Gottesman, Rebecca F.

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

Background and Purpose— Cardiovascular disease is a known risk factor for cognitive decline, although the mechanisms remain unclear. We hypothesize that Aβ (β-amyloid), a core pathology of Alzheimer's disease, will be associated with subclinical cardiac structure and function echocardiogram indices. Methods— Three hundred six nondemented participants from the ARIC study (Atherosclerosis Risk in Communities Study) underwent florbetapir positron emission tomography and 2D echocardiography (echo). Cross-sectional associations between echo markers of left ventricular structure and function and global cortical Aβ (≥1.2 standardized uptake value ratio were evaluated using multivariable logistic regression with interaction terms when appropriate. Results— Participants ranged in age from 67 to 88 years, were 57% female and 42% black. Per 1 cm increase in end-diastolic left ventricular diameter, the odds of elevated florbetapir standardized uptake value ratio doubled (odds ratio, 2.04 [95% CI, 1.10–3.77]), with similar findings when excluding mild cognitive impairment (odds ratio, 2.61 [95% CI, 1.22–5.59]). Conclusions— We have demonstrated a significant association between a marker of left ventricular structure and elevated florbetapir standardized uptake value ratio, identified using positron emission tomography. Ongoing prospective work will help determine if changes in cardiac structure and function either precede, or occur simultaneously with deposition of amyloid.

OBJECTIVES Cardiac troponin T, measured using a high‐sensitive assay (hs‐cTnT), and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) are associated with increased stroke risk and perhaps with cognitive decline. However, few well‐designed prospective studies with extended follow‐up have been conducted. We aimed to estimate the association of hs‐cTnT and NT‐proBNP with 15‐year cognitive change in the Atherosclerosis Risk in Communities (ARIC) study. DESIGN Prospective cohort study. SETTING Four US communities. PARTICIPANTS A total of 9114 and 9108 participants from the Atherosclerosis Risk in Communities study for analyses of hs‐cTnT and NT‐proBNP, respectively. MEASUREMENTS We examined association of hs‐cTnT and NT‐proBNP with 15‐year change (1996‐1998 to 2011‐2013) in three cognitive tests of executive function (Digit Symbol Substitution Test), verbal learning memory (Delayed Word Recall Test), and semantic fluency (Word Fluency Test), and an overall score combining the three tests using multivariable linear mixed effect models. We conducted several sensitivity analyses including multiple imputations to address bias due to missing data and attrition, and we compared associations within groups combining hs‐cTnT and NT‐proBNP into a three‐level categorical variable. RESULTS At baseline (1996‐1998), mean age was 63.4 (standard deviation [SD] = 5.7) years; 56.4% were women, and 17.5% were black. The hs‐cTnT at baseline was not associated with cognitive change in any measure. Some evidence indicated accelerated decline in verbal learning and memory when comparing those in the highest with the lowest NT‐proBNP quintiles; however, this association was not replicated when considering clinically relevant cutoffs or deciles of exposure in survivors. Sensitivity analyses were consistent with our primary analyses. There was little evidence to support effect modification by any considered factors. People with highest levels of both biomarkers had excessive decline in global z scores vs people with lowest levels (−.34; 95% confidence interval = −.63 to −.04). CONCLUSION Markers of myocardial injury and stretch were not associated with cognitive decline following 15 years among survivors, but when combined together they were suggestive in post hoc analysis. Whether this represents targets of intervention should be examined in the future. J Am Geriatr Soc 67:2353–2361, 2019

OBJECTIVE We sought to examine associations in older adults among diabetes, glycemic control, diabetes duration, and biomarkers of hyperglycemia with incident mild cognitive impairment (MCI) and incident dementia. RESEARCH DESIGN AND METHODS We conducted a prospective analysis of 5,099 participants from the Atherosclerosis Risk in Communities (ARIC) Study who attended the fifth (2011–2013) exam. Cognitive status was assessed during follow-up via telephone calls, death certificate codes, surveillance, and a follow-up examination (2016–2017). We defined incident cognitive impairment as incident MCI or incident dementia in persons dementia-free at the index examination; we also examined each outcome separately. Diabetes was defined using self-report, medications, or HbA1c ≥6.5%; poor glycemic control in persons with diabetes was defined as HbA1c ≥7%. We examined the following biomarkers of hyperglycemia: HbA1c, fructosamine, glycated albumin, and 1,5-anhydroglucitol. RESULTS Mean age at baseline was 76 years, 59% were female, and 21% were black. Diabetes (hazard ratio [HR] 1.14 [95% CI 1.00, 1.31]), poor glycemic control in persons with diabetes (HR 1.31 [95% CI 1.05, 1.63]), and longer diabetes duration (≥5 vs. <5 years; HR 1.59 [95% CI 1.23, 2.07]) were significantly associated with incident cognitive impairment. We found a J-shaped association between HbA1c and incident dementia. Glycated albumin and fructosamine were also associated with incident dementia, independently of HbA1c. HbA1c and fructosamine were also associated with incident MCI. CONCLUSIONS Diabetes status, poor glycemic control, and longer diabetes duration were associated with worse cognitive outcomes over a median follow-up of 5 years.