Journal of Alzheimer's Disease - Volume 69, issue 2

Authors: McGurran, Hugo | Glenn, Jordan M. | Madero, Erica N. | Bott, Nicholas T.

Article Type: Review Article

Abstract:  Alzheimer’s disease (AD) is the most common form of dementia. With an aging population and no disease modifying treatments available, AD is quickly becoming a global pandemic. A substantial body of research indicates that lifestyle behaviors contribute to the development of AD, and that it may be worthwhile to approach AD like other chronic diseases such as cardiovascular disease, in which prevention is paramount. Exercise is an important lifestyle behavior that may influence the course and pathology of AD, but the biological mechanisms underpinning these effects remain unclear. This review focuses on how exercise can modify four possible mechanisms which …are involved with the pathology of AD: oxidative stress, inflammation, peripheral organ and metabolic health, and direct interaction with AD pathology. Exercise is just one of many lifestyle behaviors that may assist in preventing AD, but understanding the systemic and neurobiological mechanisms by which exercise affects AD could help guide the development of novel pharmaceutical agents and non-pharmacological personalized lifestyle interventions for at-risk populations. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, cardiovascular, exercise, inflammation, insulin, oxidative stress, tau

DOI: 10.3233/JAD-180958

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 311-338, 2019

Authors: Ding, Yuanting | Lei, Lijuan | Lai, Chencen | Tang, Zhi

Article Type: Review Article

Abstract: Tauopathies are a specific type of slow and progressive neurodegeneration, which involves intracellular deposition of fibrillar material composed of abnormal hyperphosphorylation of the microtubule associated protein (MAP) tau. Despite many years of intensive research, our understanding of the molecular events that lead to neurodegeneration is far from complete. No effective therapeutic treatments have been defined, and questions surround the validity and utility of existing animal models. It is an urgent need to develop a novel animal model to study the underlying neurodegenerative mechanisms of tauopathies. Zebrafish models of tauopathies could complement existing models by providing an in vivo platform …for genetic and chemical screens in order to identify new therapeutic targets and compounds, meanwhile zebrafish models have permitted discovery of unique characteristics of these genes that could have been difficultly observed in other models. Novel transgenic zebrafish models expressing wild-type or mutant forms of human 4R-tau in neurons have recently been reported. These studies show disease-relevant changes including tau hyperphosphorylation, aggregation and somato-dendritic relocalization. This review highlights the availability of transgenic tau zebrafish models that allow more detailed biochemical studies of tau in the zebrafish CNS to characterize solubility, fibril morphology and further clarify phosphorylation proceedings. Furthermore, a deeper knowledge of the zebrafish brain and a better characterization of tau caused by alterations in neurodegenerative disorders are needed. Show more

Keywords: Alzheimer’s disease, tau protein, tauopathies, zebrafish

DOI: 10.3233/JAD-180917

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 339-353, 2019

Authors: Li, Shiping | Yin, Junxiang | Nielsen, Megan | Beach, Thomas G. | Guo, Li | Shi, Jiong

Article Type: Research Article

Abstract: Background: Emerging evidence shows tau acetylation has been observed in Alzheimer’s disease (AD) brain at early Braak stages and is involved in regulating tau early accumulation. However, the effects of deacetylase Sirtuin 3 (Sirt3) on tau acetylation and its aggregations are unclear. Objective: We studied the effects of Sirt3 on tau acetylation and its aggregations. Methods: We investigated the protein levels of Sirt3 and tangle tau in human postmortem brains slices from AD, mild cognitive impairment, and age- and education-matched cognitively normal subjects, and AD model mice. We also measured tau acetylation levels in hippocampal HT22 …cells after Sirt3 knockdown or overexpression. Results: The level of Sirt3 was inversely related with tau protein in brain slices from both human being and AD model mice. Mechanistically, tau acetylation decreased dramatically with Sirt3 overexpression, while tau acetylation increased after Sirt3 knockdown in hippocampal HT22 cells. Conclusions: Sirt3 may play a role in tau acetylation and could be a potential target for novel therapy to alleviate tau accumulation. Show more

Keywords: Acetylation, Alzheimer’s disease, Sirtuin, tau

DOI: 10.3233/JAD-190014

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 355-362, 2019

Authors: Roy, Upasana | Heredia-Muñoz, Mónica T. | Stute, Lara | Höfling, Corinna | Matysik, Jörg | Meijer, Johanna H. | Roßner, Steffen | Alia, A.

