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Background: Studies of the neurovascular contribution to dementia have largely focused on cerebral small vessel disease (CSVD), but the role of intracranial atherosclerotic disease (ICAD) remains unknown in the general population. The objective of this study was to determine the risk of incident dementia from ICAD after adjusting for CSVD and cardiovascular risk factors in a US community-based cohort., Methods: We acquired brain magnetic resonance imaging examinations from 2011 through 2013 in 1980 Black and White participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective cohort conducted in 4 US communities. Magnetic resonance imaging examinations included high-resolution vessel wall magnetic resonance imaging and magnetic resonance angiography to identify ICAD. Of these participants, 1590 without dementia, without missing covariates, and with adequate magnetic resonance image quality were followed through 2019 for incident dementia. Associations between ICAD and incident dementia were assessed using Cox proportional hazard ratios adjusted for CSVD (characterized by white matter hyperintensities, lacunar infarctions, and microhemorrhages), APOE4 genotype (apolipoprotein E gene ε4), and cardiovascular risk factors., Results: The mean age (SD) of study participants was 77.4 (5.2) years. ICAD was detected in 34.6% of participants. After a median follow-up of 5.6 years, 286 participants developed dementia. Compared with participants without ICAD, the fully adjusted hazard ratios (95% CIs) for incident dementia in participants with any ICAD, with ICAD only causing stenosis ≤50%, and with ICAD causing stenosis >50% in ≥1 vessel were 1.57 (1.17-2.11), 1.41 (1.02-1.95), and 1.94 (1.32-2.84), respectively. ICAD was associated with dementia even among participants with low white matter hyperintensities burden, a marker of CSVD., Conclusions: ICAD was associated with an increased risk of incident dementia, independent of CSVD, APOE4 genotype, and cardiovascular risk factors. The increased risk of dementia was evident even among participants with low CSVD burden, a group less likely to be affected by vascular dementia, and in participants with ICAD causing only low-grade stenosis. Our results suggest that ICAD may partially mediate the effect that cardiovascular risk factors have on the brain leading to dementia. Both ICAD and CSVD must be considered to understand the vascular contributions to cognitive decline., Competing Interests: None.

ARIC (Atherosclerosis Risk In Communities) initiated community-based surveillance in 1987 for myocardial infarction and coronary heart disease (CHD) incidence and mortality and created a prospective cohort of 15,792 Black and White adults ages 45 to 64 years. The primary aims were to improve understanding of the decline in CHD mortality and identify determinants of subclinical atherosclerosis and CHD in Black and White middle-age adults. ARIC has examined areas including health disparities, genomics, heart failure, and prevention, producing more than 2,300 publications. Results have had strong clinical impact and demonstrate the importance of population-based research in the spectrum of biomedical research to improve health., Competing Interests: Funding Support and Author Disclosures The ARIC study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under contract nos. HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I. Neurocognitive data are collected by U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, and 2U01HL096917 from the National Institutes of Health (National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; National Institute on Aging; and National Institute on Deafness and Other Communication Disorders) and with previous brain magnetic resonance imaging examinations funded by R01-HL70825 and biomarkers by R01-HL134320 from the National Heart, Lung, and Blood Institute. Dr. Coresh has received investigator-initiated grant support from the National Institutes of Health and National Kidney Foundation (the National Kidney Foundation received research support from industry) and has served as a scientific advisor to Healthy.io and Alike. Dr. Ballantyne has received significant (>$10,000) grant/research support (all paid to institution, not individual) from Abbott Diagnostic, Akcea, Amgen, Esperion, Novartis, Regeneron, Roche Diagnostic, the National Institutes of Health, the American Heart Association, and American Diabetes Association; and has served as a consultant for Abbott Diagnostics, Akcea, Althera, Amarin (significant), Amgen, Arrowhead, AstraZeneca, Corvidia, Denka Seiken (significant), Esperion, Gilead, Janssen, Matinas BioPharma Inc., New Amsterdam (significant), Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostic, and Sanofi-Synthelabo (significant). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier Inc.)

