Investigating Angiogenic Mediators as Biomarkers and Targets for Rescuing Small Vessel Disease in a Model of VCID

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Project Summary 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 placental growth factor (PLGF) due to its upregulation in hypoxic environments, which is found in arteriolosclerosis. Our preliminary data suggests that patients with VCID have increased PLGF concentrations compared to controls. Additionally, previous studies have shown that PLGF induces degradation of the extracellular matrix and the blood brain barrier, which are initiating steps in formation of microhemorrhages. This proposal first seeks to evaluate whether plasma PLGF is upregulated in patients with increased levels of SVD pathology, as measured in post-mortem neuropathological evaluation (Aim 1a) and whether PLGF has a tight spatial co-localization with SVD pathology in human tissue (Aim 1b). This will demonstrate the viability of PLGF as a fluid biomarker for SVD pathology. Secondly, we will use a diet to induce a well-established model of VCID in PLGF-KO transgenic mice, to evaluate the role of PLGF on 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. This mechanism can then be used to develop novel therapeutics in order to halt the progression of VCID. Through this proposal and under the mentorship of Dr. Wilcock and Dr. Jicha at the Sanders-Brown Center on Aging, the applicant will investigate the utility of PLGF as a modifiable fluid biomarker for SVD. In doing so, the applicant will be trained in immunoassay-based biomarker discovery, statistical linear modeling, clinical patient evaluation, immunohistochemistry, pathological histology evaluation, and oral and written scientific communications for a future career as an independent physician-scientist.