%0 Journal Article %J J Alzheimers Dis %D 2023 %T Aspirin Use and Risk of Alzheimer's Disease: A 2-Sample Mendelian Randomization Study. %A Ding, Pingjian %A Gorenflo, Maria P %A Zhu, Xiaofeng %A Xu, Rong %X

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

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

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

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

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

%B J Alzheimers Dis %V 92 %P 989-1000 %8 2023 Apr 04 %G eng %N 3 %R 10.3233/JAD-220787 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Effect of Pathway-Specific Polygenic Risk Scores for Alzheimer's Disease (AD) on Rate of Change in Cognitive Function and AD-Related Biomarkers Among Asymptomatic Individuals. %A Xu, Yuexuan %A Vasiljevic, Eva %A Deming, Yuetiva K %A Jonaitis, Erin M %A Koscik, Rebecca L %A Van Hulle, Carol A %A Lu, Qiongshi %A Carboni, Margherita %A Kollmorgen, Gwendlyn %A Wild, Norbert %A Carlsson, Cynthia M %A Johnson, Sterling C %A Zetterberg, Henrik %A Blennow, Kaj %A Engelman, Corinne D %X

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

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

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

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

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

%B J Alzheimers Dis %V 94 %P 1587-1605 %8 2023 Aug 15 %G eng %N 4 %R 10.3233/JAD-230097 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Effects of 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 Excessive Sedentary Time Is Associated with Cognitive Decline in Older Patients with Minor Ischemic Stroke. %A Liang, Hongtao %A Yin, Xiang %A Chen, Tian %A Zhang, Yan %A Zhang, Qin %A Lin, Jie %A Yin, Huan %A Tang, Jinghua %A He, Yingyi %A Xia, Ping %A Zhu, Yongping %A Li, Haihua %A Mo, Yongbiao %A Li, Yongyong %A Wang, Ying %A Yang, Xiao %A Hu, Zicheng %X

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

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

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

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

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

%B J Alzheimers Dis %V 96 %P 173-181 %8 2023 Oct 24 %G eng %N 1 %R 10.3233/JAD-230008 %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 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 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 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 Alzheimer's Disease Diagnostics Using miRNA Biomarkers and Machine Learning. %A Xu, Amy %A Kouznetsova, Valentina L %A Tsigelny, Igor F %X

BACKGROUND: The current standard for Alzheimer's disease (AD) diagnosis is often imprecise, as with memory tests, and invasive or expensive, as with brain scans. However, the dysregulation patterns of miRNA in blood hold potential as useful biomarkers for the non-invasive diagnosis and even treatment of AD.

OBJECTIVE: The goal of this research is to elucidate new miRNA biomarkers and create a machine-learning (ML) model for the diagnosis of AD.

METHODS: We utilized pathways and target gene networks related to confirmed miRNA biomarkers in AD diagnosis and created multiple models to use for diagnostics based on the significant differences among miRNA expression between blood profiles (serum and plasma).

RESULTS: The best performing serum-based ML model, trained on filtered disease-specific miRNA datasets, was able to identify miRNA biomarkers with 92.0% accuracy and the best performing plasma-based ML model, trained on filtered disease-specific miRNA datasets, was able to identify miRNA biomarkers with 90.9% accuracy. Through analysis of AD implicated miRNA, thousands of descriptors reliant on target gene and pathways were created which can then be used to identify novel biomarkers and strengthen disease diagnosis.

CONCLUSION: Development of a ML model including miRNA and their genomic and pathway descriptors made it possible to achieve considerable accuracy for the prediction of AD.

%B J Alzheimers Dis %V 86 %P 841-859 %8 2022 Mar 22 %G eng %N 2 %R 10.3233/JAD-215502 %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 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 Aspirin Use with Reduced Risk of Developing Alzheimer's Disease in Elderly Ischemic Stroke Patients: A Retrospective Cohort Study. %A Gorenflo, Maria P %A Davis, Pamela B %A Kendall, Ellen K %A Olaker, Veronica R %A Kaelber, David C %A Xu, Rong %X

BACKGROUND: Currently there are no effective therapies to prevent or halt the development of Alzheimer's disease (AD). Multiple risk factors are involved in AD, including ischemic stroke (IS). Aspirin is often prescribed following IS to prevent blood clot formation. Observational studies have shown inconsistent findings with respect to the relationship between aspirin use and the risk of AD.

OBJECTIVE: To investigate the relationship between aspirin therapy after IS and the new diagnosis of AD in elderly patients.

METHODS: This retrospective cohort study leveraged a large database that contains over 90 million electronic health records to compare the hazard rates of AD after IS in elderly patients prescribed aspirin versus those not prescribed aspirin after propensity-score matching for relevant confounders.

RESULTS: At 1, 3, and 5 years after first IS, elderly patients prescribed aspirin were less likely to develop AD than those not prescribed aspirin: Hazard Ratio = 0.78 [0.65,0.94], 0.8 1 [0.70,0.94], and 0.76 [0.70,0.92].

CONCLUSION: Our findings suggest that aspirin use may prevent AD in patients with IS, a subpopulation at high risk of developing the disease.

%B J Alzheimers Dis %V 91 %P 697-704 %8 2023 Jan 17 %G eng %N 2 %R 10.3233/JAD-220901 %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 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 Comparative Analysis of Alzheimer's Disease Cerebrospinal Fluid Biomarkers Measurement by Multiplex SOMAscan Platform and Immunoassay-Based Approach. %A Timsina, Jigyasha %A Gomez-Fonseca, Duber %A Wang, Lihua %A Do, Anh %A Western, Dan %A Álvarez, Ignacio %A Aguilar, Miquel %A Pastor, Pau %A Henson, Rachel L %A Herries, Elizabeth %A Xiong, Chengjie %A Schindler, Suzanne E %A Fagan, Anne M %A Bateman, Randall J %A Farlow, Martin %A Morris, John C %A Perrin, Richard %A Moulder, Krista %A Hassenstab, Jason %A Chhatwal, Jasmeer %A Mori, Hiroshi %A Sung, Yun Ju %A Cruchaga, Carlos %X

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

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

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

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

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

%B J Alzheimers Dis %V 89 %P 193-207 %8 2022 Aug 30 %G eng %N 1 %R 10.3233/JAD-220399 %0 Journal Article %J J Alzheimers Dis %D 2022 %T 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 Effect of Probiotic Bifidobacterium breve in Improving Cognitive Function and Preventing Brain Atrophy in Older Patients with Suspected Mild Cognitive Impairment: Results of a 24-Week Randomized, Double-Blind, Placebo-Controlled Trial. %A Asaoka, Daisuke %A Xiao, Jinzhong %A Takeda, Tsutomu %A Yanagisawa, Naotake %A Yamazaki, Takahiro %A Matsubara, Yoichiro %A Sugiyama, Hideki %A Endo, Noemi %A Higa, Motoyuki %A Kasanuki, Koji %A Ichimiya, Yosuke %A Koido, Shigeo %A Ohno, Kazuya %A Bernier, Francois %A Katsumata, Noriko %A Nagahara, Akihito %A Arai, Heii %A Ohkusa, Toshifumi %A Sato, Nobuhiro %K Aged %K Aged, 80 and over %K Atrophy %K Bifidobacterium breve %K Brain %K Cognition %K Cognitive Dysfunction %K Double-Blind Method %K Humans %K Probiotics %X

BACKGROUND: Probiotics have been reported to ameliorate cognitive impairment.

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

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

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

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

%B J Alzheimers Dis %V 88 %P 75-95 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35570493?dopt=Abstract %R 10.3233/JAD-220148 %0 Journal Article %J J Alzheimers Dis %D 2022 %T HMGCS2-Induced Autophagic Degradation of Tau Involves Ketone Body and ANKRD24. %A Hu, Li-Tian %A Xie, Xiao-Yong %A Zhou, Gui-Feng %A Wen, Qi-Xin %A Song, Li %A Luo, Biao %A Deng, Xiao-Juan %A Pan, Qiu-Ling %A Chen, Guo-Jun %X

BACKGROUND: Accumulation of hyperphosphorylated Tau (pTau) contributes to the formation of neurofibrillary tangles in Alzheimer's disease (AD), and targeting Tau/pTau metabolism has emerged as a therapeutic approach. We have previously reported that mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2 (HMGCS2) is involved in AD by promoting autophagic clearance of amyloid-β protein precursor via ketone body-associated mechanism, whether HMGCS2 may also regulate Tau metabolism remains elusive.

OBJECTIVE: The present study was to investigate the role of HMGCS2 in Tau/p degradation.

METHODS: The protein levels of Tau and pTau including pT217 and pT181, as well as autophagic markers LAMP1 and LC3-II were assessed by western blotting. The differentially regulated genes by HMGCS2 were analyzed by RNA sequencing. Autophagosomes were assessed by transmission electron microscopy.

RESULTS: HMGCS2 significantly decreased Tau/pTau levels, which was paralleled by enhanced formation of autophagic vacuoles and prevented by autophagic regulators chloroquine, bafilomycin A1, 3-methyladenine, and rapamycin. Moreover, HMGCS2-induced alterations of LAMP1/LC3-II and Tau/pTau levels were mimicked by ketone body acetoacetate or β-hydroxybutyrate. Further RNA-sequencing identified ankyrin repeat domain 24 (ANKRD24) as a target gene of HMGCS2, and silencing of ANKRD24 reduced LAMP1/LC3-II levels, which was accompanied by the altered formation of autophagic vacuoles, and diminished the effect of HMGCS2 on Tau/pTau.

CONCLUSION: HMGCS2 promoted autophagic clearance of Tau/pTau, in which ketone body and ANKRD24 played an important role.

%B J Alzheimers Dis %V 91 %P 407-426 %8 2023 Jan 03 %G eng %N 1 %R 10.3233/JAD-220640 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Relationship Between Weight-Change Patterns and Cognitive Function: A Retrospective Study. %A Gong, Hong-Jian %A Tang, Xingyao %A Chai, Yin-He %A Qiao, Yu-Shun %A Xu, Hui %A Patel, Ikramulhaq %A Zhang, Jin-Yan %A Simó, Rafael %A Zhou, Jian-Bo %X

BACKGROUND: Obesity has been linked to cognitive impairment. However, how changes in body mass index (BMI) over the life course influence cognitive function remains unclear.

OBJECTIVE: The influence of distinct weight-change patterns from young adulthood to midlife and late adulthood on cognitive function in older adults was explored.

METHODS: A total of 5,809 individuals aged≥60 years were included and categorized into four groups on the basis of BMI change patterns. Cognitive function was assessed using four cognition tests in the baseline survey. The relationship between the weight-change patterns and cognition was evaluated using regression models.

RESULTS: In comparison with participants who remained at non-obese, those moving from the non-obese to obese weight-change pattern from young (25 years of age) to middle adulthood showed lower Digit Symbol Substitution Test (DSST) scores (β= -1.28; 95% confidence interval [CI]: -2.24 to -0.32). A non-obese to obese change pattern from age 25 years of age to 10 years before baseline was associated with a higher risk of DSST impairment (odds ratio = 1.40; 95% CI: 1.09 to 1.79). In comparison with participants whose heaviest weight was recorded after 60 years of age, those with the heaviest weight between 18 and 40 years of age had lower DSST scores (β= -1.46; 95% CI: -2.77 to -1.52).

CONCLUSION: Our results suggest that the transition from the non-obese to obese category in early adulthood and appearance of the heaviest weight between 18 and 40 years of age are associated with lower cognitive function in later life.

%B J Alzheimers Dis %V 91 %P 1085-1095 %8 2023 Jan 31 %G eng %N 3 %R 10.3233/JAD-220788 %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 Sex-Specific Patterns of Body Mass Index Relationship with White Matter Connectivity. %A Rahmani, Farzaneh %A Wang, Qing %A McKay, Nicole S %A Keefe, Sarah %A Hantler, Nancy %A Hornbeck, Russ %A Wang, Yong %A Hassenstab, Jason %A Schindler, Suzanne %A Xiong, Chengjie %A Morris, John C %A Benzinger, Tammie L S %A Raji, Cyrus A %X

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

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

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

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

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

%B J Alzheimers Dis %V 86 %P 1831-1848 %8 2022 Apr 19 %G eng %N 4 %R 10.3233/JAD-215329 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cerebrospinal Fluid Amyloid-β Oligomer Levels in Patients with Idiopathic Normal Pressure Hydrocephalus. %A Kawamura, Kaito %A Miyajima, Masakazu %A Nakajima, Madoka %A Kanai, Mitsuyasu %A Motoi, Yumiko %A Nojiri, Shuko %A Akiba, Chihiro %A Ogino, Ikuko %A Xu, Hanbing %A Kamohara, Chihiro %A Yamada, Shinya %A Karagiozov, Kostadin %A Ikeuchi, Takeshi %A Kondo, Akihide %A Arai, Hajime %X

BACKGROUND: The amyloid-β oligomers, consisting of 10-20 monomers (AβO10-20), have strong neurotoxicity and are associated with cognitive impairment in Alzheimer's disease (AD). However, their role in patients with idiopathic normal pressure hydrocephalus (iNPH) is poorly understood.

OBJECTIVE: We hypothesized that cerebrospinal fluid (CSF) AβO10-20 accumulates in patients with iNPH, and its clearance after CSF shunting contributes to neurological improvement. We measured CSF AβO10-20 levels before and after CSF shunting in iNPH patients evaluating their diagnostic and prognostic role.

METHODS: We evaluated two iNPH cohorts: "evaluation" (cohort-1) with 32 patients and "validation" (cohort-2) with 13 patients. Comparison cohorts included: 27 neurologically healthy controls (HCs), and 16 AD, 15 Parkinson's disease (PD), and 14 progressive supranuclear palsy (PSP) patients. We assessed for all cohorts CSF AβO10-20 levels and their comprehensive clinical data. iNPH cohort-1 pre-shunting data were compared with those of comparison cohorts, using cohort-2 for validation. Next, we compared cohort-1's clinical and CSF data: 1) before and after CSF shunting, and 2) increased versus decreased AβO10-20 levels at baseline, 1 and 3 years after shunting.

RESULTS: Cohort-1 had higher CSF AβO10-20 levels than the HCs, PD, and PSP cohorts. This result was validated with data from cohort-2. CSF AβO10-20 levels differentiated cohort-1 from the PD and PSP groups, with an area under receiver operating characteristic curve of 0.94. AβO10-20 levels in cohort-1 decreased after CSF shunting. Patients with AβO10-20 decrease showed better cognitive outcome than those without.

CONCLUSION: AβO10-20 accumulates in patients with iNPH and is eliminated by CSF shunting. AβO10-20 can be an applicable diagnostic and prognostic biomarker.

%B J Alzheimers Dis %V 83 %P 179-190 %8 2021 Aug 31 %G eng %N 1 %R 10.3233/JAD-210226 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Diagnosing Mild Cognitive Impairment Among Racially Diverse Older Adults: Comparison of Consensus, Actuarial, and Statistical Methods. %A Devlin, Kathryn N %A Brennan, Laura %A Saad, Laura %A Giovannetti, Tania %A Hamilton, Roy H %A Wolk, David A %A Xie, Sharon X %A Mechanic-Hamilton, Dawn %X

BACKGROUND: Actuarial and statistical methods have been proposed as alternatives to conventional methods of diagnosing mild cognitive impairment (MCI), with the aim of enhancing diagnostic and prognostic validity, but have not been compared in racially diverse samples.

OBJECTIVE: We compared the agreement of consensus, actuarial, and statistical MCI diagnostic methods, and their relationship to race and prognostic indicators among diverse older adults.

METHODS: Participants (N = 354; M age = 71; 68% White, 29% Black) were diagnosed with MCI or normal cognition (NC) according to clinical consensus, actuarial neuropsychological criteria (Jak/Bondi), and latent class analysis (LCA). We examined associations with race/ethnicity, longitudinal cognitive and functional change, and incident dementia.

RESULTS: MCI rates by consensus, actuarial criteria, and LCA were 44%, 53%, and 41%, respectively. LCA identified three MCI subtypes (memory; memory/language; memory/executive) and two NC classes (low normal; high normal). Diagnostic agreement was substantial, but agreement of the actuarial method with consensus and LCA was weaker than the agreement between consensus and LCA. Among cases classified as MCI by actuarial criteria only, Black participants were over-represented, and outcomes were generally similar to those of NC participants. Consensus diagnoses best predicted longitudinal outcomes overall, whereas actuarial diagnoses best predicted longitudinal functional change among Black participants.

CONCLUSION: Consensus diagnoses optimize specificity in predicting dementia, but among Black older adults, actuarial diagnoses may be more sensitive to early signs of decline. Results highlight the need for cross-cultural validity in MCI diagnosis and should be explored in community- and population-based samples.

%B J Alzheimers Dis %V 85 %P 627-644 %8 2022 Jan 18 %G eng %N 2 %R 10.3233/JAD-210455 %0 Journal Article %J J Alzheimers Dis %D 2021 %T 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 High Fat Diet Mediates Amyloid-β Cleaving Enzyme 1 Phosphorylation and SUMOylation, Enhancing Cognitive Impairment in APP/PS1 Mice. %A Bao, Jian %A Liang, Zheng %A Gong, Xiaokang %A Yu, Jing %A Xiao, Yifan %A Liu, Wei %A Wang, Xiaochuan %A Wang, Jian-Zhi %A Shu, Xiji %X

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in older adults and extracellular accumulation of amyloid-β (Aβ) is one of the two characterized pathologies of AD. Obesity is significantly associated with AD developing factors. Several studies have reported that high fat diet (HFD) influenced Aβ accumulation and cognitive performance during AD pathology. However, the underlying neurobiological mechanisms have not yet been elucidated.

OBJECTIVE: The objective of this study was to explore the underlying neurobiological mechanisms of HFD influenced Aβ accumulation and cognitive performance during AD pathology.

METHODS: 2.5-month-old male APP/PS1 mice were randomly separated into two groups: 1) the normal diet (ND) group, fed a standard diet (10 kcal%fat); and 2) the HFD group, fed a high fat diet (40 kcal%fat, D12492; Research Diets). After 4 months of HFD or ND feeding, mice in the two groups were subjected for further ethological, morphological, and biochemical analyses.

RESULTS: A long-term HFD diet significantly increased perirenal fat and impaired dendritic integrity and aggravated neurodegeneration, and augmented learning and memory deficits in APP/PS1 mice. Furthermore, the HFD increased beta amyloid cleaving enzyme 1 (BACE1) dephosphorylation and SUMOylation, resulting in enhanced enzyme activity and stability, which exacerbated the deposition of amyloid plaques.

CONCLUSION: Our study demonstrates that long-term HFD consumption aggravates amyloid-β accumulation and cognitive impairments, and that modifiable lifestyle factors, such as obesity, can induce BACE1 post-modifications which may contribute to AD pathogenesis.

%B J Alzheimers Dis %V 85 %P 863-876 %8 2022 Jan 18 %G eng %N 2 %R 10.3233/JAD-215299 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Loneliness, Not Social Support, Is Associated with Cognitive Decline and Dementia Across Two Longitudinal Population-Based Cohorts. %A Freak-Poli, Rosanne %A Wagemaker, Nina %A Wang, Rui %A Lysen, Thom S %A Ikram, M Arfan %A Vernooij, Meike W %A Dintica, Christina S %A Vernooij-Dassen, Myrra %A Melis, Rene J M %A Laukka, Erica J %A Fratiglioni, Laura %A Xu, Weili %A Tiemeier, Henning %X

BACKGROUND: Poor social health is likely associated with cognitive decline and risk of dementia; however, studies show inconsistent results. Additionally, few studies separate social health components or control for mental health.

OBJECTIVE: To investigate whether loneliness and social support are independently associated with cognitive decline and risk of dementia, and whether depressive symptoms confound the association.

METHODS: We included 4,514 participants from the population-based Rotterdam Study (RS; aged 71±7SD years) followed up to 14 years (median 10.8, interquartile range 7.4-11.6), and 2,112 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K; aged 72±10SD years) followed up to 10 years (mean 5.9±1.6SD). At baseline, participants were free of major depression and scored on the Mini-Mental State Examination (MMSE) ≥26 for RS and ≥25 for SNAC-K. We investigated loneliness, perceived social support, and structural social support (specifically marital status and number of children). In both cohorts, dementia was diagnosed and cognitive function was repeatedly assessed with MMSE and a global cognitive factor (g-factor).

RESULTS: Loneliness was prospectively associated with a decline in the MMSE in both cohorts. Consistently, persons who were lonely had an increased risk of developing dementia (RS: HR 1.34, 95%CI 1.08-1.67; SNAC-K: HR 2.16, 95%CI 1.12-4.17). Adjustment for depressive symptoms and exclusion of the first 5 years of follow-up did not alter results. Neither perceived or structural social support was associated with cognitive decline or dementia risk.

CONCLUSION: Loneliness, not social support, predicted cognitive decline and incident dementia independently of depressive symptoms.

%B J Alzheimers Dis %V 85 %P 295-308 %8 2022 Jan 04 %G eng %N 1 %R 10.3233/JAD-210330 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Lung Function Impairment and the Risk of Incident Dementia: The Rotterdam Study. %A Xiao, Tian %A Wijnant, Sara R A %A Licher, Silvan %A Terzikhan, Natalie %A Lahousse, Lies %A Ikram, M Kamran %A Brusselle, Guy G %A Ikram, M Arfan %X

BACKGROUND: The etiology of dementia may partly be underpinned by impaired lung function via systemic inflammation and hypoxia.

OBJECTIVE: To prospectively examine the association between chronic obstructive pulmonary disease (COPD) and subclinical impairments in lung function and the risk of dementia.

METHODS: In the Rotterdam Study, we assessed the risk of incident dementia in participants with Preserved Ratio Impaired Spirometry (PRISm; FEV1/FVC≥0.7, FEV1 < 80% predicted) and in participants with COPD (FEV1/FVC < 0.7) compared to those with normal spirometry (controls; FEV1/FVC≥0.7, FEV1≥80% predicted). Hazard ratios (HRs) with 95% confidence intervals (CI) for dementia were adjusted for age, sex, education attainment, smoking status, systolic blood pressure, body mass index, triglycerides, comorbidities and Apolipoprotein E (APOE) genotype.

RESULTS: Of 4,765 participants, 110 (2.3%) developed dementia after 3.3 years. Compared to controls, participants with PRISm, but not COPD, had an increased risk for all-type dementia (adjusted HRPRISm 2.70; 95% CI, 1.53-4.75; adjusted HRCOPD 1.03; 95% CI, 0.61-1.74). These findings were primarily driven by men and smokers. Similarly, participants with FVC% predicted values in the lowest quartile compared to those in the highest quartile were at increased risk of all-type dementia (adjusted HR 2.28; 95% CI, 1.31-3.98), as well as Alzheimer's disease (AD; adjusted HR 2.13; 95% CI, 1.13-4.02).

CONCLUSION: Participants with PRISm or a low FVC% predicted lung function were at increased risk of dementia, compared to those with normal spirometry or a higher FVC% predicted, respectively. Further research is needed to elucidate whether this association is causal and how PRISm might contribute to dementia pathogenesis.

%B J Alzheimers Dis %V 82 %P 621-630 %8 2021 Jul 20 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34057085?dopt=Abstract %R 10.3233/JAD-210162 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Mortality After Ischemic Stroke in Patients with Alzheimer's Disease Dementia and Other Dementia Disorders. %A Zupanic, Eva %A von Euler, Mia %A Winblad, Bengt %A Xu, Hong %A Secnik, Juraj %A Kramberger, Milica Gregoric %A Religa, Dorota %A Norrving, Bo %A Garcia-Ptacek, Sara %K Aged %K Aged, 80 and over %K Comorbidity %K Dementia %K Female %K Fibrinolytic Agents %K Humans %K Incidence %K Ischemic Stroke %K Male %K Registries %K Survival Rate %K Sweden %K Thrombolytic Therapy %X

BACKGROUND: Stroke and dementia are interrelated diseases and risk for both increases with age. Even though stroke incidence and age-standardized death rates have decreased due to prevention of stroke risk factors, increased utilization of reperfusion therapies, and other changes in healthcare, the absolute numbers are increasing due to population growth and aging.

OBJECTIVE: To analyze predictors of death after stroke in patients with dementia and investigate possible time and treatment trends.

METHODS: A national longitudinal cohort study 2007-2017 using Swedish national registries. We compared 12,629 ischemic stroke events in patients with dementia with matched 57,954 stroke events in non-dementia controls in different aspects of patient care and mortality. Relationship between dementia status and dementia type (Alzheimer's disease and mixed dementia, vascular dementia, other dementias) and death was analyzed using Cox regressions.

RESULTS: Differences in receiving intravenous thrombolysis between patients with and without dementia disappeared after the year 2015 (administered to 11.1% dementia versus 12.3% non-dementia patients, p = 0.117). One year after stroke, nearly 50% dementia and 30% non-dementia patients had died. After adjustment for demographics, mobility, nursing home placement, and comorbidity index, dementia was an independent predictor of death compared with non-dementia patients (HR 1.26 [1.23-1.29]).

CONCLUSION: Dementia before ischemic stroke is an independent predictor of death. Over time, early and delayed mortality in patients with dementia remained increased, regardless of dementia type. Patients with≤80 years with prior Alzheimer's disease or mixed dementia had higher mortality rates after stroke compared to patients with prior vascular dementia.

%B J Alzheimers Dis %V 81 %P 1253-1261 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33935077?dopt=Abstract %R 10.3233/JAD-201459 %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 Serum Uric Acid May Aggravate Alzheimer's Disease Risk by Affecting Amyloidosis in Cognitively Intact Older Adults: The CABLE Study. %A Li, Lin-Lin %A Ma, Ya-Hui %A Bi, Yan-Lin %A Sun, Fu-Rong %A Hu, Hao %A Hou, Xiao-He %A Xu, Wei %A Shen, Xue-Ning %A Dong, Qiang %A Tan, Lan %A Yang, Jiu-Long %A Yu, Jin-Tai %X

BACKGROUND: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer's disease (AD) pathology remains unclear.

OBJECTIVE: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD.

METHODS: We analyzed cognitively intact participants (n = 839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-β [Aβ], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models.

RESULTS: Levels of SUA in the preclinical AD elevated compared with the healthy controls (p = 0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p = 0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aβ1 - 42 (p = 0.019) and Aβ1 - 42/Aβ1 - 40 (p = 0.027) were decreased and CSF p-Tau/Aβ1 - 42 (p = 0.009) and t-Tau/Aβ1 - 42 (p = 0.043) were increased with the highest (>  75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them.

CONCLUSION: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA.

%B J Alzheimers Dis %V 81 %P 389-401 %8 2021 May 04 %G eng %N 1 %R 10.3233/JAD-201192 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Sustained Hippocampal Neural Plasticity Questions the Reproducibility of an Amyloid-β-Induced Alzheimer's Disease Model. %A Paulo, Sara L %A Ribeiro-Rodrigues, Leonor %A Rodrigues, Rui S %A Mateus, Joana M %A Fonseca-Gomes, João %A Soares, Rita %A Diógenes, Maria J %A Solá, Susana %A Sebastião, Ana M %A Ribeiro, Filipa F %A Xapelli, Sara %X

BACKGROUND: The use of Alzheimer's disease (AD) models obtained by intracerebral infusion of amyloid-β (Aβ) has been increasingly reported in recent years. Nonetheless, these models may present important challenges.