Objective: To determine changes in the incidence of dementia between 1988 and 2015., Methods: This analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex., Results: Of 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person-years in individuals aged 65-69 years to 65 per 1,000 person-years for those aged 85-89 years. The incidence rate of dementia declined by 13% per calendar decade (95% confidence interval [CI], 7%-19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%-32%] vs 8% [0%-15%])., Conclusion: The incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Aims: Systolic time intervals change in the progress of cardiac dysfunction. The usefulness of left ventricular ejection time (LVET) to predict cardiovascular morbidity, however, is unknown., Methods and Results: We studied middle-aged African-Americans from one of four cohorts of the Atherosclerosis Risk in Communities study (Jackson cohort, n=1980) who underwent echocardiography between 1993 and 1995. Left ventricular ejection time was measured by pulsed-wave Doppler of the left ventricular outflow tract and related to outcomes. A shorter LVET was associated with younger age, male sex, higher diastolic blood pressure, higher proportion of diabetes, higher heart rate, higher blood glucose levels and worse fractional shortening. During a median follow-up of 17.6 years, 384 (19%) had incident heart failure (HF), 158 (8%) had a myocardial infarction, and 587 (30%) died. In univariable analysis, a lower LVET was significantly associated with increased risk of all events (P<0.05 for all). However, after multivariable adjustment for age, sex, hypertension, diabetes, body mass index, heart rate, systolic and diastolic blood pressure, fractional shortening and left atrial diameter, LVET remained an independent predictor only of incident HF [hazard ratio 1.07 (1.02-1.14), P=0.010 per 10 ms decrease]. In addition, LVET provided incremental prognostic information to the known risk factors included in the Framingham risk score, in regard to predicting all outcomes except for myocardial infarction., Conclusion: Left ventricular ejection time is an independent predictor of incident HF in a community-based cohort and provides incremental prognostic information on the risk of future HF and death when added to known risk prediction models., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

The human sense of smell decreases with age, and a poor sense of smell are among the most important prodromal symptoms of several neurodegenerative diseases. Recent evidence further suggests a racial difference in the sense of smell among U.S. older adults. However, no genome-wide association study (GWAS) on the sense of smell has been conducted in African-Americans (AAs). We performed the first genome-wide meta-analysis of the sense of smell among 1979 AAs and 6582 European-Americans (EAs) from three U.S. aging cohorts. In the AA population, we identified nine novel regions (KLF4-ACTL7B, RAPGEF2-FSTL5, TCF4-LOC100505474, PCDH10, KIAA1751, MYO5B, MIR320B1-CD2, NR5A2-LINC00862, SALL1-C16orf97) that were associated with the sense of smell (P < 5 × 10 -8 ). Many of these regions have been previously linked to neuropsychiatric (schizophrenia or epilepsy) or neurodegenerative (Parkinson's or Alzheimer's disease) diseases associated with a decreased sense of smell. In the EA population, we identified two novel loci in or near RASGRP1 and ANXA2P3 associated with sense of smell. In conclusion, this study identified several ancestry-specific loci that are associated with the sense of smell in older adults. While these findings need independent confirmation, they may lead to novel insights into the biology of the sense of smell in older adults and its relationships to neuropsychological and neurodegenerative diseases.

