%0 Journal Article %J J Alzheimers Dis %D 2023 %T Best Medicine for Dementia: The Life-Long Defense of the Brain. %A Andersson, Marcus J %A Stone, Jonathan %K Aging %K Alzheimer Disease %K Brain %K Cognitive Dysfunction %K Dementia %K Humans %X

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

%B J Alzheimers Dis %V 94 %P 51-66 %8 2023 %G eng %N 1 %R 10.3233/JAD-230429 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Insights into the Pathophysiology of Alzheimer's Disease and Potential Therapeutic Targets: A Current Perspective. %A Rajah Kumaran, Kesevan %A Yunusa, Suleiman %A Perimal, Enoch %A Wahab, Habibah %A Müller, Christian P %A Hassan, Zurina %K Aged %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Humans %K Neurofibrillary Tangles %K Oxidative Stress %K Plaque, Amyloid %K tau Proteins %X

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

%B J Alzheimers Dis %V 91 %P 507-530 %8 2023 %G eng %N 2 %R 10.3233/JAD-220666 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Linking Air Pollution Exposure to Blood-Based Metabolic Features in a Community-Based Aging Cohort with and without Dementia. %A Kalia, Vrinda %A Kulick, Erin R %A Vardarajan, Badri %A Gu, Yian %A Manly, Jennifer J %A Elkind, Mitchell S V %A Kaufman, Joel D %A Jones, Dean P %A Baccarelli, Andrea A %A Mayeux, Richard %A Kioumourtzoglou, Marianthi-Anna %A Miller, Gary W %K Aged %K Aging %K Air Pollutants %K Air Pollution %K Dementia %K Environmental Exposure %K Humans %K Nitrogen Dioxide %K Particulate Matter %X

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

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

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

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

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

%B J Alzheimers Dis %V 96 %P 1025-1040 %8 2023 Nov 21 %G eng %N 3 %R 10.3233/JAD-230122 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Preventing Neurocognitive Decline in Adults Aging with HIV: Implications for Practice and Research. %A Cody, Shameka L %A Miller, Gabe H %A Fazeli, Pariya L %A Wang, Ge %A Li, Wei %A Goodin, Burel R %A Vance, David E %K Aging %K Alzheimer Disease %K Comorbidity %K HIV Infections %K Humans %X

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

%B J Alzheimers Dis %V 95 %P 753-768 %8 2023 %G eng %N 3 %R 10.3233/JAD-230203 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Re-Addressing Dementia by Network Medicine and Mechanism-Based Molecular Endotypes. %A Pacheco Pachado, Mayra %A Casas, Ana I %A Elbatreek, Mahmoud H %A Nogales, Cristian %A Guney, Emre %A Espay, Alberto J %A Schmidt, Harald H H W %K Aging %K Alzheimer Disease %K Amyloid %K Amyloid beta-Peptides %K Brain %K Humans %X

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

%B J Alzheimers Dis %V 96 %P 47-56 %8 2023 %G eng %N 1 %R 10.3233/JAD-230694 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Oral Health Status in Subjects with Amnestic Mild Cognitive Impairment and Alzheimer's Disease: Data from the Zabút Aging Project. %A Panzarella, Vera %A Mauceri, Rodolfo %A Baschi, Roberta %A Maniscalco, Laura %A Campisi, Giuseppina %A Monastero, Roberto %K Aging %K Alzheimer Disease %K Case-Control Studies %K Cognitive Dysfunction %K Cohort Studies %K Humans %K Male %K Neuropsychological Tests %K Oral Health %K Quality of Life %X

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

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

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

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

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

%B J Alzheimers Dis %V 87 %P 173-183 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32508326?dopt=Abstract %R 10.3233/JAD-200385 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Rheumatoid Arthritis, Cognitive Impairment, and Neuroimaging Biomarkers: Results from the Mayo Clinic Study of Aging. %A Vassilaki, Maria %A Crowson, Cynthia S %A Davis Iii, John M %A Duong, Stephanie Q %A Jones, David T %A Nguyen, Aivi %A Mielke, Michelle M %A Vemuri, Prashanthi %A Myasoedova, Elena %K Aged %K Aging %K Alzheimer Disease %K Amyloid %K Amyloid beta-Peptides %K Amyloidosis %K Arthritis, Rheumatoid %K Biomarkers %K Brain %K Cognitive Dysfunction %K Female %K Fluorodeoxyglucose F18 %K Humans %K Magnetic Resonance Imaging %K Male %K Neuroimaging %K Positron-Emission Tomography %X

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

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

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

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

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

%B J Alzheimers Dis %V 89 %P 943-954 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35964191?dopt=Abstract %R 10.3233/JAD-220368 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Is Engagement in Intellectual and Social Leisure Activities Protective Against Dementia Risk? Evidence from the English Longitudinal Study of Ageing. %A Almeida-Meza, Pamela %A Steptoe, Andrew %A Cadar, Dorina %K Aged %K Aged, 80 and over %K Aging %K Dementia %K Female %K Humans %K Incidence %K Leisure Activities %K Life Style %K Longitudinal Studies %K Male %K Marital Status %K Middle Aged %K Proportional Hazards Models %K Sex Factors %K Social Behavior %K Surveys and Questionnaires %K Survival Analysis %K United Kingdom %X

BACKGROUND: Studies have suggested that mentally stimulating activities and socially engaged lifestyles may reduce dementia risk; however, it is unclear which activities are more beneficial.

OBJECTIVE: We investigated intellectual and social leisure activities in relation to dementia incidence and explored the modifying role of sex and marital status in these associations.

METHODS: The sample was comprised of 8,030 participants aged 50+ from the English Longitudinal Study of Ageing, who joined at wave 1 (2002-2003), or waves 3 (2006-2007), or 4 (2008-2009). The end of the study period was wave 8 (2016-2017). Subdistribution hazard models investigated the role of leisure activities grouped into intellectual and social domains in relation to dementia while accounting for the risk of death. Subsequent analyses were conducted with individual leisure activities.

RESULTS: During the study period of up to 15 years, 412 participants developed dementia, and 2,192 died. We found that increased engagement in the intellectual activities' domain was associated with a decreased dementia incidence (SHR 0.85, 95% CI 0.76-0.96, p = 0.007), independent of the risk of death in married individuals, but not in those who were single, divorced, or widowed. Individual analyses for each leisure activity showed independent associations for reading newspapers in females (SHR 0.65, 95% CI 0.49-0.84, p = 0.001), mobile phone usage in males (SHR 0.61, 95% CI 0.45-0.84, p = 0.002), and having hobbies for married individuals (SHR 0.70, 95% CI 0.51-0.95, p = 0.02).

CONCLUSION: We found that intellectual leisure activities contribute to lower dementia risk in a representative population of English adults, suggesting intervention opportunities.

%B J Alzheimers Dis %V 80 %P 555-565 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554903?dopt=Abstract %R 10.3233/JAD-200952 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Locus Coeruleus in Aging and Alzheimer's Disease: A Postmortem and Brain Imaging Review. %A Beardmore, Rebecca %A Hou, Ruihua %A Darekar, Angela %A Holmes, Clive %A Boche, Delphine %K Aging %K Alzheimer Disease %K Animals %K Autopsy %K Brain Stem %K Humans %K Locus Coeruleus %K Magnetic Resonance Imaging %K Melanins %K Mice %K Norepinephrine %K Rats %K tau Proteins %X

The locus coeruleus (LC), a tiny nucleus in the brainstem and the principal site of noradrenaline synthesis, has a major role in regulating autonomic function, arousal, attention, and neuroinflammation. LC dysfunction has been linked to a range of disorders; however particular interest is given to the role it plays in Alzheimer's disease (AD). The LC undergoes significant neuronal loss in AD, thought to occur early in the disease process. While neuronal loss in the LC has also been suggested to occur in aging, this relationship is less clear as the findings have been contradictory. LC density has been suggested to be indicative of cognitive reserve and the evidence for these claims will be discussed. Recent imaging techniques allowing visualization of the LC in vivo using neuromelanin-sensitive MRI are developing our understanding of the role of LC in aging and AD. Tau pathology within the LC is evident at an early age in most individuals; however, the relationship between tau accumulation and neuronal loss and why some individuals then develop AD is not understood. Neuromelanin pigment accumulates within LC cells with age and is proposed to be toxic and inflammatory when released into the extracellular environment. This review will explore our current knowledge of the LC changes in both aging and AD from postmortem, imaging, and experimental studies. We will discuss the reasons behind the susceptibility of the LC to neuronal loss, with a focus on the role of extracellular neuromelanin and neuroinflammation caused by the dysfunction of the LC-noradrenaline pathway.

%B J Alzheimers Dis %V 83 %P 5-22 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34219717?dopt=Abstract %R 10.3233/JAD-210191 %0 Journal Article %J J Alzheimers Dis %D 2021 %T MIND Diet, Common Brain Pathologies, and Cognition in Community-Dwelling Older Adults. %A Dhana, Klodian %A James, Bryan D %A Agarwal, Puja %A Aggarwal, Neelum T %A Cherian, Laurel J %A Leurgans, Sue E %A Barnes, Lisa L %A Bennett, David A %A Schneider, Julie A %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid %K Autopsy %K Brain %K Chicago %K Cognition %K Diet, Mediterranean %K Female %K Humans %K Independent Living %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Surveys and Questionnaires %X

BACKGROUND: MIND diet, a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension diet, is associated with a slower cognitive decline and lower risk of Alzheimer's disease (AD) dementia in older adults.

OBJECTIVE: We aim to examine whether the association of the MIND diet with cognition is independent of common brain pathologies.

METHODS: Utilizing data from the Rush Memory and Aging Project (MAP), a longitudinal clinical-pathologic study, we studied 569 decedents with valid dietary data, cognitive testing proximate to death, and complete autopsy data at the time of these analyses. A series of regression analyses were used to examine associations of the MIND diet, dementia-related brain pathologies, and global cognition proximate to death adjusting for age, sex, education, APOEɛ4, late-life cognitive activities, and total energy intake.

RESULTS: A higher MIND diet score was associated with better global cognitive functioning proximate to death (β= 0.119, SE = 0.040, p = 0.003), and neither the strength nor the significance of association changed substantially when AD pathology and other brain pathologies were included in the model. The β-estimate after controlling for global AD pathology was 0.111 (SE = 0.037, p = 0.003). The MIND diet-cognition relationship remained significant when we restricted our analysis to individuals without mild cognitive impairment at the baseline (β= 0.121, SE = 0.042, p = 0.005) or in people diagnosed with postmortem diagnosis of AD based on NIA-Reagan consensus recommendations (β= 0.114, SE = 0.050, p = 0.023).

CONCLUSION: MIND diet is associated with better cognitive functioning independently of common brain pathology, suggesting that the MIND diet may contribute to cognitive resilience in the elderly.

%B J Alzheimers Dis %V 83 %P 683-692 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34334393?dopt=Abstract %R 10.3233/JAD-210107 %0 Journal Article %J J Alzheimers Dis %D 2021 %T New Frontiers in the Prevention, Diagnosis, and Treatment of Alzheimer's Disease. %A Guzmán-Martínez, Leonardo %A Calfío, Camila %A Farías, Gonzalo A %A Vilches, Cristian %A Prieto, Raul %A Maccioni, Ricardo B %K Acupuncture Therapy %K Aging %K Alzheimer Disease %K Biomarkers %K Dietary Supplements %K Early Diagnosis %K Humans %K Medicine, Chinese Traditional %K Meditation %K Quality of Life %K Treatment Outcome %X

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

%B J Alzheimers Dis %V 82 %P S51-S63 %8 2021 %G eng %N s1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33523002?dopt=Abstract %R 10.3233/JAD-201059 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Role of Microglia in Sporadic Alzheimer's Disease. %A Streit, Wolfgang J %A Khoshbouei, Habibeh %A Bechmann, Ingo %K Aging %K Alzheimer Disease %K Humans %K Microglia %X

Microglia constitute the brain's immune system and their involvement in Alzheimer's disease has been discussed. Commonly, and in line with the amyloid/neuroinflammation cascade hypothesis, microglia have been portrayed as potentially dangerous immune effector cells thought to be overactivated by amyloid and producing neurotoxic inflammatory mediators that lead to neurofibrillary degeneration. We disagree with this theory and offer as an alternative the microglial dysfunction theory stating that microglia become impaired in their normally neuroprotective roles because of aging, i.e., they become senescent and aging neurons degenerate because they lack the needed microglial support for their survival. Thus, while the amyloid cascade theory relies primarily on genetic data, the dysfunction theory incorporates aging as a critical etiological factor. Aging is the greatest risk factor for the sporadic (late-onset) and most common form of Alzheimer's disease, where fully penetrant genetic mutations are absent. In this review, we lay out and discuss the human evidence that supports senescent microglial dysfunction and conflicts with the amyloid/neuroinflammation idea.

