Small vessel disease contributions to neurodegeneration in Alzheimer's disease

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PROJECT SUMMARY/ABSTRACT Brain atrophy is a common correlate of dementia. Majority of older persons with dementia have comorbid cerebral small vessel disease (SVD) and Alzheimer’s disease (AD) pathology. The spectrum of SVD includes both small vessel pathologies and diverse tissue injuries. Differing biologic processes may contribute towards the etiology of brain atrophy in vulnerable brain regions, including the hippocampus, a structural brain change seen on MRI proximate to cognitive decline. The interplay between SVD and AD is complex, with evidence to suggest microglia inflammation may be important. To date, very little research has focused on the interplay between SVD, AD, and microglia inflammation in the context of regional brain volume. The objective of this study is to examine the association of neuropathologic and MRI SVD markers with regional brain volumes and identify the effects of comorbid AD pathology and microglia inflammation. This K01 will integrate neuropathology, neuroimaging, and cognitive data from three community-based studies, the Religious Orders Study, the Memory and Aging Project, and Minority Aging and Research Study. Specifically, this proposal will use state-of-the-art methods to capture novel digital morphometric changes from post-mortem brain tissue, use MRI-defined quantitative volume measures in susceptible brain regions, examine differing SVD markers with regional brain volumes, examine in-vivo longitudinal SVD changes, and extend analyses in African Americans. Primary aims are 1) Examine the relationship between SVD markers, AD pathology, and regional brain volume, 2) Determine the role of microglia inflammation with SVD markers and regional brain volume, and 3) Identify associations between SVD markers, regional brain volume, and cognitive decline. An exploratory aim 4) will examine the relationship between SVD markers and regional brain volume in African Americans. My mentorship team has extensive experience with large epidemiological studies of aging and dementia and will provide expert guidance through the research methods and complimentary training plan. Specific areas of mentorship expertise include translational neuropathology, neuroimaging, biostatistics, health disparities, and cognition . Their expertise will be augmented by the interdisciplinary training programat Rush Alzheimer’s Disease Center (RADC), and cutting- edge resources within the RADC Cores (Neuropathology, Neuroimaging and Biomarker, and Biostatistics). Together, the proposed research and training plan provides the framework from which I can launch a successful independent research career.