Background: Olfactory impairment is common among older adults; however, data are largely limited to whites., Methods: We conducted pooled analyses of two community-based studies: the Atherosclerosis Risk in Communities study (ARIC, 1,398 blacks and 4,665 whites), and the Health, Aging, and Body Composition study (Health ABC, 958 blacks and 1,536 whites) to determine the prevalence of anosmia and associated factors for black and white older adults in the United States., Results: The overall prevalence of anosmia was 22.3% among blacks and 10.4% among whites. Blacks had a markedly higher odds of anosmia compared to whites in age and sex adjusted analyses (odds ratio [OR] 2.96, 95% confidence interval [CI] = 2.59-3.38). In both blacks and whites, higher anosmia prevalence was associated with older age and male sex. The highest prevalence was found in black men 85 years or older (58.3%), and the lowest in white women aged 65-69 years (2.4%). Higher education level, lower cognitive score, ApoE ε4, daytime sleepiness, poorer general health status, lower body mass index, and Parkinson disease were associated with higher prevalence of anosmia in one or both races. However, the racial difference in anosmia remained statistically significant after adjusting for these factors (fully adjusted OR = 1.76, 95%CI: 1.50-2.07). Results were comparable between the two cohorts., Discussion: Anosmia is common in older adults, particularly among blacks. Further studies are needed to identify risk factors for anosmia and to investigate racial disparities in this sensory deficit., (Published by Oxford University Press on behalf of The Gerontological Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Prior studies suggest being overweight may be protective against poor functional outcomes in older adults., Methods: Body mass index (BMI, kg/m2) was measured over 25 years across five visits (1987-2011) among Atherosclerosis Risk in Communities Study participants (baseline Visit 1 n = 15,720, aged 45-64 years). Gait speed was measured at Visit 5 ("late-life", aged ≥65 years, n = 6,229). BMI trajectories were examined using clinical cutpoints and continuous mixed models to estimate effects of patterns of BMI change on gait speed, adjusting for demographics and comorbidities., Results: Mid-life BMI (baseline visit; 55% women; 27% black) was associated with late-life gait speed 25 years later; gait speeds were 94.3, 89.6, and 82.1 cm/s for participants with baseline normal BMI (<25), overweight (25 ≤ BMI < 30), and obese (BMI ≥ 30) (p < .001). In longitudinal analyses, late-life gait speeds were 96.9, 88.8, and 81.3 cm/s for participants who maintained normal, overweight, and obese weight status, respectively, across 25 years (p < .01). Increasing BMI over 25 years was associated with poorer late-life gait speeds; a 1%/year BMI increase for a participant with a baseline BMI of 22.5 (final BMI 28.5) was associated with a 4.6-cm/s (95% confidence interval: -7.0, -1.8) slower late-life gait speed than a participant who maintained a baseline BMI of 22.5., Conclusion: Being overweight in older age was not protective of mobility function. Maintaining a normal BMI in mid- and late-life may help preserve late-life mobility., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: We performed single-variant and gene-based association analyses of plasma amyloid-β (aβ) concentrations using whole exome sequence from 1,414 African and European Americans. Our goal was to identify genes that influence plasma aβ42 concentrations and aβ42:aβ40 ratios in late middle age (mean = 59 years), old age (mean = 77 years), or change over time (mean = 18 years)., Methods: Plasma aβ measures were linearly regressed onto age, gender, APOE ε4 carrier status, and time elapsed between visits (fold-changes only) separately by race. Following inverse normal transformation of the residuals, seqMeta was used to conduct race-specific single-variant and gene-based association tests while adjusting for population structure. Linear regression models were fit on autosomal variants with minor allele frequencies (MAF)≥1%. T5 burden and Sequence Kernel Association (SKAT) gene-based tests assessed functional variants with MAF≤5%. Cross-race fixed effects meta-analyses were Bonferroni-corrected for the number of variants or genes tested., Results: Seven genes were associated with aβ in late middle age or change over time; no associations were identified in old age. Single variants in KLKB1 (rs3733402; p = 4.33x10-10) and F12 (rs1801020; p = 3.89x10-8) were significantly associated with midlife aβ42 levels through cross-race meta-analysis; the KLKB1 variant replicated internally using 1,014 additional participants with exome chip. ITPRIP, PLIN2, and TSPAN18 were associated with the midlife aβ42:aβ40 ratio via the T5 test; TSPAN18 was significant via the cross-race meta-analysis, whereas ITPRIP and PLIN2 were European American-specific. NCOA1 and NT5C3B were associated with the midlife aβ42:aβ40 ratio and the fold-change in aβ42, respectively, via SKAT in African Americans. No associations replicated externally (N = 725)., Conclusion: We discovered age-dependent genetic effects, established associations between vascular-related genes (KLKB1, F12, PLIN2) and midlife plasma aβ levels, and identified a plausible Alzheimer's Disease candidate gene (ITPRIP) influencing cell death. Plasma aβ concentrations may have dynamic biological determinants across the lifespan; plasma aβ study designs or analyses must consider age.

