhi %A Tang, Qi %A Othman, Ahmed A %A Robieson, Weining Z %A Gault, Laura M %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cholinesterase Inhibitors %K Disease Progression %K Dose-Response Relationship, Drug %K Double-Blind Method %K Female %K Humans %K Indans %K International Cooperation %K Male %K Medication Adherence %K Middle Aged %K Piperidines %K Psychiatric Status Rating Scales %K Treatment Outcome %X

BACKGROUND: ABT-126 is a potent, selective α7 nicotinic acetylcholine receptor agonist with putative procognitive effects as a monotherapy in treating Alzheimer's disease (AD).

OBJECTIVE: This randomized, double-blind, placebo-controlled multicenter study (NCT01549834) investigated the efficacy and safety of ABT-126 in subjects with mild-to-moderate AD who were taking stable doses of acetylcholinesterase inhibitors (AChEIs).

METHODS: Subjects received 25 mg ABT-126 (n = 143), 75 mg ABT-126 (n = 145), or placebo (n = 146) once daily for 24 weeks. Subjects who completed the 24-week double-blind study were eligible to enroll in a 28-week open-label extension study (NCT01690195) and received 75 mg ABT-126 daily. The primary efficacy endpoint was the change from baseline to week 24 in the 11-item total score of the Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog).

RESULTS: Neither dose of ABT-126 demonstrated significant improvement compared with placebo in the primary efficacy endpoint. However, 25 mg ABT-126 demonstrated significant improvement compared with placebo in ADAS-Cog scores at week 4 (least squares mean difference, -1.21; standard error, 0.51; p <  0.010, one-sided); 75 mg ABT-126 did not demonstrate significant improvements in ADAS-Cog scores compared with placebo at any time point. A treatment effect was not observed for any secondary efficacy measures of cognition, function, or global improvement. ABT-126 was generally well tolerated; the most common adverse events were agitation, constipation, diarrhea, fall, and headache.

CONCLUSIONS: Overall, the efficacy profile of ABT-126 did not warrant further development as add-on therapy to AChEIs to treat mild-to-moderate AD.

%B J Alzheimers Dis %V 51 %P 1237-47 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967214?dopt=Abstract %R 10.3233/JAD-150978 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Efficacy and Safety of Sustained Release Donepezil High Dose versus Immediate Release Donepezil Standard Dose in Japanese Patients with Severe Alzheimer's Disease: A Randomized, Double-Blind Trial. %A Homma, Akira %A Atarashi, Hirotsugu %A Kubota, Naoki %A Nakai, Kenya %A Takase, Takao %K Aged %K Alzheimer Disease %K Cholinesterase Inhibitors %K Delayed-Action Preparations %K Double-Blind Method %K Female %K Humans %K Indans %K Japan %K Male %K Mental Status Schedule %K Nootropic Agents %K Outpatients %K Piperidines %K Psychiatric Status Rating Scales %K Severity of Illness Index %K Treatment Outcome %X

BACKGROUND: Donepezil is an established treatment for mild, moderate, and severe Alzheimer's disease (AD). An international study demonstrated superior efficacy of sustained release (SR) 23 mg/day donepezil over immediate release (IR) 10 mg/day donepezil for cognitive function, but not global function in moderate-to-severe AD.

OBJECTIVE: To demonstrate the superiority of SR 23 mg/day donepezil over IR 10 mg/day donepezil in Japanese patients with severe AD (SAD).

METHODS: In this multicenter, randomized, double-blind, parallel-group study, Japanese outpatients with SAD were randomly assigned to continue IR 10 mg/day or switch to SR 23 mg/day for 24 weeks. Endpoints included the Severe Impairment Battery (SIB), Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus), and safety.

RESULTS: Overall, 166 and 185 patients were randomized to receive IR 10 mg/day and SR 23 mg/day, respectively. SR 23 mg/day was not statistically superior to IR 10 mg/day by SIB (least squares mean difference [LSMD]: 0.0; 95% confidence interval [CI]: -1.7, 1.8; p = 0.981) or CIBIC-plus (LSMD: 0.2; 95% CI: 0.0, 0.4; p = 0.080). Common adverse events in the SR 23 mg group were decreased appetite, vomiting, diarrhea, and contusion. Safety findings were consistent with known safety profiles of donepezil.

CONCLUSION: SR 23 mg/day donepezil was not superior to IR 10 mg/day donepezil regarding the efficacy endpoints for Japanese SAD. Considering that a 10 mg/day dose is approved for SAD in Japan, the present findings suggest that IR 10 mg/day donepezil is the optimal dosage for Japanese patients with SAD.

%B J Alzheimers Dis %V 52 %P 345-57 %8 2016 03 11 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967222?dopt=Abstract %R 10.3233/JAD-151149 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Empirically Defining Trajectories of Late-Life Cognitive and Functional Decline. %A Hochstetler, Helen %A Trzepacz, Paula T %A Wang, Shufang %A Yu, Peng %A Case, Michael %A Henley, David B %A Degenhardt, Elisabeth %A Leoutsakos, Jeannie-Marie %A Lyketsos, Constantine G %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Apolipoprotein E4 %K Cognition Disorders %K Databases, Factual %K Dementia %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Male %K Middle Aged %K Neuroimaging %K Neuropsychological Tests %K Surveys and Questionnaires %X

BACKGROUND: Alzheimer's disease (AD) is associated with variable cognitive and functional decline, and it is difficult to predict who will develop the disease and how they will progress.

OBJECTIVE: This exploratory study aimed to define latent classes from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database who had similar growth patterns of both cognitive and functional change using Growth Mixture Modeling (GMM), identify characteristics associated with those trajectories, and develop a decision tree using clinical predictors to determine which trajectory, as determined by GMM, individuals will most likely follow.

METHODS: We used ADNI early mild cognitive impairment (EMCI), late MCI (LMCI), AD dementia, and healthy control (HC) participants with known amyloid-β status and follow-up assessments on the Alzheimer's Disease Assessment Scale - Cognitive Subscale or the Functional Activities Questionnaire (FAQ) up to 24 months postbaseline. GMM defined trajectories. Classification and Regression Tree (CART) used certain baseline variables to predict likely trajectory path.

RESULTS: GMM identified three trajectory classes (C): C1 (n = 162, 13.6%) highest baseline impairment and steepest pattern of cognitive/functional decline; C3 (n = 819, 68.7%) lowest baseline impairment and minimal change on both; C2 (n = 211, 17.7%) intermediate pattern, worsening on both, but less steep than C1. C3 had fewer amyloid- or apolipoprotein-E ɛ4 (APOE4) positive and more healthy controls (HC) or EMCI cases. CART analysis identified two decision nodes using the FAQ to predict likely class with 82.3% estimated accuracy.

CONCLUSIONS: Cognitive/functional change followed three trajectories with greater baseline impairment and amyloid and APOE4 positivity associated with greater progression. FAQ may predict trajectory class.

%B J Alzheimers Dis %V 50 %P 271-82 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639960?dopt=Abstract %R 10.3233/JAD-150563 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Enalapril Alone or Co-Administered with Losartan Rescues Cerebrovascular Dysfunction, but not Mnemonic Deficits or Amyloidosis in a Mouse Model of Alzheimer's Disease. %A Ongali, Brice %A Nicolakakis, Nektaria %A Tong, Xing-Kang %A Aboulkassim, Tahar %A Imboden, Hans %A Hamel, Edith %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloidosis %K Analysis of Variance %K Animals %K Antihypertensive Agents %K Cerebrovascular Disorders %K Cholinesterases %K Disease Models, Animal %K Drug Combinations %K Enalapril %K Female %K Glial Fibrillary Acidic Protein %K Humans %K Losartan %K Male %K Maze Learning %K Memory Disorders %K Mice %K Mice, Transgenic %K Mutation %X

The co-administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II (AngII) receptor blockers (ARB) that bind angiotensin type 1 receptors (AT1R) may protect from Alzheimer's disease (AD) better than each treatment taken alone. We tested the curative potential of the non brain-penetrant ACEi enalapril (3 mg/kg/day) administered for 3 months either alone or in combination with the brain penetrant ARB losartan (10 mg/kg/day) in aged (∼15 months) transgenic mice overexpressing a mutated form of the human amyloid-β protein precursor (AβPP, thereafter APP mice). We studied cerebrovascular function, protein levels of oxidative stress markers (superoxide dismutases SOD1, SOD2 and the NADPH oxidase subunit p67phox), amyloid-β (Aβ) pathology, astrogliosis, cholinergic innervation, AT1R and angiotensin IV receptor (AT4R) levels, together with cognitive performance. Both treatments normalized cerebrovascular reactivity and p67phox protein levels, but they did not reduce the cerebrovascular levels of SOD1. Combined treatment normalized cerebrovascular SOD2 levels, significantly attenuated astrogliosis, but did not reduce the increased levels of cerebrovascular AT1R. Yet, combined therapy enhanced thioflavin-S labeled Aβ plaque burden, a tendency not significant when Aβ1 - 42 plaque load was considered. None of the treatments rescued cognitive deficits, cortical AT4R or cholinergic innervation. We conclude that both treatments normalized cerebrovascular function by inhibiting the AngII-induced oxidative stress cascade, and that the positive effects of the combined therapy on astrogliosis were likely due to the ability of losartan to enter brain parenchyma. However, enalapril did not potentiate, and may even dampen, the reported cognitive benefits of losartan, raising caution when selecting the most appropriate antihypertensive therapy in AD patients.

%B J Alzheimers Dis %V 51 %P 1183-95 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923013?dopt=Abstract %R 10.3233/JAD-150868 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evaluation of Cerebrospinal Fluid Assay Variability in Alzheimer's Disease. %A White, Matthew T %A Shaw, Leslie M %A Xie, Sharon X %K Alzheimer Disease %K Amyloid beta-Peptides %K Area Under Curve %K Biomarkers %K Databases, Factual %K Female %K Humans %K Likelihood Functions %K Male %K Peptide Fragments %K Phosphorylation %K ROC Curve %K tau Proteins %X

Studies of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have indicated that much of the variability observed in the biomarkers may be due to measurement error. Biomarkers are often obtained with measurement error, which may make the diagnostic biomarker appear less effective than it truly is. In the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, technical replicates of CSF biomarkers are available; the National Alzheimer's Coordinating Center database contains longitudinal replicates of CSF biomarkers. We focus on the area under the receiver operating characteristic curve (AUC) as the measure of diagnostic effectiveness for differentiating AD from normal cognition using CSF biomarkers and compare AUC estimates obtained by a more standard, naïve method (which uses a single observation per subject and ignores measurement error) to a maximum likelihood (ML) based method (which uses all replicates per subject and adjusts for measurement error). The choice of analysis method depends upon the noise to signal ratio (i.e., the magnitude of the measurement error variability relative to the true biomarker variability); moderate to high ratios may significantly bias the naïve AUC estimate, and the ML-based method would be preferred. The noise to signal ratios were low for the ADNI biomarkers but high for the tTau and pTau biomarkers in NACC. Correspondingly, the naïve and ML-based AUC estimates were nearly identical in the ADNI data but dissimilar for the tTau and pTau biomarkers in the NACC data. Therefore, using the naïve method is adequate for analysis of CSF biomarkers in the ADNI study, but the ML method is recommended for the NACC data.

%B J Alzheimers Dis %V 51 %P 463-70 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890778?dopt=Abstract %R 10.3233/JAD-151045 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Examining the Relationship Between Autobiographical Memory Impairment and Carer Burden in Dementia Syndromes. %A Kumfor, Fiona %A Teo, Drusilla %A Miller, Laurie %A Lah, Suncica %A Mioshi, Eneida %A Hodges, John R %A Piguet, Olivier %A Irish, Muireann %K Adaptation, Psychological %K Aged %K Alzheimer Disease %K Analysis of Variance %K Behavioral Symptoms %K Caregivers %K Female %K Frontotemporal Dementia %K Humans %K Male %K Memory Disorders %K Memory, Episodic %K Middle Aged %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Statistics as Topic %X

BACKGROUND: Autobiographical memory (ABM) refers to the capacity to remember one's own past, and is known to be central for supporting one's identity and sense of self. This capacity is commonly affected in Alzheimer's disease (AD), as well as semantic dementia (SD) and behavioral-variant frontotemporal dementia (bvFTD). Importantly, ABM plays a critical social function, facilitating relationship intimacy and empathy, and thus loss of ABM may also negatively affect families and carers.

OBJECTIVE: To explore the relationship between ABM disruption and carer burden in AD, SD, and bvFTD, and establish whether characteristic ABM profiles differentially relate to carer burden across dementia syndromes.

METHODS: We recruited 12 AD, 10 SD, and 13 bvFTD patients and their primary carer. All participants completed the Autobiographical Interview to assess memory for recent and remote events. Carers completed: the Zarit Burden Interview; Depression, Anxiety and Stress Scale (DASS-21); and the Intimate Bond Measure (IBM).

RESULTS: In AD, loss of recent ABM was associated with worse psychological wellbeing of carers on the DASS-21. In contrast in SD, remote ABM dysfunction was associated with SD patients showing greater controlling behavior within their intimate relationships. In bvFTD, surprisingly, despite pervasive ABM impairment, no relationship between extent of ABM loss and carer burden was observed.

CONCLUSION: These preliminary results reveal that ABM impairment impacts on patients' families and carers and suggest that these influences vary according to the pattern of ABM dysfunction. Disease-specific interventions focusing on preserved aspects of ABM may improve quality of life for both patients and carers.

%B J Alzheimers Dis %V 51 %P 237-48 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836163?dopt=Abstract %R 10.3233/JAD-150740 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Familial Presenilin Mutations and Sporadic Alzheimer's Disease Pathology: Is the Assumption of Biochemical Equivalence Justified? %A Roher, Alex E %A Maarouf, Chera L %A Kokjohn, Tyler A %K Alzheimer Disease %K Amyloid beta-Peptides %K Brain %K Humans %K Mutation %K Presenilins %X

Studies of presenilin (PSEN) gene mutations producing early onset Alzheimer's disease (AD) have helped elucidate the pathogenic mechanisms of dementia and guided clinical trials of potential therapeutic interventions. Although familial and sporadic forms of AD share features, it is unclear if the two are precisely equivalent. In addition, PSEN mutations do not all produce a single phenotype, but exhibit substantial variability in clinical manifestations, which are related to the position and chemical nature of their amino acid substitutions as well as ratios of critical molecules such as Aβ40 and Aβ42. These differences complicate the interpretation of critical clinical trial results and their desired extrapolation to sporadic AD treatment. In this perspective, we examine differences between familial AD and sporadic AD as well as attributes shared by these uniquely arising disturbances in brain biochemical homeostasis that culminate in dementia.

%B J Alzheimers Dis %V 50 %P 645-58 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757189?dopt=Abstract %R 10.3233/JAD-150757 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Fibrillar Amyloid-β Accumulation Triggers an Inflammatory Mechanism Leading to Hyperphosphorylation of the Carboxyl-Terminal End of Tau Polypeptide in the Hippocampal Formation of the 3×Tg-AD Transgenic Mouse. %A Ontiveros-Torres, Miguel Ángel %A Labra-Barrios, María Luisa %A Díaz-Cintra, Sofía %A Aguilar-Vázquez, Azucena Ruth %A Moreno-Campuzano, Samadhi %A Flores-Rodríguez, Paola %A Luna-Herrera, Claudia %A Mena, Raúl %A Perry, George %A Florán-Garduño, Benjamín %A Luna-Muñoz, José %A Luna-Arias, Juan Pedro %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Disease Models, Animal %K Female %K Hippocampus %K Humans %K Male %K Mice, Inbred C57BL %K Mice, Transgenic %K Neuroglia %K Phosphorylation %K Plaque, Amyloid %K Presenilin-1 %K Pyramidal Cells %K tau Proteins %X

Alzheimer's disease (AD) is a degenerative and irreversible disorder whose progressiveness is dependent on age. It is histopathologically characterized by the massive accumulation of insoluble forms of tau and amyloid-β (Aβ) asneurofibrillary tangles and neuritic plaques, respectively. Many studies have documented that these two polypeptides suffer several posttranslational modifications employing postmortem tissue sections from brains of patients with AD. In order to elucidate the molecular mechanisms underlying the posttranslational modifications of key players in this disease, including Aβ and tau, several transgenic mouse models have been developed. One of these models is the 3×Tg-AD transgenic mouse, carrying three transgenes encoding APPSWE, S1M146V, and TauP301L proteins. To further characterize this transgenicmouse, we determined the accumulation of fibrillar Aβ as a function of age in relation to the hyperphosphorylation patterns of TauP301L at both its N- and C-terminus in the hippocampal formation by immunofluorescence and confocal microscopy. Moreover, we searched for the expression of activated protein kinases and mediators of inflammation by western blot of wholeprotein extracts from hippocampal tissue sections since 3 to 28 months as well. Our results indicate that the presence of fibrillar Aβ deposits correlates with a significant activation of astrocytes and microglia in subiculum and CA1 regions of hippocampus. Accordingly, we also observed a significant increase in the expression of TNF-α associated to neuritic plaques and glial cells. Importantly, there is an overexpression of the stress activated protein kinases SAPK/JNK and Cdk-5 in pyramidal neurons, which might phosphorylate several residues at the C-terminus of TauP301L. Therefore, the accumulation of Aβ oligomers results in an inflammatory environment that upregulates kinases involved in hyperphosphorylation of TauP301L polypeptide.

%B J Alzheimers Dis %V 52 %P 243-69 %8 2016 03 22 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031470?dopt=Abstract %R 10.3233/JAD-150837 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Fluoxetine Treatment Induces Seizure Behavior and Premature Death in APPswe/PS1dE9 Mice. %A Sierksma, Annerieke S R %A de Nijs, Laurence %A Hoogland, Govert %A Vanmierlo, Tim %A van Leeuwen, Fred W %A Rutten, Bart P F %A Steinbusch, Harry W M %A Prickaerts, Jos %A van den Hove, Daniel L A %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Anticonvulsants %K Body Weight %K Disease Models, Animal %K Fluoxetine %K Humans %K Logistic Models %K Male %K Mice, Inbred C57BL %K Mice, Transgenic %K Neuroprotective Agents %K Presenilin-1 %K Seizures %X

Treatment of Alzheimer's disease (AD) patients with the antidepressant fluoxetine is known to improve memory and cognitive function. However, the mechanisms underlying these effects are largely unknown. To unravel these mechanisms, we aimed to treat APPswe/PS1dE9 mice with fluoxetine. Unexpectedly, with time, an increased number of animals displayed seizure behavior and died. Although spontaneous behavioral seizures have been reported previously in this mouse model, the observation of seizures and death consequential to fluoxetine treatment is new. Our results warrant further research on the underlying mechanisms as this may refine the treatment of AD patients.

%B J Alzheimers Dis %V 51 %P 677-82 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890781?dopt=Abstract %R 10.3233/JAD-151066 %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 Future Dementia Severity is Almost Entirely Explained by the Latent Variable δ's Intercept and Slope. %A Palmer, Raymond F %A Royall, Donald R %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition %K Cognitive Dysfunction %K Factor Analysis, Statistical %K Female %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Psychiatric Status Rating Scales %X

BACKGROUND: Structural equation models (SEM) can explicitly distinguish dementia-relevant variance in cognitive task performance. The resulting latent construct "δ" (for dementia) provides a relatively "error free" continuously varying dementia-specific phenotype.

OBJECTIVE: To estimate δ's change over time (Δδ) and determine Δδ's predictive validity using future dementia status as an outcome.

METHODS: Data from n = 2,191 participants of the Texas Alzheimer's Research and Care Consortium (TARCC) were used to construct a latent growth curve model of longitudinal change over four years using five cognitive measures and one measure of Instrumental Activities of Daily Living. Four final latent factors, including baseline δ and Δδ, were simultaneously entered as predictors of wave 4 dementia severity, as estimated by the Clinical Dementia Rating Scale "sum of boxes" (CDR).

RESULTS: All observed measures exhibited significant change [χ2 = 1,152 (df = 229); CFI = 0.968; RMSEA = 0.043]. The final model demonstrated excellent fit to the data [χ2 = 543 (df = 245); CFI = 0.991; RMSEA = 0.023]. All latent indicator loadings were significant, yielding four distinct factors. After adjustment for demographic covariates and baseline CDR scores, d and Δd were significantly independently associated with CDR4, explaining 25% and 49% of its variance, respectively. The latent variable g' significantly explained 3% of CDR4 variance independently of d and Δd. Δg' was not significantly associated with CDR4. Baseline CDR explained 16% of CDR4 variance.

CONCLUSIONS: Future dementia severity is almost entirely explained by the latent construct δ's intercept and slope.

