Hearing intervention versus health education control to reduce cognitive decline in older adults with hearing loss in the USA (ACHIEVE): a multicentre, randomised controlled trial.

BACKGROUND: Hearing loss is associated with increased cognitive decline and incident dementia in older adults. We aimed to investigate whether a hearing intervention could reduce cognitive decline in cognitively healthy older adults with hearing loss. METHODS: The ACHIEVE study is a multicentre, parallel-group, unmasked, randomised controlled trial of adults aged 70-84 years with untreated hearing loss and without substantial cognitive impairment that took place at four community study sites across the USA. Participants were recruited from two study populations at each site: (1) older adults participating in a long-standing observational study of cardiovascular health (Atherosclerosis Risk in Communities [ARIC] study), and (2) healthy de novo community volunteers. Participants were randomly assigned (1:1) to a hearing intervention (audiological counselling and provision of hearing aids) or a control intervention of health education (individual sessions with a health educator covering topics on chronic disease prevention) and followed up every 6 months. The primary endpoint was 3-year change in a global cognition standardised factor score from a comprehensive neurocognitive battery. Analysis was by intention to treat. This trial was registered at ClinicalTrials.gov, NCT03243422. FINDINGS: From Nov 9, 2017, to Oct 25, 2019, we screened 3004 participants for eligibility and randomly assigned 977 (32·5%; 238 [24%] from ARIC and 739 [76%] de novo). We randomly assigned 490 (50%) to the hearing intervention and 487 (50%) to the health education control. The cohort had a mean age of 76·8 years (SD 4·0), 523 (54%) were female, 454 (46%) were male, and most were White (n=858 [88%]). Participants from ARIC were older, had more risk factors for cognitive decline, and had lower baseline cognitive scores than those in the de novo cohort. In the primary analysis combining the ARIC and de novo cohorts, 3-year cognitive change (in SD units) was not significantly different between the hearing intervention and health education control groups (-0·200 [95% CI -0·256 to -0·144] in the hearing intervention group and -0·202 [-0·258 to -0·145] in the control group; difference 0·002 [-0·077 to 0·081]; p=0·96). However, a prespecified sensitivity analysis showed a significant difference in the effect of the hearing intervention on 3-year cognitive change between the ARIC and de novo cohorts (pinteraction=0·010). Other prespecified sensitivity analyses that varied analytical parameters used in the total cohort did not change the observed results. No significant adverse events attributed to the study were reported with either the hearing intervention or health education control. INTERPRETATION: The hearing intervention did not reduce 3-year cognitive decline in the primary analysis of the total cohort. However, a prespecified sensitivity analysis showed that the effect differed between the two study populations that comprised the cohort. These findings suggest that a hearing intervention might reduce cognitive change over 3 years in populations of older adults at increased risk for cognitive decline but not in populations at decreased risk for cognitive decline. FUNDING: US National Institutes of Health.

Educational Attainment and Dementia: Mediation by Mid-Life Vascular Risk Factors.

INTRODUCTION: Lower education is associated with higher burden of vascular risk factors in mid-life and higher risk of dementia in late life. We aim to understand the causal mechanism through which vascular risk factors potentially mediate the relationship between education and dementia. METHODS: In a cohort of 13,368 Black and White older adults in the Atherosclerosis Risk in Communities Study, we assessed the relationship between education (grade school, high school without graduation, high school graduate or equivalent, college, graduate/professional school) and dementia among all participants and among those with incident stroke. Cox models were adjusted for age, race-center (a variable stratified by race and field center), sex, apolipoprotein E (APOE) ε4 genotype, and family history of cardiovascular disease. Causal mediation models assessed mediation by mid-life systolic blood pressure, fasting blood glucose, body mass index, and smoking. RESULTS: More education was associated with 8 to 44% lower risk of dementia compared to grade school-level education in a dose-response pattern, while the relationship between education and post-stroke dementia was not statistically significant. Up to 25% of the association between education and dementia was mediated through mid-life vascular risk factors, with a smaller percentage mediated for lower levels of education. INTERPRETATION: A substantial proportion of the relationship between education and dementia was mediated through mid-life vascular risk factors. However, risk factor modification is unlikely to fully address the large educational disparities in dementia risk. Prevention efforts must also address disparities in socioeconomic resources leading to divergent early-life education and other structural determinants of mid-life vascular risk factors. ANN NEUROL 2023;94:13-26.

