Vascular hemodynamics and markers of preclinical and subclinical vascular brain injury and dementia

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Project Summary This K01 proposal describes the career development activities and research plan that will facilitate the candidate's transition to an independent investigator in the areas of vascular hemodynamics, vascular brain injury, and dementia. The candidate has a background in cardiovascular physiology and epidemiology, including training in quantitative methods and primary and secondary analysis of vascular hemodynamics data from arterial tonometry and ultrasound. The grant will provide the applicant with additional needed training in neurovascular and brain imaging (i.e., magnetic resonance imaging and positron emission tomography), vascular and Alzheimer's disease dementia, bioethics, and grantsmanship through a combination of immersive training, coursework, mentoring, and selected readings. The candidate has assembled a team of multidisciplinary mentors and advisors who have an outstanding record of academic achievement and research expertise in the areas of vascular hemodynamics, target organ damage, vascular brain injury, and dementia. Additionally, the mentoring team members have extensive experience in mentoring junior faculty toward research independence. The proposed research will contribute to the field and complement the candidate's plan for career development training activities. The research activities will capitalize on the candidate's emerging expertise and experience in vascular hemodynamics and epidemiology with the mentors' and advisors' expertise in neurovascular function, preclinical dementia, and subclinical brain injury. The research includes multiple specific aims that will be achieved over the course of the award period. The aims include: (1) To assess relations of measures of aortic stiffness, pressure pulsatility, and microvascular function with preclinical β-amyloid and tau burden in the brain in Framingham Heart Study (FHS) Third Generation participants; (2) To assess relations of measures of aortic stiffness and pressure pulsatility with longitudinal progression of subclinical brain vascular injury in FHS Third Generation participants; and (3) To assess relations of measures of aortic stiffness and pressure pulsatility with (A) markers of cerebrovascular remodeling and (B) preclinical β-amyloid burden in the brain in a pilot subset of black/African-American participants in the Jackson Heart Study. This work seeks to elucidate nascent vascular factors that contribute to the pathophysiology of vascular brain injury and dementia, which may represent novel targets for prevention. Additionally, this work seeks to increase our understanding of health disparities of cardio- and cerebrovascular diseases.