KL2 Scholar Scope - ProBDNF/BDNF EV Expression to Predict Cognitive Decline with VCID

Amanda Trout Abstract Vascular contributions to Cognitive Impairment and Dementia (VCID) encompasses a spectrum of cerebrovascular changes ranging from the often catastrophic damage following acute stroke to the chronic, progressive, and dementia-associated small vessel disease (SVD). Since the extent of vascular injury causing ischemia can vary greatly, a key barrier for early/ presymptomatic detection of VCID is identifying a biomarker for cognitive changes associated with all ischemic cerebrovascular injury. One understudied yet highly-relevant source for plasma biomarkers of cerebrovascular injury are extracellular vesicles (EVs). EVs are small (30-150 nm) lipid bound particles, released from all cells, that are able to transfer cargo, including proteins and nucleic acids, from one cell to another. Content within the EV is cell type-specific and a direct response of the cellular environment. Brain-derived neurotrophic factor (BDNF) is a neurotrophin found in EVs that preserves brain structure and function during aging, is neuroprotective, and correlates negatively to cognitive decline. BDNF exists in the pro (i.e., uncleaved) and mature forms, with elevated proBDNF associated with neuronal apoptosis. I hypothesize that systemic circulating concentrations of proBDNF/BDNF in EVs will be a highly sensitive biomarker for predicting cognitive changes with VCID. To investigate this hypothesis, I propose the following specific aims: Identify EV proBDNF/BDNF expression acutely (SA.1A) and longitudinal (SA.1B) during a large vessel stroke and longitudinally in SVD (SA.2) as a predictor of subsequent cognitive impairment. Successful completion of these studies will advance the field and suggest at therapies for VCID.