A Novel Creatinine Muscle Index Based on Creatinine Filtration: Associations with Frailty and Mortality.

SIGNIFICANCE STATEMENT: Low muscle mass is related to frailty and increased mortality in older adults. However, muscle mass is not easily assessed in routine clinical practice. This paper describes a novel creatinine muscle index (CMI) on the basis of serum creatinine and cystatin C. CMI was moderately associated with frailty among older adults. A significantly higher proportion of individuals with weak grip strength were in the lowest tertile of CMI. The index was also associated with mortality. These results are consistent with the hypothesis that creatinine filtration may be an index of muscle mass, which may have utility in clinical practice. BACKGROUND: Low muscle mass is related to frailty and increased mortality in older adults. However, muscle mass is not easily assessed in routine clinical practice. METHODS: This study describes a novel creatinine muscle index (CMI) on the basis of serum creatinine and cystatin C in a community-based sample of older adults from the Atherosclerosis Risk in Communities Study. Analyses included 4639 participants who attended visit 5 (2011-2013) and 12,786 participants who attended visit 2 (1990-1992). CMI was defined as creatinine filtration (the product of serum creatinine times eGFR on the basis of cystatin C) and was analyzed in sex-specific tertiles. Cross-sectional associations of CMI with a frailty trichotomy, defined by the number (robust [0]/prefrail [1-2]/frail [3-5]) of five frailty components (weight loss, slowness, exhaustion, weakness, and low physical activity), were studied using polychotomous logistic regression and binary logistic regression with each frailty component. Cox regression was used to estimate associations of CMI at visit 5 and visit 2 with mortality. Models were adjusted for demographics, clinical variables, and comorbid conditions. RESULTS: CMI (tertile 1 versus 3) was moderately associated with frailty (visit 5: adjusted odds ratio 4.23 [95% confidence interval (CI), 2.02 to 8.87] in men and 2.34 [95% CI, 1.41 to 3.89] in women) and with mortality (visit 5: adjusted hazard ratio 1.45 [95% CI, 1.08 to 1.94] in men and 1.55 [95% CI, 1.13 to 2.12] in women; similar results were seen at visit 2). CONCLUSION: Lower CMI was associated with frailty and increased mortality, two clinical outcomes known to be associated with decreased muscle mass. Creatinine filtration may be an index of muscle mass and have utility in clinical practice, particularly at low levels.

Patterns of cognitive domain abnormalities enhance discrimination of dementia risk prediction: The ARIC study.

INTRODUCTION: The contribution of neuropsychological assessments to risk assessment for incident dementia is underappreciated. METHODS: We analyzed neuropsychological testing results in dementia-free participants in the Atherosclerosis Risk in Communities (ARIC) study. We examined associations of index domain-specific neuropsychological test performance with incident dementia using cumulative incidence curves and Cox proportional hazards models. RESULTS: Among 5296 initially dementia-free participants (mean [standard deviation] age of 75.8 [5.1] years; 60.1% women, 22.2% Black) over a median follow-up of 7.9 years, the covariate-adjusted hazard ratio varied substantially depending on the pattern of domain-specific performance and age, in an orderly manner from single domain language abnormalities (lowest risk) to single domain executive or memory abnormalities, to multidomain abnormalities including memory (highest risk). DISCUSSION: By identifying normatively defined cognitive abnormalities by domains based on neuropsychological test performance, there is a conceptually orderly and age-sensitive spectrum of risk for incident dementia that provides valuable information about the likelihood of progression. HIGHLIGHTS: Domain-specific cognitive profiles carry enhanced prognostic value compared to mild cognitive impairment. Single-domain non-amnestic cognitive abnormalities have the most favorable prognosis. Multidomain amnestic abnormalities have the greatest risk for incident dementia. Patterns of domain-specific risks are similar by sex and race.

Vascular risk, gait, behavioral, and plasma indicators of VCID.

