CAPSTONE: Central And Peripheral STrOke inflammatioN with Exosomes

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Project Summary/Abstract Intracerebral hemorrhage (ICH) is a severe neurological disorder with no proven treatment. There is increasing evidence that inflammation contributes to ICH outcomes, but the underlying mechanisms remain largely unknown. ICH disproportionately affects ethnic/racial minorities and young people. Our preliminary data confirms reports that ICH survivors have a high rate of progressive cognitive decline, plausibly initiated by the aggressive ICH inflammatory response. Exosomes are extracellular vesicles released from cells into the circulating blood; by analyzing exosomes released from neurons and microglia, brain-specific inflammatory pathophysiology can be assessed by testing circulating plasma. Exosomes transport microRNA (miRNA) that are powerful regulators of gene expression. In our preliminary studies, three inflammatory mediators emerged as particularly salient in post-ICH inflammation and promising for additional analysis in a larger study: monocytes, interleukin-8 (IL-8), and miRNA (miR)-181a. We propose the CAPSTONE (Central And Peripheral STrOke inflammatioN with Exosomes) study that will enroll 250 ICH subjects previously recruited into the ROSE-LAWN study (Recovery of StrokE, Longitudinal Assessment With Neuroimaging, R01NS120493). CAPSTONE will utilize plasma, peripheral blood, and functional/cognitive outcomes from ROSE-LAWN; serial plasma and blood samples will be analyzed from baseline, three months, and 18 months after ICH. Through the following aims, we will pursue our overall goal to identify transcriptomic biomarkers associated with six-month functional outcome and long-term progressive cognitive decline. Specific Aim 1 will determine miRNA in neuronal- and microglial-derived exosomes that correlate with six-month functional outcome and long- term progressive cognitive decline (~24 months after ICH). We hypothesize that decreased miR-181a in neuronal and microglial exosomes will predict worse near-term functional outcome and greater long-term cognitive decline. Specific Aim 2 will determine mRNA and miRNA in peripheral leukocytes that correlate with six-month functional outcome and long-term progressive cognitive decline (~24 months after ICH). We hypothesize that decreased miR-181a and increased CXCL8 and IL-8 will predict worse functional outcome and greater long-term cognitive decline. Specific Aim 3 will explore the interactions between central and peripheral inflammatory processes post-ICH. We hypothesize that decreased miR-181a in neuronal- and microglial-derived exosomes will be associated with increased CXCL8 and IL-8 from peripheral leukocytes. Post-ICH inflammation is an interplay of both brain-derived and systemic pathology, but the associated molecular mechanisms remain poorly understood. By analyzing circulating blood (i.e., systemic) and cell-specific exosomes in plasma (i.e., brain derived), CAPSTONE seeks to provide substantial insight regarding these inflammatory processes. This research also addresses the NINDS priorities of recovery, imaging, and vascular cognitive impairment.