%B J Alzheimers Dis %V 49 %P 521-9 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444763?dopt=Abstract %R 10.3233/JAD-150254 %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 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 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 Greater than the Sum of Its Parts: δ can be Constructed from Item Level Data. %A Royall, Donald R %A Palmer, Raymond F %A Matsuoka, Teruyuki %A Kato, Yuka %A Taniguchi, Shogo %A Ogawa, Mayu %A Fujimoto, Hiroshi %A Okamura, Aiko %A Shibata, Keisuke %A Nakamura, Kaeko %A Nakaaki, Shutaro %A Koumi, Hiroyuki %A Mimura, Masaru %A Fukui, Kenji %A Narumoto, Jin %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Executive Function %K Female %K Humans %K Japan %K Male %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K ROC Curve %K United States %X

"δ", a latent variable constructed from cognitive performance and functional status measures, can accurately diagnose dementia. The minimal assessment needed is unknown. We have constructed a δ homolog, "dTEXAS", from Telephone Executive Assessment Scale (TEXAS) items, and validated it in a convenience sample of Japanese persons (n = 176). dTEXAS scores correlated strongly with both Instrumental Activities of Daily Living (IADL) (r = -0.86, p <  0.001) and Clinical Dementia Rating Scale (CDR) (r = 0.71, p <  0.001). Constructed independently of their diagnoses, dTEXAS scores accurately distinguished dementia versus controls (area under the receiver operating curve [(AUC; ROC) = 0.92], dementia versus mild cognitive impairment (MCI) (AUC = 0.80) and controls versus MCI (AUC = 0.74). These AUCs are higher than those of multiple observed executive measures, as reported recently by Matsuoka et al., 2014. A dTEXAS score of -0.58 best discriminated between dementia versus controls with 90.1% sensitivity and 80.0% specificity.

%B J Alzheimers Dis %V 49 %P 571-9 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444760?dopt=Abstract %R 10.3233/JAD-150250 %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 Hemisphere Asymmetry of Response to Pharmacologic Treatment in an Alzheimer's Disease Mouse Model. %A Manousopoulou, Antigoni %A Saito, Satoshi %A Yamamoto, Yumi %A Al-Daghri, Nasser M %A Ihara, Masafumi %A Carare, Roxana O %A Garbis, Spiros D %K Alzheimer Disease %K Animals %K Brain %K Disease Models, Animal %K Functional Laterality %K Male %K Mice, Transgenic %K Nootropic Agents %K Proteome %K Tetrazoles %X

The aim of this study was to examine hemisphere asymmetry of response to pharmacologic treatment in an Alzheimer's disease mouse model using cilostazol as a chemical stimulus. Eight-month-old mice were assigned to vehicle or cilostazol treatment for three months and hemispheres were analyzed using quantitative proteomics. Bioinformatics interpretation showed that following treatment, aggregation of blood platelets significantly decreased in the right hemisphere whereas neurodegeneration significantly decreased and synaptic transmission increased in the left hemisphere only. Our study provides novel evidence on cerebral laterality of pharmacologic activity, with important implications in deciphering regional pharmacodynamic effects of existing drugs thus uncovering novel hemisphere-specific therapeutic targets.

%B J Alzheimers Dis %V 51 %P 333-8 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836196?dopt=Abstract %R 10.3233/JAD-151078 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Heterogeneity of Cognitive Anosognosia and its Variation with the Severity of Dementia in Patients with Alzheimer's Disease. %A Avondino, Emilie %A Antoine, Pascal %K Agnosia %K Alzheimer Disease %K Attention %K Chi-Square Distribution %K Cognition Disorders %K Dementia %K Female %K Humans %K Male %K Memory %K Neuropsychological Tests %K Predictive Value of Tests %K Prospective Studies %K Psychiatric Status Rating Scales %K Severity of Illness Index %X

Currently, the lack of awareness of deficits, i.e., anosognosia, is a major obstacle in the healthcare circuit that delays the diagnosis of Alzheimer's disease (AD). However, a clear framework is lacking in the literature related to this phenomenon in terms of its definition, mechanisms, and objects. The aim of this study is to assess the different levels of cognitive anosognosia using a prediction-performance procedure and to identify the potential correlates of these levels. A sample of patients with probable AD was divided into three groups according to the severity of dementia (mild (MiD), moderate (MoD), and moderately severe (MSD) dementia), ranked according to the results of the Mini-Mental State Examination. We observed the following three scores: the real score, the prediction score, and the anosognosia score. These scores were calculated based on the prediction-performance task MISAwareness from the Dementia Rating Scale for cognitive processes (i.e., Attention, Initiation, Conceptualization, Construction, and Memory). We obtained a strong plateau effect between the MiD and MoD groups for anosognosia scores for actual performance or prediction for both the level of overall functioning and for specific processes. The sole exception was the result for memory processes. Moreover, the profiles of the patients' responses on the Memory subscale were substantially different and, indeed, opposite from those for the other processes. The main results confirm the multidimensionality of anosognosia and its variability with the stage of dementia and specifically implicate memory processes that indicate a cleavage between memory and other cognitive functions.

%B J Alzheimers Dis %V 50 %P 89-99 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26638866?dopt=Abstract %R 10.3233/JAD-150496 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Heterogeneous Language Profiles in Patients with Primary Progressive Aphasia due to Alzheimer's Disease. %A Louwersheimer, Eva %A Keulen, M Antoinette %A Steenwijk, Martijn D %A Wattjes, Mike P %A Jiskoot, Lize C %A Vrenken, Hugo %A Teunissen, Charlotte E %A van Berckel, Bart N M %A van der Flier, Wiesje M %A Scheltens, Philip %A van Swieten, John C %A Pijnenburg, Yolande A L %K Aged %K Alzheimer Disease %K Aphasia, Primary Progressive %K Atrophy %K Biomarkers %K Brain %K Female %K Humans %K Language %K Language Tests %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Organ Size %K Positron-Emission Tomography %K Retrospective Studies %X

BACKGROUND: The logopenic variant of Primary Progressive Aphasia (lvPPA) is associated with underlying Alzheimer's disease (AD) pathology and characterized by impaired single word retrieval and repetition of phrases and sentences.

OBJECTIVE: We set out to study whether logopenic aphasia is indeed the prototypic language profile in PPA patients with biomarker evidence of underlying AD pathology and to correlate language profiles with cortical atrophy patterns on MRI.

METHODS: Inclusion criteria: (I) clinical diagnosis of PPA; (II) CSF profile and/or PiB-PET scan indicative for amyloid pathology; (III) availability of expert language evaluation. Based on language evaluation, patients were classified as lvPPA (fulfilling lvPPA core criteria), lvPPA extended (fulfilling core criteria plus other language disturbances), or PPA unclassifiable (not fulfilling lvPPA core criteria). Cortical atrophy patterns on MRI were visually rated and quantitative measurements of cortical thickness were performed using FreeSurfer.

RESULTS: We included 22 patients (age 67±7 years, 50% female, MMSE 21±6). 41% were classified as lvPPA, 36% as lvPPA extended with additional deficits in language comprehension and/or confrontation naming, and 23% as PPA unclassifiable. By both qualitative and quantitative measurements, patients with lvPPA showed mild global cortical atrophy on MRI, whereas patients with lvPPA extended showed more focal cortical atrophy, predominantly at the left tempo-parietal side. For PPA unclassifiable, qualitative measurements revealed a heterogeneous atrophy pattern.

CONCLUSION: Although most patients fulfilled the lvPPA criteria, we found that their language profiles were heterogeneous. The clinical and radiological spectrum of PPA due to underlying AD pathology is broader than pure lvPPA.

%B J Alzheimers Dis %V 51 %P 581-90 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890751?dopt=Abstract %R 10.3233/JAD-150812 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Hierarchical Distribution of the Tau Cytoskeletal Pathology in the Thalamus of Alzheimer's Disease Patients. %A Rüb, Udo %A Stratmann, Katharina %A Heinsen, Helmut %A Del Turco, Domenico %A Ghebremedhin, Estifanos %A Seidel, Kay %A den Dunnen, Wilfred %A Korf, Horst-Werner %K Alzheimer Disease %K Cytoskeleton %K Humans %K tau Proteins %K Thalamus %X

In spite of considerable progress in neuropathological research on Alzheimer's disease (AD), knowledge regarding the exact pathoanatomical distribution of the tau cytoskeletal pathology in the thalamus of AD patients in the advanced Braak and Braak AD stages V or VI of the cortical cytoskeletal pathology is still fragmentary. Investigation of serial 100 μm-thick brain tissue sections through the thalamus of clinically diagnosed AD patients with Braak and Braak AD stage V or VI cytoskeletal pathologies immunostained with the anti-tau AT8 antibody, along with the affection of the extraterritorial reticular nucleus of the thalamus, reveals a consistent and severe tau immunoreactive cytoskeletal pathology in the limbic nuclei of the thalamus (e.g., paraventricular, anterodorsal and laterodorsal nuclei, limitans-suprageniculate complex). The thalamic nuclei integrated into the associative networks of the human brain (e.g., ventral anterior and mediodorsal nuclei) are only mildly affected, while its motor precerebellar (ventral lateral nucleus) and sensory nuclei (e.g., lateral and medial geniculate bodies, ventral posterior medial and lateral nuclei, parvocellular part of the ventral posterior medial nucleus) are more or less spared. The highly stereotypical and characteristic thalamic distribution pattern of the AD-related tau cytoskeletal pathology represents an anatomical mirror of the hierarchical topographic distribution of the cytoskeletal pathology in the interconnected regions of the cerebral cortex of AD patients. These pathoanatomical parallels support the pathophysiological concept of a transneuronal spread of the disease process of AD along anatomical pathways. The AD-related tau cytoskeletal pathology in the thalamus most likely contributes substantially to the neuropsychiatric disease symptoms (e.g., dementia), attention deficits, oculomotor dysfunctions, altered non-discriminative aspects of pain experience of AD patients, and the disruption of their waking and sleeping patterns.

%B J Alzheimers Dis %V 49 %P 905-15 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519431?dopt=Abstract %R 10.3233/JAD-150639 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Hippocampal Lipid Homeostasis in APP/PS1 Mice is Modulated by a Complex Interplay Between Dietary DHA and Estrogens: Relevance for Alzheimer's Disease. %A Díaz, Mario %A Fabelo, Noemí %A Casañas-Sánchez, Verónica %A Marin, Raquel %A Gómez, Tomás %A Quinto-Alemany, David %A Pérez, José A %K Acyl Coenzyme A %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Analysis of Variance %K Animals %K Disease Models, Animal %K Docosahexaenoic Acids %K Dose-Response Relationship, Drug %K Estrogens %K Gene Expression Regulation %K Hippocampus %K Homeostasis %K Humans %K Lipid Metabolism %K Mice %K Mice, Transgenic %K Mutation %K Presenilin-1 %K RNA, Messenger %X

Current evidence suggests that lipid homeostasis in the hippocampus is affected by different genetic, dietary, and hormonal factors, and that its deregulation may be associated with the onset and progression of Alzheimer's disease (AD). However, the precise levels of influence of each of these factors and their potential interactions remain largely unknown, particularly during neurodegenerative processes. In the present study, we have performed multifactorial analyses of the combined effects of diets containing different doses of docosahexaenoic acid (DHA), estrogen status (ovariectomized animals receiving vehicle or 17β-estradiol), and genotype (wild-type or transgenic APP/PS1 mice) in hippocampal lipid profiles. We have observed that the three factors affect lipid classes and fatty acid composition to different extents, and that strong interactions between these factors exist. The most aberrant lipid profiles were observed in APP/PS1 animals receiving DHA-poor diets and deprived of estrogens. Conversely, wild-type animals under a high-DHA diet and receiving estradiol exhibited a lipid profile that closely resembled that of the hippocampus of control animals. Interestingly, though the lipid signatures of APP/PS1 hippocampi markedly differed from wild-type, administration of a high-DHA diet in the presence of estrogens gave rise to a lipid profile that approached that of control animals. Paralleling changes in lipid composition, patterns of gene expression of enzymes involved in lipid biosynthesis were also altered and affected by combination of experimental factors. Overall, these results indicate that hippocampal lipid homeostasis is strongly affected by hormonal and dietary conditions, and that manipulation of these factors might be incorporated in AD therapeutics.

%B J Alzheimers Dis %V 49 %P 459-81 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519437?dopt=Abstract %R 10.3233/JAD-150470 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A History of In Vivo Neutron Activation Analysis in Measurement of Aluminum in Human Subjects. %A Mohseni, Hedieh K %A Chettle, David R %K Aluminum %K Alzheimer Disease %K Humans %K Neutron Activation Analysis %X

Aluminum, as an abundant metal, has gained widespread use in human life, entering the body predominantly as an additive to various foods and drinking water. Other major sources of exposure to aluminum include medical, cosmetic, and occupational routes. As a common environmental toxin, with well-known roles in several medical conditions such as dialysis encephalopathy, aluminum is considered a potential candidate in the causality of Alzheimer's disease. Aluminum mostly accumulates in the bone, which makes bone an indicator of the body burden of aluminum and an ideal organ as a proxy for the brain. Most of the techniques developed for measuring aluminum include bone biopsy, which requires invasive measures, causing inconvenience for the patients. There has been a considerable effort in developing non-invasive approaches, which allow for monitoring aluminum levels for medical and occupational purposes in larger populations. In vivo neutron activation analysis, a method based on nuclear activation of isotopes of elements in the body and their subsequent detection, has proven to be an invaluable tool for this purpose. There are definite challenges in developing in vivo non-invasive techniques capable of detecting low levels of aluminum in healthy individuals and aluminum-exposed populations. The following review examines the method of in vivo neutron activation analysis in the context of aluminum measurement in humans focusing on different neutron sources, interference from other activation products, and the improvements made in minimum detectable limits and patient dose over the past few decades.

%B J Alzheimers Dis %V 50 %P 913-26 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890739?dopt=Abstract %R 10.3233/JAD-150595 %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 Parahippocampus Connectivity in Mild Cognitive Impairment and Alzheimer's Disease. %A Liu, Jieqiong %A Zhang, Xinqing %A Yu, Chunshui %A Duan, Yunyun %A Zhuo, Junjie %A Cui, Yue %A Liu, Bing %A Li, Kuncheng %A Jiang, Tianzi %A Liu, Yong %K Aged %K Alzheimer Disease %K Apolipoproteins E %K Brain Mapping %K Cognitive Dysfunction %K Female %K Hippocampus %K Humans %K Limbic System %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Neural Pathways %K Rest %K Severity of Illness Index %X

BACKGROUND: The parahippocampal gyrus (PHG) is an important region of the limbic system that plays an important role in episodic memory. Elucidation of the PHG connectivity pattern will aid in the understanding of memory deficits in neurodegenerative diseases.

OBJECTIVE: To investigate if disease severity associated altered PHG connectivity in Alzheimer's disease (AD) exists.

METHODS: We evaluated resting-state functional magnetic resonance imaging data from 18 patients with amnestic mild cognitive impairment (MCI), 35 patients with AD, and 21 controls. The PHG connectivity pattern was examined by calculating Pearson's correlation coefficients between the bilateral PHG and whole brain. Group comparisons were performed after controlling for the effects of age and gender. The functional connectivity strength in each identified region was correlated with the MMSE score to evaluate the relationship between connectivity and cognitive ability.

RESULTS: Several brain regions of the default mode network showed reduced PHG connectivity in the AD patients, and PHG connectivity was associated with disease severity in the MCI and AD subjects. More importantly, correlation analyses showed that there were positive correlations between the connectivity strengths of the left PHG-PCC/Pcu and left PHG-left MTG and the Mini-Mental State Examination, indicating that with disease progression from MCI to severe AD, damage to the functional connectivity of the PHG becomes increasingly severe.

CONCLUSIONS: These results indicate that disease severity is associated with altered PHG connectivity, contributing to knowledge about the reduction in cognitive ability and impaired brain activity that occur in AD/MCI. These early changes in the functional connectivity of the PHG might provide some potential clues for identification of imaging markers for the early detection of MCI and AD.

%B J Alzheimers Dis %V 49 %P 1051-64 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599055?dopt=Abstract %R 10.3233/JAD-150727 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Incidence of Benzodiazepine and Related Drug Use in Persons with and without Alzheimer's Disease. %A Saarelainen, Laura %A Taipale, Heidi %A Koponen, Marjaana %A Tanskanen, Antti %A Tolppanen, Anna-Maija %A Tiihonen, Jari %A Hartikainen, Sirpa %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Antipsychotic Agents %K Benzodiazepines %K Cohort Studies %K Female %K Finland %K Humans %K Incidence %K Male %K Middle Aged %K Substance-Related Disorders %X

BACKGROUND: Benzodiazepines and related drugs (BZDR) are occasionally used to treat certain symptoms of Alzheimer's disease (AD). However, the risks related to BZDR use are high in older persons. Although frequent BZDR use has been reported in persons with AD, no previous study has focused specifically on the incidence of BZDR use in this population.

OBJECTIVE: We investigated the incidence of BZDR use in persons with and without AD during a five-year follow-up.

METHODS: The Finnish nationwide, register-based MEDALZ cohort includes all AD cases who received a clinically verified AD diagnosis in 2005-2011 (n = 70,718) and their matched comparison persons. Incidence of BZDR, including benzodiazepines (lorazepam, oxazepam, temazepam, alprazolam, chlordiazepoxide, diazepam, and nitrazepam) and Z-drugs (zolpidem and zopiclone), use was investigated in the cohort from two years before to three years after the diagnosis of AD. Further, initial BZDRs were investigated.

RESULTS: The incidence of BZDR use was higher in persons with AD starting from 12 months before the diagnosis and peaked at six months after the diagnosis of AD (incidence rate ratio [IRR] = 2.6, 95% confidence interval [CI] = 2.5-2.8). Benzodiazepines were more frequently initiated by persons with AD, with the incidence peaking at six months after the diagnosis (IRR = 4.5, 95% CI = 4.1-4.9) and remaining over three times higher than in comparison persons until three years after the diagnosis.

CONCLUSION: Early symptomatic treatment with BZDRs is contrary to AD treatment guidelines. As BZDRs impair cognition, the observed early treatment with BZDRs may complicate the monitoring of AD treatment effectiveness.

%B J Alzheimers Dis %V 49 %P 809-18 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484930?dopt=Abstract %R 10.3233/JAD-150630 %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 Intrinsic Activity of Medial-Temporal Lobe Subregions is Associated with Decreased Cortical Thickness of Medial-Parietal Areas in Patients with Alzheimer's Disease Dementia. %A Pasquini, Lorenzo %A Scherr, Martin %A Tahmasian, Masoud %A Myers, Nicholas E %A Ortner, Marion %A Kurz, Alexander %A Förstl, Hans %A Zimmer, Claus %A Grimmer, Timo %A Akhrif, Atae %A Wohlschläger, Afra M %A Riedl, Valentin %A Sorg, Christian %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Memory Disorders %K Middle Aged %K Nerve Net %K Parietal Lobe %K Temporal Lobe %X

In Alzheimer's disease (AD), disrupted connectivity between medial-parietal cortices and medial-temporal lobes (MTL) is linked with increased MTL local functional connectivity, and parietal atrophy is associated with increased MTL memory activation. We hypothesized that intrinsic activity in MTL subregions is increased and associated with medial-parietal degeneration and impaired memory in AD. To test this hypothesis, resting-state-functional and structural-MRI was assessed in 22 healthy controls, 22 mild cognitive impairment patients, and 21 AD-dementia patients. Intrinsic activity was measured by power-spectrum density of blood-oxygenation-level-dependent signal, medial-parietal degeneration by cortical thinning. In AD-dementia patients, intrinsic activity was increased for several right MTL subregions. Raised intrinsic activity in dentate gyrus and cornu ammonis 1 was associated with cortical thinning in posterior cingulate cortices, and at-trend with impaired delayed recall. Critically, increased intrinsic activity in the right entorhinal cortex was associated with ipsilateral posterior cingulate degeneration. Our results provide evidence that in AD, intrinsic activity in MTL subregions is increased and associated with medial-parietal atrophy. Results fit a model in which medial-parietal degeneration contributes to MTL dysconnectivity from medial-parietal cortices, potentially underpinning disinhibition-like changes in MTL activity.

%B J Alzheimers Dis %V 51 %P 313-26 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836175?dopt=Abstract %R 10.3233/JAD-150823 %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 Integrated Analysis of Alzheimer's Disease and Schizophrenia Dataset Revealed Different Expression Pattern in Learning and Memory. %A Li, Wen-Xing %A Dai, Shao-Xing %A Liu, Jia-Qian %A Wang, Qian %A Li, Gong-Hua %A Huang, Jing-Fei %K Adult %K Aged %K Aged, 80 and over %K Algorithms %K Alzheimer Disease %K Bayes Theorem %K Brain %K Datasets as Topic %K Gene Expression Profiling %K Humans %K Learning %K Memory %K Microarray Analysis %K Middle Aged %K Schizophrenia %K Schizophrenic Psychology %K Young Adult %X

Alzheimer's disease (AD) and schizophrenia (SZ) are both accompanied by impaired learning and memory functions. This study aims to explore the expression profiles of learning or memory genes between AD and SZ. We downloaded 10 AD and 10 SZ datasets from GEO-NCBI for integrated analysis. These datasets were processed using RMA algorithm and a global renormalization for all studies. Then Empirical Bayes algorithm was used to find the differentially expressed genes between patients and controls. The results showed that most of the differentially expressed genes were related to AD whereas the gene expression profile was little affected in the SZ. Furthermore, in the aspects of the number of differentially expressed genes, the fold change and the brain region, there was a great difference in the expression of learning or memory related genes between AD and SZ. In AD, the CALB1, GABRA5, and TAC1 were significantly downregulated in whole brain, frontal lobe, temporal lobe, and hippocampus. However, in SZ, only two genes CRHBP and CX3CR1 were downregulated in hippocampus, and other brain regions were not affected. The effect of these genes on learning or memory impairment has been widely studied. It was suggested that these genes may play a crucial role in AD or SZ pathogenesis. The different gene expression patterns between AD and SZ on learning and memory functions in different brain regions revealed in our study may help to understand the different mechanism between two diseases.

