Precursors of Stroke Incidence and Prognosis

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PROJECT SUMMARY/ABSTRACT Post-stroke cognitive impairment and dementia (PS-VCID) are major contributors to Alzheimer’s disease and related dementias (ADRD), occurring in 30% of stroke survivors. An individual’s complex life-course exposure to vascular risk factors, along with the varying prevalence and incidence of cardiovascular risk factors among the U.S. population, make study of the link between life-course exposure to cardiovascular risk factors and ADRD a priority. Furthermore, the ability to accurately estimate an individual’s risk for PS-VCID at a particular timepoint in life, even before a stroke occurs, is critical for planning personalized and public health interventions to improve brain health and resilience. Risk factors such as obesity and dyslipidemia have gained epidemic proportions in the U.S., but their causal role and contribution to PS-VCID risk are undefined. Further, PS-VCID risk prediction tools using multimodal data and in multiple racial groups are not available. This proposal seeks to leverage FHS data and resources to generate an understanding of PS-VCID trends and determinants, to collaborate with REGARDS and ARIC study investigators to develop and validate in bi-racial participants comprehensive PS- VCID risk prediction tools (including incorporation of a measure of social determinant of health), to study the causal relations of obesity and dyslipidemia with PS-VCID, to explore repurposing of available drug treatments, and to inform prevention strategies and treatment targets for PS-VCID. Specific Aims include: Aim 1, to describe trends in PS-VCID risk in community dwelling individuals; Aim 2, to evaluate the life-course correlates of PS- VCID using novel machine learning methods to exame the relation of repeated exposure measures, assessed prospectively over seven decades, with PS-VCID, including i) Framingham Stroke Risk Profile components, ii) lipid fractions, iii) obesity indicators, iv) hypertension types, and v) multi-organ disease; Aim 3, to develop two PS-VCID risk prediction tools (PS-VCID risk scores) for i) clinical risk assessment (based on cardiovascular risk factors, obesity measures, and dyslipidemia) and ii) use in research (with addition of brain imaging-derived factors quantifying global cerebral small vessel disease burden, global gray matter volume and cortical thickness, social factors (Area deprivation index) and genetic factors based on identification of the optimal polygenic risk score for each vascular risk factor). Scores will be developed in the well-characterized FHS and REGARDS cohorts, and then assessed and validated in the ARIC study. Aim 4, to study the causal relation of obesity and dyslipidemia with PS-VCID and explore drug repurposing strategies in an instrumental variable analyses framework.