Article Type: Research Article

Abstract: In Alzheimer’s disease (AD), disturbances in the circadian rhythm and sleep-wake cycle are frequently observed. Both are controlled by the master clock: the suprachiasmatic nucleus (SCN), which was reported in postmortem studies of AD subjects to be compromised. However, the influence of age and gender on the biophysical integrity and subtle microstructural changes of SCN and mechanistic connections between SCN dysfunction and AD progression in vivo remain to be explored. In the present study, we utilized state-of-the-art in vivo magnetic resonance relaxation measurements in combination with immunohistochemistry to follow microstructural changes in SCN of the Tg2576 mouse model …of AD. Longitudinal monitoring of in vivo T2 relaxation with age shows significant shortening of T2 values in the SCN of transgenic mice and more substantially in female transgenic than aged-matched controls. Multiexponential T2 analysis detected a unique long T2 component in SCN of transgenic mice which was absent in wild-type mice. Immunohistochemical examination revealed significantly elevated numbers of activated astrocytes and an increase in the astrocyte to neuron ratio in SCN of transgenic compared to wild-type mice. This increase was more substantial in female than in male transgenic mice. In addition, low GABA production in SCN of transgenic mice was detected. Our results offer a brief appraisal of SCN dysfunction in AD and demonstrate that inflammatory responses may be an underlying perpetrator for the changes in circadian rhythmicity and sleep disturbance in AD and could also be at the root of marked sex disparities observed in AD subjects. Show more

Keywords: Alzheimer’s disease, gender difference, suprachiasmatic nucleus, T2 relaxation time, Tg2576 mouse model

DOI: 10.3233/JAD-190037

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 363-375, 2019

Authors: Goetghebeur, Pascal J.D. | Wesnes, Keith A. | Targum, Steven D.

Article Type: Research Article

Abstract: Recent fMRI studies in human identified that pattern separation ability is associated with increased activity in the hippocampal dentate gyrus (DG), whereas no such DG changes are seen during pattern completion. Disruption to neurogenesis in the DG has been associated with Alzheimer’s disease (AD). In a post-hoc analysis of two large unsuccessful AD clinical trials, we examined the effect of D-cycloserine (DCS) on a specific object pattern separation measure, a component of the picture recognition task from the Cognitive Drug Research (CDR) system. This task yields a measure of pattern separation and a measure of pattern completion. Study data …were available for 756 AD patients with dementia, randomized to several doses of DCS. Data were available at week 2, 6, 14, and 26 for 732, 707, 653, and 559 patients, respectively. None of the DCS doses had a statistically significant benefit over placebo on pattern completion. However, the DCS 15 mg BID dose significantly increased accuracy over placebo on the pattern separation measure by 5.1%. Further, the magnitude of the benefit of DCS 15 mg BID over placebo was almost doubled relative to the whole study population in a subset of patients whose pattern separation scores were≥2 standard deviations poorer than the CDR norm of age-matched healthy individuals at baseline. These post-hoc analyses suggest a potential value of the pattern separation task for evaluating compounds promoting neurogenesis. Further, the use of a restrictive pattern separation eligibility criterion might facilitate signal detection. Show more

Keywords: Alzheimer’s disease, dementia, D-cycloserine, neurogenesis, pattern separation

DOI: 10.3233/JAD-181094

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 377-383, 2019

Authors: Ashford, J. Wesson | Tarpin-Bernard, Franck | Ashford, Curtis B. | Ashford, Miriam T.

Article Type: Research Article

Abstract: Based on clinical observations of severe episodic memory (EM) impairment in dementia of Alzheimer’s disease (AD), a brief, computerized EM test was developed for AD patient evaluation. A continuous recognition task (CRT) was chosen because of its extensive use in EM research. Initial experience with this computerized CRT (CCRT) showed patients were very engaged in the test, but AD patients had marked failure in recognizing repeated images. Subsequently, the test was administered to audiences, and then a two-minute online version was implemented (http://www.memtrax.com ). The online CCRT shows 50 images, 25 unique and 25 repeats, which subjects respectively either try …to remember or indicate recognition as quickly as possible. The pictures contain 5 sets of 5 images of scenes or objects (e.g., mountains, clothing, vehicles, etc.). A French company (HAPPYneuron, SAS) provided the test for 2 years, with these results. Of 18,477 individuals, who indicated sex and age 21–99 years and took the test for the first time, 18,007 individuals performed better than chance. In this group, age explained 1.5% of the variance in incorrect responses and 3.5% of recognition time variance, indicating considerable population variability. However, when averaging for specific year of age, age explained 58% of percent incorrect variance and 78% of recognition time variance, showing substantial population variability but a major age effect. There were no apparent sex effects. Further studies are indicated to determine the value of this CCRT as an AD screening test and validity as a measure of EM impairment in other clinical conditions. Show more

