Cerebral amyloid angiopathy (CAA) leads to cerebrovascular deposition of ss-amyloid resulting in vessel fragility and intracerebral hemorrhage (ICH). The high prevalence of white matter disease in CAA is possibly secondary to vessel dysfunction and vascular insufficiency. In the context of an ongoing NIH-funded prospective cohort study, this project aims to test the hypotheses that both the degree and location of white matter disease in CAA is an independent contributor to neurologic and functional impairment. The applicant is a junior faculty member in the Department of Neurology at Massachusetts General Hospital and Assistant Professor of Neurology at Harvard Medical School. It is the applicant's career goal to obtain expertise in the clinical and radiologic investigation of vascular diseases of white matter. He plans to obtain the necessary didactic training specific to this proposal during the grant period using an extensive multidisciplinary institutional network. He will not only take advantage of the Mentor's K24-funded training program in patient-oriented research (5K24NS056207-02), but will have an individualized training program tailored to his specific research interests. Through the rigorous research and educational training associated with this award the applicant seeks to become an independent clinician-investigator in the field of cerebral small vessel disease. The applicant's primary mentor, Dr. Steven Greenberg, is currently Professor of Neurology at Harvard Medical School and Co-Director of the MGH Neurology Clinical Trials Unit. He is an internationally recognized leader in intracerebral hemorrhage and CAA with numerous prominent publications in the field. Dr. Greenberg has developed a very strong research program involving numerous multidisciplinary subspecialties. Dr. A. Gregory Sorensen, the Associate Director of the Martinos Center for Bioimaging will be applicant's co-mentor for this proposal. As one of the leaders in field of MRI research, Dr. Sorensen is strongly committed to aiding the applicant in the elements of study design and data analysis pertaining to radiological imaging. The applicant is attached to both the MGH Stroke Service and the MGH Memory Disorders Unit (MDU). The MGH Stroke Service is a nationally recognized referral center for patients with acute or chronic cerebrovascular diseases with state-of-the-art neuroimaging facilities. The service will provide an exposure to the entire spectrum of cerebrovascular disease, including the approximately 120 cases per year of intracerebral hemorrhage, the focus of the applicant's study. The Memory Disorders Unit was first established in 1982 and is an integral part of the Massachusetts Alzheimer's Disease Research Center (ADRC) which has an ongoing NIH-funded clinical research study enrolling patients affected with all types of memory disorders, including vascular dementia and CAA. It was established by Dr. John Growdon and currently led by Dr. Bradley Hyman, two highly-renowned investigators. Three specific hypotheses will be tested: (1) extent of white matter disease (as measured by WMH volume and mean DTI measures) in CAA is associated with gait and balance dysfunction, cognitive impairment and disability, (2) the anatomic location of white matter disease (measured in regions of interest (ROIs) and voxel- based analysis) correlates with these outcome measures and (3) the progression of white matter disease (measured by increase in WMH volume and mean DTI measures in longitudinal follow-up) in CAA results in a measurable increase in these neurological deficits. Degree of gait and balance impairment will be assessed using established qualitative and quantitative measures. The extent of white matter disease on T2-weighted MRI sequences will be evaluated using validated volumetric methods. The location of white matter disease will be assessed using voxel-based analysis of high-resolution MRI sequences. Repeat MRIs at 16 and 36 months will be similarly evaluated to assess degree white matter disease progression and its impact on the measured outcomes. As the pathology of advanced CAA represents a relatively homogenous microvascular process, it serves an ideal model of cerebral vessel dysfunction. The data resulting from the proposed study would have significant implications for not only those patients with CAA-related intracerebral hemorrhage, but the broader elderly population with clinically "silent" CAA. Unlike other common small vessel diseases such as arteriolosclerosis, CAA remains difficult to diagnose early in its course. The results from this study could potentially help identify those patients with "asymptomatic" CAA prior to ICH or cognitive impairment, thus being of paramount importance for future trials aimed at preventing the devastating effects of this disease.
As the pathology of advanced CAA represents a relatively homogenous microvascular process, it serves an ideal model of cerebral vessel dysfunction. The data resulting from the proposed study would have significant implications for not only those patients with CAA-related intracerebral hemorrhage, but the broader elderly population with clinically silent CAA. Unlike other common small vessel diseases such as arteriolosclerosis, CAA remains difficult to diagnose early in its course. The results from this study could potentially help identify those patients with asymptomatic CAA prior to ICH or cognitive impairment, thus being of paramount importance for future trials aimed at preventing the devastating effects of this disease.
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