A Precision Medicine Approach To Study Targetable Pathways in Vascular Dementia

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Dr. Elahi is an early career physician-scientist with specialty training in neurodegenerative disease and experience in biomarker development, who seeks to develop her career at the VA. By combining her clinical and molecular biology training, Dr. Elahi's long-term goal is to contribute to a better understanding of vascular pathways in neurodegenerative disorders in order to improve early diagnoses and development of disease-modifying treatments that will alter the cognitive trajectory of so many individuals affected with vascular disease and at risk of dementia. In order to achieve this goal, Dr. Elahi seeks additional training to develop her knowledge and skills in two major domains: (1) leadership in medicine, by starting a specialized clinic at the VA and UCSF, to evaluate veterans with VCID from a variety of causes, high systemic vascular disease / risk, strokes, TBI, auto-immune disease, and neurodegenerative disease and to undertake their enrollment into research, (2) advancement of her scientific skills in multi-modal data-driven analytical approaches for unbiased biomarker discovery. To better understand VCID, we need novel tools that can handle both the complexity of human disease as well as the noisy nature of human-based biological and clinical data. Thus, novel approaches and methods are needed. As a physician-scientist, Dr. Elahi is uniquely suited to pursue cutting-edge approaches to advancement of diagnostics in VCID. However, with clinical training and responsibilities, she has not had the opportunity to acquire adequate knowledge of unbiased biomarker discovery projects, nor the important opportunity to develop her skills in advanced data-driven analytics. In this application, Dr. Elahi proposes to use her clinical expertise in neurodegenerative disease and technical expertise in exosomal technologies to undertake hypothesis-driven modelling of contributions of endothelial inflammation and pathogenic angiogenesis to adverse clinical and radiographic brain outcomes in VCID (Aims 1 and 2). While in Aim 3, in collaboration with her VA mentor, Dr. Ferguson, she will for the first time undertake the analysis of multi-dimensional data, including exosomal proteomics, brain imaging, retinal imaging, clinical variables and cognitive scores. The scope of the work proposed is aligned with Dr. Elahi’s goal of becoming a leader in translational VCID research. The hypothesis and data-driven aims will provide complimentary approaches to cutting-edge research in the field of neurodegenerative disease. This Aim will provide the opportunity to undertake data-driven discovery of discrete clinical-biomarker endophenotypes within a heterogenous cohort of subjects. This research is expected to advance understanding of VCID with diagnostic and therapeutic relevance and prepare Dr. Elahi for leadership in precision medicine approaches in VCID research. To ensure success of the scientific and training goals of this work, Dr. Elahi has assembled a world-class team of leaders in vascular neurology and neuroscience (Swanson), neurodegenerative disease (Miller), data science in neurological disease (Ferguson), and advisors/collaborators in: epidemiology of vulnerable populations and causal inference (Glymour), mutli-modal neuroimaging (Rosen), and cognition in VCID (Kramer). Dr. Elahi’s training will involve a combination of individual tutorials with her mentors and scientific advisors, hands-on experience, and formal coursework. The proposed research will provide Dr. Elahi with data for a larger prospective study of microvascular disease in the veteran population with heterogenous etiologies: chronic and acute CVD related to systemic vascular risk, TBI, and auto-immune/inflammatory disorders. She will propose a Merit Review application submitted before the end of the CDA period. Dr. Elahi is enthusiastically committed to improving the cognitive and mental health of Veterans through research, and with her proposed project and training, she will develop a thriving research program in VCID at the VA.