%B J Alzheimers Dis %V 51 %P 417-25 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890750?dopt=Abstract %R 10.3233/JAD-150807 %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 Intranasal TAT-haFGF Improves Cognition and Amyloid-β Pathology in an AβPP/PS1 Mouse Model of Alzheimer's Disease. %A Lou, Guofeng %A Zhang, Qihao %A Xiao, Fei %A Xiang, Qi %A Su, Zhijian %A Huang, Yadong %K Administration, Intranasal %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Brain %K Cognition Disorders %K Disease Models, Animal %K Fibroblast Growth Factors %K Gene Products, tat %K Humans %K Injections, Intraventricular %K Maze Learning %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Movement %K Mutation %K Peptide Fragments %K Plaque, Amyloid %K Presenilin-1 %X

Neurotoxic amyloid-β (Aβ) peptide causing cognitive function disabilities is one of the most characteristic pathological features in Alzheimer's disease (AD). A novel fusion protein, TAT-haFGF, was administrated to AβPP/PS1 transgenic mice by intravenous (IV) injection and intranasal (IN) delivery, respectively, for 5 weeks to compare the pharmacodynamics between the two routes of administration. Our results showed that IN administration of TAT-haFGF improved cognition and reduced Aβ plaques more significantly in AβPP/PS1 mice, when compared with IV injection. Our new findings suggest that TAT-haFGF might be a promising new therapy to attenuate AD pathological process.

%B J Alzheimers Dis %V 51 %P 985-90 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890786?dopt=Abstract %R 10.3233/JAD-151121 %0 Journal Article %J J Alzheimers Dis %D 2016 %T JNK: A Putative Link Between Insulin Signaling and VGLUT1 in Alzheimer's Disease. %A Rodriguez-Perdigon, Manuel %A Solas, Maite %A Ramirez, Maria Javier %K Aged %K Alzheimer Disease %K Animals %K Brain %K Corticosterone %K Disease Models, Animal %K Female %K Humans %K Insulin %K Insulin Resistance %K Male %K MAP Kinase Kinase 4 %K Mice, Inbred C57BL %K Mitogen-Activated Protein Kinase 1 %K Neuroprotective Agents %K RNA, Messenger %K Vesicular Glutamate Transport Protein 1 %X

In the present work, the involvement of JNK in insulin signaling alterations and its role in glutamatergic deficits in Alzheimer's disease (AD) has been studied. In postmortem cortical tissues, pJNK levels were increased, while insulin signaling and the expression of VGLUT1 were decreased. A significant correlation was found between reduced expression of insulin receptor and VGLUT1. The administration of a JNK inhibitor reversed the decrease in VGLUT1 expression found in a mice model of insulin resistance. It is suggested that activation of JNK in AD inhibits insulin signaling which could lead to a decreased expression of VGLUT1, therefore contributing to the glutamatergic deficit in AD.

%B J Alzheimers Dis %V 50 %P 963-7 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836159?dopt=Abstract %R 10.3233/JAD-150659 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Korean Size/Weight Attribute Test: A Semantic Knowledge Test for Korean Older Adults and Brain-Imaging Evidence. %A Yoo, Yongjoon %A Shin, Seong A %A Park, Soowon %A Lee, Ji-Hye %A Youn, Jung-Hae %A Kim, Yu Kyeong %A Lee, Jun-Young %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Analysis of Variance %K Brain %K Dementia %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Republic of Korea %K ROC Curve %K Semantics %X

BACKGROUND: A standardized tool for evaluating semantic knowledge of the Korean population is needed.

OBJECTIVE: The purpose of this study was to develop a neuropsychological test for the evaluation of semantic knowledge in the Korean elderly population.

METHODS: The Korean version of the Size/Weight Attribute Test (SWAT-K) was developed in reference to the original version. The diagnostic validity of SWAT-K was evaluated with 95 elderly outpatients [67 normal controls; 18 with Alzheimer's disease (AD); 10 with semantic-variant progressive aphasia (SV-PPA)]. Voxel-based morphometry (VBM) was employed to examine associations between SWAT-K scores and morphological changes of the brain.

RESULTS: SWAT-K could discriminate the three subject groups (normal >AD, p <  0.001; AD >SV-PPA, p = 0.040), whereas Boston Naming Test could not distinguish SV-PPA from AD. ROC curve analysis confirmed high levels of sensitivity (0.90) and specificity (0.93) for SWAT-K. The test's inter-rater reliability (ICC = 0.827) and test-retest reliability (ICC = 0.666) were assessed as well. VBM found a significant positive correlation (uncorrected p <  0.005, k >  100) between SWAT-K scores and gray matter volume in right inferior frontal cortex (T = 4.08, k = 191) and bilateral temporal cortices (left, T = 4.42, k = 135; right, T = 3.55, k = 253), the areas the most affected in SV-PPA.

CONCLUSIONS: SWAT-K is a sensitive and reliable test for evaluating semantic knowledge in the Korean elderly population. Strong positive correlations between SWAT-K scores and the brain areas responsible for semantic processing further corroborate the validity of SWAT-K.

%B J Alzheimers Dis %V 49 %P 377-86 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484915?dopt=Abstract %R 10.3233/JAD-150492 %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 Latent Dementia Phenotype δ is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment. %A Koppara, Alexander %A Wolfsgruber, Steffen %A Kleineidam, Luca %A Schmidtke, Klaus %A Frölich, Lutz %A Kurz, Alexander %A Schulz, Stefanie %A Hampel, Harald %A Heuser, Isabella %A Peters, Oliver %A Reischies, Friedel M %A Jahn, Holger %A Luckhaus, Christian %A Hüll, Michael %A Gertz, Hermann-Josef %A Schröder, Johannes %A Pantel, Johannes %A Rienhoff, Otto %A Rüther, Eckart %A Henn, Fritz %A Wiltfang, Jens %A Maier, Wolfgang %A Jessen, Frank %A Kornhuber, Johannes %A Wagner, Michael %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognitive Dysfunction %K Dementia %K Disease Progression %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Phenotype %K Predictive Value of Tests %K Retrospective Studies %K tau Proteins %X

BACKGROUND: The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials.

OBJECTIVE: To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI).

METHODS: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences.

RESULTS: In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aβ42/tau ratio indicative of AD (n = 340, AUC = 0.78, p <  0.001), and predicted incident dementia within 1-3 years of follow-up (n = 525, AUC = 0.84, p <  0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects.

CONCLUSION: These findings support the interpretation of δ as a construct capturing the disease-related "essence" of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research.

%B J Alzheimers Dis %V 49 %P 547-60 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484902?dopt=Abstract %R 10.3233/JAD-150257 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Lewy Bodies, Vascular Risk Factors, and Subcortical Arteriosclerotic Leukoencephalopathy, but not Alzheimer Pathology, are Associated with Development of Psychosis in Alzheimer's Disease. %A Fischer, Corinne E %A Qian, Winnie %A Schweizer, Tom A %A Millikin, Colleen P %A Ismail, Zahinoor %A Smith, Eric E %A Lix, Lisa M %A Shelton, Paul %A Munoz, David G %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition Disorders %K Databases, Factual %K Dementia, Vascular %K Female %K Hemorrhage %K Humans %K Lewy Bodies %K Male %K Middle Aged %K Psychiatric Status Rating Scales %K Psychotic Disorders %K Retrospective Studies %K Risk Factors %K Severity of Illness Index %K Surveys and Questionnaires %X

BACKGROUND: The neuropathological correlates of psychosis in Alzheimer's disease (AD) is unclear, with some studies reporting a correlation between psychosis and increased AD pathology while others have found no association.

OBJECTIVE: To determine the demographic, clinical, and neuropathological features associated with psychotic symptoms in clinically attributed and neuropathologically proven AD.

METHOD: We separately reviewed two overlapping groups of clinically diagnosed (cAD) AD patients with neuropathology data and neuropathologically definite (npAD) cases (regardless of clinical diagnosis) from the NACC database, and explored the relationships between psychosis and clinical variables, neuropathologic correlates, and vascular risk factors. Delusions and hallucinations, defined according to the NPI-Q, were analyzed separately.

RESULTS: 1,073 subjects in the database fulfilled our criteria (890 cAD and 728 npAD patients). 34% of cAD and 37% of npAD had psychotic symptoms during their illness. Hallucinations were associated with greater cognitive and functional impairments on the MMSE and CDR, while delusional patients showed less impairment on CDR, consistent across cAD and npAD groups. Burden of AD pathology appears to relate to presence of psychotic symptoms in the clinical AD group, but this result is not confirmed in the neuropathologically confirmed group suggesting the findings in the clinical group were due to misdiagnosis of AD. Lewy body pathology, subcortical arteriosclerotic leukoencephalopathy, and vascular risk factors, including a history of hypertension and diabetes, were associated with the development of psychosis.

METHOD: Vascular and Lewy body pathologies and vascular risk factors are important modifiers of the risk of psychosis in AD.

%B J Alzheimers Dis %V 50 %P 283-95 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682680?dopt=Abstract %R 10.3233/JAD-150606 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Linguistic Features Identify Alzheimer's Disease in Narrative Speech. %A Fraser, Kathleen C %A Meltzer, Jed A %A Rudzicz, Frank %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Diagnosis, Computer-Assisted %K Factor Analysis, Statistical %K Female %K Humans %K Language Disorders %K Linguistics %K Logistic Models %K Machine Learning %K Male %K Mental Status Schedule %K Middle Aged %K Narration %K Photic Stimulation %K Speech %K Verbal Behavior %X

BACKGROUND: Although memory impairment is the main symptom of Alzheimer's disease (AD), language impairment can be an important marker. Relatively few studies of language in AD quantify the impairments in connected speech using computational techniques.

OBJECTIVE: We aim to demonstrate state-of-the-art accuracy in automatically identifying Alzheimer's disease from short narrative samples elicited with a picture description task, and to uncover the salient linguistic factors with a statistical factor analysis.

METHODS: Data are derived from the DementiaBank corpus, from which 167 patients diagnosed with "possible" or "probable" AD provide 240 narrative samples, and 97 controls provide an additional 233. We compute a number of linguistic variables from the transcripts, and acoustic variables from the associated audio files, and use these variables to train a machine learning classifier to distinguish between participants with AD and healthy controls. To examine the degree of heterogeneity of linguistic impairments in AD, we follow an exploratory factor analysis on these measures of speech and language with an oblique promax rotation, and provide interpretation for the resulting factors.

RESULTS: We obtain state-of-the-art classification accuracies of over 81% in distinguishing individuals with AD from those without based on short samples of their language on a picture description task. Four clear factors emerge: semantic impairment, acoustic abnormality, syntactic impairment, and information impairment.

CONCLUSION: Modern machine learning and linguistic analysis will be increasingly useful in assessment and clustering of suspected AD.

%B J Alzheimers Dis %V 49 %P 407-22 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484921?dopt=Abstract %R 10.3233/JAD-150520 %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 Memory Profiles in Behavioral-Variant Frontotemporal Dementia and Alzheimer's Disease. %A Schubert, Samantha %A Leyton, Cristian E %A Hodges, John R %A Piguet, Olivier %K Alzheimer Disease %K Aniline Compounds %K Brain %K Diagnosis, Differential %K Disease Progression %K Executive Function %K Female %K Follow-Up Studies %K Frontotemporal Dementia %K Humans %K Longitudinal Studies %K Male %K Memory %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %K Radiopharmaceuticals %K Thiazoles %X

BACKGROUND: Alzheimer's disease (AD) and behavioral-variant of frontotemporal dementia (bvFTD) can present with an overlapping neuropsychological profile, which often hinders their clinical differentiation.

OBJECTIVE: To compare changes over time in memory, general cognition tasks, and functional scales between bvFTD and AD.

METHODS: Consecutive cases diagnosed with probable bvFTD (n = 22) and typical AD (n = 31) with at least two clinical visits were selected. Of these, 13 (9 AD, 4 bvFTD) underwent Pittsburgh compound B PET scan, which supported the clinical diagnosis in all cases. Mixed-model regressions were used to estimate the differential rate of decline on selected tasks between cohorts.

RESULTS: Analyses demonstrated that, despite equivalent baseline performance, bvFTD patients experienced a more rapid functional deterioration and a steeper decline in global cognition than AD patients. At baseline, both groups were impaired on executive function and memory tasks compared to controls, but these deficits were more marked in the bvFTD group. In addition, performance on these domains continued to decline more rapidly in this group.

CONCLUSIONS: Neither the initial neuropsychological assessment nor projected performances can reliably distinguish the totality of bvFTD and AD individuals. Nevertheless, annual rates of progression on cognitive tasks provide valuable information and will potentially help establish the impact of future therapeutic treatments in these dementia syndromes.

%B J Alzheimers Dis %V 51 %P 775-82 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890749?dopt=Abstract %R 10.3233/JAD-150802 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Longitudinal Protein Changes in Blood Plasma Associated with the Rate of Cognitive Decline in Alzheimer's Disease. %A Sattlecker, Martina %A Khondoker, Mizanur %A Proitsi, Petroula %A Williams, Stephen %A Soininen, Hilkka %A Kłoszewska, Iwona %A Mecocci, Patrizia %A Tsolaki, Magda %A Vellas, Bruno %A Lovestone, Simon %A Dobson, Richard Jb %K Aged %K Alzheimer Disease %K Biomarkers %K Cognition %K Cognitive Dysfunction %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Mental Status Schedule %K Neuropsychological Tests %X

Biomarkers of Alzheimer's disease (AD) progression are needed to support the development of urgently needed disease modifying drugs. We employed a SOMAscan assay for quantifying 1,001 proteins in blood samples from 90 AD subjects, 37 stable mild cognitive impaired (MCI) subjects, 39 MCI subjects converting to AD within a year and 69 controls at baseline and one year follow up. We used linear mixed effects models to identify proteins changing significantly over one year with the rate of cognitive decline, which was quantified as the reduction in Mini Mental State Examination (MMSE) scores. Additionally, we investigated proteins changing differently across disease groups and during the conversion from MCI to AD. We found that levels of proteins belonging to the complement cascade increase significantly in fast declining AD patients. Longitudinal changes in the complement cascade might be a surrogate biomarker for disease progression. We also found that members of the cytokine-cytokine receptor interaction pathway change during AD when compared to healthy aging subjects.

%B J Alzheimers Dis %V 49 %P 1105-14 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599049?dopt=Abstract %R 10.3233/JAD-140669 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Low Plasma Cholinesterase Activities are Associated with Deficits in Spatial Orientation, Reduced Ability to Perform Basic Activities of Daily Living, and Low Body Mass Index in Patients with Progressed Alzheimer's Disease. %A Dingova, Dominika %A Fazekas, Tomas %A Okuliarova, Petra %A Strbova, Jaroslava %A Kucera, Matej %A Hrabovska, Anna %K Acetylcholinesterase %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Blood Chemical Analysis %K Body Mass Index %K Butyrylcholinesterase %K Female %K Hospitalization %K Humans %K Male %K Middle Aged %K Orientation, Spatial %X

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by a central cholinergic deficit. Non-neuronal cholinergic changes are, however, described as well. Here we focused on possible changes in the activity of the plasma cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), in hospitalized AD patients. We analyzed plasma AChE and BChE activities with regards to age, gender, body mass index (BMI), cognitive functions, and ability to perform activities of daily living in AD patients in comparison to healthy subjects. We observed lower AChE activity and trend toward lower BChE activity in AD patients, which both correlated with low BMI. AD patients unable to perform basic activities of daily living (feeding, bathing, dressing, and grooming) showed reduced plasma AChE activities, while worse spatial orientation was linked to lower BChE activities. Three out of four AD patients with the lowest BChE activities died within one year. In conclusion, progressed AD was accompanied by lower plasma AChE activity and trend toward lower BChE activity, which correlated with BMI and deficits in different components of the AD.

%B J Alzheimers Dis %V 51 %P 801-13 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890780?dopt=Abstract %R 10.3233/JAD-151060 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Lower Prevalence of Alzheimer's Disease among Tibetans: Association with Religious and Genetic Factors. %A Huang, Fukai %A Shang, Ying %A Luo, Yuandai %A Wu, Peng %A Huang, Xue %A Tan, Xiaohui %A Lu, Xingyi %A Zhen, Lifang %A Hu, Xianda %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Clusterin %K Cognition Disorders %K Cross-Sectional Studies %K Female %K Genetic Association Studies %K Genetic Predisposition to Disease %K Humans %K Logistic Models %K Male %K Middle Aged %K Neuropsychological Tests %K Polymorphism, Single Nucleotide %K Psychiatric Status Rating Scales %K Religion %K Risk Factors %K Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization %K Tibet %X

BACKGROUND: The prevalence of dementia differs among racial groups, the highest prevalence being in Latin America (8.5%) compared to sub-Saharan African regions (2-4%). The most common type of dementia is Alzheimer's disease (AD).

OBJECTIVE: To estimate the prevalence of AD in the Qinghai-Tibet plateau and to investigate the related factors.

METHODS: This was a cross-sectional, multistage cluster sampling design survey. Data was collected from May 2014 to September 2014 from 4,060 Tibetan aged >60 years. Participants underwent clinical examinations and neuropsychological evaluations. MALDI-TOF was used to test the genotypes of CLU, TFAM, TP53INP1, IGHV1-67, CR1, ApoE, and BIN1. Logistic regression models were used to ascertain the associations with AD.

RESULTS: The prevalence of AD among Tibetan individuals aged >60 years was 1.33% (95% CI: 0.98-1.69). The CLU haplotypes AA+GA (odds ratio (OR) = 4.483; 95% CI: 1.069-18.792) of rs2279590 was correlated with AD. The CLU haplotypes GG+GC (OR = 0.184; 95% CI: 0.038-0.888) of rs9331888 and kowtow (OR = 0.203; 95% CI 0.046-0.896) were negatively correlated with AD.

CONCLUSION: A low prevalence of AD was found in Tibetans from the Qinghai-Tibet plateau. Multivariate analysis might suggest that regular "mind-body" religious meditative activities may be negatively associated with AD in this population, as well as the CLU genotype at rs9331888.

%B J Alzheimers Dis %V 50 %P 659-67 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757186?dopt=Abstract %R 10.3233/JAD-150697 %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 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 A Meta-Analysis of Alzheimer's Disease Incidence and Prevalence Comparing African-Americans and Caucasians. %A Steenland, Kyle %A Goldstein, Felicia C %A Levey, Allan %A Wharton, Whitney %K African Americans %K Alzheimer Disease %K Community Health Planning %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Prevalence %X

BACKGROUND: Several studies have shown higher Alzheimer's disease (AD) incidence rates are in African-Americans (AAs) than Caucasians (CCs). If this finding is consistent across studies, it raises important etiologic questions regarding factors responsible for this discrepancy. It also affects the likely public health burden of AD in the US in the future, as the non-Caucasian population becomes the majority.

OBJECTIVE: Estimate the AA/CC rate ratio for AD incidence across all available studies.

METHODS: We conducted a meta-analysis of population-based studies for the rate ratio (RR) of AD incidence for AAs versus CCs, after identifying six relevant studies from the literature. We calculated an AA/CC rate ratio across all studies using inverse-variance weighting, and assessed inter-study heterogeneity. Using these incidence data, as well as data on survival after diagnosis, and on all-cause mortality, we also estimated the US prevalence of AD among AAs and CCs.

RESULTS: There were six population-based studies with data comparing AD incidence between AAs and CCs, with an estimated 370 AA and 640 CC incident cases. The meta-analysis RR showed that the AD rate for AAs was 64% higher than for CCs (RR = 1.64 (95% CI 1.35-2.00)) 1.35-2.00)), with no evidence of heterogeneity. We estimated the current US AD prevalence for ages 65-90 to be 5.5% for CCs, and 8.6% for AAs (prevalence ratio 1.56).

CONCLUSION: AAs have an increased risk of incident and prevalent AD compared to CCs for reasons which are unknown, but are hypothesized to reflect biological, psychological, and socioeconomic factors.