Olfactory dysfunction is common among older adults and affects their safety, nutrition, quality of life, and mortality. More importantly, the decreased sense of smell is an early symptom of neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer disease. However, the genetic determinants for the sense of smell have been poorly investigated. We here performed the first genome-wide meta-analysis on the sense of smell among 6252 US older adults of European descent from the Atherosclerosis Risk in Communities (ARIC) study, the Health, Aging, and Body Composition (Health ABC) study, and the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). Genome-wide association study analysis was performed first by individual cohorts and then meta-analyzed using fixed-effect models with inverse variance weights. Although no SNPs reached genome-wide statistical significance, we identified 13 loci with suggestive evidence for an association with the sense of smell (Pmeta < 1 × 10). Of these, 2 SNPs at chromosome 17q21.31 (rs199443 in NSF, P = 3.02 × 10; and rs2732614 in KIAA1267-LRRC37A, P = 6.65 × 10) exhibited cis effects on the expression of microtubule-associated protein tau (MAPT, 17q21.31) in 447 frontal-cortex samples obtained postmortem and profiled by RNA-seq (P < 1 × 10). Gene-based and pathway-enrichment analyses further implicated MAPT in regulating the sense of smell in older adults. Similar results were obtained after excluding participants who reported a physician-diagnosed PD or use of PD medications. In conclusion, we provide preliminary evidence that the MAPT locus may play a role in regulating the sense of smell in older adults and therefore offer a potential genetic link between poor sense of smell and major neurodegenerative diseases., Competing Interests: XH received research grants and consultation fees from NIEHS, NIH, and GE. Other authors declare no competing financial interests.

Objective: Cardiac changes of hypertensive pregnancy include left ventricular hypertrophy (LVH) and diastolic dysfunction. These are thought to regress postpartum. We hypothesised that women with a history of hypertensive pregnancy would have altered LV geometry and function when compared with women with only normotensive pregnancies., Methods: In this cohort study, we analysed echocardiograms of 2637 women who participated in the Family Blood Pressure Program. We compared LV mass and function in women with hypertensive pregnancies with those with normotensive pregnancies., Results: Women were evaluated at a mean age of 56 years: 427 (16%) had at least one hypertensive pregnancy; 2210 (84%) had normotensive pregnancies. Compared with women with normotensive pregnancies, women with hypertensive pregnancy had a greater risk of LVH (OR: 1.42; 95% CI 1.01 to 1.99, p=0.05), after adjusting for age, race, research network of the Family Blood Pressure Program, education, parity, BMI, hypertension and diabetes. When duration of hypertension was taken into account, this relationship was no longer significant (OR: 1.19; CI 0.08 to 1.78, p=0.38). Women with hypertensive pregnancies also had greater left atrial size and lower mitral E/A ratio after adjusting for demographic variables. The prevalence of systolic dysfunction was similar between the groups., Conclusions: A history of hypertensive pregnancy is associated with LVH after adjusting for risk factors; this might be explained by longer duration of hypertension. This finding supports current guidelines recommending surveillance of women following a hypertensive pregnancy, and sets the stage for longitudinal echocardiographic studies to further elucidate progression of LV geometry and function after pregnancy., Clinical Trial Registrations: GENOA- NCT00005269; HyperGEN- NCT00005267; Sapphire- NCT00005270; GenNet- NCT00005268., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background and Purpose: Unrecognized or unreported stroke-like symptoms, called covert symptoms, occur in persons free of clinical stroke. Whether covert symptoms are associated with subclinical brain infarcts (SBIs) is unknown. This study examined the association between covert stroke-like symptoms and SBI/stroke in persons with no history of stroke or transient ischemic attack., Methods: A total of 1881 Atherosclerosis Risk in Communities (ARIC) participants free of clinical stroke or transient ischemic attack (40% male, 50% black, 47-70 years) were queried for covert symptoms and underwent cerebral MRI during the baseline MRI visit. Symptoms were reassessed after 3 years at Visit 4 (n=1001; 39% male, 50% black) and approximately 10 years with a follow-up MRI (n=1006; 40% male, 50% black, 61-83 years)., Results: Covert symptoms were associated with prevalent SBI (OR, 1.94; 95% CI, 1.21-3.11; P=0.006). No support was found for associations between baseline MRI symptoms and SBI at the follow up MRI visit. In participants without SBI at baseline, symptoms at Visit 4 (OR, 2.96; 1.23-7.13; P=0.016) and symptoms at the follow-up MRI visit (OR, 4.29; 2.51-7.33; P<0.001) were associated with a combined outcome of new SBI/clinical stroke on follow-up MRI. Covert symptoms at follow-up MRI visit were also associated with having new SBI (OR, 2.26; 1.18-4.32; P=0.014) on the follow-up MRI that were not seen on the baseline MRI., Conclusions: Covert neurological symptoms were associated with prevalent SBI, and when ascertained at the time of follow-up MRI, with new SBI. Covert symptoms may reflect heightened risk for infarcts.

