This is a competitive renewal of our two prior studies: "Methods of Predicting DCI in aSAH" (R01- NR004339-01), and "Role of 20-HETE on vasospasm-induced ischemia after aSAH" (R01NR004339-05). It is the long-term goal of this research to improve patient outcomes by utilizing biomarker-directed early- intervention strategies to reduce ischemic complications after aSAH. In the previous support period, our team identified key vasoactive metabolites, ET-1 and 20-HETE, which were predictive of cerebrovascular complications and long term outcomes. As the logical extension of this work, we propose to examine the key gene variants that regulate the production, degradation, and ion channel effects of these metabolites as they relate to DCI and neuropsychological outcomes. We hypothesize that variants in biomarker pathway genes will significantly contribute to the variability in biomarker concentrations, complications, and outcomes after aSAH.
The specific aims of this proposal are to determine the relationship between elevated cerebrospinal fluid (CSF) biomarkers (ET-1, 20-HETE, and EETs) and specific gene variants that lead to variation in their production and/or degradation;to examine the direct and mediated effects of gene variants in ET-1, 20-HETE, and EET pathways through CSF biomarkers on DCI, and to examine the direct and mediated effects of gene variants in ET-1, 20-HETE, and EET pathways through CSF biomarkers on functional and neuropsychological (NP) outcomes. We will recruit 192 patients with SAH (ages 18-75 years) in order to achieve a final sample of 145 patients available at twelve month follow up assessment. These subjects coupled with the 372 patients recruited to date will allow for the identification of the key genetic variants and the mediating effects of biomarker concentrations on DCI and NP outcomes. Elucidation of these relationships will allow for future development and evaluation of predictive models for identification of patients at high risk for cerebrovascular complications and poor outcomes after aSAH, thereby, allowing for directed intervention strategies to improve outcomes in this highly heterogeneous, understudied patient population.
Data from the proposed study, currently unexplored in persons with aneurysmal subarachnoid hemorrhage, will impact public health by serving as the basis for both therapeutic interventions designed to decrease the cascade of events that ultimately result in delayed cerebral ischemia and interventions to help patients compensate for long term deficiencies in physical and neuropsychological function.
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