INTRODUCTION: Cost-effective screening tools for vascular contributions to cognitive impairment and dementia (VCID) has significant implications. We evaluated non-imaging indicators of VCID using magnetic resonance imaging (MRI)-measured white matter (WM) damage and hypothesized that these indicators differ based on age. METHODS: In 745 participants from the Mayo Clinic Study of Aging (≥50 years of age) with serial WM assessments from diffusion MRI and fluid-attenuated inversion recovery (FLAIR)-MRI, we examined associations between baseline non-imaging indicators (demographics, vascular risk factors [VRFs], gait, behavioral, plasma glial fibrillary acidic protein [GFAP], and plasma neurofilament light chain [NfL]) and WM damage across three age tertiles. RESULTS: VRFs and gait were associated with diffusion changes even in low age strata. All measures (VRFs, gait, behavioral, plasma GFAP, plasma NfL) were associated with white matter hyperintensities (WMHs) but mainly in intermediate and high age strata. DISCUSSION: Non-imaging indicators of VCID were related to WM damage and may aid in screening participants and assessing outcomes for VCID. HIGHLIGHTS: Non-imaging indicators of VCID can aid in prediction of MRI-measured WM damage but their importance differed by age. Vascular risk and gait measures were associated with early VCID changes measured using diffusion MRI. Plasma markers explained variability in WMH across age strata. Most non-imaging measures explained variability in WMH and vascular WM scores in intermediate and older age groups. The framework developed here can be used to evaluate new non-imaging VCID indicators proposed in the future.

Peripheral Neuropathy and Vision and Hearing Impairment in US Adults With and Without Diabetes.

We aimed to assess the associations of peripheral neuropathy (PN) with vision and hearing impairment among adults aged ≥40 years who attended the lower-extremity disease exam for the National Health and Nutrition Examination Survey (United States, 1999-2004). Overall, 11.8% (standard error (SE), 0.5) of adults had diabetes, 13.2% (SE, 0.5) had PN (26.6% (SE, 1.4) with diabetes, 11.4% (SE, 0.5) without diabetes), 1.6% (SE, 0.1) had vision impairment, and 15.4% (SE, 1.1) had hearing impairment. The prevalence of vision impairment was 3.89% (95% CI: 2.99, 5.05) among adults with PN and 1.29% (95% CI: 1.04, 1.60) among adults without PN (P < 0.001). After adjustment, PN was associated with vision impairment overall (odds ratio (OR) = 1.48, 95% confidence interval (CI): 1.03, 2.13) and among adults without diabetes (OR = 1.80, 95% CI: 1.17, 2.77) but not among adults with diabetes (P for interaction = 0.018). The prevalence of hearing impairment was 26.5% (95% CI: 20.4, 33.7) among adults with PN and 14.2% (95% CI: 12.4, 16.3) among adults without PN (P < 0.001). The association of PN with moderate/severe hearing impairment was significant overall (OR = 2.55, 95% CI: 1.40, 4.64) and among adults without diabetes (OR = 3.26, 95% CI: 1.80, 5.91). Overall, these findings suggest an association between peripheral and audiovisual sensory impairment that is unrelated to diabetes.

Association of Lung Function With Cognitive Decline and Incident Dementia in the Atherosclerosis Risk in Communities Study.

We examined the associations between lung function and incident dementia and cognitive decline in 12,688 participants in the ARIC Study who provided lung function measurements in 1990-1992. Cognitive tests were administered up to 7 times, and dementia was ascertained through 2019. We used shared parameter models to jointly fit proportional hazard models and linear mixed-effect models to estimate lung-function-associated dementia rate and cognitive change, respectively. Higher forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were associated with reduced dementia (n = 2,452 persons developed dementia); hazard ratios per 1-L increase in FEV1 and FVC were 0.79 (95% confidence interval (CI): 0.71, 0.89) and 0.81 (95% CI: 0.74, 0.89), respectively. Each 1-L increase in FEV1 and FVC was associated with a 0.08-standard deviation (SD) (95% CI: 0.05, 0.12) and a 0.05-SD (95% CI: 0.02, 0.07) attenuation of 30-year cognitive decline, respectively. A 1% increase in FEV1/FVC ratio was associated with 0.008-SD (95% CI: 0.004, 0.012) less cognitive decline. We observed statistical interaction between FEV1 and FVC, suggesting that cognitive declines depended on values of specific FEV1 and FVC (as compared with FEV1, FVC, or FEV1/FVC ratio models that suggested linear incremental associations). Our findings may have important implications for reducing the burden of cognitive decline that is attributable to environmental exposures and associated lung function impairment.

Dementia occurring over a 32-year follow-up attributable to hypertension observed at different ages: Implications for dementia prevention.

