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Background: Cardiovascular health may be used for prevention of cerebral vascular disease; however, data on the association of cardiovascular health across midlife and late-life with late-life cerebral vascular disease are lacking. Our aim was to examine whether midlife or late-life cardiovascular health as well as changes of cardiovascular health within midlife and between midlife and late-life were associated with prevalence of magnetic resonance imaging markers of cerebral vascular disease at late-life. Methods: Prospective cohort study including 1638 participants from the Atherosclerosis Risk in Communities Study who took part in 2 visits at midlife (mean ages, 53 and 59 years), and a late-life visit (mean age, 76 years). A cardiovascular health Life’s Simple 7 score (range, 0–12/0–14, depending on diet availability) including 6 out of 7 items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Participants underwent 3T brain magnetic resonance imaging scans in late-life visit. Outcomes were white matter hyperintensity volume, microbleeds, and lacunar, subcortical, and cortical infarcts at late-life. Linear and logistic regression models were used to assess the associations of cardiovascular health in midlife and late-life, and improvement of cardiovascular health within midlife, and from midlife to late-life with magnetic resonance imaging markers of cerebral vascular disease, adjusting for potential confounders. Results: A higher cardiovascular health in midlife, improvement of cardiovascular health within midlife, higher cardiovascular health at late-life, and improvement of cardiovascular health from midlife to late-life were associated with a lower prevalence of cerebral vascular disease markers. For example, improvement in cardiovascular health (per point) from midlife to late-life was associated with smaller white matter hyperintensity volume (β, −0.07 [95% CI, −0.10 to −0.04]) and lower odds of microbleeds (odds ratio, 0.93 [0.90–0.97]), lacunar (odds ratio, 0.93 [0.89–0.97]), subcortical (odds ratio, 0.93 [0.89–0.97]), and cortical infarcts (odds ratio, 0.92 [0.87–0.97]). Conclusions: Improving cardiovascular health within midlife and from midlife to late-life may prevent development of cerebral vascular disease.

Background and ObjectivesHigher scores in Life's Simple 7 (LS7), a metric for cardiovascular and brain health, have been associated with lower risk of dementia. It is uncertain whether this association holds among those with high genetic risk of dementia. Our objective is to evaluate the extent that LS7 may offset dementia risk across the range of genetic risk.MethodsParticipants in the Atherosclerosis Risk in Communities (ARIC) Study were followed from 1987–1989 to 2019. We derived midlife LS7 scores and generated genetic risk scores (GRS) using genome-wide summary statistics of Alzheimer disease, which have been used to study the genetic risk for dementia. Incident dementia was ascertained based on the criteria of the National Institute on Aging–Alzheimer's Association workgroups and Diagnostic and Statistical Manual of Mental Disorders. The associations of the GRS and LS7 with incident dementia were evaluated using Cox regression.ResultsThis study included 8,823 European American (EA) and 2,738 African American (AA) participants (mean age at baseline 54 years). We observed 1,603 cases of dementia among EA participants and 631 among AA participants (median follow-up 26.2 years). Higher GRS were associated with higher risk of dementia (EA, hazard ratio [HR] per SD 1.44, 95% CI 1.37, 1.51; AA, HR 1.26, 95% CI 1.16, 1.36). Among EA participants, higher LS7 scores were consistently associated with lower risk of dementia across quintiles of GRS, including the highest quintile (HR per point 0.91, 95% CI 0.87, 0.96). Among AA participants, the associations between LS7 and incident dementia within stratum of GRS had the same direction as among EA participants, although wide CIs and smaller sample sizes limited reliable inferences.DiscussionAcross strata of GRS, higher midlife LS7 scores were associated with lower risk of dementia. Larger sample sizes from diverse populations are needed to obtain more reliable estimates of the effects of modifiable health factors on dementia risk within genetic risk strata in each ancestry group.

Stress, social isolation, and changes in health behaviors during the COVID-19 pandemic period may have a lasting influence on health. Here, the correlation between current or prior demographic, social and health related characteristics, including psychosocial factors with perceived impact of the COVID-19 pandemic assessed by questionnaire during the early pandemic period is evaluated among 770 participants of the Baltimore Longitudinal Study of Aging. In multinomial logistic regression models participants with higher pre-pandemic personal mastery, a construct related to self-efficacy, were more likely to report "both positive and negative" impact of the pandemic than a solely "negative" impact (OR: 2.17, 95% CI: 1.29-3.65). Higher perceived stress and frequent contact with family prior to the pandemic were also associated with pandemic impact. These observations highlight the relevance of psychosocial factors in the COVID-19 pandemic experience and identify characteristics that may inform interventions in future public health crises.

Introduction: Physical function decline is associated with poor outcomes, including disability and death. Late-life vascular risk burden is associated with faster physical decline, but earlier life course influence is still unknown. We hypothesized that higher mid-life vascular risk is associated with faster late-life physical function decline. Methods: We studied 5,481 adults at visit 5 (mean [SD] age=75.8 [5.0], range=67-91 years, 58% women, 21% Black) without stroke or Parkinson disease. Mid-life hypertension (≥140/90 mm Hg or treatment), diabetes (≥126 mg/dL or treatment), high cholesterol (≥240 mg/dL or treatment), and current smoking were assessed at visit 1 (age=45-64 years) and across visits 1-4. Late-life physical function in the Short Physical Performance Battery (SPPB) was assessed at visits 5-7 (median follow-up: 4.8 years). Random-slope, random-intercept linear mixed models tested interactions between rate of SPPB decline and mid-life risk factors, adjusted for visit 5 age, sex, race-site, education, BMI, coronary heart disease, and heart failure. Results: Mid-life hypertension (+57% decline: 0.47 per 5 years, 95% CI: 0.30-0.64, p Conclusions: Older adults with mid-life hypertension and diabetes had faster rates of late-life physical function decline. Midlife control of blood pressure and diabetes may ameliorate late-life functional decline.

Introduction: Slowed gait speed in older adults is associated higher vascular disease burden, greater risk of dementia, and falls. Gait mat measurement technology captures speed as well as additional gait parameters, with potential importance for better risk prediction and identification in older adults, but normative data are needed. We assessed correlations between mat-measured gait speed and gait parameters to identify potential targets for future gait research. We hypothesized that gait parameters would not correlate with overall mat-measured gait speed as strongly as overall gait speed correlates within repeat trials of mat or stopwatch-measured trials. Methods: Participants (n = 402, mean age: 81 years, 54% women, 19% Black race) from the Atherosclerosis Risk in Communities Study completed two consecutive usual pace walks on Zeno Walkway™ gait mats at visit 8. Two-hundred thirty-six participants additionally completed two 4-meter usual pace walks timed by stopwatch. We assessed validity using the difference between the faster of two trials each for mat- and stopwatch-measured gait speed using Bland-Altman plots, and Pearson’s correlations, and examined reliability with consecutive trials within measurement type. We reported mean, standard deviation, range, and correlation of 37 gait parameters with gait speed, as well as intra-person variability (coefficient of variation) and parameter asymmetry between footfalls. Results: Participants had an average gait speed of 0.92 m/sec (SD 0.19 m/sec) measured by mat and 0.99 m/sec (SD 0.21 m/sec) by stopwatch. Mat-measured gait speed was strongly correlated with stopwatch measured speed (Pearson’s Correlation 0.85). Mat-measured walks were on average 0.08 m/sec faster than paired stopwatch-measured walks (standard deviation of difference 0.11 m/sec, p Conclusions: Gait mat technology shows high reliability and high correlation with stop-watch measurement in older adults in the ARIC population. Additional gait parameters were largely not strongly correlated with gait speed, including step-to-step measures of variability and asymmetry, suggesting avenues for future research to evaluate gait differences more granularly as more sensitive indicators of health risk in older adults.

