Limbic-predominant age-related TDP-43 encephalopathy, ADNC pathology, and cognitive decline in aging

ObjectiveTo examine the impact of 3 pathologic groups, pure limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy (LATE) neuropathologic changes (NC), pure Alzheimer disease neuropathologic change (ADNC), and mixed ADNC with LATE-NC, on late-life cognitive decline.MethodsData came from 1,356 community-based older persons who completed detailed annual cognitive testing and systematic neuropathologic examination at autopsy to identify LATE-NC, ADNC, and other age-related pathologies. Persons were categorized into (0) a group without a pathologic diagnosis of LATE or ADNC (n = 378), (1) LATE-NC without ADNC (n = 91), (2) ADNC without LATE-NC (n = 535), and (3) mixed ADNC with LATE-NC (n = 352). We used mixed-effect models to examine the group associations with rate of decline in global cognition and 5 cognitive domains and then examined whether age modified associations.ResultsCompared to those without LATE-NC or ADNC, those with pure LATE-NC had a faster decline in global cognition (p = 0.025) and episodic memory (p = 0.002); however, compared to persons with pure ADNC, those with pure LATE-NC showed a slower decline. Those with mixed ADNC with LATE-NC showed the fastest decline compared to those with either pathology alone. Persons ≥90 years of age with mixed ADNC with LATE-NC had slower cognitive decline compared to those ≤89 years of age.ConclusionPersons with pure LATE-NC follow a slower trajectory compared to those with pure ADNC. Those with mixed LATE/ADNC have a steeper decline than individuals with either pathology alone. In addition, age may modify the effect of pathology on cognitive decline. These findings have important implications for the development of biomarkers and prognosis for late-life cognitive decline.Classification of evidenceThis study provides Class I evidence that LATE-NC and Alzheimer disease pathologic changes are associated with different trajectories of late-life cognitive decline.

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The PRIAMO study: age- and sex-related relationship between prodromal constipation and disease phenotype in early Parkinson’s disease

Journal of Neurology ◽

10.1007/s00415-020-10156-3 ◽

2020 ◽

Author(s):

Marina Picillo ◽

◽

Raffaele Palladino ◽

Roberto Erro ◽

Rossella Alfano ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Older Patients ◽

Disease Phenotype ◽

Mixed Effect ◽

Mixed Effect Models ◽

Age Related ◽

Attention Memory ◽

The Impact ◽

Early Parkinson’S Disease

Abstract Objectives To explore the impact of sex and age on relationship between prodromal constipation and disease phenotype in Parkinson’s disease at early stages. Methods A total of 385 Parkinson’s disease patients from the PRIAMO study were classified according to the presence of prodromal constipation and followed for 24 months. Multivariable mixed-effect models were applied. All analyses were performed separately for sex (64.1% men) and median age (different by sex: 67 years-old in men and 68 years-old in women). Results As for sex, prodromal constipation was associated with greater odds of attention/memory complaints and apathy symptoms in women only. As for age, prodromal constipation was associated with lower cognitive and higher apathy scores in older patients only. Conclusions Prodromal constipation anticipates lower cognitive performances and more severe apathy since the earliest stages in women and older patients. Sex- and age-related heterogeneity of prodromal markers of Parkinson’s disease may impact disease phenotype.

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Influence of Cognitive Reserve on Cognitive Trajectories: Role of Brain Pathologies

Neurology ◽

10.1212/wnl.0000000000012728 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012728

Author(s):

Xuerui Li ◽

Ruixue Song ◽

Xiuying Qi ◽

Hui Xu ◽

Wenzhe Yang ◽

...

Keyword(s):

Working Memory ◽

Cognitive Function ◽

Episodic Memory ◽

Cognitive Reserve ◽

Late Life ◽

Mixed Effect ◽

Mixed Effect Models ◽

Global Cognition

Background and Objectives:Evidence on the association of the cognitive reserve (CR) with the cognitive trajectories is limited. We aimed to examine the influence of CR indicator on domain-specific cognitive trajectories taking brain pathologies into account.Methods:Within the Rush Memory and Aging Project, 1,697 dementia-free participants (mean age: 79.6 years) were followed up to 21 years. CR indicator encompassing education, early-life, mid-life, and late-life cognitive activities, and late-life social activity was ascertained at baseline and categorized as tertiles (the lowest, middle, and highest). Global cognition, episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed were assessed annually with 19 tests, from which composite scores were derived. During the follow-up, 648 died and underwent autopsies to evaluate brain pathologies. Data were analyzed using linear mixed-effect models.Results:Among the participants, the score of the CR indicator ranged from -8.00 to 5.74 (mean: 0.00±2.23). In multi-adjusted mixed-effect models, compared to the lowest CR, the highest was related to a slower decline in global cognition (β=0.028, 95% confidence interval [CI]: 0.012 to 0.043), episodic memory (β=0.028, 95% CI: 0.010 to 0.047) and working memory (β=0.019, 95% CI: 0.005 to 0.033) during the follow-up. In brain pathological data analysis, the association of the highest CR with cognitive function changes remained significant among participants with high Alzheimer’s disease pathology or gross infarcts.Discussion:High CR indicator is associated with preserved global cognitive function, episodic memory, and working memory, even in the presence of brain pathologies. Our findings highlight the important role of high CR accumulation in the prevention of cognitive decline.