INTRODUCTION: The fraction of dementia attributable to hypertension might vary depending on the age of the population considered and the age through which dementia occurs. METHODS: In the Atherosclerosis Risk in Communities study, we quantified population attributable fractions (PAF) of dementia by age 80 and 90 from hypertension assessed at ages of 45-54 (n = 7572), 55-64 (n = 12,033), 65-74 (n = 6561), and 75-84 (n = 2086). RESULTS: The PAF for dementia by age 80 from all non-normal blood pressure at ages 45-54 was 15.3% (95% confidence interval [CI] = 6.9%-22.3%), 19.1% (95% CI = 9.9%-26.9%) at ages 55-64, and 19.9% (95% CI = -4.4%-38.5%) at ages 65-74. The strongest PAFs were from stage 2 hypertension (11.9%-21.3%). For dementia by age 90, PAFs from non-normal blood pressure up through age 75 were smaller (10.9%-13.8%), and non-significant by age 75-84. DISCUSSION: Interventions targeting hypertension even in early late life might reduce a sizeable proportion of dementia. HIGHLIGHTS: We estimated prospective population attributable risks of dementia for hypertension. 15%-20% of dementia cases by age 80 are from non-normal blood pressure (BP). Associations between hypertension and dementia persisted through age 75. Midlife to early late-life BP control might reduce a large proportion of dementia.

The association of perceived discrimination with dementia risk in Black older adults.

INTRODUCTION: Non-Hispanic Black, compared to non-Hispanic White, older adults are at increased risk for dementia. This may be due partly to greater exposure to psychosocial stressors, such as discrimination; however, few studies have examined this association. METHODS: We examined the association of perceived discrimination (e.g., everyday, lifetime, and discrimination burden) with dementia risk in 1583 Black adults co-enrolled in the Atherosclerosis Risk in Communities (ARIC) Study and the Jackson Heart Study (JHS). Perceived discrimination (defined continuously and using tertiles) was assessed at JHS Exam 1 (2000-2004; mean age ± SD:66.2 ± 5.5) and related to dementia risk through ARIC visit 6 (2017) using covariate-adjusted Cox proportional hazards models. RESULTS: Associations of perceived everyday, lifetime, and burden of discrimination with dementia risk were not supported in age-adjusted models or demographic- and cardiovascular health-adjusted models. Results were similar across sex, income, and education. DISCUSSION: In this sample, associations between perceived discrimination and dementia risk were not supported. HIGHLIGHTS: In Black older adults perceived discrimination not associated with dementia risk. Younger age and greater education linked to greater perceived discrimination. Older age and less education among factors associated with dementia risk. Factors increasing exposure to discrimination (education) are also neuroprotective.

Associations of Peripheral Neuropathy Defined by Monofilament Insensitivity with Mild Cognitive Impairment and Dementia in Older Adults.

INTRODUCTION: The aim of this study was to assess the association of peripheral neuropathy (PN) as defined by monofilament insensitivity with mild cognitive impairment (MCI) and dementia in older adults with and without diabetes. METHODS: We conducted a cross-sectional analysis of 3,362 Black and White participants in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) who underwent monofilament testing at visit 6 (2016-2017, age 71-94 years). Participants' cognitive status was classified by an adjudication committee as cognitively normal, MCI, or dementia after completing a comprehensive battery of neurocognitive assessments. We used logistic regression to evaluate the association of PN with MCI or dementia overall and stratified by diabetes status after adjusting for traditional dementia risk factors. We also compared age-adjusted brain MRI measures among a subset (N = 1,095) of participants with versus without PN. RESULTS: Overall, the prevalence of MCI (21.9% vs. 16.7%) and dementia (7.8% vs. 3.9%) were higher among participants with versus without PN (both p < 0.05). After adjustment, PN was positively associated with MCI or dementia in the overall study population (OR 1.45, 95% CI 1.23, 1.73). Results were similar by diabetes status (diabetes: OR 1.38, 95% CI 1.03-1.87; no diabetes: OR 1.48, 95% CI 1.20-1.83; p-for-interaction = 0.46). Age-adjusted total and lobar brain volumes were significantly lower in participants with versus without PN (both, p < 0.05). DISCUSSION/CONCLUSIONS: PN as defined by monofilament insensitivity was associated with cognitive status independent of vascular risk factors and regardless of diabetes status. Our findings support a connection between PN and cognitive impairment, even in the absence of diabetes.

