Jayandra J. Himali

Association of MRI markers of vascular brain injury with incident stroke, mild cognitive impairment, dementia, and mortality: the Framingham Offspring Study.

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.

Prevalence and Correlates of Silent Cerebral Infarcts in the Framingham Offspring Study

Background and Purpose— Previous estimates of the prevalence of silent cerebral infarction (SCI) on MRI in community-based samples have varied between 5.8% and 17.7% depending on age, ethnicity, presence of comorbidities, and imaging techniques. We document the prevalence and risk factors associated with SCI at midlife in the community-based Framingham sample. Methods— Our study sample comprised 2040 Framingham Offspring (53% female; mean age, 62±9 years) who attended the sixth examination (1996–1998), underwent volumetric brain MRI (1999–2005,) and were free of clinical stroke at MRI. We examined the age- and sex-specific prevalences and the clinical correlates of SCI using multivariable logistic regression models. Results— At least 1 SCI was present in 10.7% of participants; 84% had a single lesion. SCI was largely located in the basal ganglia (52%), other subcortical (35%) areas, and cortical areas (11%). Prevalent SCI was associated with the Framingham Stroke Risk Profile score (OR, 1.27; 95% CI, 1.10–1.46); stage I hypertension was determined by JNC-7 criteria (OR,1.56; CI,1.15–2.11), an elevated plasma homocysteine in the highest quartile (OR, 2.23; CI, 1.42–3.51), atrial fibrillation (OR, 2.16; CI, 1.07–4.40), carotid stenosis >25% (OR, 1.62; 1.13–2.34), and increased carotid intimal-medial thickness above the lowest quintile (OR, 1.65; CI, 1.22–2.24). Conclusion— The prevalence and distribution of SCI in the Framingham Offspring are comparable to previous estimates. Risk factors previously associated with clinical stroke were also found to be associated with midlife SCI. Our results support current guidelines emphasizing early detection and treatment of stroke risk factors.

Effects of systolic blood pressure on white-matter integrity in young adults in the Framingham Heart Study: a cross-sectional study

BACKGROUND Previous studies have identified effects of age and vascular risk factors on brain injury in elderly individuals. We aimed to establish whether the effects of high blood pressure in the brain are evident as early as the fifth decade of life. METHODS In an investigation of the third generation of the Framingham Heart Study, we approached all participants in 2009 to ask whether they would be willing to undergo MRI. Consenting patients underwent clinical assessment and cerebral MRI that included T1-weighted and diffusion tensor imaging to obtain estimates of fractional anisotropy, mean diffusivity, and grey-matter volumes. All images were coregistered to a common minimum deformation template for voxel-based linear regressions relating fractional anisotropy, mean diffusivity, and grey-matter volumes to age and systolic blood pressure, with adjustment for potential confounders. FINDINGS 579 (14·1%) of 4095 participants in the third-generation cohort (mean age 39·2 years, SD 8·4) underwent brain MRI between June, 2009 and June, 2010. Age was associated with decreased fractional anisotropy and increased mean diffusivity in almost all cerebral white-matter voxels. Age was also independently associated with reduced grey-matter volumes. Increased systolic blood pressure was linearly associated with decreased regional fractional anisotropy and increased mean diffusivity, especially in the anterior corpus callosum, the inferior fronto-occipital fasciculi, and the fibres that project from the thalamus to the superior frontal gyrus. It was also strongly associated with reduced grey-matter volumes, particularly in Brodmanns area 48 on the medial surface of the temporal lobe and Brodmanns area 21 of the middle temporal gyrus. INTERPRETATION Our results suggest that subtle vascular brain injury develops insidiously during life, with discernible effects even in young adults. These findings emphasise the need for early and optimum control of blood pressure. FUNDING National Institutes of Health and National Heart, Lung, and Blood Institute; National Institute on Aging; and National Institute of Neurological Disorders and Stroke.