Introduction: Cardiovascular health may be used for prevention of cerebral vascular disease. We evaluated whether improvement of cardiovascular health within midlife and from midlife to late-life were each associated with lower prevalence of MRI markers of cerebral vascular disease at late-life. Methods: 1,638 participants from the Atherosclerosis Risk in Communities (ARIC) Study took part in two visits at midlife (mean ages 53 at ARIC visit 1 and 59 at visit 3), and a late-life visit (mean age 76). A cardiovascular health Life’s Simple 7 score (range 0-12/0-14, depending on diet availability) including six/seven items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Participants underwent 3T brain MRI scans in 2011-2013 (late-life visit). Outcomes were white matter hyperintensity volume, microbleeds, and lacunar, subcortical, and cortical infarcts at late-life. Linear and logistic regression models were used to assess the associations of cardiovascular health with MRI markers of cerebral vascular disease. Results: Thirty nine percent of participants had high cardiovascular health at midlife visit 1, 32% at midlife visit 3, and 33% at late-life. Improvement of cardiovascular health within midlife and from midlife to late-life were each associated with a lower prevalence of cerebral vascular disease markers. For example, improvement in cardiovascular health (per point) from midlife to late-life was associated with smaller white matter hyperintensity volume (Beta:-0.07 [95%CI:-0.10,-0.04]), and lower odds of microbleeds (OR:0.93 [0.90,0.97]), lacunar (OR:0.93 [0.89,0.97)], subcortical (OR:0.93 [0.89,0.97])], and cortical infarcts (OR:0.92 [0.87,0.97)] (Figure). Conclusions: Improving cardiovascular health within midlife and from midlife to late-life may prevent development of cerebral vascular disease.

Background and ObjectivesTo evaluate the association between midlife plasma amyloid-β (Aβ1-42, Aβ1-40, Aβ42:Aβ40) and risk of mild cognitive impairment (MCI) and dementia.MethodsPlasma Aβ42 and Aβ40 were retrospectively measured with a fluorometric bead-based immunoassay in a subsample of the Atherosclerosis Risk in Communities cohort study. We investigated the relationship of plasma Aβ42, Aβ40, and Aβ42:Aβ40 ratio measured in midlife and late life and the change from midlife to late life to risk of MCI, dementia, and combined MCI/dementia outcomes in late life (from 2011–2019). We used multinomial logistic regressions estimating relative risk ratios (RRRs) of these cognitive outcomes vs cognitively normal adjusted for age, sex, education, site-race, APOE, hypertension, diabetes, and body mass index.ResultsA total of 2,284 participants were included (midlife mean age 59.2 ± 5.2, 57% female, 22% Black). Each doubling of midlife Aβ42:Aβ40 was associated with 37% lower risk of MCI/dementia (RRR 0.63, 95% confidence interval [CI] 0.46–0.87), but only up to approximately the median (spline model threshold 0.20). Every 1-SD increase in plasma Aβ42 (10 pg/mL) was associated with 13% lower risk of MCI/dementia (RRR 0.87, 95% CI 0.77–0.98), whereas every 1-SD increase in plasma Aβ40 (67 pg/mL) was associated with 15% higher risk of MCI/dementia (RRR 1.15, 95% CI 1.01–1.29). Associations were comparable but slightly weaker statistically when models were repeated using late-life plasma Aβ predictors. Aβ42 and Aβ40 increased from midlife to late life, but changes were not associated with cognitive outcomes.DiscussionMidlife measurement of plasma Aβ may have utility as a blood-based biomarker indicative of risk for future cognitive impairment.

Hearing and vision impairments are risk factors for cognitive decline; less is known about dual sensory impairment. This study quantifies the association between dual sensory impairment and 8-year change in memory among older adults.Data (N = 5552) were from the National Health and Aging Trends Study. Memory (immediate/delayed word recall, subjective memory) was measured annually (2011 to 2019). Hearing and vision impairments were measured by self-report. Association between dual sensory impairment and 8-year change in memory was assessed using multivariate linear mixed effect models and generalized logistic mixed models.Rate of memory decline was most accelerated among participants with dual sensory impairment. For example, 8-year decline in delayed word recall was -1.03 (95% confidene interval: -1.29, -0.77) for dual sensory impairment versus -0.79 (-0.92, -0.67) for single and -0.56 (-0.63, -0.48) for no impairment.Older adults with dual sensory impairment may be at particularly higher risk for cognitive decline.

A primary goal of longitudinal studies is to examine trends over time. Reported results from these studies often depend on strong, unverifiable assumptions about the missing data. Whereas the risk of substantial bias from missing data is widely known, analyses exploring missing-data influences are commonly done either ad hoc or not at all. This article outlines one of the three primary recognized approaches for examining missing-data effects that could be more widely used, i.e. the shared-parameter model (SPM), and explains its purpose, use, limitations and extensions. We additionally provide synthetic data and reproducible research code for running SPMs in SAS, Stata and R programming languages to facilitate their use in practice and for teaching purposes in epidemiology, biostatistics, data science and related fields. Our goals are to increase understanding and use of these methods by providing introductions to the concepts and access to helpful tools.

Background Hearing loss is prevalent and associated with adverse functional outcomes in older adults. Prevention thus has far-reaching implications, yet few modifiable risk factors have been identified. Hypertension may contribute to age-related hearing loss, but epidemiologic evidence is mixed. We studied a prospective cohort of 3343 individuals from the Atherosclerosis Risk in Communities study, aged 44–65 years at baseline with up to 30 years of follow-up. Methods Hearing was assessed in late life (2016–2017) using a better-ear audiometric pure tone average (0.5, 1, 2, 4 kHz) and the Quick Speech-in-Noise (QuickSIN) test. Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or antihypertensive medication use. Midlife hypertension was defined by hypertension at 2 consecutive visits between 1987–1989 and 1996–1998. Late-life hypertension was defined in 2016–2017. Late-life low blood pressure was defined as a systolic blood pressure less than 90 mmHg or diastolic blood pressure less than 60 mmHg, irrespective of antihypertensive medication use. Associations between blood pressure patterns from mid- to late life and hearing outcomes were assessed using multivariable-adjusted linear regression. Results Compared to persistent normotension, persistent hypertension from mid- to late life was associated with worse central auditory processing (difference in QuickSIN score = −0.66 points, 95% CI: −1.14, −0.17) but not with audiometric hearing. Conclusions Participants with persistent hypertension had poorer late-life central auditory processing. These findings suggest that hypertension may be more strongly related to hearing-related changes in the brain than in the cochlea.

Objectives:Vision and hearing impairments affect 55% of people aged 60+ years and are associated with lower cognitive test performance; however, tests rely on vision, hearing, or both. We hypothesized that scores on tests that depend on vision or hearing are different among those with vision or hearing impairments, respectively, controlling for underlying cognition.Methods:Leveraging cross-sectional data from the Baltimore Longitudinal Study of Aging (BLSA) and the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), we used item response theory to test for differential item functioning (DIF) by vision impairment (better eye presenting visual acuity worse than 20/40) and hearing impairment (better ear .5–4 kHz pure-tone average > 25 decibels).Results:We identified DIF by vision impairment for tests whose administrations do not rely on vision [e.g., Delayed Word Recall both in ARIC-NCS: .50 logit difference between impaired and unimpaired (p = .04) and in BLSA: .62 logits (p = .02)] and DIF by hearing impairment for tests whose administrations do not rely on hearing [Digit Symbol Substitution test in BLSA: 1.25 logits (p = .001) and Incidental Learning test in ARIC-NCS: .35 logits (p = .001)]. However, no individuals had differences between unadjusted and DIF-adjusted measures of greater than the standard error of measurement.Conclusions:DIF by sensory impairment in cognitive tests was independent of administration characteristics, which could indicate that elevated cognitive load among persons with sensory impairment plays a larger role in test performance than previously acknowledged. While these results were unexpected, neither of these samples are nationally representative and each has unique selection factors; thus, replication is critical.

