Search

Background Sleep apnea (SA) has been linked to an increased risk of dementia in numerous observational studies; whether this is driven by neurodegenerative, vascular, or other mechanisms is not clear. We sought to examine the bidirectional causal relationships between SA, Alzheimer disease (AD), coronary artery disease (CAD), and ischemic stroke using Mendelian randomization. Methods and Results Using summary statistics from 4 recent, large genome‐wide association studies of SA (n=523 366), AD (n=94 437), CAD (n=1 165 690), and stroke (n=1 308 460), we conducted bidirectional 2‐sample Mendelian randomization analyses. Our primary analytic method was fixed‐effects inverse variance–weighted (IVW) Mendelian randomization; diagnostics tests and sensitivity analyses were conducted to verify the robustness of the results. We identified a significant causal effect of SA on the risk of CAD (odds ratio [ORIVW]=1.35 per log‐odds increase in SA liability [95% CI=1.25–1.47]) and stroke (ORIVW=1.13 [95% CI=1.01–1.25]). These associations were somewhat attenuated after excluding single‐nucleotide polymorphisms associated with body mass index (ORIVW=1.26 [95% CI=1.15–1.39] for CAD risk; ORIVW=1.08 [95% CI=0.96–1.22] for stroke risk). SA was not causally associated with a higher risk of AD (ORIVW=1.14 [95% CI=0.91–1.43]). We did not find causal effects of AD, CAD, or stroke on risk of SA. Conclusions These results suggest that SA increased the risk of CAD, and the identified causal association with stroke risk may be confounded by body mass index. Moreover, no causal effect of SA on AD risk was found. Future studies are warranted to investigate cardiovascular pathways between sleep disorders, including SA, and dementia.

Abstract Depressive symptoms may either be a risk factor or prodromal to dementia. Investigating this association in midlife may help clarify the role of depression in cognitive aging. We aimed to identify trajectories in depressive symptoms in early to mid-life and related cognitive and brain outcomes in midlife. This study includes 3944 Black and White participants (ages 26−45 years at baseline) from the Coronary Artery Risk Development in Young Adults (CARDIA) study with 20 years of follow-up. Depressive symptoms were assessed using the Center for Epidemiological Studies Depression scale at five time points over 20 years. Growth mixture modeling (GMM) was used to identify depressive symptom trajectories. Participants completed a neuropsychological battery 20 years after baseline, including the Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop Test, Montreal Cognitive Assessment (MoCA), and category and letter fluency tests. A sub-sample of participants (n = 662) underwent brain magnetic resonance imaging (MRI) to characterize gray matter volumes and white matter hyperintensities (WMHs). We identified four classes of depressive symptom trajectories: a “declining” class (n = 286, 7.3%) with initially high symptoms and subsequent decline, a class with consistently high symptoms (“steady high”; n = 264, 6.7%), a class with late increases in symptoms (“increasing”; n = 277, 7%), and a class with consistently low symptoms (“steady low”; n = 3117, 79.0%). The steady high and the increasing classes had poorer performance on all cognitive tests, while the declining class had poorer performance on the DSST, verbal fluency, and MoCA. Compared to the steady low symptom class, the steady high class had lower volumes in the entorhinal cortex (β: −180.80, 95% CI: −336.69 to −24.91) and the amygdala (β: −40.97, 95% CI: −74.09 to −7.85), the increasing class had more WMHs (β: 0.55, 95% CI: 0.22 to 0.89), and the declining class was not significantly different in any brain measures. Trajectories in depressive symptoms in young to mid-adulthood show distinct cognitive and brain phenotypes in midlife. Steady high depressive symptoms may represent a group that is at risk for dementia, whereas increasing symptoms in midlife may be associated with white matter damage.

Rationale & Objective: The extent to which depression affects the progression of chronic kidney disease (CKD) and leads to adverse clinical outcomes remains inadequately understood. We examined the association of depressive symptoms (DS) and antidepressant medication use on clinical outcomes in 4,839 adults with nondialysis CKD. Study Design: Observational cohort study. Setting and Participants: Adults with mild to moderate CKD who participated in the multicenter Chronic Renal Insufficiency Cohort Study (CRIC). Exposure: The Beck Depression Inventory (BDI) was used to quantify DS. Antidepressant use was identified from medication bottles and prescription lists. Individual effects of DS and antidepressants were examined along with categorization as follows: (1) BDI

Abstract Background Dementia is defined as a cognitive decline that affects functional status. Longitudinal ageing surveys often lack a clinical diagnosis of dementia though measure cognition and daily function over time. We used unsupervised machine learning and longitudinal data to identify transition to probable dementia. Methods Multiple Factor Analysis was applied to longitudinal function and cognitive data of 15,278 baseline participants (aged 50 years and more) from the Survey of Health, Ageing, and Retirement in Europe (SHARE) (waves 1, 2 and 4–7, between 2004 and 2017). Hierarchical Clustering on Principal Components discriminated three clusters at each wave. We estimated probable or “Likely Dementia” prevalence by sex and age, and assessed whether dementia risk factors increased the risk of being assigned probable dementia status using multistate models. Next, we compared the “Likely Dementia” cluster with self-reported dementia status and replicated our findings in the English Longitudinal Study of Ageing (ELSA) cohort (waves 1–9, between 2002 and 2019, 7840 participants at baseline). Results Our algorithm identified a higher number of probable dementia cases compared with self-reported cases and showed good discriminative power across all waves (AUC ranged from 0.754 [0.722–0.787] to 0.830 [0.800–0.861]). “Likely Dementia” status was more prevalent in older people, displayed a 2:1 female/male ratio, and was associated with nine factors that increased risk of transition to dementia: low education, hearing loss, hypertension, drinking, smoking, depression, social isolation, physical inactivity, diabetes, and obesity. Results were replicated in ELSA cohort with good accuracy. Conclusions Machine learning clustering can be used to study dementia determinants and outcomes in longitudinal population ageing surveys in which dementia clinical diagnosis is lacking.

Strategies to prevent or delay Alzheimer's disease and related dementias (AD/ADRD) are urgently needed, and blood pressure (BP) management is a promising strategy. Yet the effects of different BP control strategies across the life course on AD/ADRD are unknown. Randomized trials may be infeasible due to prolonged follow-up and large sample sizes. Simulation analysis is a practical approach to estimating these effects using the best available existing data. However, existing simulation frameworks cannot estimate the effects of BP control on both dementia and cardiovascular disease. This manuscript describes the design principles, implementation details, and population-level validation of a novel population-health microsimulation framework, the MIchigan ChROnic Disease SIMulation (MICROSIM), for The Effect of Lower Blood Pressure over the Life Course on Late-life Cognition in Blacks, Hispanics, and Whites (BP-COG) study of the effect of BP levels over the life course on dementia and cardiovascular disease. MICROSIM is an agent-based Monte Carlo simulation designed using computer programming best practices. MICROSIM estimates annual vascular risk factor levels and transition probabilities in all-cause dementia, stroke, myocardial infarction, and mortality in a nationally representative sample of US adults 18+ using the National Health and Nutrition Examination Survey (NHANES). MICROSIM models changes in risk factors over time, cognition and dementia using changes from a pooled dataset of individual participant data from 6 US prospective cardiovascular cohort studies. Cardiovascular risks were estimated using a widely used risk model and BP treatment effects were derived from meta-analyses of randomized trials. MICROSIM is an extensible, open-source framework designed to estimate the population-level impact of different BP management strategies and reproduces US population-level estimates of BP and other vascular risk factors levels, their change over time, and incident all-cause dementia, stroke, myocardial infarction, and mortality.