OBJECTIVE: We have focused on canonical mechanisms of hippocampal-related neural plasticity to characterize a rat model obtained by an intracerebroventricular (icv) injection of soluble amyloid-β42 (Aβ42).

METHODS: Animal behavior was evaluated in the elevated plus maze, Y-Maze spontaneous or forced alternation, Morris water maze, and open field, starting 2 weeks post-Aβ42 infusion. Hippocampal neurogenesis was assessed 3 weeks after Aβ42 injection. Aβ deposition, tropomyosin receptor kinase B levels, and neuroinflammation were appraised at 3 and 14 days post-Aβ42 administration.

RESULTS: We found that immature neuronal dendritic morphology was abnormally enhanced, but proliferation and neuronal differentiation in the dentate gyrus was conserved one month after Aβ42 injection. Surprisingly, animal behavior did not reveal changes in cognitive performance nor in locomotor and anxious-related activity. Brain-derived neurotrophic factor related-signaling was also unchanged at 3 and 14 days post-Aβ icv injection. Likewise, astrocytic and microglial markers of neuroinflammation in the hippocampus were unaltered in these time points.

CONCLUSION: Taken together, our data emphasize a high variability and lack of behavioral reproducibility associated with these Aβ injection-based models, as well as the need for its further optimization, aiming at addressing the gap between preclinical AD models and the human disorder.

%B J Alzheimers Dis %V 82 %P 1183-1202 %8 2021 Aug 03 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34151790?dopt=Abstract %R 10.3233/JAD-201567 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Comorbidity of Cerebrovascular and Alzheimer's Disease in Aging. %A Xia, Ying %A Yassi, Nawaf %A Raniga, Parnesh %A Bourgeat, Pierrick %A Desmond, Patricia %A Doecke, James %A Ames, David %A Laws, Simon M %A Fowler, Christopher %A Rainey-Smith, Stephanie R %A Martins, Ralph %A Maruff, Paul %A Villemagne, Victor L %A Masters, Colin L %A Rowe, Christopher C %A Fripp, Jurgen %A Salvado, Olivier %X

BACKGROUND: Cerebrovascular disease often coexists with Alzheimer's disease (AD). While both diseases share common risk factors, their interrelationship remains unclear. Increasing the understanding of how cerebrovascular changes interact with AD is essential to develop therapeutic strategies and refine biomarkers for early diagnosis.

OBJECTIVE: We investigate the prevalence and risk factors for the comorbidity of amyloid-β (Aβ) and cerebrovascular disease in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing, and further examine their cross-sectional association.

METHODS: A total of 598 participants (422 cognitively normal, 89 with mild cognitive impairment, 87 with AD) underwent positron emission tomography and structural magnetic resonance imaging for assessment of Aβ deposition and cerebrovascular disease. Individuals were categorized based on the comorbidity status of Aβ and cerebrovascular disease (V) as Aβ-V-, Aβ-V+, Aβ+V-, or Aβ+V+.

RESULTS: Advancing age was associated with greater likelihood of cerebrovascular disease, high Aβ load and their comorbidity. Apolipoprotein E ɛ4 carriage was only associated with Aβ positivity. Greater total and regional WMH burden were observed in participants with AD. However, no association were observed between Aβ and WMH measures after stratification by clinical classification, suggesting that the observed association between AD and cerebrovascular disease was driven by the common risk factor of age.

CONCLUSION: Our observations demonstrate common comorbid condition of Aβ and cerebrovascular disease in later life. While our study did not demonstrate a convincing cross-sectional association between Aβ and WMH burden, future longitudinal studies are required to further confirm this.

%B J Alzheimers Dis %V 78 %P 321-334 %8 2020 Oct 27 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32986666?dopt=Abstract %R 10.3233/JAD-200419 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Exploration of Plasma Lipids in Mild Cognitive Impairment due to Alzheimer's Disease. %A Bergland, Anne Katrine %A Proitsi, Petroula %A Kirsebom, Bjørn-Eivind %A Soennesyn, Hogne %A Hye, Abdul %A Larsen, Alf Inge %A Xu, Jin %A Legido-Quigley, Cristina %A Rajendran, Lawrence %A Fladby, Tormod %A Aarsland, Dag %X

BACKGROUND: Lipids have important structural roles in cell membranes and changes to these membrane lipids may influence β- and γ-secretase activities and thus contribute to Alzheimer's disease (AD) pathology.

OBJECTIVE: To explore baseline plasma lipid profiling in participants with mild cognitive impairment (MCI) with and without AD pathology.

METHODS: We analyzed 261 plasma lipid profiles using reversed phase chromatography mass spectrometry in cerebrospinal fluid amyloid positive (Aβ+) or negative (Aβ-) participants with MCI as compared to controls. Additionally, we analyzed the potential associations of plasma lipid profiles with performance on neuropsychological tests at baseline and after two years.

RESULTS: Sphingomyelin (SM) concentrations, particularly, SM(d43:2), were lower in MCI Aβ+ individuals compared to controls. Further, SM(d43:2) was also nominally reduced in MCI Aβ+ individuals compared to MCI Aβ-. No plasma lipids were associated with performance on neuropsychological tests at baseline or between the two time points after correction for multiple testing.

CONCLUSION: Reduced plasma concentrations of SM were associated with AD.

%B J Alzheimers Dis %V 77 %P 1117-1127 %8 2020 Sep 29 %G eng %N 3 %R 10.3233/JAD-200441 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Glucose Fluctuations Are Linked to Disrupted Brain Functional Architecture and Cognitive Impairment. %A Xia, Wenqing %A Luo, Yong %A Chen, Yu-Chen %A Chen, Huiyou %A Ma, Jianhua %A Yin, Xindao %X

BACKGROUND: Type 2 diabetes mellitus (T2DM) accelerates cognitive decline, which is believed to be triggered by aberrant neural activity.

OBJECTIVE: To explore how glucose fluctuations impact brain functional architecture and cognition in T2DM patients.

METHODS: T2DM patients were divided according to glycemic variability, forming two categories: patients with fluctuating glucose levels and patients with stable glucose levels. Degree centrality (DC) was calculated within the cerebral gray matter of each participant and was compared among the two patient groups and a healthy control group. The relationships between glucose fluctuations and aberrant DC and cognitive performance, as well as the relationship between aberrant DC and cognitive performance, were further explored.

RESULTS: Compared with T2DM patients with stable glucose levels, T2DM patients with fluctuating glucose levels exhibited significantly worse performance on the Montreal Cognitive Assessment, Trail Making Test-B (TMT-B), and verbal fluency test (VFT), as well as significant decreases in DC in certain regions, most of which were within the default mode network. In the combined T2DM group, the mean amplitude of glycemic excursions (MAGE) was positively correlated with TMT-B scores and negatively correlated with VFT scores. Moreover, the MAGE was negatively correlated with DC in the left medial prefrontal cortex (mPFC). In addition, TMT-B scores were negatively correlated with reduced DC in the left mPFC.

CONCLUSION: These findings further contribute to the mounting evidence of the effects of glycemic variability on the diabetic brain. Tightened control of glucose fluctuations might prevent cognitive decline and changes in brain functional architecture in T2DM individuals.

%B J Alzheimers Dis %V 74 %8 2020 Mar 24 %G eng %N 2 %R 10.3233/JAD-191217 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Influence of Comorbidity of Cerebrovascular Disease and Amyloid-β on Alzheimer's Disease. %A Yassi, Nawaf %A Hilal, Saima %A Xia, Ying %A Lim, Yen Ying %A Watson, Rosie %A Kuijf, Hugo %A Fowler, Christopher %A Yates, Paul %A Maruff, Paul %A Martins, Ralph %A Ames, David %A Chen, Christopher %A Rowe, Christopher %A Villemagne, Victor %A Salvado, Olivier %A Desmond, Patricia M %A Masters, Colin L %X

BACKGROUND: Quantifying the contribution of cerebrovascular disease to the clinical and pathological profile of Alzheimer's disease is challenging.

OBJECTIVE: We aimed to determine the influence of cerebrovascular disease, amyloid-β (Aβ), and their comorbidity on cognitive decline, hippocampal atrophy, and Aβ deposition, by evaluating data from the Australian Imaging, Biomarker and Lifestyle Study of Ageing.

METHODS: Two-hundred and eighteen participants underwent Aβ PET, MRI, and cognitive assessment at 18-month intervals for up to 90 months. Aβ status was determined on baseline PET. Participants were also classified as V + on baseline MRI if they had≥1 large cortical infarcts, subcortical infarcts, or cortical cerebral microinfarcts; or white matter hyperintensity volume greater than the 90th percentile of healthy controls. Linear mixed models were conducted comparing slopes of change in cognition, hippocampal volume, and Aβ load between the four resultant groups.

RESULTS: Mean age at baseline was 74 years (range 59-96). One-hundred and fifteen participants were cognitively normal, 54 had mild cognitive impairment, and 49 had Alzheimer's disease. Compared to the Aβ-/V- group, the Aβ+/V- and Aβ+/V+groups showed significantly faster cognitive decline and hippocampal atrophy over 90 months. V + status was associated with greater cognitive decline (Cohen's d = 0.85, p < 0.001) and hippocampal atrophy (d = 2.05, p < 0.001) in the Aβ+group but not in the Aβ- group. V + status was not associated with Aβ accumulation in any group.

CONCLUSION: Comorbidity of cerebrovascular disease and Aβ was associated with cognitive decline and neurodegeneration. Cerebrovascular disease was not associated with the rate of Aβ accumulation.

%B J Alzheimers Dis %V 73 %P 897-907 %8 2020 Feb 04 %G eng %N 3 %R 10.3233/JAD-191028 %0 Journal Article %J J Alzheimers Dis %D 2020 %T The Prevalence of Dementia: A Systematic Review and Meta-Analysis. %A Cao, Qing %A Tan, Chen-Chen %A Xu, Wei %A Hu, Hao %A Cao, Xi-Peng %A Dong, Qiang %A Tan, Lan %A Yu, Jin-Tai %X

Dementia is a severe neurodegenerative disorder and it can be categorized into several subtypes by different pathogenic causes. We sought to comprehensively analyzed the prevalence of dementia from perspectives of geographic region (Asia, Africa, South America, and Europe/North America), age, and gender. We searched PubMed and EMBASE for relevant articles on dementia published from January 1985 to August 2019. In these studies, analyses were stratified by geographic region, age, and gender. Meta-regression was conducted to identify if there were significant differences between groups. We included forty-seven studies. Among the individuals aged 50 and over in the community, the pooled prevalence for all-cause dementia, Alzheimer's disease, and vascular dementia were 697 (CI95%: 546-864) per 10,000 persons, 324 (CI95%: 228-460) per 10,000 persons, and 116 (CI95%: 86-157) per 10,000 persons, respectively. In our study, the prevalence of all-type dementia in individuals aged 100 years and older (6,592 per 10,000 cases) is 244 times higher than in those aged 50-59 (27 per 10,000 cases). The number of people living with dementia approximately doubles every five years. The prevalence was greater in women than in men (788 cases versus 561 cases per 10,000 persons) in overall analysis. In individuals aged 60 to 69 years, AD prevalence in females was 1.9 times greater than that in males (108 cases versus 56 cases per 10,000 persons), while the prevalence of VaD was 1.8 times greater in males than in females (56 cases versus 32 cases per 10,000 persons). Prevalence rate was higher in Europe and North America than in Asia, Africa, and South America.

%B J Alzheimers Dis %V 73 %P 1157-1166 %8 2020 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/31884487?dopt=Abstract %R 10.3233/JAD-191092 %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 2020 %T Vascular Risk Factors and Alzheimer's Disease: Blood-Brain Barrier Disruption, Metabolic Syndromes, and Molecular Links. %A He, Jin-Ting %A Zhao, Xin %A Xu, Lei %A Mao, Cui-Ying %X

Alzheimer's disease (AD) is a neurodegenerative disorder, marked by cortical and hippocampal deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles and cognitive impairment. Studies indicate a prominent link between cerebrovascular abnormalities and the onset and progression of AD, where blood-brain barrier (BBB) dysfunction and metabolic disorders play key risk factors. Pericyte degeneration, endothelial cell damage, astrocyte depolarization, diminished tight junction integrity, and basement membrane disarray trigger BBB damage. Subsequently, the altered expression of low-density lipoprotein receptor-related protein 1 and receptor for advanced glycation end products at the microvascular endothelial cells dysregulate Aβ transport across the BBB. White matter lesions and microhemorrhages, dyslipidemia, altered brain insulin signaling, and insulin resistance contribute to tau and Aβ pathogenesis, and oxidative stress, mitochondrial damage, inflammation, and hypoperfusion serve as mechanistic links between pathophysiological features of AD and ischemia. Deregulated calcium homeostasis, voltage gated calcium channel functioning, and protein kinase C signaling are also common mechanisms for both AD pathogenesis and cerebrovascular abnormalities. Additionally, APOE polymorphic alleles that characterize impaired cerebrovascular integrity function as primary genetic determinants of AD. Overall, the current review enlightens key vascular risk factors for AD and underscores pathophysiologic relationship between AD and vascular dysfunction.

%B J Alzheimers Dis %V 73 %P 39-58 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31815697?dopt=Abstract %R 10.3233/JAD-190764 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Association of Cognitive Function with Amyloid-β and Tau Proteins in the Vitreous Humor. %A Wright, Lauren M %A Stein, Thor D %A Jun, Gyungah %A Chung, Jaeyoon %A McConnell, Kate %A Fiorello, Marissa %A Siegel, Nicole %A Ness, Steven %A Xia, Weiming %A Turner, Kelley L %A Subramanian, Manju L %X

BACKGROUND: The eye may serve as source for diagnostic testing for early detection of Alzheimer's disease (AD). Examination of amyloid-β (Aβ) and tau protein content in human vitreous and its correlation to neuro-cognition may improve ocular-based AD detection methods.

OBJECTIVE: To evaluate levels of Aβ and tau protein in human vitreous humor and investigate the clinical predictive role of these proteins as early diagnostic markers of AD.

METHODS: A prospective, single-center, multi-surgeon cohort study. Vitreous humor samples from 80 eyes were measured quantitatively for Aβ40-42, pTau, and tTau. Linear regression was used to test associations between AD biomarker levels, Mini-Mental State Exam (MMSE), and serum apolipoprotein E (APOE) allele status, with adjustment for age, sex, and education level of patients.

RESULTS: Lower MMSE scores were significantly associated with lower levels of vitreous Aβ40 (p = 0.015), Aβ42 (p = 0.0066), and tTau (p = 0.0085), and these biomarkers were not associated with any pre-existing eye conditions. Presence of the ɛ4 allele and the ɛ2 allele approached significance with reduced Aβ40 level (p = 0.053) and increased p-Tau level (p = 0.056), respectively.

CONCLUSION: Patients with poor cognitive function have significantly lower vitreous humor levels of AD-related biomarkers Aβ40, Aβ42, and tTau. These biomarkers do not correlate with underlying eye conditions, suggesting their specificity in association with cognitive change. This is the first study to our knowledge to correlate cognition with AD-related proteins in the vitreous humor. Results suggest ocular proteins may have a role for early dementia detection in individuals at risk for AD.

%B J Alzheimers Dis %V 68 %P 1429-1438 %8 2019 Apr 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30856114?dopt=Abstract %R 10.3233/JAD-181104 %0 Journal Article %J J Alzheimers Dis %D 2019 %T A Brief Ischemic Postconditioning Protects Against Amyloid-β Peptide Neurotoxicity by Downregulating MLK3-MKK3/6-P38MAPK Signal in Rat Hippocampus. %A Li, Hui %A Luo, Xiao-Bing %A Xu, Yan %A Hou, Xiao-Yu %X

BACKGROUND: Oligomeric amyloid-β peptide (Aβ) is associated with dysfunctional neuronal networks and neuronal loss in the development of Alzheimer's disease (AD). Ischemic postconditioning protects against post-ischemic excitotoxicity, oxidative stress, and inflammatory process that have also been implicated in the pathogenesis of AD. Evaluating the roles of ischemic postconditioning in oligomeric Aβ-induced neurotoxicity and underlying signal events may provide potential strategy for medical therapy in AD.

OBJECTIVES: The aim of the present study was to explore whether and how a brief ischemic postconditioning protects against Aβ neurotoxicity in rat hippocampus.

METHODS: Oligomeric Aβ25-35 (20 nmol/rat) or Aβ1-42 (5 nmol/rat) was infused by intracerebroventricular injection in adult male Sprague-Dawley rats. Ischemic postconditioning, a brief episode of global brain ischemia (3 min), was conducted at 1, 3, or 7 days after Aβ treatment, respectively.

RESULTS: A brief ischemic postconditioning reduced neuronal loss and inhibited the activation of MLK3, MKK3/6, and P38MAPKs in rat hippocampal CA1 and CA3 subfields after Aβ oligomer infusion. An N-methyl-D-aspartate (NMDA) receptor antagonist amantadine, but not non-NMDA receptor antagonist CNQX, reversed the MLK3-MKK3/6-P38MAPK signal events and beneficial effect of ischemic postconditioning on neuronal survival. Such reversion was also realized by NVP-AAM077, a GluN2A-subunit-selective NMDA receptor antagonist. Moreover, posttreatment with low doses of NMDA (5 nmol-40 nmol/rat) suppressed the Aβ-induced P38MAPK signaling and imitated the neuroprotection of ischemic postconditioning against Aβ neurotoxicity.

CONCLUSIONS: Ischemic postconditioning provides neuroprotection against Aβ neurotoxicity by moderate upregulation of NMDA receptor signaling, especially GluN2A-containing NMDA receptor pathway, and thereafter downregulation of MLK3-MKK3/6-P38MAPK signal events.

%B J Alzheimers Dis %V 71 %P 671-684 %8 2019 Sep 17 %G eng %N 2 %R 10.3233/JAD-190207 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Gut Microbiota Alteration and Its Time Course in a Tauopathy Mouse Model. %A Sun, Bin-Lu %A Li, Wei-Wei %A Wang, Jun %A Xu, Ya-Li %A Sun, Hao-Lun %A Tian, Ding-Yuan %A Wang, Yan-Jiang %A Yao, Xiu-Qing %X

Emerging evidence suggests that gut microbiota dysbiosis plays a role in neurodegenerative disorders. However, whether the composition and diversity of the gut microbiota are altered in tauopathies remains largely unknown. This study was aimed to examine the diversity and composition of the gut microbiota in tauopathies, as well as the correlation with pathological changes in the brain. We collected fecal samples from 32 P301L tau transgenic mice and 32 age- and gender-matched littermate mice at different ages. The 16S ribosomal RNA sequencing technique was used to analyze the microbiota composition in feces. Brain tau pathology levels were measured by immunohistochemistry. The diversity and composition of the gut microbiota significantly changed with aging. At the phylum level, the relative abundance of Bacteroidetes was increased, while Firmicutes were decreased in P301L mice compared with that in Wt mice after 3 months of age. In addition, Actinobacteria was decreased in P301L mice at 3 and 6 months of age, meanwhile Tenericutes was decreased in P301L mice at 10 months of age. Moreover, several specific macrobiota were highly associated with the levels of paired helical filament-tau or pT231-tau protein in the brain. Our findings suggest that gut microbiota changed with aging, as well as in the tauopathy mice model. Modulation of the gut microbiota may be a potential strategy for treatment of tauopathy.

%B J Alzheimers Dis %V 70 %P 399-412 %8 2019 Jul 23 %G eng %N 2 %R 10.3233/JAD-181220 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Neuron-Specific Apolipoprotein E4 (1-272) Fragment Induces Tau Hyperphosphorylation and Axonopathy via Triggering Endoplasmic Reticulum Stress. %A Liang, Tao %A Xue, Feixiao %A Hang, Weijian %A Wen, Bin %A Zhang, Qianying %A Chen, Jiehui %A Liu, Xiaofeng %A Chen, Juan %X

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD). It is shown that apoE4 preferentially undergoes aberrant cleavage in neurons, yielding neurotoxic C-terminal-truncated apoE4 fragment. Endoplasmic reticulum (ER) stress has also been known to be involved in the pathogenesis of AD. However, little is known about the contribution of ER stress to the neurotoxicity of apoE4 fragment. In the present study, we established the neuron-specific expression human C-terminal-truncated apoE4(1-272) fragment transgenic mice and also transfected apoE4(1-272) fragment in neuroblastoma N2a cells. We found that human apoE4(1-272) fragment could trigger ER stress as evidenced by increasing the expression of ER stress markers both in vivo and in vitro. Meanwhile, the apoE4(1-272) transgenic mice presented obviously AD-like neuropathological changes, including the impairment of spatial learning and memory, prominent axonal morphological changes, and hyperphosphorylation of tau. At the same time, we also found that glycogen synthase kinase-3 activities were significantly increased. Furthermore, these neuropathological changes, especially tau hyperphosphorylation and axonal transport impairment, were significantly rescued by the ER stress protector 4-phenylbutyric acid (4-PBA) in apoE4(1-272)-transfected N2a cells. Pretreatment with 4-PBA not only decreased the protein expression of immunoglobulin binding protein (BiP) and C/EBP-homologous protein (CHOP), but also significantly reversed these defects in axonal transport. These results suggested that the neurotoxic effects of apoE4(1-272) fragment found in AD subjects, at least in part, through triggering ER stress and inducing tau hyperphosphorylation, led to the enduring impairment of axonal transport.

%B J Alzheimers Dis %V 71 %P 597-611 %8 2019 Sep 17 %G eng %N 2 %R 10.3233/JAD-190419 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Small Molecule Amyloid-β Protein Precursor Processing Modulators Lower Amyloid-β Peptide Levels via cKit Signaling. %A Chen, Ci-Di %A Zeldich, Ella %A Khodr, Christina %A Camara, Kaddy %A Tung, Tze Yu %A Lauder, Emma C %A Mullen, Patrick %A Polanco, Taryn J %A Liu, Yen-Yu %A Zeldich, Dean %A Xia, Weiming %A Van Nostrand, William E %A Brown, Lauren E %A Porco, John A %A Abraham, Carmela R %X

Alzheimer's disease (AD) is characterized by the accumulation of neurotoxic amyloid-β (Aβ) peptides consisting of 39-43 amino acids, proteolytically derived fragments of the amyloid-β protein precursor (AβPP), and the accumulation of the hyperphosphorylated microtubule-associated protein tau. Inhibiting Aβ production may reduce neurodegeneration and cognitive dysfunction associated with AD. We have previously used an AβPP-firefly luciferase enzyme complementation assay to conduct a high throughput screen of a compound library for inhibitors of AβPP dimerization, and identified a compound that reduces Aβ levels. In the present study, we have identified an analog, compound Y10, which also reduced Aβ. Initial kinase profiling assays identified the receptor tyrosine kinase cKit as a putative Y10 target. To elucidate the precise mechanism involved, AβPP phosphorylation was examined by IP-western blotting. We found that Y10 inhibits cKit phosphorylation and increases AβPP phosphorylation mainly on tyrosine residue Y743, according to AβPP751 numbering. A known cKit inhibitor and siRNA specific to cKit were also found to increase AβPP phosphorylation and lower Aβ levels. We also investigated a cKit downstream signaling molecule, the Shp2 phosphatase, and found that known Shp2 inhibitors and siRNA specific to Shp2 also increase AβPP phosphorylation, suggesting that the cKit signaling pathway is also involved in AβPP phosphorylation and Aβ production. We further found that inhibitors of both cKit and Shp2 enhance AβPP surface localization. Thus, regulation of AβPP phosphorylation by small molecules should be considered as a novel therapeutic intervention for AD.

%B J Alzheimers Dis %V 67 %P 1089-1106 %8 2019 Feb 12 %G eng %N 3 %R 10.3233/JAD-180923 %0 Journal Article %J J Alzheimers Dis %D 2019 %T An UNC5C Allele Predicts Cognitive Decline and Hippocampal Atrophy in Clinically Normal Older Adults. %A Yang, Hyun-Sik %A Chhatwal, Jasmeer P %A Xu, Jishu %A White, Charles C %A Hanseeuw, Bernard %A Rabin, Jennifer S %A Papp, Kathryn V %A Buckley, Rachel F %A Schultz, Aaron P %A Properzi, Michael J %A Gatchel, Jennifer R %A Amariglio, Rebecca E %A Donovan, Nancy J %A Mormino, Elizabeth C %A Hedden, Trey %A Marshall, Gad A %A Rentz, Dorene M %A Johnson, Keith A %A De Jager, Philip L %A Sperling, Reisa A %X

BACKGROUND: The UNC5C rs3846455G allele has been linked to poor cognitive resilience against age-related neuropathologies, but this association remains to be replicated, and the allele's effect on hippocampal neurodegeneration needs to be examined.

OBJECTIVE: To further validate the association between rs3846455G and faster cognitive decline, especially among cognitively normal older adults, and to assess whether rs3846455G predicts accelerated hippocampal volume loss in older adults.

METHODS: We assessed participants in the Harvard Aging Brain Study (HABS), a longitudinal cohort study of older adults who were clinically normal at baseline. To avoid bias from population admixture, analyses were limited to participants of European descent with longitudinal neuroimaging data (n = 174). Linear mixed effect models were used to examine the effect of rs3846455G on longitudinal change of the Preclinical Alzheimer Cognitive Composite (PACC) and MRI-measured bilateral hippocampal volume, adjusting for baseline amyloid-β (Aβ) measured by the cortical Pittsburgh Compound B PET distributed volume ratio. We also tested whether hippocampal atrophy mediates the association between rs3846455G and greater PACC decline through a mediation analysis.

RESULTS: rs3846455G was associated with greater PACC decline (β= -0.087/year, 95% CI -0.169 to -0.005, p = 0.039) after controlling for baseline Aβ. Further, rs3846455G predicted accelerated hippocampal atrophy after controlling for baseline Aβ (β= -57.3 mm3/year, 95% CI -102.8 to -11.9, p = 0.014). The association between rs3846455G and greater PACC decline was partially mediated by accelerated hippocampal atrophy (mediated effect (relative scale) = -0.014, 95% CI -0.032 to -6.0×10-4, p = 0.039).

CONCLUSION: UNC5C rs3846455G predicts greater cognitive decline and accelerated hippocampal atrophy in clinically normal older adults.

%B J Alzheimers Dis %V 68 %P 1161-1170 %8 2019 Apr 8 %G eng %N 3 %R 10.3233/JAD-180788 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Abnormal Functional Brain Networks in Mild Cognitive Impairment and Alzheimer's Disease: A Minimum Spanning Tree Analysis. %A Wang, Bin %A Miao, Liwen %A Niu, Yan %A Cao, Rui %A Li, Dandan %A Yan, Pengfei %A Guo, Hao %A Yan, Tianyi %A Wu, Jinglong %A Xiang, Jie %X

Alzheimer's disease (AD) disrupts the topological architecture of whole-brain connectivity. Minimum spanning tree (MST), which captures the most important connections in a network, has been considered an unbiased method for brain network analysis. However, the alterations in the MST of functional brain networks during the progression of AD remain unclear. Here, we performed an MST analysis to examine the alterations in functional networks among normal controls (NCs), mild cognitive impairment (MCI) patients, and AD patients. We identified substantial differences in the connections among the three groups. The maximum betweenness centrality, leaf number, and tree hierarchy of the MSTs showed significant group differences, indicating a more star-like topology in the MCI patients and a more line-like topology in the NCs and AD patients. These findings may correspond to changes in the core of the functional brain networks. For nodal properties (degree and betweenness centrality), we determined that brain regions around the cingulate gyrus, occipital lobes, subcortex, and inferior temporal gyrus showed significant differences among the three groups and contributed to the global topological alterations. The leaf number and tree hierarchy, as well as the nodal properties, were significantly correlated with clinical features in the MCI and AD patients, which demonstrated that more star-to-line topology changes were associated with worse cognitive performance in these patients. These findings indicated that MST properties could capture slight alterations in network topology, particularly for the differences between NCs and MCI patients, and may be applicable as neuroimaging markers of the early stage of AD.