Hypertension status among spouses is known to be concordant, but previous studies relied on history rather than direct measurement, and few data exist on treatment and control between spouses. The goal of this study was to estimate the spousal association of hypertension status, treatment, and control in adults. The authors identified and analyzed data on 4,500 pairs from the Atherosclerosis Risk in Communities (ARIC) cohort, which sampled middle-aged adults and their spouses in 1986-1989, with 3 follow-up visits 3 years apart. Generalized estimating equations were used in logistic regression analyses to calculate the odds ratio of a spouse's being hypertensive on the basis of the other spouse's hypertension status across 4 visits, adjusting for age, race, body mass index, smoking status, and sodium intake in both individuals. There are marginally increased odds of hypertension for spouses married to someone with hypertension (odds ratio (OR) = 1.15, 95% confidence interval (CI): 1.06, 1.25). Treatment was positively associated between spouses (OR = 1.35, 95% CI: 1.10, 1.67). Control was suggestive of an association, although it was not statistically significant (OR = 1.21, 95% CI: 0.93, 1.56). In middle-aged adults, hypertension status and treatment were moderately associated between spouses after controlling for shared environment. Physicians may target hypertension education and prevention to spouses as a pair rather than as 2 separate patients.

Endothelin-1 (ET-1), a circulating vasoactive peptide with potent vasoconstricting and mitogenic properties, may contribute to target-organ damage in hypertension. We investigated whether plasma levels of C-terminal pro-endothelin-1 (CT-pro-ET-1) are associated with left ventricular (LV) mass and aortic root diameter in African-American adults with hypertension. Plasma CT-pro-ET-1 was measured by an immunoluminometric assay in 1041 African Americans (65±9 years, 72% women) with hypertension. LV mass and aortic root diameter were measured according to the American Society of Echocardiography guidelines, and LV mass was indexed by height to the power 2.7 (LVMi). Multivariable regression analyses were used to assess whether plasma CT-pro-ET-1 was associated with LVMi and aortic root diameter, independent of potential confounding variables. Plasma CT-pro-ET-1 was modestly correlated with LVMi (r=0.21, P<0.0001) and aortic root diameter (r=0.09, P=0.004). In separate multivariable regression models that adjusted for age, sex, body mass index, total and high-density lipoprotein cholesterol, smoking history, diabetes, history of myocardial infarction or stroke, and blood pressure-lowering medication and statin use, log CT-pro-ET-1 was significantly associated with greater LVMi (P=0.001) and larger aortic root diameter (P=0.006). CT-pro-ET-1 is independently associated with LVMi and aortic root diameter and may be a marker of target-organ damage in African-Americans adults with hypertension.

