MICROGLIAL, INFLAMMATORY AND OMICS MARKERS OF CEREBRAL SMALL VESSEL DISEASE IN THE CHARGE CONSORTIUM

Cerebral Small Vessel Disease (SVD) is an important, potentially modifiable factor for clinical dementia. Recent data suggest that the age-specific incidence of dementia may be decreasing, partly as a result of bettermanagement of vascular risk factors, lending urgency to dementia prevention trials but a major impediment isthe absence of circulating biomarkers for tracking onset and progression of SVD. Brain MRI imaging markers are the current gold standard for SVD but are too expensive and burdensome for repeated assessments.Recent genetic studies, including from the Cohorts for Heart & Aging Research in Genomic Epidemiology(CHARGE) consortium, implicate microglial inflammation and astroglia in the biology of SVD and dementia.We propose to measure 2 circulating biomarkers of microglial inflammation (sCD-14 and YKL-40) and amarker of astroglial injury (GFAP) in ~17,000 persons (including 4000 minority participants, 6000 with >2MRI) across 5 CHARGE population-based cohorts. Specifcally, we will (1) examine the association of the novel biomarkers with (a) previously collectedMRI-defined SVD (white matter hyperintensities, lacunar infarcts and cerebral microbleeds), and in personsunder age 70, sensitive MRI measures of early, preclinical SVD such as fractional anisotropy on diffusion-weighted imaging, regional cortical thinning and perivascular spaces; (b) previously collected measures ofcognitive function; and (c) neurocognitive and vascular consequences of SVD (dementia and stroke).We will use a Mendelian Randomization framework and existing genetic data to examine causal relationshipsbetween the novel biomarkers and MRI, neurocognitive, and clinical outcomes. (2) We will assess the incremental predictive utility of the novel biomarkers over (a) vascular riskfactor profiles such as the Framingham Stroke Risk Prediction score; (b) over a panel of previously measured`candidate' biomarkers for SVD including CRP, IL6, TNF-alpha, fibrinogen, BNP, urine albumin, tHcy, ST2,GDF15, TnI, BDNF, VEGF, MMP-9, beta-amyloid, clusterin and APOE and (c) we will identify a parsimonious set of biomarkers that best predict presence of SVD and risk of cognitive decline, stroke and dementia. In summary we propose to leverage extensive available data to identify and validate a novelcirculating biomarker profile of glial cell dysfunction that will improve our understanding of SVD biology andhelp in the prediction of SVD and its associated adverse neurological outcomes.