INTRODUCTION Hearing impairment is associated with poor cognitive test performance in older adults. However, hearing's impact on cognitive test completion is poorly described, and missing cognitive data due to hearing impairment could misestimate the association. METHODS We investigated if hearing impairment is associated with missing neurocognitive scores in 3678 adults (72-94 years). Hearing impairment was defined by the better-ear pure tone average of speech-frequency thresholds (0.5-4 kHz) >25 decibels. RESULTS Hearing impairment was associated with greater missingness on all auditory-only tests, including Logical Memory (prevalence ratio [PR] comparing ≥ moderate impairment vs normal hearing:1.68, 95% confidence interval [CI] 1.26, 2.25) and Digits Backwards (PR 1.62; 95% CI 1.21, 2.17); and two non-auditory tests, Boston Naming (PR 1.61; 95% CI 1.21, 2.17) and Trail Making B (PR 1.55; 95% CI 1.29, 1.86). Models that imputed missing cognitive scores showed the strongest hearing-cognition associations. DISCUSSION Older adults with hearing impairment are less likely to complete cognitive testing, thereby underestimating the hearing impairment-cognition relationship.

Personalized medicine is care that is tailored to an individual patient. In contrast, randomized trials are designed to report evidence of benefits and harms “on average”. The average trial participant though, is often healthier than older patients seen in clinical practice. A variety of methods have been proposed which offer improvements to traditional (but questionable) practices of one-subgroup-at-a-time examinations of treatment effect heterogeneity, but translating evidence from these advancements has received less attention. Data Science initiatives have allowed broader data sharing, data harmonization and data synthesizing approaches, as well as an enormous maturing of interactive visualization techniques. Motivated by the SPRINT study and using advanced approaches of marginalized standardization and the Predictive Approaches to Treatment effect Heterogeneity (PATH) statement, we show how researchers, regulators, clinicians and patients can "find themselves" on the treatment effect continuum and be better informed of potential individualized evidence through interactive visualizations.

The formation of spermatozoa starts with a germ-line stem cell creating a pool of progenitor cells or undifferentiated spermatogonia. There is a requirement for these progenitor cells to be stimulated by retinoic acid (RA) to enter differentiation and ultimately form spermatocytes, undergo meiosis, form spermatids, and ultimately spermatozoa. After the stimulation by RA, which occurs at sites in the seminiferous tubules, it takes ~35 days to complete this complex process. As a result, the adult testis contains germ cells in all possible states of differentiation, and the isolation of individual cell types or study of functional aspects of the cycle of the seminiferous epithelium is very difficult. We describe the use of WIN 18 446—an inhibitor of RA synthesis followed by injection of RA as a mechanism for the synchronization of spermatogenesis to one to three stages of the cycle of the seminiferous epithelium. The result is that only one to four germ cell types are prevalent during the first wave of spermatogenesis. In the adult only a predictable few stages of the cycle are present throughout the entire testis enriching the targeted cells or stages of the cycle.

Background Multisystem dysregulation (Dm) shows promise as a metric of aging and predicts mortality. However, Dm needs to be studied with less severe endpoints indicating modifiable aging stages. Physical function, reflecting healthy longevity rather than just longevity, is more relevant to the goals of geroscience but has not been well investigated. Methods We tested the association of midlife Dm and its change over ~20 years with physical function in later life in 5 583 the Atherosclerosis Risk in Communities Study cohort participants (baseline mean age 54.7). Dm quantifies the multivariate statistical deviation of 17 physiologically motivated biomarkers relative to their distribution in a young healthy sample at baseline. Physical function was assessed from grip strength and the Short Physical Performance Battery (SPPB). Associations were quantified using linear regression and ordinal logistic regression adjusting for age, sex, race, and education. Results Each unit increment in midlife Dm was associated with 1.71 times the odds of having a lower SPPB score. Compared to the first quartile of midlife Dm, the odds ratios of having a lower SPPB score were 1.25, 1.56, and 2.45, respectively, for the second–fourth quartiles. Similar graded association patterns were observed for each SPPB component test and grip strength. An inverse monotonic relationship also was observed between the annual growth rate of Dm and physical function. Conclusion Greater Dm and progression in midlife were associated with lower physical function in later life. Future studies on the factors that lead to the progression of Dm may highlight opportunities to preserve physical function.

Spermatogenesis is a highly organized and regulated process that requires the constant production of millions of gametes over the reproductive lifetime of the mammalian male. This is possible because of an active stem cell pool and an ordered entry into the germ cell developmental sequence. The ordered entry is a result of the synthesis and action of retinoic acid allowing for the onset of spermatogonial differentiation and an irreversible commitment to spermatogenesis. The periodic appearance and actions of retinoic acid along the seminiferous tubules is a result of the interactions between germ cells and Sertoli cells that result in the generation and maintenance of the cycle of the seminiferous epithelium and is the subject of this review.

Imaging markers of cerebrovascular disease and Alzheimer’s disease (AD) are implicated in mobility impairment in older adults, but few studies have examined these relationships longitudinally in a racially-diverse population-based sample. At Visit 5 (2011–13) of the ARIC Study, 1859 participants had usual pace gait speed (cm/s) assessed and brain MRI (mean age = 76.3, 28.5% Black) and PET (n = 343; mean age = 75.9, 42.6% Black) measures including total/regional brain volume (cm(3)), white matter hyperintensities (WMH; cm(3)), infarcts (present/absent), microbleeds (count) and global beta-amyloid (Aβ). Participants returned at Visit 6 (n = 1264, 2016–17) and Visit 7 (n = 1108, 2018–19) for follow-up gait speed assessments. We used linear regression to estimate effects of baseline infarct presence, higher microbleed count, and a one interquartile range (IQR) poorer measures of continuous predictors (−1 IQR total brain volume, temporal-parietal lobe meta region of interest(ROI); +1 IQR WMH volume, global Aβ SUVR) on cross-sectional gait speed and change in gait speed adjusting for age, sex, education, study site, APOE e4, estimated intracranial volume, BMI, and cardiovascular risk factors. Cross-sectionally, slower gait speed outcome was associated with higher WMH volume, −3.38 cm/s (95%CI:−4.71, −2.04), infarct presence, −5.60 cm/s (−7.69, −3.51), microbleed count, −2.20 cm/s (−3.20, −0.91), smaller total brain volume, −9.26 cm/s (−12.1, −6.43), and smaller temporal-parietal lobe ROI −6.28 cm/s (−8.28, −4.28). Longitudinally, faster gait speed outcome decline was associated with higher WMH volume, −0.27 cm/s/year, (−0.51, −0.03) and higher global Aβ SUVR, −0.62 cm/s/year (−1.20, −0.03). Both cerebrovascular and AD pathology may contribute to mobility decline commonly seen with aging.

Laboratory and epidemiological studies have shown that short sleep time is associated with obesity. In this study, we conducted a post-GWAS analysis to test genetic correlation between children’s sleep and obesity due to linkage disequilibrium (LD) SNPs, shared genes and pathways. Our analysis showed that genetic heritability was 0.14 (p-value = 0.0005) and 0.41 (p-value = 1.18E−24) for children’s sleep and obesity, respectively, but genetic correlation due to LD SNPs was insignificant. Gene associations at children’s GWAS were measured based on SNP associations and ranked by their uniform score (U-score). After adjusting for gene size, measured as the number of independent SNPs, children’s sleep and obesity GWAS had significant gene correlation (r = 0.23). Pathway enrichment analysis showed that “Suz12 target genes” was the significant pathway for both children’s sleep and obesity; pathways were significantly shared among top enriched pathways with an OR of 8.1–59.4; and significant correlation coefficient of pathway U-score was r = 0.36. Analysis of sleep time and obesity GWAS variants for all ages in the NHGRI-EBI GWAS Catalog also presented significant pathway correlation (r = 0.30). The “PAX3-FOXO1 target genes” was the significant pathway for all-age obesity phenotype and ranked as the second top associated pathway for all-age sleep time. Our study suggested that genetic correlation of children’s sleep time and obesity is attributed to genes with pleiotropy effects and common pathway regulations that may contain only weak SNP associations.

