The Framingham Heart Study (FHS) has, during the 33 years that the Precursors of Stroke Incidence and Prognosis (PSIP) grant has been funded, prospectively identified 2290 incident stroke and TIA events in 15,442 participants and made landmark contributions to the our understanding of stroke risk factors. It has also described 50-year temporal trends in stroke risk, and crafted a widely used Framingham Stroke Risk Profile (FSRP). In parallel, FHS has prospectively accrued data on incident mild cognitive impairment and dementia, 1-3 rounds of brain MRI and detailed cognitive assessment (N~7000 persons) and a wealth of genomic, lifestyle, vascular risk factor and biomarker data. In this renewal we propose to continue stroke surveillance, to identify additional stroke risk factors and temporal trends, especially in adults <55 years, and to use the rich data available in FHS to understand vascular contributions to dementia. The burden of stroke is dwarfed by the burden of subclinical vascular brain injury (VBI). VBI assessed with objective imaging measures, is a risk factor for stroke and for vascular cognitive impairment and dementia (VCID). However, there is considerable heterogeneity in the association between conventional MRI measures of VBI and cognitive performance. We hypothesize that some of this discrepancy will be due to differences in brain blood flow (imaged with pseudocontinuous arterial spin labeling [pCASL]), white matter integrity (detectable by diffusion tensor imaging [DTI]), functional connectivity (assessed by fcMRI) and concomitant AD pathology (assessed using PIB-PET amyloid burden). We also posit that variability in risk of VCID might be further explained by exploring individual differences in genetic susceptibility, lifestyle and exposure to risk factors. Finally, we postulate that factors determining VCID in persons with and without stroke will overlap. We propose the following Specific Aims:
Aim 1 : To continue surveillance for stroke and transient ischemic attack (TIA) in surviving FHS participants (n~8000, aged 28-107 years), using existing standardized protocols and introducing web-based physician examinations. We will further explore clinical, risk factor, biomarker and (in conjunction with large consortia) genetic risk factors associated with stroke allowing us to expand and refine the FSRP. We propose to especially focus on young stroke and the study of TIA with diffusion-weighted abnormalities.
Aim 2 : To examine the burden of VBI after stroke/TIA using 3TMRI, MRA, pCASL, fcMRI and PIB-PET at 6 months and 2 years after the event in 75 cases, and in 75 age- and sex-matched controls. We will relate these measures to VCID assessed with a 60 min detailed cognitive assessment, repeatedly used in prior FHS exams.
Aim 3 : To assess the range of VBI and VCI in 200 persons without clinical stroke, selecting 100 each from the two extremes of the stroke risk (FSRP) spectrum, using the same imaging and cognitive measures as in Aim 2.
Aim 4 : To identify genetic, lifestyle, vascular and biomarker determinants of VBI, VCI, VCID among FHS participants, utilizing traditional and novel, targeted and exploratory statistical modeling.
The Framingham Heart study (FHS) has studied risk factors and temporal trends in stroke for 6 decades, helping shape public policy, and has developed a widely used stroke risk prediction tool; we now propose to continue the stroke surveillance, including younger adults in whom the risk of stroke may be increasing. Further, clinical stroke represents the `tip of the iceberg' with much vascular brain injury being covert, but resulting in cognitive impairment and dementia. We will study vascular brain injury and cognitive impairment among FHS participants, with and without a stroke, using the latest imaging technologies and will combine these data with already collected genetic, lifestyle and risk factor data to better understand the biology of vascular cognitive impairment and to improve risk prediction for stroke and dementia.
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