Abstract The notion of “biological aging” as distinct from chronological aging has been of increasing interest in psychiatry, and many studies have explored associations of stress and psychiatric illness with accelerated biological aging. The “epigenetic clocks” are one avenue of this research, wherein “biological age” is estimated using DNA methylation data from specific CpG dinucleotide sites within the human genome. Many iterations of the epigenetic clocks have been developed, but the GrimAge clock continues to stand out for its ability to predict morbidity and mortality. Several studies have now explored associations of stress, PTSD, and MDD with GrimAge acceleration (GrimAA). While stress, PTSD, and MDD are distinct psychiatric entities, they may share common mechanisms underlying accelerated biological aging. Yet, no one has offered a review of the evidence on associations of stress and stress-related psychopathology with GrimAA. In this review, we identify nine publications on associations of stress, PTSD, and MDD with GrimAA. We find that results are mixed both within and across each of these exposures. However, we also find that analytic methods — and specifically, the choice of covariates — vary widely between studies. To address this, we draw upon popular methods from the field of clinical epidemiology to offer (1) a systematic framework for covariate selection, and (2) an approach to results reporting that facilitates analytic consensus. Although covariate selection will differ by the research question, we encourage researchers to consider adjustment for tobacco, alcohol use, physical activity, race, sex, adult socioeconomic status, medical comorbidity, and blood cell composition.

Abstract Background Urgency-type urinary incontinence affects one in four older community-dwelling women and overlaps with other common aging-associated health syndromes such as cognitive impairment, physical mobility impairment, and depression. Observational studies have raised concern about potentially higher rates of delirium and dementia in older adults taking anticholinergic bladder medications, but few prospective data are available to evaluate the effects of these and other pharmacologic treatments for urgency incontinence on cognition and other multisystem functional domains important to older women. Methods The TRIUMPH study is a randomized, double-blinded, 3-arm, parallel-group trial comparing the multisystem effects of anticholinergic versus beta-3-adrenergic agonist bladder therapy and versus no active bladder anti-spasmodic pharmacotherapy in older women with urgency incontinence. Women aged 60 years and older (target N = 270) who have chronic urgency-predominant urinary incontinence and either normal or mildly impaired cognition at baseline are recruited from the community by investigators based in northern California, USA. Participants are randomized in equal ratios to take identically encapsulated oral anticholinergic bladder therapy (in the form of tolterodine 2 mg extended release [ER]), oral beta-3 adrenergic agonist bladder therapy (mirabegron 25 mg ER), or placebo daily for 24 weeks, with the option of participant-directed dose titration (to tolterodine 4 mg ER, mirabegron 50 mg ER, or matching placebo daily). Participants also receive patient-oriented information and instructions about practicing first-line behavioral management strategies for incontinence. The primary outcome is change in composite cognitive function over 24 weeks assessed by a comprehensive battery of cognitive tests, with a secondary exploration of the persistence of change at 36 weeks. Secondary outcomes include changes over 24 and 36 weeks in domain-specific cognitive function; frequency, severity, and impact of urgency-associated urinary symptoms; physical function and balance; sleep quality and daytime sleepiness; psychological function; and bowel function. Discussion The TRIUMPH trial addresses the need for rigorous evidence to guide counseling and decision-making for older women who are weighing the potential multisystem benefits and risks of pharmacologic treatments for urgency incontinence in order to preserve their day-to-day functioning, quality of life, and independence in older age. Trial registration ClinicalTrials.gov NCT05362292. Registered on May 5, 2022.

Woldemariam et al. use electronic medical records to explore comorbidities in individuals with Alzheimer’s Disease stratified by four identified race and ethnicity categories. Whilst most comorbidities are similar, a few comorbidities, including respiratory diseases, are associated with Black- and Latine- identified individuals.

Human cognitive performance is a key function whose biological foundations have been partially revealed by genetic and brain imaging studies. The sleep electroencephalogram (EEG) is tightly linked to structural and functional features of the central nervous system and serves as another promising biomarker. We used data from MrOS, a large cohort of older men and cross-validated regularized regression to link sleep EEG features to cognitive performance in cross-sectional analyses. In independent validation samples 2.5–10% of variance in cognitive performance can be accounted for by sleep EEG features, depending on the covariates used. Demographic characteristics account for more covariance between sleep EEG and cognition than health variables, and consequently reduce this association by a greater degree, but even with the strictest covariate sets a statistically significant association is present. Sigma power in NREM and beta power in REM sleep were associated with better cognitive performance, while theta power in REM sleep was associated with worse performance, with no substantial effect of coherence and other sleep EEG metrics. Our findings show that cognitive performance is associated with the sleep EEG (r = 0.283), with the strongest effect ascribed to spindle-frequency activity. This association becomes weaker after adjusting for demographic (r = 0.186) and health variables (r = 0.155), but its resilience to covariate inclusion suggest that it also partially reflects trait-like differences in cognitive ability.

Abstract Objective Expression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population‐based level are necessary to broaden generalizability to community settings. Methods Circulating GFAP levels were assayed using a Simoa HD‐1 analyzer in 4338 adults without prevalent dementia from four longitudinal community‐based cohort studies. The associations between GFAP levels with general cognition, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein E ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all‐cause and Alzheimer's disease dementia were evaluated with adjusted Cox proportional hazard models. Meta‐analysis was performed on the estimates derived from each cohort using random‐effects models. Results Meta‐analyses indicated that higher circulating GFAP associated with lower general cognition (ß = −0.09, [95% confidence interval [CI]: −0.15 to −0.03], p = 0.005), but not with total brain or hippocampal volume (p > 0.05). However, each standard deviation unit increase in log‐transformed GFAP levels was significantly associated with a 2.5‐fold higher risk of incident all‐cause dementia (Hazard Ratio [HR]: 2.47 (95% CI: 1.52–4.01)) and Alzheimer's disease dementia (HR: 2.54 [95% CI: 1.42–4.53]) over up to 15‐years of follow‐up. Interpretation Results support the potential role of circulating GFAP levels for aiding dementia risk prediction and improving clinical trial stratification in community settings.

Abstract Introduction To determine if cardiovascular risk factor (CVRF) burden is associated with Alzheimer's disease (AD) biomarkers and whether they synergistically associate with cognition. Methods We cross‐sectionally studied 1521 non‐demented Mexican American (52%) and non‐Hispanic White individuals aged ≥50 years. A composite score was calculated by averaging the z‐scores of five cognitive tests. Plasma β‐amyloid (Aβ) 42/40, total tau (t‐tau), and neurofilament light (NfL) were assayed using Simoa. CVRF burden was assessed using the Framingham Risk Score (FRS). Results Compared to low FRS (< 10% risk), high FRS (≥ 20% risk) was independently associated with increased t‐tau and NfL. High FRS was significantly associated with higher NfL only among Mexican American individuals. Intermediate or high FRS (vs. low FRS) were independently associated with lower cognition, and the association remained significant after adjusting for plasma biomarkers. Hypertension synergistically interacted with t‐tau and NfL (p < 0.05). Discussion CVRFs play critical roles, both through independent and neurodegenerative pathways, on cognition.

Abstract Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10−6) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

Abstract. Alzheimer disease (AD) is the most common type of dementia characterized by the progressive cognitive and social decline. Clinical drug targets have heavily focused on the amyloid hypothesis, with amyloid beta (Aβ), and tau proteins as key pathophysiologic markers of AD. However, no effective treatment has been developed so far, which prompts researchers to focus on other aspects of AD beyond Aβ, and tau proteins. Additionally, there is a mounting epidemiologic evidence that various environmental factors influence the development of dementia and that dementia etiology is likely heterogenous. In the past decades, new risk factors or potential etiologies have been widely studied. Here, we review several novel epidemiologic and clinical research developments that focus on sleep, hypoxia, diet, gut microbiota, and hearing impairment and their links to AD published in recent years. At the frontiers of AD research, these findings and updates could be worthy of further attention.