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Individual variation in brain microstructural-cognition relationships in aging

10.1101/2021.02.19.431732 ◽

2021 ◽

Author(s):

Raihaan Patel ◽

Clare E. Mackay ◽

Michelle G. Jansen ◽

Gabriel A. Devenyi ◽

M. Clare O’Donoghue ◽

...

Keyword(s):

Cognitive Decline ◽

Cognitive Performance ◽

Late Life ◽

Older Age ◽

Data Driven ◽

Semantic Fluency ◽

Cognitive Domains ◽

Age Related ◽

Brain Microstructure ◽

Age Related Cognitive Decline

AbstractWhile all individuals are susceptible to age-related cognitive decline, significant inter- and intra-individual variability exists. However, the sources of this variation remain poorly understood. Here, we examined the association between 30-year trajectories of cognitive decline and multimodal indices of brain microstructure and morphology in older age. We used the Whitehall II Study, an extensively characterised cohort using 3T brain magnetic resonance images acquired at older age (mean age = 69.52 ± 4.9) and 5 repeated cognitive performance assessments between mid-life (mean age = 53.2 ± 4.9 years) and late-life (mean age = 67.7 ± 4.9). Using non-negative matrix factorization, we identified 10 brain microstructural components that integrate measures of cortical thickness, surface area, fractional anisotropy, and mean and radial diffusivities. We observed two modes of variance that describe the association between cognition and brain microstructure. The first describes variations in 5 microstructural components associated with low mid-life performance across multiple cognitive domains, decline in reasoning abilities, but a relative maintenance of lexical and semantic fluency from mid-to-late life. The second describes variations in 5 microstructural components that are associated with low mid-life performance in lexical fluency, semantic fluency and short-term memory performance, but a retention of abilities in multiple domains from mid-to-late life. The extent to which a subject loads onto a latent variables predicts their future cognitive performance 3.2 years later (mean age = 70.87 ± 4.9). This data-driven approach highlights a complex pattern of brain-behavior relationships, wherein the same individuals express both decline and maintenance in function across cognitive domains and in brain structural features.Significance StatementAlthough declines in cognitive performance are an established aspect of aging, inter- and intra-individual variation exists. Nevertheless, the sources of this variation remain unclear. We analyse a unique sample to examine associations between 30-year trajectories of cognitive decline and multimodal indices of brain anatomy in older age. Using data-driven techniques, we find that age-related cognitive decline is not uniform. Instead, each individual expresses a mixture of maintenance and decline across cognitive domains, that are associated with a mixture of preservation and degeneration of brain structure. Further, we find the primary determinants of late-life cognitive performance are mid-life performance and higher brain surface area. These results suggest that early and mid-life preventative measures may be needed to reduce age-related cognitive decline.

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SAT-LB115 Metformin-Use Is Associated With Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults With Type 2 Diabetes Mellitus: The Sydney Memory and Ageing Study

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.2055 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Katherine Samaras ◽

Steve Makkar ◽

John D Crawford ◽

Nicole A Kochan ◽

Wei Wen ◽

...

Keyword(s):