%B J Alzheimers Dis %V 65 %P 1093-1107 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149457?dopt=Abstract %R 10.3233/JAD-180603 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease rs11767557 Variant Regulates EPHA1 Gene Expression Specifically in Human Whole Blood. %A Liu, Guiyou %A Zhang, Yan %A Wang, Longcai %A Xu, Jianyong %A Chen, Xiaoyun %A Bao, Yunjuan %A Hu, Yang %A Jin, Shuilin %A Tian, Rui %A Bai, Weiyang %A Zhou, Wenyang %A Wang, Tao %A Han, Zhifa %A Zong, Jian %A Jiang, Qinghua %K Alzheimer Disease %K Case-Control Studies %K China %K Gene Expression %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Polymorphism, Single Nucleotide %K Receptor, EphA1 %K Risk Assessment %X

Large-scale genome-wide association studies have reported EPHA1 rs11767557 variant to be associated with Alzheimer's disease (AD) risk in the European population. However, it is still unclear how this variant functionally contributes to the underlying disease pathogenesis. The rs11767557 variant is located approximately 3 kb upstream of EPHA1 gene. We think that rs11767557 may modify the expression of nearby genes such as EPHA1 and further cause AD risk. Until now, the potential association between rs11767557 and the expression of nearby genes has not been reported in previous studies. Here, we evaluate the potential expression association between rs11767557 and EPHA1 using multiple large-scale eQTLs datasets in human brain tissues and the whole blood. The results show that rs11767557 variant could significantly regulate EPHA1 gene expression specifically in human whole blood. These findings may further provide important supplementary information about the regulating mechanisms of rs11767557 variant in AD risk.

%B J Alzheimers Dis %V 61 %P 1077-1088 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332039?dopt=Abstract %R 10.3233/JAD-170468 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Amyloid-β25-35 Upregulates Endogenous Neuroprotectant Neuroglobin via NFκB Activation in vitro. %A Liu, Ning %A Yu, Zhanyang %A Xun, Yu %A Shu, Pan %A Yue, Yiwei %A Yuan, Shishan %A Jiang, Yinghua %A Huang, Zixuan %A Yang, Xiaoping %A Feng, Xing %A Xiang, Shuanglin %A Wang, Xiaoying %X

Neuroglobin (Ngb) has been reported to be increased in early and moderately advanced Alzheimer's disease (AD) stages but declined in the severe stage. However, its regulatory mechanisms and pathophysiological roles in the disease remain to be defined. In this study, we found that Ngb expression was significantly upregulated by low dose Aβ25-35, the neurotoxic fragment of Aβ1 - 40 and Aβ1 - 42, but was not further increased by a higher dose of Aβ25-35. Mutation analysis and supershift assay demonstrated that transcription factor Nuclear Factor κB (NFκB), κB2 and κB3 sites located in mouse Ngb promoter region were involved in dynamic regulation of Ngb expression in response to different doses of Aβ25-35 stimulation. In addition, we found that suppression of endogenous Ngb expression exacerbated Aβ25-35-induced neuronal cell death and mitochondrial dysfunction. Our results indicate that endogenous Ngb expression may be upregulated by low dose Aβ25-35, which is responsible for protecting against Aβ25-35-mediated neurotoxicity. These experimental findings suggest that upregulation of endogenous Ngb expression might be an effective intervention approach for AD.

%B J Alzheimers Dis %V 64 %P 1163-1174 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010125?dopt=Abstract %R 10.3233/JAD-180163 %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 Automated Multi-Atlas Segmentation of Hippocampal and Extrahippocampal Subregions in Alzheimer's Disease at 3T and 7T: What Atlas Composition Works Best? %A Xie, Long %A Shinohara, Russell T %A Ittyerah, Ranjit %A Kuijf, Hugo J %A Pluta, John B %A Blom, Kim %A Kooistra, Minke %A Reijmer, Yael D %A Koek, Huiberdina L %A Zwanenburg, Jaco J M %A Wang, Hongzhi %A Luijten, Peter R %A Geerlings, Mirjam I %A Das, Sandhitsu R %A Biessels, Geert Jan %A Wolk, David A %A Yushkevich, Paul A %A Wisse, Laura E M %X

BACKGROUND: Multi-atlas segmentation, a popular technique implemented in the Automated Segmentation of Hippocampal Subfields (ASHS) software, utilizes multiple expert-labelled images ("atlases") to delineate medial temporal lobe substructures. This multi-atlas method is increasingly being employed in early Alzheimer's disease (AD) research, it is therefore becoming important to know how the construction of the atlas set in terms of proportions of controls and patients with mild cognitive impairment (MCI) and/or AD affects segmentation accuracy.

OBJECTIVE: To evaluate whether the proportion of controls in the training sets affects the segmentation accuracy of both controls and patients with MCI and/or early AD at 3T and 7T.

METHODS: We performed cross-validation experiments varying the proportion of control subjects in the training set, ranging from a patient-only to a control-only set. Segmentation accuracy of the test set was evaluated by the Dice similarity coeffiecient (DSC). A two-stage statistical analysis was applied to determine whether atlas composition is linked to segmentation accuracy in control subjects and patients, for 3T and 7T.

RESULTS: The different atlas compositions did not significantly affect segmentation accuracy at 3T and for patients at 7T. For controls at 7T, including more control subjects in the training set significantly improves the segmentation accuracy, but only marginally, with the maximum of 0.0003 DSC improvement per percent increment of control subject in the training set.

CONCLUSION: ASHS is robust in this study, and the results indicate that future studies investigating hippocampal subfields in early AD populations can be flexible in the selection of their atlas compositions.

%B J Alzheimers Dis %V 63 %P 217-225 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614654?dopt=Abstract %R 10.3233/JAD-170932 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Berberine Alleviates Tau Hyperphosphorylation and Axonopathy-Associated with Diabetic Encephalopathy via Restoring PI3K/Akt/GSK3β Pathway. %A Wang, Shanshan %A He, Benhong %A Hang, Weijian %A Wu, NingHua %A Xia, Liangtao %A Wang, Xu %A Zhang, Qianying %A Zhou, Xinwen %A Feng, Zuohua %A Chen, Qingjie %A Chen, Juan %X

BACKGROUND: Axonopathy is closely linked to the development of diabetic encephalopathy induced by type II diabetes (T2D). Berberine has been shown to cross the blood-brain barrier and holds promising effect for neuronal damage in diabetes.

OBJECTIVE: The present study investigated the protective effect and the underlying mechanism of berberine on neuronal axonopathy in both in vitro and in vivo models.

METHODS: High glucose/high fat diet and streptozotocin injection-induced T2D rat model was used. Berberine was administered p.o. to T2D rat model for 10 weeks. Morris water maze test, in vivo neuronal tracing, immunohistochemistry, and western blot analysis were performed to evaluate the protective effects of berberine in T2D-induced diabetic encephalopathy rats. Primary cultured neurons were used to further explore the underlying mechanisms in vitro.

RESULTS: Berberine dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Berberine significantly attenuated memory impairment, axonopathy, and tau hyperphosphorylation, and also restored PI3K/Akt/GSK3β signaling pathway in T2D rats. In vitro, berberine induced an increase in the phosphorylation of PI3K/Akt as well as GSK3β in high glucose-treated primary neurons. Furthermore, berberine-induced PI3K/Akt activation also resulted in the dephosphorylation of tau protein, which could improve axonal transport impairment in high glucose-treated primary neurons. Pretreated neurons with LY294002, an inhibitor of PI3K, partially blocked berberine-inhibited tau phosphorylation and berberine-activated PI3K/Akt signaling pathway.

CONCLUSIONS: Berberine exerts the protective effect against cognitive deficits by improving tau hyperphosphorylation and the axonal damage through restoring PI3K/Akt/GSK3β signaling pathway.

%B J Alzheimers Dis %V 65 %P 1385-1400 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30175975?dopt=Abstract %R 10.3233/JAD-180497 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Can 11C-PiB-PET Relative Delivery R1 or 11C-PiB-PET Perfusion Replace 18F-FDG-PET in the Assessment of Brain Neurodegeneration? %A Oliveira, Francisco P M %A Moreira, Ana Paula %A de Mendonça, Alexandre %A Verdelho, Ana %A Xavier, Carolina %A Barroca, Dalila %A Rio, Joana %A Cardoso, Eva %A Cruz, Ângela %A Abrunhosa, Antero %A Castelo-Branco, Miguel %X

BACKGROUND: Pittsburgh Compound B (PiB) positron emission tomography (PET) is used to visualize in vivo amyloid plaques in the brain. Frequently the PiB examinations are complemented with a fluorodeoxyglucose (FDG) PET scan to further assess neurodegeneration.

OBJECTIVE: Our goal is to identify alternative correlates of FDG images by assessing which kinetic methods originate PiB derived relative delivery ratio (R1) images that can be correlated with the FDG images, and to compare them with PiB perfusion (pPiB) images obtained from the early-phase of PiB acquisition.

METHODS: We selected 52 patients with cognitive impairment who underwent a dynamic PiB and FDG acquisitions. To compute the R1 images, two simplified reference tissue models (SRTM and SRTM2) and two multi-linear reference tissue models (MRTM and MRTM2) were used. The pPiB images were obtained in two different time intervals.

RESULTS: All six types of images were of good quality and highly correlated with the FDG images (mean voxelwise within-subjects r > 0.92). The higher correlation was found for FDG-R1(MRTM). Regarding the voxelwise regional correlation, the higher mean all brain correlations was r = 0.825 for FDG-R1(MRTM) and statistically significant in the whole brain analysis.

CONCLUSION: All R1 and pPiB images here tested have potential to assess the metabolic impact of neurodegeneration almost as reliably as the FDG images. However, this is not enough to validate these images for a single-subject analysis compared with the FDG image, and thus they cannot yet be used clinically to replace the FDG image before such evaluation.

%B J Alzheimers Dis %V 65 %P 89-97 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30056421?dopt=Abstract %R 10.3233/JAD-180274 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Ceftriaxone Improves Cognitive Function and Upregulates GLT-1-Related Glutamate-Glutamine Cycle in APP/PS1 Mice. %A Fan, ShuJuan %A Xian, XiaoHui %A Li, Li %A Yao, XiaoGuang %A Hu, YuYan %A Zhang, Min %A Li, WenBin %X

Alzheimer's disease (AD) is characterized by progressive impairment of learning, memory, and cognitive deficits. Glutamate is the major excitatory neurotransmitter in the central nervous system and plays an important role in learning, memory, and cognition. The homeostasis and reutilization of glutamate are dependent on astrocytic uptake by glutamate transporter-1 (GLT-1) and the subsequent glutamate-glutamine cycle. Increasing evidence showed impairments in GLT-1 expression and uptake activity and glutamate-glutamine cycle in AD. Ceftriaxone (Cef) has been reported to upregulate the expression and uptake of GLT-1. Therefore, the present study was undertaken to explore whether Cef can improve cognitive deficits of APP/PS1 mice in early stage of AD by upregulating GLT-1 expression, and then promoting the glutamate-glutamine cycle. It was shown that Cef treatment significantly alleviated the cognitive deficits measured by Morris water maze test and upregulated GLT-1 protein expression in the hippocampus of APP/PS1 mice. Particularly, the activity of glutamine synthetase (GS) and the protein expression of system N glutamine transporter 1 (SN1), which are the key factors involved in the glutamate-glutamine cycle, were significantly upregulated as well after the Cef treatment. Furthermore, inhibition of GLT-1 uptake activity by dihydrokainic acid, an inhibitor of GLT-1, blocked the Cef-induced improvement on the cognitive deficits, GS activity, and SN1 expression. The above results suggested that Cef could improve cognitive deficits of APP/PS1 mice in early stage of AD by upregulating the GLT-1 expression, GS activity, and SN1 expression, which would lead to stimulating the glutamate-glutamine cycle.

%B J Alzheimers Dis %V 66 %P 1731-1743 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30452416?dopt=Abstract %R 10.3233/JAD-180708 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Changes in Expression Profiles Revealed by Transcriptomic Analysis in Peripheral Blood Mononuclear Cells of Alzheimer's Disease Patients. %A Leandro, Giovana Silva %A Evangelista, Adriane Feijó %A Lobo, Romulo Rebouças %A Xavier, Danilo Jordão %A Moriguti, Julio César %A Sakamoto-Hojo, Elza Tiemi %X

Alzheimer's disease (AD) is an age-related neurodegenerative pathology associated with accumulation of DNA damage. Inflammation and cell cycle alterations seem to be implicated in the pathogenesis of AD, although the molecular mechanisms have not been thoroughly elucidated to date. The aim of the present study was to evaluate whether peripheral blood mononuclear cells (PBMCs) of AD patients display alterations in gene expression profiles, focusing on finding markers that might improve the diagnosis of AD. Blood samples were collected from 22 AD patients and 13 healthy individuals to perform genome-wide mRNA expression. We found 593 differentially expressed genes in AD compared to controls, from which 428 were upregulated, and 165 were downregulated. By performing a gene set enrichment analysis, we observed pathways involved in inflammation, DNA damage response, cell cycle, and neuronal processes. Moreover, functional annotation analyses indicated that differentially expressed genes are strongly related to pathways associated with the cell cycle and the immune system. The results were compared with those of an independent study on hippocampus samples, and a number of genes in common between both studies were identified as potential peripheral biomarkers for AD, including DUSP1, FOS, SLC7A2, RGS1, GFAP, CCL2, ANGPTL4, and SSPN. Taken together, our results demonstrate that PBMCs of AD patients do present alterations in gene expression profiles, and these results are comparable to those previously reported in the literature for AD neurons, supporting the hypothesis that blood peripheral mononuclear cells express molecular changes that occur in the neurons of AD patients.

%B J Alzheimers Dis %V 66 %P 1483-1495 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400085?dopt=Abstract %R 10.3233/JAD-170205 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Chinese Herbal Medicine for Vascular Dementia: A Systematic Review and Meta-Analysis of High-Quality Randomized Controlled Trials. %A Xu, Qing-Qing %A Shan, Chun-Shuo %A Wang, Yong %A Shi, Yi-Hua %A Zhang, Qi-Hao %A Zheng, Guo-Qing %X

BACKGROUND: Vascular dementia (VaD) is the second common form of dementia and Chinese herbal medicine (CHM) has been used for aging-related disorders for thousands of years. However, there is still a lack of scientific evidence using CHM for VaD.

OBJECTIVE: To conduct a systematic review to assess the current evidence available for the effectiveness and safety of CHM for VaD.

METHODS: Six databases were searched for high-quality randomized-controlled clinical trials that met the requirements of at least 4 of the 7 domains of the Cochrane risk of bias tool from their inception to February 2017. RevMan 5.3 was applied for data analysis.

RESULTS: Forty studies with 42 comparisons and 3,572 individuals were included. The studies investigated the CHM versus placebo (n = 4), CHM versus western conventional treatment (WCT) (n = 36), and CHM plus WCT versus WCT (n = 2). Meta-analysis showed that CHM for VaD could improve Mini-Mental State Examination (MMSE), the Activities of Daily Living, Hasegawa's dementia scale, and clinical effective rate but had statistically similar effect based on Blessed Behavior Scale (BBS) outcome when compared with WCTs. When compared with placebo, CHMs were more beneficial in improving MMSE but showed no significant difference in BBS scores. CHM as adjuvant therapy exerted an additive anti-VaD benefit on MMSE scores. The participants of CHM group had fewer adverse events than that of the placebo group or WCT group.

CONCLUSION: The findings of the present study support, at least to an extent, that CHM can be recommended for routine use for treatment of VaD.

%B J Alzheimers Dis %V 62 %P 429-456 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439346?dopt=Abstract %R 10.3233/JAD-170856 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Circulatory Levels of Toxic Metals (Aluminum, Cadmium, Mercury, Lead) in Patients with Alzheimer's Disease: A Quantitative Meta-Analysis and Systematic Review. %A Xu, Lin %A Zhang, Wenchao %A Liu, Xianchen %A Zhang, Cuili %A Wang, Pin %A Zhao, Xiulan %X

BACKGROUND: Environmental exposure to toxic metals has been postulated to play a role in the pathophysiological processes of Alzheimer's disease (AD). However, the circulatory levels of toxic metals in AD patients are not consistent in previous studies.

OBJECTIVE: To systematically assess levels of toxic metals (aluminum, mercury, cadmium, lead) in the circulation (blood, serum/plasma) of AD patients and controls.

METHODS: PubMed, Web of Science, Science Direct, Cochrane Library, and the China National Knowledge Infrastructure (CNKI) were systematically searched to identify studies published up to January 1, 2017. Meta-analyses were performed using random-effects models and the pooled standardized mean difference (SMD) were reported with 95% confidence intervals (CI).

RESULTS: We identified 17, 7, 8, and 10 studies for aluminum, mercury, cadmium, and lead, respectively. Meta-analyses showed significantly elevated circulatory levels of aluminum (SMD = 1.08, 95% CI: 0.66, 1.50), mercury (SMD = 0.55, 95% CI, 0.15, 0.95), and cadmium (SMD = 0.62, 95% CI: 0.12, 1.11), whereas lower levels of lead (SMD = -0.23, 95% CI: -0.38, -0.07) in AD patients than in controls. Publication bias was only observed for aluminum studies, but the "trim and fill" analysis showed that the publication bias did not alter the direction of the effect. Sensitivity analyses showed no studies from the pooled analysis changed the results.

CONCLUSION: Compared to controls, circulatory levels of aluminum, mercury, and cadmium are significantly higher but the levels of lead were reduced in AD patients. These findings suggest that elevated aluminum, mercury, and cadmium in the circulation, especially in serum may play a role in the progression of AD.

%B J Alzheimers Dis %V 62 %P 361-372 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439342?dopt=Abstract %R 10.3233/JAD-170811 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Diosgenin Attenuates Lipopolysaccharide-Induced Parkinson's Disease by Inhibiting the TLR/NF-κB Pathway. %A Li, Bingyu %A Xu, Pengli %A Wu, Shuyan %A Jiang, Zhixian %A Huang, Zhijian %A Li, Qian %A Chen, Danhong %X

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of dopaminergic neurons in the substantia nigra. Diosgenin is a natural steroid saponin which was shown to play a beneficial role in Alzheimer's disease.

OBJECTIVE: This study sought to investigate the potential effect of diosgenin on a rat model of PD.

METHODS: Sprague Dawley rats were subjected to intra-striatal injection of lipopolysaccharide (LPS) and treated with diosgenin. Stepping, Whisker, and Cylinder tests were carried out to determine the motor function, and the expression of tyrosine hydroxylase was detected by immunohistochemistry. The levels of multiple proinflammatory cytokines, oxidative stress related factors and proteins involved in Toll-like receptor (TLR)/nuclear factor kappa B (NF-κB) pathway were measured. The synergistic effect of environment enrichment on diosgenin was also investigated.

RESULTS: Intra-striatal injection of LPS caused motor deficits in rats, induced inflammatory response and oxidative stress response, and activated the TLR/NF-κB pathway both in vivo and in vitro. Diosgenin could attenuate the LPS-induced alterations. Enriched environment enhanced the effect of diosgenin to ameliorate the LPS-induced motor deficits in rats and decreased the protein levels of TLR2, TLR4, and nuclear NF-κB in diosgenin treated PD rats.

CONCLUSION: Diosgenin had a beneficial effect in LPS-induced rat PD models, by suppressing the TLR/NF-κB signaling pathway. Environmental enrichment could play a synergistic effect with diosgenin, by enhancing the inhibitory effect of diosgenin on the TLR/ NF-κB signaling pathway.

%B J Alzheimers Dis %V 64 %P 943-955 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29966203?dopt=Abstract %R 10.3233/JAD-180330 %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 The Down-Expression of ACE and IDE Exacerbates Exogenous Amyloid-β Neurotoxicity in CB2R-/- Mice. %A Wang, Lin %A Shi, Fang-Xiao %A Xu, Wei-Qi %A Cao, Yun %A Li, Na %A Li, Man %A Wang, Qun %A Wang, Jian-Zhi %A Tian, Qing %A Yu, Li-Kai %A Zhou, Xin-Wen %X

Alzheimer's disease (AD) is characterized by neuritic plaques and neurofibrillary tangles. It is reported that enzymatic degradation of amyloid-β (Aβ) plays a pivotal role in Aβ accumulation and type-2 cannabinoid receptor (CB2R) participates in Aβ processing in the brain; however, the underlying mechanisms remain unclear. We determined that Aβ degradation-related proteins are significantly different between CB2R-/- mice and wild-type (WT) mice via proteomic analysis. Moreover, the data demonstrated that the angiotensin converting enzyme (ACE) and insulin-degrading enzyme (IDE) levels are substantially attenuated, and the Aβ level is significantly enhanced in CB2R-/--Aβ1 - 42 mice compared with that of WT-Aβ1 - 42 mice. Furthermore, Aβ-mediated synaptic dysfunction, the loss of memory associated proteins, and the suppression of glutamatergic transmission are more severe in CB2R-/--Aβ1 - 42 mice than that in WT-Aβ1 - 42 mice. CB2R activation could decrease Aβ1 - 40 and Aβ1 - 42 levels and enhance ACE and IDE levels with its selective agonist JWH133; however, AM630 (CB2R antagonist) abrogates all changes induced by JWH133 in N2a cells with AβPP overexpression. Taken together, our study demonstrated that the deletion of CB2R reduces exogenous Aβ degradation and aggravates the toxicity of Aβ via the reduction of ACE and IDE, which suggests that CB2R is involved in the onset of AD and a potential therapeutic target for AD.

%B J Alzheimers Dis %V 64 %P 957-971 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29991137?dopt=Abstract %R 10.3233/JAD-180142 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early Tau Burden Correlates with Higher Rate of Atrophy in Transentorhinal Cortex. %A Xie, Long %A Das, Sandhitsu R %A Wisse, Laura E M %A Ittyerah, Ranjit %A Yushkevich, Paul A %A Wolk, David A %X

Neurofibrillary tangle (NFT) pathology is linked to neurodegeneration in the medial temporal lobe (MTL). Using a tailored pipeline, we correlated atrophy rate, as measured from retrospective longitudinal MRI, with NFT burden, measured from 18F-AV-1451 PET, within MTL regions of earliest NFT pathology. In amyloid-β positive but not amyloid-β negative individuals, we found significant correlation between 18F-AV-1451 uptake and atrophy rate that was strongest in the transentorhinal cortex, the first region with NFT pathology. This supports the role of NFTs in driving neurodegeneration and the utility of 18F-AV-1451 PET and structural measurement of transentorhinal cortex in tracking early tau-mediated disease progression.

%B J Alzheimers Dis %V 62 %P 85-92 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439350?dopt=Abstract %R 10.3233/JAD-170945 %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 of Music Therapy on Cognition, Psychiatric Symptoms, and Activities of Daily Living in Patients with Alzheimer's Disease. %A Lyu, Jihui %A Zhang, Jingnan %A Mu, Haiyan %A Li, Wenjie %A Champ, Mei %A Xiong, Qian %A Gao, Tian %A Xie, Lijuan %A Jin, Weiye %A Yang, Wan %A Cui, Mengnan %A Gao, Maolong %A Li, Mo %X

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, affecting millions of older people worldwide. However, pharmacological therapies have not achieved desirable clinical efficacy in the past decades. Non-pharmacological therapies have been receiving increased attention to treat dementia in recent years.

OBJECTIVE: This study explores the effects of music therapy on cognitive function and mental wellbeing of patients with AD.

METHODS: A total number of 298 AD patients with mild, moderate, or severe dementia participated in the study. The participants with each grade of severity were randomly divided into three groups, which were a singing group, a lyric reading group, and a control group. These three groups received different interventions for three months. All participants underwent a series of tests on cognitive functions, neuropsychological symptoms, and activities of daily living at baseline, three months, and six months.

RESULTS: The analysis shows that music therapy is more effective for improving verbal fluency and for alleviating the psychiatric symptoms and caregiver distress than lyrics reading in patients with AD. Stratified analysis shows that music therapy is effective for enhancing memory and language ability in patients with mild AD and reducing the psychiatric symptoms and caregiver distress in patients with moderate or severe AD. However, no significant effect was found for activities of daily living in patients with mild, moderate, or severe AD.

CONCLUSION: This study suggests that music therapy is effective in enhancing cognitive function and mental wellbeing and can be recommended as an alternative approach to manage AD associated symptoms.

%B J Alzheimers Dis %V 64 %P 1347-1358 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29991131?dopt=Abstract %R 10.3233/JAD-180183 %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 Glucagon-Like Peptide-2 Receptor is Involved in Spatial Cognitive Dysfunction in Rats After Chronic Cerebral Hypoperfusion. %A Xie, Yan-Chun %A Yao, Zhao-Hui %A Yao, Xiao-Li %A Pan, Jian-Zhen %A Zhang, Shao-Feng %A Zhang, Yong %A Hu, Ji-Chang %X

Chronic cerebral hypoperfusion (CCH) affects the aging population and especially patients with neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. CCH is closely related to the cognitive dysfunction in these diseases. Glucagon-like peptide-2 receptor (GLP2R) mRNA and protein are highly expressed in the gut and in hippocampal neurons. This receptor is involved in the regulation of food intake and the control of energy balance and glucose homeostasis. The present study employed behavioral techniques, electrophysiology, western blotting, immunohistochemistry, quantitative real time polymerase chain reaction (qRT-PCR), and Golgi staining to investigate whether the expression of GLP2R changes after CCH and whether GLP2R is involved in cognitive impairment caused by CCH. Our findings show that CCH significantly decreased hippocampal GLP2R mRNA and protein levels. GLP2R upregulation could prevent CCH-induced cognitive impairment. It also improved the CCH-induced impairment of long-term potentiation and long-term depression. Additionally, GLP2R modulated after CCH the AKT-mTOR-p70S6K pathway in the hippocampus. Moreover, an upregulation of the GLP2R increased the neurogenesis in the dentate gyrus, neuronal activity, and density of dendritic spines and mushroom spines in hippocampal neurons. Our findings reveal the involvement of GLP2R via a modulation of the AKT-mTOR-p70S6K pathway in the mechanisms underlying CCH-induced impairments of spatial learning and memory. We suggest that the GLP2R and the AKT-mTOR-p70S6K pathway in the hippocampus are promising targets to treat cognition deficits in CCH.