%B J Alzheimers Dis %V 50 %P 71-6 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639973?dopt=Abstract %R 10.3233/JAD-150778 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Meta-Analysis of Transcriptome Data Related to Hippocampus Biopsies and iPSC-Derived Neuronal Cells from Alzheimer's Disease Patients Reveals an Association with FOXA1 and FOXA2 Gene Regulatory Networks. %A Wruck, Wasco %A Schröter, Friederike %A Adjaye, James %K Alzheimer Disease %K Biopsy %K Cells, Cultured %K Gene Regulatory Networks %K Hepatocyte Nuclear Factor 3-alpha %K Hepatocyte Nuclear Factor 3-beta %K Hippocampus %K Humans %K Induced Pluripotent Stem Cells %K Transcriptome %X

Although the incidence of Alzheimer's disease (AD) is continuously increasing in the aging population worldwide, effective therapies are not available. The interplay between causative genetic and environmental factors is partially understood. Meta-analyses have been performed on aspects such as polymorphisms, cytokines, and cognitive training. Here, we propose a meta-analysis approach based on hierarchical clustering analysis of a reliable training set of hippocampus biopsies, which is condensed to a gene expression signature. This gene expression signature was applied to various test sets of brain biopsies and iPSC-derived neuronal cell models to demonstrate its ability to distinguish AD samples from control. Thus, our identified AD-gene signature may form the basis for determination of biomarkers that are urgently needed to overcome current diagnostic shortfalls. Intriguingly, the well-described AD-related genes APP and APOE are not within the signature because their gene expression profiles show a lower correlation to the disease phenotype than genes from the signature. This is in line with the differing characteristics of the disease as early-/late-onset or with/without genetic predisposition. To investigate the gene signature's systemic role(s), signaling pathways, gene ontologies, and transcription factors were analyzed which revealed over-representation of response to stress, regulation of cellular metabolic processes, and reactive oxygen species. Additionally, our results clearly point to an important role of FOXA1 and FOXA2 gene regulatory networks in the etiology of AD. This finding is in corroboration with the recently reported major role of the dopaminergic system in the development of AD and its regulation by FOXA1 and FOXA2.

%B J Alzheimers Dis %V 50 %P 1065-82 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890743?dopt=Abstract %R 10.3233/JAD-150733 %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 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 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 Molecular markers of amnestic mild cognitive impairment among Mexican Americans. %A Edwards, Melissa %A Hall, James %A Williams, Benjamin %A Johnson, Leigh %A O'Bryant, Sid %K Aged %K Alzheimer Disease %K Area Under Curve %K Biomarkers %K Cognitive Dysfunction %K Female %K Humans %K Male %K Mexican Americans %K Middle Aged %K Neuropsychological Tests %K Proteome %K Sensitivity and Specificity %K United States %X

BACKGROUND: Mexican Americans face a significant health disparity when it comes to Alzheimer's disease (AD) as they present with higher rates of the disease and develop AD at an earlier age compared to other ethnic groups. Recent work identified a proteomic profile of AD among this population; however, no work to date has sought to examine the biological profile of pre-AD among Mexican Americans.

OBJECTIVE: This study aims to identify an amnestic mild cognitive impairment (aMCI) proteomic profile among Mexican Americans.

METHODS: Data were analyzed from 284 Mexican American participants (aMCI, n = 73; normal controls, n = 211) from the Health & Aging Brain among Latino Elders study. Fasting serum samples were analyzed using a multi-plex biomarker assay platform. A biomarker profile was generated using random forest analyses.

RESULTS: Among aMCI cases, the biomarker profile was found to be largely inflammatory with the top three markers shown to include TNFα, IL10, and TARC. The overall diagnostic accuracy of the biomarkers in detecting aMCI was 96% (sensitivity = 0.82; specificity = 0.97). Inclusion of clinical variables with the selected biomarkers did not impact the overall detection accuracy (area under the curve = 0.96) but led to a slight improvement in specificity (specificity = 0.99) and decrease in sensitivity (sensitivity = 0.74).

CONCLUSION: The biomarker profile of aMCI was shown to be different from our previously generated AD profile among Mexican Americans, which was largely metabolic in nature. The findings implicate a possible interplay between inflammatory and metabolic processes and additional work is needed to further examine this.

%B J Alzheimers Dis %V 49 %P 221-8 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444793?dopt=Abstract %R 10.3233/JAD-150553 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Molecular Signaling Mechanisms of Natural and Synthetic Retinoids for Inhibition of Pathogenesis in Alzheimer's Disease. %A Chakrabarti, Mrinmay %A McDonald, Alexander J %A Will Reed, J %A Moss, Melissa A %A Das, Bhaskar C %A Ray, Swapan K %K Alzheimer Disease %K Animals %K Brain %K Humans %K Mice %K Neurons %K Retinoid X Receptors %K Retinoids %K Signal Transduction %K Tretinoin %X

Retinoids, which are vitamin A derivatives, interact through retinoic acid receptors (RARs) and retinoid X receptors (RXRs) and have profound effects on several physiological and pathological processes in the brain. The presence of retinoic acid signaling is extensively detected in the adult central nervous system, including the amygdala, cortex, hypothalamus, hippocampus, and other brain areas. Retinoids are primarily involved in neural patterning, differentiation, and axon outgrowth. Retinoids also play a key role in the preservation of the differentiated state of adult neurons. Impairment in retinoic acid signaling can result in neurodegeneration and progression of Alzheimer's disease (AD). Recent studies demonstrated severe deficiencies in spatial learning and memory in mice during retinoic acid (vitamin A) deprivation indicating its significance in preserving memory function. Defective cholinergic neurotransmission plays an important role in cognitive deficits in AD. All-trans retinoic acid is known to enhance the expression and activity of choline acetyltransferase in neuronal cell lines. Activation of RAR and RXR is also known to impede the pathogenesis of AD in mice by inhibiting accumulation of amyloids. In addition, retinoids have been shown to inhibit the expression of chemokines and pro-inflammatory cytokines in microglia and astrocytes, which are activated in AD. In this review article, we have described the chemistry and molecular signaling mechanisms of natural and synthetic retinoids and current understandings of their therapeutic potentials in prevention of AD pathology.

%B J Alzheimers Dis %V 50 %P 335-52 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682679?dopt=Abstract %R 10.3233/JAD-150450 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Multifunctional Effect of Human Serum Albumin Reduces Alzheimer's Disease Related Pathologies in the 3xTg Mouse Model. %A Ezra, Assaf %A Rabinovich-Nikitin, Inna %A Rabinovich-Toidman, Polina %A Solomon, Beka %K Albumins %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Blood-Brain Barrier %K Brain %K Calcium %K Cell Line, Tumor %K Cognition Disorders %K Disease Models, Animal %K Drug Delivery Systems %K Encephalitis %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mutation %K Neuroblastoma %K Neuropsychological Tests %K Peptide Fragments %K Presenilin-1 %K tau Proteins %X

Alzheimer's disease (AD), the prevalent dementia in the elderly, involves many related and interdependent pathologies that manifests simultaneously, eventually leading to cognitive impairment and death. No treatment is currently available; however, an agent addressing several key pathologies simultaneously has a better therapeutic potential. Human serum albumin (HSA) is a highly versatile protein, harboring multifunctional properties that are relevant to key pathologies underlying AD. This study provides insight into the mechanism for HSA's therapeutic effect. In vivo, a myriad of beneficial effects were observed by pumps infusing HSA intracerebroventricularly, for the first time in an AD 3xTg mice model. A significant effect on amyloid-β (Aβ) pathology was observed. Aβ1-42, soluble oligomers, and total plaque area were reduced. Neuroblastoma SHSY5Y cell line confirmed that the reduction in Aβ1-42 toxicity was due to direct binding rather than other properties of HSA. Total and hyperphosphorylated tau were reduced along with an increase in tubulin, suggesting increased microtubule stability. HSA treatment also reduced brain inflammation, affecting both astrocytes and microglia markers. Finally, evidence for blood-brain barrier and myelin integrity repair was observed. These multidimensional beneficial effects of intracranial administrated HSA, together or individually, contributed to an improvement in cognitive tests, suggesting a non-immune or Aβ efflux dependent means for treating AD.

%B J Alzheimers Dis %V 50 %P 175-88 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682687?dopt=Abstract %R 10.3233/JAD-150694 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Multimodal Magnetic Resonance Imaging in Alzheimer's Disease Patients at Prodromal Stage. %A Eustache, Pierre %A Nemmi, Federico %A Saint-Aubert, Laure %A Pariente, Jérémie %A Péran, Patrice %K Aged %K Alzheimer Disease %K Biomarkers %K Brain %K Cognitive Dysfunction %K Diffusion Tensor Imaging %K Female %K Fluorodeoxyglucose F18 %K Humans %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Multimodal Imaging %K Neuropsychological Tests %K Organ Size %K Positron-Emission Tomography %K Prodromal Symptoms %K Radiopharmaceuticals %X

One objective of modern neuroimaging is to identify markers that can aid in diagnosis, monitor disease progression, and impact long-term drug analysis. In this study, physiopathological modifications in seven subcortical structures of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) were characterized by simultaneously measuring quantitative magnetic resonance parameters that are sensitive to complementary tissue characteristics (e.g., volume atrophy, shape changes, microstructural damage, and iron deposition). Fourteen MCI patients and fourteen matched, healthy subjects underwent 3T-magnetic resonance imaging with whole-brain, T1-weighted, T2*-weighted, and diffusion-tensor imaging scans. Volume, shape, mean R2*, mean diffusivity (MD), and mean fractional anisotropy (FA) in the thalamus, hippocampus, putamen, amygdala, caudate nucleus, pallidum, and accumbens were compared between MCI patients and healthy subjects. Comparisons were then performed using voxel-based analyses of R2*, MD, FA maps, and voxel-based morphometry to determine which subregions showed the greatest difference for each parameter. With respect to the micro- and macro-structural patterns of damage, our results suggest that different and distinct physiopathological processes are present in the prodromal phase of AD. MCI patients had significant atrophy and microstructural changes within their hippocampi and amygdalae, which are known to be affected in the prodromal stage of AD. This suggests that the amygdala is affected in the same, direct physiopathological process as the hippocampus. Conversely, atrophy alone was observed within the thalamus and putamen, which are not directly involved in AD pathogenesis. This latter result may reflect another mechanism, whereby atrophy is linked to indirect physiopathological processes.

%B J Alzheimers Dis %V 50 %P 1035-50 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836151?dopt=Abstract %R 10.3233/JAD-150353 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Music and Memory in Alzheimer's Disease and The Potential Underlying Mechanisms. %A Peck, Katlyn J %A Girard, Todd A %A Russo, Frank A %A Fiocco, Alexandra J %K Alzheimer Disease %K Auditory Perception %K Autonomic Nervous System %K Dopamine %K Humans %K Memory Disorders %K Music Therapy %X

With population aging and a projected exponential expansion of persons diagnosed with Alzheimer's disease (AD), the development of treatment and prevention programs has become a fervent area of research and discovery. A growing body of evidence suggests that music exposure can enhance memory and emotional function in persons with AD. However, there is a paucity of research that aims to identify specific underlying neural mechanisms associated with music's beneficial effects in this particular population. As such, this paper reviews existing anecdotal and empirical evidence related to the enhancing effects of music exposure on cognitive function and further provides a discussion on the potential underlying mechanisms that may explain music's beneficial effect. Specifically, this paper will outline the potential role of the dopaminergic system, the autonomic nervous system, and the default network in explaining how music may enhance memory function in persons with AD.

%B J Alzheimers Dis %V 51 %P 949-59 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967216?dopt=Abstract %R 10.3233/JAD-150998 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neuronal activity and amyloid plaque pathology: an update. %A Ovsepian, Saak V %A O'Leary, Valerie B %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid Precursor Protein Secretases %K Amyloidosis %K Animals %K Disease Models, Animal %K Humans %K Mice %K Mice, Transgenic %K Neurons %K Plaque, Amyloid %K Prosencephalon %K Seizures %X

A breakthrough in Alzheimer's disease (AD) research came with the discovery of the link between activity-dependent release of amyloid-β (Aβ) from neurons and formation of amyloid plaques. Along with elucidating the cellular basis of behavioral-dependent fluctuations in Aβ levels in the brain, insights have been gained toward understanding the mechanisms that warrant selective vulnerability of various forebrain circuits to amyloid pathology. The notion of elevated activity as a source of excessive Aβ production and plaque formation is, however, in conflict with ample electrophysiological data, which demonstrate exceedingly intense activity (both intrinsic and synaptic) of neurons in several brain regions that are spared or marginally affected by amyloid plaques of AD. Thus, the link between the functional load of brain circuits and their vulnerability to amyloidosis, while evident, is also complex and remains poorly understood. Here, we discuss emerging data suggestive of a major role for super-intense synchronous activity of cortical and limbic networks in excessive Aβ production and plaque formation. It is proposed that dense recurrent wiring of associative areas prone to epileptic seizures might be of critical relevance to their higher susceptibility to plaque pathology and related functional impairments.

%B J Alzheimers Dis %V 49 %P 13-9 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444792?dopt=Abstract %R 10.3233/JAD-150544 %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 Non-Verbal Episodic Memory Deficits in Primary Progressive Aphasias are Highly Predictive of Underlying Amyloid Pathology. %A Ramanan, Siddharth %A Flanagan, Emma %A Leyton, Cristian E %A Villemagne, Victor L %A Rowe, Christopher C %A Hodges, John R %A Hornberger, Michael %K Aged %K Alzheimer Disease %K Amyloid %K Aniline Compounds %K Aphasia, Primary Progressive %K Brain %K Diagnosis, Differential %K Female %K Humans %K Logistic Models %K Male %K Memory, Episodic %K Neuropsychological Tests %K Positron-Emission Tomography %K Radiopharmaceuticals %K Speech Perception %K Thiazoles %X

Diagnostic distinction of primary progressive aphasias (PPA) remains challenging, in particular for the logopenic (lvPPA) and nonfluent/agrammatic (naPPA) variants. Recent findings highlight that episodic memory deficits appear to discriminate these PPA variants from each other, as only lvPPA perform poorly on these tasks while having underlying amyloid pathology similar to that seen in amnestic dementias like Alzheimer's disease (AD). Most memory tests are, however, language based and thus potentially confounded by the prevalent language deficits in PPA. The current study investigated this issue across PPA variants by contrasting verbal and non-verbal episodic memory measures while controlling for their performance on a language subtest of a general cognitive screen. A total of 203 participants were included (25 lvPPA; 29 naPPA; 59 AD; 90 controls) and underwent extensive verbal and non-verbal episodic memory testing, with a subset of patients (n = 45) with confirmed amyloid profiles as assessed by Pittsburgh Compound B and PET. The most powerful discriminator between naPPA and lvPPA patients was a non-verbal recall measure (Rey Complex Figure delayed recall), with 81% of PPA patients classified correctly at presentation. Importantly, AD and lvPPA patients performed comparably on this measure, further highlighting the importance of underlying amyloid pathology in episodic memory profiles. The findings demonstrate that non-verbal recall emerges as the best discriminator of lvPPA and naPPA when controlling for language deficits in high load amyloid PPA cases.

%B J Alzheimers Dis %V 51 %P 367-76 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890745?dopt=Abstract %R 10.3233/JAD-150752 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Normal Amplitude of Electroretinography and Visual Evoked Potential Responses in AβPP/PS1 Mice. %A Leinonen, Henri %A Lipponen, Arto %A Gurevicius, Kestutis %A Tanila, Heikki %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Contrast Sensitivity %K Disease Models, Animal %K Electroencephalography %K Electroretinography %K Evoked Potentials, Visual %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mutation %K Photic Stimulation %K Presenilin-1 %K Reaction Time %X

Alzheimer's disease has been shown to affect vision in human patients and animal models. This may pose the risk of bias in behavior studies and therefore requires comprehensive investigation. We recorded electroretinography (ERG) under isoflurane anesthesia and visual evoked potentials (VEP) in awake amyloid expressing AβPPswe/PS1dE9 (AβPP/PS1) and wild-type littermate mice at a symptomatic age. The VEPs in response to patterned stimuli were normal in AβPP/PS1 mice. They also showed normal ERG amplitude but slightly shortened ERG latency in dark-adapted conditions. Our results indicate subtle changes in visual processing in aged male AβPP/PS1 mice specifically at a retinal level.

%B J Alzheimers Dis %V 51 %P 21-6 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836173?dopt=Abstract %R 10.3233/JAD-150798 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Novel Selective Calpain 1 Inhibitors as Potential Therapeutics in Alzheimer's Disease. %A Fà, Mauro %A Zhang, Hong %A Staniszewski, Agnieszka %A Saeed, Faisal %A Shen, Li W %A Schiefer, Isaac T %A Siklos, Marton I %A Tapadar, Subhasish %A Litosh, Vladislav A %A Libien, Jenny %A Petukhov, Pavel A %A Teich, Andrew F %A Thatcher, Gregory R J %A Arancio, Ottavio %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Cysteine Proteinase Inhibitors %K Disease Models, Animal %K Dose-Response Relationship, Drug %K Fear %K Glycoproteins %K Hippocampus %K Humans %K In Vitro Techniques %K Long-Term Potentiation %K Maze Learning %K Memory %K Mice %K Mice, Inbred ICR %K Mice, Transgenic %K Mutation %K Patch-Clamp Techniques %K Peptide Fragments %K Presenilin-1 %K Spectrin %X

Alzheimer's disease, one of the most important brain pathologies associated with neurodegenerative processes, is related to overactivation of calpain-mediated proteolysis. Previous data showed a compelling efficacy of calpain inhibition against abnormal synaptic plasticity and memory produced by the excess of amyloid-β, a distinctive marker of the disease. Moreover, a beneficial effect of calpain inhibitors in Alzheimer's disease is predictable by the occurrence of calpain hyperactivation leading to impairment of memory-related pathways following abnormal calcium influxes that might ensue independently of amyloid-β elevation. However, molecules currently available as effective calpain inhibitors lack adequate selectivity. This work is aimed at characterizing the efficacy of a novel class of epoxide-based inhibitors, synthesized to display improved selectivity and potency towards calpain 1 compared to the prototype epoxide-based generic calpain inhibitor E64. Both functional and preliminary toxicological investigations proved the efficacy, potency, and safety of the novel and selective calpain inhibitors NYC438 and NYC488 as possible therapeutics against the disease.

%B J Alzheimers Dis %V 49 %P 707-21 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484927?dopt=Abstract %R 10.3233/JAD-150618 %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 The Online Environment: A Key Variable in the Ethical Response to Complementary and Alternative Medicine for Alzheimer's Disease. %A Robillard, Julie M %K Alzheimer Disease %K Complementary Therapies %K Humans %X

Racine et al.'s Ethics Review highlights the challenges associated with the use of complementary and alternative medicine (CAM) in the context of early diagnosis of Alzheimer's disease (AD). As CAM are increasingly promoted and sold on the Internet, the unregulated online environment has the potential to significantly impact the health and well-being of the aging demographic, and in particular of individuals concerned about AD. In this response, the ethical challenges specific to the online environment are discussed and solutions are put forward to empower the aging population to maximize the benefits of the online environment while minimizing the potential harms of misinformation, conflict of interest, and other ethical concerns.

%B J Alzheimers Dis %V 51 %P 11-3 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836156?dopt=Abstract %R 10.3233/JAD-150641 %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 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 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 A Pathway Based Classification Method for Analyzing Gene Expression for Alzheimer's Disease Diagnosis. %A Voyle, Nicola %A Keohane, Aoife %A Newhouse, Stephen %A Lunnon, Katie %A Johnston, Caroline %A Soininen, Hilkka %A Kloszewska, Iwona %A Mecocci, Patrizia %A Tsolaki, Magda %A Vellas, Bruno %A Lovestone, Simon %A Hodges, Angela %A Kiddle, Steven %A Dobson, Richard Jb %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoproteins E %K Cohort Studies %K Datasets as Topic %K Female %K Gene Expression %K Gene Expression Profiling %K Humans %K Male %K Models, Genetic %K Oligonucleotide Array Sequence Analysis %K Signal Transduction %X

BACKGROUND: Recent studies indicate that gene expression levels in blood may be able to differentiate subjects with Alzheimer's disease (AD) from normal elderly controls and mild cognitively impaired (MCI) subjects. However, there is limited replicability at the single marker level. A pathway-based interpretation of gene expression may prove more robust.

OBJECTIVES: This study aimed to investigate whether a case/control classification model built on pathway level data was more robust than a gene level model and may consequently perform better in test data. The study used two batches of gene expression data from the AddNeuroMed (ANM) and Dementia Case Registry (DCR) cohorts.

METHODS: Our study used Illumina Human HT-12 Expression BeadChips to collect gene expression from blood samples. Random forest modeling with recursive feature elimination was used to predict case/control status. Age and APOE ɛ4 status were used as covariates for all analysis.

RESULTS: Gene and pathway level models performed similarly to each other and to a model based on demographic information only.

CONCLUSIONS: Any potential increase in concordance from the novel pathway level approach used here has not lead to a greater predictive ability in these datasets. However, we have only tested one method for creating pathway level scores. Further, we have been able to benchmark pathways against genes in datasets that had been extensively harmonized. Further work should focus on the use of alternative methods for creating pathway level scores, in particular those that incorporate pathway topology, and the use of an endophenotype based approach.