Background: Insufficient support for balancing career and family responsibilities hinders retention of physician-scientists. Programs to improve retention of this important group of faculty are crucial. Understanding the experiences of program implementers is key to refining and improving program offerings. Methods: We conducted an interpretive, descriptive, and qualitative study as part of an ongoing evaluation of the Doris Duke Charitable Foundation's Fund to Retain Clinical Scientists (FRCS) awards. We conducted telephone interviews with 12 program directors representing all 10 US medical schools who received the Doris Duke funding in 2016. Results: Of the 12 participants, 10 were women (83.3%). Participating program directors perceived the FRCS award as capable of producing paradigmatic changes regarding how responsibilities at home and work in academic medicine are viewed and integrated by early-career faculty members. The main qualitative themes that captured directors' experiences implementing the program were as follows: (1) championing a new paradigm of support, (2) lessons learned while implementing the new paradigm, (3) results of the new paradigm, and (4) sustaining the paradigm. Conclusions: These findings may help to inform development of similar programs to retain and support the career progress of physician-scientists with extraprofessional caregiving responsibilities. The interviews illuminate ways in which the Doris Duke FRCS award has driven institutional culture change by normalizing discussion and prompted reassessment of extraprofessional challenges and how best to aid early-career faculty members in overcoming these challenges.

BackgroundCardiovascular disease risk factors play a critical role in brain aging. The metabolic syndrome (MetS), a constellation of cardiovascular risk factors, has been associated with poorer cognition in old age; however, it is unclear if it is connected to brain health earlier in life.MethodsWe investigated the association of MetS (n = 534, 18.5%) vs. no MetS (n = 2,346, 81.5%) with cognition in midlife within the prospective study, Coronary Artery Risk Development in Young Adults (CARDIA). At midlife (mean age 50), MetS was defined using National Cholesterol Education Program guidelines. At the 5-year follow-up, a cognitive battery was administered including tests of processing speed (Digit Symbol Substitution Test, DSST), executive function (the Stroop Test), verbal memory (Rey Auditory Verbal Learning Test, RAVLT), verbal fluency (category and letter fluency), and global cognitive function (Montreal Cognitive Assessment, MoCA). A sub-sample (n = 453) underwent brain MRI.ResultsParticipants with MetS had worse performance on tests of verbal fluency, processing speed, executive function, and verbal memory (p < 0.05), but not on global cognition. MetS was also associated with lower frontal, parietal, temporal, and total white matter integrity (p < 0.05), as assessed with fractional anisotropy.ConclusionsMetS is associated with lower cognition and microstructural brain alterations already at midlife, suggesting that MetS should be targeted earlier in life in order to prevent adverse brain and cognitive outcomes.

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease (CVD) risk factors that have been linked to cognitive decline. Whether NAFLD is associated with cognitive performance in midlife remains uncertain. Methods Coronary Artery Risk Development in Young Adults study participants with CT examination and cognitive assessment at Y25 (2010–2011; n = 2809) were included. Cognitive function was reassessed at Y30. NAFLD was defined according to liver attenuation and treated both continuously and categorically (using ≤ 40 and ≤ 51 Hounsfield units to define severity) after exclusion for other causes of liver fat. Cognitive tests including the Digit Symbol Substitution (processing speed), Rey Auditory Verbal Learning (verbal memory), and Stroop (executive function) were analyzed with standardized z-scores. Linear models were constructed to (a) examine the cross-sectional associations of NAFLD with cognitive scores and (b) evaluate its predictive role in 5-year change in cognitive performance. Results Participants’ mean age (Y25) was 50.1 (SD 3.6) years (57% female; 48% black), with 392 (14%) having mild NAFLD and 281 (10%) having severe NAFLD. NAFLD was positively associated with CVD risk factors and inversely associated with cognitive scores. However, after adjustment for CVD risk factors, no associations were shown between NAFLD and cognitive scores (all βs ≈ 0). Similarly, no associations were observed with 5-year cognitive decline. CVD history, hypertension, smoking, diabetes and hypertriglyceridemia showed stronger associations with baseline cognitive scores and were predictive of subsequent cognitive decline (all P ≤ .05). Conclusion Among middle-aged adults, inverse associations between NAFLD and cognitive scores were attenuated after adjustment for CVD risk factors, with the latter predictive of poorer cognitive performance both at baseline and follow-up.

Abstract Efforts to characterize the late effects of traumatic brain injury (TBI) have been in progress for some time. In recent years much of this activity has been directed towards reporting of chronic traumatic encephalopathy (CTE) in former contact sports athletes and others exposed to repetitive head impacts. However, the association between TBI and dementia risk has long been acknowledged outside of contact sports. Further, growing experience suggests a complex of neurodegenerative pathologies in those surviving TBI, which extends beyond CTE. Nevertheless, despite extensive research, we have scant knowledge of the mechanisms underlying TBI-related neurodegeneration (TReND) and its link to dementia. In part, this is due to the limited number of human brain samples linked to robust demographic and clinical information available for research. Here we detail a National Institutes for Neurological Disease and Stroke Center Without Walls project, the COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI), designed to address current limitations in tissue and research access and to advance understanding of the neuropathologies of TReND. As an international, multidisciplinary collaboration CONNECT-TBI brings together multiple experts across 13 institutions. In so doing, CONNECT-TBI unites the existing, comprehensive clinical and neuropathological datasets of multiple established research brain archives in TBI, with survivals ranging minutes to many decades and spanning diverse injury exposures. These existing tissue specimens will be supplemented by prospective brain banking and contribute to a centralized route of access to human tissue for research for investigators. Importantly, each new case will be subject to consensus neuropathology review by the CONNECT-TBI Expert Pathology Group. Herein we set out the CONNECT-TBI program structure and aims and, by way of an illustrative case, the approach to consensus evaluation of new case donations.

Abstract Background Whether high blood pressure has a causal effect on cognitive function as early as middle age is unclear. We investigated whether high blood pressure (BP) causally impairs cognitive function at midlife using Mendelian Randomization (MR). Methods We applied a two-sample MR approach to investigate the causal relationship between BP and midlife cognitive performance measured by the Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test (RAVLT), and Stroop Interference test. We used a total of 109 genetic polymorphisms with established associations with BP as instrumental variables and estimated gene-cognitive function association in 1369 middle-aged adults (Mean age (SD): 50.8 (3.3), 54.0% women) from the CARDIA study. Results A 10 mmHg increment in genetically-predicted systolic, diastolic, or pulse pressure was associated with a 4.9 to 7.7-point lower DSST score (P = 0.002, SBP; P = 0.005, DBP and P = 0.008, PP), while a 10 mmHg increment in genetically-predicted SBP was associated with a 0.7 point lower RAVLT and a 2.3 point higher Stroop (P = 0.046 and 0.011, respectively). Conclusions This MR analysis shows that high BP, especially SBP, is causally associated with poorer processing speed, verbal memory, and executive function during midlife. These findings emphasize the need for further investigation of the role and mechanisms of BP dysregulation on cognitive health in middle age and perhaps, more broadly, across the lifespan.

BackgroundAdults with cardiovascular disease risk factors (CVRFs) are also at increased risk of developing cognitive decline and dementia. However, it is often difficult to study the relationships between CVRFs and cognitive function because cognitive assessment typically requires time-consuming in-person neuropsychological evaluations that may not be feasible for real-world situations. ObjectiveWe conducted a proof-of-concept study to determine if the association between CVRFs and cognitive function could be detected using web-based, self-administered cognitive tasks and CVRF assessment. MethodsWe recruited 239 participants aged ≥50 years (mean age 62.7 years, SD 8.8; 42.7% [n=102] female, 88.7% [n=212] White) who were enrolled in the Health eHeart Study, a web-based platform focused on cardiac disease. The participants self-reported CVRFs (hypertension, high cholesterol, diabetes, and atrial fibrillation) using web-based health surveys between August 2016 and July 2018. After an average of 3 years of follow-up, we remotely evaluated episodic memory, working memory, and executive function via the web-based Posit Science platform, BrainHQ. Raw data were normalized and averaged into 3 domain scores. We used linear regression models to examine the association between CVRFs and cognitive function. ResultsCVRF prevalence was 62.8% (n=150) for high cholesterol, 45.2% (n=108) for hypertension, 10.9% (n=26) for atrial fibrillation, and 7.5% (n=18) for diabetes. In multivariable models, atrial fibrillation was associated with worse working memory (β=-.51, 95% CI -0.91 to -0.11) and worse episodic memory (β=-.31, 95% CI -0.59 to -0.04); hypertension was associated with worse episodic memory (β=-.27, 95% CI -0.44 to -0.11). Diabetes and high cholesterol were not associated with cognitive performance. ConclusionsSelf-administered web-based tools can be used to detect both CVRFs and cognitive health. We observed that atrial fibrillation and hypertension were associated with worse cognitive function even in those in their 60s and 70s. The potential of mobile assessments to detect risk factors for cognitive aging merits further investigation.