%B J Alzheimers Dis %V 66 %P 1559-1576 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30452417?dopt=Abstract %R 10.3233/JAD-180782 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The GWAS Risk Genes for Depression May Be Actively Involved in Alzheimer's Disease. %A Ni, Hua %A Xu, Min %A Zhan, Gui-Lai %A Fan, Yu %A Zhou, Hejiang %A Jiang, Hong-Yan %A Lu, Wei-Hong %A Tan, Liwen %A Zhang, Deng-Feng %A Yao, Yong-Gang %A Zhang, Chen %X

Depression is one of the most frequent psychiatric symptoms observed in people during the development of Alzheimer's disease (AD). We hypothesized that genetic factors conferring risk of depression might affect AD development. In this study, we screened 31 genes, which were located in 19 risk loci for major depressive disorder (MDD) identified by two recent large genome-wide association studies (GWAS), in AD patients at the genomic and transcriptomic levels. Association analysis of common variants was performed by using summary statistics of the International Genomics of Alzheimer's Project (IGAP), and association analysis of rare variants was conducted by sequencing the entire coding region of the 31 MDD risk genes in 107 Han Chinese patients with early-onset and/or familial AD. We also quantified the mRNA expression alterations of these MDD risk genes in brain tissues of AD patients and AD mouse models, followed by protein-protein interaction network prediction to show their potential effects in AD pathways. We found that common and rare variants of L3MBTL2 were significantly associated with AD. mRNA expression levels of 18 MDD risk genes, in particular SORCS3 and OAT, were differentially expressed in AD brain tissues. 13 MDD risk genes were predicted to physically interact with core AD genes. The involvement of HACE1, NEGR1, and SLC6A15 in AD was supported by convergent lines of evidence. Taken together, our results showed that MDD risk genes might play an active role in AD pathology and supported the notion that depression might be the "common cold" of psychiatry.

%B J Alzheimers Dis %V 64 %P 1149-1161 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010129?dopt=Abstract %R 10.3233/JAD-180276 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Harpagoside Rescues the Memory Impairments in Chronic Cerebral Hypoperfusion Rats by Inhibiting PTEN Activity. %A Chen, Chen %A Zhang, Haifeng %A Xu, Hongliang %A Xue, Rui %A Zheng, Yake %A Wu, Tianwen %A Lian, Yajun %X

Vascular dementia (VaD) is the second most common dementia worldwide. Unlike Alzheimer's disease, VaD does not yet have effective therapeutic drugs. Harpagoside is the most important component extracted from Harpagophytum procumbens, a traditional Chinese medicine that has been widely used. The neuroprotective effects of harpagoside have been studied in Aβ- and MPTP-induced neurotoxicity. However, whether harpagoside is protective against VaD is not clear. In this study, with the use of chronic cerebral hypoperfusion rats, a well-known VaD model, we demonstrated that chronic administration (two months) of harpagoside was able to restore both the spatial learning/memory and fear memory impairments. Importantly, the protective effects of harpagoside were not due to alterations in the physiological conditions, metabolic parameters, or locomotor abilities of the rats. Meanwhile, we found that harpagoside suppressed the overactivation of PTEN induced by CCH by enhancing PTEN phosphorylation. Furthermore, harpagoside elevated the activity of Akt and inhibited the activity of GSK-3β, downstream effectors of PTEN. Overall, our study suggested that harpagoside treatment might be a potential therapeutic drug targeting the cognitive impairments of VaD.

%B J Alzheimers Dis %V 63 %P 445-455 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614669?dopt=Abstract %R 10.3233/JAD-171170 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Honokiol Alleviates Cognitive Deficits of Alzheimer's Disease (PS1V97L) Transgenic Mice by Activating Mitochondrial SIRT3. %A Li, Haitao %A Jia, Jianping %A Wang, Wei %A Hou, Tingting %A Tian, Yuanruhua %A Wu, Qiaoqi %A Xu, Lingzhi %A Wei, Yiping %A Wang, Xiu %X

Accumulating evidence has demonstrated that mitochondrial dysfunction is a prominent early event in the progression of Alzheimer's disease (AD). Whether protecting mitochondrial function can reduce amyloid-β oligomer (AβO)-induced neurotoxicity in PS1V97L transgenic mice remains unknown. In this study, we examined the possible protective effects of honokiol (HKL) on mitochondrial dysfunction induced by AβOs in neurons, and cognitive function in AD PS1V97Ltransgenic mice. We determined that HKL increased mitochondrial sirtuin 3 (SIRT3) expression levels and activity, which in turn markedly improved ATP production and weakened mitochondrial reactive oxygen species production. We demonstrated that the enhanced energy metabolism and attenuated oxidative stress of HKL restores AβO-mediated mitochondrial dysfunction in vitro and in vivo. Consequently, memory deficits in the PS1V97L transgenic mice were rescued by HKL in the early stages. These results suggest that HKL has therapeutic potential for delaying the onset of AD symptoms by alleviating mitochondrial impairment and increasing hyperactivation of SIRT3 in the pathogenesis of preclinical AD.

%B J Alzheimers Dis %V 64 %P 291-302 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865070?dopt=Abstract %R 10.3233/JAD-180126 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Increased Risk of Dementia in Subjective Cognitive Decline if CT Brain Changes are Present. %A Sacuiu, Simona %A Eckerström, Marie %A Johansson, Lena %A Kern, Silke %A Sigström, Robert %A Xinxin, Guo %A Östling, Svante %A Skoog, Ingmar %X

BACKGROUND: Subjective cognitive decline (SCD) has low predictive value for incident dementia.

OBJECTIVES: We examined whether CT detectable brain changes add predictive value to SCD in a population sample with high scores on the Mini-Mental State Examination.

METHODS: Subjective reports of memory and executive function were gathered in a non-demented population sample ≥70 years (n = 921). CT-brain was performed at baseline (n = 626). Brain atrophy, infarcts, and white matter lesions (WMLs) were classified using visual ratings. Dementia incidence was evaluated periodically during 12 years.

RESULTS: The prevalence of SCD was 32.5% among individuals without dementia. During follow-up, 151 individuals (16.4%) developed dementia. The risk of dementia was increased in SCD, and increased further with WMLs and cortical atrophy present. However, the positive predictive values for incident dementia were low, 25% in SCD and 41% in SCD with WMLs and cortical atrophy.

CONCLUSION: Our observations add clinical value to the use of SCD and CT to select relevant populations for interventions against dementia, but more stringent screening methods are necessary to reach individuals at risk.

%B J Alzheimers Dis %V 66 %P 483-495 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320572?dopt=Abstract %R 10.3233/JAD-180073 %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 Low Accuracy of Brief Cognitive Tests in Tracking Longitudinal Cognitive Decline in an Asian Elderly Cohort. %A Phua, April Ka Sin %A Hiu, Shaun Kuan Wei %A Goh, Win King %A Ikram, Mohammad Kamran %A Venketasubramanian, Narayanaswamy %A Tan, Boon Yeow %A Chen, Christopher Li-Hsian %A Xu, Xin %X

BACKGROUND: Researchers have questioned the utility of brief cognitive tests such as the Mini-Mental Status Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in serial administration and suggested that brief cognitive tests may not accurately track changes in Global Cognition.

OBJECTIVE: To examine the accuracy of longitudinal changes on brief cognitive tests in reflecting progression in Global Cognition measured using comprehensive neuropsychological assessments.

METHODS: Two hundred and seven participants were assessed with the MMSE, MoCA, and a validated comprehensive neuropsychological battery. Global z-scores on the battery were derived and used to assess overall and significant (≥0.5 standard deviation) decline on Global Cognition. Different patterns of decline on MMSE/MoCA were classified. Accuracy was examined using receiver operating characteristic curve, and sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were reported.

RESULTS: The overall ability of MMSE/MoCA change scores to discriminate participants who did and did not decline on Global Cognition was fair-to-moderate (AUC [95% CI] = 0.71 [0.64-0.78] & 0.73 [0.66-0.80] for overall decline; 0.78 [0.70-0.85] & 0.80 [0.73-0.86] for significant decline, respectively). Changes in MMSE/MoCA had low accuracy in identifying significant Global Cognitive Decline (PPV = 0.41 & 0.46, respectively) but high accuracy in ruling out significant decline and identifying cognitively stable participants (NPV = 0.89 & 0.88, respectively).

CONCLUSION: There is limited utility in brief cognitive tests for tracking cognitive decline. Instead, they should be used for identifying participants who remain cognitively stable on follow up. These results accentuate the importance of acknowledging the limitations of brief cognitive tests when assessing cognitive change.

%B J Alzheimers Dis %V 62 %P 409-416 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439344?dopt=Abstract %R 10.3233/JAD-170831 %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 Proteomic Profiling of Mouse Brains Exposed to Blast-Induced Mild Traumatic Brain Injury Reveals Changes in Axonal Proteins and Phosphorylated Tau. %A Chen, Mei %A Song, Hailong %A Cui, Jiankun %A Johnson, Catherine E %A Hubler, Graham K %A DePalma, Ralph G %A Gu, Zezong %A Xia, Weiming %X

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by two pathological hallmarks: Tau-containing neurofibrillary tangles and amyloid-β protein (Aβ)-containing neuritic plaques. The goal of this study is to understand mild traumatic brain injury (mTBI)-related brain proteomic changes and tau-related biochemical adaptations that may contribute to AD-like neurodegeneration. We found that both phosphorylated tau (p-tau) and the ratio of p-tau/tau were significantly increased in brains of mice collected at 3 and 24 h after exposure to 82-kPa low-intensity open-field blast. Neurological deficits were observed in animals at 24 h and 7 days after the blast using Simple Neuroassessment of Asymmetric imPairment (SNAP) test, and axon/dendrite degeneration was revealed at 7 days by silver staining. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to analyze brain tissue labeled with isobaric mass tags for relative protein quantification. The results from the proteomics and bioinformatic analysis illustrated the alterations of axonal and synaptic proteins in related pathways, including but not being limited to substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis, suggesting a potential axonal damage caused by blast-induced mTBI. Among altered proteins found in brains suffering blast, microtubule-associated protein 1B, stathmin, neurofilaments, actin binding proteins, myelin basic protein, calcium/calmodulin-dependent protein kinase, and synaptotagmin I were representative ones involved in altered pathways elicited by mTBI. Therefore, TBI induces elevated phospho-tau, a pathological feature found in brains of AD, and altered a number of neurophysiological processes, supporting the notion that blast-induced mTBI as a risk factor contributes to AD pathogenesis. LC/MS-based profiling has presented candidate target/pathways that could be explored for future therapeutic development.

%B J Alzheimers Dis %V 66 %P 751-773 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30347620?dopt=Abstract %R 10.3233/JAD-180726 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Risk Factors of Rapid Cognitive Decline in Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis. %A Song, Ya-Nan %A Wang, Ping %A Xu, Wei %A Li, Jie-Qiong %A Cao, Xi-Peng %A Yu, Jin-Tai %A Tan, Lan %X

BACKGROUND: The conclusions about risk factors for rapid cognitive decline (RCD) in Alzheimer's disease (AD) and mild cognitive impairment (MCI) remain contradictory.

OBJECTIVE: To explore the factors predicting RCD in AD and MCI.

METHODS: We searched the PubMed, EMBASE, and the Cochrane Library from inception to May 27, 2017 for studies investigating factors associated with faster cognitive progression in AD and MCI. Effect sizes were meta-analyzed using fixed-effects and random-effects models.

RESULTS: Fifty-three studies with 14,330 patients (12,396 AD and 1,934 MCI) were included in the systematic review. The following factors were identified to increase the risk of RCD in AD: Apolipoprotein E4 (ApoE4) (SMD [95% CI]: 0.52 [0.06,0.98]), early age at onset (SMD [95% CI]: -0.42 [-0.71, -0.13]), high level of education (RR = 2.05, 95% CI = 1.26 to 3.33), early appearance of extrapyramidal signs (RR = 2.18; 95% CI = 1.30 to 3.67), and neuropsychiatric conditions including hallucination (RR = 2.01, 95% CI = 1.40 to 2.87), strolling (RR = 1.99, 95% CI = 1.38 to 2.86), agitation (RR = 1.66, 95% CI = 1.23 to 2.24), and psychosis (RR = 1.42, 95% CI = 1.07 to 1.89). Instead, advanced age (≥75 years) (RR = 0.96, 95% CI = 0.93 to 0.99), diabetes (RR = 0.57; 95% CI = 0.35 to 0.93), and multidrug therapy (RR = 0.61, 95% CI = 0.60 to 0.62) would lower the risk of RCD. Furthermore, systematic research also reviewed seven risk factors associated with RCD in MCI.

CONCLUSION: ApoE4, early onset, early appearance of extrapyramidal signs, high education level, and neuropsychiatric conditions might increase the risk of RCD while older age, diabetes, and multidrug therapy were the protective factors for AD.

%B J Alzheimers Dis %V 66 %P 497-515 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320579?dopt=Abstract %R 10.3233/JAD-180476 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Stimulation of SIRT1 Attenuates the Level of Oxidative Stress in the Brains of APP/PS1 Double Transgenic Mice and in Primary Neurons Exposed to Oligomers of the Amyloid-β Peptide. %A Dong, Yang-Ting %A Cao, Kun %A Tan, Long-Chun %A Wang, Xiao-Ling %A Qi, Xiao-Lan %A Xiao, Yan %A Guan, Zhi-Zhong %X

In the study, we examined whether the silent information regulator 1 (SIRT1) can attenuate oxidative stress in the brains of mice carrying the APP/PS1 double mutation and/or in primary neonatal rat neurons exposed to oligomers of amyloid-β peptide (AβOs). Starting at 4 or 8 months of age, the transgenic mice were treated with resveratrol (RSV, a stimulator of SIRT1) or suramin (an inhibitor) (each 20 mg/kg BW/day) for two months. The primary neurons were exposed to AβOs (0.5 μM) for 48 h and thereafter RSV (20 μM) or suramin (300 mg/ml) for 24 h. Cell viability was assessed by the CCK-8 assay; SIRT1 protein and mRNA determined by western blotting and real-time PCR, respectively; senile plaques examined immunohistochemically; ROS monitored by flow cytometry; and the contents of OH-, H2O2, O2·-, and MDA, and the activities of SOD and GSH-Px measured by standard biochemical procedures. In comparison to wild-type mice or untreated primary neurons, the expression of SIRT1 was significantly lower in the brains of APP/PS1 mice or neurons exposed to AβOs. In these same systems, increased numbers of senile plaques and a high level of oxidative stress were apparent. Interestingly, these two latter changes were attenuated by treatment with RSV, but enhanced by suramin. These findings indicate that SIRT1 may be neuroprotective.

%B J Alzheimers Dis %V 63 %P 283-301 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614660?dopt=Abstract %R 10.3233/JAD-171020 %0 Journal Article %J J Alzheimers Dis %D 2018 %T White Matter Hyperintensity Predicts the Risk of Incident Cognitive Decline in Community Dwelling Elderly. %A Ding, Ding %A Xiong, Yunyun %A Zhao, Qianhua %A Guo, Qihao %A Chu, Shuguang %A Chu, Winnie W C %A Luo, Jianfeng %A Liang, Xiaoniu %A Zheng, Li %A Hong, Zhen %A Wong, Lawrence K S %A Mok, Vincent C T %K Aged %K China %K Cognitive Dysfunction %K Female %K Humans %K Independent Living %K Kaplan-Meier Estimate %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K White Matter %X

BACKGROUND: Unlike western countries, data on white matter hyperintensity (WMH) in community dwelling elderly in Asian population is very limited.

OBJECTIVE: To examine the relation between baseline WMH burden and the risk of incident cognitive decline in a community-based cohort with Chinese-dwelling elderly.

METHODS: We prospectively evaluated the incident cognitive decline for 226 participants in the Shanghai Aging Study. Baseline WMH severity was visually rated by the age-related white matter changes (ARWMC) scale based on MRI. Cox proportional hazards regression model was used to estimate the relative risk (RR) of total ARWMC scale, global ARWMC score, presence of lacune and microbleed, for incident cognitive decline by adjusting potential confounders.

RESULTS: Forty subjects were identified with incident cognitive decline (new onset 34 mild cognitive impairment and 6 dementia) during a median duration of 6 years follow-up. The incidence of cognitive decline was 3.0 (95% confidence interval [CI] 2.2-4.1) per 100 person-years. Increasing total ARWMC scale [RR1.21 (95% CI 1.06-1.39), p = 0.004)], confluent WMH [RR3.16 (95% CI 1.50-6.64), p = 0.002), and presence of lacunes [RR 2.73 (95% CI 1.21-6.15)] at baseline were independent predictors of incident cognitive decline.

CONCLUSION: Our study demonstrated that confluent WMH may increase the risk of incident cognitive decline by 3 folds in community dwelling subjects. Small vessel disease may cause heavy burden of cognitive impairment in the elderly in China.

%B J Alzheimers Dis %V 61 %P 1333-1341 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376875?dopt=Abstract %R 10.3233/JAD-170876 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Alteration of ZiBuPiYin Recipe on Proteomic Profiling of Forebrain Postsynaptic Density of db/db Mice with Diabetes-Associated Cognitive Decline. %A Chen, Jing %A Zhan, Libin %A Lu, Xiaoguang %A Xiao, Chi %A Sun, Nijing %X

Diabetes-associated cognitive decline (DACD) is a brain injury induced by diabetes mellitus, with cognitive impairment as the major symptom. Growing evidence has revealed that DACD is correlated with disruptions in synapses involved in cognition. Within synapses, more specifically in areas of postsynaptic density (PSD), there is a high concentration of proteins that receive and transduce synaptic information. In the present study, to identify the differentially expressed PSD proteins among DACD mice, ZiBuPiYin recipe (ZBPYR)-treated DACD mice and control mice, we applied isobaric tags for relative and absolute quantitation (iTRAQ) with LC-MS/MS technology, by which three biological replicates and three technical replicates were examined. A total of 24 and 23 differentially expressed proteins were observed in control versus DACD mice and in DACD versus ZBPYR-treated DACD mice, respectively. Notably, we found 'Protein processing in endoplasmic reticulum' and 'PI3K-Akt signaling pathway' might be impaired in DACD pathogenesis, while Growth factor receptor-bound protein 2 might be a crucial protein as a molecular target of the neuroprotective effects of ZBPYR. To our knowledge, this is the first study to provide a reference proteome map for DACD and ZBPYR-treated DACD mouse forebrain PSD to aid understanding the underlying mechanisms of DACD and ZBPYR.

%B J Alzheimers Dis %V 56 %P 471-489 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27886008?dopt=Abstract %R 10.3233/JAD-160691 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Altered Gut Microbiota in a Mouse Model of Alzheimer's Disease. %A Zhang, Ling %A Wang, Ying %A Xiayu, Xia %A Shi, Changhua %A Chen, Wei %A Song, Nan %A Fu, Xinjing %A Zhou, Rui %A Xu, Yan-Feng %A Huang, Lan %A Zhu, Hua %A Han, Yunlin %A Qin, Chuan %X

The topic of gut microbiota is currently attracting considerable interest as a potential factor in Alzheimer's disease (AD). However, the extent and time course of alterations in the gut microbiota, and their effects on AD pathology remain uncertain. Herein, we compared the fecal microbiomes and fecal short chain fatty acid composition (SCFAs) between wild-type and AD model mice at different ages under strictly controlled specific pathogen free conditions, and also conducted microscopic investigations of intestinal structures. Our results showed that the microbiota composition and diversity were perturbed and the level of SCFAs was reduced in AD mice, predicting alterations in more than 30 metabolic pathways, which may be associated with amyloid deposition and ultrastructural abnormalities in AD mouse intestine. These findings indicate that AD pathology might not only affect brain function directly, but also exacerbate cognitive deficits through reducing the level of SCFAs via alterations of gut microbiota induced by intestinal amyloid deposition. Our data may support a role of gut microbiota, and suggest a novel route for therapeutic intervention in AD.

%B J Alzheimers Dis %V 60 %P 1241-1257 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036812?dopt=Abstract %R 10.3233/JAD-170020 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Anesthesia/Surgery Induces Cognitive Impairment in Female Alzheimer's Disease Transgenic Mice. %A Zhang, Ce %A Zhang, Yiying %A Shen, Yuan %A Zhao, Guoqing %A Xie, Zhongcong %A Dong, Yuanlin %X

Anesthesia and/or surgery may promote Alzheimer's disease (AD) by accelerating its neuropathogenesis. Other studies showed different findings. However, the potential sex difference among these studies has not been well considered, and it is unknown whether male or female AD patients are more vulnerable to develop postoperative cognitive dysfunction. We therefore set out to perform a proof of concept study to determine whether anesthesia and surgery can have different effects in male and female AD transgenic (Tg) mice, and in female AD Tg plus Cyclophilin D knockout (CypD KO) mice. The mice received an abdominal surgery under sevoflurane anesthesia (anesthesia/surgery). Fear Conditioning System (FCS) was used to assess the cognitive function. Hippocampal levels of synaptic marker postsynaptic density 95 (PSD-95) and synaptophysin (SVP) were measured using western blot analysis. Here we showed that the anesthesia/surgery decreased the freezing time in context test of FCS at 7 days after the anesthesia/surgery in female, but not male, mice. The anesthesia/surgery reduced hippocampus levels of synaptic marker PSD-95 and SVP in female, but not male, mice. The anesthesia/surgery induced neither reduction in freezing time in FCS nor decreased hippocampus levels of PSD-95 and SVP in the AD Tg plus CypD KO mice. These data suggest that the anesthesia/surgery induced a sex-dependent cognitive impairment and reduction in hippocampus levels of synaptic markers in AD Tg mice, potentially via a mitochondria-associated mechanism. These findings could promote clinical investigations to determine whether female AD patients are more vulnerable to the development of postoperative cognitive dysfunction.

%B J Alzheimers Dis %V 57 %P 505-518 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269788?dopt=Abstract %R 10.3233/JAD-161268 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Anti-Amyloid-β and Neuroprotective Properties of a Novel Tricyclic Pyrone Molecule. %A Maezawa, Izumi %A Zou, Bende %A Di Lucente, Jacopo %A Cao, William S %A Pascual, Conrado %A Weerasekara, Sahani %A Zhang, Man %A Xie, Xinmin Simon %A Hua, Duy H %A Jin, Lee-Way %X

There is an urgent unmet need for new therapeutics for Alzheimer's disease (AD), the most common cause of dementia in the elderly. Therapeutic approaches targeting amyloid-β (Aβ) and its downstream toxicities have become major strategies in AD drug development. We have taken a rational design approach and synthesized a class of tricyclic pyrone (TP) compounds that show anti-Aβ and other neuroprotective actions. The in vivo efficacy of a lead TP named CP2 to ameliorate AD-like pathologies has been shown in mouse models. Here we report the selection and initial characterization of a new lead TP70, which exhibited an anti-Aβ therapeutic index even higher than CP2. Moreover, TP70 was able to reduce oxidative stress, inhibit acyl-coenzyme A:cholesterol acyltransferase (ACAT), and upregulate the expression of ATP-binding cassette subfamily A, member 1 (ABCA1), actions considered neuroprotective in AD. TP70 further showed excellent pharmacokinetic properties, including brain penetration and oral availability. When administered to 5xFAD mice via intraperitoneal or oral route, TP70 enhanced the overall solubility and decreased the level of cerebral Aβ, including both fibrillary and soluble Aβ species. Interestingly, TP70 enhanced N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic potential (EPSP) in the hippocampal CA1 area, increased the magnitude of NMDA-dependent hippocampal long-term potentiation (LTP), a cellular model of learning and memory, and prevented the Aβ oligomer-impaired LTP. Significantly, a single dose of TP70 administered to aged 5xFAD mice was effective in mitigating the impaired LTP induction, recorded at 24 h after administration. Our results support a potential of TP70 in clinical development for AD in view of its synergistic neuroprotective actions, ability to positively modulate NMDA receptor-mediated hippocampal plasticity, and favorable pharmacokinetic properties in rodents.

%B J Alzheimers Dis %V 58 %P 559-574 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28482635?dopt=Abstract %R 10.3233/JAD-161175 %0 Journal Article %J J Alzheimers Dis %D 2017 %T AQP4 Association with Amyloid Deposition and Astrocyte Pathology in the Tg-ArcSwe Mouse Model of Alzheimer's Disease. %A Yang, Jing %A Zhang, Rui %A Shi, Changhe %A Mao, Chengyuan %A Yang, Zhihua %A Suo, Zhenhe %A Torp, Reidun %A Xu, Yuming %X

Amyloid-β deposition in senile plaques is one of the main pathological changes in Alzheimer's disease (AD). We previously reported that aquaporin-4 (AQP4) is redistributed within the astrocytes in cerebral amyloid angiopathy in the tg-ArcSwe mouse model of AD, suggesting that AQP4 may participate in amyloid-β deposition. However, the role of AQP4 in plaque formation is not currently clear. The objective of the current study was to explore the AQP4 distribution within plaques in the tg-ArcSwe mice in more depth by the combined application of immunofluorescence cytochemistry and immunogold electron microscopy. In addition, the astrocyte marker, glial fibrillary acidic protein (GFAP), was studied in association with AQP4. We demonstrated a robust upregulation of AQP4 expression in areas of plaques. Compared to GFAP, AQP4 appeared predominantly at later stages of plaque formation, in older mice, and within the processes of astrocytes. In combination with GFAP, AQP4 differentiated plaques into three progression stages under light microscopy. This suggests that AQP4 expression was associated with amyloid deposition and astrocyte pathology in the Tg-ArcSwe mouse model of AD. This provides novel proof for the involvement of AQP4 in the process of amyloid deposition in AD.

%B J Alzheimers Dis %V 57 %P 157-169 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222512?dopt=Abstract %R 10.3233/JAD-160957 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Dietary Lycopene Supplementation Improves Cognitive Performances in Tau Transgenic Mice Expressing P301L Mutation via Inhibiting Oxidative Stress and Tau Hyperphosphorylation. %A Yu, Lixia %A Wang, Weiguang %A Pang, Wei %A Xiao, Zhonghai %A Jiang, Yugang %A Hong, Yan %X

BACKGROUND: Oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD) and other tauopathies and participates in their development by promoting hyperphosphorylation of microtubule-associated protein tau. Lycopene, as an effective antioxidant, combined with vitamin E seemed to be additive against oxidative stress.

OBJECTIVE: The present study was undertaken to examine whether lycopene or lycopene/vitamin E could exert protective effects on memory deficit and oxidative stress in tau transgenic mice expressing P301L mutation.

MATERIALS AND METHODS: P301L transgenic mice were assigned to three groups: P301L group (P301L), P301L+lycopene (Lyc), and P301L+lycopene/vitamin E (Lyc+VE). Age-matched C57BL/6J mice as wild type controls (Con) were used in the present study. Spatial memory was assessed by radial arm while passive memories were evaluated by step-down and step-through tests. Levels of tau phosphorylation were detected by western blot. Oxidative stress biomarkers were measured in the serum using biochemical assay kits.

RESULTS: Compared with the control group, P301L mice displayed significant spatial and passive memory impairments, elevated malondialdehyde (MDA) levels and decreased glutathione peroxidase (GSH-Px) activities in serum, and increased tau phosphorylation at Thr231/Ser235, Ser262, and Ser396 in brain. Supplementations of lycopene or lycopene/vitamin E could significantly ameliorate the memory deficits, observably decreased MDA concentrations and increased GSH-Px activities, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites.

CONCLUSIONS: Our findings indicated that the combination of lycopene and vitamin E antioxidants acted in a synergistic fashion to bring significant effects against oxidative stress in tauopathies.