Vital exhaustion, defined as excessive fatigue, feelings of demoralization, and increased irritability, has been identified as a risk factor for incident and recurrent cardiac events, but there are no population-based prospective studies of this association in US samples. We examined the predictive value of vital exhaustion for incident myocardial infarction or fatal coronary heart disease in middle-aged men and women in 4 US communities. Participants were 12,895 black or white men and women enrolled in the Atherosclerosis Risk In Communities (ARIC) study cohort and followed for the occurrence of cardiac morbidity and mortality from 1990 through 2002 (maximum follow-up 13.0 years). Vital exhaustion was assessed using the 21-item Maastricht Questionnaire and scores were partitioned into approximate quartiles for statistical analyses. High vital exhaustion (fourth quartile) predicted adverse cardiac events in age-, gender-, and race-center-adjusted analyses (1.69, 95% confidence interval 1.40 to 2.05) and in analyses further adjusted for educational level, body mass index, plasma low-density lipoprotein and high-density lipoprotein cholesterol levels, systolic and diastolic blood pressure levels, diabetes mellitus, cigarette smoking status, and pack-years of cigarette smoking (1.46, 95% confidence interval 1.20 to 1.79). Risk for adverse cardiac events increased monotonically from the first through the fourth quartile of vital exhaustion. Probabilities of adverse cardiac events over time were significantly higher in people with high vital exhaustion compared to those with low exhaustion (p = 0.002). In conclusion, vital exhaustion predicts long-term risk for adverse cardiac events in men and women, independent of established biomedical risk factors.

Background: We hypothesized that physical activity (PA), which is often associated with reduced risk of ischemic stroke, may also be associated with reduced risk of subclinical cerebral infarcts., Objectives: We studied the cross-sectional association between PA and subclinical cerebral infarcts among African-Americans in the Atherosclerosis Risk in Communities (ARIC) Study., Methods: PA self-reported at baseline and images from cerebral MRI examination obtained 6 years later were evaluated for presence and location of subclinical infarcts > or = 3 mm in size. After exclusions, 944 participants were eligible for study., Results: The results suggested an inverse relationship between odds of having a subclinical cerebral infarct and level of PA on several measures, although the multivariable adjusted odds ratios (OR) were statistically significant only for the sport score. A 1-unit increase in the sport score, indicating more leisure PA, was associated with an adjusted OR for having a subclinical cerebral infarct of 0.62 (0.44-0.87), with a statistically significant monotonic trend across quartiles of the score (P = 0.01). There was no association of work scores with subclinical infarcts., Conclusions: In African-Americans, sport PA was inversely related to subclinical MRI-detected cerebral infarcts assessed six years later.

Myeloperoxidase (MPO) is an enzymatic mediator of several inflammatory cascades and higher serum levels have been associated with increased risk of adverse cardiovascular events. We investigated the association of serum MPO with the ankle-brachial index (ABI) and peripheral arterial disease (PAD) in a bi-ethnic cohort of African-Americans and non-Hispanic white individuals. Participants included 1324 African-Americans (mean age 64 years, 71% women) and 1237 non-Hispanic white individuals (mean age 59 years, 57% women) belonging to hypertensive sibships. Serum levels of MPO were measured by solid phase sandwich immunoassay. ABI was measured using a standard protocol and PAD was defined as an ABI < 0.90. Multivariable regression analysis using generalized estimating equations were performed to assess whether serum MPO levels were associated with ABI and the presence of PAD. After adjustment for age and sex, higher MPO levels were significantly associated with lower ABI and the presence of PAD in African-Americans (p = 0.004 and p = 0.005, respectively) and in non-Hispanic white individuals (p = 0.001 and p = 0.016, respectively). After additional adjustment for conventional risk factors (diabetes, smoking status, total and high-density lipoprotein cholesterol, waist circumference, hypertension), prior history of myocardial infarction or stroke, and medication use (statins, aspirin, estrogen), higher MPO levels remained significantly associated with lower ABI and the presence of PAD in both African-Americans (p = 0.008 and p = 0.010, respectively) and non-Hispanic white individuals (p = 0.001 and p = 0.018, respectively). We conclude that higher MPO levels are associated with lower ABI and the presence of PAD in African-Americans and non-Hispanic white individuals.