%B J Alzheimers Dis %V 79 %P 961-968 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33361603?dopt=Abstract %R 10.3233/JAD-201248 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Age-Related Changes in the Spatial Frequency Threshold of Male and Female 3xTg-AD Mice Using OptoMotry. %A King, Jillian L %A Wong, Aimée A %A Brown, Richard E %K Aging %K Alzheimer Disease %K Animals %K Disease Models, Animal %K Female %K Humans %K Male %K Maze Learning %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Sex Characteristics %K tau Proteins %K Vision, Ocular %X

Visual impairments and retinal abnormalities occur in patients with Alzheimer's disease (AD) and in mouse models of AD. It is important to know the visual ability of mouse models of AD to ensure that age-related cognitive deficits are not confounded by visual impairments. Using OptoMotry, the spatial frequency thresholds of male and female 3xTg-AD mice did not differ from their B6129SF2 wildtype controls between 1-18 months of age, but females had higher spatial frequency thresholds than males. However, the differences were quite small, and the visual ability of all mice was comparable to that of C57BL/6 mice.

%B J Alzheimers Dis %V 62 %P 591-596 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480178?dopt=Abstract %R 10.3233/JAD-170805 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association of Low-Level Ozone with Cognitive Decline in Older Adults. %A Cleary, Ekaterina Galkina %A Cifuentes, Manuel %A Grinstein, Georges %A Brugge, Doug %A Shea, Thomas B %K Age Distribution %K Aged %K Aged, 80 and over %K Aging %K Air Pollutants %K Cognitive Dysfunction %K Female %K Humans %K Male %K Mental Status and Dementia Tests %K Middle Aged %K Ozone %K Regression Analysis %K Retrospective Studies %K United States %X

Increasing evidence points to an association of airborne pollutant exposure with respiratory, cardiovascular, and neurological pathology. We examined whether or not ground-level ozone or fine particulate matter ≤ 2.5 μm in diameter (PM2.5) was associated with accelerated cognitive decline. Using repeated measures mixed regression modeling, we analyzed cognitive performance of a geographically diverse sampling of individuals from the National Alzheimer's Coordinating Center between 2004-2008. Ambient air concentrations of ozone and PM2.5 were established using a space-time Hierarchical Bayesian Model that statistically merged air monitor data and modeled air quality estimates. We then compared the ambient regional concentrations of ozone and PM2.5 with the rate of cognitive decline in residents within those regions. Increased levels of ozone correlated with an increased rate of cognitive decline, following adjustment for key individual and community-level risk factors. Furthermore, individuals harboring one or more APOE4 alleles exhibited a faster rate of cognitive decline. The deleterious association of ozone was confined to individuals with normal cognition who eventually became cognitively impaired as opposed to those who entered the study with baseline impairment. In contrast to ozone, we did not observe any correlation between ambient PM2.5 and cognitive decline at regulatory limits set by the Environmental Protection Agency. Our findings suggest that prolonged exposure to ground-level ozone may accelerate cognitive decline during the initial stages of dementia development.

%B J Alzheimers Dis %V 61 %P 67-78 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103040?dopt=Abstract %R 10.3233/JAD-170658 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dilated Perivascular Spaces in the Centrum Semiovale Begin to Develop in Middle Age. %A Ishikawa, Masatsune %A Yamada, Shigeki %A Yamamoto, Kazuo %K Adult %K Aged %K Aged, 80 and over %K Aging %K Cerebral Amyloid Angiopathy %K Corpus Callosum %K Cross-Sectional Studies %K Female %K Humans %K Japan %K Logistic Models %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Multivariate Analysis %K Prospective Studies %K Young Adult %X

BACKGROUND: Dilated perivascular spaces in the centrum semiovale (CSO-PVS) are closely related to small vessel disease. However, recent studies have revealed that cerebral amyloid angiopathy can cause dilation of the CSO-PVS and obstruction of interstitial fluid flow along the intramural periarterial drainage.

OBJECTIVE: To examine the severity and age-related prevalence of CSO-PVS through magnetic resonance imaging (MRI) and investigate their clinically relevant factors.

METHODS: This study included 1,060 subjects who participated in our brain program. The subjects ranged from 23 to 83 years in age and were active in society. The frequencies of the MRI abnormalities of small vessel diseases, including CSO-PVS, were examined. The CSO-PVS severity was classified into three grades: G0, G1, G2, according to the visual rating. The subjects were divided into five age groups and their age-related frequencies were also studied. Using the clinico-laboratory data of 712 subjects, the clinically relevant factors of CSO-PVS were investigated using logistic regression analysis.

RESULTS: The frequencies of all G0 ("normal") MRI abnormalities significantly decreased with age. A high prevalence of G2 CSO-PVS was observed (24%) in the youngest group aged≤39 years, whereas other MRI abnormalities in this group were not or rarely observed. In multivariable logistic regression analyses, G2 CSO-PVS was found to be closely associated with age, hypertension, and the estimated glomerular filtration ratio.

CONCLUSIONS: This study reveals that CSO-PVS begin to develop in subjects aged less than 39 years. Age-related changes are involved. Further studies are necessary to elucidate the pathophysiological role of the CSO-PVS.

%B J Alzheimers Dis %V 61 %P 1619-1626 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376866?dopt=Abstract %R 10.3233/JAD-170755 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Executive and Language Subjective Cognitive Decline Complaints Discriminate Preclinical Alzheimer's Disease from Normal Aging. %A Valech, Natalia %A Tort-Merino, Adrià %A Coll-Padrós, Nina %A Olives, Jaume %A León, María %A Rami, Lorena %A Molinuevo, José Luis %K Aged %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognitive Dysfunction %K Executive Function %K Factor Analysis, Statistical %K Female %K Humans %K Language %K Male %K Middle Aged %K Neuropsychological Tests %K Self Report %X

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

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

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

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

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

%B J Alzheimers Dis %V 61 %P 689-703 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254090?dopt=Abstract %R 10.3233/JAD-170627 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Long Journey into Aging, Brain Aging, and Alzheimer's Disease Following the Oxidative Stress Tracks. %A Mecocci, Patrizia %A Boccardi, Virginia %A Cecchetti, Roberta %A Bastiani, Patrizia %A Scamosci, Michela %A Ruggiero, Carmelinda %A Baroni, Marta %K Aging %K Alzheimer Disease %K Animals %K Brain %K Humans %K Oxidative Stress %X

The Editors of the Journal of Alzheimer's Disease invited Professor Patrizia Mecocci to contribute a review article focused on the importance and implications of her research on aging, brain aging, and senile dementias over the last years. This invitation was based on an assessment that she was one of the journal's top authors and a strong supporter of the concept that oxidative stress is a major contributor to several alterations observed in age-related conditions (sarcopenia, osteoporosis) and, more significantly, in brain aging suggesting a pivotal role in the pathogenesis and progression of one of the most dramatic age-related diseases, Alzheimer's disease (AD). Her first pioneering research was on the discovery of high level of 8-hydroxy-2'-deoxyguanosine (OH8dG), a marker of oxidation in nucleic acids, in mitochondrial DNA isolated from cerebral cortex. This molecule increases progressively with aging and more in AD brain, supporting the hypothesis that oxidative stress, a condition of unbalance between the production of reactive oxygen species and antioxidants, gives a strong contribution to the high incidence of AD in old age subjects. OH8dG also increases in peripheral lymphocyte from AD subjects, suggesting that AD is not only a cerebral but also a systemic disease. The role of antioxidants, particularly vitamin E and zinc, were also studied in longevity and in cognitive decline and dementia. This review shows the main findings from Mecocci's laboratory related to oxidative stress in aging, brain aging, and AD and discusses the importance and implications of some of the major achievements in this field of research.

%B J Alzheimers Dis %V 62 %P 1319-1335 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad170732?id=journal-of-alzheimers-disease%2Fjad170732 %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562533?dopt=Abstract %R 10.3233/JAD-170732 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Reduced Gray Matter Volume of the Thalamus and Hippocampal Region in Elderly Healthy Adults with no Impact of APOE ɛ4: A Longitudinal Voxel-Based Morphometry Study. %A Squarzoni, Paula %A Duran, Fabio Luis Souza %A Busatto, Geraldo F %A Alves, Tania Correa Toledo de Ferraz %K Aged %K Aging %K Apolipoprotein E4 %K Atrophy %K Cross-Sectional Studies %K Female %K Gray Matter %K Healthy Volunteers %K Hippocampus %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Organ Size %K Thalamus %X

BACKGROUND: Many cross-sectional voxel-based morphometry (VBM) investigations have shown significant inverse correlations between chronological age and gray matter (GM) volume in several brain regions in healthy humans. However, few VBM studies have documented GM decrements in the healthy elderly with repeated MRI measurements obtained in the same subjects. Also, the extent to which the APOE ɛ4 allele influences longitudinal findings of GM reduction in the healthy elderly is unclear.

OBJECTIVE: Verify whether regional GM changes are associated with significant decrements in cognitive performance taking in account the presence of the APOE ɛ4 allele.

METHODS: Using structural MRI datasets acquired in 55 cognitively intact elderly subjects at two time-points separated by approximately three years, we searched for voxels showing significant GM reductions taking into account differences in APOE genotype.

RESULTS: We found global GM reductions as well as regional GM decrements in the right thalamus and left parahippocampal gyrus (p < 0.05, family-wise error corrected for multiple comparisons over the whole brain). These findings were not affected by APOE ɛ4.

CONCLUSIONS: Irrespective of APOE ɛ4, longitudinal VBM analyses show that the hippocampal region and thalamus are critical sites where GM shrinkage is greater than the degree of global volume reduction in healthy elderly subjects.

%B J Alzheimers Dis %V 62 %P 757-771 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480170?dopt=Abstract %R 10.3233/JAD-161036 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Role of ASK1/p38 Cascade in a Mouse Model of Alzheimer's Disease and Brain Aging. %A Hasegawa, Yu %A Toyama, Kensuke %A Uekawa, Ken %A Ichijo, Hidenori %A Kim-Mitsuyama, Shokei %K Aging %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Aspartic Acid Endopeptidases %K Avoidance Learning %K Disease Models, Animal %K Gene Expression Regulation %K MAP Kinase Kinase Kinase 5 %K MAP Kinase Signaling System %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Presenilin-1 %K Reaction Time %X

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

%B J Alzheimers Dis %V 61 %P 259-263 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154282?dopt=Abstract %R 10.3233/JAD-170645 %0 Journal Article %J J Alzheimers Dis %D 2018 %T SPARCL1 Accelerates Symptom Onset in Alzheimer's Disease and Influences Brain Structure and Function During Aging. %A Seddighi, Sahba %A Varma, Vijay R %A An, Yang %A Varma, Sudhir %A Beason-Held, Lori L %A Tanaka, Toshiko %A Kitner-Triolo, Melissa H %A Kraut, Michael A %A Davatzikos, Christos %A Thambisetty, Madhav %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Brain %K Calcium-Binding Proteins %K Cerebrovascular Circulation %K Cognition Disorders %K Extracellular Matrix Proteins %K Female %K Humans %K Independent Living %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Polymorphism, Single Nucleotide %K Positron-Emission Tomography %X

We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer's disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed incident AD showed accelerated memory loss prior to disease onset. Next, we compared longitudinal changes in brain volumes (MRI; n = 120 participants; follow-up = 6.4 years; 826 scans) and resting-state cerebral blood flow (rCBF; 15O-water PET; n = 81 participants; follow-up = 7.7 years; 664 scans) in cognitively normal participants. Cognitively normal minor allele carriers of rs9998212 showed accelerated atrophy in several global, lobar, and regional brain volumes. Minor allele carriers of both SNPs showed longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology. Our findings suggest that SPARCL1 accelerates AD pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging.

%B J Alzheimers Dis %V 61 %P 401-414 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154276?dopt=Abstract %R 10.3233/JAD-170557 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Information and Communication Technologies for the Activities of Daily Living in Older Patients with Dementia: A Systematic Review. %A D'Onofrio, Grazia %A Sancarlo, Daniele %A Ricciardi, Francesco %A Panza, Francesco %A Seripa, Davide %A Cavallo, Filippo %A Giuliani, Francesco %A Greco, Antonio %K Activities of Daily Living %K Aging %K Databases, Bibliographic %K Dementia %K Humans %K Medical Informatics %K Self-Help Devices %X

BACKGROUND: Significant innovations have been introduced in recent years in the application of information and communication technologies (ICTs) to support healthcare for patients with dementia.

