Hypertension, dyslipidemia, hyperinsulinemia, glucose intolerance, and abdominal adiposity are facets of the metabolic syndrome, and are predictors of stroke and vascular dementia. Prior to overt cerebrovascular disease, subtle cognitive deficits are noted in persons with these cardiovascular (CV) risk factors. However, the biological mechanisms linking CV risk factors to poorer cognitive function are poorly understood. Subtle deficits in cognitive function and accompanying brain abnormalities may constitute early markers of elevated cerebrovascular risk among older adults with CV risk factors. The first specific aim of this competing continuation project is to examine whether, in 250 stroke-free, non-demented and non-diabetic older adults (ages 60-80+), 90 from our initial R29 project combined with 160 from this proposed project, CV risk factors - systolic and diastolic blood pressure, blood glucose, insulin, dyslipidemia, and abdominal adiposity - are associated with the poorer outcomes on: (1) neuropsychological test performance; (2) magnetic resonance imaging (MRI) ratings of white matter hyperintensities, silent infarction, and brain atrophy; (3) magnetic resonance angiography (MRA) ratings of stenosis of the large cerebral and cervicocerebral arteries; and (4) relative ratios of cerebral:cerebellar perfusion as assessed by single photon emission computed tomography (SPECT). The second specific aim is to examine whether MRI, MRA, and SPECT indices of subtle brain abnormalities mediate the relation between CV risk factors and poorer cognitive function. The cumulative burden of the CV risk factors and brain abnormalities will be examined in relation to domains of cognitive function, as will individual risk factors and brain abnormalities. To our knowledge, this will be the first study to examine whether several interrelated CV risk factors are associated with diminished cognitive function via several biologically plausible brain mechanisms in otherwise healthy older adults. Structural equation modeling will be used to examine patterns of interrelations among these variables and directly test brain abnormalities as potential mediators of the CV risk factor-cognition relation. Understanding the pathogenesis of cognitive impairment associated with CV risk factors in older adults may lead to enhanced efforts in prevention and intervention to reduce cerebrovascular risk, preserve cognitive functioning, and improve quality of life.
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