Factors underlying gastroparesis are not well defined. We hypothesized that multiple systems may be involved in patients with gastroparesis symptoms and performed a comparative physiologic study. We studied 43 consecutive eligible patients with gastroparetic symptoms categorized by GI symptoms, metabolic status, illness quantification, and gastric physiology. Patients were evaluated by two methods in each of five core areas: inflammatory, autonomic, enteric, electrophysiologic, and hormonal with abnormalities examined by correlations. Patients had similar GI symptoms regardless of baseline gastric emptying or diabetic/idiopathic status, and all patients demonstrated abnormalities in each of the 5 areas studied. Nearly all patients presented with elevated markers of serum TNFα (88%) and serum IL-6 (91%); elevated cutaneous electrogastrogram frequency (95%); and interstitial cells of Cajal count abnormalities (inner: 97%, outer: 100%). Measures of inflammation correlated with a number of autonomic, enteric anatomy, electrophysiologic and hormonal abnormalities. We conclude that patients with the symptoms of gastroparesis have multiple abnormalities, when studied by traditional, as well as newer, diagnostic assessments. Inflammation appears to be a fundamental abnormality that affects other organ systems in symptomatic patients. Future work on gastroparetic syndromes and their treatment may benefit from a focus on the diffuse nature of their illness, diverse pathophysiologic mechanisms involved, especially the possible causes of underlying inflammation and disordered hormonal status. This study is registered with Clinicaltrials.gov under study # NCT03178370 https://clinicaltrials.gov/ct2/show/NCT03178370 .

Introduction: Frailty, an increased vulnerability to stressors, is associated with adverse health outcomes. Cardiovascular disease (CVD) is associated with frailty, but whether circulating cardiac biomarkers of subclinical myocardial injury and strain (e.g., high-sensitivity cardiac troponin T [hs-cTnT] and natriuretic peptide [NT-proBNP]) are associated with frailty is unknown. Methods: We conducted a cross-sectional analysis of levels of hs-cTnT and NT-proBNP assessed among participants of the ARIC study at visit 5 (2011-2013, mean age: 75.5 years, 42% male, 21% Black). We used the Fried frailty phenotype that counts the presence of each component (weight loss, low physical activity, slow gait, exhaustion, and low grip strength) to classify participants as frail (≥3), pre-frail (1-2), or robust (0 components). Participants without prevalent CVD (stroke, myocardial infarction, or heart failure) were classified into hs-cTnT and NT-proBNP quartiles; those with prevalent CVD were considered in a separate group. Using adjusted multinomial logistic regression models, we tested the hypothesis that hs-cTnT and NT-proBNP are positively associated with odds of being pre-frail and frail, vs. robust. Results: Among 5,162 participants, 1,039 had prevalent CVD (20%), 2,447 (48%) were pre-frail, and 358 (7%) frail. Biomarker concentrations had graded associations with frailty and pre-frailty, vs. robust. Estimates comparing the 4 th vs. 1 st quartile, (e.g., hs-cTnT frail vs. robust OR=4.37 [95% CI: 2.69-7.09]) were similar to those observed for prevalent CVD vs. 1 st quartile (e.g., hs-cTnT frail vs. robust OR=5.11 [3.19-8.17]). All frailty components were positively associated with cardiac biomarker concentrations and CVD (Table), except exhaustion with NT-proBNP. Conclusions: Cardiac biomarker concentrations, even in the absence of CVD, may help identify people at greater risk for frailty. Future research should examine the role of changes in biomarkers from mid-life on the risk of frailty

Introduction: Modifiable risk factors (including cardiovascular traits) are associated with dementia risk. However, it is unknown which risk factors have the greatest influence on dementia rates in the United States, or how that varies by race/ethnicity. Objective: For all Americans and separately by race and ethnicity, we calculated population attributable fractions (PAFs) of dementia for 12 potentially modifiable risk factors: low education, hearing loss, traumatic brain injury, hypertension, excessive alcohol consumption, obesity, smoking, depression, social isolation, physical inactivity, diabetes, and air pollution. Methods: Assuming a causal relationship between risk factors and dementia, we calculated PAFs for dementia using relative risks and prevalence estimates for each risk factor. We used relative risks from recent meta-analyses and prevalence estimates from nationally representative cross-sectional survey data (e.g., NHANES). We estimated prevalence separately by race/ethnicity. We calculated the PAF (for all Americans and separately by race and ethnicity) for each dementia risk factor and a combined PAF accounting for correlations between exposures. Results: In the total population, 42.6% of dementia cases were attributable to the 12 risk factors we considered. The estimated PAF of these risk factors was greater for Black and Hispanic Americans (47.5% and 47.3%, respectively) than it was for White and Asian Americans (41.3% and 37.8%, respectively). The greatest fractions of dementia cases were attributable to key cardiovascular traits: hypertension (20.2%), obesity (20.9%), and physical inactivity (20.1%). These factors were highest within each racial and ethnic group, though the proportions varied (Figure 1). Conclusions: A large fraction of dementia cases are attributable to potentially modifiable factors, especially for Black and Hispanic Americans. Further research is needed to test whether intervening on these factors reduces dementia risk.

Introduction: Apart from stroke, cognitive change after incident myocardial infarction (MI) is unclear. We aim to determine associations between incident MI and acute and long-term changes in cognitive function, controlling for risk factors and pre-MI cognitive trajectories, censoring for stroke. Methods: We performed a pooled analysis of 31,377 participants, ≥18 years, free of MI and dementia, from 6 longitudinal cohort studies (1971-2017): Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study. Outcomes were changes in global cognition (primary), memory, and executive function. Linear mixed-effects models were used to estimate the association between incident MI and acute cognitive decline at the time of MI (Model A), and decline in cognition over the years after MI (Model B). Results: Median study follow up was 6.4 years (IQR 4.9-19.7 years) and 1,047 participants had incident MI. Incident MI was associated with significant acute decline in global cognition and executive function, but not memory, after the MI event (Models A, Table 1). After including change in cognitive function (slope) after incident MI in the model, the effect estimates indicating acute declines in global cognition and executive function were not significant (Models B, Table 1). However, participants with incident MI demonstrated significantly faster declines in global cognition (-0.15 points/year faster [95% CI, -0.21 to -0.10]), memory (-0.13 points/year faster [95% CI, -0.23 to -0.04]), and executive function (-0.14 points/year faster [95% CI, -0.20 to -0.08]) compared to those without MI (Models B, Table 1). Conclusions: Incident MI is associated with faster declines in global cognition, memory, and executive function over years following the MI event.

Spermatogonial differentiation is a process that commits germ cells to the complex process of spermatogenesis. Spermatogonial differentiation is mediated by the action of retinoic acid, which triggers major morphological and transcriptional changes. While these transcriptional changes have been well explored, there has been little effort devoted to epigenetic regulation surrounding spermatogonial development. This study aimed to uncover the timing and dynamics of chromatin organization during spermatogonial development within the context of these transcriptional changes. Using germ cell synchrony and the assay for transposase accessible chromatin and next generation sequencing (ATAC-seq) to isolate subpopulations of developing spermatogonia and identify accessible regions within their genome, we found that 50% of accessible regions in undifferentiated spermatogonia were condensed following retinoic acid action within 18 h. Surprisingly, genes with known functional relevance during spermatogonial development were accessible at all times, indicating that chromatin state does not impact transcription at these sites. While there was an overall decrease in gene accessibility during spermatogonial development, we found that transcriptionally active regions were not predictive of chromatin state.

Introduction: Sudden cardiac death (SCD) is an important public health problem. About 356,000 people suffer SCD in the U.S., accounting for 15% of all deaths. The ankle-brachial index (ABI) is a simple, non-invasive measure of subclinical atherosclerosis. The aim of this study was to determine the relation between ABI and SCD in a middle-aged biracial general population. Methods: All ARIC (Atherosclerosis Risk in Communities) study subjects with a documented ABI measurement between 1987 and 1989 were included in the study. ABI was categorized as abnormal (≤0.9), borderline (0.9-1), normal [1-1.4], and non-compressible (>1.4). SCD was defined as a sudden pulseless condition presumed to be caused by a ventricular tachyarrhythmia in a previously stable individual. All SCD cases were adjudicated by a committee of cardiac electrophysiologists, cardiologists, and internists. Results: Of the 15,135 participants followed for a median of 23.5 years, 558 (3.7%) developed SCD (1.96 cases per 1000 person-years). Abnormal or borderline ABIs were associated with an elevated risk of SCD (HRs with 95 % CIs 2.27 [1.64-3.14] and 1.52 [1.17-1.96], respectively) in comparison to normal ABI. The association between abnormal ABI and SCD remained significant after adjustment for traditional cardiovascular risk factors, but not for borderline ABI (HR 1.63 [1.15-2.32] and 1.24 [0.94-1.63]) (Table). Conclusions: Abnormal ABI is independently associated with risk of SCD in a biracial general population. ABI could be incorporated into a future risk SCD prediction model.

