Microvascular mechanisms underlying white matter lesions in older adults

PROJECT SUMMARY This proposal presents a plan for the candidate’s career enhancement that focuses on studying hemodynamic etiology of white matter lesions (WML) in the context of risk for Alzheimer’s disease (AD). The goal is to uncover physiological mechanisms that may inform development of therapies for reducing WML-related cognitive decline in older adults at elevated risk for AD. Candidate: The candidate is an Instructor of Radiology at Harvard Medical School and Massachusetts General Hospital. His research interests are to explore relationships between microvascular physiology and AD by developing novel methods for imaging microvascular function as markers of disease. The candidate’s academic training has provided a foundation in magnetic resonance imaging (MRI) methods, with a focus in cerebrovascular diseases. His research efforts thus far have resulted in a publication record, conference awards, and success in obtaining funding that demonstrate his strong potential to develop into a successful investigator. However, there are gaps between the candidate’s background in MRI methods development and his current interests in small vessel disease in aging and dementia. The candidate’s plan for career enhancement addresses these gaps with training in aging and dementia, small vessel disease, and human study design. This coursework will be complemented with experimental training that leverages his background in MRI of microvascular function to bridge his transition to independence. Research: AD is expected to impact 13.8 million Americans by 2050, necessitating a more complete understanding of the etiology and the development of markers for diagnosis and progression. Beta-amyloid plaques and neurofibrillary tangles characterize AD pathology, but WMLs of presumed small vessel origin are an independent contributor to cognitive decline in AD patients. The high prevalence of WML in patients with AD suggests that cerebrovascular disease may play an important role in the pathophysiology of AD. However, the physiological mechanisms contributing to the development of WML remain unclear. A better understanding of the microvascular physiology associated with the formation of these white matter lesions may inform the development of therapies aimed at preventing or delaying associated cognitive decline in AD patients. A critical barrier to understanding relevant physiology is the lack of sensitive methods for noninvasively measuring microvascular function in white matter. The objective of this work is to apply sensitive MRI protocols at 7 Tesla for measuring white matter hemodynamics towards answering focused questions regarding hemodynamic function in older adults at elevated risk for AD. Results will also inform the design of longitudinal human studies examining the role of promising microvascular markers in stratifying high risk individuals for preventative therapies aimed at reducing the burden of WML burden-related cognitive decline.