Keywords: Aging, Alzheimer’s disease, cognition, cognitive impairment, dementia, episodic memory, memory, reaction time, recognition

DOI: 10.3233/JAD-190167

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 385-399, 2019

Authors: Karran, Martha | Guerrero-Berroa, Elizabeth | Schmeidler, James | Lee, Pearl G. | Alexander, Neil | Nabozny, Martina | West, Rebecca K. | Beeri, Michal Schnaider | Sano, Mary | Silverman, Jeremy M.

Article Type: Research Article

Abstract: Background: Type 2 diabetes mellitus (T2DM) is prevalent in the general United States population, and in the veteran population. T2DM has consistently been linked to increased risk for cognitive impairment, dementia, and Alzheimer’s disease. Computerized cognitive training (CCT) is practical and inexpensive cognitive interventions that is an alternative to medication. Objective: To report the recruitment methods and challenges to date in an ongoing two-site randomized controlled trial (RCT) of CCT on cognitive function and T2DM management in an older non-demented veteran population. Methods: Veterans are recruited primarily by targeted mailings or by direct contact at clinics …and presentations. Results: From 1,459 original contacts, 437 expressed initial interest, 111 provided informed consent, and 97 completed baseline assessments. Participants from the two VA Medical Centers differed in demographics and baseline characteristics. Comparing recruitment methods, the proportion of individuals contacted who were ultimately consented was significantly less from mailings (5%) than other sources (20%), primarily face– to-face clinic visits (χ 2 (1) = 38.331, p  < 0.001). Conclusions: Mailings are cost-effective, but direct contact improved recruitment. Not using or lacking access to computers and ineligibility were major reasons for non-participation. Within-site comparisons of demographically diverse sites can address confounding of demographic and other site differences. Show more

Keywords: Cognition, computer games, research subject recruitment, type 2 diabetes mellitus, veterans, Clinical Trials registration number, NCT01736124

DOI: 10.3233/JAD-180952

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 401-411, 2019

Authors: Yuen, Kimberley | Rashidi-Ranjbar, Neda | Verhoeff, Nicolaas Paul L.G. | Kumar, Sanjeev | Gallagher, Damien | Flint, Alastair J. | Herrmann, Nathan | Pollock, Bruce G. | Mulsant, Benoit H. | Rajji, Tarek K. | Voineskos, Aristotle N. | Fischer, Corinne E. | Mah, Linda | for the PACt-MD Study Group

Article Type: Research Article

Abstract: Background: Previous studies examining the link between neuropsychiatric symptoms (NPS) and biomarkers of Alzheimer’s disease (AD) may be confounded by remitted or past history of psychiatric illness, which in itself is associated with AD biomarkers such as reduced medial temporal lobe (MTL) volume. Objective: We examined associations between mood and anxiety-related NPS and MTL in older adults with mild cognitive impairment (MCI) free of lifetime history of depression. We hypothesized an inverse relationship between NPS severity and MTL. Methods: Forty-two MCI participants without current or past history of depression or other major psychiatric illness were assessed …using the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Correlation and regression analyses were performed between selected NPI-Q items and regional MTL volumes from structural magnetic resonance imaging. Results: Sleep disturbances were inversely associated with several regional volumes within the MTL. Sleep disturbances remained significantly correlated with left hippocampal and amygdala volume following correction for multiple comparisons. In contrast, depression and anxiety were not correlated with MTL. Conclusions: The relationship between reduced MTL and sleep, but not with depressed or anxious states, in MCI free of lifetime history of depression, suggests a potential mechanism for sleep as a risk factor for AD. The current findings highlight the importance of accounting for remitted psychiatric conditions in studies of the link between NPS and AD biomarkers and support the need for further research on sleep as clinical biomarker of AD and target for AD prevention. Show more

Keywords: Alzheimer’s disease, depression, medial temporal lobe, mild cognitive impairment, neuroimaging biomarkers, neuropsychiatric symptoms, sleep

DOI: 10.3233/JAD-190160

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 413-421, 2019

Authors: Pershing, Suzann | Henderson, Victor W. | Bundorf, M. Kate | Lu, Ying | Rahman, Moshiur | Andrews, Chris A. | Goldstein, Mary | Stein, Joshua D.