The BLSA is an invaluable resource for the study of human aging with uniquely rich measures taken longitudinally on a continuous replenishment cohort since 1958. Tremendous interest has been expressed by the United States and international research communities in expanded access to and use of BLSA data to address emerging scientific questions. Here, we will describe recent study leadership initiatives into: (1) making the BLSA data more FAIR (Findable, Accessible, Interoperable, and Reusable), (2) growing a BLSA data ecosystem that enables scalable sharing, and (3) leveraging and developing platforms for accessing the ecosystem. Lastly, we will demonstrate current platform functions that empower researchers to find and access BLSA data, metadata, protocols, code and supporting materials to make new discoveries.

We hypothesized that poorer cerebral perfusion could impair mobility, particularly at lower systolic blood pressure (SBP). Cerebral perfusion was measured via arterial spin-labelled (ASL)-MRI in community-dwelling adults of the Mayo Clinic Study of Aging. Usual-pace gait speed was assessed over 5.6 meters on an electronic mat. Linear regression models estimated cross-sectional gait speed associations with ASL and modifying effects of age and SBP, adjusting for sex and body mass index. Results report differences in gait speed (meter/second) per standard deviation (SD) lower ASL or SBP (mean=139.1 mmHg, SD=19.7 mmHg). Among 479 participants (aged 31-94 years; mean age 67.6 years; 44% women; mean gait speed 1.17m/s), relationships of ASL with gait speed varied by age and SBP (ASL-x-age interaction: p

We examined cross-sectional associations between microstructural integrity of the brain and olfaction in 1417 participants from the ARIC Study who completed MRI scans in 2011-2013 (mean age=76±2 years, 41% male). Microstructural integrity was measured by two diffusion tensor imaging measures, fractional anisotropy (FA, higher=better) and mean diffusivity (MD, higher=worse), and olfaction by a 12-item odor-identification test. In multivariable linear regression models, higher FA in several regions was associated with better olfaction, with the strongest association in the stria terminalis [β:0.333 (95%CI:0.188, 0.478) per standard deviation (SD) higher FA]. Higher MD was associated with lower olfaction in almost all regions, but associations were strongest for some temporal sub-regions [for example, hippocampus, β:-0.796 (95%CI: -0.942, -0.651) per SD higher MD]. Our findings suggest that neuronal microstructural integrity is an important predictor of olfaction; this may also have important implications in understanding early dementia neuropathology as olfaction is affected very early in dementia.

BackgroundDementia is a major health concern for which prevention and treatment strategies remain elusive. Lowering high blood pressure with specific antihypertensive medications (AHMs) could reduce the burden of disease. We investigated whether specific AHM classes reduced the risk for dementia.MethodsWe did a meta-analysis of individual participant data from eligible observational studies published between Jan 1, 1980, and Jan 1, 2019. Cohorts were eligible for inclusion if they prospectively recruited community-dwelling adults; included more than 2000 participants; collected data for dementia events over at least 5 years; had measured blood pressure and verified use of AHMs; included in-person exams, supplemented with additional data, to capture dementia events; and had followed up cases for mortality. We assessed the association of incident dementia and clinical Alzheimer's disease with use of five AHM classes, within strata of baseline high (systolic blood pressure [SBP] ≥140 mm Hg or diastolic blood pressure [DBP] ≥90 mm Hg) and normal (SBP

Late-life measures of white matter microstructural integrity may predict cognitive status, cognitive decline, and incident MCI or dementia. We considered participants of the Atherosclerosis Risk in Communities (ARIC) study who underwent cognitive assessment and neuroimaging in 2011-2013 and were followed through 2016-2017 (n=1775 for analyses of prevalent MCI and dementia, baseline cognitive performance, and longitudinal cognitive change, n=889 for analyses of incident MCI, dementia, or death). Cross-sectionally, both overall white matter fractional anisotropy and overall white matter mean diffusivity were strongly associated with baseline cognitive performance and risk of prevalent MCI or dementia. Longitudinally, greater overall white matter mean diffusivity was associated with accelerated cognitive decline, as well as incident MCI, incident dementia, and mortality, but white matter fractional anisotropy was not robustly associated with cognitive change or incident cognitive impairment. Both cross-sectional and longitudinal associations were attenuated after additionally adjusting for likely downstream pathologic changes. Increased white matter mean diffusivity may provide an early indication of dementia pathogenesis.

To examine the impact of moderate to vigorous intensity physical activity (MVPA) trajectories during midlife and older adulthood with subsequent fall risk in later life. Cross-temporal analyses were conducted in 15,792 participants (27% black, 55% women) aged 45 to 64 years enrolled in the Atherosclerosis Risk in Communities (ARIC) Study. MVPA was collected at Exams 1 (1987–89), 3 (1993–95) and 5 (2011–13) using the ARIC/Baecke questionnaire. Latent class growth analysis was used to identify the MVPA trajectory groups. Reported falls outcomes were collected in 2013–14, 2015–16, and 2016–17. Generalized Linear Models were used to estimate associations of baseline predictors with trajectory class membership, as well as associations of trajectory classes with any falling (adjusted incident relative risks, aIRR) and with number of falls (adjusted relative rates, aRR). Four primary trajectory classes emerged, reflecting longitudinal patterns of maintained high (48%), maintained low (22%), increasing (14%) and decreasing (15%) MVPA. After adjustment for covariates, the decreasing MVPA trajectory group had a 14% higher risk of reporting any falling compared to the maintained high MVPA group [aIRR = 1.14 (1.01, 1.28)]. When compared to the maintained high MVPA group, the maintained low and decreasing group had a 28% [aRR = 1.28 (1.14, 1.44)] and 27% [aRR = 1.27 (1.17, 1.38)] higher rate in the reported number of falls, respectively. Findings support public health campaigns targeting habitual MVPA or exercise for fall prevention and suggest that interventions should be initiated in midlife; a time when individuals may be more able and willing to change behavior.

Objective: To investigate whether APOE ε4 genotype—an established risk factor for dementia—is associated with earlier age at diagnosis in addition to increased risk overall and in secondary analysis by race and sex. Methods: We followed up 13,782 dementia-free individuals (n = 10,137 White, n = 3,645 Black, baseline age 60–66 years) in the Atherosclerosis Risk in Communities study for up to 30 years. Dementia was operationalized using standardized algorithms incorporating longitudinal cognitive change, proxy report, and hospital or death certificate dementia codes. We used a mixture of generalized gamma distributions to simultaneously estimate time to dementia, time to dementia-free death, and the proportion of individuals with dementia, by APOE ε4 status (≥1 vs. no alleles). Results: Median age of dementia onset among APOE ε4 carriers was 81.7 (Blacks) and 83.3 years (Whites) compared with 82.6 (Blacks) and 85.7 years (Whites) in non-APOE ε4 carriers (p > 0.05 Blacks; p < 0.01 Whites). Age of dementia diagnosis did not differ by sex in ε4 carriers, but among non-carriers, average age was earlier in males than females regardless of race. APOE ε4 carriers had on average a higher proportion of diagnoses; results did not differ by race or sex. Conclusions: APOE ε4 carrier status is associated with earlier age of dementia diagnosis with differences across race and sex. These findings clarify the causal role of APOE in dementia etiology, which could help better identify at-risk subgroups and may help facilitate better research trial recruitment and design.

