Microvascular Dysfunction in Cerebral Small Vessel Disease and Stroke

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Project Summary/Abstract Dr. Mark Etherton is a Vascular Neurologist at Massachusetts General Hospital (MGH) whose goal is to become an independent, clinical research scientist with expertise in neuroimaging of cerebral small vessel disease and ischemic stroke. The research aims of this proposal are three-fold: (1) to elucidate the relationship between white matter microvascular function and ischemic tissue outcomes; (2) to advance knowledge on how chronic microvascular dysfunction contributes to white matter structural injury and ischemic stroke outcomes; and (3) to determine the relationship between early plasma and neuroimaging surrogates of microvascular function in small vessel disease-mediated ischemic stroke. The proposed study capitalizes on the clinical research environment of the MGH Stroke Research Center and two unique acute ischemic stroke databases with Dynamic Susceptibility Contrast MRI. The current proposal will analyze these two prospectively enrolled acute ischemic stroke cohorts in combination with a prospective, longitudinal study coupling functional neuroimaging with plasma biomarker analysis. Successful completion of this research study will advance knowledge on how white matter microvascular dysfunction contributes to infarct growth and poor functional outcomes after stroke. This research will yield important pathophysiological insights regarding the complex interrelations of microvascular dysfunction and cerebral small vessel disease, which may contribute to improved stroke prevention, risk stratification, and individualized therapies to improve post-stroke outcomes in patients with small vessel disease. This application proposes a focused training plan with specific measures of proficiency that extends Dr. Etherton’s prior training and research activities in ischemic stroke and diffusion tensor imaging analysis of global white matter integrity by providing necessary new and formal training in (1) neuroimaging of microvascular function; (2) fundamentals of blood-brain barrier biology; and (3) experimental design/statistical analysis. Training will involve individual and research team meetings with an interdisciplinary network of world-renowned mentors and collaborators; formal didactics in neuroimaging, blood-brain barrier biology, clinical trial design, statistical analysis, and responsible conduct of research; educational seminars; and formal neuroimaging training activities. His training plan leverages the resources of world-class environments at MGH, the Martinos Center for Biomedical Imaging, and the Harvard School of Public Health. The mentorship of primary mentor Dr. Natalia Rost, co-mentors Drs. Ona Wu, Cenk Ayata, and Steven Greenberg, along with collaborators Drs. Bruce Rosen, Hanzhang Lu, and Lori Chibnik will ensure Dr. Etherton achieves his training plan goals and milestones. The integrated research and training plans outlined in this application will significantly advance Dr. Etherton’s research career and provide the skillset necessary to pursue an independent program of patient-oriented research studying the mechanisms of microvascular dysfunction in cerebral small vessel disease and stroke.