Background and Aims: South Africa is a middle-income country with high levels of income inequality and a rapidly aging population and increasing dementia prevalence. Little is known about which risk factors for dementia are important and how they differ by social determinants of health as well as key demographic characteristics such as sex and wealth. We sought to calculate the population attributable risks (PARs) for established potentially modifiable risk factors for dementia among these different groups.Methods: We obtained risk factor prevalence from population-based surveys for established dementia risk factors (diabetes, midlife hypertension, midlife obesity, physical inactivity, depression, smoking, low educational attainment, social isolation). We used relative risk estimates reported in previous meta-analyses and estimated PARs using Levin's formula and accounting for communality. We tested for one-way and two-way interactions by sex and wealth using Pearson's χ2. In stratified analyses, we performed tests for trend using logistic regression.Results: The prevalence of established risk factors for dementia ranged from 5% for depression to 64% for low education. After accounting for communality, the risk factors contributing the greatest PAR were low education (weighted PAR 12%, 95% CI 7% to 18%), physical inactivity (9, 5–14%), and midlife hypertension (6, 5–14%). Together, 45% of dementia cases may be attributable to modifiable risk factors (95% CI 25–59%). We found significant interactions (p < 0.005) between sex, wealth, or both (sex * wealth) and each risk factor except social isolation and physical activity. Low education was inversely associated with wealth in both male and female. The PAR for midlife hypertension, obesity, and diabetes was associated with increasing wealth, and was higher in female. In contrast, the PAR for smoking was higher in male (8% vs. 2%) and was associated with increasing wealth among female only. We found that either a strategy of large reductions in selected risk factors with the highest PAR (midlife hypertension, smoking, physical inactivity) or small reductions across all risk factors could potentially reduce dementia cases by as many as 250,000 by 2050.Discussions: The potential impact on dementia risk by decreasing exposure to established dementia risk factors is large and differs by sex and social determinants of health like wealth. Risk factor PAR should inform national and local health policy dementia initiatives in South Africa including which risk factors to target in the whole population and which to target in high-risk groups for maximum public health benefit.

Background: Growing evidence has suggested a link between poor sleep quality and increased risk of dementia. However, little is known about the association between sleep timing, an important behavior marker of circadian rhythms, and dementia risk in older adults, and whether this is independent of sleep duration or quality.Methods: We included data from 1,051 community-dwelling older men and women (aged≥ 60y) without dementia from the Shanghai Aging Study. At baseline, participants reported sleep timing, duration, and quality using the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI). Dementia diagnosis over the following 7.3 years was determined by neurologists using DSM-IV criteria. We used Cox proportional hazards models to examine the association between bedtime (before 9 p.m., after 11 p.m. vs. 9–11 p.m.), rise time (before 6 a.m., after 8 a.m. vs. 6–8 a.m.), and risk of dementia.Results: A total of 238 (22.8%), 675 (64.5%), and 133 (12.7%) participants reported going to bed before 9 p.m., between 9 and 11 p.m., and after 11 p.m., respectively, while 272 (26%), 626 (59.9%), and 148 (14.2%) reported getting up before 6 a.m., between 6 and 8 a.m., and after 8 a.m., respectively. Participants who reported going to bed earlier had a lower education level, were less likely to be smokers, more likely to have hypertension or diabetes, and had longer sleep duration but poorer sleep quality compared to those who reported a later bedtime. We found 47 incidents of dementia among 584 participants followed up over an average of 7.3 years. After adjustment for demographics, education, income, body mass index, depressive symptoms, smoking, alcohol use, physical activity, comorbidities, APOE4 genotype, and baseline MMSE, those with a bedtime of before 9 p.m. were two times more likely to develop dementia [hazard ratio (HR)=2.16 (95%CI: 1.06–4.40)], compared to those going to bed between 9 and 11 p.m. Later bedtime (i.e., after 11 p.m.) showed the opposite but had a non-significant association with dementia risk (HR=0.15, 95%CI: 0.02–1.29). We did not find an association for rise time and risk of dementia.Conclusion: Earlier sleep timing in older adults without dementia was associated with an increased risk of dementia. Future studies should examine the underlying mechanisms of this association and explore the usefulness of sleep timing as a preclinical marker for dementia.

Background Airflow obstruction is associated with cognitive dysfunction but studies have not assessed how emphysema, a structural phenotype of lung disease, might be associated with cognitive function independent from pulmonary function measured by spirometry. We aimed to determine the relationship between the presence of visually detectable emphysema on chest computed tomography (CT) imaging and cognitive function. Methods We examined 2491 participants, mean age of 50 years, from the Coronary Artery Risk Development in Young Adults study who were assessed for the presence of emphysema on chest CT imaging and had cognitive function measured 5 years later with a battery of six cognitive tests. Results Of those assessed, 172 (7%) had emphysema. After adjusting for age, sex, height, study centre, race, body mass index, education and smoking, visual emphysema was significantly associated with worse performance on most cognitive tests. Compared to those without emphysema, participants with emphysema performed worse on cognitive testing: 0.39 sd units lower (95% CI −0.53– −0.25) on the Montreal Cognitive Assessment, 0.27 sd units lower (95% CI −0.42– −0.12) on the Rey Auditory Verbal Learning Test, 0.29 sd units lower (95% CI −0.43– −0.14) on the Digit Symbol Substitution Test and 0.25 sd units lower (95% CI −0.42– −0.09) on letter fluency. Further adjustment for forced expiratory volume in 1 s (FEV1), peak FEV1 and annualised FEV1 decline did not attenuate these associations. Conclusions The presence of emphysema on chest CT is associated with worse cognitive function, independent of airflow obstruction. These data suggest that emphysema may be a novel risk factor for cognitive impairment.

Background To determine if accelerometer measured sedentary behavior (SED), light‐intensity physical activity (LPA), and moderate‐to‐vigorous–intensity physical activity (MVPA) in midlife is prospectively associated with cognitive function. Methods and Results Participants were 1970 adults enrolled in the CARDIA (Coronary Artery Risk Development in Young Adults) study who wore an accelerometer in 2005 to 2006 (ages 38–50 years) and had cognitive function assessments completed 5 and/or 10 years later. SED, LPA, and MVPA were measured by an ActiGraph 7164 accelerometer. Cognitive function tests included the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop Test. Compositional isotemporal substitution analysis examined associations of SED, LPA, and MVPA with repeated measures of the cognitive function standardized scores. In men, statistical reallocation of 30 minutes of LPA with 30 minutes of MVPA resulted in an estimated difference of SD 0.07 (95% CI, 0.01–0.14), SD 0.09 (95% CI, 0.02–0.17), and SD −0.11 (95% CI, −0.19 to −0.04) in the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop scores, respectively, indicating better performance. Associations were similar when reallocating time in SED with MVPA, but results were less robust. Reallocation of time in SED with LPA resulted in an estimated difference of SD −0.05 (95% CI, −0.06 to −0.03), SD −0.03 (95% CI, −0.05 to −0.01), and SD 0.05 (95% CI, 0.03– 0.07) in the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop scores, respectively, indicating worse performance. Associations were largely nonsignificant among women. Conclusions Our findings support the idea that for men, higher‐intensity activities (MVPA) may be necessary in midlife to observe beneficial associations with cognition.