%B J Alzheimers Dis %V 57 %P 475-482 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269786?dopt=Abstract %R 10.3233/JAD-161216 %0 Journal Article %J J Alzheimers Dis %D 2017 %T DNA Methylation and Tag SNPs of the BDNF Gene in Conversion of Amnestic Mild Cognitive Impairment into Alzheimer's Disease: A Cross-Sectional Cohort Study. %A Xie, Bing %A Liu, Zanchao %A Liu, Wenxuan %A Jiang, Lei %A Zhang, Rui %A Cui, Dongsheng %A Zhang, Qingfu %A Xu, Shunjiang %X

Alzheimer's disease (AD) is a complex multifactorial disease influenced by both genetic and epigenetic factors. This study was aimed to evaluate the interaction between brain-derived neurotrophic factor (BDNF) promoter methylation status and tag single nucleotide polymorphisms (tag SNPs) on amnestic mild cognitive impairment (aMCI) and its conversion to AD. A total of 506 aMCI patients and 728 cognitive normal controls were included in the cross-sectional analysis. Patients (n = 458) from aMCI cohort were selected in the 5-year longitudinal study and classified into two groups: aMCI-stable group (n = 330) and AD-conversion group (n = 128). BDNF promoter methylation was detected by bisulfite-PCR amplification and pyrosequencing. Seven tag SNPs were genotyped by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Elevation of BDNF promoter methylation status was associated with aMCI and AD conversion. The higher methylation levels at CpG5 site showed significant main interactive effects between group and time (F = 8.827, p = 0.005). Genetic analysis revealed rs2030324 and rs6265 were associated with aMCI and rs6265 was associated with AD conversion. The interaction between DNA methylation of CpG5 and AA genotype of rs6265 had a risk role in the development of aMCI (p = 0.019, OR = 1.233, 95% CI: 1.117-1.303) and its progression to AD (p = 0.003, OR = 1.399, 95% CI: 1.198-1.477). The interactions between DNA methylation (CpG5) of the BDNF gene promoter and the tag SNP (rs6265) play important roles in the etiology of aMCI and its conversion to AD.

%B J Alzheimers Dis %V 58 %P 263-274 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28387675?dopt=Abstract %R 10.3233/JAD-170007 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Elevation of Peripheral BDNF Promoter Methylation Predicts Conversion from Amnestic Mild Cognitive Impairment to Alzheimer's Disease: A 5-Year Longitudinal Study. %A Xie, Bing %A Xu, Yao %A Liu, Zanchao %A Liu, Wenxuan %A Jiang, Lei %A Zhang, Rui %A Cui, Dongsheng %A Zhang, Qingfu %A Xu, Shunjiang %X

Epigenetic aberrations have been identified as biomarkers to predict the risk of Alzheimer's disease (AD). This study aimed to evaluate whether altered DNA methylation status of BDNF promoter could be used as potential epigenetic biomarkers for predicting the progression from amnestic mild cognitive impairment (aMCI) to AD. A total of 506 aMCI patients and 728 cognitively normal controls were recruited in the cross-sectional analyses. Patients (n = 458) from aMCI cohort were classified into two groups after 5-year follow-up: aMCI-stable group (n = 330) and AD-conversion group (n = 128). DNA methylation of BDNF promoter was detected by bisulfite-PCR amplification and pyrosequencing. The DNA methylation levels of CpG1 and CpG2 in promoter I and CpG5 and CpG6 in promoter IV of BDNF gene were significantly higher in the aMCI group than in the control group at baseline and also were increased in the conversion group compared with the non-conversion group at 5-year follow up time point. CpG5 in BDNF promoter IV had the highest AUC of 0.910 (95% CI: 0.817-0.983, p < 0.05). Kaplan-Meier analysis showed a significant AD conversion propensity for aMCI patients with high methylation levels of CpG5 (HR = 1.96, 95% CI: 1.07-2.98, p < 0.001). Multivariate Cox regression analysis revealed elevated methylation status of CpG5 was a significant independent predictor for AD conversion (HR = 3.51, p = 0.013). These results suggest that elevation of peripheral BDNF promoter methylation might be used as potential epigenetic biomarkers for predicting the conversion from aMCI to AD.

%B J Alzheimers Dis %V 56 %P 391-401 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27935556?dopt=Abstract %R 10.3233/JAD-160954 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Experiences of People with Dementia and Their Caregivers in Dementia Diagnosis. %A Lian, Yan %A Xiao, Lily Dongxia %A Zeng, Fan %A Wu, Xianmu %A Wang, Zhen %A Ren, Hui %X

BACKGROUND: People can live well with dementia if they are diagnosed early and receive early interventions and appropriate dementia management and care. However, dementia is currently under-detected and under-diagnosed. The diagnosis rate is around 50% only in higher-income countries and 5-10% only in low- and middle-income countries. Studies on consumers' experiences in engaging in dementia diagnosis in a socio-cultural context are much needed in order to generate research evidence to inform person-centered dementia care and services.

OBJECTIVE: The aim of the study was to understand the experiences of people with dementia and their caregivers in engaging in dementia diagnosis.

METHODS: An interpretative study design informed by Gadamer's hermeneutic principles was applied to the present study to achieve the aim of the study. The study was strengthened by applying a social ecological framework to the study design. In total, 23 participants contributed to the interviews or focus group. Thematic analysis was applied to data analysis.

RESULTS: Four themes were determined from data and described as: capabilities to detect the memory loss in an early stage, perceptions and beliefs of dementia in the community, different journeys toward the diagnosis and expectations of a smooth journey for others. These findings illuminate a social ecological perspective of improving early detection and timely diagnosis of dementia in the community settings.

CONCLUSION: The findings of this study have implications for policy, resource, and practice development. Consumers expect that government subsidized dementia care services in primary care and specialist care settings are needed in order to enable consumer-driven timely diagnosis and dementia management in home care settings.

%B J Alzheimers Dis %V 59 %P 1203-1211 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731450?dopt=Abstract %R 10.3233/JAD-170370 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Impaired Center-Surround Suppression in Patients with Alzheimer's Disease. %A Zhuang, Xianbo %A Chen, Yanxiu %A Zhuang, Xianpeng %A Xing, Tao %A Chen, Tuanzhi %A Jiang, Guisheng %A Yang, Xiafeng %X

Alzheimer's disease (AD) is often associated with declined visual processing abilities. Here we tested whether the functions of center-surround suppression- a hallmark property in the visual system- are altered by AD. To this end, we recruited three groups of participants (AD, elderly, and young) in a motion direction discrimination task, in which we measured the temporal duration threshold of a  drifting Gabor with varying stimulus sizes. We first replicated the phenomena of center-surround suppression that the required duration for discriminating a high contrast grating decreases with increasing stimulus size. We then showed that the magnitudes of suppression varied among the three groups. There was progressive reduction of suppression in the elderly and AD groups compared with the young group. Interestingly, we found that the levels of suppression can predict the severity of dementia in the AD group. Our results suggest that AD is associated with impaired center-surround functions in the visual motion processing pathway.

%B J Alzheimers Dis %V 55 %P 1101-1108 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767987?dopt=Abstract %R 10.3233/JAD-160603 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Increased Serum miR-206 Level Predicts Conversion from Amnestic Mild Cognitive Impairment to Alzheimer's Disease: A 5-Year Follow-up Study. %A Xie, Bing %A Liu, Zanchao %A Jiang, Lei %A Liu, Wei %A Song, Mei %A Zhang, Qingfu %A Zhang, Rui %A Cui, Dongsheng %A Wang, Xueyi %A Xu, Shunjiang %X

Evidence suggests that individuals with amnestic mild cognitive impairment (aMCI) tend to progress to probable Alzheimer's disease (AD) with aging. This study was performed to examine whether circulating miRNAs could be potential predictors for the progression of aMCI to AD. A total of 458 patients with aMCI were included in this study, and the clinical data were collected at two time points: the baseline and the follow-up assessment. These aMCI patients were classified into two groups after 5 years: aMCI-stable group (n = 330) and AD-conversion group (n = 128). The expression of miR-206 and miR-132 and the levels of BDNF and SIRT1 in serum were detected using a quantitative real-time RT-PCR (qPCR) and the ELISA method, respectively. Kaplan-Meier method (Log-rank test) was used for univariate survival analysis. Cox proportional hazard model was used to estimate the prognostic value of miRNAs in conversion from aMCI to AD. At the baseline, serum levels of miR-206 in aMCI-AD group were significantly elevated compared to aMCI-aMCI group and the same trend was found at 5-year follow-up time point as well. There were no significant differences in serum levels of miR-132 between the conversion and non-conversion group at both time points. Kaplan-Meier analysis showed significant correlation between AD conversion and higher serum levels of miR-206 for aMCI patients (HR = 3.60, 95% CI: 2.51- 5.36, p < 0.001). Multivariate Cox regression analysis revealed that serum miR-206 and its target BDNF were significant independent predictors for AD conversion (HR = 4.22, p < 0.001). These results suggested that increased serum miR-206 level might be a potential predictor of conversion from aMCI to AD.

%B J Alzheimers Dis %V 55 %P 509-520 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662297?dopt=Abstract %R 10.3233/JAD-160468 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Integration of Multilocus Genetic Risk into the Default Mode Network Longitudinal Trajectory during the Alzheimer's Disease Process. %A Su, Fan %A Shu, Hao %A Ye, Qing %A Xie, Chunming %A Yuan, Baoyu %A Zhang, Zhijun %A Bai, Feng %X

The aim of the study was to investigate the cognitive significance of the changes in default mode network (DMN) during the process of Alzheimer's disease (AD) and the genetic basis that drives the alteration. Eighty-seven subjects with mild cognitive impairment (MCI) and 131 healthy controls (HC) were employed at baseline, and they had the genetic risk scores (GRS) based on the GWAS-validated AD-related top loci. Eleven MCIs who converted to AD (c-MCIs), 32 subjects who remained stable (nc-MCIs), and 56 HCs participated in the follow-up analyses after an average of 35 months. Decreased functional connectivity (FC) within temporal cortex was identified for MCIs at baseline, which was partially determined by the GRS; moreover, compensations may occur within the frontal-parietal brain to maintain relatively intact cognition. During the follow-ups, c-MCIs exhibited more FC declines within the prefrontal-parietal lobes and parahippocampal gyrus/hippocampus than the HCs and nc-MCIs. The GRS did not significantly vary among the three groups, whereas associations were identified at risky alleles and FC declines in all AD spectra. Interestingly, the influence of APOEɛ4 varied as the disease progressed; APOEɛ4 was associated with longitudinal FC decreases only for HCs in the single variance-based analyses and deteriorated DMN integration in nc-MCIs by combining the effects of other loci. However, the GRS without APOEɛ4 predicted FC decline for converters. It is suggested that the integration of multilocus genetic risk predicted the longitudinal trajectory of DMN and may be used as a clinical strategy to track AD progression.

%B J Alzheimers Dis %V 56 %P 491-507 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035927?dopt=Abstract %R 10.3233/JAD-160787 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Intensive 'Brain Training' Intervention Fails to Reduce Amyloid Pathologies or Cognitive Deficits in Transgenic Mouse Models of Alzheimer's Disease. %A Anderson, Maria %A Xu, Feng %A Ou-Yang, Ming-Hsuan %A Davis, Judianne %A Van Nostrand, William E %A Robinson, John K %X

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia in the elderly. Amyloid-β protein (Aβ) depositions in both the brain parenchyma and the cerebral vasculature are recognized as important pathological components that contribute to the cognitive impairments found in individuals with AD. Because pharmacological options have been minimally effective in treating cognitive impairment to date, interest in the development of preventative lifestyle intervention strategies has increased in the field. One controversial strategy, cognitive-specific stimulation, has been studied previously in human participants and has been widely commercialized in the form of 'brain-training games.' In the present study, we developed a highly controlled, isolated cognitive training intervention program for mice. Two transgenic mouse lines, one that develops Aβ deposition largely in brain parenchyma, and another in the cerebral microvasculature, progressed through a series of domain-specific tasks for an average of 4 months. Despite the high intensity and duration of the intervention, we found little evidence of positive benefits for AD amyloid pathologies and post-training cognitive testing in these two models. Taken together, these results support the current evidence in human studies that cognitive-specific stimulation does not lead to a measurable reduction in AD pathology or an improvement in general brain health.

%B J Alzheimers Dis %V 55 %P 1109-1121 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767989?dopt=Abstract %R 10.3233/JAD-160674 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Multifunctional Compound AD-35 Improves Cognitive Impairment and Attenuates the Production of TNF-α and IL-1β in an Aβ25-35-induced Rat Model of Alzheimer's Disease. %A Li, Lin %A Xu, Shaofeng %A Liu, Lifei %A Feng, Rentian %A Gong, Yongxiang %A Zhao, Xuyang %A Li, Jiang %A Cai, Jie %A Feng, Nan %A Wang, Ling %A Wang, Xiaoliang %A Peng, Ying %X

The dyshomeostasis of transition metal ions, accumulation of amyloid-β (Aβ) senile plaques and neuroinflammatory response found in the brain of patients with Alzheimer's disease (AD) have been suggested to be involved in AD pathogenesis. Novel compounds capable of targeting metal-Aβ species and neuroinflammation would be valuable. AD-35 is such a patented small-molecule compound derived from innovative modification of the chemical structure of donepezil. This compound could moderately inhibit acetylcholinesterase and metal-induced Aβ aggregation in vitro and showed disassembly of Aβ aggregates. The effects of AD-35 on cognitive impairments and neuroinflammatory changes caused by intracerebroventricular injection of Aβ25-35 were studied in rats. Compared to sham group, Aβ25-35 injection significantly led to learning and memory deficits, astrocyte activation, and pro-inflammatory cytokines releases (TNF-α and IL-1β). Further studies indicated that the phosphorylation of extracellular signal-regulated kinase was involved in astrocyte activation and pro-inflammatory cytokines production. Oral administration of AD-35 could markedly attenuate Aβ25-35 injection-induced astrocyte activation, pro-inflammatory cytokines TNF-α and IL-1β release, and memory deficits. On the contrary, donepezil only showed inhibition of IL-1β production, but failed to block astrocyte activation and TNF-α production. These results showed that AD-35 would be a novel multi-mechanism drug for the prevention and/or treatment of AD.

%B J Alzheimers Dis %V 56 %P 1403-1417 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157092?dopt=Abstract %R 10.3233/JAD-160587 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Pazopanib Reduces Phosphorylated Tau Levels and Alters Astrocytes in a Mouse Model of Tauopathy. %A Javidnia, Monica %A Hebron, Michaeline L %A Xin, Yue %A Kinney, Nikolas G %A Moussa, Charbel E-H %X

Hyperphosphorylation and aggregation of tau protein is a critical factor in many neurodegenerative diseases. These diseases are increasing in prevalence, and there are currently no cures. Previous work from our group and others has shown that tyrosine kinase inhibitors (TKIs) can stimulate autophagy, decrease pathological proteins, and improve symptoms in models of neurodegeneration. Here we examined the role of pazopanib in mouse models that express either human mutant P301L tau (TauP301L) or triple mutant amyloid precursor protein (3x-AβPP). The TauP301L mouse expresses P301L tau under the control of a prion promoter in both neurons and astrocytes, reminiscent of some human tauopathies. Pazopanib crosses the blood-brain barrier with no detectable peripheral off-side effects, and decreases p-tau in TauP301L mice. Pazopanib reaches a brain concentration sufficient for inhibition of several tyrosine kinases, including vascular endothelial growth factor receptors (VEGFRs). Further, pazopanib does not affect microglia but reduces astrocyte levels toward nontransgenic controls in TauP301L mice. Pazopanib does not alter amyloid beta levels or astrocytes in 3x-AβPP mice but modulates a number of inflammatory markers (IP-10, MIP-1α, MIP-1β, and RANTES). These data suggest that pazopanib may be involved in p-tau clearance and modulation of astrocytic activity in models of tauopathies.

%B J Alzheimers Dis %V 60 %P 461-481 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869476?dopt=Abstract %R 10.3233/JAD-170429 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Pen-2 and Presenilin are Sufficient to Catalyze Notch Processing. %A Hu, Chen %A Xu, Junjie %A Zeng, Linlin %A Li, Ting %A Cui, Mei-Zhen %A Xu, Xuemin %X

Presenilin-1 (PS1) or presenilin-2 (PS2), nicastrin (NCT), anterior pharynx-defective 1 (Aph-1), and presenilin enhancer-2 (Pen-2) have been considered the minimal essential subunits required to form an active γ-secretase complex. Besides PS, which has been widely believed to function as the catalytic subunit of the complex, the functional roles of the other subunits in the γ-secretase complex remain debatable. In the current study, we set out to determine the role of Pen-2 in γ-secretase activity. To this end, using knockout cells in combination with siRNA and immunoprecipitation approaches, our results revealed that Pen-2 together with presenilin are sufficient to form a functionally active enzyme to process Notch. Specifically, our data demonstrated that Pen-2 plays a crucial role in substrate binding, a mechanism by which Pen-2 contributes directly to the catalytic mechanism of γ-secretase activity. Our data also suggested that there may be different requirements for components to process AβPP and Notch. This information would be important for therapeutic strategy aimed at inhibition or modulation of γ-secretase activity.

%B J Alzheimers Dis %V 56 %P 1263-1269 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28234257?dopt=Abstract %R 10.3233/JAD-161094 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Prevalence, Risk Factors, and Complaints Screening Tool Exploration of Subjective Cognitive Decline in a Large Cohort of the Chinese Population. %A Hao, Lixiao %A Wang, Xiaoni %A Zhang, Ling %A Xing, Yue %A Guo, Qihao %A Hu, Xiaochen %A Mu, Bin %A Chen, Yili %A Chen, Guanqun %A Cao, Jing %A Zhi, Xiaodong %A Liu, Jiaojiao %A Li, Xuanyu %A Yang, Liu %A Li, Jiachen %A Du, Wenying %A Sun, Yu %A Wang, Ting %A Liu, Zhen %A Liu, Zheng %A Zhao, Xuexue %A Li, Hongyan %A Yu, Yang %A Wang, Xue %A Jia, Jianguo %A Han, Ying %X

BACKGROUND: Substantial studies have reported the prevalence and the affecting factors of subjective cognitive decline (SCD). The complaints screening scale has also been used for probing. However, little is known in China.

OBJECTIVE: To investigate the prevalence and risk factors of SCD, and explore an SCD complaints screening scale in China.

METHODS: Stratified cluster random sampling was conducted. 2,689 residents aged 60-80 years completed questionnaire 1. 814 residents were included for clinical and neuropsychological evaluations. Two standards were used to make the diagnosis of mild cognitive impairment (MCI) and SCD, and a preliminary screening rate comparison was carried out. Finally, we assessed the risk factors of SCD and the correlation between the SCD-questionnaire 9 (SCD-Q9) and the Auditory Verbal Learning Test-Long Delay Free Recall (AVLT-LR).

RESULTS: 1) Standard 1 (ADNI2): the prevalence of SCD was 18.8% (95% CI = 14.7-22.9%) and zero conformed to six criteria (SCD plus). 2) Standard 2 (Jak/Bondi): the prevalence of SCD was 14.4% (95% CI = 10.7-18.1%). 3) Standard 1 had a relatively higher "false" positive rate, whereas Standard 2 had higher "false" negative rate. 4) Age, low education, fewer close friends, and daily drinking were independent risk factors for SCD progressing to MCI. 5) Total points of SCD-Q9 were negatively correlated to the value of AVLT-LR.

CONCLUSIONS: The prevalence of SCD is high in the ShunYi District in Beijing, China. Age, low education, less social support, and daily drinking are independent risk factors. The brief SCD-Q9 can be used as a reference.

%B J Alzheimers Dis %V 60 %P 371-388 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869471?dopt=Abstract %R 10.3233/JAD-170347 %0 Journal Article %J J Alzheimers Dis %D 2017 %T proBDNF Accelerates Brain Amyloid-β Deposition and Learning and Memory Impairment in APPswePS1dE9 Transgenic Mice. %A Chen, Jia %A Zhang, Tao %A Jiao, Shusheng %A Zhou, Xinfu %A Zhong, Jinhua %A Wang, Yanjiang %A Liu, Juan %A Deng, Juan %A Wang, Shuiping %A Xu, Zhiqiang %X

BACKGROUND: Alzheimer's disease (AD) is pathologically known for the amyloid-β (Aβ) deposition, neurofibrillary tangles, and neuronal loss in the brain. The precursor of brain-derived neurotrophic factor (proBDNF) before proteolysis has opposing functions to its mature form in neuronal survival and neurite growth. However, the role of proBDNF in the pathogenesis of AD remains unclear.

OBJECTIVE: To investigate the effects of proBDNF on neurons in vitro, and on learning and memory impairment and brain Aβ production in a transgenic AD mouse model (APPswePS1dE9).

METHODS: We here examined the effects of proBDNF on the viability (MTT assay) and neurite growth (morphologic measurement) of the primary neurons in vitro. After the intracerebroventricular injection of adeno-associated virus-proBDNF (AAV-proBDNF), we then investigated the learning and memory impairment (Morris water maze) and Aβ deposition in the brains of the AD mice.

RESULTS: The results showed that proBDNF could inhibit neuronal viability and neurite growth in vitro, enhance Aβ levels, and accelerate its deposition in the brain, which was consistent with the learning and memory impairment of AD mice, likely dependent on the membrane receptor of p75NTR.

CONCLUSIONS: Our findings suggest that proBDNF may exert a crucially negative effect during AD pathogenesis andprogression.

%B J Alzheimers Dis %V 59 %P 941-949 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697556?dopt=Abstract %R 10.3233/JAD-161191 %0 Journal Article %J J Alzheimers Dis %D 2017 %T PSD-93 Attenuates Amyloid-β-Mediated Cognitive Dysfunction by Promoting the Catabolism of Amyloid-β. %A Yu, Linjie %A Liu, Yi %A Yang, Hui %A Zhu, Xiaolei %A Cao, Xiang %A Gao, Jun %A Zhao, Hui %A Xu, Yun %X

Amyloid-β (Aβ) is a key neuropathological hallmark of Alzheimer's disease (AD). Postsynaptic density protein 93 (PSD-93) is a key scaffolding protein enriched at postsynaptic sites. The aim of the present study was to examine whether PSD-93 overexpression could alleviate Aβ-induced cognitive dysfunction in APPswe/PS1dE9 (APP/PS1) mice by reducing Aβ levels in the brain. The level of PSD-93 was significantly decreased in the hippocampus of 6-month-old APP/PS1 mice compared with that in wild-type mice. Following lentivirus-mediated PSD-93 overexpression, cognitive function, synaptic function, and amyloid burden were investigated. The open field test, Morris water maze test, and fear condition test revealed that PSD-93 overexpression ameliorated spatial memory deficits in APP/PS1 mice. The facilitation of long-term potentiation induction was observed in APP/PS1 mice after PSD-93 overexpression. The expression of somatostatin receptor 4 (SSTR4) and neprilysin was increased, while the amyloid plaque load and Aβ levels were decreased in the brains of APP/PS1 mice. Moreover, PSD-93 interacted with SSTR4 and affected the level of SSTR4 on cell membrane, which was associated with the ubiquitination. Together, these findings suggest that PSD-93 attenuates spatial memory deficits and decreases amyloid levels in APP/PS1 mice, which might be associated with Aβ catabolism, and overexpression of PSD-93 might be a potential therapy for AD.

%B J Alzheimers Dis %V 59 %P 913-927 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697571?dopt=Abstract %R 10.3233/JAD-170320 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Radiopharmaceuticals for Assessment of Altered Metabolism and Biometal Fluxes in Brain Aging and Alzheimer's Disease with Positron Emission Tomography. %A Xie, Fang %A Peng, Fangyu %X

Aging is a risk factor for Alzheimer's disease (AD). There are changes of brain metabolism and biometal fluxes due to brain aging, which may play a role in pathogenesis of AD. Positron emission tomography (PET) is a versatile tool for tracking alteration of metabolism and biometal fluxes due to brain aging and AD. Age-dependent changes in cerebral glucose metabolism can be tracked with PET using 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG), a radiolabeled glucose analogue, as a radiotracer. Based on different patterns of altered cerebral glucose metabolism, 18F-FDG PET was clinically used for differential diagnosis of AD and Frontotemporal dementia (FTD). There are continued efforts to develop additional radiopharmaceuticals or radiotracers for assessment of age-dependent changes of various metabolic pathways and biometal fluxes due to brain aging and AD with PET. Elucidation of age-dependent changes of brain metabolism and altered biometal fluxes is not only significant for a better mechanistic understanding of brain aging and the pathophysiology of AD, but also significant for identification of new targets for the prevention, early diagnosis, and treatment of AD.

%B J Alzheimers Dis %V 59 %P 527-536 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28671127?dopt=Abstract %R 10.3233/JAD-170280 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Rapidly Progressive Frontotemporal Dementia Associated with MAPT Mutation G389R. %A Sun, Lin %A Chen, Kathryn %A Li, Xia %A Xiao, Shifu %X

Frontotemporal dementia includes a large spectrum of neurodegenerative disorders. Here, we report the case of a young patient with MAPT mutation G389R, who was 27 years old when he progressively developed severe behavioral disturbances. Initially, he presented with slowly progressive personality change. After 1 year, he exhibited moderate dementia with extrapyramidal and pyramidal symptoms. MRI showed frontotemporal atrophy. He rapidly progressed to severe dementia 3 years after onset. Genetic testing revealed a heterozygous guanine to cytosine mutation at the first base of codon 389 (c.1165G>A) of MAPT, the tau gene, resulting in a glycine to arginine substitution in the patient and two unaffected relatives. We predicted the model of mutant tau protein through I-TASSER software, and speculated the structural change of tau protein caused by mutant site. We also detected the MAPT gene transcript and methylation of samples from peripheral blood leucocytes in an attempt to explain the possible mechanisms of incomplete penetrance, although there were not positive findings. This case is remarkable because of the early onset and rapid progression of the disease.

%B J Alzheimers Dis %V 55 %P 777-785 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802239?dopt=Abstract %R 10.3233/JAD-160802 %0 Journal Article %J J Alzheimers Dis %D 2017 %T SH2B1 is Involved in the Accumulation of Amyloid-β42 in Alzheimer's Disease. %A Shen, Yijun %A Xia, Yiling %A Meng, Shiquan %A Lim, Nastasia K H %A Wang, Wenan %A Huang, Fude %X

Alzheimer's disease (AD) is characterized by deficits in learning and memory abilities, as well as pathological changes of amyloid-β (Aβ) plaque and neurofibrillary tangle formation in the brain. Insulin has been identified as a modulator of the neuronal pathways involved in learning and memory, and is also implicated as a modulator of Aβ and tau metabolism. Disrupted insulin signaling pathways are evident in AD patients and it is understood that type 2 diabetes can increase the risk of developing AD, suggesting a possible link between metabolic disorders and neurodegeneration. SH2B1 is a key protein in the insulin signaling pathway involved in regulating the activity of the insulin receptor. To further identify the role of the insulin signaling pathway in the pathology of AD, SH2B (dSH2B homologue in flies) in neurons was partially knocked out or overexpressed in an AD Drosophila model expressing Aβ42. Partial knockout of neuronal SH2B in the Aβ42-expressing Drosophila had a detrimental effect on mobility and neurotransmission, and increased levels and intraneuronal accumulation of Aβ42, as assessed by ELISA and immunostaining. Alternatively, partial overexpression of neuronal SH2B in the Aβ42-expressing Drosophila improved lifespan, mobility, and neurotransmission, as well as decreased levels and intraneuronal accumulation of Aβ42. Thus, SH2B1 may be an upstream modulator of Aβ metabolism, acting to inhibit Aβ accumulation, and has a role in the pathogenesis of AD. SH2B1 may therefore have potential as a therapeutic target for this common form of dementia.