Cardiac Index Is Associated With Brain Aging The Framingham Heart Study

Background— Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury. We hypothesized that cardiac function, as measured by cardiac index, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community. Methods and Results— Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1504 Framingham Offspring Cohort participants free of clinical stroke, transient ischemic attack, or dementia (age, 61±9 years; 54% women). Neuropsychological and brain MRI variables were related to cardiac MRI–assessed cardiac index (cardiac output/body surface area). In multivariable-adjusted models, cardiac index was positively related to total brain volume (P=0.03) and information processing speed (P=0.02) and inversely related to lateral ventricular volume (P=0.048). When participants with clinically prevalent cardiovascular disease were excluded, the relation between cardiac index and total brain volume remained (P=0.02). Post hoc comparisons revealed that participants in the bottom cardiac index tertile (values <2.54) and middle cardiac index tertile (values between 2.54 and 2.92) had significantly lower brain volumes (P=0.04) than participants in the top cardiac index tertile (values >2.92). Conclusions— Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging.

Red blood cell omega-3 fatty acid levels and markers of accelerated brain aging

Objective: Higher dietary intake and circulating levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been related to a reduced risk for dementia, but the pathways underlying this association remain unclear. We examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort. Methods: We related RBC DHA and EPA levels in dementia-free Framingham Study participants (n = 1,575; 854 women, age 67 ± 9 years) to performance on cognitive tests and to volumetric brain MRI, with serial adjustments for age, sex, and education (model A, primary model), additionally for APOE ϵ4 and plasma homocysteine (model B), and also for physical activity and body mass index (model C), or for traditional vascular risk factors (model D). Results: Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2–4) had lower total brain and greater white matter hyperintensity volumes (for model A: β ± SE = −0.49 ± 0.19; p = 0.009, and 0.12 ± 0.06; p = 0.049, respectively) with persistence of the association with total brain volume in multivariable analyses. Participants with lower DHA and ω-3 index (RBC DHA+EPA) levels (Q1 vs Q2–4) also had lower scores on tests of visual memory (β ± SE = −0.47 ± 0.18; p = 0.008), executive function (β ± SE = −0.07 ± 0.03; p = 0.004), and abstract thinking (β ± SE = −0.52 ± 0.18; p = 0.004) in model A, the results remaining significant in all models. Conclusion: Lower RBC DHA levels are associated with smaller brain volumes and a “vascular” pattern of cognitive impairment even in persons free of clinical dementia.

Visceral fat is associated with lower brain volume in healthy middle-aged adults.

Midlife obesity has been associated with an increased risk of dementia. The underlying mechanisms are poorly understood. Our aim was to examine the cross‐sectional association of body mass index (BMI), waist circumference (WC), waist‐to‐hip ratio (WHR), and computed tomography (CT)‐based measurements of subcutaneous (SAT) and visceral (VAT) adipose tissue with various magnetic resonance imaging (MRI) markers of brain aging in middle‐aged community adults.

Relations of arterial stiffness and endothelial function to brain aging in the community

Objective: To determine the association of arterial stiffness and pressure pulsatility, which can damage small vessels in the brain, with vascular and Alzheimer-type brain aging. Methods: Stroke- and dementia-free Framingham Offspring Study participants (n = 1,587, 61 ± 9 years, 45% male) underwent study of tonometric arterial stiffness and endothelial function (1998–2001) and brain MRI and cognition (1999–2002). We related carotid-femoral pulse wave velocity (CFPWV), mean arterial and central pulse pressure, and endothelial function to vascular brain aging by MRI (total cerebral brain volume [TCBV], white matter hyperintensity volume, silent cerebral infarcts) and vascular and Alzheimer-type cognitive aging (Trails B minus Trails A and logical memory-delayed recall, respectively). Results: Higher CFPWV was associated with lower TCBV, greater white matter hyperintensity volume, and greater prevalence of silent cerebral infarcts (all p < 0.05). Each SD greater CFPWV was associated with lower TCBV equivalent to 1.2 years of brain aging. Mean arterial and central pulse pressure were associated with greater white matter hyperintensity volume (p = 0.005) and lower TCBV (p = 0.02), respectively, and worse verbal memory (both p < 0.05). Associations of tonometry variables with TCBV and white matter hyperintensity volume were stronger among those aged 65 years and older vs those younger than 65 years (p < 0.10 for interaction). Brachial artery endothelial function was unrelated to MRI measures (all p > 0.05). Conclusions: Greater arterial stiffness and pressure pulsatility are associated with brain aging, MRI vascular insults, and memory deficits typically seen in Alzheimer dementia. Future investigations are warranted to evaluate the potential impact of prevention and treatment of unfavorable arterial hemodynamics on neurocognitive outcomes.

