Multiethnic Validation of VCID biomarkers in South Texas

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ABSTRACT Cerebral small vessel disease (CSVD) contributes considerably to the global burden of dementia. As vascular diseases can be both prevented and safely treated, there is a great potential for interventions to reduce the burden of dementia. However, more research is needed to develop suitable biomarkers of cerebral small vessel contributions to cognitive impairment and dementia (VCID). The National Institute of Neurological Disorders and Stroke (NINDS) has supported the MarkVCID initiative to advance the identification and validation of biomarkers for VCID across seven sites and a coordinating center. As one contributing site, our team has led the development of two candidate biomarkers, helped define and harmonize all protocols, and joined multisite validation with the recruitment of the largest Hispanic sample from a single site. In this proposal, we seek to include a more diverse population across South Texas, including Hispanic and African Americans, from Houston and San Antonio, stroke and dementia clinics, primary care, and population studies. We further propose additional validation of candidate biomarkers in the rich datasets of four cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium that have legacy data (MRI, dementia) and biospecimens (plasma, serum, brain autopsy). As a MarkVCID site, we aim to perform a comprehensive, longitudinal validation of candidate biomarkers of CSVD in a diverse sample. We aim to recruit 400 participants over age 55 years with subjective cognitive complaints, mild cognitive impairment, or early dementia of presumed vascular etiology and retain at least 320 of them over the 5-year follow-up; ~60 will be persons seen in the UH3 phase and will have 7 years of follow- up. We will perform a comprehensive examination to collect medical history, biospecimens (blood, CSF), imaging (MRI with cerebrovascular reactivity, optical coherence tomography angiography), and neuropsychological data (cognition, CDR) following the protocols developed during the UH2/UH3 phases of the MarkVCID consortium. We will perform a follow-up examination with interim phone screenings for cognitive status and continuous dementia surveillance via consensus conferences. Further, we will offer brain autopsies to consenting participants for the assessment of clinicopathological correlates of VCID biomarkers. We will measure selected fluid and imaging biomarkers following established kit protocols and perform longitudinal clinical validation of biomarkers according to their pre-specified hypotheses. Finally, we will perform additional validation in four cohorts of the CHARGE consortium. Data, biospecimens, and results will be shared with the consortium and external qualified investigators through the designated MarkVCID coordinating center. Our team will have strong leadership with the PIs of the UH3 Seshadri, Fornage (multiple PI), Tracy (Co-I), a proven, young Co-I now taking over as Contact PI (Satizabal), and the addition of an exceptional stroke trials leader (Savitz).