%B J Alzheimers Dis %V 55 %P 835-847 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802221?dopt=Abstract %R 10.3233/JAD-160233 %0 Journal Article %J J Alzheimers Dis %D 2017 %T SORL1 Variants Show Different Association with Early-Onset and Late-Onset Alzheimer's Disease Risk. %A Liu, Guiyou %A Sun, Jing-Yi %A Xu, Meiling %A Yang, Xiao-Yi %A Sun, Bao-Liang %X

A recent study sequenced the full coding region of SORL1 in 1,255 early-onset Alzheimer's disease (EOAD) cases and 1,938 control individuals, and investigated the contribution of genetic variability in SORL1 to EOAD risk in a European cohort. This study identified six common variants and five low frequency variants in the SORL1 coding sequence. However, none of these 11 variants was significantly associated with EOAD risk after adjusting for multiple testing. We consider whether these 11 SORL1 variants identified in European EOAD contribute to late-onset Alzheimer's disease (LOAD) risk in individuals of European ancestry. Here, we investigated these 11 SORL1 variants identified in European EOAD and LOAD risk in individuals of European ancestry using a large-scale LOAD GWAS. Our results indicate that three genetic variants rs2070045, rs2276412, and rs17125548 as well as their tagged genetic variants contribute to LOAD risk in European population. We further investigate whether these variants could affect SORL1 expression using multiple expression quantitative trait loci (eQTLs) datasets. Our findings suggest that three genetic variants rs2070045, rs1699102, and rs3824968 could significantly regulate SORL1 expression in human brain tissues. We believe that our findings further provide important supplementary information about the involvement of the SORL1 variants in LOAD risk.

%B J Alzheimers Dis %V 58 %P 1121-1128 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527213?dopt=Abstract %R 10.3233/JAD-170005 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tai Chi Chuan and Baduanjin Increase Grey Matter Volume in Older Adults: A Brain Imaging Study. %A Tao, Jing %A Liu, Jiao %A Liu, Weilin %A Huang, Jia %A Xue, Xiehua %A Chen, Xiangli %A Wu, Jinsong %A Zheng, Guohua %A Chen, Bai %A Li, Ming %A Sun, Sharon %A Jorgenson, Kristen %A Lang, Courtney %A Hu, Kun %A Chen, Shanjia %A Chen, Lidian %A Kong, Jian %X

The aim of this study is to investigate and compare how 12-weeks of Tai Chi Chuan and Baduanjin exercise can modulate brain structure and memory function in older adults. Magnetic resonance imaging and memory function measurements (Wechsler Memory Scale-Chinese revised, WMS-CR) were applied at both the beginning and end of the study. Results showed that both Tai Chi Chuan and Baduanjin could significantly increase grey matter volume (GMV) in the insula, medial temporal lobe, and putamen after 12-weeks of exercise. No significant differences were observed in GMV between the Tai Chi Chuan and Baduanjin groups. We also found that compared to healthy controls, Tai Chi Chuan and Baduanjin significantly improved visual reproduction subscores on the WMS-CR. Baduanjin also improved mental control, recognition, touch, and comprehension memory subscores of the WMS-CR compared to the control group. Memory quotient and visual reproduction subscores were both associated with GMV increases in the putamen and hippocampus. Our results demonstrate the potential of Tai Chi Chuan and Baduanjin exercise for the prevention of memory deficits in older adults.

%B J Alzheimers Dis %V 60 %P 389-400 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869478?dopt=Abstract %R 10.3233/JAD-170477 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases. %A Nilson, Ashley N %A English, Kelsey C %A Gerson, Julia E %A Whittle, T Barton %A Crain, C Nicolas %A Xue, Judy %A Sengupta, Urmi %A Castillo-Carranza, Diana L %A Zhang, Wenbo %A Gupta, Praveena %A Kayed, Rakez %X

It is well-established that inflammation plays an important role in Alzheimer's disease (AD) and frontotemporal lobar dementia (FTLD). Inflammation and synapse loss occur in disease prior to the formation of larger aggregates, but the contribution of tau to inflammation has not yet been thoroughly investigated. Tau pathologically aggregates to form large fibrillar structures known as tangles. However, evidence suggests that smaller soluble aggregates, called oligomers, are the most toxic species and form prior to tangles. Furthermore, tau oligomers can spread to neighboring cells and between anatomically connected brain regions. In addition, recent evidence suggests that inspecting the retina may be a window to brain pathology. We hypothesized that there is a relationship between tau oligomers and inflammation, which are hallmarks of early disease. We conducted immunofluorescence and biochemical analyses on tauopathy mice, FTLD, and AD subjects. We showed that oligomers co-localize with astrocytes, microglia, and HMGB1, a pro-inflammatory cytokine. Additionally, we show that tau oligomers are present in the retina and are associated with inflammatory cells suggesting that the retina may be a valid non-invasive biomarker for brain pathology. These results suggest that there may be a toxic relationship between tau oligomers and inflammation. Therefore, the ability of tau oligomers to spread may initiate a feed-forward cycle in which tau oligomers induce inflammation, leading to neuronal damage, and thus more inflammation. Further mechanistic studies are warranted in order to understand this relationship, which may have critical implications for improving the treatment of tauopathies.

%B J Alzheimers Dis %V 55 %P 1083-1099 %G ENG %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716675?dopt=Abstract %R 10.3233/JAD-160912 %0 Journal Article %J J Alzheimers Dis %D 2017 %T TMEM230 Accumulation in Granulovacuolar Degeneration Bodies and Dystrophic Neurites of Alzheimer's Disease. %A Siedlak, Sandra L %A Jiang, Yinfei %A Huntley, Mikayla L %A Wang, Luwen %A Gao, Ju %A Xie, Fei %A Liu, Jingyi %A Su, Bo %A Perry, George %A Wang, Xinglong %X

Transmembrane Protein 230 (TMEM230) is a newly identified protein associated with Parkinson's disease (PD) found in Lewy bodies and Lewy neurites of patients with PD or dementia with Lewy body disease. However, TMEM230 has not yet been investigated in the most common neurodegenerative disorder, Alzheimer's disease (AD). Here, we demonstrate that the expression of TMEM230 is specifically increased in neurons in AD patients. Importantly, both granulovacuolar degeneration (GVD) and dystrophic neurites (DNs), two prominent characteristic pathological structures associated with AD, contain TMEM230 aggregates. TMEM230 immunoreactivity can be detected in neurofibrillary tangles-containing neurons and hyperphosphorylated tau positive DNs. TMEM230 accumulation is also noted around senile plaques. These findings identifying TMEM230 as a component of GVD and DNs suggest TMEM230 dysregulation as a likely mechanism playing an important role in the pathogenesis of AD.

%B J Alzheimers Dis %V 58 %P 1027-1033 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527219?dopt=Abstract %R 10.3233/JAD-170190 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Urine AD7c-NTP Predicts Amyloid Deposition and Symptom of Agitation in Patients with Alzheimer's Disease and Mild Cognitive Impairment. %A Zhang, Nan %A Zhang, Liling %A Li, Yan %A Gordon, Marc L %A Cai, Li %A Wang, Ying %A Xing, Mengya %A Cheng, Yan %X

BACKGROUND: Expression of neuronal thread protein (NTP), which is considered to be related to neuritic sprouting and neuronal death, may be elevated in brain tissue, cerebrospinal fluid, and even urine in patients with Alzheimer's disease (AD).

OBJECTIVE: In this study, we analyzed the correlation between urine AD-associated NTP (AD7c-NTP) level, and amyloid-β (Aβ) deposition, and clinical symptoms in AD and mild cognitive impairment (MCI).

METHODS: Twenty-two patients with mild to moderate AD and 8 subjects with MCI were recruited. Aβ deposition was measured with [11C]-labeled Pittsburgh compound B (PiB)-positron emission tomography (PET) in all participants. Urine AD7c-NTP levels were measured using enzyme-linked immunosorbent assay. Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory (NPI) were used to evaluate cognitive function and behavioral psychological symptoms, respectively.

RESULTS: Fourteen (63.6%) of AD patients and 2 (25.0%) of MCI subjects were Aβ positive on PiB-PET. There was a significant difference in urine AD7c-NTP level between Aβ positive (2.27±2.22 ng/ml) and negative (0.55±0.60 ng/ml) subjects (p = 0.018). Using 1.46 ng/ml as a cut-off value, 68.8% of Aβ positive subjects showed elevated urine AD7c-NTP level, and 92.9% of Aβ negative subjects showed normal urine AD7c-NTP level. There were no relationships between urine AD7c-NTP level and MMSE and total NPI scores. However, AD7c-NTP level positively correlated with agitation score on NPI.

CONCLUSIONS: Urine AD7c-NTP had high specificity and moderate sensitivity in predicting Aβ deposition among patients with cognitive impairment. Furthermore, urine AD7c-NTP level strongly correlated with the symptom of agitation.

%B J Alzheimers Dis %V 60 %P 87-95 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28777752?dopt=Abstract %R 10.3233/JAD-170383 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Visuospatial Functioning in Cerebral Amyloid Angiopathy: A Pilot Study. %A Valenti, Raffaella %A Charidimou, Andreas %A Xiong, Li %A Boulouis, Gregoire %A Fotiadis, Panagiotis %A Ayres, Alison %A Riley, Grace %A Kuijf, Hugo J %A Reijmer, Yael D %A Pantoni, Leonardo %A Gurol, M Edip %A Davidsdottir, Sigurros %A Greenberg, Steven M %A Viswanathan, Anand %X

Cerebral amyloid angiopathy (CAA) is a contributor to cognitive impairment in the elderly. We hypothesized that the posterior cortical predilection of CAA would cause visual-processing impairment. We systematically evaluated visuospatial abilities in 22 non-demented CAA patients. Neurocognitive evaluation demonstrated visuoperceptual impairment (23% on Benton Facial Recognition Test [BFRT] and 13.6% on Benton Judgment of Line Orientation Test [BJLO]). BFRT was inversely correlated with white matter hyperintensities volume and BJLO with parietal cerebral microbleeds. This pilot study highlights the presence of visual-processing deficits in CAA. The impairment could be related to global disease severity in addition to local brain injury.

%B J Alzheimers Dis %V 56 %P 1223-1227 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222510?dopt=Abstract %R 10.3233/JAD-160927 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Aberrant Spontaneous Brain Activity in Patients with Mild Cognitive Impairment and concomitant Lacunar Infarction: A Resting-State Functional MRI Study. %A Ni, Ling %A Liu, Renyuan %A Yin, Zhenyu %A Zhao, Hui %A Nedelska, Zuzana %A Hort, Jakub %A Zhou, Fei %A Wu, Wenbo %A Zhang, Xin %A Li, Ming %A Yu, Haiping %A Zhu, Bin %A Xu, Yun %A Zhang, Bing %K Aged %K Aged, 80 and over %K Brain %K Brain Mapping %K Cognitive Dysfunction %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Rest %K Stroke, Lacunar %X

BACKGROUND: Lacunar infarctions (LI) have been associated with a cognitive decline and an increased risk of dementia. Whether and how the pattern of spontaneous brain activity in patients with mild cognitive impairment (MCI) differs in subjects with and without concomitant LI remains unclear.

OBJECTIVE: To compare the pattern of spontaneous brain activity in MCI patients with versus those without LI using resting-state functional magnetic resonance imaging (rs-fMRI).

METHODS: Forty-eight MCI patients, including 22 with LI [MCI-LI] and 26 without LI [MCI-no LI], and 28 cognitive normal subjects underwent rs-fMRI post-processed using regional homogeneity (ReHo) and the amplitude of low-frequency fluctuation (ALFF) methods.

RESULTS: Compared with cognitively normal subjects, the MCI-LI patients had decreased ReHo in the precuneus/cuneus (Pcu/CU) and insula; decreased ALFF in the Pcu/CU and frontal lobe; and increased ALFF and ReHo in the temporal lobe. While the MCI-no LI group had increased ReHo and ALFF in the bilateral hippocampus and parahippocampal gyrus, frontal lobe, and decreased ALFF and ReHo in the temporal lobe. Compared with the MCI-no LI patients, those with MCI-LI had decreased ALFF in the frontal lobe; decreased ReHo in the Pcu/CU and insula; and increased ALFF and ReHo in the temporal lobe (p <  0.05, AlphaSim corrected). In MCI-LI patients, the MOCA scores showed a relatively weak correlation with ALFF values in the medial frontal gyrus (r = 0.432, p = 0.045) (of borderline significance after Bonferroni correction).

CONCLUSIONS: The spontaneous brain activities in MCI-LI were distinct from MCI-no LI. The probable compensatory mechanism observed in MCI-no LI might be disrupted in MCI with LI due to vascular damage.

%B J Alzheimers Dis %V 50 %P 1243-54 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836013?dopt=Abstract %R 10.3233/JAD-150622 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Age-Related Changes in the Synaptic Density of Amyloid-β Protein Precursor and Secretases in the Human Cerebral Cortex. %A Pliássova, Anna %A Canas, Paula M %A Xavier, Ana Carolina %A da Silva, Beatriz S %A Cunha, Rodrigo A %A Agostinho, Paula %X

Amyloid-β protein precursor (AβPP) is involved in synaptic formation and function. In the human cingulate cortex, AβPP was preferentially located in the presynaptic active zone as in rodents, indicating a preserved subsynaptic AβPP distribution across species and brain regions. Synaptic AβPP immunoreactivity was decreased with aging in cortical samples collected from autopsies of males (20-80 years), whereas the synaptic levels of α-secretase (ADAM10) and β-secretase (BACE1) did not significantly change. Decreased AβPP levels may be related to lower allostasis of synapses in the aged brain and their greater susceptibility to dysfunction characteristic of the onset of neurodegenerative disorders.

%B J Alzheimers Dis %V 52 %P 1209-14 %8 2016 Apr 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104908?dopt=Abstract %R 10.3233/JAD-160213 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Aging as a Precipitating Factor in Chronic Restraint Stress-Induced Tau Aggregation Pathology, and the Protective Effects of Rosmarinic Acid. %A Shan, Ye %A Wang, Dan-Dan %A Xu, Yu-Xia %A Wang, Chu %A Cao, Lan %A Liu, Yun-Sheng %A Zhu, Cui-Qing %K Aging %K Animals %K Antioxidants %K Brain %K Cinnamates %K Corticotropin-Releasing Hormone %K Depsides %K Disease Models, Animal %K HEK293 Cells %K HSP90 Heat-Shock Proteins %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Microscopy, Immunoelectron %K NIMA-Interacting Peptidylprolyl Isomerase %K Peptidylprolyl Isomerase %K Phosphorylation %K Precipitating Factors %K Receptors, Corticotropin %K Restraint, Physical %K Stress, Psychological %K tau Proteins %K Transfection %X

Stress is an important risk factor of Alzheimer's disease (AD). It has been evidenced that stress could induce tau phosphorylation and increase tau insolubility in brain; however, little is known about the interactional effect of stress with aging on tauopathy. Therefore, we explored the effects of aging on stress-induced tauopathy and the potential mechanism in mouse model of chronic restraint stress (CRS). Here we found that in general, the level of phosphorylated tau (P-tau) was higher in brain of middle-aged mice than that in adult mice under physiological conditions. CRS-induced tau phosphorylation and its insolubility were more prominent in middle-aged mice. The increase of AT8-labeled insoluble P-tau was dramatic in middle-aged mice, which was highly ubiquitinated but did not form PHF structures. The levels of chaperones were relatively lower in middle-aged mice brain; CRS further reduced the expression, especially for HDJ2/HSP40. CRS also suppressed the expression of Pin1, the peptidylprolyl cis/trans isomerase, in middle-aged mice but not in adult mice. Downregulation of HSP40 or Pin1 caused an increase of transfected extraneous tau in 293 cells. Rosmarinic acid (RA) could effectively suppress the elevation of P-tau and insoluble P-tau formation induced by CRS, and reversed the abnormal changes of chaperones and Pin1 particularly in middle-aged mice. Taken together, our findings provided evidence that aging could be a promoting factor in stress-induced tauopathy, which was relevant with malregulation of chaperones and Pin1, and RA might be a promising beneficial agent for stress-induced tauopathy.

%B J Alzheimers Dis %V 49 %P 829-44 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26577520?dopt=Abstract %R 10.3233/JAD-150486 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Alcohol Consumption and Incident Dementia: Evidence from the Sydney Memory and Ageing Study. %A Heffernan, Megan %A Mather, Karen A %A Xu, Jing %A Assareh, Amelia A %A Kochan, Nicole A %A Reppermund, Simone %A Draper, Brian %A Trollor, Julian N %A Sachdev, Perminder %A Brodaty, Henry %X

Alcohol consumption is a potentially modifiable risk factor for dementia, but the literature is not completely consistent. This inconsistency may be partly due to an interaction with the apolipoprotein E (APOE) genotype, an established risk factor for Alzheimer's dementia. The aim of this study was to examine whether alcohol consumption is associated with incident dementia or decline in specific cognitive domains over 4 years, and if this effect is modified by APOEɛ4 status. Non-demented community dwelling older adults (70-90 years) from an ongoing longitudinal study were assessed for cognitive impairment in attention/processing speed, language, executive function, visuospatial ability, and memory. Incident dementia was diagnosed according to DSM-IV criteria. Compared to those who did not drink in the previous 12 months, neither low consumption (HR 0.64 95% CI 0.3-1.4) or risky consumption (HR 0.58 95% CI 0.2-1.5) was associated with incident dementia. Carriers of the APOEɛ4 allele were more likely to develop dementia, but there was no significant interaction with alcohol consumption.

%B J Alzheimers Dis %V 52 %P 529-38 %8 2016 Mar 29 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031466?dopt=Abstract %R 10.3233/JAD-150537 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Alzheimer's Disease Risk Genes and Lipid Regulators. %A El Gaamouch, Farida %A Jing, Ping %A Xia, Jiahong %A Cai, Dongming %X

Brain lipid homeostasis plays an important role in Alzheimer's disease (AD) and other neurodegenerative disorders. Aggregation of amyloid-β peptide is one of the major events in AD. The complex interplay between lipids and amyloid-β accumulation has been intensively investigated. The proportions of lipid components including phospholipids, sphingolipids, and cholesterol are roughly similar across different brain regions under physiological conditions. However, disruption of brain lipid homeostasis has been described in AD and implicated in disease pathogenesis. Moreover, studies suggest that analysis of lipid composition in plasma and cerebrospinal fluid could improve our understanding of the disease development and progression, which could potentially serve as disease biomarkers and prognostic indicators for AD therapies. Here, we summarize the functional roles of AD risk genes and lipid regulators that modulate brain lipid homeostasis including different lipid species, lipid complexes, and lipid transporters, particularly their effects on amyloid processing, clearance, and aggregation, as well as neuro-toxicities that contribute to AD pathogenesis.

%B J Alzheimers Dis %V 53 %P 15-29 %8 2016 Apr 23 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27128373?dopt=Abstract %R 10.3233/JAD-160169 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Associations between a Capsaicin-Rich Diet and Blood Amyloid-β Levels and Cognitive Function. %A Liu, Cheng-Hui %A Bu, Xian-Le %A Wang, Jun %A Zhang, Tao %A Xiang, Yang %A Shen, Lin-Lin %A Wang, Qing-Hua %A Deng, Bo %A Wang, Xin %A Zhu, Chi %A Yao, Xiu-Qing %A Zhang, Meng %A Zhou, Hua-Dong %A Wang, Yan-Jiang %X

BACKGROUND: Capsaicin-rich diets are common worldwide. Capsaicin has been shown to have favorable effects on various diseases including atherosclerosis, cardiovascular diseases, stroke, obesity, hypertension, cancer, and gastrointestinal and inflammatory diseases. The impact of capsaicin on Alzheimer's disease (AD), which is the most common form of dementia in the elderly, remains unknown.

OBJECTIVE: To investigate the correlations of capsaicin intake with cognition and blood markers of AD.

METHODS: A total of 338 participants aged 40 years or older were enrolled from communities. Dietary habits regarding chili pepper consumption were collected using a Food Frequency Questionnaire (FFQ). Cognitive function was measured using the Chinese version of the Mini-Mental State Examination (MMSE). Blood amyloid-β (Aβ)40 and Aβ42 were measured with ELISA kits.

RESULTS: In univariate analysis, MMSE scores (r = 0.209, p < 0.001), serum Aβ40 levels (r = -0.149, p = 0.006), the ratio of Aβ42/Aβ40 (r = 0.11, p = 0.043) and total serum Aβ levels (r = -0.097, p = 0.075), but not serum Aβ42 levels (r = 0.17, p = 0.757), were significantly correlated with total capsaicin diet scores. In multivariate analysis, total capsaicin diet scores were positively associated with MMSE scores and inversely associated with serum Aβ40 levels, and total serum Aβ levels, but not serum Aβ42 levels and the ratio of Aβ42/Aβ40, after adjustment for age, gender, educational level, smoking history, alcohol consumption, body mass index (BMI) and comorbidities.

CONCLUSION: These findings suggest that a capsaicin-rich diet may exert favorable effects on AD blood biomarkers and cognitive function in middle-aged and elderly adults.

%B J Alzheimers Dis %V 52 %P 1081-8 %8 2016 Apr 08 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079706?dopt=Abstract %R 10.3233/JAD-151079 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Biomarker Exposure-Response Analysis in Mild-To-Moderate Alzheimer's Disease Trials of Bapineuzumab. %A Russu, Alberto %A Samtani, Mahesh N %A Xu, Steven %A Adedokun, Omoniyi J %A Lu, Ming %A Ito, Kaori %A Corrigan, Brian %A Raje, Sangeeta %A Liu, Enchi %A Brashear, H Robert %A Styren, Scot %A Hu, Chuanpu %X

BACKGROUND: Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimer's disease (AD) patients.

OBJECTIVE: To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling.

METHODS: Biomarker data from two Phase III studies were combined to model the impact of bapineuzumab exposure on week-71 change from baseline in brain amyloid burden by 11C-labeled Pittsburgh compound B (PiB) PET imaging (global cortical average of the Standardized Uptake Value ratio values), cerebrospinal fluid (CSF) phosphorylated (p)-tau concentrations, and brain volumetrics (brain boundary shift integral) by magnetic resonance imaging. Bapineuzumab or placebo was administered as a 1-hour intravenous infusion every 13 weeks for 78 weeks. Pharmacokinetic/pharmacodynamic modeling helped determine the most appropriate exposure-response model and estimate the impact of disease-relevant covariates (baseline biomarker value, APOE*E4 allele copy number, and baseline disease status as measured by Mini-Mental State Examination score) on the three biomarkers.

RESULTS: Linear exposure-response relationships with negative and significant slope terms were observed for PiB PET and CSF p-tau concentration. Baseline biomarker value and APOE*E4 carrier status were significant covariates for both biomarkers. No exposure-response relationship on brain boundary shift integral was detected.

CONCLUSIONS: Bapineuzumab treatment induced exposure-dependent reductions in brain amyloid burden. Effects on CSF p-tau concentrations were significant only in APOE*E4 carriers. No apparent influence of bapineuzumab exposure on brain volume could be demonstrated.

%B J Alzheimers Dis %V 53 %P 535-46 %8 2016 May 03 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163805?dopt=Abstract %R 10.3233/JAD-151065 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebral Amyloid Angiopathy (CAA)-Related Inflammation: Comparison of Inflammatory CAA and Amyloid-β-Related Angiitis. %A Chu, Shuguang %A Xu, Feijia %A Su, Ya %A Chen, Hong %A Cheng, Xin %K Apolipoproteins E %K Cerebral Amyloid Angiopathy %K Headache %K Humans %K Inflammation %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Seizures %K Vasculitis, Central Nervous System %X

Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a relatively rare syndrome of reversible encephalopathy and could be divided into two subtypes of inflammatory CAA (ICAA) and amyloid-β-related angiitis (ABRA) according to histopathology. We present a case of pathologically proved ABRA with partial seizures and headache, and a focal lesion in the right temporal lobes on magnetic resonance imaging. Summarized from previous 139 ABRA and ICAA cases, ABRA is preferred when the lesion is enhanced on MRI and requires combination drug therapy, while ICAA is highly suspected with ApoE genotype of ɛ4/ɛ4. More clinical markers for diagnosis of CAA-ri warrant further researches.

%B J Alzheimers Dis %V 51 %P 525-32 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890776?dopt=Abstract %R 10.3233/JAD-151036 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cholesteryl Ester Transfer Protein Intimately Involved in Dyslipidemia-Related Susceptibility to Cognitive Deficits in Type 2 Diabetic Patients. %A Sun, Jie %A Cai, Rongrong %A Huang, Rong %A Wang, Pin %A Tian, Sai %A Sun, Haixia %A Xia, Wenqing %A Wang, Shaohua %X

BACKGROUND: Cholesteryl ester transfer protein (CETP) is involved in diabetic dyslipidemia.

OBJECTIVE: We aim to test the hypothesis that CETP might be of importance in mediating dyslipidemia-related susceptibility to cognitive deficits in diabetic patients.

METHODS: We recruited 190 type 2 diabetic patients and divided them into two groups according to the Montreal Cognitive Assessment (MoCA) score. The association between CETP and cognitive decline was analyzed with logistic regression and stratification.

RESULTS: There were 110 diabetic patients with mild cognition impairment (MCI) and 80 healthy cognition subjects as controls. Dyslipidemia is more common among diabetic patients with MCI; they had a significant increase of serum CETP concentrations, which was negatively correlated with MoCA (r = -0.638; p < 0.001). Negative correlations were also found between the serum CETP concentration with the Auditory Verbal Learning Test (r = -0.266; p = 0.008), indicating memory deficit. Logistic regression analysis revealed that CETP concentration was an independent factor of diabetic MCI (p < 0.001). Further stratification study showed that high serum levels of CETP was an independent risk factor of MCI in diabetic patients with a low density lipoproteins level ≥2.59 mmol/L, or high density lipoproteins level ≤1.0 mmol/L for men and ≤1.3 mmol/L for women, or TG level ≥1.7 mmol/L, after adjusting for age, sex, education, and glucose control (all ps < 0.05).

CONCLUSIONS: CETP was intimately involved in dyslipidemia-related susceptibility to cognitive decline, especially memory function in type 2 diabetic patients.