%B J Alzheimers Dis %V 49 %P 659-69 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484910?dopt=Abstract %R 10.3233/JAD-150440 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Patients with Mild Alzheimer's Disease Fail When Using Their Working Memory: Evidence from the Eye Tracking Technique. %A Fernández, Gerardo %A Manes, Facundo %A Politi, Luis E %A Orozco, David %A Schumacher, Marcela %A Castro, Liliana %A Agamennoni, Osvaldo %A Rotstein, Nora P %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Eye Movements %K Female %K Humans %K Linear Models %K Magnetic Resonance Imaging %K Male %K Memory Disorders %K Memory, Short-Term %K Mental Recall %K Mental Status Schedule %K Predictive Value of Tests %K Semantics %K Verbal Learning %X

Patients with Alzheimer's disease (AD) develop progressive language, visuoperceptual, attentional, and oculomotor changes that can have an impact on their reading comprehension. However, few studies have examined reading behavior in AD, and none have examined the contribution of predictive cueing in reading performance. For this purpose we analyzed the eye movement behavior of 35 healthy readers (Controls) and 35 patients with probable AD during reading of regular and high-predictable sentences. The cloze predictability of words N - 1, and N + 1 exerted an influence on the reader's gaze duration. The predictabilities of preceding words in high-predictable sentences served as task-appropriate cues that were used by Control readers. In contrast, these effects were not present in AD patients. In Controls, changes in predictability significantly affected fixation duration along the sentence; noteworthy, these changes did not affect fixation durations in AD patients. Hence, only in healthy readers did predictability of upcoming words influence fixation durations via memory retrieval. Our results suggest that Controls used stored information of familiar texts for enhancing their reading performance and imply that contextual-word predictability, whose processing is proposed to require memory retrieval, only affected reading behavior in healthy subjects. In AD patients, this loss reveals impairments in brain areas such as those corresponding to working memory and memory retrieval. These findings might be relevant for expanding the options for the early detection and monitoring in the early stages of AD. Furthermore, evaluation of eye movements during reading could provide a new tool for measuring drug impact on patients' behavior.

%B J Alzheimers Dis %V 50 %P 827-38 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836011?dopt=Abstract %R 10.3233/JAD-150265 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Patterns of Brain Iron Accumulation in Vascular Dementia and Alzheimer's Dementia Using Quantitative Susceptibility Mapping Imaging. %A Moon, Yeonsil %A Han, Seol-Heui %A Moon, Won-Jin %K Aged %K Aging %K Alzheimer Disease %K Brain %K Brain Mapping %K Cognition %K Dementia, Vascular %K Female %K Humans %K Imaging, Three-Dimensional %K Iron %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Retrospective Studies %K Severity of Illness Index %X

BACKGROUND: Emerging evidence suggests that the excessive accumulation of iron in subcortical and deep gray matter has been related to dementia. However, the presence and pattern of iron accumulation in vascular dementia (VaD) and Alzheimer's disease (AD) are rarely investigated.

OBJECTIVE: To examine and compare the pattern and presence of brain iron accumulation of VaD and AD using quantitative susceptibility mapping (QSM).

MATERIALS AND METHODS: Twelve patients with VaD, 27 patients with AD, and 18 control subjects were recruited in this institutional review-board approved study. Susceptibility maps were reconstructed from a three-dimensional multiecho spoiled gradient-echo sequence. Four regions of interest were drawn manually on QSM images, namely the globus pallidus, putamen, caudate nucleus, and pulvinar nucleus of the thalamus. Comparisons of patient demographics, and iron concentrations among the VaD, AD, and control subjects were assessed using analysis of variance and post-hoc analyses. The relationships of age and cognitive state with susceptibility values were assessed using partial correlation analysis.

RESULTS: In VaD and AD, overall susceptibility values were higher than those of control subjects. A significant difference in susceptibility values was found in the putamen and caudate nucleus (p <  0.001 and p = 0.002, respectively). However, susceptibility values did not differ between VaD and AD. Age and cognitive deficit severity were not related to susceptibility values in the VaD and AD groups.

CONCLUSION: Increased iron deposition in the putamen and caudate nucleus in VaD and AD patients was not associated with age or the severity of cognitive deficits. Further evaluations are needed to determine the temporal changes in iron load and their diagnostic role in dementia pathology.

%B J Alzheimers Dis %V 51 %P 737-45 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890777?dopt=Abstract %R 10.3233/JAD-151037 %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 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 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 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 Post Hoc Analyses of ApoE Genotype-Defined Subgroups in Clinical Trials. %A Kennedy, Richard E %A Cutter, Gary R %A Wang, Guoqiao %A Schneider, Lon S %K Alzheimer Disease %K Apolipoprotein E4 %K Clinical Trials as Topic %K Cognitive Dysfunction %K Data Interpretation, Statistical %K Humans %K Research Design %X

BACKGROUND: Many post hoc analyses of clinical trials in Alzheimer's disease (AD) and mild cognitive impairment (MCI) are in small Phase 2 trials. Subject heterogeneity may lead to statistically significant post hoc results that cannot be replicated in larger follow-up studies.

OBJECTIVE: We investigated the extent of this problem using simulation studies mimicking current trial methods with post hoc analyses based on ApoE4 carrier status.

METHODS: We used a meta-database of 24 studies, including 3,574 subjects with mild AD and 1,171 subjects with MCI/prodromal AD, to simulate clinical trial scenarios. Post hoc analyses examined if rates of progression on the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) differed between ApoE4 carriers and non-carriers.

RESULTS: Across studies, ApoE4 carriers were younger and had lower baseline scores, greater rates of progression, and greater variability on the ADAS-cog. Up to 18% of post hoc analyses for 18-month trials in AD showed greater rates of progression for ApoE4 non-carriers that were statistically significant but unlikely to be confirmed in follow-up studies. The frequency of erroneous conclusions dropped below 3% with trials of 100 subjects per arm. In MCI, rates of statistically significant differences with greater progression in ApoE4 non-carriers remained below 3% unless sample sizes were below 25 subjects per arm.

CONCLUSIONS: Statistically significant differences for ApoE4 in post hoc analyses often reflect heterogeneity among small samples rather than true differential effect among ApoE4 subtypes. Such analyses must be viewed cautiously. ApoE genotype should be incorporated into the design stage to minimize erroneous conclusions.

%B J Alzheimers Dis %V 50 %P 1205-15 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836180?dopt=Abstract %R 10.3233/JAD-150847 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Posterior Accumulation of Tau and Concordant Hypometabolism in an Early-Onset Alzheimer's Disease Patient with Presenilin-1 Mutation. %A Smith, Ruben %A Wibom, Moa %A Olsson, Tomas %A Hägerström, Douglas %A Jögi, Jonas %A Rabinovici, Gil D %A Hansson, Oskar %K Adult %K Age of Onset %K Alzheimer Disease %K Amyloid beta-Peptides %K Aniline Compounds %K Benzothiazoles %K Brain %K Brain Mapping %K Fluorodeoxyglucose F18 %K Humans %K Magnetic Resonance Imaging %K Male %K Positron-Emission Tomography %K Presenilin-1 %K Radiopharmaceuticals %K tau Proteins %X

It is unclear whether the distribution of tau pathology differs between cases with early-onset familial Alzheimer's disease (AD) and sporadic AD. We present positron emission tomography (PET) data from a young patient with a presenilin-1 mutation (Thr116Asn). 18F-flutemetamol PET showed a distribution of amyloid-β fibrils similar to sporadic AD. However, the pattern of tau pathology, revealed using 18F-AV1451 PET, showed higher uptake in posterior cingulate, precuneus, parietal and occipital cortices compared to late-onset sporadic AD. Further, the tau pathology, but not amyloid pathology, exhibited a very clear inverse relationship with 18F-fluorodeoxyglucose-metabolism, indicating neuronal hypometabolism in regions affected by tau aggregates.

%B J Alzheimers Dis %V 51 %P 339-43 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836192?dopt=Abstract %R 10.3233/JAD-151004 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Prediction of Progressive Mild Cognitive Impairment by Multi-Modal Neuroimaging Biomarkers. %A Xu, Lele %A Wu, Xia %A Li, Rui %A Chen, Kewei %A Long, Zhiying %A Zhang, Jiacai %A Guo, Xiaojuan %A Yao, Li %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Aniline Compounds %K Biomarkers %K Brain %K Cognitive Dysfunction %K Disease Progression %K Ethylene Glycols %K Female %K Fluorodeoxyglucose F18 %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Positron-Emission Tomography %K Predictive Value of Tests %K Psychiatric Status Rating Scales %K Sensitivity and Specificity %X

For patients with mild cognitive impairment (MCI), the likelihood of progression to probable Alzheimer's disease (AD) is important not only for individual patient care, but also for the identification of participants in clinical trial, so as to provide early interventions. Biomarkers based on various neuroimaging modalities could offer complementary information regarding different aspects of disease progression. The current study adopted a weighted multi-modality sparse representation-based classification method to combine data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, from three imaging modalities: Volumetric magnetic resonance imaging (MRI), fluorodeoxyglucose (FDG) positron emission tomography (PET), and florbetapir PET. We included 117 normal controls (NC) and 110 MCI patients, 27 of whom progressed to AD within 36 months (pMCI), while the remaining 83 remained stable (sMCI) over the same time period. Modality-specific biomarkers were identified to distinguish MCI from NC and to predict pMCI among MCI. These included the hippocampus, amygdala, middle temporal and inferior temporal regions for MRI, the posterior cingulum, precentral, and postcentral regions for FDG-PET, and the hippocampus, amygdala, and putamen for florbetapir PET. Results indicated that FDG-PET may be a more effective modality in discriminating MCI from NC and in predicting pMCI than florbetapir PET and MRI. Combining modality-specific sensitive biomarkers from the three modalities boosted the discrimination accuracy of MCI from NC (76.7%) and the prediction accuracy of pMCI (82.5%) when compared with the best single-modality results (73.6% for MCI and 75.6% for pMCI with FDG-PET).

%B J Alzheimers Dis %V 51 %P 1045-56 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923024?dopt=Abstract %R 10.3233/JAD-151010 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Predictive factors for disease progression in patients with early-onset Alzheimer's disease. %A Yoon, Bora %A Shim, Yong S %A Park, Hee-Kyung %A Park, Sun Ah %A Choi, Seong Hye %A Yang, Dong Won %K Activities of Daily Living %K Adult %K Age Factors %K Aged %K Alleles %K Alzheimer Disease %K Apolipoproteins E %K Disease Progression %K Female %K Genotype %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Middle Aged %K Neuropsychological Tests %K Risk Factors %K Sex Factors %X

BACKGROUND: Only a few studies have investigated disease progression in patients with early-onset Alzheimer's disease (EOAD). Therefore, the aim of this study was to investigate disease progression in patients with EOAD and the influence of various factors, such as gender, education, and apolipoprotein E (APOE) genotype on disease progression.

METHODS: A total of 288 EOAD patients were enrolled in the study. Linear mixed models were used to investigate the rate of cognitive and functional decline in terms of age at onset, gender, education, follow-up period, and APOE genotype.

RESULTS: EOAD patients showed an annual decline of -1.54 points/years in the Korean version mini-mental examination score, an annual increase of 3.46 points/year in the Seoul instrumental activities of daily living (SIADL) score, and an annual increase of 1.15 points/year in the clinical dementia rating scale-sum of boxes score. After stratification, higher educated patients showed faster disease progression in all three parameters, and female patients demonstrated faster disease progression as assessed by the SIADL score. Age at onset and APOE genotype had no influence on disease progression.

CONCLUSION: We confirmed the rate of disease progression in Korean patients with EOAD in real-life hospital-based clinical practice. The results of this study suggest that education and female gender, not APOE genotype, may be important as independent strong predictive factors for disease progression in patients with EOAD.

%B J Alzheimers Dis %V 49 %P 85-91 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444786?dopt=Abstract %R 10.3233/JAD-150462 %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 Response to Cholinesterase Inhibitors Treatment of Alzheimer's Disease: Date Mining from the TREDEM Registry. %A Gallucci, Maurizio %A Spagnolo, Pierpaolo %A Aricò, Maria %A Grossi, Enzo %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cerebrovascular Disorders %K Cholinesterase Inhibitors %K Female %K Humans %K Life Style %K Male %K Marital Status %K Mental Status Schedule %K Neural Networks (Computer) %K Neuropsychological Tests %K Occupations %K Outpatients %K Prognosis %K Registries %K Treatment Outcome %X

BACKGROUND: The pharmacological treatment of Alzheimer's disease (AD) is based largely on cholinesterase inhibitors (ChEI).

OBJECTIVE: To investigate whether or not some non-pharmacological and contextual factors measured prior to starting treatment such as past occupation, lifestyles, marital status, degree of autonomy and cognitive impairment, living alone or with others, and the degree of brain atrophy are associated with a better response to ChEI treatment.

METHODS: Eighty-four AD and six AD with cerebrovascular disease (AD + CVD) outpatients of Treviso Dementia (TREDEM) Registry, with an average cholinesterase inhibitors treatment length of four years, were considered. The outpatients had undergone a complete evaluation and some non-pharmacological and contextual factors were collected. We defined responder a patient with a delta score T0 - T1 equal or inferior to 2.0 points per year of MMSE and a non-responder a patient with a delta score T0 - T1 superior to 2.0 points per year. In order to identify hidden relationships between variables related to response and non-response, we use a special kind of artificial neural network called Auto-CM, able to create a semantic connectivity map of the variables considered in the study.

RESULTS: A higher cognitive profile, a previous intellectual occupation, healthier lifestyles, being married and not living alone, a higher degree of autonomy, and lower degree of brain atrophy at baseline resulted in affecting the response to long-term ChEI therapy.

CONCLUSION: Non-pharmacological and contextual factors appear to influence the effectiveness of treatment with ChEI in the long term.

%B J Alzheimers Dis %V 50 %P 969-79 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836164?dopt=Abstract %R 10.3233/JAD-150747 %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 Prevention Trials in Alzheimer's Disease: Current Status and Future Perspectives. %A Wang, Jun %A Tan, Lan %A Yu, Jin-Tai %K Alzheimer Disease %K Biomarkers %K Clinical Trials as Topic %K Humans %X

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Over the past 20 years, both pharmacological and lifestyle interventions have been studied for AD prevention, but the overall results have been disappointing. The majority of disappointing results have raised questions and great challenges for the future of AD prevention trials. Ongoing advances in the knowledge of pathogenesis, in the identification of novel targets, in improved outcome measures, and in identification and validation of biomarkers may lead to effective strategies for AD prevention. In this paper, we review the selection of participants and interventions, trial design, outcome assessments, and promising biomarkers in prevention trials, and summarize the lessons learned from completed trials and perspectives from ongoing trials in AD prevention. Selection of optimal participants and interventions, coupled with more refined outcomes and more efficient trial design, may have the capacity to deliver a new era of preventive discovery in this challenging area.

%B J Alzheimers Dis %V 50 %P 927-45 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836177?dopt=Abstract %R 10.3233/JAD-150826 %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 Prospective Memory Impairments in Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia: Clinical and Neural Correlates. %A Dermody, Nadene %A Hornberger, Michael %A Piguet, Olivier %A Hodges, John R %A Irish, Muireann %K Aged %K Alzheimer Disease %K Atrophy %K Brain %K Brain Mapping %K Female %K Frontotemporal Dementia %K Humans %K Magnetic Resonance Imaging %K Male %K Memory Disorders %K Memory, Episodic %K Middle Aged %K Neuropsychological Tests %X

BACKGROUND: Prospective memory (PM) refers to a future-oriented form of memory in which the individual must remember to execute an intended action either at a future point in time (Time-based) or in response to a specific event (Event-based). Lapses in PM are commonly exhibited in neurodegenerative disorders including Alzheimer's disease (AD) and frontotemporal dementia (FTD), however, the neurocognitive mechanisms driving these deficits remain unknown.

OBJECTIVE: To investigate the clinical and neural correlates of Time- and Event-based PM disruption in AD and the behavioral-variant FTD (bvFTD).

METHODS: Twelve AD, 12 bvFTD, and 12 healthy older Control participants completed a modified version of the Cambridge Prospective Memory test, which examines Time- and Event-based aspects of PM. All participants completed a standard neuropsychological assessment and underwent whole-brain structural MRI.

RESULTS: AD and bvFTD patients displayed striking impairments across Time- and Event-based PM relative to Controls, however, Time-based PM was disproportionately affected in the AD group. Episodic memory dysfunction and hippocampal atrophy were found to correlate strongly with PM integrity in both patient groups, however, dissociable neural substrates were also evident for PM performance across dementia syndromes.

CONCLUSION: Our study reveals the multifaceted nature of PM dysfunction in neurodegenerative disorders, and suggests common and dissociable neurocognitive mechanisms, which subtend these deficits in each patient group. Future studies of PM disturbance in dementia syndromes will be crucial for the development of successful interventions to improve functional independence in the patient's daily life.

%B J Alzheimers Dis %V 50 %P 425-41 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682697?dopt=Abstract %R 10.3233/JAD-150871 %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 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 Resting-State Cardiac Workload is Related to Both Increased Neocortical Aggregation of Amyloid-β and Relative Impairments in Spatial Working Memory in Pre-Clinical Alzheimer's Disease. %A Santos, Cláudia Yang %A Lim, Yen Ying %A Wu, Wen-Chih %A Machan, Jason Timothy %A Polynice, Shahena %A Schindler, Rachel %A Maruff, Paul %A Snyder, Peter Jeffrey %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Blood Pressure %K Disease Progression %K Female %K Heart Rate %K Humans %K Male %K Maze Learning %K Memory Disorders %K Middle Aged %K Neocortex %K Neuropsychological Tests %K Positron-Emission Tomography %K Protein Aggregation, Pathological %K Workload %X

We sought to determine whether there is any association between a cardiac workload marker, rate pressure product (RPP), working memory, and cortical amyloid-β (Aβ) burden in 63 cognitively normal midlife adults (Mage = 62.8 years; range = 55 to 75 years) at risk for Alzheimer's disease (AD). The results show a small-to-moderate relationship between increasing cardiac workload (at rest) and neocortical amyloidosis in individuals at the preclinical stage of AD. Moreover, increasing RPP was linearly related to increasing relative impairments on a spatial working memory task (R2 = 0.30), but only for those individuals with neuroimaging evidence suggestive of preclinical AD. These results support a relationship between the aggregation of Aβ protein plaques in the neocortex, increased cognitive impairment, and more inefficient myocardial oxygen use in the absence of significant metabolic demands.

%B J Alzheimers Dis %V 50 %P 127-31 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639961?dopt=Abstract %R 10.3233/JAD-150576 %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 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 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 The Role of Ethnicity in Alzheimer's Disease: Findings From The C-PATH Online Data Repository. %A Chen, Huei-Yang %A Panegyres, Peter K %K African Americans %K Age Factors %K Aged %K Alaska Natives %K Alzheimer Disease %K Apolipoproteins E %K Asian Continental Ancestry Group %K Clinical Trials as Topic %K Comorbidity %K Databases, Factual %K European Continental Ancestry Group %K Female %K Hispanic Americans %K Humans %K Indians, North American %K Internet %K Logistic Models %K Male %K Oceanic Ancestry Group %K Risk %K Sex Factors %X

BACKGROUND: Ethnic minorities seem to be at an increased risk of Alzheimer's disease (AD). However, little is known about ethnic differences and the risks of early onset AD (EOAD).

OBJECTIVE: Cognitive function changes over time and odds of EOAD by ethnicity were analyzed by the mixed model and the logistic regression.

METHODS: Information on demographics, self-reported co-morbidities, cognitive functions (MMSE and ADAS-COG), and ApoE genotypes were collected for 6,500 subjects with AD obtained from the placebo arm of clinical trials; this data was examined by ethnicities: Caucasian, Asian, African American, Hispanic, and other minorities--including Native Alaskans, Americans, and Hawaiians.

RESULTS: Of the total subjects, Caucasians accounted for 89.0% , followed by 4.7% Asians, 2.7% African Americans, 2.4% Hispanics, and 1.2% Native Americans, Alaskans, and Hawaiians. Age, gender, EOAD status, co-morbidities, family history of AD, and ApoE genotypes were significantly different by ethnicity. ApoE ɛ2 allele is possibly overrepresented in the Native Americans, Africans, Hawaiians, and African Americans. A significant interaction with time, ethnicity, and cognitive performance was found, indicating more cognitive deterioration in other minorities than Caucasians for mini-mental state (p <  0.01). After adjusting for co-morbidities and gender, the odds of EOAD among African Americans (OR: 1.6, 95% CI: 1.1-2.4) and Native Alaskans, Americans, and Hispanics (OR: 2.1, 95% CI: 1.2-3.5) were significantly higher, compared with Caucasians.

CONCLUSIONS: Ethnicity may impact AD through age of onset, co-morbidities, family history, ApoE gene status, and cognitive change over time. The greater odds of EOAD among African Americans, Alaskans, and Hawaiians suggest that some ethnicities may be at risk of AD at a younger age.

%B J Alzheimers Dis %V 51 %P 515-23 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890783?dopt=Abstract %R 10.3233/JAD-151089 %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 Shared Genetic Etiology between Type 2 Diabetes and Alzheimer's Disease Identified by Bioinformatics Analysis. %A Gao, Lei %A Cui, Zhen %A Shen, Liang %A Ji, Hong-Fang %K Alzheimer Disease %K Apolipoprotein C-I %K Computational Biology %K Databases, Factual %K Diabetes Mellitus, Type 2 %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Lipid Metabolism %K Male %K Polymorphism, Single Nucleotide %X

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two major health issues, and increasing evidence in recent years supports the close connection between these two diseases. The present study aimed to explore the shared genetic etiology underlying T2D and AD based on the available genome wide association studies (GWAS) data collected through August 2014. We performed bioinformatics analyses based on GWAS data of T2D and AD on single nucleotide polymorphisms (SNPs), gene, and pathway levels, respectively. Six SNPs (rs111789331, rs12721046, rs12721051, rs4420638, rs56131196, and rs66626994) were identified for the first time to be shared genetic factors between T2D and AD. Further functional enrichment analysis found lipid metabolism related pathways to be common between these two disorders. The findings may have important implications for future mechanistic and interventional studies for T2D and AD.

