Sex Steroids and IGF1 in the CNS Following aSAH and Their Relationship to Patient Outcomes

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PROJECT SUMMARY Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating neurologic insult that accounts for more than 25% of stroke related deaths. Survival after aSAH is often complicated by the development of delayed cerebral ischemia (DCI) and long term disability. Although aneurysm repair techniques have improved, predictors of risk for poor outcomes or interventions that substantially improve outcomes remain elusive. Based on evidence from the literature and our preliminary data, we believe that sex steroids are promising biomarkers following neurological injury including aSAH, but there is a gap in understanding their individual and collective roles in pathophysiology and outcome in humans, specifically following aSAH. Sex steroids control local inflammation, mediate vasodilation and are known molecular regulators of cell survival. IGF1 is a peptide hormone that exerts pro- survival signals in virtually every cell type, including the neurons, glia, and micro-vessels of the neurovascular unit and has been linked to estrogen mediated neuroprotection. Biomarker concentration and bioactivity are influenced by genetic predisposition. We posit that neuroprotective properties of sex steroids following aSAH depend on a complex balance between sex steroids, IGF1, and genetic factors - linkages that previously have not been investigated. The goal of this proposed project is to better determine (1) the biological underpinnings of sex steroids and IGF1 in the central nervous system following aSAH and (2) their relationships with patient outcomes. Our highly successfully research team will utilize a well characterized and longitudinally phenotyped cohort of 536 aSAH patients with linked DNA, plasma and cerebrospinal fluid (CSF) samples which are available from an existing aSAH biorepository to: 1) examine the relationship between sex steroid and IGF1 concentrations during the first 14 days following aSAH to the development of DCI and 3- and 12-month patient outcomes; 2) examine the ability of plasma to predict CSF levels of biomarkers indicative of the brain's response to injury for patients without CSF access; and 3) determine the ability of polymorphisms in candidate genes specific to the sex steroid and IGF1 biosynthetic pathway to differentiate patients at risk for DCI and poor outcomes at 3- and 12-months following aSAH. Cross-sectional and trajectory models will be generated from daily aSAH plasma and CSF sex steroid levels (i.e., E2, E1, testosterone and androstenedione) measured by liquid chromatography-tandem mass spectrometry and IGF1 concentrations measured by ELISA. The Custom iPLEX MassArray platform will be used to examine candidate genes involved in the biosynthetic pathway of sex steroids and IGF1. Results from this proposed study will (1) lead to a better determination of the biologic underpinnings and mechanisms for variability in patient outcomes after aSAH, (2) identify stable genetic predictors of unfavorable outcomes (i.e. death and disability), and (3) inform the development of evidence-based personalized interventions (e.g., receptor modulators) to mitigate the burden and consequences of aSAH.