Background and Purpose— White matter hyperintensities and MRI-defined brain infarcts (BIs) have individually been related to stroke, dementia, and mortality in population-based studies, mainly in older people. Their significance in middle-aged community-dwelling persons and the relative importance of these associations remain unclear. We simultaneously assessed the relation of white matter hyperintensities and BI with incident stroke, mild cognitive impairment, dementia, and mortality in a middle-aged community-based cohort. Methods— A total of 2229 Framingham Offspring Study participants aged 62±9 years underwent volumetric brain MRI and neuropsychological testing (1999 to 2005). Incident stroke, dementia, and mortality were prospectively ascertained and for 1694 participants in whom a second neuropsychological assessment was performed (2005 to 2007), incident mild cognitive impairment was evaluated. All outcomes were related to white matter hyperintensities volume (WMHV), age-specific extensive WMHV and BI adjusting for age and gender. Results— Extensive WMHV and BI were associated with an increased risk of stroke (hazard ratio [HR]=2.28, 95% CI: 1.02 to 5.13; HR=2.84, 95% CI: 1.32 to 6.10). WMHV, extensive WMHV, and BI were associated with an increased risk of dementia (HR=2.22, 95% CI: 1.32 to 3.72; HR=3.97, 95% CI: 1.10 to 14.30; HR=6.12, 95% CI: 1.82 to 20.54) independently of vascular risk factors and interim stroke. WMHV and extensive WMHV were associated with incident amnestic mild cognitive impairment in participants aged ≥60 years only (OR=2.47, 95% CI: 1.31 to 4.66 and OR=1.49, 95% CI: 1.14 to 1.97). WMHV and extensive WMHV were associated with an increased risk of death (HR=1.38, 95% CI: 1.13 to 1.69; HR=2.27, 95% CI: 1.41 to 3.65) independent of vascular risk factors and of interim stroke and dementia. Conclusions— In a large community-based sample of middle-aged adults, BI predicted an increased risk of stroke and dementia independent of vascular risk factors. White matter hyperintensities portended an increased risk of stroke, amnestic mild cognitive impairment, dementia, and death independent of vascular risk factors and interim vascular events.

Background and Purpose— Carotid atherosclerosis has been associated with increased risk of stroke and poorer cognitive performance in older adults. The relation of carotid atherosclerosis to cognitive impairment and MRI indices of ischemia and aging in midlife is less clear. Methods— We studied 1975 Framingham Offspring Study participants free of stroke and dementia with available carotid ultrasound, brain MRI, and neuropsychological testing. We related common and internal carotid artery intima-media thickness and internal carotid stenosis to large white matter hyperintensity (>1 SD above age-specific mean), total brain volume, hippocampal volume, silent cerebral infarcts, and neuropsychological measures of verbal memory, executive function, and nonverbal memory measures. Results— We observed that internal carotid artery intima-media thickness, but not common carotid artery intima-media thickness, was associated with higher prevalence of silent cerebral infarcts (OR, 1.21; 95% CI, 1.03–1.43; P <0.05), large white matter hyperintensity (OR, 1.19; 95% CI, 1.03–1.38; P <0.05), lower total brain volume (−0.05 per SD; P <0.05), and poorer performance in verbal memory (−0.06 per SD; P <0.05) and nonverbal memory measures (−0.08 per SD; P <0.01), but not with hippocampal volume. Internal carotid stenosis ≥25% was associated with a higher prevalence of large white matter hyperintensity (adjusted OR, 1.77; 95% CI, 1.25–2.53) and lower total brain volume (−0.11 per SD; P =0.042) but not with silent cerebral infarcts or hippocampal volume. Internal carotid stenosis ≥50% was associated with higher prevalence of silent cerebral infarcts (OR, 2.53; 95% CI, 1.17–5.44), large white matter hyperintensity (OR, 2.35; 95% CI, 1.08–5.13), and poorer performance on executive function (−0.39 per SD; P <0.05), but not with total brain volume or hippocampal volume. Conclusions— Carotid atherosclerosis markers were associated with MRI indices of brain ischemia and aging and with cognitive impairment in a community-based sample of middle-aged adults. Our data suggest that internal carotid artery intima-media thickness may be a better marker for cognitive impairment than common carotid artery intima-media thickness.

Background and Purpose—: Cerebral microbleeds (CMBs) are associated with increased risk of stroke and poor cognition. Vascular risk factors and medications used for stroke prevention may increase the risk of CMB. We examined the prevalence of CMB and the association of these risk factors with CMB, postulating that risk factors for cerebral amyloid angiopathy would be associated with lobar CMB and markers of hypertensive vasculopathy with deep CMB. Methods —: We include 1965 Framingham Original and Offspring participants (age, 66.5±11.0 years; 54% women) and evaluated the age- and sex-specific prevalence of CMB. We related various vascular and genetic (apolipoprotein E [ APOE ]) risk factors and medication use to the presence of CMB overall and stratified by brain location (deep, lobar, or mixed). Results —: CMBs were observed in 8.8% of participants, being mostly lobar (63%). CMB prevalence increased with age ( P <0.0001) and was higher in men ( P <0.001). Hypertension increased risk of any CMB, and in deep and mixed locations ( P <0.05), and low total cholesterol and APOE ε4 increased risk of lobar CMB ( P <0.05). Statin use increased risk of lobar and mixed location CMB ( P <0.05). The latter association was not affected by adjustment for cholesterol levels or concomitant medication use. Conclusions —: We observed the expected association of hypertension with deep CMB and low cholesterol and APOE ε4 with lobar CMB. In addition, statin use was independently associated with CMB risk. This potential adverse effect of statin use needs to be examined in other cohorts.

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.

Background— Data relating parental history of stroke to stroke risk in offspring remain surprisingly inconsistent, largely because of heterogeneity of study design and the absence of verified, as opposed to historical, data on parental stroke status. Methods and Results— We determined whether prospectively verified parental occurrence of stroke increased incident stroke risk among offspring in a community-based sample by studying 3443 stroke-free Framingham offspring (53% female; mean age, 48±14 years) with verified parental stroke status (by 65 years of age) who attended the first, third, fifth, and/or seventh offspring examinations and were followed up for up to 8 years after each baseline examination. Over up to 11 029 such person-observation periods (77 534 person-years), we documented 106 parental strokes by 65 years of age and 128 offspring strokes (74 parental and 106 offspring strokes were ischemic). Using multivariable Cox models adjusted for age, sex, sibship, and baseline stroke risk factors, we observed that parental stroke, both all stroke generally and ischemic stroke specifically, was associated with an increased risk of incident stroke of the same type in the offspring (hazard ratio, 2.79; 95% confidence interval, 1.68 to 4.66; P <0.001 for all stroke; and hazard ratio, 3.15; 95% confidence interval, 1.69 to 5.88; P <0.001 for ischemic stroke). This was true for both maternal and paternal stroke. Conclusions— Documented parental stroke by 65 years of age was associated with a 3-fold increase in risk of offspring stroke. This increased risk persisted after adjustment for conventional stroke risk factors. Thus, verified parental stroke may serve as a clinically useful risk marker of an individual’s propensity to stroke.