Predictive accuracy of acute astroglial compromise biomarkers after traumatic brain injury

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ABSTRACT The absence of fast, simple, and reliable ways to accurately diagnose and monitor the status of patients suffering from traumatic brain injury (TBI) is a significant public health burden. In neurotrauma research there is a large disconnect between bench and bedside that prevents new discoveries from being more easily translated into the clinic. To that end, this project will establish the injury foundation for new blood-based biomarkers that will inform on the magnitude of brain tissue wounding beyond tissue loss, to enable early and objective assessment of the burden of injury across the spectrum of TBI severities. Astroglial health and vulnerability following injury are important drivers for continued protection of neurons, because of their key roles in the neuro- vascular unit, including providing metabolites, orchestrating blood flow and maintaining the blood-brain barrier. Consequently, traumatic astroglial wounding contributes to brain energy deficits, ion imbalance, edema, barrier leak and neuronal death, because neurons are heavily co-dependent on normal astroglial function. The team recently identified a novel brain specific panel of Astroglial Injury Defined (AID) biomarkers comprised of two cell wounding released markers and cell death generated protein fragments. Importantly, AID markers are clinically validated in several cohorts for assessing severe and mild TBI patients. In reverse translational studies AID markers early and accurately predicted functional recovery after neurotrauma. In this proposal, mild and moderate severity levels of cortical contusion in male and female rat will be used to assess AID biomarker levels and their association with early astroglial injury pathophysiologies, as well as overall outcome. The over-arching hypotheses are that: the acute post-injury rise and temporal profiles of AID biomarkers will significantly correlate with the magnitude of early astroglial injury, and will accurately predict behavioral dysfunction and final structural outcome. This will be accomplished in phase 1 of this proposal over two aims focusing on: (1) correlating serum-based biomarkers to acute brain metabolic depression and astroglial microstructural wounding evidence, and (2) determining longitudinal biomarker profiles and their prediction of chronic injury burden and behavioral outcomes. Phase 1 milestones will: (1) validate AID markers for correlation to cerebro-metabolic and microstructural evidence of injury severity at acute post-injury times, and (2) demonstrate accuracy of AID markers to predict the microstructural and behavioral deficits or recovery chronically. Success in meeting these milestones by passing multiple statistical criteria will result in transition to phase 2 which will repeat the mild injury experiment to assess reproducibility, and conduct new studies on a closed head injury to assess the effect of single versus repeat injury, thus determining applicability across models. Fidelity of these biomarkers as accurate correlates of the initial injury magnitude will ultimately translate and guide diagnostic monitoring of TBI patients, enable severity stratification of clinical trials, and provide better prognosis for recovery.