Association of Metabolic Dysregulation With Volumetric Brain Magnetic Resonance Imaging and Cognitive Markers of Subclinical Brain Aging in Middle-Aged Adults: The Framingham Offspring Study

OBJECTIVE Diabetic and prediabtic states, including insulin resistance, fasting hyperglycemia, and hyperinsulinemia, are associated with metabolic dysregulation. These components have been individually linked to increased risks of cognitive decline and Alzheimer’s disease. We aimed to comprehensively relate all of the components of metabolic dysregulation to cognitive function and brain magnetic resonance imaging (MRI) in middle-aged adults. RESEARCH DESIGN AND METHODS Framingham Offspring participants who underwent volumetric MRI and detailed cognitive testing and were free of clinical stroke and dementia during examination 7 (1998–2001) constituted our study sample (n = 2,439; 1,311 women; age 61 ± 9 years). We related diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin, and glycohemoglobin levels to cross-sectional MRI measures of total cerebral brain volume (TCBV) and hippocampal volume and to verbal and visuospatial memory and executive function. We serially adjusted for age, sex, and education alone (model A), additionally for other vascular risk factors (model B), and finally, with the inclusion of apolipoprotein E-ε4, plasma homocysteine, C-reactive protein, and interleukin-6 (model C). RESULTS We observed an inverse association between all indices of metabolic dysfunction and TCBV in all models (P < 0.030). The observed difference in TCBV between participants with and without diabetes was equivalent to approximately 6 years of chronologic aging. Diabetes and elevated glycohemoglobin, HOMA-IR, and fasting insulin were related to poorer executive function scores (P < 0.038), whereas only HOMA-IR and fasting insulin were inversely related to visuospatial memory (P < 0.007). CONCLUSIONS Metabolic dysregulation, especially insulin resistance, was associated with lower brain volumes and executive function in a large, relatively healthy, middle-aged, community-based cohort.

Parental Occurrence of Stroke and Risk of Stroke in Their Children The Framingham Study

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 individuals propensity to stroke.

Relation of Left Ventricular Ejection Fraction to Cognitive Aging (from the Framingham Heart Study)

Heart failure is a risk factor for Alzheimers disease and cerebrovascular disease. In the absence of heart failure, it was hypothesized that left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community. Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected from 1,114 Framingham Heart Study Offspring Cohort participants free from clinical stroke or dementia (aged 40 to 89 years, mean age 67 ± 9 years, 54% women). Neuropsychological and neuroimaging markers of brain aging were related to cardiac MRI-assessed LVEF. In multivariable-adjusted linear regressions, LVEF was not associated with any brain aging variable (p values >0.15). However, LVEF quintile analyses yielded several U-shaped associations. Compared to the referent (quintile 2 to 4), the lowest quintile (quintile 1) LVEF was associated with lower mean cognitive performance, including Visual Reproduction Delayed Recall (β = -0.27, p <0.001) and Hooper Visual Organization Test (β = -0.27, p <0.001). Compared to the referent, the highest quintile (quintile 5) LVEF values also were associated with lower mean cognitive performance, including Logical Memory Delayed Recall (β = -0.18, p = 0.03), Visual Reproduction Delayed Recall (β = -0.17, p = 0.03), Trail Making Test Part B - Part A (β = -0.22, p = 0.02), and Hooper Visual Organization Test (β = -0.20, p = 0.02). Findings were similar when analyses were repeated excluding prevalent cardiovascular disease. In conclusion, although these observational cross-sectional data cannot establish causality, they suggest a nonlinear association between LVEF and measures of accelerated cognitive aging.