INTRODUCTION A data-driven index of dementia risk based on magnetic resonance imaging (MRI), the Alzheimer's Disease Pattern Similarity (AD-PS) score, was estimated for participants in the Atherosclerosis Risk in Communities (ARIC) study. METHODS AD-PS scores were generated for 839 cognitively non-impaired individuals with a mean follow-up of 4.86 years. The scores and a hypothesis-driven volumetric measure based on several brain regions susceptible to AD were compared as predictors of incident cognitive impairment in different settings. RESULTS Logistic regression analyses suggest the data-driven AD-PS scores to be more predictive of incident cognitive impairment than its counterpart. Both biomarkers were more predictive of incident cognitive impairment in participants who were White, female, and apolipoprotein E gene (APOE) e4 carriers. Random forest analyses including predictors from different domains ranked the AD-PS scores as the most relevant MRI predictor of cognitive impairment. CONCLUSIONS Overall, the AD-PS scores were the stronger MRI-derived predictors of incident cognitive impairment in cognitively non-impaired individuals.

Introduction: Age-related homeostatic dysregulation (Dm), characterized by multi-biomarker composite measures, has shown promise as a rate-of-aging metric. We tested the association of midlife Dm and its change over ~20 years of follow-up with later life physical function. Methods: We studied 4617 ARIC cohort participants (mean age 54.8 years, 58% female, 20% Black) who completed in-person examinations from 1990-92 (baseline) through 2011-13. Dm quantifies the multivariate statistical deviation of 15 physiology-motivated biomarkers from the distribution in a healthy sample at baseline. Midlife Dm was grouped by quartiles (higher quartiles indicating greater homeostatic dysregulation) and temporal change in Dm was quantified continuously. Physical function was assessed in 2011-13 and included measures from the Short Physical Performance Battery (SPPB) including repeated chair stands, balance, 4-meter walk and grip strength. Associations were quantified using linear regression and ordinal logistic regression as applicable, adjusting for age, sex, race, and education. Results: A graded association was observed between midlife Dm and physical functional performance in late life (Table). Compared to the 1 st quartile of midlife Dm, the odds ratio of a lower SPPB score in late life was 1.19 (95%CI 1.04, 1.35) for the 2 nd quartile, 1.63 (1.41, 1.90) for the 3 rd quartile, and 3.14 (2.60, 3.79) for the 4 th quartile. Similar associations were observed for each of SPPB components and grip strength, either modeled ordinally or continuously. Each standard deviation increase in 10-year Dm change was associated with ~2-3 times the odds of having a poorer physical functional performance. Conclusions: Greater homeostatic dysregulation at midlife and increases in dysregulation during follow-up were associated with poorer physical function in late life. Insights into the factors that lead to progression of multisystem deterioration during midlife may highlight opportunities to preserve functional abilities in late life.

Introduction: Greater late-life physical function decline is associated with incident adverse outcomes including disability and death. Hypertension is the strongest risk factor for stroke, the major cause of physical disability. Hypertension in mid-life has previously been associated with poor physical functioning in late-life; however, more evidence is needed to evaluate whether higher blood pressure in mid-life is associated with the rate of physical function decline during late-late in the absence of stroke. We hypothesized that elevated blood pressure in mid-life would be associated with greater physical function declines in late life. Methods: We studied 5,559 older adults in the ARIC Study (Visit 5; mean age: 75.8 years; range: 66.7-90.9 years; 58% women; 21% Black/79% White) without prior stroke or Parkinson disease who completed the Short Physical Performance Battery (SPPB, scored 0-12). Repeated SPPB assessments occurred at Visits 6 and 7 (median follow-up: 4.2 years). The exposure was a history of elevated blood pressure (BP) (Visit 1; mean age: 52.0 years; mean gap between mid- and late-life exams: 23.7 years). BP was modeled both categorically (hypertensive: SBP 140+ mmHg, DBP 90+ mmHg, or antihypertensive medication use; pre-hypertensive: SBP 120-139 mmHg or DBP 80-89 mmHg; else normotensive) and continuously. Random-slope, random-intercept mixed models with an independent covariance structure tested the association between BP and SPPB score change, adjusted for age, sex, race-site, BMI, education, heart disease and heart failure. Continuous analysis also adjusted for antihypertensive medication use. Results: SPPB scores declined an average of 1.60 points per 10 years (95% CI: -1.75, -1.46; p Conclusions: Elevated BP in mid-life provides insight into the rate of physical function decline decades later, with higher mid-life systolic blood pressure corresponding with steeper declines in late-life physical function even in the absence of stroke. Future research should investigate whether elevated blood pressure at multiple points in mid-life further informs the association.

Background Both education and cardiovascular risk factors are strongly associated with dementia risk. However, it is not clear whether these associations persist or vary among individuals with high genetic risk for Alzheimer’s disease. We examined the interactive relationship between lifestyle and genetic dementia risk factors in a prospective cohort study. Methods Our data came from the Atherosclerosis Risk in Communities study participants (n = 13 715; baseline age 45–64; 25% Black; 55% female), who were followed for incident dementia from 1987 through 2017. We used Cox proportional hazard models to estimate the risk of dementia (ascertained through in-person examination, telephone cognitive screeners, and/or hospital and death records) associated with baseline education and cardiovascular risk factors (measured using the American Heart Association’s “Life Simple 7”) among ε4 carriers and non-carriers separately. We also examined differences by race and sex. Results Two thousand two hundred and twenty-six incident dementia cases occurred over a median 25 years of follow-up. Lower educational attainment and poorer cardiovascular health were associated with greater risk of incident dementia. There was an education by apolipoprotein E (APOE) status interaction (p = .005) whereby the association of education and dementia was weaker for ε4 carriers (HR college graduates vs less than high school: 0.71 [0.59–0.84] than non-carriers (0.54 [0.47–0.63]). There was no interaction between APOE status and cardiovascular health on dementia risk. These relationships did not vary significantly by race or sex. Conclusions Education and cardiovascular health were associated with lower dementia risk regardless of APOE genotype, though the protective effects of education were somewhat diminished among ε4 carriers.

Background Antiplatelets, anticoagulants, and statins are commonly prescribed for various indications. The associations between these medications and the risk of intracerebral hemorrhage (ICH) and cerebral microbleeds (CMBs) are unclear. Methods and Results We performed a retrospective study of the ARIC (Atherosclerosis Risk in Communities) study cohort, recruited from 4 US communities in 1987 to 1989 with follow‐up. In 2011 to 2013, a subset (N=1942) underwent brain magnetic resonance imaging with CMB evaluation. Time‐varying and any antiplatelet, anticoagulant, or statin use was evaluated at subsequent study visits in participants not on each medication at baseline. To determine the hazard of ICH and odds of CMB by medication use, logistic and Cox proportional hazard models were built, respectively, adjusting for the propensity to take the medication, concomitant use of other medications, and cognitive, genetic, and radiographic data. Of 15 719 individuals during up to 20 years of follow‐up, 130 participants experienced an ICH. The adjusted hazard of ICH was significantly lower among participants taking an antiplatelet at the most recent study visit before ICH versus nonusers (hazard ratio [HR], 0.53; 95% CI, 0.30–0.92). Statin users had a significantly lower hazard of an ICH compared with nonusers (adjusted HR, 0.13; 95% CI, 0.05–0.34). There was no association of CMB and antiplatelet, anticoagulant, or statin use in adjusted models. Conclusions In this US community‐based study, antiplatelet and statin use were associated with lower ICH hazard, whereas no association was noted between CMBs and antiplatelets, anticoagulants, and statins. Further study is needed to understand the differential roles of these medications in cerebral microhemorrhages and macrohemorrhages.

