NRSA: Zachary Winder: Investigating Angiogenic Mediators as Biomarkers and Targets for Rescuing Small Vessel Disease in a Model of VCID Year 3

Dementia is a disorder characterized by a significant decline from baseline in one or more cognitive domains that interferes with independence. Prevalence of dementia worldwide is estimated at 50 million with that number expected to triple by 2030, coming with a cost of roughly $2 trillion. Vascular Contributions to Cognitive Impairment and Dementia (VCID) is the second leading cause of dementia and is the umbrella term used to characterize patients with cognitive dysfunction as a result of cerebrovascular pathology. Small vessel disease (SVD) is one type of cerebrovascular pathology that is found in roughly 50% of patients with VCID. Common neuropathological findings associated with SVD include microinfarctions, microhemorrhages, and arteriolosclerosis. While MRI identifies larger infarctions and microbleeds, it is limited by resolution of the scan. Therefore, identification of these pathologies has proven difficult outside of post-mortem evaluation. White matter hyperintensities (WMH) on MRI have become the standard used to evaluate SVD; but are limited by their cost and lack of targetable mechanisms for preventing progression of the disease. In this proposal, we explore the role of angiogenic mediators as modifiable fluid biomarkers, which can be used to evaluate SVD and potentially altered to decrease progression of SVD. We focus on angiogenic mediators like vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PLGF) due to their upregulation in hypoxic environments, which are found in arteriolosclerosis. Our preliminary data suggests that patients with VCID have increased VEGF-A and PLGF concentrations compared to controls. Also, plasma VEGF-A is elevated in patients with an increased neuroinflammatory response in cases of mild cognitive impairment due to cerebrovascular disease. Additionally, previous studies have shown that these angiogenic mediators induce degradation of the extracellular matrix and the blood brain barrier, which are initiating steps in formation of microhemorrhages. This proposal first seeks to define the association between VEGF-A/PLGF and SVD pathology by comparing plasma samples from patients grouped by the evidence of arteriolosclerosis and microinfarctions (Aim 1). This will demonstrate the viability of VEGF-A and PLGF as fluid biomarkers of SVD pathology. Secondly, we will use a diet to induce a wellestablished model of VCID in PLGF-KO transgenic mice, to evaluate the role of PLGF on the development of microhemorrhages (Aim 2). This aim will help support our hypothesis that reducing availability of PLGF will reduce the burden of microhemorrhages in patients with SVD. Overall, this proposal will investigate the utility of VEGF-A and PLGF as modifiable fluid biomarkers for SVD; while also training the applicant in immunoassaybased biomarker discovery, statistical linear modeling, immunohistochemistry, pathological histology evaluation, mouse colony management, and oral and written scientific communications for a future career as an independent physician-scientist. Contact PD/PI: Winder, Zachary Project Summary/