%B J Alzheimers Dis %V 50 %P 13-7 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639962?dopt=Abstract %R 10.3233/JAD-150580 %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 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 Spatial Navigation in Preclinical Alzheimer's Disease. %A Allison, Samantha L %A Fagan, Anne M %A Morris, John C %A Head, Denise %K Aged %K Alzheimer Disease %K Biomarkers %K Educational Status %K Female %K Humans %K Learning %K Male %K Neuropsychological Tests %K Prodromal Symptoms %K Psychomotor Performance %K ROC Curve %K Spatial Navigation %K tau Proteins %K User-Computer Interface %X

Although several previous studies have demonstrated navigational deficits in early-stage symptomatic Alzheimer's disease (AD), navigational abilities in preclinical AD have not been examined. The present investigation examined the effects of preclinical AD and early-stage symptomatic AD on spatial navigation performance. Performance on tasks of wayfinding and route learning in a virtual reality environment were examined. Comparisons were made across the following three groups: Clinically normal without preclinical AD (n = 42), clinically normal with preclinical AD (n = 13), and early-stage symptomatic AD (n = 16) groups. Preclinical AD was defined based on cerebrospinal fluid Aβ42 levels below 500 pg/ml. Preclinical AD was associated with deficits in the use of a wayfinding strategy, but not a route learning strategy. Moreover, post-hoc analyses indicated that wayfinding performance had moderate sensitivity and specificity. Results also confirmed early-stage symptomatic AD-related deficits in the use of both wayfinding and route learning strategies. The results of this study suggest that aspects of spatial navigation may be particularly sensitive at detecting the earliest cognitive deficits of AD.

%B J Alzheimers Dis %V 52 %P 77-90 %8 2016 02 09 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967209?dopt=Abstract %R 10.3233/JAD-150855 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Specific Features of Subjective Cognitive Decline Predict Faster Conversion to Mild Cognitive Impairment. %A Fernández-Blázquez, Miguel A %A Ávila-Villanueva, Marina %A Maestú, Fernando %A Medina, Miguel %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Cognitive Dysfunction %K Disease Progression %K Female %K Follow-Up Studies %K Genotyping Techniques %K Humans %K Kaplan-Meier Estimate %K Male %K Neuropsychological Tests %K Perception %K Prodromal Symptoms %K Prognosis %K Prospective Studies %K Time Factors %X

BACKGROUND: Alzheimer's disease (AD) is a silent disorder that needs the earliest possible intervention in order to reduce its high economic and social impact. It has been recently suggested that subjective cognitive decline (SCD) appears at preclinical stages many years before the onset of AD. Therefore, SCD could become an ideal target for early therapeutic intervention.

OBJECTIVE: The goal of this study was to evaluate the clinical significance of SCD on the conversion from a cognitively healthy stage to a mild cognitive impairment (MCI) in one-year follow-up.

METHODS: A total of 608 cognitively intact individuals from the Vallecas Project's cohort, a community-based prospective study to identify early markers of AD, were enrolled in this study. Participants were classified in three groups: i) No Complaints (NCg), ii) Subjects with complaints in one or more cognitive domains (SCDg), and iii) Subjects who, besides complaints, fulfilled the features of SCD Plus proposed by the International Working Group of SCD (SCD-Pg).

RESULTS: Individuals were followed up for a mean of 13.1 months (range 10.7-22.4). During this time, 41 volunteers developed MCI (6.7% of total sample). The conversion rate for SCD-Pg (18.9%) was significantly higher than SCDg (5.6%) and NCg (4.9%).

CONCLUSION: Specific features associated with SCD may help to identify individuals at high risk of fast conversion to MCI. These results highlight the importance of a close follow-up of subjects with SCD-P and include them in early intervention programs because of their increased risk for the development of MCI.

%B J Alzheimers Dis %V 52 %P 271-81 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060949?dopt=Abstract %R 10.3233/JAD-150956 %0 Journal Article %J J Alzheimers Dis %D 2016 %T T3D-959: A Multi-Faceted Disease Remedial Drug Candidate for the Treatment of Alzheimer's Disease. %A Tong, Ming %A Deochand, Chetram %A Didsbury, John %A de la Monte, Suzanne M %K Alzheimer Disease %K Analysis of Variance %K Animals %K Animals, Newborn %K Antibiotics, Antineoplastic %K Antipsychotic Agents %K Blood Glucose %K Body Weight %K Brain %K Choline O-Acetyltransferase %K Disease Models, Animal %K Dose-Response Relationship, Drug %K Glial Fibrillary Acidic Protein %K Glucosephosphate Dehydrogenase %K In Vitro Techniques %K Maze Learning %K Myelin Basic Protein %K Neurotoxicity Syndromes %K Organ Culture Techniques %K PPAR delta %K PPAR gamma %K Rats %K Rats, Long-Evans %K Spatial Learning %K Streptozocin %X

BACKGROUND: T3D-959, a dual PPAR-δ/PPAR γ nuclear receptor agonist and former diabetes drug candidate, has been repositioned as an Alzheimer's disease (AD)-modifying therapy.

OBJECTIVE: This study examines the effectiveness and mechanisms of T3D-959's therapeutic effects using in vivo and ex vivo rat models of sporadic AD.

METHODS: A sporadic AD model was generated by intracerebral (i.c.) administration of streptozotocin (STZ). Control and i.c. STZ treated rats were gavaged with saline or T3D-959 (0.3 to 3.0 mg/kg/day) for 28 days. Spatial learning and memory were evaluated using the Morris water maze test. Frontal lobe slice cultures generated 24 hours after i.c. STZ or vehicle were used to study early effects of T3D-959 (0.5-1.0 μM) on viability and molecular markers of AD.

RESULTS: T3D-959 significantly improved spatial learning and memory in i.c STZ-treated rats. Mechanistically, T3D-959 significantly improved culture viability and brain morphology, reduced levels of oxidative stress and Aβ, and normalized expression of phospho-tau, choline acetyltransferase, and myelin-associated glycoprotein. Protective effects occurred even at the lowest tested dose of T3D-959.

CONCLUSIONS: Pre-clinical proof of concept has been demonstrated that T3D-959 can improve multiple pathologies of AD resulting in significant improvements in cognitive function and molecular and biochemical indices of neurodegeneration. These results support the theses that (1) effective disease modification in AD can be achieved by targeting relevant nuclear receptors, and (2) treating AD as a metabolic disease has the potential to be disease remedial. A Phase 2a trial of T3D-959 in mild-to-moderate AD patients has been initiated (ClinicalTrials.gov identifier NCT02560753).

%B J Alzheimers Dis %V 51 %P 123-38 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836193?dopt=Abstract %R 10.3233/JAD-151013 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Targretin Improves Cognitive and Biological Markers in a Patient with Alzheimer's Disease. %A Pierrot, Nathalie %A Lhommel, Renaud %A Quenon, Lisa %A Hanseeuw, Bernard %A Dricot, Laurence %A Sindic, Christian %A Maloteaux, Jean-Marie %A Octavea, Jean-Noël %A Ivanoiu, Adrian %K Aged %K Alzheimer Disease %K Amyloidogenic Proteins %K Biomarkers %K Cognition Disorders %K Humans %K Male %K Mental Recall %K Neuropsychological Tests %K Receptors, Retinoic Acid %K tau Proteins %K Tetrahydronaphthalenes %X

We present the effects of Targretin® (bexarotene) on cognition and biomarkers in a patient with mild Alzheimer's disease (AD). Targretin® is a Retinoic X Receptor (RXR) agonist shown to improve synaptic and cognitive functions in animal models of AD by increasing neuronal cholesterol efflux. After 6 months of treatment with Targretin® 300 mg/day, memory improved by about 40% and the tau protein in the cerebrospinal fluid decreased by about 20% . No significant side effects were noticed. This observation in a single patient indicates that Targretin® may improve memory performance and biological markers at an early stage of AD.

%B J Alzheimers Dis %V 49 %P 271-6 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444777?dopt=Abstract %R 10.3233/JAD-150405 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Tau Accumulation in Primary Motor Cortex of Variant Alzheimer's Disease with Spastic Paraparesis. %A Lyoo, Chul Hyoung %A Cho, Hanna %A Choi, Jae Yong %A Hwang, Mi Song %A Hong, Sang Kyoon %A Kim, Yun Joong %A Ryu, Young Hoon %A Lee, Myung Sik %K Adult %K Aged %K Alzheimer Disease %K Aniline Compounds %K Brain Mapping %K Carbolines %K Female %K Humans %K Male %K Motor Cortex %K Mutation, Missense %K Paraparesis, Spastic %K Positron-Emission Tomography %K Presenilin-1 %K Radiopharmaceuticals %K Stilbenes %K tau Proteins %X

We studied topographic distribution of tau and amyloid-β in a patient with variant Alzheimer's disease with spastic paraparesis (VarAD) by comparing AD patients. The proband developed progressive memory impairment, dysarthria, and spastic paraparesis at age 23. Heterozygous missense mutation (L166P) was found in exon 6 of presenilin-1 gene. The proband showed prominently increased amyloid binding in striatum and cerebellum and asymmetrical tau binding in the primary sensorimotor cortex contralateral to the side more affected by spasticity. We suspect that upper motor neuron dysfunctions may be attributed to excessive abnormal tau accumulation rather than amyloid-β in the primary motor cortex.

%B J Alzheimers Dis %V 51 %P 671-5 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890779?dopt=Abstract %R 10.3233/JAD-151052 %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 Three-Dimensional Eigenbrain for the Detection of Subjects and Brain Regions Related with Alzheimer's Disease. %A Zhang, Yudong %A Wang, Shuihua %A Phillips, Preetha %A Yang, Jiquan %A Yuan, Ti-Fei %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Datasets as Topic %K Early Diagnosis %K Female %K Humans %K Image Interpretation, Computer-Assisted %K Imaging, Three-Dimensional %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Sensitivity and Specificity %K Young Adult %X

BACKGROUND: Considering that Alzheimer's disease (AD) is untreatable, early diagnosis of AD from the healthy elderly controls (HC) is pivotal. However, computer-aided diagnosis (CAD) systems were not widely used due to its poor performance.

OBJECTIVE: Inspired from the eigenface approach for face recognition problems, we proposed an eigenbrain to detect AD brains. Eigenface is only for 2D image processing and is not suitable for volumetric image processing since faces are usually obtained as 2D images.

METHODS: We extended the eigenbrain to 3D. This 3D eigenbrain (3D-EB) inherits the fundamental strategies in either eigenface or 2D eigenbrain (2D-EB). All the 3D brains were transferred to a feature space, which encoded the variation among known 3D brain images. The feature space was named as the 3D-EB, and defined as eigenvectors on the set of 3D brains. We compared four different classifiers: feed-forward neural network, support vector machine (SVM) with linear kernel, polynomial (Pol) kernel, and radial basis function kernel.

RESULTS: The 50x10-fold stratified cross validation experiments showed that the proposed 3D-EB is better than the 2D-EB. SVM with Pol kernel performed the best among all classifiers. Our "3D-EB + Pol-SVM" achieved an accuracy of 92.81% ± 1.99% , a sensitivity of 92.07% ± 2.48% , a specificity of 93.02% ± 2.22% , and a precision of 79.03% ± 2.37% . Based on the most important 3D-EB U1, we detected 34 brain regions related with AD. The results corresponded to recent literature.

CONCLUSIONS: We validated the effectiveness of the proposed 3D-EB by detecting subjects and brain regions related to AD.

%B J Alzheimers Dis %V 50 %P 1163-79 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836190?dopt=Abstract %R 10.3233/JAD-150988 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Timely Diagnosis for Alzheimer's Disease: A Literature Review on Benefits and Challenges. %A Dubois, Bruno %A Padovani, Alessandro %A Scheltens, Philip %A Rossi, Andrea %A Dell'Agnello, Grazia %K Alzheimer Disease %K Databases, Bibliographic %K Humans %K Time Factors %X

BACKGROUND: Timely diagnosis of Alzheimer's disease (AD) refers to a diagnosis at the stage when patients come to the attention of clinicians because of concerns about changes in cognition, behavior, or functioning and can be still free of dementia and functionally independent.

OBJECTIVES: To comprehensively review existing scientific evidence on the benefits and potential challenges of making a timely diagnosis of AD.

METHODS: Relevant studies were identified by searching electronic databases (Medline, Embase) and bibliographies for studies published in English between 1 January 2000 and 2 June 2014 on the consequences of a timely diagnosis of AD.

RESULTS: Nine studies were identified that investigated the consequences of diagnosing AD at the initial stages; none were specifically focused on prodromal AD. A timely diagnosis potentially offers the opportunities of early intervention, implementation of coordinated care plans, better management of symptoms, patient safety, cost savings, and postponement of institutionalization. Barriers to making a timely diagnosis include stigma, suicide risk, lack of training, diagnostic uncertainty, shortage of specialized diagnostic services, and the reluctance of healthcare providers to make a diagnosis when no effective disease-modifying options are available.

CONCLUSIONS: Despite its potential benefits, few published studies have explored the advantages or risks of a timely diagnosis of AD. In light of the cultural shift toward diagnosis at the initial stage of the disease continuum, when the patient does not yet have dementia, more investigations are needed to evaluate the benefits and address the barriers that may impede making a timely AD diagnosis.

%B J Alzheimers Dis %V 49 %P 617-31 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484931?dopt=Abstract %R 10.3233/JAD-150692 %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 Two Phase 2 Multiple Ascending-Dose Studies of Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate Alzheimer's Disease. %A Pasquier, Florence %A Sadowsky, Carl %A Holstein, Ann %A Leterme, Ghislaine Le Prince %A Peng, Yahong %A Jackson, Nicholas %A Fox, Nick C %A Ketter, Nzeera %A Liu, Enchi %A Ryan, J Michael %K Adjuvants, Immunologic %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Antipsychotic Agents %K Dose-Response Relationship, Drug %K Female %K Follow-Up Studies %K Humans %K Interferon-gamma %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Recombinant Fusion Proteins %K Saponins %K Single-Blind Method %K Treatment Outcome %X

Vanutide cridificar (ACC-001), an immunotherapeutic vaccine, is a potentially disease-modifying therapy that aims to reduce brain amyloid-β (Aβ) plaques in patients with Alzheimer's disease (AD). ACC-001 was evaluated in two phase 2a, multicenter, randomized, third party-unblinded, placebo-controlled, multiple ascending-dose studies of ACC-001 (3μg, 10μg, 30μg) with and without QS-21 adjuvant that enrolled patients with mild-to-moderate AD (n = 245). Patients were treated with up to five doses of study vaccine or placebo and followed for safety and tolerability (primary objective) and anti-Aβ IgG immunogenicity (secondary objective) up to 12 months after the last vaccination. Exploratory assessments included cognitive/functional measures, brain magnetic resonance imaging (MRI) volumetry, and pharmacodynamic markers in plasma and cerebrospinal fluid (CSF). The most frequent treatment-emergent adverse events (≥10%) were local injection reactions and headache. Amyloid-related imaging abnormalities with vasogenic edema occurred in two (0.8%) patients (ACC-001 30μg + QS-21; ACC-001 10μg). ACC-001 + QS-21 elicited consistently higher peak and sustained anti-Aβ IgG titers compared with ACC-001 alone. Plasma Aβx-40 was significantly higher in all ACC-001 + QS-21 groups versus placebo (weeks 16-56), with no evidence of dose response. Exploratory cognitive evaluations, volumetric brain MRI, and CSF biomarkers did not show differences or trends between treatment groups and placebo. ACC-001 with or without QS-21 adjuvant has an acceptable safety profile in patients with mild-to-moderate AD.

%B J Alzheimers Dis %V 51 %P 1131-43 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967206?dopt=Abstract %R 10.3233/JAD-150376 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Unraveling Alzheimer's: Making Sense of the Relationship between Diabetes and Alzheimer's Disease1. %A Schilling, Melissa A %K Alzheimer Disease %K Amyloid beta-Peptides %K Amylose %K Diabetes Mellitus %K Humans %K Insulin %K Insulysin %X

Numerous studies have documented a strong association between diabetes and Alzheimer's disease (AD). The nature of the relationship, however, has remained a puzzle, in part because of seemingly incongruent findings. For example, some studies have concluded that insulin deficiency is primarily at fault, suggesting that intranasal insulin or inhibiting the insulin-degrading enzyme (IDE) could be beneficial. Other research has concluded that hyperinsulinemia is to blame, which implies that intranasal insulin or the inhibition of IDE would exacerbate the disease. Such antithetical conclusions pose a serious obstacle to making progress on treatments. However, careful integration of multiple strands of research, with attention to the methods used in different studies, makes it possible to disentangle the research on AD. This integration suggests that there is an important relationship between insulin, IDE, and AD that yields multiple pathways to AD depending on the where deficiency or excess in the cycle occurs. I review evidence for each of these pathways here. The results suggest that avoiding excess insulin, and supporting robust IDE levels, could be important ways of preventing and lessening the impact of AD. I also describe what further tests need to be conducted to verify the arguments made in the paper, and their implications for treating AD.

%B J Alzheimers Dis %V 51 %P 961-77 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967215?dopt=Abstract %R 10.3233/JAD-150980 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Unstable Body Mass Index and Progression to Probable Alzheimer's Disease Dementia in Patients with Amnestic Mild Cognitive Impairment. %A Ye, Byoung Seok %A Jang, Eun Young %A Kim, Seong Yoon %A Kim, Eun-Joo %A Park, Sun Ah %A Lee, Yunhwan %A Hong, Chang Hyung %A Choi, Seong Hye %A Yoon, Bora %A Yoon, Soo Jin %A Na, Hae Ri %A Lee, Jae-Hong %A Jeong, Jee H %A Kim, Hee Jin %A Na, Duk L %A Seo, Sang Won %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Body Mass Index %K Body Weight %K Cognitive Dysfunction %K Dementia %K Disease Progression %K Female %K Humans %K Kaplan-Meier Estimate %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Registries %X

BACKGROUND AND OBJECTIVE: We investigated the influence of body mass index (BMI) status at baseline and changes in BMI over a follow-up period on the development of dementia in amnestic mild cognitive impairment (aMCI) patients.

METHODS: The longitudinal data of 747 aMCI patients were used to investigate the relationships among baseline BMI status, subsequent changes in BMI (median follow-up duration: 1.6 years, interquartile range: 1.0-2.3 years), and risk of progression to probable Alzheimer's disease dementia (pADD). The aMCI patients were classified into underweight, normal weight, overweight, and obese subgroups, and further categorized into increased BMI, stable BMI, and decreased BMI subgroups during follow-up using a 4% mean annual change in BMI cut-off value.

RESULTS: Compared to the normal weight group, the underweight group had a higher risk of pADD (hazard ratio [HR]: 1.89, 95% confidence interval [CI]: 1.07-3.37) while the obese group had a lower risk (HR: 0.70, 95% CI: 0.49-0.999). After controllingfor baseline BMI status, the decreased BMI (HR: 2.29, 95% CI: 1.41-3.72) and increased BMI (HR: 3.96, 95% CI: 2.62-6.00) groups were at increased risk of progression to pADD.

CONCLUSIONS: Our findings suggested that underweight at baseline was associated with a higher risk of progression to pADD, while obesity at baseline predicted a lower risk. Furthermore, significant changes in BMI during the follow-up period reflected an increased risk of progression to pADD, regardless of BMI status at baseline.

%B J Alzheimers Dis %V 49 %P 483-91 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484923?dopt=Abstract %R 10.3233/JAD-150556 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Usefulness of an Integrated Analysis of Different Memory Tasks to Predict the Progression from Mild Cognitive Impairment to Alzheimer's Disease: The Episodic Memory Score (EMS). %A Marra, Camillo %A Gainotti, Guido %A Fadda, Lucia %A Perri, Roberta %A Lacidogna, Giordano %A Scaricamazza, Eugenia %A Piccininni, Chiara %A Quaranta, Davide %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Disease Progression %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Male %K Memory, Episodic %K Mental Recall %K Neuropsychological Tests %K ROC Curve %X

Taking into the account both the severity and the consistency of performances obtained on memory tests by patients with amnestic mild cognitive impairment (aMCI) could improve the power to predict their progression to Alzheimer's disease. For this purpose, we constructed the Episodic Memory Score (EMS), which is obtained by subdividing in tertiles performances obtained at baseline in verbal (RAVLT) and visual episodic memory (Rey-Osterrieth Figure-delayed recall) and giving a score ranging from 1 (worst result) to 3 (best result) to results falling within each tertile. The EMS was computed for each patient by summing the tertile score obtained on each memory task, so that the total score ranged from 4 (worst performance) to 12 (best performance). The aMCI sample consisted of 198 subjects who completed the two-year follow-up, at the end of which 55 subjects had converted to dementia. The mean EMS score obtained by aMCI converters was significantly lower than that of aMCI-stable patients. In detecting conversion to dementia, the comparison between EMS and individual memory scores obtained at baseline was made by computing ROC curves, and estimating the respective area under the curve (AUC). The EMS had a larger AUC than the individual memory scores. At baseline aMCI converters performed worse than non-converters not only on memory tasks, but also on executive functions tasks. However, in a multiple variables logistic regression analysis in which all scores showing statistically significant differences between aMCI-converters and aMCI-stable were entered, the EMS was the only reliable predictor of progression from aMCI to dementia.