Abstract Introduction Mexican Americans remain severely underrepresented in Alzheimer's disease (AD) research. The Health & Aging Brain among Latino Elders (HABLE) study was created to fill important gaps in the existing literature. Methods Community‐dwelling Mexican Americans and non‐Hispanic White adults and elders (age 50 and above) were recruited. All participants underwent comprehensive assessments including an interview, functional exam, clinical labs, informant interview, neuropsychological testing, and 3T magnetic resonance imaging (MRI) of the brain. Amyloid and tau positron emission tomography (PET) scans were added at visit 2. Blood samples were stored in the Biorepository. Results Data was examined from n = 1705 participants. Significant group differences were found in medical, demographic, and sociocultural factors. Cerebral amyloid and neurodegeneration imaging markers were significantly different between Mexican Americans and non‐Hispanic Whites. Discussion The current data provide strong support for continued investigations that examine the risk factors for and biomarkers of AD among diverse populations.

Abstract Background The current project sought to evaluate the impact that white matter hyperintensities (WMH) have on executive function in cognitively normal Mexican Americans, an underserved population with onset and more rapid progression of dementia. Methods Data from 515 participants (360 female) enrolled in the Health and Aging Brain Study: Health Disparities project were analyzed. Participants underwent clinical evaluation, cognitive testing, and a brain MRI. Linear regression was used to predict the effect of total WMH volume on cognitive test scores. Age, sex, and education were entered as covariates. Results Regression analysis showed that WMH volume significantly predicted executive function. WMH also predicted global cognition and attention scores, although not significantly after adjusting for age. Conclusion In this sample of cognitively normal Mexican Americans, we found that WMH volume was associated with lower scores in a measure of executive function, after accounting for age, sex, and education.

Introduction: Little is known about risk factors of dementia in Latin American countries. We aimed to identify socio–demographic, health and lifestyle risk factors of incident dementia in Cuban older adults.Methods: Data were from 1,846 participants in the Cuban cohort of the 10/66 Dementia Research Group. Participants completed questionnaires, health examinations, and cognitive tests at baseline (2003–2006) and 4.5 years later (2007–2010). Associations between risk factors (baseline) and incident dementia (follow-up) were examined using logistic regression.Results: Just over 9% of participants developed dementia. Overall, older age and low physical activity were associated with incident dementia. In those 65–74 years of age, depression, stroke and low physical activity were associated with incident dementia. In those ≥75 years of age, low physical activity, never eating fish, and smoking were associated with incident dementia.Conclusions: Modifiable lifestyle factors play an important role in developing dementia in Cuban older adults. This knowledge opens up opportunities for preventive strategies.

ObjectiveInvestigate whether socioeconomic status (SES) was related to brain volume in aging related regions, and if so, determine whether this relationship was mediated by lifestyle factors that are known to associate with risk of dementia in a population-based sample of community dwelling middle-aged adults.MethodsWe studied 645 (41% black) participants (mean age 55.3±3.5) from the Coronary Artery Risk Development in Young Adults (CARDIA) study who underwent brain magnetic resonance imaging. SES was operationalized as a composite measure of annual income and years of education. Gray matter volume was estimated within the insular cortex, thalamus, cingulate, frontal, inferior parietal, and lateral temporal cortex. These regions are vulnerable to age-related atrophy captured by the Spatial Pattern of Atrophy for Recognition of Brain Aging (SPARE-BA) index. Lifestyle factors of interest included physical activity, cognitive activity (e.g. book/newspaper reading), smoking status, alcohol consumption, and diet. Multivariable linear regressions tested the association between SES and brain volume. Sobel mediation analyses determined if this association was mediated by lifestyle factors. All models were age, sex, and race adjusted.ResultsHigher SES was positively associated with brain volume (β = .109 SE = .039; p < .01) and smoking status significantly mediated this relationship (z = 2.57). With respect to brain volume, smoking accounted for 27% of the variance (β = -.179 SE = .065; p < .01) that was previously attributed to SES.ConclusionTargeting smoking cessation could be an efficacious means to reduce the health disparity of low SES on brain volume and may decrease vulnerability for dementia.

Abstract Introduction Ability to determine dementia prevalence in low‐ and middle‐income countries (LMIC) remains challenging because of frequent lack of data and large discrepancies in dementia case ascertainment. Methods High likelihood of dementia was determined with hierarchical clustering after principal component analysis applied in 10 population surveys of aging: HRS (USA, 2014), SHARE (Europe and Israel, 2015), MHAS (Mexico, 2015), ELSI (Brazil, 2016), CHARLS (China, 2015), IFLS (Indonesia, 2014–2015), LASI (India, 2016), SAGE‐Ghana (2007), SAGE‐South Africa (2007), SAGE‐Russia (2007–2010). We approximated dementia prevalence using weighting methods. Results Estimated numbers of dementia cases were: China, 40.2 million; India, 18.0 million; Russia, 5.2 million; Europe and Israel, 5.0 million; United States, 4.4 million; Brazil, 2.2 million; Mexico, 1.6 million; Indonesia, 1.3 million; South Africa, 1.0 million; Ghana, 319,000. Discussion Our estimations were similar to prior ones in high‐income countries but much higher in LMIC. Extrapolating these results globally, we suggest that almost 130 million people worldwide were living with dementia in 2015.

Chronic kidney disease (CKD) is associated with an increased risk of cognitive decline, but the mechanisms remain poorly defined. We sought to determine the relation between serum inflammatory markers and risk of cognitive decline among adults with CKD. Methods: We studied 757 adults aged ≥55 years with CKD participating in the Chronic Renal Insufficiency Cohort Cognitive study. We measured interleukin (IL)−1β, IL-1 receptor antagonist, IL-6, tumor necrosis factor (TNF)−α, high-sensitivity C-reactive protein (hs-CRP), and fibrinogen in baseline plasma samples. We assessed cognitive function at regular intervals in 4 domains and defined incident impairment as a follow-up score more than 1 SD poorer than the group mean. Results: The mean age of the sample was 64.3 ± 5.6 years, and the mean follow-up was 6.2 ± 2.5 years. At baseline, higher levels of each inflammatory marker were associated with poorer age-adjusted performance. In analyses adjusted for baseline cognition, demographics, comorbid conditions, and kidney function, participants in the highest tertile of hs-CRP, the highest tertile of fibrinogen, and the highest tertile of IL-1β had an increased risk of impairment in attention compared to participants in the lowest tertile of each marker. Participants in the highest versus lowest tertile of TNF-α had a lower adjusted risk of impairment in executive function. There was no association between other inflammatory markers and change in cognitive function. Discussion: Among adults with CKD, higher levels of hs-CRP, fibrinogen, and IL-1β were associated with a higher risk of impairment in attention. Higher levels of TNF-α were associated with a lower risk of impaired executive function.

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.

Mild traumatic brain injury in the Veteran population is frequently comorbid with pain, post-traumatic stress disorder, and/or depression. However, not everyone exposed to mild traumatic brain injury experiences these comorbidities and it is unclear what factors contribute to this variability. The objective of this study was to identify comorbidity phenotypes among Post-9/11 deployed Veterans with no or mild traumatic brain injury and examine the association of comorbidity phenotypes with adverse outcomes. We found that Veterans with mild traumatic brain injury (n = 93,003) and no brain injury (n = 434,378) were mean age of 32.0 (SD 9.21) on entering Department of Veterans Health Administration care, were predominantly Caucasian non-Hispanic (64.69%), and served in the Army (61.31%). Latent class analysis revealed five phenotypes in each subcohort; Moderately Healthy and Mental Health phenotypes were common to both. The Healthy phenotype was found only in no brain injury. Unique phenotypes in mild traumatic brain injury included Moderately Healthy+Decline, Polytrauma, and Polytrauma+Improvement. There was substantial variation in adverse outcomes. The Polytrauma+Improvement phenotype had the lowest likelihood of adverse outcomes. There were no differences between Moderately Healthy+Decline and Polytrauma phenotypes. Phenotypes of comorbidity vary significantly by traumatic brain injury status including divergence in phenotypes (and outcomes) over time in the mild traumatic brain injury subcohort. Understanding risk factors for the divergence between Polytrauma vs. Polytrauma+Improvement and Moderately Healthy vs. Moderately Healthy+Decline, will improve our ability to proactively mitigate risk, better understand the early patterns of comorbidity that are associated with neurodegenerative sequelae following mild traumatic brain injury, and plan more patient-centered care.

