Retinal vessel caliber and cognitive performance: the multi-ethnic study of atherosclerosis (MESA).

Retinal vessel calibers share anatomic and physiologic characteristics with the cerebral vasculature and can be visualized noninvasively. In light of the known microvascular contributions to brain health and cognitive function, we aimed to determine if, in a community based-study, retinal vessel calibers and change in caliber over 8 years are associated with cognitive function or trajectory. Participants in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort who completed cognitive testing at Exam 5 (2010-2012) and had retinal vascular caliber measurements (Central Retinal Artery and Vein Equivalents; CRAE and CRVE) at Exam 2 (2002-2004) and Exam 5 were included. Using multivariable linear regression, we evaluated the association of CRAE and CRVE from Exam 2 and Exam 5 and their change between the two exams with scores on tests of global cognitive function (Cognitive Abilities Screening Instrument; CASI), processing speed (Digit Symbol Coding; DSC) and working memory (Digit Span; DS) at Exam 5 and with subsequent change in cognitive scores between Exam 5 and Exam 6 (2016-2018).The main effects are reported as the difference in cognitive test score per SD increment in retinal vascular caliber with 95% confidence intervals (CI). A total of 4334 participants (aged 61.6 ± 9.2 years; 53% female; 41% White) completed cognitive testing and at least one retinal assessment. On multivariable analysis, a 1 SD larger CRAE at exam 5 was associated with a lower concomitant CASI score (- 0.24, 95% CI - 0.46, - 0.02). A 1 SD larger CRVE at exam 2 was associated with a lower subsequent CASI score (- 0.23, 95%CI - 0.45, - 0.01). A 1 SD larger CRVE at exam 2 or 5 was associated with a lower DSC score [(- 0.56, 95% CI - 1.02, - 0.09) and - 0.55 (95% CI - 1.03, - 0.07) respectively]. The magnitude of the associations was relatively small (2.8-3.1% of SD). No significant associations were found between retinal vessel calibers at Exam 2 and 5 with the subsequent score trajectory of cognitive tests performance over an average of 6 years. Wider retinal venular caliber was associated with concomitant and future measures of slower processing speed but not with later cognitive trajectory. Future studies should evaluate the utility of these measures in risk stratification models from a clinical perspective as well as for screening on a population level.

Association of Age-Related Hearing Impairment With Physical Functioning Among Community-Dwelling Older Adults in the US.

Importance: Hearing impairment, a common treatable condition, may contribute to poorer physical function with aging. Objective: To assess whether hearing impairment is associated with poorer physical function, reduced walking endurance, and faster decline in physical function. Design, Setting, and Participants: In this cohort study, cross-sectional and longitudinal analyses were performed using data from the 2011 to 2019 period of the Atherosclerosis Risk in Communities study, a population-based study of community-dwelling adults at 4 sites in the US. Exposures: Hearing thresholds (per 10 dB) assessed with pure tone audiometry and categorized as normal hearing or mild, moderate, or severe hearing impairment. Main Outcomes and Measures: Physical function was assessed using the short physical performance battery (SPPB), with composite scores ranging from 0 to 12. A composite score of 6 or less and a score for each component (balance, gait speed, and chair stands) of 2 or less indicated poor performance. Walking endurance was assessed using a 2-minute fast-paced walk test. Tobit regression models adjusted for sociodemographic factors and medical history were used to calculate the mean differences in SPPB composite scores; logistic regression models, to estimate the odds ratios (ORs) of low SPPB composite and component scores; and linear mixed-effects models, to estimate the mean rate of change in SPPB composite scores over time. Results: Of the 2956 participants (mean [SD] age, 79 [4.6] years) who attended study visit 6 between 2016 and 2017, 1722 (58.3%) were women, and 2356 (79.7%) were White. As determined by pure tone audiometry, 973 (33%) participants had normal hearing, 1170 (40%) had mild hearing impairment, 692 (23%) had moderate hearing impairment, and 121 (4%) had severe hearing impairment. In the Tobit regression model, severe hearing impairment was associated with a lower mean SPPB score (ß, -0.82; 95% CI, -0.34 to -1.30) compared with normal hearing. In fully adjusted logistic regression models, hearing impairment was associated with higher odds of low physical performance scores (severe impairment vs normal hearing: OR for composite physical performance, 2.51 [95% CI, 1.47-4.27]; OR for balance, 2.58 [95% CI, 1.62-4.12]; OR for gait speed, 2.11 [95% CI, 1.03-4.33]). Over time (2 to 3 visits; maximum, 8.9 years), participants with hearing impairment had faster declines in SPPB compared with those with normal hearing (moderate hearing impairment × time interaction, -0.34 [-0.52 to -0.16]). In adjusted models for walking endurance, participants with moderate or severe hearing impairment walked a mean distance of -2.81 m (95% CI, -5.45 to -0.17 m) and -5.31 m (95% CI, -10.20 to -0.36 m) than those with normal hearing, respectively, during the 2-minute walk test. Conclusions and Relevance: In this cohort study, hearing impairment was associated with poorer performance, faster decline in physical function, and reduced walking endurance. The results of the longitudinal analysis suggest that hearing impairment may be associated with poorer physical function with aging. Whether management of hearing impairment could delay decline in physical function requires further investigation.