%B J Alzheimers Dis %V 54 %P 175-84 %8 2016 Aug 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497473?dopt=Abstract %R 10.3233/JAD-160053 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Clinical utility of the informant AD8 as a dementia case finding instrument in primary healthcare. %A Chan, Qun Lin %A Xu, Xin %A Shaik, Muhammad Amin %A Chong, Steven Shih Tsze %A Hui, Richard Jor Yeong %A Chen, Christopher Li-Hsian %A Dong, YanHong %K Aged %K Aged, 80 and over %K Dementia %K Female %K Humans %K Language %K Logistic Models %K Male %K Mass Screening %K Middle Aged %K Neuropsychological Tests %K Primary Health Care %K Reproducibility of Results %K ROC Curve %K Sensitivity and Specificity %K Singapore %K Surveys and Questionnaires %X

The informant AD8 has excellent discriminant ability for dementia case finding in tertiary healthcare settings. However, its clinical utility for dementia case finding at the forefront of dementia management, primary healthcare, is unknown. Therefore, we recruited participants from two primary healthcare centers in Singapore and measured their performance on the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), and a local formal neuropsychological battery, in addition to the AD8. Logistic regression was conducted to examine the associations between demographic factors and dementia. Area under the receiver operating characteristics (ROC) curve analysis was used to establish the optimal cut-off points for dementia case finding. Of the 309 participants recruited, 243 (78.7%) had CDR = 0, 22 (7.1%) CDR = 0.5, and 44 (14.2%) CDR ≥1. Age was strongly associated with dementia, and the optimal age for dementia case finding in primary healthcare settings was ≥75 years. In this age group, the AD8 has excellent dementia case finding capability and was superior to the MMSE and equivalent to the MoCA [AD8 AUC (95% CI): 0.95 (0.91-0.99), cut-off: ≥3, sensitivity: 0.90, specificity: 0.88, PPV: 0.79 and NPV: 0.94; MMSE AUC (95% CI): 0.87 (0.79-0.94), p = 0.04; MoCA AUC (95% CI): 0.88 (0.82-0.95), p = 0.06]. In conclusion, the AD8 is well suited for dementia case finding in primary healthcare settings.

%B J Alzheimers Dis %V 49 %P 121-7 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444776?dopt=Abstract %R 10.3233/JAD-150390 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cognitive Profile and its Association with Neuroimaging Markers of Non-Demented Cerebral Amyloid Angiopathy Patients in a Stroke Unit. %A Xiong, Li %A Davidsdottir, Sigurros %A Reijmer, Yael D %A Shoamanesh, Ashkan %A Roongpiboonsopit, Duangnapa %A Thanprasertsuk, Sekh %A Martinez-Ramirez, Sergi %A Charidimou, Andreas %A Ayres, Alison M %A Fotiadis, Panagiotis %A Gurol, Edip %A Blacker, Deborah L %A Greenberg, Steven M %A Viswanathan, Anand %K Aged %K Atrophy %K Brain %K Cerebral Amyloid Angiopathy %K Cognition %K Cognition Disorders %K Female %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Stroke %X

BACKGROUND: Cerebral amyloid angiopathy (CAA) is increasingly recognized as a cause of cognitive impairment in the elderly, but the cognitive profile in patients with the disease has not been well characterized.

OBJECTIVE: To characterize the neuropsychological profile of CAA patients without dementia and to determine the association between cognitive performance in different domains and neuroimaging lesions characteristic of CAA.

METHODS: Fifty-eight non-demented CAA patients were compared to 138 cognitively normal subjects using a standard neuropsychological test battery. Total brain volume (TBV), white matter hyperintensities, number of lobar cerebral microbleeds, hippocampal volume, and cortical superficial siderosis in all CAA patients were assessed. The association between these neuroimaging markers and neuropsychological performance in different cognitive domains in the CAA group were analyzed.

RESULTS: Patients with CAA had significantly worse performance on all individual neuropsychological domains tested, when compared to the cognitive normal group. The cognitive decline of CAA patients was most noticeable in tests for processing speed with a Z score of -1.92±1.56 (mean±SD), then followed by executive function (-0.93±1.01), episodic memory (-0.87±1.29), semantic fluency (-0.73±1.06), and attention (-0.42±0.98). TBV of the CAA patients was correlated with processing speed (β= 0.335, p = 0.03) and executive function (β= 0.394, p = 0.01).

CONCLUSIONS: Non-demented patients with CAA had cognitive deficits in multiple areas. Lower TBV was related to slower processing speed and worse executive function.

%B J Alzheimers Dis %V 52 %P 171-8 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060947?dopt=Abstract %R 10.3233/JAD-150890 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Comparative Study Evaluating the Impact of Physical Exercise on Disease Progression in a Mouse Model of Alzheimer's Disease. %A Maliszewska-Cyna, Ewelina %A Xhima, Kristiana %A Aubert, Isabelle %X

Evidence suggests that physical exercise can serve as a preventive strategy against Alzheimer's disease (AD). In contrast, much less is known about the impact of exercise when it is introduced after cognitive deficits are established. Using the TgCRND8 mouse model of amyloidosis, we compared the effects of exercise as an intervention strategy aimed at altering disease progression. Voluntary running for 1 month or 2 months was introduced in 3-month-old TgCRND8 mice, which exhibit amyloid-beta (Aβ) plaque pathology and cognitive deficits at this age. Specifically, we examined Aβ plaque load, spatial memory, and neurogenesis in the dentate gyrus in the hippocampus. After 1 month of running, TgCRND8 mice spent more time in the novel arm of the Y-maze compared to the familiar arms, indicating improved memory. The levels of doublecortin (a marker of immature neurons) were increased in TgCRND8 mice running for 1 month, but with no significant difference in the number of new mature neurons or plaque burden. As the disease progressed, running prevented further deficits in the Y-maze performance and hippocampal neurogenesis and it reduced plaque load pathology in TgCRND8 mice running for 2 months, compared to non-running transgenics. Therefore, the impact of running on memory, neurogenesis, and amyloid pathology was of greater significance when sustained through later stages of the disease.

%B J Alzheimers Dis %V 53 %P 243-57 %8 2016 May 06 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163797?dopt=Abstract %R 10.3233/JAD-150660 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cycloheximide Treatment Causes a ZVAD-Sensitive Protease-Dependent Cleavage of Human Tau in Drosophila Cells. %A Geng, Junhua %A Xia, Lu %A Li, Wanjie %A Zhao, Changqi %A Dou, Fei %K Animals %K Apoptosis %K Caspase 3 %K Cell Line %K Cycloheximide %K Drosophila %K Drosophila Proteins %K Drug Evaluation, Preclinical %K Humans %K Oligopeptides %K Peptide Hydrolases %K Protease Inhibitors %K Protein Synthesis Inhibitors %K tau Proteins %K Time %X

Neurofibrillary tangles are the main pathological feature of Alzheimer's disease. Insoluble tau protein is the major component of neurofibrillary tangles. Defects in the tau protein degradation pathway in neurons can lead to the accumulation of tau and its subsequent aggregation. Currently, contradictory results on the tau degradation pathway have been reported by different groups. This discrepancy is most likely due to different cell lines and methods used in those studies. In this study, we found that cycloheximide treatment induced mild activation of a ZVAD-sensitive protease in Drosophila Kc cells, resulting in cleavage of tau at its C-terminus; this cleavage could generate misleading tau protein degradation pattern results depending on the antibodies used in the assay. Because cycloheximide is a broadly used chemical reagent for the study of protein degradation, the unexpected artificial effect we observed here indicates that cycloheximide is not suitable for the study of tau degradation. Other methods, such as inducible expression systems and pulse-chase assays, may be more appropriate for studying tau degradation under physiological conditions.

%B J Alzheimers Dis %V 49 %P 1161-8 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599052?dopt=Abstract %R 10.3233/JAD-150423 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Decreased Inter-Hemispheric Functional Connectivity in Cognitively Intact Elderly APOE ɛ4 Carriers: A Preliminary Study. %A Luo, Xiao %A Qiu, Tiantian %A Xu, Xiaojun %A Huang, Peiyu %A Gu, Quanquan %A Shen, Zhujing %A Yu, Xinfeng %A Jia, YunLu %A Guan, Xiaojun %A Song, Ruirui %A Zhang, Minming %K Aged %K Aging %K Apolipoprotein E4 %K Brain %K Brain Mapping %K Female %K Functional Laterality %K Genotyping Techniques %K Heterozygote %K Humans %K Magnetic Resonance Imaging %K Male %K Memory %K Neuropsychological Tests %K Rest %X

The apolipoprotein E (APOE) ɛ4 allele is the best-known genetic risk factor for developing sporadic Alzheimer's disease (AD). According to neuroimaging studies, the APOE ɛ4 allele is associated with localized altered brain function. However, in long-range circuitry, APOE ɛ4 allele-related alterations in functional communication between hemispheres have rarely been directly investigated. We examined the alteration of resting-state functional connectivity (RSFC) between inter-hemispheric homotopic regions in cognitively intact, elderly APOE ɛ4 carriers. The voxel-mirrored homotopic connectivity method was used to assess the inter-hemispheric RSFC. The current study included 13 cognitively intact, elderly APOE ɛ4 carriers (with at least one copy of APOE ɛ4 allele) and 22 well-matched ɛ3 homozygotes. Comparisons between the two groups were conducted, and subsequently, the correlation between the differential inter-hemispheric RSFC and cognitive ability was analyzed. Compared with ɛ3 homozygotes, APOE ɛ4 carriers showed decreased inter-hemispheric RSFC in the bilateral medial temporal lobe (MTL) and orbital frontal cortex (OFC). Moreover, in APOE ɛ4 carriers, the inter-hemispheric RSFC of the MTL correlated with the Wechsler Memory Scale-Logical Memory (WMS-LM) (immediate and delayed performance, r = 0.64, p <  0.05; r = 0.65, p <  0.05, respectively), and the inter-hemispheric RSFC of the OFC correlated with the WMS-LM delayed performance (r = 0.71, p <  0.05). In our study, the presence of the APOE ɛ4 allele was linked with decreased inter-hemispheric RSFC, which was attributed to memory performance in carriers.

%B J Alzheimers Dis %V 50 %P 1137-48 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836191?dopt=Abstract %R 10.3233/JAD-150989 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Different Expression Patterns of Amyloid-β Protein Precursor Secretases in Human and Mouse Hippocampal Neurons: A Potential Contribution to Species Differences in Neuronal Susceptibility to Amyloid-β Pathogenesis. %A Xu, Zhi-Qiang %A Huang, Huang %A Chen, Ya-Li %A Gao, Yun-Ying %A Xu, Jun %A Marshall, Charles %A Cai, Zhi-You %A Xiao, Ming %K ADAM10 Protein %K Amyloid beta-Peptides %K Amyloid Precursor Protein Secretases %K Animals %K Antibodies %K Aspartic Acid Endopeptidases %K Cell Count %K Dose-Response Relationship, Drug %K Female %K Gene Expression Regulation %K Hippocampus %K Humans %K Low Density Lipoprotein Receptor-Related Protein-1 %K Male %K Mice %K Mice, Transgenic %K Middle Aged %K Mutation %K Neurons %K Peptide Fragments %K Presenilin-1 %K Species Specificity %K Time Factors %X

Extensive loss of hippocampal neurons serves a pathological basis for irreversible cognitive impairment in patients with Alzheimer's disease (AD). However, this characteristic cannot be replicated by transgenic mouse models, and its underlying mechanisms are unclear. Here, we present evidence that different expression patterns of amyloid-β protein precursor (AβPP) secretases in human and mouse hippocampal neurons are a decisive cause of species difference in the susceptibility to Aβ pathogenesis. Cell bodies of both pyramidal and granular neurons did not appear to undergo Aβ deposits in the 10-month-old transgenic mutant human AβPP/presenilin-1 (PS1) mice. They expressed high levels of non-amyloidogenic α-secretase, and its neuroprotective products soluble AβPPα, but low levels of amyloidogenic β-secretase and γ-secretase, and a neurotoxic product, Aβ42 peptide. Unlike those found in the mouse, human hippocampal neuronal cell bodies expressed β-secretase and γ-secretase, but not α-secretase, which could increase Aβ generation, thus undergoing death in response to various pathological conditions. Increased hippocampal neuronal apoptosis at 48 h following local microinjection of α-secretase antibody ADAM10 into the hippocampus of AβPP/PS1 mice further suggests that high α-secretase expression in mouse neuronal cell bodies is a factor in the paucity of neuronal loss in AD-like pathology. Therefore, selective down-regulation of brain α-secretase in transgenic AD models will better replicate the disease spectrum, including decreased brain soluble AβPPα levels and massive neuronal loss in AD patients, and be beneficial for preclinical therapeutic evaluation of AD.

%B J Alzheimers Dis %V 51 %P 179-95 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836155?dopt=Abstract %R 10.3233/JAD-150634 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Effects of APOE Genotypes on the Anterior and Posterior Subnetworks of Default Mode Network in Amnestic Mild Cognitive Impairment. %A Yuan, Baoyu %A Xie, Chunming %A Shu, Hao %A Liao, Wenxiang %A Wang, Zan %A Liu, Duan %A Zhang, Zhijun %X

BACKGROUND: The apolipoprotein E (APOE) ɛ4 carriers are at increased risk of developing Alzheimer's disease (AD) while the ɛ2 carriers appear to be protected against the disease. The default mode network (DMN), based in ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC), consists of functionally differentiable anterior and posterior subnetworks.

OBJECTIVE: This study was to investigate whether there are differential effects of APOE polymorphisms on DMN subnetworks in amnestic mild cognitive impairment (aMCI).

METHODS: Functional connectivity (FC) analyses were performed in DMN subnetworks in 74 aMCI (9 APOE ɛ2ɛ3, 44 ɛ3ɛ3, and 21 ɛ3ɛ4) and 105 healthy controls (HC; 32 APOE ɛ2ɛ3, 39 ɛ3ɛ3, and 34 ɛ3ɛ4). Logistic regression analysis was performed to obtain a model for classifying aMCI and HC.

RESULTS: Significant interactions of APOE by aMCI on FCs were found in right cerebellum posterior lobe, left lingual gyrus, and right middle cingulate cortex in the vmPFC subnetwork, and bilateral fusiform gyrus, left inferior frontal gyrus, and left precuneus in the PCC subnetwork. The impairment of episodic memory for ɛ4-carriers in aMCI negatively correlated with altered FC between vmPFC and right middle cingulate cortex, while positively correlated with altered FC between PCC and left fusiform gyrus. A model composed of episodic memory and FCs dexterity correctly classified 89.4% of aMCI and HC.

CONCLUSIONS: APOE ɛ4 and ɛ2 alleles differentially mediate anterior and posterior DMN subnetworks. Furthermore, it further suggests that the anterior and posterior DMN subnetworks in aMCI play an opposing role on the impairment of episodic memory.

%B J Alzheimers Dis %V 54 %P 1409-1423 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589521?dopt=Abstract %R 10.3233/JAD-160353 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Disrupted Brain Network in Progressive Mild Cognitive Impairment Measured by Eigenvector Centrality Mapping is Linked to Cognition and Cerebrospinal Fluid Biomarkers. %A Qiu, Tiantian %A Luo, Xiao %A Shen, Zhujing %A Huang, Peiyu %A Xu, Xiaojun %A Zhou, Jiong %A Zhang, Minming %X

Mild cognitive impairment (MCI) is a heterogeneous condition associated with a high risk of progressing to Alzheimer's disease (AD). Although functional brain network alterations have been observed in progressive MCI (pMCI), the underlying pathological mechanisms of network alterations remain unclear. In the present study, we evaluated neuropsychological, imaging, and cerebrospinal fluid (CSF) data at baseline across a cohort of: 21 pMCI patients, 33 stable MCI (sMCI) patients, and 29 normal controls. Fast eigenvector centrality mapping (fECM) based on resting-state functional MRI (rsfMRI) was used to investigate brain network organization differences among these groups, and we further assessed its relation to cognition and AD-related pathology. Our results demonstrated that pMCI had decreased eigenvector centrality (EC) in left temporal pole and parahippocampal gyrus, and increased EC in left middle frontal gyrus compared to sMCI. In addition, compared to normal controls, patients with pMCI showed decreased EC in right hippocampus and bilateral parahippocampal gyrus, and sMCI had decreased EC in right middle frontal gyrus and superior parietal lobule. Correlation analysis showed that EC in the left temporal pole was related to Wechsler Memory Scale-Revised Logical Memory (WMS-LM) delay score (r = 0.467, p = 0.044) and total tau (t-tau) level in CSF (r = -0.509, p = 0.026) in pMCI. Our findings implicate EC changes of different brain network nodes in the prognosis of pMCI and sMCI. Importantly, the association between decreased EC of brain network node and pathological changes may provide a deeper understanding of the underlying pathophysiology of pMCI.

%B J Alzheimers Dis %V 54 %P 1483-1493 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589525?dopt=Abstract %R 10.3233/JAD-160403 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Distinct Patterns of Cognitive Aging Modified by Education Level and Gender among Adults with Limited or No Formal Education: A Normative Study of the Mini-Mental State Examination. %A Xie, Haiqun %A Zhang, Chengguo %A Wang, Yukai %A Huang, Shuyun %A Cui, Wei %A Yang, Wenbin %A Koski, Lisa %A Xu, Xiping %A Li, Youbao %A Zheng, Meili %A He, Mingli %A Fu, Jia %A Shi, Xiuli %A Wang, Kai %A Tang, Genfu %A Wang, Binyan %A Huo, Yong %K Adult %K Aged %K Aged, 80 and over %K China %K Cognition Disorders %K Cognitive Aging %K Educational Status %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Reference Values %K Rural Population %K Sex Characteristics %X

BACKGROUND: Dementia is increasingly prevalent due to rapid aging of the population, but under-recognized among people with low education levels. This is partly due to a lack of appropriate and precise normative data, which underestimates cognitive aging in the use of screening tools for dementia.

OBJECTIVE: We aimed to improve the precision of screening for cognitive impairment, by characterizing the patterns of cognitive aging and derived normative data of the Mini-Mental State Examination (MMSE) for illiterate and low-educated populations.

METHODS: This community-based study included data from 2,280 individuals aged 40 years or older from two rural areas. Multiple linear modeling examined the effect of aging on cognition reflected by the MMSE, stratified by education level and gender. Threshold effect of age on cognition was performed using a smoothing function.

RESULTS: The majority of participants (60.4%) were illiterate or had attended only primary school (24.6%). The effect of aging on cognition varied by gender and education. Primary-school educated females and males remained cognitively stable up to 62 and 71 years of age, respectively, with MMSE score declining 0.4 and 0.8 points/year in females and males thereafter. Illiterates females scored 2.3 points lower than illiterate males, and scores for both declined 0.2 points/year. According to these results, normative data stratified by age, education and gender was generated.

CONCLUSION: This study suggests gender and educational differences exist in cognitive aging among adults with limited or no formal education. To improve screening precision for cognitive impairment with the use of MMSE in low-educated population, age, gender, and education level should be considered.

%B J Alzheimers Dis %V 49 %P 961-9 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26756324?dopt=Abstract %R 10.3233/JAD-143066 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Do Chinese Researchers Conduct Ethical Research and Use Ethics Committee Review in Clinical Trials of Anti-Dementia Drugs? An Analysis of Biomedical Publications Originating from China. %A Zeng, Lingfeng %A Liang, Weixiong %A Pan, Jianke %A Cao, Ye %A Liu, Jun %A Wang, Qi %A Wang, Lu %A Zou, Yuanping %A Wang, Kezhu %A Kong, Lingshuo %A Xie, Hui %A Xu, Weihua %A Li, Weirong %A Zhao, Wei %A Mi, Suiqing %A Chen, Yunbo %A Cheng, Shuyi %A Li, Xiaoyan %A Cao, Qian %A Zeng, Xing %A Wang, Ningsheng %X

BACKGROUND: Medical research using human participants must conform to the basic ethical principles found in the Declaration of Helsinki (DoH) of the World Medical Association.

OBJECTIVE: The purpose of this review was to assess whether journals in China have improved in regard to the fulfillment of ethical disclosure procedures for clinical trials of anti-dementia drugs.

METHODS: Four medical databases were searched for articles reporting clinical trials of oral anti-dementia drugs published in China in 2003, 2009, and 2014. The frequencies of reporting of informed consent from participants (ICP), approval of a regional ethical committee (REC), reference to DoH, and study registration were estimated respectively. Statistical analyses were conducted with SPSS v21 software.

RESULTS: Among those randomized controlled trials published in 2003, 2009, and 2014, disclosure of REC approval was present for 2.67%, 1.15%, and 6.84%; statements of ICP were included in 9.33%, 7.76%, and 17.34%; reference to DoH was found for 4.00%, 1.44%, and 7.45%; and study registration reporting was included in 2.67%, 2.59%, and 9.28%, respectively. Improvements to reporting rates between 2009 and 2014 were seen, with more than twice as many trials reporting REC approval, ICP, reference to DoH, and study registration compared with 2009.

CONCLUSION: Compared with 2003 and 2009, reporting rates for REC approval, ICP, reference to DoH, and study registration for clinical trials of anti-dementia drugs were enhanced in 2014 in the major medical journals of China. However, biomedical publications without definite statements of ethical considerations remain common, and this continues to be seen in Chinese journals. It is imperative that measures are taken to reinforce the ethical protection in clinical trials in China.

%B J Alzheimers Dis %V 52 %P 813-23 %8 2016 Mar 25 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031471?dopt=Abstract %R 10.3233/JAD-150858 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Early Cognitive Deficits in Type 2 Diabetes: A Population-Based Study. %A Marseglia, Anna %A Fratiglioni, Laura %A Laukka, Erika J %A Santoni, Giola %A Pedersen, Nancy L %A Bäckman, Lars %A Xu, Weili %X

Evidence links type 2 diabetes to dementia risk. However, our knowledge on the initial cognitive deficits in diabetic individuals and the factors that might promote such deficits is still limited. This study aimed to identify the cognitive domains initially impaired by diabetes and the factors that play a role in this first stage. Within the population-based Swedish National Study on Aging and Care-Kungsholmen, 2305 cognitively intact participants aged ≥60 y were identified. Attention/working memory, perceptual speed, category fluency, letter fluency, semantic memory, and episodic memory were assessed. Diabetes (controlled and uncontrolled) and prediabetes were ascertained by clinicians, who also collected information on vascular disorders (hypertension, heart diseases, and stroke) and vascular risk factors (VRFs, including smoking and overweight/obesity). Data were analyzed with linear regression models. Overall, 196 participants (8.5%) had diabetes, of which 144 (73.5%) had elevated glycaemia (uncontrolled diabetes); 571 (24.8%) persons had prediabetes. In addition, diabetes, mainly uncontrolled, was related to lower performance in perceptual speed (β - 1.10 [95% CI - 1.98, - 0.23]), category fluency (β - 1.27 [95% CI - 2.52, - 0.03]), and digit span forward (β - 0.35 [95% CI - 0.54, - 0.17]). Critically, these associations were present only among APOEɛ4 non-carriers. The associations of diabetes with perceptual speed and category fluency were present only among participants with VRFs or vascular disorders. Diabetes, especially uncontrolled diabetes, is associated with poorer performance in perceptual speed, category fluency, and attention/primary memory. VRFs, vascular disorders, and APOE status play a role in these associations.

%B J Alzheimers Dis %V 53 %P 1069-78 %8 2016 Jun 15 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27314527?dopt=Abstract %R 10.3233/JAD-160266 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Efficacy and Safety of MMFS-01, a Synapse Density Enhancer, for Treating Cognitive Impairment in Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial. %A Liu, Guosong %A Weinger, Jason G %A Lu, Zhong-Lin %A Xue, Feng %A Sadeghpour, Safa %K Aged %K Anxiety %K Butyrates %K Cognition %K Cognition Disorders %K Double-Blind Method %K Emotions %K Female %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Nootropic Agents %K Sleep %K Synapses %K Treatment Outcome %X

BACKGROUND: Cognitive impairment is a major problem in elderly, affecting quality of life. Pre-clinical studies show that MMFS-01, a synapse density enhancer, is effective at reversing cognitive decline in aging rodents.

OBJECTIVE: Since brain atrophy during aging is strongly associated with both cognitive decline and sleep disorder, we evaluated the efficacy of MMFS-01 in its ability to reverse cognitive impairment and improve sleep.

METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-designed trial in older adult subjects (age 50-70) with cognitive impairment. Subjects were treated with MMFS-01 (n = 23) or placebo (n = 21) for 12 weeks and cognitive ability, sleep quality, and emotion were evaluated. Overall cognitive ability was determined by a composite score of tests in four major cognitive domains.

RESULTS: With MMFS-01 treatment, overall cognitive ability improved significantly relative to placebo (p = 0.003; Cohen's d = 0.91). Cognitive fluctuation was also reduced. The study population had more severe executive function deficits than age-matched controls from normative data and MMFS-01 treatment nearly restored their impaired executive function, demonstrating that MMFS-01 may be clinically significant. Due to the strong placebo effects on sleep and anxiety, the effects of MMFS-01 on sleep and anxiety could not be determined.

CONCLUSIONS: The current study demonstrates the potential of MMFS-01 for treating cognitive impairment in older adults.

%B J Alzheimers Dis %V 49 %P 971-90 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519439?dopt=Abstract %R 10.3233/JAD-150538 %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 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 GSK-3β is Dephosphorylated by PP2A in a Leu309 Methylation-Independent Manner. %A Chu, Dandan %A Tan, Jianxin %A Xie, Shutao %A Jin, Nana %A Yin, Xiaomin %A Gong, Cheng-Xin %A Iqbal, Khalid %A Liu, Fei %K Animals %K Brain %K Carboxylic Ester Hydrolases %K Cell Line, Transformed %K Dose-Response Relationship, Drug %K Enzyme Inhibitors %K Excitatory Amino Acid Agonists %K Glycogen Synthase Kinase 3 %K Glycogen Synthase Kinase 3 beta %K Humans %K Kainic Acid %K Leucine %K Luminescent Proteins %K Male %K Methylation %K Mice %K Phosphorylation %K Protein O-Methyltransferase %K Protein Phosphatase 2 %K RNA, Small Interfering %K Serine %K tau Proteins %X

Hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase-3β (GSK-3β) and protein phosphate 2A (PP2A) are crucial enzymes to regulate tau phosphorylation. GSK-3β activity is regulated by its inhibitory phosphorylation at Ser9. We previously reported the cross-talk between GSK-3β and PP2A signaling and showed that PP2A could dephosphorylate GSK-3β at Ser9. Here, we investigated the dephosphorylation of GSK-3β in brain extracts in the presence of phosphatase inhibitors and found that a PP2A-like phosphatase activity was required for dephosphorylation of GSK-3β at Ser9. PP2A interacted with GSK-3β and suppressed its Ser9 phosphorylation in vitro and in HEK-293FT cells. Activity of PP2A negatively correlated to the level of phosphorylated GSK-3β in kainic acid-induced excitotoxic mouse brain. Alteration of methylation of the catalytic subunit of PP2A (PP2Ac) at Leu309 did not affect GSK-3β phosphorylation. These findings suggest that Leu309 methylation is not required for PP2A to dephosphorylate GSK-3β at Ser9.