OBJECTIVE: In the present systematic review, our goal is to keep track of ICT concepts and approaches to support the range of activities of daily living for people with dementia and to provide a snapshot of the effect that technology is having on patients' self-reliance.

METHODS: We reviewed the literature and identified systematic reviews of cohort studies and other authoritative reports. Our selection criteria included: (1) activities of daily living, (2) ICT, and (3) dementia.

RESULTS: We identified 56 studies published between 2000 and 2015, of which 26 met inclusion criteria. The present systematic review revealed many ICT systems that could purportedly support the range of activities of daily living for patients with dementia. The results showed five research bodies: 1) technologies used by patients with dementia, 2) technologies used by caregivers, 3) monitoring systems, 4) ambient assistive living with ICTs, and 5) tracking and wayfinding.

CONCLUSIONS: There is a potential for ICTs to support dementia care at home and to improve quality of life for caregivers, reducing healthcare costs and premature institutional care for these patients.

%B J Alzheimers Dis %V 57 %P 927-935 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304297?dopt=Abstract %R 10.3233/JAD-161145 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Age and its association with low insulin and high amyloid-β peptides in blood. %A Li, Huajie %A Zhu, Haihao %A Wallack, Max %A Mwamburi, Mkaya %A Abdul-Hay, Samer O %A Leissring, Malcolm A %A Qiu, Wei Qiao %K Age Distribution %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Biomarkers %K Cognition Disorders %K Cross-Sectional Studies %K Female %K Humans %K Insulin %K Islet Amyloid Polypeptide %K Linear Models %K Male %K Middle Aged %K Multivariate Analysis %K Peptide Fragments %X

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

%B J Alzheimers Dis %V 49 %P 129-37 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444783?dopt=Abstract %R 10.3233/JAD-150428 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Age-Dependent Regulation of the Blood-Brain Barrier Influx/Efflux Equilibrium of Amyloid-β Peptide in a Mouse Model of Alzheimer's Disease (3xTg-AD). %A Do, Tuan Minh %A Dodacki, Agnès %A Alata, Wael %A Calon, Frederic %A Nicolic, Sophie %A Scherrmann, Jean-Michel %A Farinotti, Robert %A Bourasset, Fanchon %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K ATP Binding Cassette Transporter, Sub-Family G, Member 1 %K ATP Binding Cassette Transporter, Sub-Family G, Member 2 %K ATP-Binding Cassette Transporters %K Biological Transport %K Blood-Brain Barrier %K Brain %K Carbon Isotopes %K Cholesterol %K Disease Models, Animal %K Humans %K Lipoproteins %K Mice %K Mice, Transgenic %K P-Glycoproteins %K Peptide Fragments %K Receptors, LDL %K Sucrose %K Tritium %K Tumor Suppressor Proteins %X

The involvement of transporters located at the blood-brain barrier (BBB) has been suggested in the control of cerebral Aβ levels, and thereby in Alzheimer's disease (AD). However, little is known about the regulation of these transporters at the BBB in animal models of AD. In this study, we investigated the BBB expression of Aβ influx (Rage) and efflux (Abcb1-Abcg2-Abcg4-Lrp-1) transporters and cholesterol transporter (Abca1) in 3-18-month-old 3xTg-AD and control mice. The age-dependent effect of BBB transporters regulation on the brain uptake clearance (Clup) of [3H]cholesterol and [3H]Aβ1 - 40 was then evaluated in these mice, using the in situ brain perfusion technique. Our data suggest that transgenes expression led to the BBB increase in Aβ influx receptor (Rage) and decrease in efflux receptor (Lrp-1). Our data also indicate that mice have mechanisms counteracting this increased net influx. Indeed, Abcg4 and Abca1 are up regulated in 3- and 3/6-month-old 3xTg-AD mice, respectively. Our data show that the balance between the BBB influx and efflux of Aβ is maintained in 3 and 6-month-old 3xTg-AD mice, suggesting that Abcg4 and Abca1 control the efflux of Aβ through the BBB by a direct (Abcg4) or indirect (Abca1) mechanism. At 18 months, the BBB Aβ efflux is significantly increased in 3xTg-AD mice compared to controls. This could result from the significant up-regulation of both Abcg2 and Abcb1 in 3xTg-AD mice compared to control mice. Thus, age-dependent regulation of several Aβ and cholesterol transporters at the BBB could ultimately limit the brain accumulation of Aβ.

%B J Alzheimers Dis %V 49 %P 287-300 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484906?dopt=Abstract %R 10.3233/JAD-150350 %0 Journal Article %J J Alzheimers Dis %D 2016 %T 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 Apolipoprotein E Related Co-Morbidities and Alzheimer's Disease. %A Singhrao, Sim K %A Harding, Alice %A Chukkapalli, Sasanka %A Olsen, Ingar %A Kesavalu, Lakshmyya %A Crean, StJohn %K Aging %K Alzheimer Disease %K Animals %K Apolipoprotein E4 %K Cardiovascular Diseases %K Comorbidity %K Diabetes Mellitus, Type 2 %K Humans %K Mice %K Periodontal Diseases %X

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

%B J Alzheimers Dis %V 51 %P 935-48 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923007?dopt=Abstract %R 10.3233/JAD150690 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Serum Vitamin D with the Risk of Incident Dementia and Subclinical Indices of Brain Aging: The Framingham Heart Study. %A Karakis, Ioannis %A Pase, Matthew P %A Beiser, Alexa %A Booth, Sarah L %A Jacques, Paul F %A Rogers, Gail %A DeCarli, Charles %A Vasan, Ramachandran S %A Wang, Thomas J %A Himali, Jayandra J %A Annweiler, Cedric %A Seshadri, Sudha %K Adult %K Aging %K Brain %K Cohort Studies %K Dementia %K Female %K Humans %K Incidence %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Multivariate Analysis %K Neuropsychological Tests %K Regression Analysis %K Risk %K Sensitivity and Specificity %K Vitamin D %X

BACKGROUND: Identifying nutrition- and lifestyle-based risk factors for cognitive impairment and dementia may aid future primary prevention efforts.

OBJECTIVE: We aimed to examine the association of serum vitamin D levels with incident all-cause dementia, clinically characterized Alzheimer's disease (AD), MRI markers of brain aging, and neuropsychological function.

METHODS: Framingham Heart Study participants had baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations measured between 1986 and 2001. Vitamin D status was considered both as a continuous variable and dichotomized as deficient (<10 ng/mL), or at the cohort-specific 20th and 80th percentiles. Vitamin D was related to the 9-year risk of incident dementia (n = 1663), multiple neuropsychological tests (n = 1291) and MRI markers of brain volume, white matter hyperintensities and silent cerebral infarcts (n = 1139).

RESULTS: In adjusted models, participants with vitamin D deficiency (n = 104, 8% of the cognitive sample) displayed poorer performance on Trail Making B-A (β= -0.03 to -0.05±0.02) and the Hooper Visual Organization Test (β= -0.09 to -0.12±0.05), indicating poorer executive function, processing speed, and visuo-perceptual skills. These associations remained when vitamin D was examined as a continuous variable or dichotomized at the cohort specific 20th percentile. Vitamin D deficiency was also associated with lower hippocampal volumes (β= -0.01±0.01) but not total brain volume, white matter hyperintensities, or silent brain infarcts. No association was found between vitamin D deficiency and incident all-cause dementia or clinically characterized AD.

CONCLUSIONS: In this large community-based sample, low 25(OH)D concentrations were associated with smaller hippocampal volume and poorer neuropsychological function.

%B J Alzheimers Dis %V 51 %P 451-61 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890771?dopt=Abstract %R 10.3233/JAD-150991 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Characterization of Amyloid-β Deposits in Bovine Brains. %A Vallino Costassa, Elena %A Fiorini, Michele %A Zanusso, Gianluigi %A Peletto, Simone %A Acutis, Pierluigi %A Baioni, Elisa %A Maurella, Cristiana %A Tagliavini, Fabrizio %A Catania, Marcella %A Gallo, Marina %A Faro, Monica Lo %A Chieppa, Maria Novella %A Meloni, Daniela %A D'Angelo, Antonio %A Paciello, Orlando %A Ghidoni, Roberta %A Tonoli, Elisa %A Casalone, Cristina %A Corona, Cristiano %K Aging %K Amyloid beta-Peptides %K Animals %K Apolipoproteins E %K Blotting, Western %K Brain %K Cattle %K Extracellular Space %K Gene Frequency %K Genotyping Techniques %K Glial Fibrillary Acidic Protein %K Immunohistochemistry %K Intracellular Space %K Neuroglia %K Neurons %K Polymorphism, Genetic %K Presenilin-1 %K Presenilin-2 %K Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization %X

Amyloid-β (Aβ) deposits are seen in aged individuals of many mammalian species that possess the same aminoacid sequence as humans. This study describes Aβ deposition in 102 clinically characterized cattle brains from animals aged 0 to 20 years. Extracellular and intracellular Aβ deposition was detected with 4G8 antibody in the cortex, hippocampus, and cerebellum. X-34 staining failed to stain Aβ deposits, indicating the non β-pleated nature of these deposits. Western blot analysis and surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry revealed in Tris, Triton, and formic acid fractions the presence of different Aβ peptides, characterized mainly by C-terminally truncated forms. Exploration of the genetic variability of APOE, PSEN1, and PSEN2 genes involved in Alzheimer's disease pathogenesis revealed several previously unreported polymorphisms. This study demonstrates certain similarities between Aβ deposition patterns exhibited in cattle brains and those in the human brain in early stages of aging. Furthermore, the identification of the same Aβ peptides reported in humans, but unable to form aggregates, supports the hypothesis that cattle may be protected against amyloid plaque formation.

%B J Alzheimers Dis %V 51 %P 875-87 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890772?dopt=Abstract %R 10.3233/JAD-151007 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Characterizing Aging, Mild Cognitive Impairment, and Dementia with Blood-Based Biomarkers and Neuropsychology. %A Kleinschmidt, Martin %A Schoenfeld, Robby %A Göttlich, Claudia %A Bittner, Daniel %A Metzner, Jürgen Erich %A Leplow, Bernd %A Demuth, Hans-Ulrich %K Activities of Daily Living %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Aging %K Amyloid beta-Peptides %K Analysis of Variance %K Apolipoproteins E %K Biomarkers %K Case-Control Studies %K Cognitive Dysfunction %K Cross-Sectional Studies %K Cytokines %K Dementia %K Female %K Humans %K Male %K Memory Disorders %K Middle Aged %K Neuropsychological Tests %K Young Adult %X

BACKGROUND: Current treatment in Alzheimer's disease (AD) is initiated at a stage where the brain already has irreversible structural deteriorations. Therefore, the concept of treatment prior to obvious cognitive deficits has become widely accepted, and simple biochemical tests to discriminate normal aging from prodromal or demented stages are now common practice.

OBJECTIVE: The objective of the study was the differentiation of controls, mild cognitive impairment (MCI) and AD patients by novel blood-based assays in combination with neuropsychological tests.

METHODS: In a cross-sectional study, 143 subjects aged 18 to 85 years were recruited. All participants were classified by a comprehensive neuropsychological assessment. Blood samples were analyzed for several amyloid-β (Aβ) species, pro-inflammatory markers, anti-Aβ autoantibodies, and ApoE allele status, respectively.

RESULTS: Plasma Aβ1-42 was significantly decreased in MCI and AD compared to age-matched controls, whereas Aβ1-40 did not differ, but increases with age in healthy controls. The Aβ1-42 to Aβ1-40 ratio was stepwise decreased from age-matched controls via MCI to AD, and shows a clear correlation with memory scores. Reduced Aβ1-42 and Aβ1-42 to Aβ1-40 ratio have strongly correlated with carrying ApoE ɛ4 allele. Autoantibodies against pyroglutamate-modified Aβ, but only a certain subclass, were significantly decreased in AD compared to MCI and age-matched controls, whereas autoantibodies against the unmodified N-terminus of Aβ did not differ.

CONCLUSION: Comprehensive sample preparation and assay standardization enable reliable usage of plasma Aβ for diagnosis of MCI and AD. Anti-pGlu-Aβ autoantibodies correlate with cognition, but not with ApoE, supporting the associated plasma Aβ analysis with additional and independent information.