Peripheral Neuropathy and All-Cause and Cardiovascular Mortality in U.S. Adults : A Prospective Cohort Study.

BACKGROUND: Growing evidence indicates that peripheral neuropathy (PN) is common even in the absence of diabetes. However, the clinical sequelae of PN have not been quantified in the general population. OBJECTIVE: To assess the associations of PN with all-cause and cardiovascular mortality in the general adult population of the United States. DESIGN: Prospective cohort study. SETTING: NHANES (National Health and Nutrition Examination Survey), 1999 to 2004. PARTICIPANTS: 7116 adults aged 40 years or older who had standardized monofilament testing for PN. MEASUREMENTS: Cox regression to evaluate the associations of PN with all-cause and cardiovascular mortality after adjustment for demographic and cardiovascular risk factors, overall and stratified by diabetes status. RESULTS: The overall prevalence of PN (±SE) was 13.5% ± 0.5% (27.0% ± 1.4% in adults with diabetes and 11.6% ± 0.5% in adults without diabetes). During a median follow-up of 13 years, 2128 participants died, including 488 of cardiovascular causes. Incidence rates (per 1000 person-years) of all-cause mortality were 57.6 (95% CI, 48.4 to 68.7) in adults with diabetes and PN, 34.3 (CI, 30.3 to 38.8) in adults with PN but no diabetes, 27.1 (CI, 23.4 to 31.5) in adults with diabetes but no PN, and 13.0 (CI, 12.1 to 14.0) in adults with no diabetes and no PN. In adjusted models, PN was significantly associated with all-cause mortality (hazard ratio [HR], 1.49 [CI, 1.15 to 1.94]) and cardiovascular mortality (HR, 1.66 [CI, 1.07 to 2.57]) in participants with diabetes. In those without diabetes, PN was significantly associated with all-cause mortality (HR, 1.31 [CI, 1.15 to 1.50]), but the association between PN and cardiovascular mortality was not statistically significant after adjustment (HR, 1.27 [CI, 0.98 to 1.66]). LIMITATION: Prevalent cardiovascular disease was self-reported, and PN was defined by monofilament testing only. CONCLUSION: Peripheral neuropathy was common and was independently associated with mortality in the U.S. population, even in the absence of diabetes. These findings suggest that decreased sensation in the foot may be an underrecognized risk factor for death in the general population. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute of the National Institutes of Health.

The association of motoric cognitive risk with incident dementia and neuroimaging characteristics: The Atherosclerosis Risk in Communities Study.

INTRODUCTION: Motoric cognitive risk (MCR), a clinical syndrome characterized by slow gait speed and subjective cognitive complaints, has been associated with dementia risk. The neuropathological features underlying MCR remain poorly understood. METHODS: The Atherosclerosis Risk in Communities (ARIC) community-based cohort study classified participants using standardized criteria as MCR+/- and mild cognitive impairment (MCI)+/- at study baseline (2011-2013). We examined the 5-year dementia risk and baseline brain structural/molecular abnormalities associated with MCR+ and MCI+ status. RESULTS: Of 5023 nondemented participants included, 204 were MCR+ and 1030 were MCI+. Both MCR+ and MCI+ participants demonstrated increased dementia risk. The pattern of structural brain abnormalities associated with MCR+ differed from that of MCI+. Whereas MCI+ was associated with comparatively smaller volumes in brain regions vulnerable to Alzheimer's disease pathology, MCR+ status was associated with smaller volumes in frontoparietal regions and greater white matter abnormalities. DISCUSSION: MCR may represent a predementia syndrome characterized by prominent white matter abnormalities and frontoparietal atrophy.

Subclinical Vascular Disease Burden and Premature Mortality Among Middle-aged Adults: the Atherosclerosis Risk in Communities Study.