%B J Alzheimers Dis %V 49 %P 365-75 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484916?dopt=Abstract %R 10.3233/JAD-150497 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Gx-50 Inhibits Neuroinflammation via α7 nAChR Activation of the JAK2/STAT3 and PI3K/AKT Pathways. %A Shi, Shi %A Liang, Dongli %A Bao, Min %A Xie, Yilin %A Xu, Wangjie %A Wang, Lianyun %A Wang, Zhaoxia %A Qiao, Zhongdong %K Acrylamides %K alpha7 Nicotinic Acetylcholine Receptor %K Amyloid beta-Peptides %K Analysis of Variance %K Animals %K Anti-Inflammatory Agents %K Cell Line, Transformed %K Cytokines %K Enzyme Inhibitors %K Enzyme-Linked Immunosorbent Assay %K Gene Expression Regulation %K Janus Kinase 2 %K Mice %K Microglia %K Phosphatidylinositol 3-Kinases %K Protein Binding %K RNA, Messenger %K Signal Transduction %X

Recent studies have revealed that the α7 nicotinic acetylcholine receptor (α7 nAChR) is a critical link between inflammation and neurodegeneration, which is closely associated with Alzheimer's disease (AD). The JAK2/STAT3 and PI3K/AKT signaling pathways contribute to the neuroprotective and anti-inflammatory effects of α7nAChR. Our previous studies have shown that treatment with gx-50 improves cognitive function and is neuroprotective. Here, we investigated the effect of gx-50 on α7 nAChR and Aβ-induced inflammation in microglia. First, the binding affinity of gx-50 to α7 nAChR was examined using the fluorescence-based Octet RED system, and the expression of α7 nAChR was detected using real-time PCR and western blotting. We also investigated downstream events of α7 nAChR activity, including the translocation of p-STAT3 and the phosphorylation of JAK2, STAT3, PI3K, and AKT. Finally, the effect of gx-50 on Aβ-induced inflammation via α7 nAChR-mediated signaling pathways was investigated using cytokine assays. The results showed that gx-50 is able to act as a specific ligand to activate α7 nAChR, which then upregulates the JAK2/STAT3 and PI3K/AKT signaling pathways to inhibit the secretions of pro-inflammatory cytokines, such as IL-1β. In conclusion, the results suggest that gx-50 could inhibit the Aβ-induced inflammatory response in microglia via α7 nAChR activity, which might be a successful therapeutic target against AD.

%B J Alzheimers Dis %V 50 %P 859-71 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836188?dopt=Abstract %R 10.3233/JAD-150963 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Influence of Incipient Dementia on Hospitalization for Primary Care Sensitive Conditions: A Population-Based Cohort Study. %A Pimouguet, Clément %A Rizzuto, Debora %A Fastbom, Johan %A Lagergren, Mårten %A Fratiglioni, Laura %A Xu, Weili %K Acute Disease %K Age Factors %K Aged %K Aged, 80 and over %K Chronic Disease %K Dementia %K Female %K Follow-Up Studies %K Hospitalization %K Humans %K Logistic Models %K Longitudinal Studies %K Male %K Primary Health Care %K Registries %K Risk %K Sensitivity and Specificity %K Socioeconomic Factors %K Sweden %X

BACKGROUND: Studies have reported that moderate/severe stages of dementia are linked to increased hospitalization rates, but little is known about the influence of incipient dementia on hospitalizations for primary care sensitive conditions (PCSCs).

OBJECTIVE: To examine the associations between incipient dementia and hospitalization outcomes, including all-cause and PCSC hospitalization.

METHODS: A total of 2,268 dementia-free participants in the Swedish National study on Aging and Care-Kungsholmen were interviewed and clinically examined at baseline. Participants aged ≥78 years were followed for 3 years, and those aged 60-72 years, for 6 years. Number of hospitalizations was retrieved from the National Patient Register. Dementia was diagnosed in accordance with Diagnostic and Statistical Manual of Mental Disorders-IV criteria. Hospitalization outcomes were compared in participants who did and did not develop dementia. Zero-inflated Poisson regressions and logistic regressions were used in data analysis.

RESULTS: During the follow-up, 175 participants developed dementia. The unadjusted PCSC admission rate was 88.2 per 1000 person-years in those who developed dementia and 25.6 per 1000 person-years in those who did not. In the fully adjusted logistic regression model, incipient dementia was associated with an increased risk of hospitalization for PCSCs (OR = 2.3, 95% CI 1.3-3.9) but not with the number of hospitalizations or with all-cause hospitalization. Risks for hospitalization for diabetes, congestive heart failure, and pyelonephritis were higher in those who developed dementia than in those who did not. About 10% participants had a PCSC hospitalization attributable to incipient dementia.

CONCLUSION: People with incipient dementia are more prone to hospitalization for PCSCs but not to all-cause hospitalization.

%B J Alzheimers Dis %V 52 %P 213-22 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060943?dopt=Abstract %R 10.3233/JAD-150853 %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 Iron Regulates Apolipoprotein E Expression and Secretion in Neurons and Astrocytes. %A Xu, He %A Perreau, Victoria M %A Dent, Krista A %A Bush, Ashley I %A Finkelstein, David I %A Adlard, Paul A %K Amyloid beta-Peptides %K Animals %K Apolipoproteins E %K Astrocytes %K Blotting, Western %K Cell Survival %K Cells, Cultured %K Cerebral Cortex %K Copper %K Ferritins %K Immunohistochemistry %K Iron %K Mice, Inbred C57BL %K Neurons %K Polymerase Chain Reaction %K Reactive Oxygen Species %K Receptors, LDL %K RNA, Messenger %K Tumor Suppressor Proteins %K Zinc %X

BACKGROUND: There is strong evidence that iron homeostasis is impaired in the aging and Alzheimer's disease (AD) brain and that this contributes to neurodegeneration. Apolipoprotein E (APOE) has been identified as the strongest genetic risk factor for AD. However, the interaction between the two has yet to be fully explored.

OBJECTIVE: This study aimed to investigate the relationship between exogenous iron levels and ApoE in neurons and astrocytes.

METHODS: Our study used primary cultured cortical neurons and astrocytes to investigate the changes in ApoE caused by iron. Western blot and RT-PCR were used to measure ApoE.

RESULTS: We observed that iron upregulated intracellular ApoE levels in both neurons and astrocytes at the post-transcriptional and transcriptional level, respectively. However, there was less full-length ApoE secreted by neurons and astrocytes after iron treatment. We speculate that this might impair brain lipid metabolism and amyloid-β clearance. In terms of ApoE receptors, we observed that neuronal LRP-1 levels were increased by the addition of exogenous iron, which could contribute to AβPP endocytosis in neurons. However, there were no significant changes in neuronal LDLR, astrocyte LDLR, or astrocyte LRP-1.

CONCLUSION: Our study reveals that iron may contribute to the pathogenesis of AD by affecting ApoE and its receptors and supports the notion that iron chelation should be investigated as a therapeutic strategy for AD.

%B J Alzheimers Dis %V 51 %P 471-87 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890748?dopt=Abstract %R 10.3233/JAD-150797 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Longitudinal Study of Impaired Intra- and Inter-Network Brain Connectivity in Subjects at High Risk for Alzheimer's Disease. %A Zhan, Yafeng %A Ma, Jianhua %A Alexander-Bloch, Aaron F %A Xu, Kaibin %A Cui, Yue %A Feng, Qianjin %A Jiang, Tianzi %A Liu, Yong %X

Alzheimer's disease (AD) is associated with abnormal resting-state network (RSN) architecture of the default mode network (DMN), the dorsal attention network (DAN), the executive control network (CON), the salience network (SAL), and the sensory-motor network (SMN). However, little is known about the disrupted intra- and inter-network architecture in mild cognitive impairment (MCI). Here, we employed a priori defined regions of interest to investigate the intra- and inter-network functional connectivity profiles of these RSNs in longitudinal participants, including normal controls (n = 23), participants with early MCI (n = 26), and participants with late MCI (n = 19). We found longitudinal alterations of functional connectivity within the DMN, where they were correlated with variation in cognitive ability. The SAL as well as the interaction between the DMN and the SAL were disrupted in MCI. Furthermore, our results demonstrate that longitudinal alterations of functional connectivity are more profound in earlier stages as opposed to later stages of the disease. The increased severity of cognitive impairment is associated with increasingly altered RSN connectivity patterns, suggesting that disruptions in functional connectivity may contribute to cognitive dysfunction and may represent a potential biomarker of impaired cognitive ability in MCI. Earlier prevention and treatment may help to delay disease progression to AD.

%B J Alzheimers Dis %V 52 %P 913-27 %8 2016 Apr 05 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060962?dopt=Abstract %R 10.3233/JAD-160008 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Modulation of miR-19 in Aluminum-Induced Neural Cell Apoptosis. %A Zhu, Mingming %A Huang, Cong %A Ma, Xiao %A Wu, Rui %A Zhu, Weiwei %A Li, Xiaoting %A Liang, Zhaofeng %A Deng, Feifei %A Zhu, Jianyun %A Xie, Wei %A Yang, Xue %A Jiang, Ye %A Wang, Shijia %A Wu, Jieshu %A Geng, Shanshan %A Xie, Chunfeng %A Zhong, Caiyun %K Aluminum %K Animals %K Apoptosis %K Brain %K Cell Line, Tumor %K Dose-Response Relationship, Drug %K Humans %K Male %K MicroRNAs %K Neurons %K Proto-Oncogene Proteins c-akt %K PTEN Phosphohydrolase %K Rats, Sprague-Dawley %K Tumor Suppressor Protein p53 %X

Neuronal cell death is an important feature of neurodegeneration. Aluminum is associated with neurodegenerative disorders, particularly Alzheimer's disease. However, the underlying mechanisms by which aluminum induces neuronal apoptosis remain to be elucidated. miR-19 is a key miRNA implicated in regulating cell survival process, while the role of miR-19 in Alzheimer's disease has not been investigated. In the present study, we showed that Aluminum maltolate (Al-malt), a lipophilic Al complex which is a common component of human diet with the ability to facilitate the entry of Al into the brain, induced apoptosis in human neuroblastoma SH-SY5Y cells, along with downregulation of miR-19a/miR-19b, upregulation of miR-19-targeted PTEN, and alterations of its downstream apoptosis related proteins including AKT, p53, Bax, and Bcl-2. miR-19 overexpression attenuated Al-malt-induced apoptosis as well as changes in the expression of apoptosis related proteins in SH-SY5Y cells. We further revealed that exposure of rats to Al-malt for 12 weeks at doses relevant to human exposure significantly elevated Al concentrations in serum and brain tissues. Al-malt dose-dependently induced apoptosis in rat brain, as evidenced by increased caspase activation and increased TUNEL staining. Consistent with in vitro results, Al-malt reduced miR-19 expression and altered the expression of apoptotic related proteins in rat brain. Taken together, our data suggest for the first time that miR-19 modulation is critically involved in Al-induced neural cell apoptosis. Findings from this study could provide new insight into the molecular mechanisms of Al-associated neurodegenerative pathogenesis.

%B J Alzheimers Dis %V 50 %P 1149-62 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836165?dopt=Abstract %R 10.3233/JAD-150763 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Multi-Vitamin B Supplementation Reverses Hypoxia-Induced Tau Hyperphosphorylation and Improves Memory Function in Adult Mice. %A Yu, Lixia %A Chen, Yuan %A Wang, Weiguang %A Xiao, Zhonghai %A Hong, Yan %X

Hypobaric hypoxia (HH) leads to reduced oxygen delivery to brain. It could trigger cognitive dysfunction and increase the risk of dementia including Alzheimer's disease (AD). The present study was undertaken in order to examine whether B vitamins (B6, B12, folate, and choline) could exert protective effects on hypoxia-induced memory deficit and AD related molecular events in mice. Adult male Kunming mice were assigned to five groups: normoxic control, hypoxic model (HH), hypoxia+vitamin B6/B12/folate (HB), hypoxia+choline (HC), hypoxia+vitamin B6/B12/folate+choline (HBC). Mice in the hypoxia, HB, HC, and HBC groups were exposed to hypobaric hypoxia for 8 h/day for 28 days in a decompression chamber mimicking 5500 meters of high altitude. Spatial and passive memories were assessed by radial arm and step-through passive test, respectively. Levels of tau and glycogen synthase kinase (GSK)-3β phosphorylation were detected by western blot. Homocysteine (Hcy) concentrations were determined using enzymatic cycling assay. Mice in the HH group exhibited significant spatial working and passive memory impairment, increased tau phosphorylation at Thr181, Ser262, Ser202/Thr205, and Ser396 in the cortex and hippocampus, and elevated Hcy levels compared with controls. Concomitantly, the levels of Ser9-phosphorylated GSK-3β were significantly decreased in brain after hypoxic treatment. Supplementations of vitamin B6/B12/folate+choline could significantly ameliorate the hypoxia-induced memory deficits, observably decreased Hcy concentrations in serum, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites through upregulating inhibitory Ser9-phosphorylated GSK-3β. Our finding give further insight into combined neuroprotective effects of vitamin B6, B12, folate, and choline on brain against hypoxia.

%B J Alzheimers Dis %V 54 %P 297-306 %8 2016 Aug 04 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27497480?dopt=Abstract %R 10.3233/JAD-160329 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neurodegeneration-Like Pathological and Behavioral Changes in an AAV9-Mediated p25 Overexpression Mouse Model. %A Zhou, Xiao %A Huang, Jianou %A Pan, Suyue %A Xu, Miaojing %A He, Rongni %A Ji, Zhong %A Hu, Yafang %X

BACKGROUND: The transgenic mice models overexpressing human p25 contribute greatly to the in vivo neurotoxic mechanism of p25 in neurodegenerative diseases. However, it is time-consuming to manipulate existing transgenic mice models.

OBJECTIVE: Here we aim to establish a novel mouse model of neurodegeneration by overexpressing p25 mediated by recombinant adeno-associated virus serotype 9 (rAAV9).

METHODS: AAV9-GFP-p25 encoding GFP-fused p25 driven by synapsin promoter, and the control, AAV9-GFP, were delivered in mice by tail-vein injection. Assessments of p25 expression, neurodegenerative pathology, and behavioral changes were performed.

RESULTS: GFP expression was detected by in vivo imaging as early as one week after virus injection. Notably, widespread expression of p25 was obviously found in cortex, hippocampus, and cerebellum in AAV9-GFP-p25 mice. Moreover, decreased hippocampus volumes in AAV9-GFP-p25 mice were detected by 7T MRI examination about one month after injection. Further, these AAV9-GFP-p25 mice exhibited progressive memory impairment from three-month to six-month after virus injection. At last, hyperphosphorylated tau, neurofibrillary tangles, activated astrocytes and microglia cells were elevated in these p25 mice at about six months after virus delivery. However, amyloid-β plaques, overt neuronal loss, and apoptosis in the hippocampus and cortex were not significantly induced by AAV9-mediated p25 overexpression.

CONCLUSION: The AAV9-mediated p25 overexpression mouse model, which is a practical model exhibiting neurodegeneration-like pathological and behavioral changes, provides an easier and time-saving method to explore the functions of p25 in vivo, as well as an alternative tool for development of drugs against neurotoxic of p25.

%B J Alzheimers Dis %V 53 %P 843-55 %8 2016 May 30 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27258419?dopt=Abstract %R 10.3233/JAD-160191 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Partial Amelioration of Synaptic and Cognitive Deficits by Inhibiting Cofilin Dephosphorylation in an Animal Model of Alzheimer's Disease. %A Deng, Yulei %A Wei, Jing %A Cheng, Jia %A Zhong, Ping %A Xiong, Zhe %A Liu, Aiyi %A Lin, Lin %A Chen, Shengdi %A Yan, Zhen %X

The loss of synaptic structure and function has been linked to the cognitive impairment of Alzheimer's disease (AD). Dysregulation of the actin cytoskeleton, which plays a key role in regulating the integrity of synapses and the transport of synaptic proteins, has been suggested to contribute to the pathology of AD. In this study, we found that glutamate receptor surface expression and synaptic function in frontal cortical neurons were significant diminished in a familial AD (FAD) model, which was correlated with the reduction of phosphorylated cofilin, a key protein regulating the dynamics of actin filaments. Injecting a cofilin dephosphorylation inhibitory peptide to FAD mice led to the partial rescue of the surface expression of AMPA and NMDA receptor subunits, as well as the partial restoration of AMPAR- and NMDAR-mediated synaptic currents. Moreover, the impaired working memory and novel object recognition memory in FAD mice were partially ameliorated by injections of the cofilin dephosphorylation inhibitory peptide. These results suggest that targeting the cofilin-actin signaling holds promise to mitigate the physiological and behavioral abnormality in AD.

%B J Alzheimers Dis %V 53 %P 1419-32 %8 2016 Jun 28 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372643?dopt=Abstract %R 10.3233/JAD-160167 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Plasma Ceramides and Neuropsychiatric Symptoms of Alzheimer's Disease. %A Xing, Yi %A Tang, Yi %A Zhao, Lina %A Wang, Qi %A Qin, Wei %A Zhang, Jin-Lan %A Jia, Jianping %X

BACKGROUND: Various evidence demonstrates the influences of ceramides on Alzheimer's disease (AD) pathogenesis. Furthermore, increased ceramides were also suggested to be related to cognitive decline. However, the association between ceramides and neuropsychiatric symptoms of AD remains unclear.

OBJECTIVE: This study sought to investigate the association between plasma ceramide levels and multiple neuropsychiatric symptoms in AD.

METHODS: A total of 98 patients and 92 cognitively normal controls participated in this study, including 56 with mild AD and 42 with moderate to severe AD. The Neuropsychiatric Inventory (NPI) was used to assess neuropsychiatric symptoms. Considering the influences of dementia severity on ceramide levels and neuropsychiatric symptoms, a subgroup analysis was conducted by dementia severity.

RESULTS: Except for C24 : 0, all ceramide species were significantly higher in AD patients than in controls. After controlling for confounding factors, the C16 : 0 and C20 : 0 levels were positively associated with delusions, and the quartiles of C22 : 0 and C24 : 0 were positively associated with depression. In the subgroup analysis, association between ceramide species and delusions were only observed in mild AD, and the association between ceramides and depression were prominent in moderate to severe AD. In mild AD, after controlling for age, gender, anti-dementia medications, diabetes status, and ApoE ɛ4 status, the C16 : 0, C20 : 0, and quartiles of C24 : 1 were associated with delusions. In moderate to severe AD, depression was associated with C22 : 0 and C24 : 0.

CONCLUSION: There were stage-specific associations between ceramides and neuropsychiatric symptoms of AD. The potential mechanisms deserve further investigation.

%B J Alzheimers Dis %V 52 %P 1029-35 %8 2016 Apr 12 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079712?dopt=Abstract %R 10.3233/JAD-151158 %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 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 Reproductive history and risk of cognitive impairment in elderly women: a cross-sectional study in eastern China. %A Li, Fu-Dong %A He, Fan %A Chen, Ting-Rui %A Xiao, Yuan-Yuan %A Lin, Shang-Tong %A Shen, Wei %A Wang, Xin-Yi %A Zhai, Yu-Jia %A Shang, Xiao-Peng %A Lin, Jun-Fen %K Aged %K Aged, 80 and over %K China %K Cognition %K Cognition Disorders %K Contraceptives, Oral %K Cross-Sectional Studies %K Estrogens %K Female %K Humans %K Intrauterine Devices %K Logistic Models %K Middle Aged %K Neuropsychological Tests %K Odds Ratio %K Postmenopause %K Psychiatric Status Rating Scales %K Reproductive History %X

BACKGROUND: Epidemiological studies suggest that proxies of higher lifetime estrogen exposure are associated with better cognitive function in postmenopausal women, but this has not been found consistently.

OBJECTIVE: To determine whether reproductive history, an important modifier of estrogen exposure across the lifetime, is associated with risk of cognitive impairment in postmenopausal women.

METHODS: We analyzed the baseline data from Zhejiang Major Public Health Surveillance Program (ZPHS) including 4,796 postmenopausal women. Cognitive impairment was assessed through the application of Mini-Mental State Examination questionnaire. Logistic regression models, controlled for an extensive range of potential confounders, were generated to examine the associations between women's reproductive history and risk of cognitive impairment in their later life.

RESULTS: The length of reproductive period was inversely associated with risk of cognitive impairment (p = 0.001). Odds ratio (OR) of cognitive impairment were 1.316 (95% CI 1.095∼1.582) for women with 5 or more times of full-term pregnancies, compared with those with 1∼4 times of full-term pregnancies. Women without incomplete pregnancy had a significant higher risk of cognitive impairment (OR = 1.194, 95% CI 1.000∼1.429), compared with the reference (1∼2 times of incomplete pregnancies). Oral contraceptive use (OR = 0.489, 95% CI 0.263∼0.910) and intrauterine device (IUD) use (OR = 0.684, 95% CI 0.575∼0.815) were associated with significantly reduced risk of cognitive impairment.

CONCLUSION: Our results indicated that shorter reproductive period, higher number of full-term pregnancies and no incomplete pregnancy history were associated with an increased risk of cognitive impairment. In contrast, oral contraceptive and IUD use corresponded to reduced risk of cognitive impairment.

%B J Alzheimers Dis %V 49 %P 139-47 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444784?dopt=Abstract %R 10.3233/JAD-150444 %0 Journal Article %J J Alzheimers Dis %D 2016 %T UCH-L1 Inhibition Decreases the Microtubule-Binding Function of Tau Protein. %A Xie, Min %A Han, Yun %A Yu, Quntao %A Wang, Xia %A Wang, Shaohui %A Liao, Xiaomei %K Animals %K Cell Line, Tumor %K Dose-Response Relationship, Drug %K HEK293 Cells %K Humans %K Immunoprecipitation %K Indoles %K Mice %K Microtubules %K Neuroblastoma %K Oximes %K Protein Binding %K Proteolysis %K RNA, Small Interfering %K tau Proteins %K Ubiquitin Thiolesterase %K Ubiquitination %X

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is critical for protein degradation and free ubiquitin recycling. In Alzheimer's disease brains, UCH-L1 is negatively related to neurofibrillary tangles whose major component is hyperphosphorylated tau protein, but the direct action of UCH-L1 on tau has not been reported. In the current study, mouse neuroblastoma Neuro2a (N2a) cells were treated by the different concentrations of UCH-L1 inhibitor LDN (2.5, 5 and 10 μM) to inhibit the hydrolase activity of UCH-L1. In addition, we also used UCH-L1 siRNA to treat the HEK293/tau441 cells to decrease the expression of UCH-L1. After LDN and UCH-L1 siRNA treatment, we used immunofluorescence, immunoprecipitation, and tau-microtubule binding assay to measure the microtubule-binding ability and post-translational modifications of tau protein. All the results presented that both inhibition of the activity and expression of UCH-L1 induced the decreased microtubule-binding ability and increased phosphorylation of tau protein. Abnormal aggregation and ubiquitination of tau protein was also observed after UCH-L1 inhibition. The above results suggested that aggregation of tau protein might be devoted to the abnormal post-translational modifications of tau protein. Our study first indicates that dysfunction of UCH-L1 most likely affected normal biological function of tau protein through decreasing degradation of ubiquitinated and hyperphosphorylated tau.

%B J Alzheimers Dis %V 49 %P 353-63 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444754?dopt=Abstract %R 10.3233/JAD-150032 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Utilization of Retinal Nerve Fiber Layer Thickness to Predict Cognitive Deterioration. %A Shi, Zhongyong %A Zhu, Yingbo %A Wang, Meijuan %A Wu, Yujie %A Cao, Jing %A Li, Chunbo %A Xie, Zhongcong %A Shen, Yuan %K Aged %K Cognition Disorders %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Male %K Nerve Fibers %K Neuropsychological Tests %K Predictive Value of Tests %K Retina %K ROC Curve %K Statistics, Nonparametric %K Tomography, Optical Coherence %X

Our previous studies have shown that longitudinal reduction in retinal nerve fiber layer (RNFL) thickness is associated with cognitive deterioration. However, whether the combination of longitudinal reduction in RNFL thickness with baseline episodic memory performance can better predict cognitive deterioration remains unknown. Therefore, we set out to re-analyze the data obtained from our previous studies with 78 elderly adults (mean age 74.4 ± 3.83 years, 48.7% male) in the community over a 25-month period. The participants were categorized as either stable participants whose cognitive status did not change (n = 60) or converted participants whose cognitive status deteriorated (n = 18). A logistic regression analysis was applied to determine a conversion score for predicting the cognitive deterioration in the participants. We found that the area under the receiver operating characteristic curve (AUC) for the multivariable model was 0.854 (95% CI 0.762-0.947) using baseline story recall as a predictor, but the AUC increased to 0.915 (95% CI 0.849-0.981) with the addition of the longitudinal reduction of RNFL thickness in the inferior quadrant. The conversion score was significantly higher for the converted participants than the stable participants (0.59 ± 0.30 versus 0.12 ± 0.19, p <  0.001). Finally, the optimal cutoff value of the conversion score (0.134) was determined by the analysis of receiver operating characteristic curve, and this conversion score generated a sensitivity of 0.944 and a specificity of 0.767 in predicting the cognitive deterioration. These findings have established a system to perform a larger scale study to further test whether the longitudinal reduction in RNFL thickness could serve as a biomarker of Alzheimer's disease.

%B J Alzheimers Dis %V 49 %P 399-405 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484909?dopt=Abstract %R 10.3233/JAD-150438 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Validation of the Total Cerebrovascular Disease Burden Scale in a Community Sample. %A Xu, Xin %A Hilal, Saima %A Collinson, Simon L %A Chan, Qun Lin %A Yi Chong, Eddie Jun %A Ikram, Mohammad Kamran %A Venketasubramanian, Narayanaswamy %A Cheng, Ching-Yu %A Wong, Tien Yin %A Chen, Christopher Li-Hsian %X

BACKGROUND: A total cerebrovascular disease (CeVD) burden scale was previously constructed and an inverse association of CeVD burden and cognition was found. However, the generalizability of the CeVD scale has not been examined.

OBJECTIVE: The objective was to validate the previously constructed total CeVD burden scale by establishing its association with cognitive function and dementia diagnosis in a community sample.

METHODS: Eligible participants were assessed on an extensive neuropsychological battery and underwent MRI scans. The total CeVD scale, comprising markers of both small- and large-vessel diseases, was derived according to previously described criteria. Association of total CeVD burden with global and domain-based cognitive performance and dementia diagnostic utility of the scale was established.

RESULTS: A total of 863 participants were included in the analysis. A stepwise association of CeVD burden score with global and domain-specific cognitive function was found. Per score increase on the total CeVD burden scale was associated with 3.6 (95% CI = 2.1-6.4) times higher odds of dementia compared to dementia-free.

DISCUSSION: The total CeVD burden scale is associated with cognition and dementia in a community sample. Longitudinal studies are required to establish the predictive ability of this scale.

%B J Alzheimers Dis %V 52 %P 1021-8 %8 2016 Apr 12 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079726?dopt=Abstract %R 10.3233/JAD-160139 %0 Journal Article %J Nat Med %D 2014 %T Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. %A Villeda, Saul A %A Plambeck, Kristopher E %A Middeldorp, Jinte %A Castellano, Joseph M %A Mosher, Kira I %A Luo, Jian %A Smith, Lucas K %A Bieri, Gregor %A Lin, Karin %A Berdnik, Daniela %A Wabl, Rafael %A Udeochu, Joe %A Wheatley, Elizabeth G %A Zou, Bende %A Simmons, Danielle A %A Xie, Xinmin S %A Longo, Frank M %A Wyss-Coray, Tony %K Age Factors %K Aging %K Animals %K Blood Transfusion %K Blotting, Western %K Cell Line %K Cognition Disorders %K Cyclic AMP Response Element-Binding Protein %K DNA Primers %K Hippocampus %K Immunohistochemistry %K Mice %K Mice, Inbred C57BL %K Microarray Analysis %K Neuronal Plasticity %K Parabiosis %K Polymerase Chain Reaction %X

As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.

%B Nat Med %V 20 %P 659-63 %8 2014 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24793238?dopt=Abstract %R 10.1038/nm.3569 %0 Journal Article %J 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 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 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