%B J Alzheimers Dis %V 50 %P 111-26 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639953?dopt=Abstract %R 10.3233/JAD-143189 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cognitive Impairment after Mild Stroke: Development and Validation of the SIGNAL2 Risk Score. %A Kandiah, Nagaendran %A Chander, Russell Jude %A Lin, Xuling %A Ng, Aloysius %A Poh, Yen Yeong %A Cheong, Chin Yee %A Cenina, Alvin Rae %A Assam, Pryseley Nkouibert %K Aged %K Aging %K Area Under Curve %K Brain %K Brain Ischemia %K Cognition Disorders %K Constriction, Pathologic %K Educational Status %K Female %K Follow-Up Studies %K Humans %K Logistic Models %K Male %K Middle Aged %K Prospective Studies %K Retrospective Studies %K Risk %K Severity of Illness Index %K Stroke %K White Matter %X

BACKGROUND: Post stroke cognitive impairment (PSCI), an important complication of strokes, has numerous risk factors. A scale adequately classifying risk of cognitive impairment 3-6 months after mild stroke will be useful for clinicians.

OBJECTIVE: To develop a risk score based on clinical and neuroimaging variables that will be useful in identifying mild ischemic stroke patients at high risk for PSCI.

METHODS: The risk score development cohort comprised of a retrospective dataset of 209 mild stroke patients with MRI confirmed infarcts, without pre-stroke cognitive impairment, and evaluated within 6 months post-stroke for PSCI. Logistic regression identified factors predictive of PSCI and a risk score was developed based on regression coefficients. The risk score was checked for stability using 10-fold cross-validation and validated in an independent prospective cohort of 185 ischemic mild stroke patients.

RESULTS: Within 6 months post-stroke, 37.32% developed PSCI in the retrospective dataset. A 15-point risk score based on age, education, acute cortical infarcts, white matter hyperintensity, chronic lacunes, global cortical atrophy, and intracranial large vessel stenosis was highly predictive of PSCI with an AUC of 0.829. 10.11% with low scores, 52.69% with moderate scores, and 74.07% with high scores developed PSCI. In the prospective validation cohort, the model had an AUC of 0.776, and exhibited similar accuracy and stability statistics at both 6 and 12 months.

CONCLUSION: The seven item risk score adequately identified mild stroke patients who are at an increased risk of developing PSCI.

%B J Alzheimers Dis %V 49 %P 1169-77 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599056?dopt=Abstract %R 10.3233/JAD-150736 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cohort Effects in the Prevalence and Survival of People with Dementia in a Rural Area in Northern Sweden. %A Wimo, Anders %A Sjölund, Britt-Marie %A Sköldunger, Anders %A Qiu, Chengxuan %A Klarin, Inga %A Nordberg, Gunilla %A von Strauss, Eva %K Aged %K Aged, 80 and over %K Aging %K Cohort Effect %K Dementia %K Female %K Humans %K Male %K Prevalence %K Risk Factors %K Rural Population %K Sex Factors %K Survival Rate %K Sweden %X

BACKGROUND: Recent studies suggest that trends in cardiovascular risk may result in a decrease in age-specific prevalence of dementia. Studies in rural areas are rare.

OBJECTIVES: To study cohort effects in dementia prevalence and survival of people with dementia in a Swedish rural area.

METHODS: Participants were from the 1995-1998 Nordanstig Project (NP) (n = 303) and the 2001-2003 Swedish National study on Aging and Care in Nordanstig (SNAC-N) (n = 384). Overall 6-year dementia prevalence and mortality in NP and SNAC-N were compared for people 78 years and older. Logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for dementia occurrence using the NP study population as the reference group. Cox regression models were used to analyze time to death.

RESULTS: The crude prevalence of dementia was 21.8% in NP and 17.4% in SNAC-N. When the NP cohort was used as the reference group, the age- and gender-adjusted OR of dementia was 0.71 (95% CI 0.48-1.04) in SNAC-N; the OR was 0.47 (0.24-0.90) for men and 0.88 (0.54-1.44) for women. In the extended model, the OR of dementia was significantly lower in SNAC-N than in the NP cohort as a whole (0.63; 0.39-0.99) and in men (0.34; 0.15-0.79), but not in women (0.81; 0.46-1.44). The Cox regression models indicated that the hazard ratio of dying was lower in the SNAC-N than NP population.

CONCLUSIONS: Trends toward a lower prevalence of dementia in high-income countries seem to be evident in this Swedish rural area, at least in men.

%B J Alzheimers Dis %V 50 %P 387-96 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639970?dopt=Abstract %R 10.3233/JAD-150708 %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 Dogs with Cognitive Dysfunction as a Spontaneous Model for Early Alzheimer's Disease: A Translational Study of Neuropathological and Inflammatory Markers. %A Schütt, Trine %A Helboe, Lone %A Pedersen, Lars Østergaard %A Waldemar, Gunhild %A Berendt, Mette %A Pedersen, Jan Torleif %K Aging %K Alzheimer Disease %K Animals %K Brain %K Cognitive Dysfunction %K Cytokines %K Denmark %K Disease Models, Animal %K Disease Progression %K Dog Diseases %K Dogs %K Female %K Humans %K Immunohistochemistry %K Longitudinal Studies %K Male %K Plaque, Amyloid %K Severity of Illness Index %K Species Specificity %K tau Proteins %K Translational Medical Research %X

Aged companion dogs with canine cognitive dysfunction (CCD) spontaneously develop varying degrees of progressive cognitive decline and particular neuropathological features correspondent to the changes associated with Alzheimer's disease (AD) in humans. The aim of the present study was to characterize certain aspects of neuropathology and inflammatory markers related to aging and CCD in dogs in comparison with human AD. Fifteen brains from aged dogs with normal cognitive function, mild cognitive impairment, or CCD were investigated and compared with two control brains from young dogs and brain sections from human AD subjects. The neuropathological investigations included evaluation of amyloid-β (Aβ) plaque deposition (N-terminally truncated and pyroglutamyl-modified Aβ included), tau pathology, and inflammatory markers in prefrontal cortex. Cortical Aβ deposition was found to be only of the diffuse subtype as no dense-core or neuritic plaques were found. The Aβ deposition followed a progressive pattern in four maturation stages. Accumulation of the Aβ peptide was also observed in the vessel walls. Both immunohistochemically and biochemically measured levels of Aβ pathology in prefrontal cortex showed a consistent positive correlation to age but not to cognitive deficit severity. No evidence of neurofibrillary tau pathology was found. The level of pro-inflammatory cytokines was generally low and showed no significant association to cognitive status. The findings of the present study support the senescent dog with spontaneous cognitive dysfunction as a valuable non-transgenic model for further investigations of the molecular events involved in the neurodegenerative processes associated with aging and early stage AD, especially the Aβ-related pathology.

%B J Alzheimers Dis %V 52 %P 433-49 %8 2016 03 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003213?dopt=Abstract %R 10.3233/JAD-151085 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Drivers: A Biologically Contextualized, Cross-Inferential View of the Epidemiology of Neurodegenerative Disorders. %A de Pedro-Cuesta, Jesús %A Martínez-Martín, Pablo %A Rábano, Alberto %A Alcalde-Cabero, Enrique %A José García López, Fernando %A Almazán-Isla, Javier %A Ruiz-Tovar, María %A Medrano, Maria-José %A Avellanal, Fuencisla %A Calero, Olga %A Calero, Miguel %K Age Factors %K Aging %K Amyloid Precursor Protein Secretases %K Apolipoproteins E %K Aspartic Acid Endopeptidases %K Creutzfeldt-Jakob Syndrome %K Environment %K Female %K Humans %K Incidence %K Male %K Neurodegenerative Diseases %K Personality %K Risk Factors %K Vascular Diseases %X

BACKGROUND: Sutherland et al. (2011) suggested that, instead of risk factors for single neurodegenerative disorders (NDDs), there was a need to identify specific "drivers", i.e., risk factors with impact on specific deposits, such as amyloid-β, tau, or α-synuclein, acting across entities.

OBJECTIVES AND METHODS: Redefining drivers as "neither protein/gene- nor entity-specific features identifiable in the clinical and general epidemiology of conformational NDDs (CNDDs) as potential footprints of templating/spread/transfer mechanisms", we conducted an analysis of the epidemiology of ten CNDDs, searching for patterns.

RESULTS: We identified seven potential drivers, each of which was shared by at least two CNDDs: 1) an age-at-exposure-related susceptibility to Creutzfeldt-Jakob disease (CJD) and several late-life CNDDs; 2) a relationship between age at onset, survival, and incidence; 3) shared genetic risk factors for CJD and late-life CNNDs; 4) partly shared personal (diagnostic, educational, behavioral, and social risk factors) predating clinical onset of late-life CNDDs; 5) two environmental risk factors, namely, surgery for sporadic CJD and amyotrophic lateral sclerosis, and Bordetella pertussis infection for Parkinson's disease; 6) reticulo-endothelial system stressors or general drivers (andropause or premenopausal estrogen deficiency, APOEɛ4, and vascular risk factors) for late-life CNDDs such as dementia/Alzheimer's disease, type-2 diabetes mellitus, and some sporadic cardiac and vascular degenerative diseases; and 7) a high, invariant incidence ratio of sporadic to genetic forms of mid- and late-life CNDDs, and type-2 diabetes mellitus.

CONCLUSION: There might be a systematic epidemiologic pattern induced by specific proteins (PrP, TDP-43, SOD1, α-synuclein, amyloid-β, tau, Langerhans islet peptide, and transthyretin) or established combinations of these.

%B J Alzheimers Dis %V 51 %P 1003-22 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923014?dopt=Abstract %R 10.3233/JAD-150884 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effect of Anserine/Carnosine Supplementation on Verbal Episodic Memory in Elderly People. %A Hisatsune, Tatsuhiro %A Kaneko, Jun %A Kurashige, Hiroki %A Cao, Yuan %A Satsu, Hideo %A Totsuka, Mamoru %A Katakura, Yoshinori %A Imabayashi, Etsuko %A Matsuda, Hiroshi %K Adult %K Aged %K Aging %K Anserine %K Brain %K Carnosine %K Cytokines %K Dietary Supplements %K Double-Blind Method %K Female %K Gene Expression Regulation %K Humans %K Image Processing, Computer-Assisted %K Male %K Memory, Episodic %K Middle Aged %K Neuropsychological Tests %K Oligonucleotide Array Sequence Analysis %K Verbal Learning %X

Our goal in this study was to determine whether or not anserine/carnosine supplementation (ACS) is capable of preserving cognitive function of elderly people. In a double-blind randomized controlled trial, volunteers were randomly assigned to an ACS or placebo group at a 1:1 ratio. The ACS group took 1.0 g of an anserine/carnosine (3:1) formula daily for 3 months. Participants were evaluated by psychological tests before and after the 3-month supplementation period. Thirty-nine healthy elderly volunteers (60-78 years old) completed the follow-up tests. Among the tests, delayed recall verbal memory assessed by the Wechsler Memory Scale-Logical Memory showed significant preservation in the ACS group, compared to the placebo group (p = 0.0128). Blood analysis revealed a decreased secretion of inflammatory cytokines, including CCL-2 and IL-8, in the ACS group. MRI analysis using arterial spin labeling showed a suppression in the age-related decline in brain blood flow in the posterior cingulate cortex area in the ACS group, compared to the placebo group (p = 0.0248). In another randomized controlled trial, delayed recall verbal memory showed significant preservation in the ACS group, compared to the placebo group (p = 0.0202). These results collectively suggest that ACS may preserve verbal episodic memory and brain perfusion in elderly people, although further study is needed.

%B J Alzheimers Dis %V 50 %P 149-59 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682691?dopt=Abstract %R 10.3233/JAD-150767 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Empirically Defining Trajectories of Late-Life Cognitive and Functional Decline. %A Hochstetler, Helen %A Trzepacz, Paula T %A Wang, Shufang %A Yu, Peng %A Case, Michael %A Henley, David B %A Degenhardt, Elisabeth %A Leoutsakos, Jeannie-Marie %A Lyketsos, Constantine G %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Apolipoprotein E4 %K Cognition Disorders %K Databases, Factual %K Dementia %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Male %K Middle Aged %K Neuroimaging %K Neuropsychological Tests %K Surveys and Questionnaires %X

BACKGROUND: Alzheimer's disease (AD) is associated with variable cognitive and functional decline, and it is difficult to predict who will develop the disease and how they will progress.

OBJECTIVE: This exploratory study aimed to define latent classes from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database who had similar growth patterns of both cognitive and functional change using Growth Mixture Modeling (GMM), identify characteristics associated with those trajectories, and develop a decision tree using clinical predictors to determine which trajectory, as determined by GMM, individuals will most likely follow.