Older Adults ◽

Heart Disease ◽

Executive Function ◽

Older People ◽

Cognitive Decline ◽

Community Dwelling ◽

Incident Dementia ◽

Ageing Study ◽

Global Cognition ◽

Rate Of Decline

Abstract Background Metformin use in diabetes has been associated with both increased and decreased dementia rates in observational studies of people with diabetes. Objective: To examine changes in global cognition and specific cognitive domains over 6 years in older adults with diabetes treated with metformin, compared to other glucose lowering medications, and to people without diabetes. Methods Data were examined from the Sydney Memory and Ageing Study, a prospective observational study of 6 years duration of 1037 non-demented community-dwelling elderly aged 70-90 at baseline, derived from a compulsory electoral roll. Neuropsychological testing was performed every 2 years with domain measures of memory, executive function, language, visuospatial function, attention and processing speed and a composite of global cognition. Data were analysed by linear mixed modelling, including age, sex, education, body mass index, heart disease, diabetes, hypertension, stroke, smoking and apolipoprotein E ε4 carriage as covariates. Results: At baseline, 123 participants had diabetes (DM) with 67 receiving metformin (DM+MF) who were similar in demographics to those not receiving metformin (DM-noMF) and those without diabetes (no-DM). Participants with diabetes had higher BMI, lower HDL- and LDL-cholesterol and more prevalent heart disease, hypertension and smoking, compared to no-DM. Over 6-years, DM+MF participants had significantly slower rates of decline in global cognition and executive function, compared to DM-noMF, adjusted for covariates. The rate of decline for each cognitive domain was similar between DM+MF and controls. No impact was found in analyses examining interactions with sex, ApoEε4 carriage or hyperlipidemia. No difference was found in the rate of decline in brain volumes between the groups over 2 years. Incident dementia was significantly higher in DM-noMF, compared to DM+MF (adjusted OR 5.29 [95% CI 1.17-23.88], p,0.05), whereas risk of incident dementia was similar between DM+MF and participants without diabetes. Conclusions: In older people with diabetes receiving metformin, rates of cognitive decline and dementia were similar to that found in people without diabetes and significantly less than that found in people with diabetes not receiving metformin. Large randomized studies in people with and without diabetes are required to determine whether these associations can be attributed to metformin alone or if other factors explain these observations. Future studies will clarify if this cheap and safe medication can be repurposed for prevention of cognitive decline in older people.

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Changes in Renal Function After Switching From TDF to TAF in HIV-Infected Individuals: A Prospective Cohort Study

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa125 ◽

2020 ◽

Vol 222 (4) ◽

pp. 637-645 ◽

Cited By ~ 1

Author(s):

Bernard Surial ◽

Bruno Ledergerber ◽

Alexandra Calmy ◽

Matthias Cavassini ◽

Huldrych F Günthard ◽

...

Keyword(s):

Cohort Study ◽

Estimated Glomerular Filtration Rate ◽

Urine Protein ◽

Mixed Effect ◽

Mixed Effect Models ◽

Tubular Markers ◽

Continued Use ◽

Tenofovir Alafenamide ◽

Renal Tubular ◽

The Impact

Abstract Background Replacing tenofovir disoproxil fumarate (TDF) with tenofovir alafenamide (TAF) improves renal tubular markers in HIV-infected individuals but the impact on estimated glomerular filtration rate (eGFR) remains unclear. Methods In all participants from the Swiss HIV Cohort Study who switched from TDF to TAF-containing antiretroviral regimen or continued TDF, we estimated changes in eGFR and urine protein-to-creatinine ratio (UPCR) after 18 months using mixed-effect models. Results Of 3520 participants (26.6% women, median age 50 years), 2404 (68.5%) switched to TAF. Overall, 1664 (47.3%) had an eGFR <90 mL/min and 1087 (30.9%) an UPCR ≥15 mg/mmol. In patients with baseline eGFR ≥90 mL/min, eGFR decreased with the use of TDF and TAF (−1.7 mL/min). Switching to TAF was associated with increases in eGFR of 1.5 mL/min (95% confidence interval [CI], .5–2.5) if the baseline eGFR was 60–89 mL/min, and 4.1 mL/min (95% CI, 1.6–6.6) if <60 mL/min. In contrast, eGFR decreased by 5.8 mL/min (95% CI, 2.3–9.3) with continued use of TDF in individuals with baseline eGFR <60 mL/min. UPCR decreased after replacing TDF by TAF, independent of baseline eGFR. Conclusions Switching from TDF to TAF improves eGFR and proteinuria in patients with renal dysfunction.

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The Impact of Flt3 Gene Mutations in Acute Promyelocytic Leukemia: A Meta-Analysis

Cancers ◽

10.3390/cancers11091311 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1311 ◽

Cited By ~ 6

Author(s):

Gledson L. Picharski ◽

Diancarlos P. Andrade ◽

Ana Luiza M. R. Fabro ◽

Luana Lenzi ◽

Fernanda S. Tonin ◽

...