BACKGROUND: Whether high burden of subclinical vascular disease (SVD) is associated with increased premature mortality among middle-aged adults is not adequately understood. The association of midlife SVD burden with premature mortality among middle-aged adults free of clinical cardiovascular disease (CVD) could provide further insights into stratifying premature death beyond clinical CVD. OBJECTIVE: To determine whether high burden of subclinical vascular disease is associated with increased premature mortality among middle-aged adults. DESIGN: We leveraged data from the Atherosclerosis Risk in Communities Study. PARTICIPANTS: Thirteen thousand eight hundred seventy-six community-dwelling blacks and whites aged 45-64 years from the Atherosclerosis Risk in Communities Study. MAIN MEASURES: Each SVD measure-ankle-brachial index, carotid intima-media thickness, and electrocardiogram-was scored 0 (no abnormalities), 1 (minor abnormalities), or 2 (major abnormalities). An index was constructed as the sum of three measures, ranging from 0 (lowest burden) to 6 (highest burden). We used the Cox proportional-hazards model to determine the association of SVD burden with premature mortality (death before age 70) among persons free of clinical CVD. We then tested the difference in point estimates between SVD and clinical CVD. KEY RESULTS: Among persons without CVD, the premature death was 1.7, 2.1, 2.5, and 3.8 per 1000 person-years among those with an SVD score of 0 (lowest burden), 1, 2, and 3-6 (highest burden), respectively. After multivariable-adjustment, highest SVD burden (score = 3-6; HR = 1.47) was significantly associated with premature death among persons initially without CVD. In the model where persons with and without CVD were included, high SVD burden (score: 3-6 vs. 0) and CVD did not have hugely different association with premature death (HR = 1.49 vs. 1.68; P = 0.32 for comparison). CONCLUSIONS: Midlife SVD burden was associated with premature mortality and it could stratify premature death beyond clinical CVD. It is important to take SVD into account when designing interventions for reducing premature mortality.

Association between Circulating Protein C Levels and Incident Dementia: The Atherosclerosis Risk in Communities Study.

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.

Microvascular Brain Disease Progression and Risk of Stroke: The ARIC Study.

BACKGROUND AND PURPOSE: Data on the significance of combined white matter hyperintensities (WMH)/lacunar brain infarcts, and their progression over time for the prediction of stroke are scarce. We studied associations between the progression in combined measures of microvascular brain disease and risk of stroke in the ARIC study (Atherosclerosis Risk in Communities). METHODS: Prospective analysis of 907 stroke-free ARIC participants who underwent a brain magnetic resonance imaging (MRI) in 1993 to 1995, a second brain MRI in 2004 to 2006, and were subsequently followed for stroke incidence through December 31, 2017 (median [25%-75%] follow-up 12.6 [8.9-13.4] years). A combined measure of microvascular brain disease was defined at each visit and categorized by progression from first to second brain MRI as no progression; mild progression (increase of ≥1 unit in WMH grade or new lacune), and moderate progression (increase of ≥1 unit in WMH grade and new lacune). All definite/probable ischemic or hemorrhagic incident strokes occurring after this second MRI, and through 2017, were included. Associations between microvascular brain disease, progression in the combined measures, and stroke incidence were studied with Cox proportional hazard models, adjusting for age, sex, race, education level, time from first to second MRI, body mass index, smoking, hypertension, diabetes mellitus, and coronary heart disease. RESULTS: At the second brain MRI (mean age 72), the distribution of the combined measure was 37% WMH grade <2 and no lacune; 57% WMH grade ≥2 or lacune; and 6% WMH grade ≥2 and lacune. No progression in the combined measures was observed in 38% of participants, 57% showed mild progression and 5% showed moderate progression. Sixty-four incident strokes occurred during the follow-up period. Compared with no change in the combined measure, moderate progression of microvascular brain disease was significantly associated with higher risk of stroke (adjusted hazard ratio, 3.00 [95% CI, 1.30-6.94]). CONCLUSIONS: Progression of microvascular brain disease, manifesting as both new lacunes and increase in WMHs grade, is related to substantial increase in long-term risk of stroke.