METHODS: We used ADNI early mild cognitive impairment (EMCI), late MCI (LMCI), AD dementia, and healthy control (HC) participants with known amyloid-β status and follow-up assessments on the Alzheimer's Disease Assessment Scale - Cognitive Subscale or the Functional Activities Questionnaire (FAQ) up to 24 months postbaseline. GMM defined trajectories. Classification and Regression Tree (CART) used certain baseline variables to predict likely trajectory path.

RESULTS: GMM identified three trajectory classes (C): C1 (n = 162, 13.6%) highest baseline impairment and steepest pattern of cognitive/functional decline; C3 (n = 819, 68.7%) lowest baseline impairment and minimal change on both; C2 (n = 211, 17.7%) intermediate pattern, worsening on both, but less steep than C1. C3 had fewer amyloid- or apolipoprotein-E ɛ4 (APOE4) positive and more healthy controls (HC) or EMCI cases. CART analysis identified two decision nodes using the FAQ to predict likely class with 82.3% estimated accuracy.

CONCLUSIONS: Cognitive/functional change followed three trajectories with greater baseline impairment and amyloid and APOE4 positivity associated with greater progression. FAQ may predict trajectory class.

%B J Alzheimers Dis %V 50 %P 271-82 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639960?dopt=Abstract %R 10.3233/JAD-150563 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Fibrillar Amyloid-β Accumulation Triggers an Inflammatory Mechanism Leading to Hyperphosphorylation of the Carboxyl-Terminal End of Tau Polypeptide in the Hippocampal Formation of the 3×Tg-AD Transgenic Mouse. %A Ontiveros-Torres, Miguel Ángel %A Labra-Barrios, María Luisa %A Díaz-Cintra, Sofía %A Aguilar-Vázquez, Azucena Ruth %A Moreno-Campuzano, Samadhi %A Flores-Rodríguez, Paola %A Luna-Herrera, Claudia %A Mena, Raúl %A Perry, George %A Florán-Garduño, Benjamín %A Luna-Muñoz, José %A Luna-Arias, Juan Pedro %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Disease Models, Animal %K Female %K Hippocampus %K Humans %K Male %K Mice, Inbred C57BL %K Mice, Transgenic %K Neuroglia %K Phosphorylation %K Plaque, Amyloid %K Presenilin-1 %K Pyramidal Cells %K tau Proteins %X

Alzheimer's disease (AD) is a degenerative and irreversible disorder whose progressiveness is dependent on age. It is histopathologically characterized by the massive accumulation of insoluble forms of tau and amyloid-β (Aβ) asneurofibrillary tangles and neuritic plaques, respectively. Many studies have documented that these two polypeptides suffer several posttranslational modifications employing postmortem tissue sections from brains of patients with AD. In order to elucidate the molecular mechanisms underlying the posttranslational modifications of key players in this disease, including Aβ and tau, several transgenic mouse models have been developed. One of these models is the 3×Tg-AD transgenic mouse, carrying three transgenes encoding APPSWE, S1M146V, and TauP301L proteins. To further characterize this transgenicmouse, we determined the accumulation of fibrillar Aβ as a function of age in relation to the hyperphosphorylation patterns of TauP301L at both its N- and C-terminus in the hippocampal formation by immunofluorescence and confocal microscopy. Moreover, we searched for the expression of activated protein kinases and mediators of inflammation by western blot of wholeprotein extracts from hippocampal tissue sections since 3 to 28 months as well. Our results indicate that the presence of fibrillar Aβ deposits correlates with a significant activation of astrocytes and microglia in subiculum and CA1 regions of hippocampus. Accordingly, we also observed a significant increase in the expression of TNF-α associated to neuritic plaques and glial cells. Importantly, there is an overexpression of the stress activated protein kinases SAPK/JNK and Cdk-5 in pyramidal neurons, which might phosphorylate several residues at the C-terminus of TauP301L. Therefore, the accumulation of Aβ oligomers results in an inflammatory environment that upregulates kinases involved in hyperphosphorylation of TauP301L polypeptide.

%B J Alzheimers Dis %V 52 %P 243-69 %8 2016 03 22 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031470?dopt=Abstract %R 10.3233/JAD-150837 %0 Journal Article %J J Alzheimers Dis %D 2016 %T "I Don't Think Of It As An Illness": Illness Representations in Mild to Moderate Dementia. %A Clare, Linda %A Quinn, Catherine %A Jones, Ian Rees %A Woods, Robert T %K Adaptation, Psychological %K Aged %K Aged, 80 and over %K Aging %K Awareness %K Caregivers %K Dementia %K Female %K Follow-Up Studies %K Humans %K Male %K Middle Aged %K Psychiatric Status Rating Scales %K Residence Characteristics %K Self Concept %K Statistics, Nonparametric %K Surveys and Questionnaires %X

The self-regulatory model proposes that illness representations influence adjustment and coping in chronic conditions. Better understanding of the illness representations held by people with dementia could help with targeting information and support so as to optimize adjustment and coping. In this mixed-methods study of illness representations among people with mild to moderate Alzheimer's, vascular, or mixed dementia we aimed to clarify the nature of the representations held, to determine whether specific profiles can be identified based on perceptions of the identity and cause of the condition, and to examine associations between these profiles and other participant characteristics. Data were collected in the second wave of the Memory Impairment and Dementia Awareness Study (MIDAS). Sixty-four people with dementia, who had been told their diagnosis at a memory clinic, completed interviews and responded to questionnaires. In each case a carer was also interviewed. Cluster analysis based on responses about identity and cause identified three profiles. 'Illness' cluster participants saw themselves as living with an illness and used diagnostic labels, 'ageing' cluster participants did not use diagnostic labels and viewed their difficulties as related to ageing, and 'no problem' cluster participants considered that they did not have any difficulties. 'Illness' cluster participants had better cognition and better awareness, but lower mood, and perceived more practical consequences, than 'ageing' cluster participants. Holding an 'illness' model may not be advantageous. Rather than encouraging adoption of such a model, it may be preferable to target information and select interventions in line with the person's representation profile.

%B J Alzheimers Dis %V 51 %P 139-50 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836172?dopt=Abstract %R 10.3233/JAD-150794 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Increase of α-Secretase ADAM10 in Platelets Along Cognitively Healthy Aging. %A Schuck, Florian %A Wolf, Dominik %A Fellgiebel, Andreas %A Endres, Kristina %K ADAM Proteins %K ADAM10 Protein %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Aging %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Analysis of Variance %K Apolipoprotein E4 %K Cognition %K Female %K Healthy Volunteers %K Humans %K Integrin beta3 %K Male %K Membrane Proteins %K Middle Aged %K Neuropsychological Tests %K Young Adult %X

ADAM10 is one of the key players in ectodomain-shedding of the amyloid-β protein precursor (AβPP). Previous research with postmortem tissue has shown reduced expression and activity of ADAM10 within the central nervous system (CNS) of Alzheimer's disease (AD) patients. Determination of cerebral ADAM10 in living humans is hampered by its transmembrane property; only the physiological AβPP cleavage product generated by ADAM10, sAβPPα, can be assessed in cerebrospinal fluid. Establishment of surrogate markers in easily accessible material therefore is crucial. It has been demonstrated that ADAM10 is expressed in platelets and that platelet amount is decreased in AD patients. Just recently it has been shown that platelet ADAM10 and cognitive performance of AD patients positively correlate. In contrast to AD patients, to our knowledge almost no information has been published regarding ADAM10 expression during normal aging. We investigated ADAM10 amount and activity in platelets of cognitively healthy individuals from three different age groups ranging from 22-85 years. Interestingly, we observed an age-dependent increase in ADAM10 levels and activity in platelets.

%B J Alzheimers Dis %V 50 %P 817-26 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757187?dopt=Abstract %R 10.3233/JAD-150737 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Korean Size/Weight Attribute Test: A Semantic Knowledge Test for Korean Older Adults and Brain-Imaging Evidence. %A Yoo, Yongjoon %A Shin, Seong A %A Park, Soowon %A Lee, Ji-Hye %A Youn, Jung-Hae %A Kim, Yu Kyeong %A Lee, Jun-Young %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Analysis of Variance %K Brain %K Dementia %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Republic of Korea %K ROC Curve %K Semantics %X

BACKGROUND: A standardized tool for evaluating semantic knowledge of the Korean population is needed.

OBJECTIVE: The purpose of this study was to develop a neuropsychological test for the evaluation of semantic knowledge in the Korean elderly population.

METHODS: The Korean version of the Size/Weight Attribute Test (SWAT-K) was developed in reference to the original version. The diagnostic validity of SWAT-K was evaluated with 95 elderly outpatients [67 normal controls; 18 with Alzheimer's disease (AD); 10 with semantic-variant progressive aphasia (SV-PPA)]. Voxel-based morphometry (VBM) was employed to examine associations between SWAT-K scores and morphological changes of the brain.

RESULTS: SWAT-K could discriminate the three subject groups (normal >AD, p <  0.001; AD >SV-PPA, p = 0.040), whereas Boston Naming Test could not distinguish SV-PPA from AD. ROC curve analysis confirmed high levels of sensitivity (0.90) and specificity (0.93) for SWAT-K. The test's inter-rater reliability (ICC = 0.827) and test-retest reliability (ICC = 0.666) were assessed as well. VBM found a significant positive correlation (uncorrected p <  0.005, k >  100) between SWAT-K scores and gray matter volume in right inferior frontal cortex (T = 4.08, k = 191) and bilateral temporal cortices (left, T = 4.42, k = 135; right, T = 3.55, k = 253), the areas the most affected in SV-PPA.

CONCLUSIONS: SWAT-K is a sensitive and reliable test for evaluating semantic knowledge in the Korean elderly population. Strong positive correlations between SWAT-K scores and the brain areas responsible for semantic processing further corroborate the validity of SWAT-K.

%B J Alzheimers Dis %V 49 %P 377-86 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484915?dopt=Abstract %R 10.3233/JAD-150492 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Metabolic Syndrome and Mild Cognitive Impairment: A Case-Control Study among Elderly in a Shanghai Suburb. %A Yao, Qian %A Jiang, Guo-Xin %A Zhou, Zhi-Ming %A Chen, Jin-Mei %A Cheng, Qi %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Aging %K Case-Control Studies %K Chi-Square Distribution %K China %K Cities %K Cognition Disorders %K Community Health Planning %K Female %K Humans %K Male %K Mental Status Schedule %K Metabolic Diseases %K Risk Factors %X

BACKGROUND: Metabolic syndrome (MetS) maybe associated with mild cognitive impairment (MCI).

OBJECTIVE: To investigate the relationship between MetS, with its individual or combined components, and MCI among elderly.

METHODS: A case-control study was conducted among the elderly aged 65 years and over in a community located in the southwestern suburb of Shanghai, China. The Chinese version of the Mini-Mental Status Examination (C-MMSE) was used to screen subjects with MCI. Associations of MetS with its individual or combined components and MCI were analyzed using conditional regression analyses with or without adjustment for gender, education, current smoking, current drinking, and physical activities.

RESULTS: There were 379 subjects with MCI and 379 gender- and age-matched healthy controls in the study. Compared with healthy controls in univariate analyses, subjects with MCI were more likely to have less time spent on physical activity, lower C-MMSE score, heavier weight, larger waistline and hipline, higher diastolic blood pressure, higher body mass index, higher abdominal obesity index, higher serum glycated hemoglobin, higher serum triglycerides, higher serum cholesterol, higher serum uric acid, and higher serum alanine aminotransferase. After multivariable adjustment, MetS was significantly associated with an increased risk of MCI (OR = 2.277; 95% CI: 1.086-4.773). Among MetS components, abdominal obesity (OR = 2.101; 95% CI: 1.224-3.608) and hypertension (OR = 2.075; 95% CI: 1.170-3.678) showed a significant association with MCI, respectively; while these two components were combined, the association was stronger (OR = 2.459; 95% CI: 1.360-4.447).

CONCLUSION: MetS and its components, particularly abdominal obesity and hypertension, were found to be significantly associated with the risk of MCI.

%B J Alzheimers Dis %V 51 %P 1175-82 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923017?dopt=Abstract %R 10.3233/JAD-150920 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Mild Cognitive Impairment and Susceptibility to Scams in Old Age. %A Han, S Duke %A Boyle, Patricia A %A James, Bryan D %A Yu, Lei %A Bennett, David A %K Aged %K Aged, 80 and over %K Aging %K Cognitive Dysfunction %K Crime Victims %K Disease Susceptibility %K Female %K Humans %K Male %K Memory, Episodic %K Middle Aged %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Residence Characteristics %K Self Report %X

BACKGROUND: Falling victim to financial scams can have a significant impact upon social and financial wellbeing and independence. A large proportion of scam victims are older adults, but whether older victims with mild cognitive impairment (MCI) are at higher risk remains unknown.