Background: Anxiety and depression continue to be significant comorbidities for people with HIV infection. We investigated the prevalence of and factors associated with anxiety and depression among adult HIV-infected patients across China.Methods: In this cross-sectional study, we described clinical and psychosocial variables related to depression and anxiety in 4103 HIV-infected persons. Doctors assessed anxiety and depression by asking patients whether they had experienced anxiety or depression in the prior month. Patients also self-administered the Hospital Anxiety and Depression (HAD) scale; those with score ≥8 on HAD-A/D were considered to be at high risk of anxiety or depression.Results: Associations between socio-demographic, psychosocial, and ART-related clinical factors and risk of depression or anxiety were investigated using multivariable logistic regression. Among patients assessed between 9/2014 and 11/2015, 27.4% had symptoms of anxiety, 32.9% had symptoms of depression, and 19.0% had both. Recentness of HIV diagnoses (P = 0.046) was associated with elevated odds of anxiety. Older age (P = 0.004), higher educational attainment (P < 0.001), employment (P = 0.001), support from family / friends (P < 0.001), and sleep disturbance (P < 0.001), and number of ART regimen switches (P = 0.046) were associated with risk of depression, while neither sex nor transmission route showed any associations. There were no significant associations with HIV-specific clinical factors including current CD4+ T cell count and current viral load.Conclusions: Prevalence of symptoms of anxiety and depression is high in this cohort of treatment-experienced HIV patients. Psychological and social-demographic factors, rather than HIV disease status, were associated with risk of depression and anxiety. This finding highlights the need to deliver interventions to address the mental health issues affecting HIV-infected persons with fully successful immune restoration across China.

Slow wave (or stage N3) sleep has been linked to a variety of cognitive processes. However, the role of stage N3 in the elderly is debated. The link between stage N3 and episodic memory may be weakened or changed in the older adult population, possibly due to several altered mechanisms impacting the cellular structure of the brain. The bases for the age-related dissociation between stage N3 and cognition are not understood. Since APOEε4 status is the strongest genetic risk factor for cognitive decline, we assessed whether the ε4 allele is associated with stage N3 sleep. Participants were from the population-based Osteoporotic Fractures in Men (MrOS) cohort with polysomnography and APOEε4 genotype data (n = 2,302, 100% male, mean age 76.6 years). Sleep stages were objectively measured using overnight in-home polysomnography and central electroencephalogram data were used to score stage N3 sleep. Cognitive function was assessed using the Modified Mini Mental State Exam (3MS). The APOE rs429358 single nucleotide polymorphism, which defines the APOEε4 allele, was genotyped using a custom genotyping array. Total time in stage N3 sleep was significantly higher (p

Clinical and epidemiological studies of older persons have implicated clusterin in Alzheimer's disease (AD) pathogenesis. In the context of identifying early biomarkers of risk, we examined associations of plasma clusterin and characteristics of AD in middle-aged individuals from the community.Subjects were 639 cognitively normal individuals (mean age 50 ± 3.5) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Clusterin was quantified using ELISA (mean 255± 31 ng/ml). Associations were assessed between clusterin and volumes of brain regions known to atrophy in early AD, including entorhinal cortex (ECV), hippocampus (HV), and medial temporal lobe (MTLV) volumes (cm3). Total brain volume (TBV) and volumes of structures affected in later AD were examined for comparison.In multivariable models, higher clusterin had a negative non-linear association with ECV (combined left and right hemispheres), and this association was influenced by the highest clusterin levels. Compared to mean clusterin, 1 and 2 standard deviation (SD) level increases in clusterin were associated with -2.1% (95% CI: -3.3,-0.9) and -7.3% (95% CI: -11.3,-3.3) lower ECV, respectively. Similar relationships were observed between clusterin and HV, although the relationship was stronger for left-side HV than the right-side. However, the association was not significant after adjusting for covariates. Negative non-linear associations between clusterin and MTLV were strongest for the left side: compared to mean clusterin, 1 and 2 SD level increases in clusterin were associated with -0.9% (95% CI: -1.9, 0.1) and -3.7% (95% CI: -7.1, -0.3) lower MTLV. There were no significant associations between clusterin and brain structures affected in later AD.In middle-aged adults unselected for AD, plasma clusterin was associated with lower volume of the entorhinal cortex, an area that atrophies early in AD. Clusterin could be informative as part of a multi-component preclinical marker for AD.

ObjectiveHigher circulating concentrations of cellular adhesion molecules (CAMs) can be used as markers of endothelial dysfunction. Given that the brain is highly vascularized, we assessed whether endothelial function is associated with cognitive performance.MethodWithin the Coronary Artery Risk Development in Young Adults (CARDIA) Study, excluding N = 54 with stroke before year 25, we studied CAMs among N = 2,690 black and white men and women in CARDIA year 7 (1992–1993, ages 25–37) and N = 2,848 in CARDIA year 15 (2000–2001, ages 33–45). We included subjects with levels of circulating soluble CAMs measured in year 7 or 15 and cognitive function testing in year 25 (2010–2011, ages 43–55). Using multiple regression analysis, we evaluated the association between CAMs and year 25 cognitive test scores: Rey Auditory Verbal Learning Test (RAVLT, memory), Digit Symbol Substitution Test (DSST, speed of processing), and the Stroop Test (executive function).ResultAll CAM concentrations were greater in year 15 vs. year 7. Adjusting for age, race, sex, education, smoking, alcohol, diet, physical activity, participants in the fourth vs. the first quartile of CARDIA year 7 of circulating intercellular adhesion molecule-1 (ICAM-1) scored worse on RAVLT, DSST, and Stroop Test (p ≤ 0.05) in CARDIA year 25. Other CAMs showed little association with cognitive test scores. Findings were similar for ICAM-1 assessed at year 15. Adjustment for possibly mediating physical factors attenuated the findings.ConclusionHigher circulating ICAM-1 at average ages 32 and 40 was associated with lower cognitive skills at average age 50. The study is consistent with the hypothesis that endothelial dysfunction is associated with worse short-term memory, speed of processing, and executive function.