Introduction: Hemostasis depends on the delicate balance between coagulants and anticoagulants. Higher levels of circulating coagulants have been associated with higher risk of cerebral infarctions and dementia. In contrast, higher levels of circulating protein C, an endogenous anticoagulant, have been associated with lower risk of cerebral infarctions, and the association between protein C levels and the risk of dementia is unknown. The goal of this study was to evaluate the association of circulating protein C levels in midlife and late life with incident dementia. Methods: Circulating protein C levels were measured using blood samples collected at the midlife baseline (1987–1989) and the late-life baseline (2011–2013) among 14,462 and 3,614 participants, respectively, in the Atherosclerosis Risk in Communities study. Protein C levels were measured using enzyme-linked immunosorbent assay at midlife and a modified aptamer-based assay at late life. Participants were followed up to 2013 from midlife and up to 2017 from late life. Incident dementia was ascertained during the follow-up periods using in-person cognitive and functional assessment, informant interviews, and International Classification of Diseases codes at hospitalization discharge and on death certificates. Cause-specific Cox regression models were used to evaluate the association between quintiles of circulating protein C and incident dementia. Results: From midlife (mean age of 54), 1,389 incident dementia events were observed over a median follow-up of 23 years. From late life (mean age of 75), 353 incident dementia events were observed over a median follow-up of 4.9 years. At both midlife and late life, circulating protein C had an inverse association with incident dementia after adjusting for demographic, vascular, and hemostatic risk factors, incident stroke as time-dependent covariate, and incorporating stabilized weights based on propensity scores (quintile 5 vs. quintile 1 as the reference, midlife hazard ratio 0.80, 95% confidence interval 0.66–0.96, p value for trend 0.04; late-life hazard ratio 0.84, 95% confidence interval: 0.55–1.28, p value for trend 0.04). Discussion/Conclusion: Circulating protein C has an inverse association with incident dementia independent of established risk factors, including stroke. Our results suggest studying anticoagulants in addition to coagulants can increase our understanding on the relationship between hemostasis and dementia.

Background We examined the relationship of midlife cardiovascular health (CVH) with late-life robustness among men and women and the impact of survivorship bias on sex differences in robustness. Methods Prospective analysis of 15 744 participants aged 45–64 (visit 1 median age: 54 years, 55% female, 27% Black) in 1987–1989 from the population-based Atherosclerosis Risk in Communities Study. CVH was operationalized according to the Life’s Simple 7 (LS7) metric of health behaviors (smoking, weight, physical activity, diet, cholesterol, blood pressure, and glucose); each behavior was scored as ideal (2 points), intermediate (1 point), or poor (0 points) and summed. Late-life robust/prefrail/frailty was defined at visit 5 (2011–2013). Multinomial regression estimated relative prevalence ratios (RPRs) of late-life robustness/prefrailty/frailty/death across overall midlife LS7 score and components, for the full visit 1 sample. Separate analyses considered visit 5 survivors-only. Results For each 1-unit greater midlife LS7 score, participants had a 37% higher relative prevalence of being robust versus frail (overall RPR = 1.37 [95% confidence interval {CI}: 1.30–1.44]; women = 1.45 [1.36–1.54]; men = 1.24 [1.13–1.36]). Among the full visit 1 sample, women had a similar 1-level higher robustness category prevalence (RPR = 1.35 [95% CI: 1.32–1.39]) than men (RPR = 1.31 [95% CI: 1.27–1.35]) for every 1-unit higher midlife LS7 score. Among survivors, men were more likely to be robust than women at lower LS7 levels; differences were attenuated and not statistically different at higher midlife LS7 levels. Conclusions Midlife CVH is positively associated with robustness in late life among men and women. Accounting for mortality in part explains documented sex differences in robustness across all levels of LS7.

Background Sudden cardiac death (SCD) is associated with severe coronary heart disease in the great majority of cases. Whether carotid intima‐media thickness (C‐IMT), a known surrogate marker of subclinical atherosclerosis, is associated with risk of SCD in a general population remains unknown. The objective of this study was to investigate the association between C‐IMT and risk of SCD. Methods and Results We examined a total of 20 862 participants: 15 307 participants of the ARIC (Atherosclerosis Risk in Communities) study and 5555 participants of the CHS (Cardiovascular Health Study). C‐IMT and common carotid artery intima‐media thickness was measured at baseline by ultrasound. Presence of plaque was judged by trained readers. Over a median of 23.5 years of follow‐up, 569 participants had SCD (1.81 cases per 1000 person‐years) in the ARIC study. Mean C‐IMT and common carotid artery intima‐media thickness were associated with risk of SCD after adjustment for traditional risk factors and time‐varying adjustors: hazard ratios (HRs) with 95% CIs for fourth versus first quartile were 1.64 (1.15–2.63) and 1.49 (1.05–2.11), respectively. In CHS, 302 participants developed SCD (4.64 cases per 1000 person‐years) over 13.1 years. Maximum C‐IMT was associated with risk of SCD after adjustment: HR (95% CI) for fourth versus first quartile was 1.75 (1.22–2.51). Presence of plaque was associated with 35% increased risk of SCD: HR (95% CI) of 1.37 (1.13–1.67) in the ARIC study and 1.32 (1.04–1.68) in CHS. Conclusions C‐IMT was associated with risk of SCD in 2 biracial community‐based cohorts. C‐IMT may be used as a marker of SCD risk and potentially to initiate early therapeutic interventions to mitigate the risk.

Introduction: Cerebrovascular small vessel disease, seen on brain imaging as lacunes and white matter hyperintensities (WMH), is a substrate for dementia in older adults. Diffusion tensor imaging (DTI) is thought to provide early signs of loss of white matter (WM) integrity due to microvascular disease and predicts WM hyperintensity volume. Retinal fundus photography provides surrogate measures of cerebral microvasculature. No studies have quantified the long-term association between retinal signs and DTI measures. Hypothesis: Microvascular retinal signs measured in midlife are associated with small vessel disease measured on brain magnetic resonance imaging (MRI) 18 years later, including reduced WM microstructural integrity (lower fractional anisotrophy [FA] and greater mean diffusivity [MD] by DTI), greater WM hyperintensity volume and greater lacune prevalence. Methods: In a biracial prospective cohort study, retinal signs were measured using fundus photography (1993-1995) with 3-T magnetic resonance imaging conducted in 2011-13. Multivariable-adjusted linear regression was used to quantify the relationships of retinal signs with WM measures. Prevalence of lacunar infarcts by retinal sign status was estimated using log binomial regression. Analyses were adjusted for age [linear and quadratic terms], education, sex, race, intracranial volume, body mass index, smoking, diabetes, hypertension, and ≥1 APOE ε4 alleles. Results: In 1829 men and women (60% [N=1100] female, 27% [N=489] black race, aged 50-72 years when retinal signs were measured), a binary measure comprised of two retinal signs suggestive of arteriolar damage due to hypertension (focal arteriolar narrowing and/or arteriovenous nicking) was associated with worse (lower) FA (standardized β=-0.19, 95% confidence interval [CI]=-0.35, -0.02), worse (higher) MD (β=0.15, 95% CI=0.00, 0.30), greater WM hyperintensity volume (β=0.15, 95% CI=0.01, 0.30), and greater prevalence of lacunes (prevalence ratio=1.33, 95% CI: 0.99, 1.80). Generalized arteriolar narrowing, measured as the central retinal arteriolar equivalent (CRAE, narrowest quartile vs. widest three quartiles) was associated with worse FA (β=-0.13, 95% CI=-0.24, -0.01) and worse MD (β=0.12, 95% CI=0.01, 0.23). Results did not differ by sex, race, hypertension status or APOE ε4 genotype. No associations were found for retinopathy, but only 56 participants had retinopathy. Conclusions: Consistent with prior work, and as expected based on a common underlying pathology, retinal signs predicted WM disease and lacunar infarcts 18 years later. Novel to this study, we found that retinal signs related to arteriolar damage also predicted loss of white matter microvascular integrity measured using DTI.