OBJECTIVE: We tested the hypothesis that older persons with MCI exhibit greater susceptibility to scams compared to those without cognitive impairment.

METHODS: Seven hundred and thirty older adults without dementia were recruited from the Rush Memory and Aging Project, a community-based epidemiologic study of aging. Participants completed a five-item self-report measure of susceptibility to scams, a battery of cognitive measures, and clinical diagnostic evaluations.

RESULTS: In models adjusted for age, education, and gender, the presence of MCI was associated with greater susceptibility to scams (B = 0.125, SE = 0.063, p-value = 0.047). Further, in analyses of the role of specific cognitive systems in susceptibility to scams among persons with MCI (n = 144), the level of performance in two systems, episodic memory and perceptual speed abilities, were associated with susceptibility.

CONCLUSIONS: Adults with MCI may be more susceptible to scams in old age than older persons with normal cognition. Lower abilities in specific cognitive systems, particularly perceptual speed and episodic memory, may contribute to greater susceptibility to scams in those with MCI.

%B J Alzheimers Dis %V 49 %P 845-51 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519434?dopt=Abstract %R 10.3233/JAD-150442 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Mitochondrial Role of SV2a Protein in Aging and Alzheimer's Disease: Studies with Levetiracetam. %A Stockburger, Carola %A Miano, Davide %A Baeumlisberger, Marion %A Pallas, Thea %A Arrey, Tabiwang N %A Karas, Michael %A Friedland, Kristina %A Müller, Walter E %K Adenosine Triphosphate %K Aging %K Alzheimer Disease %K Animals %K Brain %K Cell Line %K Cognition Disorders %K Female %K GAP-43 Protein %K Gene Expression Regulation %K Humans %K Male %K Membrane Glycoproteins %K Mitochondria %K Mitochondrial Membrane Transport Proteins %K Nerve Tissue Proteins %K Nitroprusside %K Nootropic Agents %K Piracetam %K Proteomics %K Rats %K RNA, Small Interfering %X

Aberrant neuronal network activity associated with neuronal hyperexcitability seems to be an important cause of cognitive decline in aging and Alzheimer's disease (AD). Out of many antiepileptics, only levetiracetam improved cognitive dysfunction in AD patients and AD animal models by reducing hyperexcitability. As impaired inhibitory interneuronal function, rather than overactive neurons, seems to be the underlying cause, improving impaired neuronal function rather than quieting overactive neurons might be relevant in explaining the lack of activity of the other antiepileptics. Interestingly, improvement of cognitive deficits by levetiracetam caused by small levels of soluble Aβ was accompanied by improvement of synaptic function and plasticity. As the negative effects of Aβ on synaptic plasticity strongly correlate with mitochondrial dysfunction, wehypothesized that the effect of levetiracetam on synaptic activity might be raised by an improved mitochondrial function. Accordingly, we investigated possible effects of levetiracetam on neuronal deficits associated with mitochondrial dysfunction linked to aging and AD. Levetiracetam improved several aspects of mitochondrial dysfunction including alterations of fission and fusion balance in a cell model for aging and early late-onset AD. We demonstrate for the first time, using immunohistochemistry and proteomics, that the synaptic vesicle protein 2A (SV2a), the molecular target of levetiracetam, is expressed in mitochondria. In addition, levetiracetam shows significant effect on the opening of the mitochondrial permeability transition pore. Importantly, the effects of levetiracetam were significantly abolished when SV2a was knockdown using siRNA. In conclusion, interfering with the SV2a protein at the mitochondrial level and thereby improving mitochondrial function might represent an additional therapeutic effect of levetiracetam to improve symptoms of late-onset AD.

%B J Alzheimers Dis %V 50 %P 201-15 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639968?dopt=Abstract %R 10.3233/JAD-150687 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Older Adults Taking AT1-Receptor Blockers Exhibit Reduced Cerebral Amyloid Retention. %A Nation, Daniel A %A Ho, Jean %A Yew, Belinda %K Aged %K Aged, 80 and over %K Aging %K Amyloid beta-Peptides %K Angiotensin Receptor Antagonists %K Antihypertensive Agents %K Chi-Square Distribution %K Cross-Sectional Studies %K Dementia %K Female %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Peptide Fragments %K Psychiatric Status Rating Scales %K Regression Analysis %K tau Proteins %K Time Factors %X

BACKGROUND: Evidence suggests that angiotensin II AT1-receptor blockers (ARBs) may be protective against dementia, and studies in transgenic animals indicate that this may be due to improved amyloid-β (Aβ) clearance.

OBJECTIVE: We investigated whether taking ARBs was associated with an attenuation of age-related increases in cerebral Aβ retention, and reduced progression to dementia.

METHODS: Eight hundred seventy-one stroke-free and dementia-free older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study underwent baseline lumbar puncture, and a subgroup (n = 124) underwent 12 and 24 month follow-up lumbar puncture. Participants were followed at variable intervals for clinical progression to dementia. Linear mixed models and ANCOVA compared ARBs users with those taking other antihypertensives (O-antiHTN) or no antihypertensives (No-antiHTN) on cerebrospinal fluid (CSF) Aβ and phosphorylated tau (P-tau) levels. Cox regression and chi-square analyses compared groups on progression to dementia.

RESULTS: ARBs users exhibited greater vascular risk and lower educational attainment than the No-antiHTN group. Longitudinal analyses indicated higher CSF Aβ and lower P-tau in ARBs users versus other groups. Cross-sectional analyses revealed age-related decreases in CSF Aβ in other groups but not ARBs users. ARBs users were less likely to progress to dementia and showed reduced rate of progression relative to the No-antiHTN group.

DISCUSSION: Patients taking ARBs showed an attenuation of age-related decreases in CSF Aβ, a finding that is consistent with studies done in transgenic animals. These findings may partly explain why ARBs users show reduced progression to dementia despite their lower educational attainment and greater vascular risk burden.

%B J Alzheimers Dis %V 50 %P 779-89 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757036?dopt=Abstract %R 10.3233/JAD-150487 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Oral Iron Chelator, Deferasirox, Reverses the Age-Dependent Alterations in Iron and Amyloid-β Homeostasis in Rat Brain: Implications in the Therapy of Alzheimer's Disease. %A Banerjee, Priyanjalee %A Sahoo, Arghyadip %A Anand, Shruti %A Bir, Aritri %A Chakrabarti, Sasanka %K Administration, Oral %K Aging %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Benzoates %K Brain %K Ferritins %K Gene Expression Regulation %K Iron %K Iron Chelating Agents %K Neprilysin %K NF-kappa B %K Oxidative Stress %K Peptide Fragments %K Protein Carbonylation %K Rats %K Rats, Wistar %K Receptors, Transferrin %K Spectrophotometry %K Triazoles %X

The altered metabolism of iron impacts the brain function in multiple deleterious ways during normal aging as well as in Alzheimer's disease. We have shown in this study that chelatable iron accumulates in the aged rat brain along with overexpression of transferrin receptor 1 (TfR1) and ferritin, accompanied by significant alterations in amyloid-β (Aβ) peptide homeostasis in the aging brain, such as an increased production of the amyloid-β protein precursor, a decreased level of neprilysin, and increased accumulation of Aβ42. When aged rats are given daily the iron chelator, deferasirox, over a period of more than 4 months starting from the 18th month, the age-related accumulation of iron and overexpression of TfR1 and ferritin in the brain are significantly prevented. More interestingly, the chelator treatment also considerably reverses the altered Aβ peptide metabolism in the aging brain implying a significant role of iron in the latter phenomenon. Further, other results indicate that iron accumulation results in oxidative stress and the activation of NF-κB in the aged rat brain, which are also reversed by the deferasirox treatment. The analysis of the results together suggests that iron accumulation and oxidative stress interact at multiple levels that include transcriptional and post-transcriptional mechanisms to bring about changes in the expression levels of TfR1 and ferritin and also alterations in Aβ peptide metabolism in the aging rat brain. The efficacy of deferasirox in preventing age-related changes in iron and Aβ peptide metabolism in the aging brain, as shown here, has obvious therapeutic implications for Alzheimer's disease.

%B J Alzheimers Dis %V 49 %P 681-93 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484920?dopt=Abstract %R 10.3233/JAD-150514 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Patterns of Brain Iron Accumulation in Vascular Dementia and Alzheimer's Dementia Using Quantitative Susceptibility Mapping Imaging. %A Moon, Yeonsil %A Han, Seol-Heui %A Moon, Won-Jin %K Aged %K Aging %K Alzheimer Disease %K Brain %K Brain Mapping %K Cognition %K Dementia, Vascular %K Female %K Humans %K Imaging, Three-Dimensional %K Iron %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Retrospective Studies %K Severity of Illness Index %X

BACKGROUND: Emerging evidence suggests that the excessive accumulation of iron in subcortical and deep gray matter has been related to dementia. However, the presence and pattern of iron accumulation in vascular dementia (VaD) and Alzheimer's disease (AD) are rarely investigated.

OBJECTIVE: To examine and compare the pattern and presence of brain iron accumulation of VaD and AD using quantitative susceptibility mapping (QSM).

MATERIALS AND METHODS: Twelve patients with VaD, 27 patients with AD, and 18 control subjects were recruited in this institutional review-board approved study. Susceptibility maps were reconstructed from a three-dimensional multiecho spoiled gradient-echo sequence. Four regions of interest were drawn manually on QSM images, namely the globus pallidus, putamen, caudate nucleus, and pulvinar nucleus of the thalamus. Comparisons of patient demographics, and iron concentrations among the VaD, AD, and control subjects were assessed using analysis of variance and post-hoc analyses. The relationships of age and cognitive state with susceptibility values were assessed using partial correlation analysis.

RESULTS: In VaD and AD, overall susceptibility values were higher than those of control subjects. A significant difference in susceptibility values was found in the putamen and caudate nucleus (p <  0.001 and p = 0.002, respectively). However, susceptibility values did not differ between VaD and AD. Age and cognitive deficit severity were not related to susceptibility values in the VaD and AD groups.

CONCLUSION: Increased iron deposition in the putamen and caudate nucleus in VaD and AD patients was not associated with age or the severity of cognitive deficits. Further evaluations are needed to determine the temporal changes in iron load and their diagnostic role in dementia pathology.

%B J Alzheimers Dis %V 51 %P 737-45 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890777?dopt=Abstract %R 10.3233/JAD-151037 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Performance of Hippocampus Volumetry with FSL-FIRST for Prediction of Alzheimer's Disease Dementia in at Risk Subjects with Amnestic Mild Cognitive Impairment. %A Suppa, Per %A Hampel, Harald %A Kepp, Timo %A Lange, Catharina %A Spies, Lothar %A Fiebach, Jochen B %A Dubois, Bruno %A Buchert, Ralph %K Aged %K Aging %K Alzheimer Disease %K Area Under Curve %K Cognitive Dysfunction %K Databases, Factual %K Disease Progression %K Hippocampus %K Humans %K Image Interpretation, Computer-Assisted %K Magnetic Resonance Imaging %K Neuropsychological Tests %K Organ Size %K Pattern Recognition, Automated %K Prognosis %K Reproducibility of Results %K Risk %K ROC Curve %K Sensitivity and Specificity %K Time Factors %X

MRI-based hippocampus volume, a core feasible biomarker of Alzheimer's disease (AD), is not yet widely used in clinical patient care, partly due to lack of validation of software tools for hippocampal volumetry that are compatible with routine workflow. Here, we evaluate fully-automated and computationally efficient hippocampal volumetry with FSL-FIRST for prediction of AD dementia (ADD) in subjects with amnestic mild cognitive impairment (aMCI) from phase 1 of the Alzheimer's Disease Neuroimaging Initiative. Receiver operating characteristic analysis of FSL-FIRST hippocampal volume (corrected for head size and age) revealed an area under the curve of 0.79, 0.70, and 0.70 for prediction of aMCI-to-ADD conversion within 12, 24, or 36 months, respectively. Thus, FSL-FIRST provides about the same power for prediction of progression to ADD in aMCI as other volumetry methods.