BACKGROUND:Traumatic brain injury (TBI) is extremely common across the lifespan and is an established risk factor for dementia. The cognitive profile of the large and growing population of older adults with prior TBI who do not have a diagnosis of dementia, however, has not been well described. Our aim was to describe the cognitive profile associated with prior TBI exposure among community-dwelling older adults without dementia-an understudied but potentially vulnerable population. METHODS AND FINDINGS:In this population-based cohort study, we studied 984 community-dwelling older adults (age 51 y and older and their spouses) without dementia who had been randomly selected from respondents to the 2014 wave of the Health and Retirement Study to participate in a comprehensive TBI survey and who either reported no prior TBI (n = 737) or prior symptomatic TBI resulting in treatment in a hospital (n = 247). Mean time since first TBI was 38 ± 19 y. Outcomes assessed included measures of global cognitive function, verbal episodic memory, semantic fluency, and calculation as well as a measure of subjective memory ("How would you rate your memory at the present time?"). We compared outcomes between the two TBI groups using regression models adjusting for demographics, medical comorbidities, and depression. Sensitivity analyses were performed stratified by TBI severity (no TBI, TBI without loss of consciousness [LOC], and TBI with LOC). Respondents with TBI were younger (mean age 64 ± 10 y versus 68 ± 11 y), were less likely to be female, and had higher prevalence of medical comorbidities and depression than respondents without TBI. Respondents with TBI did not perform significantly differently from respondents without TBI on any measure of objective cognitive function in either raw or adjusted models (fully adjusted: global cognitive function score 15.4 versus 15.2, p = 0.68; verbal episodic memory score 4.4 versus 4.3, p = 0.79; semantic fluency score 15.7 versus 14.0, p = 0.21; calculation impairment 22% versus 26%, risk ratio [RR] [95% CI] = 0.86 [0.67-1.11], p = 0.24). Sensitivity analyses stratified by TBI severity produced similar results. TBI was associated with significantly increased risk for subjective memory impairment in models adjusted for demographics and medical comorbidities (29% versus 24%; RR [95% CI]: 1.26 [1.02-1.57], p = 0.036). After further adjustment for active depression, however, risk for subjective memory impairment was no longer significant (RR [95% CI]: 1.18 [0.95-1.47], p = 0.13). Sensitivity analyses revealed that risk of subjective memory impairment was increased only among respondents with TBI with LOC and not among those with TBI without LOC. Furthermore, the risk of subjective memory impairment was significantly greater among those with TBI with LOC versus those without TBI even after adjustment for depression (RR [95% CI]: partially adjusted, 1.38 [1.09-1.74], p = 0.008; fully adjusted, 1.28 [1.01-1.61], p = 0.039). CONCLUSIONS:In this population-based study of community-dwelling older adults without dementia, those with prior TBI with LOC were more likely to report subjective memory impairment compared to those without TBI even after adjustment for demographics, medical comorbidities, and active depression. Lack of greater objective cognitive impairment among those with versus without TBI may be due to poor sensitivity of the cognitive battery or survival bias, or may suggest that post-TBI cognitive impairment primarily affects executive function and processing speed, which were not rigorously assessed in this study. Our findings show that among community-dwelling non-demented older adults, history of TBI is common but may not preferentially impact cognitive domains of episodic memory, attention, working memory, verbal semantic fluency, or calculation.

BackgroundThe classic view of blood pressure (BP) reactivity to psychological stress in relation to cardiovascular risks assumes that excess reactivity is worse and lower reactivity is better. Evidence addressing how stress‐induced BP reactivity in young adults is associated with midlife cognitive function is sparse. Methods and ResultsWe assessed BP reactivity during a star tracing task and a video game in adults aged 20 to 32 years. Twenty‐three years later, cognitive function was assessed with use of the Digit Symbol Substitution Test (a psychomotor speed test), the Rey Auditory Verbal Learning Test (a verbal memory test), and the modified Stroop test (an executive function test). At the time of follow‐up, participants (n=3021) had a mean age of 50.2 years; 56% were women, and 44% were black. In linear regression models adjusted for demographic and clinical characteristics including baseline and follow‐up resting BP, lower systolic BP (SBP) reactivity during the star tracing and video game was associated with worse Digit Symbol Substitution Test scores (β [SE]: 0.11 [0.02] and 0.05 [0.02], respectively) and worse performance on the Stroop test (β [SE]: −0.06 [0.02] and −0.05 [0.02]; all P

BACKGROUND:Current dementia medications have small effect sizes, many adverse effects and do not change the disease course. Therefore, it is critically important to study alternative treatment strategies. The goal of this study was to pilot-test a novel, integrative group exercise program for individuals with mild-to-moderate dementia called Preventing Loss of Independence through Exercise (PLIÉ), which focuses on training procedural memory for basic functional movements (e.g., sit-to-stand) while increasing mindful body awareness and facilitating social connection. METHODS:We performed a 36-week cross-over pilot clinical trial to compare PLIÉ with usual care (UC) at an adult day program for individuals with dementia in San Francisco, CA. Assessments of physical performance, cognitive function, physical function, dementia-related behaviors, quality of life and caregiver burden were performed by blinded assessors at baseline, 18 weeks (cross-over) and 36 weeks. Our primary outcomes were effect sizes based on between-group comparisons of change from baseline to 18 weeks; secondary outcomes were within-group comparisons of change before and after cross-over. RESULTS:Twelve individuals enrolled (7 PLIÉ, 5 UC) and 2 withdrew (1 PLIÉ, 18 weeks; 1 UC, 36 weeks). Participants were 82% women (mean age, 84 ± 4 years); caregivers were 82% daughters (mean age, 56 ± 13 years). Effect sizes were not statistically significant but suggested potentially clinically meaningful (≥ 0.25 SDs) improvement with PLIÉ versus UC for physical performance (Cohen's D: 0.34 SDs), cognitive function (0.76 SDs) and quality of life (0.83 SDs) as well as for caregiver measures of participant's quality of life (0.33 SDs) and caregiver burden (0.49 SDs). Results were similar when within-group comparisons were made before and after cross-over. CONCLUSIONS:PLIÉ is a novel, integrative exercise program that shows promise for improving physical function, cognitive function, quality of life and caregiver burden in individuals with mild-to-moderate dementia. Larger randomized, controlled trials are warranted. TRIAL REGISTRATION:ClinicalTrials.gov NCT01371214.

Brain-derived neurotrophic factor (BDNF) plays a role in the maintenance and function of neurons. Although persons with Alzheimer's disease have lower cortical levels of BDNF, evidence regarding the association between circulating BDNF and cognitive function is conflicting. We sought to determine the correlates of BDNF level and whether BDNF level was prospectively associated with cognitive decline in healthy older adults. We measured serum BDNF near baseline in 912 individuals. Cognitive status was assessed repeatedly with the modified Mini-Mental Status Examination and the Digit Symbol Substitution test over the next 10 years. We evaluated the association between BDNF and cognitive decline with longitudinal models. We also assessed the association between BDNF level and demographics, comorbidities and health behaviors. We found an association between serum BDNF and several characteristics that are also associated with dementia (race and depression), suggesting that future studies should control for these potential confounders. We did not find evidence of a longitudinal association between serum BDNF and subsequent cognitive test trajectories in older adults, although we did identify a potential trend toward a cross-sectional association. Our results suggest that serum BDNF may have limited utility as a biomarker of prospective cognitive decline.

The contribution of inflammation to deleterious aging outcomes is increasingly recognized; however, little is known about the complex relationship between interleukin-6 (IL-6) and brain structure, or how this association might change with increasing age. We examined the association between IL-6, white matter integrity, and cognition in 151 community dwelling older adults, and tested whether age moderated these associations. Blood levels of IL-6 and vascular risk (e.g., homocysteine), as well as health history information, were collected. Processing speed assessments were administered to assess cognitive functioning, and we employed tract-based spatial statistics to examine whole brain white matter and regions of interest. Given the association between inflammation, vascular risk, and corpus callosum (CC) integrity, fractional anisotropy (FA) of the genu, body, and splenium represented our primary dependent variables. Whole brain analysis revealed an inverse association between IL-6 and CC fractional anisotropy. Subsequent ROI linear regression and ridge regression analyses indicated that the magnitude of this effect increased with age; thus, older individuals with higher IL-6 levels displayed lower white matter integrity. Finally, higher IL-6 levels were related to worse processing speed; this association was moderated by age, and was not fully accounted for by CC volume. This study highlights that at older ages, the association between higher IL-6 levels and lower white matter integrity is more pronounced; furthermore, it underscores the important, albeit burgeoning role of inflammatory processes in cognitive aging trajectories.