Associations of Cardiac, Kidney, and Diabetes Biomarkers With Peripheral Neuropathy among Older Adults in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: The aim of this study was to assess the association of high-sensitivity cardiac troponin (hs-cTnT) and other cardiac, kidney, hyperglycemia, and inflammatory biomarkers with peripheral neuropathy (PN) in a community-based population. METHODS: We conducted a cross-sectional analysis of 3056 black and white participants in the Atherosclerosis Risk in Communities (ARIC) study who underwent standardized monofilament PN testing and had measures of cardiac function (hs-cTnT, N-terminal pro-B-type natriuretic peptide [NT-proBNP], and growth differentiation factor 15 [GDF15]), kidney function (serum creatinine, cystatin C, ß-2 microglobulin, urine albumin-to-creatinine ratio), hyperglycemia (fasting glucose, hemoglobin A1c [Hb A1c], fructosamine, glycated albumin, 1,5-anhydroglucitol), and inflammation (C-reactive protein) assessed at visit 6 (2016-2017; age 71-94 years). We used logistic regression to assess the associations of these biomarkers (modeled in diabetes-specific tertiles) with PN in older adults with and without diabetes after adjusting for traditional risk factors. RESULTS: In total, 33.5% of participants had PN (37.3% with diabetes and 31.9% without diabetes). There was an independent association of hs-cTnT with PN regardless of diabetes status (diabetes T3 vs. T1: odds ratio [OR], 2.15 [95% CI, 1.44-3.22]; no diabetes: OR, 2.31 [95%CI, 1.76-3.03]; P = 0.72 for interaction). Among participants without diabetes, there were also significant associations of NT-proBNP (OR, 1.40 [95% CI, 1.08-1.81]) and urine albumin-to-creatinine ratio (OR, 1.55 [95% CI, 1.22-1.97]) with PN. Associations of hyperglycemia biomarkers including Hb A1c (OR, 1.76 [95% CI, 1.22-2.54]), fructosamine (OR, 1.71 [95% CI, 1.19-2.46]), and glycated albumin (OR, 1.45 [95% CI, 1.03-2.03]) with PN were significant only among participants with diabetes. CONCLUSIONS: Overall, hs-cTnT appears to be a global marker of end organ damage, including PN. Laboratory biomarkers may be able to help us identify those individuals with PN.

Chronic Systemic Inflammation Is Associated With Symptoms of Late-Life Depression: The ARIC Study.

OBJECTIVE: The current study examined how the pattern of systemic inflammation in the decades leading up to late-life relates to depression symptoms in older adults. METHODS: Within the Atherosclerosis Risk in Communities Study, we measured high-sensitivity C-reactive protein (CRP), a nonspecific marker of systemic inflammation, at three visits: 21 years and 14 years before, and concurrent with the assessment of depression symptoms, defined using the 11-item Center for Epidemiologic Studies Depression (CESD) scale. We categorized participants into one of four groups based on their 21-year longitudinal pattern of elevated (≥3 mg/L) versus low (<3 mg/L) CRP (stable low; unstable low; unstable elevated; stable elevated). Analyses excluded participants with suspected depression during midlife. RESULTS: A total of 4,614 participants were included (age at CESD assessment: 75.5 [SD: 5.1]; 59% female; follow-up time: 20.7 years [SD: 1.0]). Compared to participants who maintained low CRP levels (stable low), participants who had elevated CRP at two of three visits (unstable elevated; ß = 0.09; 95% confidence interval [CI]: 0.02, 0.17) and participants who maintained elevated CRP at all three visits (stable elevated; ß = 0.13; 95% CI: 0.05, 0.21) had greater depression symptoms as older adults, after adjusting for confounders. After excluding participants with late-life cognitive impairment, only participants with stable elevated CRP demonstrated significantly greater late-life depression symptoms. In a secondary analysis, stable elevated CRP was associated with increased risk for clinically significant late-life depression symptoms. CONCLUSION: Chronic or repeated inflammation in the decades leading up to older adulthood is associated with late-life depression, even in the context of normal cognition.

Midlife Smaller and Larger Infarctions, White Matter Hyperintensities, and 20-Year Cognitive Decline: A Cohort Study.

