Biomarkers in the Hyperbaric Oxygen in Brain Injury Treatment Trial

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

Traumatic Brain Injury (TBI) is a major cause of death and disability both in the United States and worldwide. A critical barrier to progress in drug development for TBI is the lack of monitoring biomarkers for assessing individual patient response to treatment. At present, clinical examination remains the fundamental tool for monitoring severe TBI patients and for subject selection in clinical trials. However, these patients are typically intubated and sedated, limiting the utility of clinical examinations. Validated monitoring biomarkers will allow titration of the dose of promising therapeutics to individual subject response, while validated predictive biomarkers make clinical trials more efficient by enabling the enrollment of subjects likely to benefit. A monitoring biomarker is assessed serially over time to measure the status/extent of a disease, or to provide evidence of the effect of an intervention. Blood levels of glial fibrillary acidic protein (GFAP), Ubiquitin Carboxyl Hydrolase L1 (UCH-L1) are promising as monitoring biomarkers for TBI. The scientific premise for their role as monitoring biomarkers is as follows: 1) GFAP and UCH-L1 are both cellular proteins found in astrocytes and neurons respectively. They are predominantly brain-specific. 2) GFAP and UCH- L1 are released post-TBI in amounts that are proportional to injury severity (measured by CT or clinical exam). These biomarkers discriminate between TBI subjects with versus without intracranial hemorrhage on CT. GFAP and UCH-L1 levels can identify TBI patients with structural brain abnormalities that are seen only on MRI and not on head CT. Their levels are correlated with TBI lesion volume as measured by head CT. Put together, this evidence suggests that these biomarkers quantitatively measure the extent of neurodegeneration post- TBI. To date, the variability in GFAP and UCH-L1 levels during the first few hours following injury has not been well characterized. Therefore, it is difficult to distinguish between acute and chronic elevations of GFAP and UCH-L1 based on an initial value. We hypothesize that serial measurements of GFAP and UCH-L1 performed during the first few hours following injury may allow clinicians to distinguish between acute and chronic elevations of GFAP and UCH-L1. The specific aim for the supplementee's research project is: To determine whether there are differences in short-term (2 and 4 hour) changes in plasma GFAP and UCH-L1 levels among patients with acute neurologic injury compared to control subjects who are either 1) healthy or 2) have an acute orthopedic injury but no acute neurologic injury or 3) have a chronic neurologic injury.