Objective To review the literature systematically and perform meta-analyses to address these questions: 1) Is there evidence that self-measured blood pressure (BP) without other augmentation is superior to office-based measurement of BP for achieving better BP control or for preventing adverse clinical outcomes that are related to elevated BP? 2) What is the optimal target for BP lowering during antihypertensive therapy in adults? 3) In adults with hypertension, how do various antihypertensive drug classes differ in their benefits and harms compared with each other as first-line therapy? Methods Electronic literature searches were performed by Doctor Evidence, a global medical evidence software and services company, across PubMed and EMBASE from 1966 to 2015 using key words and relevant subject headings for randomized controlled trials that met eligibility criteria defined for each question. We performed analyses using traditional frequentist statistical and Bayesian approaches, including random-effects Bayesian network meta-analyses. Results Our results suggest that: 1) There is a modest but significant improvement in systolic BP in randomized controlled trials of self-measured BP versus usual care at 6 but not 12 months, and for selected patients and their providers self-measured BP may be a helpful adjunct to routine office care. 2) systolic BP lowering to a target of

Introduction We tested the hypothesis that poor sense of smell is associated with lower cognitive function and higher mild cognitive impairment (MCI) prevalence. Methods Olfaction, measured by the Sniffin' Sticks test, was categorized as olfactory impairment (OI) (score ≤6) or no OI (score >6). MCI was adjudicated based on review of a neuropsychological examination. Linear regression estimated the mean difference in cognitive factor scores, and log-binomial regression quantified MCI prevalence among participants with versus without OI. Results Participants with OI had lower mean factor scores (memory: −0.27 standard deviation [SD], 95% confidence interval [CI]: −0.35 to −0.19; language: −0.24 SD, 95% CI: −0.30 to −0.17; executive function/processing speed: −0.09 SD, 95% CI: −0.12 to −0.06; and general cognitive performance: −0.25 SD, 95% CI: −0.30 to −0.20). OI was also associated with MCI (n = 204; prevalence ratio = 1.56, 95% CI: 1.37, 1.78). Discussion An impaired sense of smell may serve as a readily accessible early marker of neurodegeneration and improve upon the prevailing delayed diagnoses and underascertainment of MCI/dementia.

OBJECTIVES: MRI has become an indispensable tool for brain volumetric studies, with the hippocampus an important region of interest. Automation of the MRI segmentation process has helped advance the field by facilitating the volumetric analysis of larger cohorts and more studies. FreeSurfer has emerged as the de facto standard tool for these analyses, but studies validating its output are all based on older versions. To characterize FreeSurfer’s validity, we compare several versions of FreeSurfer software with traditional hand-tracing. EXPERIMENTAL DESIGN: Using MRI images of 262 males and 402 females aged 38 to 84, we directly compare estimates of hippocampal volume from multiple versions of FreeSurfer, its hippocampal subfield routines, and our manual tracing protocol. We then use those estimates to assess asymmetry and atrophy, comparing performance of different estimators with each other and with brain atrophy measures. PRINCIPAL OBSERVATIONS: FreeSurfer consistently reports larger volumes than manual tracing. This difference is smaller in larger hippocampi or older people, with these biases weaker in version 6.0.0 than prior versions. All methods tested agree qualitatively on rightward asymmetry and increasing atrophy in older people. CONCLUSIONS: FreeSurfer saves time and money, and approximates the same atrophy measures as manual tracing, but it introduces biases that could require statistical adjustments in some studies.

Poor lung function has been linked with adverse neurocognitive outcomes including dementia, but evidence from well-designed prospective studies is limited. We therefore examined the association between lung function, as measured by forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), and dementia risk in 12,688 participants of the ARIC study, a prospective study of adults aged 46-70 years (at index visit, mean age =57y, 45% male, 76% White) from four US communities. Lung function was assessed in 1991-1992 (index visit, 76% normal, 16% obstructive, and 8% restrictive lung function), and dementia was ascertained through 2019 via in-person assessments, telephone interviews, and medical record surveillance, with adjudication of dementia with all in-person exams. A total of 2452 developed dementia over 30 years of follow-up. We used Cox proportional hazards model to estimate hazard ratio (HR) and 95% confidence intervals (CI), adjusting for potential confounders (socio-demographics, behavioral factors, cardiovascular risk factors, APOE ε4). Higher FEV1 and FVC were associated with reduced dementia risk [(HR: 0.86, 95%CI: 0.78-0.98, per 1L increase in FEV1) and (HR: 0.86, 95%CI: 0.80-0.93 per 1L increase in FVC)]. Compared to normal lung function, restrictive disease was associated with elevated dementia risk [(HR: 1.19, 95%CI: 1.01-1.41), n=168 dementia cases]; HR for obstructive disease, though modestly elevated (1.09, 95%CI: 0.96-1.24, n=713 dementia cases), was not statistically significant. Our findings of decreased dementia risk with better lung function may have important implications in reducing burden of dementia that is attributable to environmental exposures and associated lung function impairment.

Introduction The aim was to examine associations between midlife cardiovascular health (CVH) and 20-year cognitive decline among blacks and whites. Methods Midlife CVH metrics (American Heart Association's Life's Simple 7) were calculated and examined in relation to midlife and 20-year change in cognitive function among 13,270 whites and blacks from the Atherosclerosis Risk in Communities Cohort Study. We used linear mixed models to estimate adjusted associations of midlife CVH with midlife cognitive status and change. Results Higher midlife (Life's Simple 7) scores and individual metrics, particularly blood pressure and glucose, were associated with better midlife cognition and reduced 20-year decline. Midlife CVH 20-year neuroprotection was more pronounced among whites than blacks. Discussion Better midlife CVH was associated with higher midlife and reduced decline in cognitive function 20 years later. However, the benefits of midlife CVH on cognition were stronger for whites than for blacks. Our findings suggest that improved midlife CVH may promote enduring cognitive health.

AIM Osteoprotegerin (OPG) is associated with a poor prognosis in patients with heart failure with preserved ejection fraction (HFpEF). OPG has also been associated with fibrosis and collagen cross-linking, which increase arterial and left ventricle (LV) myocardial stiffness. Little is known about the relation of OPG and LV structure and function in African-Americans who are disproportionately affected by HFpEF. METHODS AND RESULTS Our analysis included 1172 participants with preserved LV ejection fraction (>50%) from the African-American cohort in the Genetic Epidemiology Network of Arteriopathy Study (mean age 63 years, 72% female). We used diastolic wall strain indicator measured by echocardiography to assess LV myocardial stiffness. Diastolic wall strain was calculated as (LV posterior thickness at end-systole - LV posterior thickness at end-diastole)/LV posterior thickness at end-systole. Associations between OPG levels and indices of arterial and LV structure and function were evaluated by using generalized linear mixed models and adjusted for possible confounders. OPG levels were correlated with age, female sex, presence of hypertension and diabetes, and lower estimated glomerular filtration rate (P

Background and Purpose— Cerebral microbleed (CMB) location (deep versus strictly lobar) may elucidate underlying pathology with deep CMBs being more associated with hypertensive vascular disease and lobar CMBs being more associated with cerebral amyloid angiopathy. The objective of this study was to determine whether neuroimaging signs of vascular disease and Alzheimer pathology are associated with different types of CMBs. Methods— Among 1677 nondemented ARIC (Atherosclerosis Risk in Communities) participants (mean age=76±5 years; 40% men; 26% black) with 3-Tesla MRI scans at the fifth examination (2011–2013), we fit multinomial logistic regression models to quantify relationships of brain volumes (Alzheimer disease signature regions, total gray matter, frontal gray matter, and white matter hyperintensity volumes), infarct frequencies (lacunar, nonlacunar, and total), and apolipoprotein E (number of ε4 alleles) with CMB location (none, deep/mixed, or strictly lobar CMBs). Models were weighted for the sample selection scheme and adjusted for age, sex, education, hypertension, ever smoking status, diabetes mellitus, race site membership, and estimated intracranial volume (brain volume models only). Results— Deep/mixed and strictly lobar CMBs had prevalences of 8% and 16%, respectively. Larger white matter hyperintensity burden, greater total infarct frequency, smaller frontal volumes (in women only), and smaller total gray matter volume were associated with greater risk of both deep and lobar CMBs relative to no CMBs. Greater white matter hyperintensity volume was also associated with greater risk of deep relative to lobar CMBs. Higher lacunar and nonlacunar infarct frequencies were associated with higher risk of deep CMBs, whereas smaller Alzheimer disease signature region volume and apolipoprotein E ε4 homozygosity were associated with greater risk of lobar CMBs. Conclusions— CMBs are a common vascular pathology in the elderly. Markers of hypertensive small-vessel disease may contribute to deep CMBs while cerebral amyloid angiopathy may drive development of lobar CMBs.