Mild cognitive impairment is often a precursor to dementia due to Alzheimer's disease, but many patients with mild cognitive impairment never develop dementia. New diagnostic criteria may lead to more patients receiving a diagnosis of mild cognitive impairment.To develop a prediction index for the 3-year risk of progression from mild cognitive impairment to dementia relying only on information that can be readily obtained in most clinical settings.382 participants diagnosed with amnestic mild cognitive impairment enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI), a multi-site, longitudinal, observational study.Demographics, comorbid conditions, caregiver report of participant symptoms and function, and participant performance on individual items from basic neuropsychological scales.Progression to probable Alzheimer's disease.Subjects had a mean (SD) age of 75 (7) years and 43% progressed to probable Alzheimer's disease within 3 years. Important independent predictors of progression included being female, resisting help, becoming upset when separated from caregiver, difficulty shopping alone, forgetting appointments, number of words recalled from a 10-word list, orientation and difficulty drawing a clock. The final point score could range from 0 to 16 (mean [SD]: 4.2 [2.9]). The optimism-corrected Harrell's c-statistic was 0.71(95% CI: 0.68-0.75). Fourteen percent of subjects with low risk scores (0-2 points, n = 124) converted to probable Alzheimer's disease over 3 years, compared to 51% of those with moderate risk scores (3-8 points, n = 223) and 91% of those with high risk scores (9-16 points, n = 35).An index using factors that can be obtained in most clinical settings can predict progression from amnestic mild cognitive impairment to probable Alzheimer's disease and may help clinicians differentiate between mild cognitive impairment patients at low vs. high risk of progression.

High adiposity is deleteriously associated with brain health, and may disproportionately affect white matter integrity; however, limited information exists regarding the mechanisms underlying the association between body mass (BMI) and white matter integrity. The present study evaluated whether vascular and inflammatory markers influence the relationship between BMI and white matter in healthy aging. We conducted a cross-sectional evaluation of white matter integrity, BMI, and vascular/inflammatory factors in a cohort of 138 healthy older adults (mean age: 71.3 years). Participants underwent diffusion tensor imaging, provided blood samples, and participated in a health evaluation. Vascular risk factors and vascular/inflammatory blood markers were assessed. The primary outcome measure was fractional anisotropy (FA) of the genu, body, and splenium (corpus callosum); exploratory measures included additional white matter regions, based on significant associations with BMI. Regression analyses indicated that higher BMI was associated with lower FA in the corpus callosum, cingulate, and fornix (p

The aim of the study was to evaluate the value of assessing white matter integrity using diffusion tensor imaging (DTI) for classification of mild cognitive impairment (MCI) and prediction of cognitive impairments in comparison to brain atrophy measurements using structural MRI. Fifty-one patients with MCI and 66 cognitive normal controls (CN) underwent DTI and T1-weighted structural MRI. DTI measures included fractional anisotropy (FA) and radial diffusivity (DR) from 20 predetermined regions-of-interest (ROIs) in the commissural, limbic and association tracts, which are thought to be involved in Alzheimer's disease; measures of regional gray matter (GM) volume included 21 ROIs in medial temporal lobe, parietal cortex, and subcortical regions. Significant group differences between MCI and CN were detected by each MRI modality: In particular, reduced FA was found in splenium, left isthmus cingulum and fornix; increased DR was found in splenium, left isthmus cingulum and bilateral uncinate fasciculi; reduced GM volume was found in bilateral hippocampi, left entorhinal cortex, right amygdala and bilateral thalamus; and thinner cortex was found in the left entorhinal cortex. Group classifications based on FA or DR was significant and better than classifications based on GM volume. Using either DR or FA together with GM volume improved classification accuracy. Furthermore, all three measures, FA, DR and GM volume were similarly accurate in predicting cognitive performance in MCI patients. Taken together, the results imply that DTI measures are as accurate as measures of GM volume in detecting brain alterations that are associated with cognitive impairment. Furthermore, a combination of DTI and structural MRI measurements improves classification accuracy.

It has been hypothesized that cellular damage caused by oxidative stress is associated with late-life depression but epidemiological evidence is limited. In the present study we evaluated the association between urinary 8-iso-prostaglandin F2α (8-iso-PGF2α), a biomarker of lipid peroxidation, and depressed mood in a large sample of community-dwelling older adults. Participants were selected from the Health, Aging and Body Composition study, a community-based longitudinal study of older persons (aged 70-79 years). The present analyses was based on a subsample of 1027 men and 948 women free of mobility disability. Urinary concentration of 8-iso-PGF2α was measured by radioimmunoassay methods and adjusted for urinary creatinine. Depressed mood was defined as a score greater than 5 on the 15-item Geriatric Depression Scale and/or use of antidepressant medications. Depressed mood was present in 3.0% of men and 5.5% of women. Depressed men presented higher urinary concentrations of 8-iso-PGF2α than non-depressed men even after adjustment for multiple sociodemographic, lifestyle and health factors (p = 0.03, Cohen's d = 0.30). This association was not present in women (depressed status-by-sex interaction p = 0.04). Our study showed that oxidative damage may be linked to depression in older men from a large sample of the general population. Further studies are needed to explore whether the modulation of oxidative stress may break down the link between late-life depression and its deleterious health consequences.

Leukocyte telomere length (LTL) is an emerging marker of biological age. Chronic inflammatory activity is commonly proposed as a promoter of biological aging in general, and of leukocyte telomere shortening in particular. In addition, senescent cells with critically short telomeres produce pro-inflammatory factors. However, in spite of the proposed causal links between inflammatory activity and LTL, there is little clinical evidence in support of their covariation and interaction.To address this issue, we examined if individuals with high levels of the systemic inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) had increased odds for short LTL. Our sample included 1,962 high-functioning adults who participated in the Health, Aging and Body Composition Study (age range: 70-79 years). Logistic regression analyses indicated that individuals with high levels of either IL-6 or TNF-α had significantly higher odds for short LTL. Furthermore, individuals with high levels of both IL-6 and TNF-α had significantly higher odds for short LTL compared with those who had neither high (OR = 0.52, CI = 0.37-0.72), only IL-6 high (OR = 0.57, CI = 0.39-0.83) or only TNF-α high (OR = 0.67, CI = 0.46-0.99), adjusting for a wide variety of established risk factors and potential confounds. In contrast, CRP was not associated with LTL.Results suggest that cumulative inflammatory load, as indexed by the combination of high levels of IL-6 and TNF-α, is associated with increased odds for short LTL. In contrast, high levels of CRP were not accompanied by short LTL in this cohort of older adults. These data provide the first large-scale demonstration of links between inflammatory markers and LTL in an older population.

ObjectiveTo investigate the longitudinal relationship between subjective and objective sleep disturbance and depressive symptoms.DesignLongitudinal.SettingThree US clinical centers.ParticipantsNine hundred fifty-two community-dwelling older women (70 y or older).MeasurementsAt baseline, subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and objective sleep measures were assessed with wrist actigraphy. Depressive symptoms were assessed with the Geriatric Depression Scale (GDS) at baseline and approximately 5 y later. The analysis was restricted to women with few (GDS 0-2) depressive symptoms at baseline.ResultsThere was an independent association between greater PSQI score (per standard deviation increase, indicating worse subjective sleep quality) at baseline and greater odds of worsening depressive symptoms (≥ 2-point increase in GDS) (Multivariate Odds Ratio [MOR] 1.19, confidence interval [CI] 1.01-1.40, P = 0.036). Higher scores specifically on the sleep quality (MOR 1.41, CI 1.13-1.77, P < 0.003) and sleep latency (MOR 1.21, CI 1.03-1.41, P = 0.018) PSQI subscales were also associated with greater odds for worsening depressive symptoms. Objective assessments revealed an association between baseline prolonged wake after sleep onset (WASO ≥ 60 min) and worsening depressive symptoms at follow-up (MOR 1.36, CI 1.01-1.84, P = 0.046). There were no associations between other objectively assessed sleep measures and worsening depressive symptoms.ConclusionsIn older women with few or no depressive symptoms at baseline, those with more subjectively reported sleep disturbance and more objectively assessed fragmentation of sleep at baseline had greater odds of worsening depressive symptoms 5 y later. Future studies investigating this relationship in more detail are indicated.CitationMaglione JE, Ancoli-Israel S, Peters KW, Paudel ML, Yaffe K, Ensrud KE, Stone KL, Study of Osteoporotic Fractures Research Group. Subjective and objective sleep disturbance and longitudinal risk of depression in a cohort of older women.