Background: Smaller (<3-mm) infarctions are associated with stroke and stroke mortality, but relationships with cognitive decline are unknown. Objective: To characterize the relationships of smaller, larger, and both smaller and larger infarctions in middle age with 20-year cognitive decline. Design: Longitudinal cohort study. Setting: Two ARIC (Atherosclerosis Risk in Communities) study sites with magnetic resonance imaging data (1993 to 1995) and up to 5 cognitive assessments over 20 years. Participants: Stroke-free participants aged 50 years or older. Measurements: Infarctions were categorized as none, smaller only, larger only (3 to 20 mm), or both smaller and larger. Global cognitive Z scores were derived from 3 cognitive tests administered up to 5 times. Mixed-effects models estimated adjusted associations between infarctions and cognitive decline. Results are the average difference in standardized cognitive decline associated with infarctions versus no infarctions. Results: Among 1884 participants (mean age, 62 years; 60% women; 50% black), 1611 (86%) had no infarctions, 50 (3%) had smaller infarctions only, 185 (10%) had larger infarctions only, and 35 (2%) had both. Participants with both smaller and larger infarctions had steeper cognitive decline by more than half an SD (difference, -0.57 SD [95% CI, -0.89 to -0.26 SD]) compared with those who had no infarctions. Amounts of cognitive decline associated with only smaller infarctions and only larger infarctions were similar and were not statistically different from that associated with no infarctions. Limitation: Few participants had only smaller infarctions or both smaller and larger infarctions, and the data lacked counts of smaller infarctions and volumes of white matter hyperintensities. Conclusion: The substantial cognitive decline from middle age associated with having both smaller and larger infarctions, but not larger infarctions alone, suggests that the combination of smaller and larger infarctions may escalate risk for cognitive decline later in life in stroke-free persons. Primary Funding Source: National Institutes of Health.

Physical activity trajectories and subsequent fall risk: ARIC Study.

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.

Association of Midlife to Late-Life Blood Pressure Patterns With Incident Dementia.

Importance: The association between late-life blood pressure (BP) and cognition may depend on the presence and chronicity of past hypertension. Late-life declines in blood pressure following prolonged hypertension may be associated with poor cognitive outcomes. Objective: To examine the association of midlife to late-life BP patterns with subsequent dementia, mild cognitive impairment, and cognitive decline. Design, Setting, and Participants: The Atherosclerosis Risk in Communities prospective population-based cohort study enrolled 4761 participants during midlife (visit 1, 1987-1989) and followed-up over 6 visits through 2016-2017 (visit 6). BP was examined over 24 years at 5 in-person visits between visits 1 and 5 (2011-2013). During visits 5 and 6, participants underwent detailed neurocognitive evaluation. The setting was 4 US communities: Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis, Minnesota. Follow-up ended on December 31, 2017. Exposures: Five groups based on longitudinal patterns of normotension, hypertension (>140/90 mm Hg), and hypotension (<90/60 mm Hg) at visits 1 to 5. Main Outcomes and Measures: Primary outcome was dementia onset after visit 5, based on Ascertain Dementia-8 informant questionnaires, Six-Item Screener telephone assessments, hospital discharge and death certificate codes, and the visit 6 neurocognitive evaluation. Secondary outcome was mild cognitive impairment at visit 6, based on the neurocognitive evaluation. Results: Among 4761 participants (2821 [59%] women; 979 [21%] black race; visit 5 mean [SD] age, 75 [5] years; visit 1 mean age range, 44-66 years; visit 5 mean age range, 66-90 years), there were 516 (11%) incident dementia cases between visits 5 and 6. The dementia incidence rate for participants with normotension in midlife (n = 833) and late life was 1.31 (95% CI, 1.00-1.72 per 100 person-years); for midlife normotension and late-life hypertension (n = 1559), 1.99 (95% CI, 1.69-2.32 per 100 person-years); for midlife and late-life hypertension (n = 1030), 2.83 (95% CI, 2.40-3.35 per 100 person-years); for midlife normotension and late-life hypotension (n = 927), 2.07 (95% CI, 1.68-2.54 per 100 person-years); and for midlife hypertension and late-life hypotension (n = 389), 4.26 (95% CI, 3.40-5.32 per 100 person-years). Participants in the midlife and late-life hypertension group (hazard ratio [HR], 1.49 [95% CI, 1.06-2.08]) and in the midlife hypertension and late-life hypotension group (HR, 1.62 [95% CI, 1.11-2.37]) had significantly increased risk of subsequent dementia compared with those who remained normotensive. Irrespective of late-life BP, sustained hypertension in midlife was associated with dementia risk (HR, 1.41 [95% CI, 1.17-1.71]). Compared with those who were normotensive in midlife and late life, only participants with midlife hypertension and late-life hypotension had higher risk of mild cognitive impairment (37 affected individuals (odds ratio, 1.65 [95% CI, 1.01-2.69]). There was no significant association of BP patterns with late-life cognitive change. Conclusions and Relevance: In this community-based cohort with long-term follow-up, sustained hypertension in midlife to late life and a pattern of midlife hypertension and late-life hypotension, compared with midlife and late-life normal BP, were associated with increased risk for subsequent dementia.