Keyword(s):

Acute Promyelocytic Leukemia ◽

Meta Analysis ◽

Gene Mutations ◽

Early Death ◽

Promyelocytic Leukemia ◽

Biomedical Literature ◽

Mixed Effect ◽

Mixed Effect Models ◽

Wbc Count ◽

The Impact

The association of FLT3 mutations with white blood cell (WBC) counts at diagnosis and early death was studied in patients with acute promyelocytic leukemia (APL). Publications indexed in databases of biomedical literature were analyzed. Potential publication bias was evaluated by analyzing the standard error in funnel plots using the estimated relative risk (RR). Mixed-effect models were used to obtain the consolidated RR. All analyses were conducted using the R statistical software package. We used 24 publications in the final meta-analysis. Of 1005 males and 1376 females included in these 24 publications, 645 had FLT3-ITD (internal tandem duplication) mutations. Information on FLT3-D835 mutations was available in 10 publications for 175 patients. Concurrent occurrence of the two mutations was rare. WBC count at diagnosis was ≥10 × 109/L in 351 patients. For patients with the FLT3-ITD mutation, RR was 0.59 for overall survival (OS) and 1.62 for death during induction. For those with FLT3-D835 mutations, the RR was 0.50 for OS and 1.77 for death during induction. RR for WBC count ≥10 × 109/L was 3.29 and 1.48 for patients with FLT3-ITD and FLT3-D835, respectively. APL patients with FLT3-ITD or FLT3-D835 are more likely to present with elevated WBC counts and poorer prognosis than those without these mutations.

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Brain Ageing, Cognition and Diet: A Review of the Emerging Roles of Food-Based Nootropics in Mitigating Age-related Memory Decline

Current Aging Science ◽

10.2174/1874609812666190311160754 ◽

2019 ◽

Vol 12 (1) ◽

pp. 2-14 ◽

Cited By ~ 1

Author(s):

Adejoke Yetunde Onaolapo ◽

Adebimpe Yemisi Obelawo ◽

Olakunle James Onaolapo

Keyword(s):

Oxidative Stress ◽

Cognitive Decline ◽

Antioxidant Defense System ◽

Food Ingredients ◽

Memory Decline ◽

Age Related ◽

Brain Ageing ◽

Nootropic Agents ◽

Age Related Cognitive Decline ◽

The Impact

Background: Age-related cognitive decline has been suggested to result from an increase in the brain neuron loss, which is attributable to continued derangement of the brain’s oxidant/ antioxidant balance. Increased oxidative stress and a concomitant decrease in the brain’s antioxidant defense system have been associated with functional senescence and organismal ageing. However, nature has configured certain foods to be rich sources of nootropic agents, with research showing that increased consumption of such foods or food ingredients may be protective against ageing-related memory decline. This knowledge is becoming increasingly valuable in an era when the boundary that separates food from medicine is becoming blurred. In this review, we examine extant literature dealing with the impact of ageing on brain structure and function, with an emphasis on the roles of oxidative stress. Secondly, we review the benefits of food-based antioxidants with nootropic effects and/or food-based nootropic agents in mitigating memory decline; with a view to improving our understanding of likely mechanisms. We also highlight some of the limitations to the use of food-based nootropics and suggest ways in which they can be better employed in the clinical management of age-related cognitive decline. Conclusion: While it is known that the human brain endures diverse insults in the process of ageing, food-based nootropics are likely to go a long way in mitigating the impacts of these insults. Further research is needed before we reach a point where food-based nootropics are routinely prescribed.

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Socio-demographic influences on trends of fish consumption during later adult life in the Whitehall II study

British Journal Of Nutrition ◽

10.1017/s0007114508971312 ◽

2008 ◽

Vol 100 (5) ◽

pp. 1116-1127 ◽

Cited By ~ 11

Author(s):

Tasnime N. Akbaraly ◽

Eric J. Brunner

Keyword(s):

Fish Consumption ◽

Demographic Factors ◽

Fish Intake ◽

Phase 3 ◽

Mixed Effect ◽

Age Related ◽

Total Fish ◽

Socio Demographic Factors ◽

Fish And Shellfish ◽

The Impact

Our aim was to investigate how socio-demographic factors influence trends and age-related trajectories of fish consumption. We examined consumption of total, fried and recommended fish (white and oily fish, and shellfish) in the Whitehall II study over 11 years in participants aged 39–59 years at phase 3. The cohort included 8358 British civil servants who completed a FFQ at phase 3 (1991–3), phase 5 (1997–9, n 5430) and phase 7 (2002–4, n 5692). Occupational grade, ethnicity, marital and retirement status were collected at each phase. To analyse changes in age-related trends of fish intake over time according to socio-demographic characteristics, we applied a random mixed-effect model. Over the follow-up a significant increase in consumption of ‘recommended’ (mean: 1·85 to 2·22 portions/week) and total fish (mean: 2·32 to 2·65 portions/week) and a decreasing trend in fried-fish intake (mean: 0·47 to 0·43 portions/week) was observed. Recommended, fried and total fish consumption differed by occupational status, ethnicity, marital status and sex. The trend of age-related fish intake diverged significantly by ethnicity. In South Asian participants (n 432), slope of recommended-fish consumption was significantly higher compared with white participants (0·077 v. 0·025 portions/week per year). For black participants (n 275) slope of fried-fish intake was significantly higher compared with white participants (0·0052 v. − 0·0025 portions/week per year). In terms of public health, our descriptive and analytical work allows detailed understanding of the impact of socio-demographic factors on fish intake and its age-related trends. Such information is valuable for food policies that seek to promote health equity.