Milk Intake at Midlife and Cognitive Decline over 20 Years. The Atherosclerosis Risk in Communities (ARIC) Study.

Background: Faster rates of cognitive decline are likely to result in earlier onset of cognitive impairment and dementia. d-galactose, a derivative of lactose, is used in animal studies to induce neurodegeneration. Milk is the primary source of lactose in the human diet, and its effects on cognitive decline have not been fully evaluated. Objective: Assess the association of milk intake with change in cognitive function over 20 years. Methods: A total of 13,751 participants of the Atherosclerosis Risk in Communities (ARIC) cohort completed a food frequency questionnaire and three neurocognitive evaluations from 1990 through 2013. Two single nucleotide polymorphisms (SNPs) were used to determine lactase persistence (LCT-13910 C/T for Whites and LCT-14010 G/C for Blacks). Mixed-effects models were used to study the association of milk intake with cognitive change. Multiple imputations by chained equations were used to account for attrition. Results: Milk intake greater than 1 glass/day was associated with greater decline in the global z-score over a 20-year period. The difference in decline was 0.10 (95% CI: 0.16, 0.03) z-scores, or an additional 10% decline, relative to the group reporting "almost never" consuming milk. Conclusions: Replication of these results is warranted in diverse populations with greater milk intake and higher variability of lactase persistence genotype.

Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified. METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts. RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample). INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

Correlates of carotid plaque presence and composition as measured by MRI: the Atherosclerosis Risk in Communities Study.

BACKGROUND: The composition of atherosclerotic plaque affects the likelihood of an atherothrombotic event, but prospective studies relating risk factors to carotid wall and plaque characteristics measured by MRI are lacking. We hypothesized that traditional risk factors are predictors of carotid wall and plaque characteristics measured 2 decades later. METHODS AND RESULTS: A high-resolution contrast-enhanced MRI examination of the carotid artery was performed in 1769 participants. Measures of carotid wall volume and maximum thickness; lipid core presence, volume and maximum area; and fibrous cap thickness were performed centrally. The sample was, on average, 70 years of age, 57% female, 81% white, and 19% black. Greater age, total and low-density lipoprotein cholesterol, male sex, white race, diabetes, hypertension, and smoking as measured at baseline were all significant predictors of increased wall volume and maximum wall thickness 18 years later. An analysis of lipid core was restricted to the 1180 participants with maximum wall thickness >/=1.5 mm. Lipid core was observed in 569 individuals (weighted percentage, 42%). Baseline age and total and low-density lipoprotein cholesterol were predictors of presence of lipid core 18 years later; however, these relationships were attenuated after adjustment for wall thickness. Concurrently measured low-density lipoprotein cholesterol was associated with greater lipid core volume, independent of wall thickness. Concurrently measured glucose and body mass index were inversely associated fibrous cap thickness. CONCLUSIONS: Traditional atherosclerosis risk factors are related to increased wall volume and wall thickness 2 decades later, but they do not discriminate characteristics of plaque composition (core and cap) independent of wall size.