%B J Alzheimers Dis %V 51 %P 867-73 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923010?dopt=Abstract %R 10.3233/JAD-150804 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Presence of Select Tau Species in Human Peripheral Tissues and Their Relation to Alzheimer's Disease. %A Dugger, Brittany N %A Whiteside, Charisse M %A Maarouf, Chera L %A Walker, Douglas G %A Beach, Thomas G %A Sue, Lucia I %A Garcia, Angelica %A Dunckley, Travis %A Meechoovet, Bessie %A Reiman, Eric M %A Roher, Alex E %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Blotting, Western %K Colon %K Enzyme-Linked Immunosorbent Assay %K Female %K Frontal Lobe %K Gray Matter %K Humans %K Immunohistochemistry %K Liver %K Male %K Neurofibrillary Tangles %K Phosphorylation %K Severity of Illness Index %K Sex Characteristics %K Skin %K Submandibular Gland %K tau Proteins %X

Tau becomes excessively phosphorylated in Alzheimer's disease (AD) and is widely studied within the brain. Further examination of the extent and types of tau present in peripheral tissues and their relation to AD is warranted given recent publications on pathologic spreading. Cases were selected based on the presence of pathological tau spinal cord deposits (n = 18). Tissue samples from sigmoid colon, scalp, abdominal skin, liver, and submandibular gland were analyzed by western blot and enzyme-linked immunosorbent assays (ELISAs) for certain tau species; frontal cortex gray matter was used for comparison. ELISAs revealed brain to have the highest total tau levels, followed by submandibular gland, sigmoid colon, liver, scalp, and abdominal skin. Western blots with antibodies recognizing tau phosphorylated at threonine 231(pT231), serine 396 and 404 (PHF-1), and an unmodified total human tau between residues 159 and 163 (HT7) revealed multiple banding patterns, some of which predominated in peripheral tissues. As submandibular gland had the highest levels of peripheral tau, a second set of submandibular gland samples were analyzed (n = 36; 19 AD, 17 non-demented controls). ELISAs revealed significantly lower levels of pS396 (p = 0.009) and pT231 (p = 0.005) in AD cases but not total tau (p = 0.18). Furthermore, pT231 levels in submandibular gland inversely correlated with Braak neurofibrillary tangle stage (p = 0.04), after adjusting for age at death, gender, and postmortem interval. These results provide evidence that certain tau species are present in peripheral tissues. Of potential importance, submandibular gland pT231 is progressively less abundant with increasing Braak neurofibrillary tangle stage.

%B J Alzheimers Dis %V 51 %P 345-56 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890756?dopt=Abstract %R 10.3233/JAD-150859 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Role of Alzheimer's and Cerebrovascular Pathology in Mediating the Effects of Age, Race, and Apolipoprotein E Genotype on Dementia Severity in Pathologically-Confirmed Alzheimer's Disease. %A Gavett, Brandon E %A John, Samantha E %A Gurnani, Ashita S %A Bussell, Cara A %A Saurman, Jessica L %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Apolipoproteins E %K Cerebrovascular Disorders %K Continental Population Groups %K Dementia %K Educational Status %K Female %K Genotype %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Models, Theoretical %X

BACKGROUND: Dementia severity can be modeled as the construct δ, representing the "cognitive correlates of functional status."

OBJECTIVE: We recently validated a model for estimating δ in the National Alzheimer's Coordinating Center's Uniform Data Set; however, the association of δ with neuropathology remains untested.

METHODS: We used data from 727 decedents evaluated at Alzheimer's Disease (AD) Centers nationwide. Participants spoke English, had no genetic abnormalities, and were pathologically diagnosed with AD as a primary or contributing etiology. Clinical data from participants' last visit prior to death were used to estimate dementia severity (δ).

RESULTS: A structural equation model using age, education, race, and apolipoprotein E (APOE) genotype (number of ɛ2 and ɛ4 alleles) as predictors and latent AD pathology and cerebrovascular disease (CVD) pathology as mediators fit the data well (RMSEA = 0.031; CFI = 0.957). AD pathology mediated the effects of age and APOE genotype on dementia severity. An older age at death and more ɛ2 alleles were associated with less AD pathology and, in turn, with less severe dementia. In contrast, more ɛ4 alleles were associated with more pathology and more severe dementia. Although age and race contributed to differences in CVD pathology, CVD pathology was not related to dementia severity in this sample of decedents with pathologically-confirmed AD.

CONCLUSIONS: Using δ as an estimate of dementia severity fits well within a structural model in which AD pathology directly affects dementia severity and mediates the relationship between age and APOE genotype on dementia severity.

%B J Alzheimers Dis %V 49 %P 531-45 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444761?dopt=Abstract %R 10.3233/JAD-150252 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Sensitivity of Neuropsychological Tests to Identify Cognitive Decline in Highly Educated Elderly Individuals: 12 Months Follow up. %A Elkana, Odelia %A Eisikovits, Osnat Reichman %A Oren, Noga %A Betzale, Vered %A Giladi, Nir %A Ash, Elissa L %K Aged %K Aged, 80 and over %K Aging %K Brain %K Cognition Disorders %K Educational Status %K Female %K Follow-Up Studies %K Humans %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Sensitivity and Specificity %K Statistics as Topic %X

Highly educated individuals have a lower risk of developing dementia and Alzheimer's disease (AD). A common assumption is that their "cognitive reserve" protects them from cognitive decline and postpones the clinical manifestation of dementia. These highly educated individuals usually obtain normal scores on cognitive screening tests, although at the same time they can experience subjective cognitive decline and difficulty in multiple cognitive domains. Although comprehensive neuropsychological evaluations usually identify subtle changes in cognition, they demand extensive resources and thus are expensive and difficult to obtain. Therefore, lack of sensitivity of screening tests on the one hand, along with difficulty to acquire a comprehensive neuropsychological evaluation on the other hand, impede identification of cognitive decline at its earliest stages in this special population. Accordingly, this study aims to identify which neuropsychological tests have the highest sensitivity to detect the earliest stages of cognitive decline among highly educated elderly [n = 27, ages 66-80 (mean = 72.6 SD = 4.54), mean education level = 17.14 (SD = 3.21 range: 12-24 years)]. Baseline scores and scores at one-year follow up were obtained. We also conducted MRI scans to characterize the relation between brain volume and cognitive performance. Results show significant reductions in RVALT, Semantic verbal Fluency, ROCF copy, and MoCA scores whereas PF, TMT, ROCF delay, digit span, and knowledge tests were not significant. The study stresses the importance of using sensitive neuropsychological tests to examine this special population and the need to create norms that combine an individual's education with age.

%B J Alzheimers Dis %V 49 %P 607-16 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484925?dopt=Abstract %R 10.3233/JAD-150562 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Strategies for improving memory: a randomized trial of memory groups for older people, including those with mild cognitive impairment. %A Kinsella, Glynda J %A Ames, David %A Storey, Elsdon %A Ong, Ben %A Pike, Kerryn E %A Saling, Michael M %A Clare, Linda %A Mullaly, Elizabeth %A Rand, Elizabeth %K Aged %K Aged, 80 and over %K Aging %K Cognitive Dysfunction %K Cross-Over Studies %K Female %K Humans %K Male %K Memory, Episodic %K Neuropsychological Tests %K Self Report %X

BACKGROUND: Governments are promoting the importance of maintaining cognitive health into older age to minimize risk of cognitive decline and dementia. Older people with amnestic mild cognitive impairment (aMCI) are particularly vulnerable to memory challenges in daily activities and are seeking ways to maintain independent living.

OBJECTIVE: To evaluate the effectiveness of memory groups for improving memory strategies and memory ability of older people, especially those with aMCI.

METHODS: 113 healthy older adults (HOA) and 106 adults with aMCI were randomized to a six-week memory group or a waitlist control condition. Outcome was evaluated through knowledge and use of memory strategies, memory ability (self-report and neuropsychological tests), and wellbeing. Assessments included a six-month follow-up.

RESULTS: Using intention to treat analyses, there were intervention effects for HOA and aMCI groups in strategy knowledge (HOA: η2= 0.20; aMCI: η2= 0.06), strategy use (HOA: η2= 0.18; aMCI: η2= 0.08), and wellbeing (HOA: η2= 0.11; aMCI: η2= 0.05). There were also intervention effects in the HOA group, but not the aMCI group, in self-reported memory ability (η2= 0.06) and prospective memory tests (η2= 0.02). By six-month follow-up, gains were found on most HOA outcomes. In the aMCI group gains were found in strategy use, and by this stage, gains in prospective memory were also found.

CONCLUSION: Memory groups can engage older people in techniques for maintaining cognitive health and improve memory performance, but more modest benefits are seen for older adults with aMCI.

%B J Alzheimers Dis %V 49 %P 31-43 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444773?dopt=Abstract %R 10.3233/JAD-150378 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Subjective Memory Complaints in APOEɛ4 Carriers are Associated with High Amyloid-β Burden. %A Zwan, Marissa D %A Villemagne, Victor L %A Doré, Vincent %A Buckley, Rachel %A Bourgeat, Pierrick %A Veljanoski, Robyn %A Salvado, Olivier %A Williams, Rob %A Margison, Laura %A Rembach, Alan %A Macaulay, S Lance %A Martins, Ralph %A Ames, David %A van der Flier, Wiesje M %A Ellis, Kathryn A %A Scheltens, Philip %A Masters, Colin L %A Rowe, Christopher C %K Aged %K Aging %K Amyloid beta-Peptides %K Aniline Compounds %K Apolipoprotein E4 %K Benzothiazoles %K Brain %K Cognition Disorders %K Female %K Genotyping Techniques %K Heterozygote %K Humans %K Logistic Models %K Male %K Neuropsychological Tests %K Positron-Emission Tomography %K Radiopharmaceuticals %K Thiazoles %X

BACKGROUND: APOEɛ4 genotype and aging have been identified as risk factors for Alzheimer's disease (AD). In addition, subjective memory complaints (SMC) might be a first clinical expression of the effect of AD pathology on cognitive functioning.

OBJECTIVE: To assess whether APOEɛ4 genotype, age, SMC, and episodic memory are risk factors for high amyloid-β (Aβ) burden in cognitively normal elderly.

METHODS: 307 cognitively normal participants (72.7 ± 6.8 years, 53% female, 55% SMC) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent amyloid PET and APOE genotyping. Logistic regression analyses were performed to determine the association of APOEɛ4 genotype, age, SMC, and episodic memory with Aβ pathology.

RESULTS: Odds of high Aβ burden were greater at an older age (OR = 3.21; 95% CI = 1.68-6.14), when SMC were present (OR = 1.90; 95% CI = 1.03-3.48), and for APOEɛ4 carriers (OR = 7.49; 95% CI = 3.96-14.15), while episodic memory was not associated with odds of high Aβ burden. Stratified analyses showed that odds of SMC for high Aβ burden were increased in specifically APOEɛ4 carriers (OR = 4.58, 95% CI = 1.83-11.49) and younger participants (OR = 3.73, 95% CI = 1.39-10.01).

CONCLUSION: Aging, APOEɛ4 genotype, and SMC were associated with high Aβ burden. SMC were especially indicative of high Aβ burden in younger participants and in APOEɛ4 carriers. These findings suggest that selection based on the presence of SMC, APOEɛ4 genotype and age may help identify healthy elderly participants with high Aβ burden eligible for secondary prevention trials.

%B J Alzheimers Dis %V 49 %P 1115-22 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639956?dopt=Abstract %R 10.3233/JAD-150446 %0 Journal Article %J J Alzheimers Dis %D 2016 %T White Matter Abnormalities Track Disease Progression in PSEN1 Autosomal Dominant Alzheimer's Disease. %A Sánchez-Valle, Raquel %A Monté, Gemma C %A Sala-Llonch, Roser %A Bosch, Beatriz %A Fortea, Juan %A Lladó, Albert %A Antonell, Anna %A Balasa, Mircea %A Bargalló, Nuria %A Molinuevo, José Luis %K Adult %K Aging %K Alzheimer Disease %K Brain %K Cohort Studies %K Diffusion Tensor Imaging %K Disease Progression %K Family %K Female %K Heterozygote %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Mutation %K Neuropsychological Tests %K Organ Size %K Presenilin-1 %K White Matter %X

PSEN1 mutations are the most frequent cause of autosomal dominant Alzheimer's disease (ADAD), and show nearly full penetrance. There is presently increasing interest in the study of biomarkers that track disease progression in order to test therapeutic interventions in ADAD. We used white mater (WM) volumetric characteristics and diffusion tensor imaging (DTI) metrics to investigate correlations with the normalized time to expected symptoms onset (relative age ratio) and group differences in a cohort of 36 subjects from PSEN1 ADAD families: 22 mutation carriers, 10 symptomatic (SMC) and 12 asymptomatic (AMC), and 14 non-carriers (NC). Subjects underwent a 3T MRI. WM morphometric data and DTI metrics were analyzed. We found that PSEN1 MC showed significant negative correlation between fractional anisotropy (FA) and the relative age ratio in the genus and body of corpus callosum and corona radiate (p <  0.05 Family-wise error correction (FWE) at cluster level) and positive correlation with mean diffusivity (MD), axial diffusivity (AxD), and radial diffusivity (RD) in the splenium of corpus callosum. SMC presented WM volume loss, reduced FA and increased MD, AxD, and RD in the anterior and posterior corona radiate, corpus callosum (p <  0.05 FWE) compared with NC. No significant differences were observed between AMC and NC in WM volume or DTI measures. These findings suggest that the integrity of the WM deteriorates linearly in PSEN1 ADAD from the early phases of the disease; thus DTI metrics might be useful to monitor the disease progression. However, the lack of significant alterations at the preclinical stages suggests that these indexes might not be good candidates for early markers of the disease.