%B J Alzheimers Dis %V 50 %P 61-70 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639965?dopt=Abstract %R 10.3233/JAD-150613 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Validation of the Spanish version of the Baylor Profound Mental Status Examination. %A Salmerón, Sergio %A Huedo, Isabel %A López-Utiel, Melisa %A Soler-Moratalla, Isabel %A Flores-Ruano, Teresa %A Fernández-Sánchez, Miguel %A Noguerón, Alicia %A Doody, Rachelle S %A Abizanda, Pedro %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition %K Cognition Disorders %K Female %K Humans %K Language %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Reproducibility of Results %K Severity of Illness Index %K Spain %X

BACKGROUND: There are no short valid instruments to evaluate cognitive status in severe Alzheimer's disease (AD) patients in the Spanish language.

OBJECTIVE: To validate the Spanish version of the Baylor Profound Mental Status Examination (BPMSE-Sp).

METHODS: The Baylor Profound Mental Status Examination (BPMSE) was translated to Spanish and back translated. Validation was conducted in 100 patients with severe probable AD with a Mini-Mental State Examination (MMSE) <12. We assessed internal consistency (Cronbach's alpha), concurrent validity (Pearson's correlations) with the MMSE, Severe Impairment Battery (SIB), Neuropsychiatric Inventory Short Form (NPI-Q) and the Functional Assessment Staging and reliability.

RESULTS: The mean age of patients was 84.9; 74% were female; 64% were institutionalized. The mean MMSE was 5.6; the mean BPMSE-Sp was 13.6; the mean BPMSE-Sp behavior was 1.2; the mean SIB was 42.2; and the mean NPI-Q was 4.7. BPMSE-Sp presented good internal consistency (Cronbach α= 0.84). There were significant correlations between the BPMSE-Sp and MMSE (r = 0.86, p <  0.001), and between the BPMSE-Sp and SIB (r = 0.92, p <  0.001). Inter-rater and test-retest reliability were in both cases excellent, ranging between 0.96 and 0.99 (p <  0.001). BPMSE-Sp had fewer floor and ceiling effects than the MMSE.

CONCLUSIONS: The BPMSE-Sp is a valid tool for use in daily practice and research in the evaluation of cognitive function of patients with severe AD.

%B J Alzheimers Dis %V 49 %P 73-8 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444781?dopt=Abstract %R 10.3233/JAD-150422 %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 Volumetric and shape analysis of the thalamus and striatum in amnestic mild cognitive impairment. %A Leh, Sandra E %A Kälin, Andrea M %A Schroeder, Clemens %A Park, Min Tae M %A Chakravarty, M Mallar %A Freund, Patrick %A Gietl, Anton F %A Riese, Florian %A Kollias, Spyros %A Hock, Christoph %A Michels, Lars %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid %K Biomarkers %K Case-Control Studies %K Cognitive Dysfunction %K Corpus Striatum %K Female %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %K Thalamus %X

Alterations in brain structures, including progressive neurodegeneration, are a hallmark in patients with Alzheimer's disease (AD). However, pathological mechanisms, such as the accumulation of amyloid and the proliferation of tau, are thought to begin years, even decades, before the initial clinical manifestations of AD. In this study, we compare the brain anatomy of amnestic mild cognitive impairment patients (aMCI, n = 16) to healthy subjects (CS, n = 22) using cortical thickness, subcortical volume, and shape analysis, which we believe to be complimentary to volumetric measures. We were able to replicate "classical" cortical thickness alterations in aMCI in the hippocampus, amygdala, putamen, insula, and inferior temporal regions. Additionally, aMCI showed significant thalamic and striatal shape differences. We observed higher global amyloid deposition in aMCI, a significant correlation between striatal displacement and global amyloid, and an inverse correlation between executive function and right-hemispheric thalamic displacement. In contrast, no volumetric differences were detected in thalamic, striatal, and hippocampal regions. Our results provide new evidence for early subcortical neuroanatomical changes in patients with aMCI, which are linked to cognitive abilities and amyloid deposition. Hence, shape analysis may aid in the identification of structural biomarkers for identifying individuals at highest risk of conversion to AD.

%B J Alzheimers Dis %V 49 %P 237-49 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444755?dopt=Abstract %R 10.3233/JAD-150080 %0 Journal Article %J J Alzheimers Dis %D 2016 %T What are the Most Frequently Impaired Markers of Neurodegeneration in ADNI Subjects? %A Andriuta, Daniela %A Moullart, Véronique %A Schraen, Susanna %A Devendeville, Agnes %A Meyer, Marc-Etienne %A Godefroy, Olivier %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Brain %K Cognitive Dysfunction %K Databases, Factual %K Female %K Fluorodeoxyglucose F18 %K Humans %K Male %K Peptide Fragments %K Phosphorylation %K Positron-Emission Tomography %K Radiopharmaceuticals %K tau Proteins %X

The aim of this study was to examine the relationship between cerebrospinal fluid (CSF) levels of biomarkers for Alzheimer's disease (AD) (Aβ1-42, t-tau, and p-tau) and 18Fluorodeoxyglucose positron emission tomography (FDG-PET) hypometabolism in subjects from the Alzheimer's Disease Neuroimaging Initiative, and specifically to determine which index of neurodegeneration was most frequently affected. The secondary objective was to determine the most frequently hypometabolic region in patients with a CSF AD signature (abnormal Aβ1-42 and abnormal p-tau). We included the 372 subjects (85 normal subjects, 212 patients with mild cognitive impairment, and 75 patients with AD) with a CSF biomarker dosage (Aβ1-42, t-tau, and p-tau) and brain FDG-PET. The relationship between FDG-PET metabolism (in five regions of interest (ROI) known to be damaged in AD) and CSF t-tau and p-tau levels was studied as a function of CSF Aβ1-42 status. FDG-PET hypometabolism and CSF t-tau and p-tau levels were correlated only in patients with an abnormal CSF Aβ1-42 level (t-tau: R2 = 0.044, p = 0.001; p-tau: R2 = 0.02, p = 0.03). In the latter patients, CSF p-tau was the most frequently (p = 0.0001) abnormal neurodegeneration marker (p-tau: 92.8%; FDG-PET: 56.5%; CSF t-tau: 59.1%). Within the five ROI of FDG PET, the angular gyrus metabolism (R2 = 0.149; p = 0.0001) was selected as the most tightly associated with CSF AD signature. The relation between CSF markers of neurodegeneration (p-tau and t-tau) and brain hypometabolism (in FDG-PET) is conditioned by presence of amyloid abnormality. This finding supports the current physiopathological model of AD. P-tau is the most frequently impaired biomarker. Using FDG PET angular gyrus hypometabolism is the most sensitive to CSF-biomarker-defined AD.

%B J Alzheimers Dis %V 51 %P 793-800 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923012?dopt=Abstract %R 10.3233/JAD-150829 %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 2016 %T White Matter Changes are Associated with Ventricular Expansion in Aging, Mild Cognitive Impairment, and Alzheimer's Disease. %A Coutu, Jean-Philippe %A Goldblatt, Alison %A Rosas, H Diana %A Salat, David H %K Aged %K Aging %K Alzheimer Disease %K Cognitive Dysfunction %K Diffusion Tensor Imaging %K Factor Analysis, Statistical %K Female %K Hippocampus %K Humans %K Imaging, Three-Dimensional %K Male %K Mental Status Schedule %K Neuropsychological Tests %K White Matter %X

White matter lesions are highly prevalent in individuals with Alzheimer's disease (AD). Although these lesions are presumed to be of vascular origin and linked to small vessel disease in older adults, little information exists about their relationship to markers of classical AD neurodegeneration. Thus, we examined the link between these white matter changes (WMC) segmented on T1-weighted MRI and imaging markers presumed to be altered due to primary AD neurodegenerative processes. Tissue microstructure of WMC was quantified using diffusion tensor imaging and the relationship of WMC properties and volume to neuroimaging markers was examined in 219 cognitively healthy older adults and individuals with mild cognitive impairment and AD using data from the Alzheimer's Disease Neuroimaging Initiative. No significant group differences in WMC properties were found. However, there were strong associations between diffusivity of WMC and ventricular volume, volume of WMC and total WM volume. In comparison, group differences in parahippocampal white matter microstructure were found for all diffusion metrics and were largely explained by hippocampal volume. Factor analysis on neuroimaging markers suggested two independent sets of covarying degenerative changes, with potentially age- and vascular-mediated tissue damage contributing to one factor and classical neurodegenerative changes associated with AD contributing to a second factor. These data demonstrate two potentially distinct classes of degenerative change in AD, with one factor strongly linked to aging, ventricular expansion, and both volume and tissue properties of white matter lesions, while the other factor related to classical patterns of cortical and hippocampal neurodegeneration in AD.

%B J Alzheimers Dis %V 49 %P 329-42 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444767?dopt=Abstract %R 10.3233/JAD-150306 %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 N Engl J Med %D 2014 %T Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. %A Doody, Rachelle S %A Thomas, Ronald G %A Farlow, Martin %A Iwatsubo, Takeshi %A Vellas, Bruno %A Joffe, Steven %A Kieburtz, Karl %A Raman, Rema %A Sun, Xiaoying %A Aisen, Paul S %A Siemers, Eric %A Liu-Seifert, Hong %A Mohs, Richard %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Antibodies, Monoclonal, Humanized %K Apolipoproteins E %K Biomarkers %K Cognition %K Double-Blind Method %K Female %K Humans %K Intention to Treat Analysis %K Male %K Neuropsychological Tests %K Severity of Illness Index %K tau Proteins %K Treatment Failure %X

BACKGROUND: Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain.

METHODS: In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the change in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment), in patients with mild Alzheimer's disease.

RESULTS: Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was -0.8 points for the ADAS-cog11 score (95% confidence interval [CI], -2.1 to 0.5; P=0.24) and -0.4 points for the ADCS-ADL score (95% CI, -2.3 to 1.4; P=0.64) in EXPEDITION 1 and -1.3 points (95% CI, -2.5 to 0.3; P=0.06) and 1.6 points (95% CI, -0.2 to 3.3; P=0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were -1.7 points in patients with mild Alzheimer's disease (95% CI, -3.5 to 0.1; P=0.06) and -1.5 in patients with moderate Alzheimer's disease (95% CI, -4.1 to 1.1; P=0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P=0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P=0.49).

CONCLUSIONS: Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. (Funded by Eli Lilly; EXPEDITION 1 and 2 ClinicalTrials.gov numbers, NCT00905372 and NCT00904683.).

%B N Engl J Med %V 370 %P 311-21 %8 2014 Jan 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24450890?dopt=Abstract %R 10.1056/NEJMoa1312889 %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 Nature %D 2014 %T A three-dimensional human neural cell culture model of Alzheimer's disease. %A Choi, Se Hoon %A Kim, Young Hye %A Hebisch, Matthias %A Sliwinski, Christopher %A Lee, Seungkyu %A D'Avanzo, Carla %A Chen, Hechao %A Hooli, Basavaraj %A Asselin, Caroline %A Muffat, Julien %A Klee, Justin B %A Zhang, Can %A Wainger, Brian J %A Peitz, Michael %A Kovacs, Dora M %A Woolf, Clifford J %A Wagner, Steven L %A Tanzi, Rudolph E %A Kim, Doo Yeon %K Alzheimer Disease %K Amyloid beta-Peptides %K Cell Culture Techniques %K Cell Differentiation %K Drug Evaluation, Preclinical %K Extracellular Space %K Glycogen Synthase Kinase 3 %K Humans %K Microtubule-Associated Proteins %K Models, Biological %K Neural Stem Cells %K Neurites %K Phosphorylation %K Presenilin-1 %K Protein Aggregation, Pathological %K Reproducibility of Results %K tau Proteins %X

Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloid-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer's disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders.

%B Nature %V 515 %P 274-8 %8 2014 Nov 13 %G eng %N 7526 %1 http://www.ncbi.nlm.nih.gov/pubmed/25307057?dopt=Abstract %R 10.1038/nature13800 %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 Neuron %D 2013 %T Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. %A Griciuc, Ana %A Serrano-Pozo, Alberto %A Parrado, Antonio R %A Lesinski, Andrea N %A Asselin, Caroline N %A Mullin, Kristina %A Hooli, Basavaraj %A Choi, Se Hoon %A Hyman, Bradley T %A Tanzi, Rudolph E %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Case-Control Studies %K Disease Models, Animal %K Genetic Predisposition to Disease %K Humans %K Matched-Pair Analysis %K Mice %K Mice, Inbred C57BL %K Mice, Knockout %K Mice, Transgenic %K Microglia %K Polymorphism, Single Nucleotide %K Reference Values %K RNA, Messenger %K Sialic Acid Binding Ig-like Lectin 3 %X

The transmembrane protein CD33 is a sialic acid-binding immunoglobulin-like lectin that regulates innate immunity but has no known functions in the brain. We have previously shown that the CD33 gene is a risk factor for Alzheimer's disease (AD). Here, we observed increased expression of CD33 in microglial cells in AD brain. The minor allele of the CD33 SNP rs3865444, which confers protection against AD, was associated with reductions in both CD33 expression and insoluble amyloid beta 42 (Aβ42) levels in AD brain. Furthermore, the numbers of CD33-immunoreactive microglia were positively correlated with insoluble Aβ42 levels and plaque burden in AD brain. CD33 inhibited uptake and clearance of Aβ42 in microglial cell cultures. Finally, brain levels of insoluble Aβ42 as well as amyloid plaque burden were markedly reduced in APP(Swe)/PS1(ΔE9)/CD33(-/-) mice. Therefore, CD33 inactivation mitigates Aβ pathology and CD33 inhibition could represent a novel therapy for AD.

%B Neuron %V 78 %P 631-43 %8 2013 May 22 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/23623698?dopt=Abstract %R 10.1016/j.neuron.2013.04.014 %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 Cell Stem Cell %D 2013 %T Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. %A Kondo, Takayuki %A Asai, Masashi %A Tsukita, Kayoko %A Kutoku, Yumiko %A Ohsawa, Yutaka %A Sunada, Yoshihide %A Imamura, Keiko %A Egawa, Naohiro %A Yahata, Naoki %A Okita, Keisuke %A Takahashi, Kazutoshi %A Asaka, Isao %A Aoi, Takashi %A Watanabe, Akira %A Watanabe, Kaori %A Kadoya, Chie %A Nakano, Rie %A Watanabe, Dai %A Maruyama, Kei %A Hori, Osamu %A Hibino, Satoshi %A Choshi, Tominari %A Nakahata, Tatsutoshi %A Hioki, Hiroyuki %A Kaneko, Takeshi %A Naitoh, Motoko %A Yoshikawa, Katsuhiro %A Yamawaki, Satoko %A Suzuki, Shigehiko %A Hata, Ryuji %A Ueno, Shu-Ichi %A Seki, Tsuneyoshi %A Kobayashi, Kazuhiro %A Toda, Tatsushi %A Murakami, Kazuma %A Irie, Kazuhiro %A Klein, William L %A Mori, Hiroshi %A Asada, Takashi %A Takahashi, Ryosuke %A Iwata, Nobuhisa %A Yamanaka, Shinya %A Inoue, Haruhisa %K Alzheimer Disease %K Amyloid beta-Peptides %K Cell Differentiation %K Cerebral Cortex %K Docosahexaenoic Acids %K Humans %K Induced Pluripotent Stem Cells %K Intracellular Space %K Models, Biological %K Mutant Proteins %K Neurons %K Oxidative Stress %K Phenotype %K Protein Structure, Quaternary %X

Oligomeric forms of amyloid-β peptide (Aβ) are thought to play a pivotal role in the pathogenesis of Alzheimer's disease (AD), but the mechanism involved is still unclear. Here, we generated induced pluripotent stem cells (iPSCs) from familial and sporadic AD patients and differentiated them into neural cells. Aβ oligomers accumulated in iPSC-derived neurons and astrocytes in cells from patients with a familial amyloid precursor protein (APP)-E693Δ mutation and sporadic AD, leading to endoplasmic reticulum (ER) and oxidative stress. The accumulated Aβ oligomers were not proteolytically resistant, and docosahexaenoic acid (DHA) treatment alleviated the stress responses in the AD neural cells. Differential manifestation of ER stress and DHA responsiveness may help explain variable clinical results obtained with the use of DHA treatment and suggests that DHA may in fact be effective for a subset of patients. It also illustrates how patient-specific iPSCs can be useful for analyzing AD pathogenesis and evaluating drugs.

%B Cell Stem Cell %V 12 %P 487-96 %8 2013 Apr 4 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/23434393?dopt=Abstract %R 10.1016/j.stem.2013.01.009 %0 Journal Article %J Lancet Neurol %D 2013 %T Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. %A Jack, Clifford R %A Knopman, David S %A Jagust, William J %A Petersen, Ronald C %A Weiner, Michael W %A Aisen, Paul S %A Shaw, Leslie M %A Vemuri, Prashanthi %A Wiste, Heather J %A Weigand, Stephen D %A Lesnick, Timothy G %A Pankratz, Vernon S %A Donohue, Michael C %A Trojanowski, John Q %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognition Disorders %K Humans %K Models, Biological %K Nonlinear Dynamics %K tau Proteins %X

In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimer's disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.

%B Lancet Neurol %V 12 %P 207-16 %8 2013 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23332364?dopt=Abstract %R 10.1016/S1474-4422(12)70291-0 %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 Lancet Neurol %D 2012 %T Cognitive reserve in ageing and Alzheimer's disease. %A Stern, Yaakov %K Aging %K Alzheimer Disease %K Animals %K Cognitive Reserve %K Humans %X

The concept of cognitive reserve provides an explanation for differences between individuals in susceptibility to age-related brain changes or pathology related to Alzheimer's disease, whereby some people can tolerate more of these changes than others and maintain function. Epidemiological studies suggest that lifelong experiences, including educational and occupational attainment, and leisure activities in later life, can increase this reserve. For example, the risk of developing Alzheimer's disease is reduced in individuals with higher educational or occupational attainment. Reserve can conveniently be divided into two types: brain reserve, which refers to differences in the brain structure that may increase tolerance to pathology, and cognitive reserve, which refers to differences between individuals in how tasks are performed that might enable some people to be more resilient to brain changes than others. Greater understanding of the concept of cognitive reserve could lead to interventions to slow cognitive ageing or reduce the risk of dementia.

%B Lancet Neurol %V 11 %P 1006-12 %8 2012 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/23079557?dopt=Abstract %R 10.1016/S1474-4422(12)70191-6 %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 Nature %D 2012 %T An epigenetic blockade of cognitive functions in the neurodegenerating brain. %A Gräff, Johannes %A Rei, Damien %A Guan, Ji-Song %A Wang, Wen-Yuan %A Seo, Jinsoo %A Hennig, Krista M %A Nieland, Thomas J F %A Fass, Daniel M %A Kao, Patricia F %A Kahn, Martin %A Su, Susan C %A Samiei, Alireza %A Joseph, Nadine %A Haggarty, Stephen J %A Delalle, Ivana %A Tsai, Li-Huei %K Acetylation %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Disease Models, Animal %K Epigenesis, Genetic %K Gene Expression Regulation %K Gene Knockdown Techniques %K Hippocampus %K Histone Deacetylase 2 %K Histones %K Humans %K Hydrogen Peroxide %K Memory Disorders %K Mice %K Neurodegenerative Diseases %K Neuronal Plasticity %K Peptide Fragments %K Phosphorylation %K Promoter Regions, Genetic %K Receptors, Glucocorticoid %K RNA Polymerase II %X

Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer's disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer's-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer's disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.

%B Nature %V 483 %P 222-6 %8 2012 Mar 8 %G eng %N 7388 %1 http://www.ncbi.nlm.nih.gov/pubmed/22388814?dopt=Abstract %R 10.1038/nature10849 %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 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 Neuron %D 2012 %T Propagation of tau pathology in a model of early Alzheimer's disease. %A de Calignon, Alix %A Polydoro, Manuela %A Suárez-Calvet, Marc %A William, Christopher %A Adamowicz, David H %A Kopeikina, Kathy J %A Pitstick, Rose %A Sahara, Naruhiko %A Ashe, Karen H %A Carlson, George A %A Spires-Jones, Tara L %A Hyman, Bradley T %K Age Factors %K Alzheimer Disease %K Animals %K Disease Models, Animal %K Disease Progression %K Entorhinal Cortex %K Epitopes %K Gene Expression Regulation %K Glial Fibrillary Acidic Protein %K Gliosis %K Hippocampus %K Humans %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mutation %K Nerve Degeneration %K Neurofibrillary Tangles %K Neurons %K RNA, Messenger %K Serine %K tau Proteins %K Tauopathies %X

Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer's disease evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and coaggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration.