Lipoprotein-associated phospholipase A2 and high-sensitivity C-reactive protein improve the stratification of ischemic stroke risk in the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND AND PURPOSE: Inflammation plays a critical role in the development of vascular disease, and increased levels of the inflammatory biomarkers, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), and high-sensitivity C-reactive protein (hs-CRP) have been shown to be associated with an increased risk for ischemic stroke. METHODS: In a prospective case-cohort (n=949) study in 12 762 apparently healthy, middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study, we first examined whether Lp-PLA(2) and hs-CRP levels improved the area under the receiver operator characteristic curve (AUC) for 5-year ischemic stroke risk. We then examined how Lp-PLA(2) and hs-CRP levels altered classification of individuals into low-, intermediate-, or high-risk categories compared with traditional risk factors. RESULTS: In a model using traditional risk factors alone, the AUC adjusted for optimism was 0.732, whereas adding hs-CRP improved the AUC to 0.743, and adding Lp-PLA(2) significantly improved the AUC to 0.752. Addition of hs-CRP and Lp-PLA(2) together in the model improved the AUC to 0.761, and the addition of the interaction between Lp-PLA(2) and hs-CRP further significantly improved the AUC to 0.774. With the use of traditional risk factors to assess 5-year risk for ischemic stroke, 86% of participants were categorized as low risk (<2%); 11%, intermediate risk (2% to 5%); and 3%, high risk (>5%). The addition of hs-CRP, Lp-PLA(2), and their interaction to the model reclassified 4%, 39%, and 34% of the low-, intermediate- and high-risk categories, respectively. CONCLUSIONS: Lp-PLA(2) and hs-CRP may be useful in individuals classified as intermediate risk for ischemic stroke by traditional risk factors.

Metals in urine and peripheral arterial disease.

Exposure to metals may promote atherosclerosis. Blood cadmium and lead were associated with peripheral arterial disease (PAD) in the 1999-2000 National Health and Nutrition Examination Survey (NHANES). In the present study we evaluated the association between urinary levels of cadmium, lead, barium, cobalt, cesium, molybdenum, antimony, thallium, and tungsten with PAD in a cross-sectional analysis of 790 participants > or =40 years of age in NHANES 1999-2000. PAD was defined as a blood pressure ankle brachial index < 0.9 in at least one leg. Metals were measured in casual (spot) urine specimens by inductively coupled plasma-mass spectrometry. After multivariable adjustment, subjects with PAD had 36% higher levels of cadmium in urine and 49% higher levels of tungsten compared with noncases. The adjusted odds ratio for PAD comparing the 75th to the 25th percentile of the cadmium distribution was 3.05 [95% confidence interval (CI), 0.97 to 9.58]; that for tungsten was 2.25 (95% CI, 0.97 to 5.24). PAD risk increased sharply at low levels of antimony and remained elevated beyond 0.1 microg/L. PAD was not associated with other metals. In conclusion, urinary cadmium, tungsten, and possibly antimony were associated with PAD in a representative sample of the U.S. population. For cadmium, these results strengthen previous findings using blood cadmium as a biomarker, and they support its role in atherosclerosis. For tungsten and antimony, these results need to be interpreted cautiously in the context of an exploratory analysis but deserve further study. Other metals in urine were not associated with PAD at the levels found in the general population.

Risk factors for progression of common carotid atherosclerosis: the Atherosclerosis Risk in Communities Study, 1987-1998.

Intima-media thickness of the common carotid arteries is a marker of atherosclerosis and has been shown to be associated with prevalent and incident coronary heart disease and with coronary heart disease risk factors. The authors examined the association of baseline risk factors or change in risk factors with change in intima-media thickness over follow-up (1987-1998) in the Atherosclerosis Risk in Communities (ARIC) population-based cohort (baseline: age 45-64 years, n = 15,792). Subjects were members of households sampled in four areas of the United States. Either not adjusting for baseline intima-media thickness or doing so with correction for its measurement error resulted in statistically significant associations of change in intima-media thickness with baseline diabetes, current smoking, high density lipoprotein cholesterol, pulse pressure, white blood cell count, and fibrinogen. The associations were of a similar order of magnitude as anticipated from the authors' cross-sectional findings. Statistically significant associations were found between change in intima-media thickness and change in low density lipoprotein cholesterol and triglycerides and with onset of diabetes and hypertension. In summary, established risk factors for coronary heart disease are associated with the rate of change of subclinical atherosclerosis.