%B J Alzheimers Dis %V 51 %P 827-35 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923015?dopt=Abstract %R 10.3233/JAD-150899 %0 Journal Article %J J Alzheimers Dis %D 2016 %T White Matter Changes are Associated with Ventricular Expansion in Aging, Mild Cognitive Impairment, and Alzheimer's Disease. %A Coutu, Jean-Philippe %A Goldblatt, Alison %A Rosas, H Diana %A Salat, David H %K Aged %K Aging %K Alzheimer Disease %K Cognitive Dysfunction %K Diffusion Tensor Imaging %K Factor Analysis, Statistical %K Female %K Hippocampus %K Humans %K Imaging, Three-Dimensional %K Male %K Mental Status Schedule %K Neuropsychological Tests %K White Matter %X

White matter lesions are highly prevalent in individuals with Alzheimer's disease (AD). Although these lesions are presumed to be of vascular origin and linked to small vessel disease in older adults, little information exists about their relationship to markers of classical AD neurodegeneration. Thus, we examined the link between these white matter changes (WMC) segmented on T1-weighted MRI and imaging markers presumed to be altered due to primary AD neurodegenerative processes. Tissue microstructure of WMC was quantified using diffusion tensor imaging and the relationship of WMC properties and volume to neuroimaging markers was examined in 219 cognitively healthy older adults and individuals with mild cognitive impairment and AD using data from the Alzheimer's Disease Neuroimaging Initiative. No significant group differences in WMC properties were found. However, there were strong associations between diffusivity of WMC and ventricular volume, volume of WMC and total WM volume. In comparison, group differences in parahippocampal white matter microstructure were found for all diffusion metrics and were largely explained by hippocampal volume. Factor analysis on neuroimaging markers suggested two independent sets of covarying degenerative changes, with potentially age- and vascular-mediated tissue damage contributing to one factor and classical neurodegenerative changes associated with AD contributing to a second factor. These data demonstrate two potentially distinct classes of degenerative change in AD, with one factor strongly linked to aging, ventricular expansion, and both volume and tissue properties of white matter lesions, while the other factor related to classical patterns of cortical and hippocampal neurodegeneration in AD.

%B J Alzheimers Dis %V 49 %P 329-42 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444767?dopt=Abstract %R 10.3233/JAD-150306 %0 Journal Article %J Nature %D 2014 %T REST and stress resistance in ageing and Alzheimer's disease. %A Lu, Tao %A Aron, Liviu %A Zullo, Joseph %A Pan, Ying %A Kim, Haeyoung %A Chen, Yiwen %A Yang, Tun-Hsiang %A Kim, Hyun-Min %A Drake, Derek %A Liu, X Shirley %A Bennett, David A %A Colaiácovo, Monica P %A Yankner, Bruce A %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Autophagy %K Brain %K Caenorhabditis elegans Proteins %K Cell Death %K Cell Nucleus %K Chromatin Immunoprecipitation %K Cognition %K DNA-Binding Proteins %K Down-Regulation %K Frontotemporal Dementia %K Gene Expression Regulation %K Humans %K Lewy Body Disease %K Longevity %K Mice %K Mild Cognitive Impairment %K Neurons %K Neuroprotective Agents %K Oxidative Stress %K Phagosomes %K Repressor Proteins %K Transcription Factors %K Up-Regulation %K Wnt Signaling Pathway %K Young Adult %X

Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer's disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

%B Nature %V 507 %P 448-54 %8 2014 Mar 27 %G eng %N 7493 %1 http://www.ncbi.nlm.nih.gov/pubmed/24670762?dopt=Abstract %R 10.1038/nature13163 %0 Journal Article %J J Am Geriatr Soc %D 2014 %T Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive training trial on cognition and everyday functioning in older adults. %A Rebok, George W %A Ball, Karlene %A Guey, Lin T %A Jones, Richard N %A Kim, Hae-Young %A King, Jonathan W %A Marsiske, Michael %A Morris, John N %A Tennstedt, Sharon L %A Unverzagt, Frederick W %A Willis, Sherry L %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Aging %K Cognition Disorders %K Cognitive Therapy %K Female %K Follow-Up Studies %K Humans %K Independent Living %K Male %K Memory Disorders %K Mental Processes %K Single-Blind Method %K United States %X

OBJECTIVES: To determine the effects of cognitive training on cognitive abilities and everyday function over 10 years.

DESIGN: Ten-year follow-up of a randomized, controlled single-blind trial (Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE)) with three intervention groups and a no-contact control group.

SETTING: Six U.S. cities.

PARTICIPANTS: A volunteer sample of 2,832 persons (mean baseline age 73.6; 26% African American) living independently.

INTERVENTION: Ten training sessions for memory, reasoning, or speed of processing; four sessions of booster training 11 and 35 months after initial training.

MEASUREMENTS: Objectively measured cognitive abilities and self-reported and performance-based measures of everyday function.

RESULTS: Participants in each intervention group reported less difficulty with instrumental activities of daily living (IADLs) (memory: effect size = 0.48, 99% confidence interval (CI) = 0.12-0.84; reasoning: effect size = 0.38, 99% CI = 0.02-0.74; speed of processing: effect size = 0.36, 99% CI = 0.01-0.72). At a mean age of 82, approximately 60% of trained participants, versus 50% of controls (P < .05), were at or above their baseline level of self-reported IADL function at 10 years. The reasoning and speed-of-processing interventions maintained their effects on their targeted cognitive abilities at 10 years (reasoning: effect size = 0.23, 99% CI = 0.09-0.38; speed of processing: effect size = 0.66, 99% CI = 0.43-0.88). Memory training effects were no longer maintained for memory performance. Booster training produced additional and durable improvement for the reasoning intervention for reasoning performance (effect size = 0.21, 99% CI = 0.01-0.41) and the speed-of-processing intervention for speed-of-processing performance (effect size = 0.62, 99% CI = 0.31-0.93).

CONCLUSION: Each Advanced Cognitive Training for Independent and Vital Elderly cognitive intervention resulted in less decline in self-reported IADL compared with the control group. Reasoning and speed, but not memory, training resulted in improved targeted cognitive abilities for 10 years.

%B J Am Geriatr Soc %V 62 %P 16-24 %8 2014 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24417410?dopt=Abstract %R 10.1111/jgs.12607 %0 Journal Article %J 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 Lancet Neurol %D 2012 %T Cognitive reserve in ageing and Alzheimer's disease. %A Stern, Yaakov %K Aging %K Alzheimer Disease %K Animals %K Cognitive Reserve %K Humans %X

The concept of cognitive reserve provides an explanation for differences between individuals in susceptibility to age-related brain changes or pathology related to Alzheimer's disease, whereby some people can tolerate more of these changes than others and maintain function. Epidemiological studies suggest that lifelong experiences, including educational and occupational attainment, and leisure activities in later life, can increase this reserve. For example, the risk of developing Alzheimer's disease is reduced in individuals with higher educational or occupational attainment. Reserve can conveniently be divided into two types: brain reserve, which refers to differences in the brain structure that may increase tolerance to pathology, and cognitive reserve, which refers to differences between individuals in how tasks are performed that might enable some people to be more resilient to brain changes than others. Greater understanding of the concept of cognitive reserve could lead to interventions to slow cognitive ageing or reduce the risk of dementia.

%B Lancet Neurol %V 11 %P 1006-12 %8 2012 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/23079557?dopt=Abstract %R 10.1016/S1474-4422(12)70191-6 %0 Journal Article %J Nature %D 2012 %T A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. %A Jonsson, Thorlakur %A Atwal, Jasvinder K %A Steinberg, Stacy %A Snaedal, Jon %A Jonsson, Palmi V %A Bjornsson, Sigurbjorn %A Stefansson, Hreinn %A Sulem, Patrick %A Gudbjartsson, Daniel %A Maloney, Janice %A Hoyte, Kwame %A Gustafson, Amy %A Liu, Yichin %A Lu, Yanmei %A Bhangale, Tushar %A Graham, Robert R %A Huttenlocher, Johanna %A Bjornsdottir, Gyda %A Andreassen, Ole A %A Jönsson, Erik G %A Palotie, Aarno %A Behrens, Timothy W %A Magnusson, Olafur T %A Kong, Augustine %A Thorsteinsdottir, Unnur %A Watts, Ryan J %A Stefansson, Kari %K Aging %K Alleles %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Aspartic Acid Endopeptidases %K Cognition %K Cognition Disorders %K Genetic Predisposition to Disease %K HEK293 Cells %K Humans %K Mutation %K Plaque, Amyloid %X

The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-β precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.

%B Nature %V 488 %P 96-9 %8 2012 Aug 2 %G eng %N 7409 %1 http://www.ncbi.nlm.nih.gov/pubmed/22801501?dopt=Abstract %R 10.1038/nature11283 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2011 %T Exercise training increases size of hippocampus and improves memory. %A Erickson, Kirk I %A Voss, Michelle W %A Prakash, Ruchika Shaurya %A Basak, Chandramallika %A Szabo, Amanda %A Chaddock, Laura %A Kim, Jennifer S %A Heo, Susie %A Alves, Heloisa %A White, Siobhan M %A Wojcicki, Thomas R %A Mailey, Emily %A Vieira, Victoria J %A Martin, Stephen A %A Pence, Brandt D %A Woods, Jeffrey A %A McAuley, Edward %A Kramer, Arthur F %K Aged %K Aging %K Brain-Derived Neurotrophic Factor %K Enzyme-Linked Immunosorbent Assay %K Exercise %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Memory %K Middle Aged %K Organ Size %K Space Perception %X

The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.

%B Proc Natl Acad Sci U S A %V 108 %P 3017-22 %8 2011 Feb 15 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21282661?dopt=Abstract %R 10.1073/pnas.1015950108 %0 Journal Article %J Nature %D 2011 %T Neuronal basis of age-related working memory decline. %A Wang, Min %A Gamo, Nao J %A Yang, Yang %A Jin, Lu E %A Wang, Xiao-Jing %A Laubach, Mark %A Mazer, James A %A Lee, Daeyeol %A Arnsten, Amy F T %K Action Potentials %K Adrenergic alpha-2 Receptor Agonists %K Aging %K Animals %K Biomedical Enhancement %K Cues %K Cyclic AMP %K Cyclic Nucleotide-Gated Cation Channels %K Guanfacine %K Humans %K Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels %K KCNQ Potassium Channels %K Macaca mulatta %K Male %K Memory, Short-Term %K Models, Neurological %K Neural Pathways %K Potassium Channel Blockers %K Potassium Channels %K Prefrontal Cortex %K Receptors, Adrenergic, alpha-2 %K Signal Transduction %K Time Factors %X

Many of the cognitive deficits of normal ageing (forgetfulness, distractibility, inflexibility and impaired executive functions) involve prefrontal cortex (PFC) dysfunction. The PFC guides behaviour and thought using working memory, which are essential functions in the information age. Many PFC neurons hold information in working memory through excitatory networks that can maintain persistent neuronal firing in the absence of external stimulation. This fragile process is highly dependent on the neurochemical environment. For example, elevated cyclic-AMP signalling reduces persistent firing by opening HCN and KCNQ potassium channels. It is not known if molecular changes associated with normal ageing alter the physiological properties of PFC neurons during working memory, as there have been no in vivo recordings, to our knowledge, from PFC neurons of aged monkeys. Here we characterize the first recordings of this kind, revealing a marked loss of PFC persistent firing with advancing age that can be rescued by restoring an optimal neurochemical environment. Recordings showed an age-related decline in the firing rate of DELAY neurons, whereas the firing of CUE neurons remained unchanged with age. The memory-related firing of aged DELAY neurons was partially restored to more youthful levels by inhibiting cAMP signalling, or by blocking HCN or KCNQ channels. These findings reveal the cellular basis of age-related cognitive decline in dorsolateral PFC, and demonstrate that physiological integrity can be rescued by addressing the molecular needs of PFC circuits.

%B Nature %V 476 %P 210-3 %8 2011 Aug 11 %G eng %N 7359 %1 http://www.ncbi.nlm.nih.gov/pubmed/21796118?dopt=Abstract %R 10.1038/nature10243 %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