%B Neuron %V 73 %P 685-97 %8 2012 Feb 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22365544?dopt=Abstract %R 10.1016/j.neuron.2011.11.033 %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 Neuron %D 2011 %T Anti-aβ therapeutics in Alzheimer's disease: the need for a paradigm shift. %A Golde, Todd E %A Schneider, Lon S %A Koo, Edward H %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Biomarkers %K Clinical Trials as Topic %K Disease Progression %K Health Services Needs and Demand %K Humans %K Translational Medical Research %X

Most current Alzheimer's disease (AD) therapies in advanced phases of development target amyloid β-peptide (Aβ) production, aggregation, or accumulation. Translational models suggest that anti-Aβ therapies may be highly effective if tested as agents to prevent or delay development of the disease or as therapies for asymptomatic patients with very early signs of AD pathology. However, anti-Aβ therapeutics are currently being tested in symptomatic patients where they are likely to be much less effective or ineffective. The lack of alignment between human clinical studies and preclinical studies, together with predictions about optimal trial design based on our understanding of the initiating role of Aβ aggregates in AD, has created a treatment versus prevention dilemma. In this perspective, we discuss why it is imperative to resolve this dilemma and suggest ways for moving forward in the hopes of enhancing the development of truly effective AD therapeutics.

%B Neuron %V 69 %P 203-13 %8 2011 Jan 27 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/21262461?dopt=Abstract %R 10.1016/j.neuron.2011.01.002 %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 Alzheimers Dement %D 2011 %T The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. %A McKhann, Guy M %A Knopman, David S %A Chertkow, Howard %A Hyman, Bradley T %A Jack, Clifford R %A Kawas, Claudia H %A Klunk, William E %A Koroshetz, Walter J %A Manly, Jennifer J %A Mayeux, Richard %A Mohs, Richard C %A Morris, John C %A Rossor, Martin N %A Scheltens, Philip %A Carrillo, Maria C %A Thies, Bill %A Weintraub, Sandra %A Phelps, Creighton H %K Alzheimer Disease %K Biomarkers %K Diagnosis, Differential %K Diagnostic Imaging %K Disease Progression %K Humans %K National Institute on Aging (U.S.) %K Practice Guidelines as Topic %K Societies, Medical %K United States %X

The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

%B Alzheimers Dement %V 7 %P 263-9 %8 2011 May %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21514250?dopt=Abstract %R 10.1016/j.jalz.2011.03.005 %0 Journal Article %J Alzheimers Dement %D 2011 %T The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. %A Albert, Marilyn S %A DeKosky, Steven T %A Dickson, Dennis %A Dubois, Bruno %A Feldman, Howard H %A Fox, Nick C %A Gamst, Anthony %A Holtzman, David M %A Jagust, William J %A Petersen, Ronald C %A Snyder, Peter J %A Carrillo, Maria C %A Thies, Bill %A Phelps, Creighton H %K Alzheimer Disease %K Biomarkers %K Cognition Disorders %K Diagnosis, Differential %K Diagnostic Imaging %K Humans %K National Institute on Aging (U.S.) %K Practice Guidelines as Topic %K Societies, Medical %K United States %X

The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of developing criteria for the symptomatic predementia phase of Alzheimer's disease (AD), referred to in this article as mild cognitive impairment due to AD. The workgroup developed the following two sets of criteria: (1) core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or cerebrospinal fluid analysis, and (2) research criteria that could be used in clinical research settings, including clinical trials. The second set of criteria incorporate the use of biomarkers based on imaging and cerebrospinal fluid measures. The final set of criteria for mild cognitive impairment due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings. Considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for use in community settings.

%B Alzheimers Dement %V 7 %P 270-9 %8 2011 May %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21514249?dopt=Abstract %R 10.1016/j.jalz.2011.03.008 %0 Journal Article %J Cell %D 2011 %T Directed conversion of Alzheimer's disease patient skin fibroblasts into functional neurons. %A Qiang, Liang %A Fujita, Ryousuke %A Yamashita, Toru %A Angulo, Sergio %A Rhinn, Herve %A Rhee, David %A Doege, Claudia %A Chau, Lily %A Aubry, Laetitia %A Vanti, William B %A Moreno, Herman %A Abeliovich, Asa %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Cell Transdifferentiation %K Cells, Cultured %K Fibroblasts %K Humans %K Neurons %K Presenilin-1 %K Presenilin-2 %K Regenerative Medicine %K Skin %X

Directed conversion of mature human cells, as from fibroblasts to neurons, is of potential clinical utility for neurological disease modeling as well as cell therapeutics. Here, we describe the efficient generation of human-induced neuronal (hiN) cells from adult skin fibroblasts of unaffected individuals and Alzheimer's patients, using virally transduced transcription regulators and extrinsic support factors. hiN cells from unaffected individuals display morphological, electrophysiological, and gene expression profiles that typify glutamatergic forebrain neurons and are competent to integrate functionally into the rodent CNS. hiN cells from familial Alzheimer disease (FAD) patients with presenilin-1 or -2 mutations exhibit altered processing and localization of amyloid precursor protein (APP) and increased production of Aβ, relative to the source patient fibroblasts or hiN cells from unaffected individuals. Together, our findings demonstrate directed conversion of human fibroblasts to a neuronal phenotype and reveal cell type-selective pathology in hiN cells derived from FAD patients.

%B Cell %V 146 %P 359-71 %8 2011 Aug 5 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21816272?dopt=Abstract %R 10.1016/j.cell.2011.07.007 %0 Journal Article %J Lancet Neurol %D 2011 %T Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. %A Kapogiannis, Dimitrios %A Mattson, Mark P %K Alzheimer Disease %K Animals %K Brain %K Cognition Disorders %K Energy Metabolism %K Humans %K Nerve Net %X

Epidemiological, neuropathological, and functional neuroimaging evidence implicates global and regional disruptions in brain metabolism and energetics in the pathogenesis of cognitive impairment. Nerve cell microcircuits are modified by excitatory and inhibitory synaptic activity and neurotrophic factors. Ageing and Alzheimer's disease cause perturbations in cellular energy metabolism, level of excitation or inhibition, and neurotrophic factor release, which overwhelm compensatory mechanisms and result in dysfunction of neuronal microcircuits and brain networks. A prolonged positive energy balance impairs the ability of neurons to adapt to oxidative and metabolic stress. Results from experimental studies in animals show how disruptions caused by chronic positive energy balance, such as diabetes, lead to accelerated cognitive ageing and Alzheimer's disease. Therapeutic interventions to allay cognitive dysfunction that target energy metabolism and adaptive stress responses (such as neurotrophin signalling) have been effective in animal models and in preliminary studies in humans.

%B Lancet Neurol %V 10 %P 187-98 %8 2011 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/21147038?dopt=Abstract %R 10.1016/S1474-4422(10)70277-5 %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 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 Ann Neurol %D 2011 %T Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. %A Jucker, Mathias %A Walker, Lary C %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K DNA-Binding Proteins %K Humans %K Neurodegenerative Diseases %K Prions %K Proteins %K tau Proteins %X

The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism-corruptive protein templating. Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prionlike induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson/Lewy body disease, Huntington disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations. However, the theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders.

%B Ann Neurol %V 70 %P 532-40 %8 2011 Oct %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22028219?dopt=Abstract %R 10.1002/ana.22615 %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 Proc Natl Acad Sci U S A %D 2011 %T Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. %A Jin, Ming %A Shepardson, Nina %A Yang, Ting %A Chen, Gang %A Walsh, Dominic %A Selkoe, Dennis J %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Blotting, Western %K Chromatography, Gel %K Dimerization %K Genetic Vectors %K Hippocampus %K Humans %K Immunohistochemistry %K Immunoprecipitation %K In Situ Nick-End Labeling %K Lentivirus %K Microscopy, Confocal %K Microtubules %K Neurites %K Phosphorylation %K Rats %K Rats, Sprague-Dawley %K tau Proteins %X

Alzheimer disease is a major cause of cognitive failure, and a pathogenically related but more subtle process accounts for many cases of mild memory symptoms in older humans. Insoluble fibrillar plaques of amyloid β-proteins (Aβ) and neurofibrillary deposits of hyperphosphorylated tau proteins are the diagnostic lesions of AD, but their temporal mechanistic relationship has long been debated. The recent recognition that small, diffusible oligomers may be the principal bioactive form of Aβ raises the key question of whether these are sufficient to initiate cytoskeletal change and neurite degeneration. A few studies have examined the effects of oligomers of synthetic Aβ peptides of one defined length at supraphysiological concentrations, but the existence of such assemblies in the AD brain is not established. Here, we isolated Aβ dimers, the most abundant form of soluble oligomer detectable in the human brain, from the cortices of typical AD subjects and found that at subnanomolar concentrations, they first induced hyperphosphorylation of tau at AD-relevant epitopes in hippocampal neurons and then disrupted the microtubule cytoskeleton and caused neuritic degeneration, all in the absence of amyloid fibrils. Application of pure, synthetic dimers confirmed the effects of the natural AD dimers, although the former were far less potent. Knocking down endogenous tau fully prevented the neuritic changes, whereas overexpressing human tau accelerated them. Coadministering Aβ N-terminal antibodies neutralized the cytoskeletal disruption. We conclude that natural dimers isolated from the AD brain are sufficient to potently induce AD-type tau phosphorylation and then neuritic dystrophy, but passive immunotherapy mitigates this.

%B Proc Natl Acad Sci U S A %V 108 %P 5819-24 %8 2011 Apr 5 %G eng %N 14 %1 http://www.ncbi.nlm.nih.gov/pubmed/21421841?dopt=Abstract %R 10.1073/pnas.1017033108 %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 2011 %T Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. %A Li, J %A Wang, Y J %A Zhang, M %A Xu, Z Q %A Gao, C Y %A Fang, C Q %A Yan, J C %A Zhou, H D %K Aged %K Alzheimer Disease %K Cerebrovascular Disorders %K Cognition Disorders %K Disease Progression %K Female %K Humans %K Incidence %K Longitudinal Studies %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Peptides %K Regression Analysis %K Residence Characteristics %K Retrospective Studies %K Risk Factors %K Statistics, Nonparametric %X

OBJECTIVE: Growing evidence suggests that vascular risk factors (VRF) contribute to cognitive decline. The aim of this study was to investigate the impact of VRF on the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD) dementia.

METHODS: A total of 837 subjects with MCI were enrolled at baseline and followed up annually for 5 years. The incidence of AD dementia was investigated. A mixed random effects regression model was used to analyze the association between VRF and the progression of MCI assessed with Mini-Mental State Examination and instrumental Activities of Daily Living. Cox proportional hazard models were used to identify the association between VRF and dementia conversion, and to examine whether treatment of VRF can prevent dementia conversion.

RESULTS: At the end of the follow-up, 298 subjects converted to AD dementia, while 352 remained MCI. Subjects with VRF had a faster progression in cognition and function relative to subjects without. VRF including hypertension, diabetes, cerebrovascular diseases, and hypercholesterolemia increased the risk of dementia conversion. Those subjects with MCI in whom all VRF were treated had a lower risk of dementia than those who had some VRF treated. Treatment of individual VRF including hypertension, diabetes, and hypercholesterolemia was associated with the reduced risk of AD conversion.

CONCLUSION: VRF increased the risk of incident AD dementia. Treatment of VRF was associated with a reduced risk of incident AD dementia. Although our findings are observational, they suggest active intervention for VRF might reduce progression in MCI to AD dementia.

%B Neurology %V 76 %P 1485-91 %8 2011 Apr 26 %G eng %N 17 %1 http://www.ncbi.nlm.nih.gov/pubmed/21490316?dopt=Abstract %R 10.1212/WNL.0b013e318217e7a4 %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 Ann Neurol %D 2010 %T APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. %A Morris, John C %A Roe, Catherine M %A Xiong, Chengjie %A Fagan, Anne M %A Goate, Alison M %A Holtzman, David M %A Mintun, Mark A %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Aniline Compounds %K Apolipoprotein E2 %K Apolipoprotein E4 %K Apolipoproteins E %K Brain %K Female %K Follow-Up Studies %K Genotype %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Peptide Fragments %K Phosphorylation %K Plaque, Amyloid %K tau Proteins %K Thiazoles %X

OBJECTIVE: To examine interactions of apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer disease (AD) in cognitively normal aging.

METHODS: Two hundred forty-one cognitively normal individuals, aged 45-88 years, had cerebral amyloid imaging studies with Pittsburgh Compound-B (PIB). Of the 241 individuals, 168 (70%) also had cerebrospinal fluid (CSF) assays of amyloid-beta(42) (Abeta(42)), tau, and phosphorylated tau (ptau(181)). All individuals were genotyped for APOE.

RESULTS: The frequency of individuals with elevated mean cortical binding potential (MCBP) for PIB rose in an age-dependent manner from 0% at ages 45-49 years to 30.3% at 80-88 years. Reduced levels of CSF Abeta(42) appeared to begin earlier (18.2% of those aged 45-49 years) and increase with age in higher frequencies (50% at age 80-88 years) than elevations of MCBP. There was a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF Abeta(42) with increased numbers of APOE4 alleles. Individuals with an APOE2 allele had no increase in MCBP with age and had higher CSF Abeta(42) levels than individuals without an APOE2 allele. There was no APOE4 or APOE2 effect on CSF tau or ptau(181).

INTERPRETATION: Increasing cerebral Abeta deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects Abeta deposition may first be lowered CSF Abeta(42), followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD.

%B Ann Neurol %V 67 %P 122-31 %8 2010 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20186853?dopt=Abstract %R 10.1002/ana.21843 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2010 %T Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways. %A Miller, Jeremy A %A Horvath, Steve %A Geschwind, Daniel H %K Alzheimer Disease %K Animals %K Brain %K Gene Expression Profiling %K Gene Regulatory Networks %K Humans %K Male %K Mice %K Presenilin-1 %K Systems Biology %X

Because mouse models play a crucial role in biomedical research related to the human nervous system, understanding the similarities and differences between mouse and human brain is of fundamental importance. Studies comparing transcription in human and mouse have come to varied conclusions, in part because of their relatively small sample sizes or underpowered methodologies. To better characterize gene expression differences between mouse and human, we took a systems-biology approach by using weighted gene coexpression network analysis on more than 1,000 microarrays from brain. We find that global network properties of the brain transcriptome are highly preserved between species. Furthermore, all modules of highly coexpressed genes identified in mouse were identified in human, with those related to conserved cellular functions showing the strongest between-species preservation. Modules corresponding to glial and neuronal cells were sufficiently preserved between mouse and human to permit identification of cross species cell-class marker genes. We also identify several robust human-specific modules, including one strongly correlated with measures of Alzheimer disease progression across multiple data sets, whose hubs are poorly-characterized genes likely involved in Alzheimer disease. We present multiple lines of evidence suggesting links between neurodegenerative disease and glial cell types in human, including human-specific correlation of presenilin-1 with oligodendrocyte markers, and significant enrichment for known neurodegenerative disease genes in microglial modules. Together, this work identifies convergent and divergent pathways in mouse and human, and provides a systematic framework that will be useful for understanding the applicability of mouse models for human brain disorders.

%B Proc Natl Acad Sci U S A %V 107 %P 12698-703 %8 2010 Jul 13 %G eng %N 28 %1 http://www.ncbi.nlm.nih.gov/pubmed/20616000?dopt=Abstract %R 10.1073/pnas.0914257107 %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 J Neurosci %D 2010 %T Memory impairment in transgenic Alzheimer mice requires cellular prion protein. %A Gimbel, David A %A Nygaard, Haakon B %A Coffey, Erin E %A Gunther, Erik C %A Laurén, Juha %A Gimbel, Zachary A %A Strittmatter, Stephen M %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Avoidance Learning %K Brain %K Disease Models, Animal %K Maze Learning %K Memory %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Nerve Degeneration %K Presenilin-1 %K PrPC Proteins %K Random Allocation %K Serotonin %K Survival Analysis %X

Soluble oligomers of the amyloid-beta (Abeta) peptide are thought to play a key role in the pathophysiology of Alzheimer's disease (AD). Recently, we reported that synthetic Abeta oligomers bind to cellular prion protein (PrP(C)) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Abeta peptide. We hypothesized that PrP(C) is essential for the ability of brain-derived Abeta to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1DeltaE9 into Prnp-/- mice to examine the necessity of PrP(C) for AD-related phenotypes. Neither APP expression nor Abeta level is altered by PrP(C) absence in this transgenic AD model, and astrogliosis is unchanged. However, deletion of PrP(C) expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/PSen1DeltaE9 transgenic mice. The AD transgenic mice with intact PrP(C) expression exhibit deficits in spatial learning and memory. Mice lacking PrP(C), but containing Abeta plaque derived from APPswe/PSen1DeltaE9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrP(C) expression dissociates Abeta accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrP(C).

%B J Neurosci %V 30 %P 6367-74 %8 2010 May 5 %G eng %N 18 %1 http://www.ncbi.nlm.nih.gov/pubmed/20445063?dopt=Abstract %R 10.1523/JNEUROSCI.0395-10.2010 %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 %0 Journal Article %J J Alzheimers Dis %D 2010 %T Neuroinflammation in Alzheimer's disease and mild cognitive impairment: a field in its infancy. %A McGeer, Edith G %A McGeer, Patrick L %K Alzheimer Disease %K Animals %K Cognition Disorders %K Humans %K Inflammation %K Neurology %X

Neuroinflammation is a prominent feature of Alzheimer disease (AD) and other chronic neurodegenerative disorders. It exacerbates the fundamental pathology by generating a plethora of inflammatory mediators and neurotoxic compounds. Inflammatory cytokines, complement components, and toxic free radicals are among the many species that are generated. Microglia attack the pathological entities and may inadvertently injure host neurons. Recent evidence indicates that microglia can be stimulated to assume an antiinflammatory state rather than a proinflammatory state which may have therapeutic potential. Proinflammatory cytokines include IL-1, IL-6 and TNF, while antiinflammatory cytokines include IL-4 and IL-10. Complement activation is a separate process which causes extensive neuronal damage in AD through assembly of the membrane attack complex. Aggregated amyloid-beta is a potent activator of human complement but not of mouse complement. This is an important difference between AD and transgenic mouse models of AD. Many so far unexplored molecules may contribute to neuroinflammation or act to inhibit it. Stable isotope labeling by amino acids in cell culture (SILAC) analysis identified 174 proteins that were upregulated by two-fold or more, and 189 that were downregulated by 2-fold or more following inflammatory stimulation of microglial-like THP-1 cells. Neurotoxicity may result from any combination of these and further exploration is clearly warranted. In addition, many small molecules may play a significant role. One example is hydrogen sulfide which appears to be an endogenous antiinflammatory agent.

%B J Alzheimers Dis %V 19 %P 355-61 %8 2010 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20061650?dopt=Abstract %R 10.3233/JAD-2010-1219 %0 Journal Article %J Curr Alzheimer Res %D 2010 %T Tau in Alzheimer disease and related tauopathies. %A Iqbal, K %A Liu, F %A Gong, C-X %A Grundke-Iqbal, I %K Alzheimer Disease %K Animals %K Humans %K Phosphorylation %K tau Proteins %K Tauopathies %X

Tau is the major microtubule associated protein (MAP) of a mature neuron. The other two neuronal MAPs are MAP1 and MAP2. An established function of MAPs is their interaction with tubulin and promotion of its assembly into microtubules and stabilization of the microtubule network. The microtubule assembly promoting activity of tau, a phosphoprotein, is regulated by its degree of phosphorylation. Normal adult human brain tau contains 2-3 moles phosphate/mole of tau protein. Hyperphosphorylation of tau depresses this biological activity of tau. In Alzheimer disease (AD) brain tau is ~three to four-fold more hyperphosphorylated than the normal adult brain tau and in this hyperphosphorylated state it is polymerized into paired helical filaments ([PHF) admixed with straight filaments (SF) forming neurofibrillary tangles. Tau is transiently hyperphosphorylated during development and during anesthesia and hypothermia but not to the same state as in AD brain. The abnormally hyperphosphorylated tau in AD brain is distinguished from transiently hyperphosphorylated tau by its ability (1) to sequester normal tau, MAP1 and MAP2 and disrupt microtubules, and (2) to self-assemble into PHF/SF. The cytosolic abnormally hyperphosphorylated tau, because of oligomerization, unlike normal tau, is sedimentable and on self-assembly into PHF/SF, loses its ability to sequester normal MAPs. Some of the tau in AD brain is truncated which also promotes its self-assembly. Tau mutations found in frontotemporal dementia apparently promote its abnormal hyperphosphorylation. Thus, the AD abnormally hyperphosphorylated tau (1) is distinguishable from both normal and transiently hyperphosphorylated taus, and (2) is inhibitory when in a cytosolic/oligomeric state but not when it is self-assembled into PHF/SF. Inhibition of abnormal hyperphosphorylation of tau offers a promising therapeutic target for AD and related tauopathies.

%B Curr Alzheimer Res %V 7 %P 656-64 %8 2010 Dec %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/20678074?dopt=Abstract