Little is known about the genetics of peripheral arterial disease (PAD). We performed linkage analyses to identify genomic regions that influence ankle-brachial index (ABI), a measure of PAD, in 1310 African Americans (AA) (mean age 62+/-9 years) and 796 non-Hispanic whites (NHW) (mean age 58+/-9 years) belonging to hypertensive sibships. ABI was determined at two sites in each lower extremity and the lower of the two average ABIs was used in the analyses after adjustment for age, age(2), sex, weight, total cholesterol, HDL cholesterol, and ever-smoking. Genotypes were measured at microsatellite marker loci spaced approximately 10cM apart across the 22 autosomes. Heritability was assessed by SOLAR and linkage analyses performed using a variance components approach. Modest heritability (h(2)) was noted for the fully adjusted ABI in each ethnic group (h(2)=0.195, P=0.002 in AA; h(2)=0.212, P=0.006 in NHW). Univariate linkage analyses demonstrated tentative evidence of linkage (multipoint LOD=1.3-2.0) for ABI on chromosomes 1p, 6q, 7q, 10p, and 16p in AA and on chromosome 3p and 3q in NHW. In conclusion, ABI is a modestly heritable trait in AA and NHW hypertensive sibships. Quantitative trait linkage analyses identified several chromosomal regions that may harbor genes influencing ABI.

Background and Purpose: Genetic factors that influence interindividual variation in levels of plasma homocysteine, a risk factor for vascular disease, are not fully understood. We performed linkage analyses to identify genomic regions that influence homocysteine levels in blacks and non-Hispanic whites., Methods: Subjects (n=2283) belonged to hypertensive sibships and included 1319 blacks (63+/-10 years, 70% women) and 964 non-Hispanic whites (61+/-7 years, 57% women). Fasting plasma homocysteine was measured by high-pressure liquid chromatography. Genotypes were measured at 366 microsatellite marker loci distributed across the 22 autosomes. Plasma homocysteine adjusted for age, sex, body mass index, serum creatinine, and estrogen use (in women) was used in the genetic analyses. Heritability and linkage analyses were performed using a variance components approach., Results: Mean (+/-SD) homocysteine levels were 10.4+/-5.27 mumol/L in blacks and 10.0+/-2.84 micromol/L in non-Hispanic whites (P=0.58 for difference). Homocysteine levels were significantly (P<0.0001) heritable in blacks (h2=0.70) and in non-Hispanic whites (h2=0.49). Linkage analyses demonstrated significant evidence of linkage (multipoint logarithm of odds> or =3.0) for homocysteine on chromosomes 1q42, 14q32, and 19p13 in blacks and on chromosomes 9q34 and 12q24 in non-Hispanic whites. Tentative evidence of linkage (logarithm of odds 1.3 to 2.0) was present on chromosomes 2q32, 7p15, 8q24, 18q21, and 20p12 in blacks and chromosomes 6q26 and 18q21 in non-Hispanic whites. Four genes in the homocysteine metabolism pathway (MTR, DNMT1, GAMT, and CARM1) were present under 2 of the significant linkage signals in blacks (chromosomes 1q42 and 19p13)., Conclusions: Plasma homocysteine is a significantly heritable trait. Linkage analyses reveal several unique genomic loci that may influence circulating levels of homocysteine and therefore susceptibility to vascular diseases including stroke.

Background: A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA-sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population., Methods: We compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol., Results: Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003)., Conclusions: These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors., (Copyright 2006 Massachusetts Medical Society.)

