Understanding the Contribution of Altered Cerebrovascular Function to the Pathology and Clinical Symptoms of Huntington Disease

PROJECT SUMMARY/ABSTRACT: This proposal seeks to establish the pathophysiological mechanisms that establish a relationship between neurovascular dysfunction, neurological impairment and brain degeneration in Huntington’s disease (HD). It builds on our growing understanding of the important of neurovascular alterations in neurodegeneration, including in HD, and takes advantage of clinical and neuroimaging expertise as well as the availability of a well-characterized cohort of HD gene-expanded individuals. Aim1 examines the cross- sectional regional changes in cerebrovascular reactivity (CVR) and tests the hypothesis that impaired CVR triggers focal brain atrophy. Aim 2 tests the specific hypothesis that impaired perfusion (CBF) occurs in HD and is associated with regionally altered CVR. Aim 3 evaluates the longitudinal neurovascular changes and the causal relationship between location and severity of these changes with rates of clinical progression and of brain atrophy. Successful achievement of these aims will establish a strong foundation for understanding key vascular mechanisms that may affect progression and HD and establish neurovascular mechanisms as important targets for future clinical drug trials in HD