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Health-related quality of life of individuals sharing a household with persons with dementia

Quality of Life Research ◽

10.1007/s11136-021-03065-z ◽

2021 ◽

Author(s):

Judith Dams ◽

Thomas Grochtdreis ◽

Hans-Helmut König

Keyword(s):

Quality Of Life ◽

Health Related Quality ◽

Mixed Effect ◽

Mixed Effect Models ◽

Related Quality ◽

Health Related ◽

Negative Effect ◽

Lower Hrqol ◽

The Impact

Abstract Introduction Previous research has found a negative effect of dementia on the health-related quality of life (HrQoL) of persons with dementia (PWD) and their primary informal caregivers. However, the impact of dementia on HrQoL of other individuals sharing a household with PWD has not been investigated to date. The current study therefore aimed to determine differences in the HrQoL between those sharing a household with PWD and those not living with PWD. In addition, factors related to the HrQoL of those sharing a household with PWD were evaluated. Methods The analyses were based on data from the German Socio-Economic Panel, using the SF-12 to measure HrQoL. Mixed-effects models were calculated to compare the HrQoL of those sharing a household with PWD and persons not living with PWD, as well as to determine factors related to the HrQoL of those sharing a household with PWD. Bootstrapping was used where residuals were not normally distributed. Results Mixed-effect models showed a significantly lower HrQoL among those sharing a household with PWD, compared to those not living with PWD. Number of diseases, number of persons in the household, marital status and educational level were significantly related to HrQoL among those sharing a household with PWD. Discussion The HrQoL of those sharing a household with PWD was reduced compared to persons not living with PWD. Further, those living with PWD in small households, or those with multi-morbidities had a lower HrQoL. Further research focusing on HrQoL in the social environment of PWD is needed.

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Not Only Diabetes but Also Prediabetes Leads to Functional Decline and Disability in Older Adults

10.2337/figshare.13477338 ◽

2021 ◽

Author(s):

Ying Shang ◽

Laura Fratiglioni ◽

Davide Liborio Vetrano ◽

Abigail Dove ◽

Anna-Karin Welmer ◽

...

Keyword(s):

Physical Function ◽

Future Development ◽

Walking Speed ◽

Functional Decline ◽

Disability Progression ◽

Mixed Effect ◽

Chair Stand ◽

Mixed Effect Models ◽

The Future ◽

The Impact

BACKGROUND: Diabetes is linked to functional decline, but the impact of prediabetes on physical function is unknown. We aimed to examine and compare the impact of prediabetes and diabetes on physical function and disability progression and to explore whether cardiovascular diseases (CVDs) mediate these associations. RESEARCH DESIGN AND METHODS: A cohort of 2,013 participants aged ≥60 from the Swedish National Study on Aging and Care in Kungsholmen, an ongoing population-based longitudinal study, was followed for up to 12 years. Physical function was measured with chair stand (s) and walking speed (m/s) tests, and disability was measured by summing the numbers of impaired basic and instrumental activities of daily living. Diabetes was identified through medical examinations or clinical records, medication use, or glycated hemoglobin (HbA1c) ≥6.5%. Prediabetes was defined as HbA1c ≥5.7–6.4% in diabetes-free participants. CVDs were ascertained through clinical examinations and the National Patient Registry. Data were analyzed using mixed effect models and mediation models. RESULTS: At baseline, 650 (32.3%) had prediabetes and 151 had diabetes (7.5%). In multi-adjusted mixed effect models, prediabetes was associated with an increased chair stand time (0.33, 95% CI 0.05 to 0.61), a decreased walking speed (-0.006, -0.010 to -0.002), and an accelerated disability progression (0.05, 95% CI 0.01 to 0.08), even after controlling for the future development of diabetes. Diabetes led to faster functional decline than prediabetes. In mediation analyses, CVDs mediated 7.1%, 7.8%, and 20.9% of the associations between prediabetes and chair stand, walking speed, and disability progression, respectively. CONCLUSIONS: Prediabetes, in addition to diabetes, is associated with faster functional decline and disability, independent of the future development of diabetes. This association may be in part mediated by CVDs.

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