Objective: To examine the association between prevalent cerebral abnormalities identified on MRI and cognitive functioning in a predominantly middle-aged, population-based study cohort., Methods: Cerebral MRI was performed on 1,538 individuals (aged 55 to 72) from the Atherosclerosis Risk in Communities (ARIC) cohort, with no history of stroke or TIA, at study sites in Forsyth County, NC, and Jackson, MS. White matter hyperintensities (WMHs), ventricular size, and sulcal size were graded by trained neuroradiologists on a semiquantitative, 10-point scale. Cognitive functioning was assessed using the Delayed Word Recall Test (DWRT), Digit Symbol Substitution Test (DSST), and Word Fluency Test (WFT)., Results: High ventricular grade was independently associated with significantly lower scores on the DWRT and DSST and greater risk (odds ratio [OR] 2.32, 95% confidence interval [CI] 1.51 to 3.56) of impaired scores (i.e., < or =10th percentile) on the DWRT. High sulcal grade was associated with a modest decrement in scores on the DWRT. The presence of coexisting high grade WMHs and silent infarcts was independently associated with lower scores on all cognitive tests and greater risk of impaired functioning on the DSST (OR 2.91, 95% CI: 1.23 to 6.89) and WFT (OR 2.28, 95% CI 1.03 to 5.08). The presence of two or more high-grade abnormalities was associated with increased risk of impaired functioning on all cognitive tests (DWRT: OR 2.23, 95% CI 1.40 to 3.55; DSST: OR 2.06, 95% CI 1.13 to 3.76; WFT: OR 2.07, 95% CI 1.23 to 3.49) independent of multiple covariates and silent infarcts., Conclusion: Common changes in brain morphology are associated with diminished cognitive functioning in middle-aged and young-elderly individuals.

Few studies have investigated whether ethnic groups differ in the prevalence of peripheral arterial disease (PAD). We compared the distribution of the ankle-brachial index (ABI), a measure of PAD, between African Americans and non-Hispanic white individuals. Subjects (n = 931) belonged to the Genetic Epidemiology Network of Arteriopathy (GENOA) study, a community-based study of hypertensive sibships, and included 453 African Americans from Jackson, Mississipi (mean age 72 +/- 6 years, 69% women) and 478 non-Hispanic white individuals from Rochester, Minnesota (mean age 58 +/- 7 years, 64% women). ABI was determined at two sites in each lower extremity and the lowest of four indices was used in the analyses. PAD was defined as an ABI of < or = 0.95. Information about conventional risk factors was derived from interviews and from blood samples drawn at the study visit. The prevalence of diabetes and hypertension was significantly higher in African Americans than in non-Hispanic white individuals. After adjusting for age, African American subjects had a lower mean ABI (women 0.97 vs 1.04, p < 0.001; men 0.96 vs 1.12, p < 0.001) and a greater prevalence of PAD (women 34% vs 22%, p = 0.010; men 33% vs 11%, p < 0.001) than their non-Hispanic white counterparts. In multiple regression analyses, African American ethnicity was a predictor of a lower ABI and the presence of PAD in each sex after adjusting for age and other conventional risk factors. In conclusion, the lower ABI and greater prevalence of PAD in African Americans than in non-Hispanic white individuals is not explained by differences in conventional risk factors. Identifying additional 'novel' risk factors that account for the ethnic differences in PAD is an important next step towards understanding why such differences exist and developing more effective strategies to reduce the burden of PAD.

Previous cross-sectional and longitudinal studies assessing the association between age and drinking are inconsistent. Evaluating 15,425 Black and White men and women from four communities, this study sought to determine whether there was a consistent relation between age and drinking in cross-sectional and longitudinal analyses and to determine change in drinking status and level of consumption (occasional, light to moderate, and heavier drinkers) at follow-up. Cross-sectional analyses of drinking were performed for Atherosclerosis Risk in Communities examinations 1 (1987-1989) and 3 (1993-1995). The changes in drinking status and level were determined for the 12,565 persons with information at both examinations. Prevalence of drinking was generally inversely associated with age in the cross-sectional analyses for all ethnic/gender groups, and drinking prevalence decreased over the 6 years of follow-up for all except Black women. Only among Black drinkers was younger age associated with a higher level of alcohol consumption in both cross-sectional and prospective analyses. Thus, whether drinking prevalence declines, the amount consumed by drinkers is decreased, or whether both factors contribute to the decrease appears to vary with ethnicity and gender. The change in drinking level was substantial with more than 40% of baseline drinkers reporting drinking cessation or a different level of consumption at follow-up.