Longitudinal validation of cerebral small vessel disease biomarkers in diverse community-based older adults without dementia

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ABSTRACT Cerebral small vessel disease (SVD) encompasses a range of common processes and pathologies (arteriolosclerosis, cerebral amyloid angiopathy, small vessel atherosclerosis, small and microscopic infarcts and bleeds, enlarged perivascular spaces, and white matter disease) that we and others have shown are associated with impaired cognition and dementia (VCID). High-quality biomarkers of SVD are critically needed to advance the diagnosis, prevention, and treatment of small vessel VCID. The mission of the MarkVCID consortium has been to identify the most promising biomarkers of SVD and conduct analytical (instrumental) validation and preliminary clinical validation. Our team at Rush University Medical Center and Illinois Institute of Technology was privileged to be active participants in this initial work. We are now eager to continue this collaborative effort with this proposal. The objective of the proposed project is to conduct rigorous longitudinal clinical validation of MarkVCID-selected biomarkers in a diverse cohort free of dementia, and to investigate the associations of these biomarkers with SVD neuropathologic indices, working synergistically with other consortium sites and contributing scientific expertise, experimental infrastructure, and scientific guidance. Specifically, we propose to recruit, enroll, and longitudinally assess a large, diverse, community-based group of older adults without dementia using MarkVCID clinical evaluation and biomarkers, to test the hypotheses that the biomarkers are associated with cognitive decline and SVD neuropathologic indices. This will be a nested sub-study of participants of the Rush Memory and Aging Project (MAP), Minority Aging Research Study (MARS), Religious Orders Study (ROS), Clinical Core (CC), and Latino Core (LATC) of the Rush Alzheimer’s Disease Research Center, which are on-going longitudinal, clinical-pathologic cohort studies of aging that recruit non-demented individuals and have high follow-up rates. MARS and CC recruit exclusively African Americans, and LATC recruits Latino older adults. Our past contributions to MarkVCID support our current aims. First, we demonstrated our ability to recruit and follow a large and diverse group of non-demented older adults, some of whom died, enabling autopsy studies. Second, we developed and made publicly available a novel biomarker of arteriolosclerosis with high performance, named ARTS, which we trained using machine learning on MRI and pathology data. Third, we contributed to the analytical and initial clinical validation of multiple MarkVCID biomarkers. Fourth, we led the MarkVCID imaging biomarkers committee and were active in all functions of the consortium. We propose to leverage our expertise and infrastructure to conduct rigorous longitudinal clinical validation of MarkVCID biomarkers in a diverse population, and to investigate the associations of these biomarkers with SVD neuropathologic indices.