Article Type: Research Article

Abstract: Background: Cataract surgery substantially improves patient quality of life. Despite the rising prevalence of dementia in the US, little is known about use of cataract surgery among this group. Objective: To evaluate the relationship between dementia status and cataract surgery. Methods: Using administrative insurance claims for a representative sample of 1,125,387 US Medicare beneficiaries who received eye care between 2006 and 2015, we compared cataract surgery rates between patients with and without dementia via multivariable regression models to adjust for patient characteristics. Main outcome measures were annual rates of cataract surgery and hazard ratio and 95% …confidence interval (CI) for receiving cataract surgery. Results: Cataract surgery was performed in 457,128 patients, 23,331 with a prior diagnosis of dementia. 16.7% of dementia patients underwent cataract surgery, compared to 43.8% of patients without dementia. 59 cataract surgeries were performed per 1000 dementia patients annually, versus 105 surgeries per 1000 nondementia patients. After adjusting for patient characteristics, dementia patients were approximately half as likely to receive cataract surgery compared to nondementia patients (adjusted HR = 0.53, 95% CI 0.53–0.54). Among the subset of patients who received a first cataract surgery, those with dementia were also less likely to receive second-eye cataract surgery (adjusted HR = 0.87, 95% CI 0.86–0.88). Conclusion: US Medicare patients with dementia are less likely to undergo cataract surgery than those without dementia. This finding has implications for quality of care and dementia progression. More information is necessary to understand why rates of cataract surgery are lower for these patients, and to identify conditions where benefits of surgery may outweigh risks. Show more

Keywords: Aging and surgery, Alzheimer’s disease, cataract surgery, dementia, eye care, ophthalmology

DOI: 10.3233/JAD-181292

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 423-432, 2019

Authors: Johansson, Lena | Guerra, Mariella | Prince, Martin | Hörder, Helena | Falk, Hanna | Stubbs, Brendon | Prina, A. Matthew

Article Type: Research Article

Abstract: Background: A growing body of evidence suggests that depression is related to dementia in older adults. Previous research has been done in high-income countries and there is a lack of studies in low- and middle income countries (LMICs). Objective: To examine the relationship between depressive symptoms and incidence of dementia in a population-based study of older adults in Latin America. Methods: The study is a part of the 10/66 Dementia Research Group’s population survey and includes 11,472 older adults (baseline mean age 74 years) from Cuba, Dominican Republic, Mexico, Peru, Puerto Rico, and Venezuela. The baseline …examinations were done in 2003-2007 and the follow-up examinations 4 years later. Semi-structured psychiatric interviews gave information about ICD-10 depression and sub-syndromal depression (i.e., ≥4 depressive symptoms) at baseline. Information on dementia were collected at the follow-up examination. Competing risk models analyzed the associations between depression and incidence of dementia and the final model were adjusted for age, sex, education, stroke, and diabetes. Separate analyses were conducted for each site and then meta-analyzed by means of fixed effect models. Results: At baseline, the prevalence of depression was 26.0% (n  = 2,980): 5.4% had ICD-10 depression and 20.6% sub-syndromal depression. During the follow-up period, 9.3% (n  = 862) developed dementia and 14.3% (n  = 1,329) deceased. In the pooled analyses, both ICD-10 depression (adjusted sub-hazard ratio (sHR) 1.63, 95% confidence interval (CI) 1.26–2.11) and sub-syndromal depression (adjusted sHR 1.28, 95% CI: 1.09–1.51) were associated with increased incidence of dementia. The Higging I2 tests showed a moderate heterogeneity across the study sites. Conclusion: Our findings suggest that late-life depression is associated with the incidence of dementia in LMICs in Latin America, which support results from earlier studies conducted in high-income countries. Show more

Keywords: Dementia, depression, developing countries, epidemiology, risk factors

DOI: 10.3233/JAD-190148

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 433-441, 2019