Research in the field of truamatic brain injury (TBI) has long been dominated by research on severe brain injury, yet mild and moderate TBI (MMTBI) comprise over 90% of all cases. The pathophysiology and severity of MMTBI are difficult to determine from clinical and radiological measures acutely. Physicians and researchers are limited by the lack of clinical tools for risk stratification of these patients soon after their injury. Many investigators have suggested that the lack of biomarkers of injury has contributed to the gap in knowledge of TBI pathophysiology and the failure of clinical trials. Biochemical markers of injury would serve to improve clinical care of these patients in many ways, such as: 1) assessing risk for intracranial bleeding;2) determining need for diagnostic imaging;3) determining need for neurosurgical intervention;4) assessing need for admission;5) helping with return to play/work/duty decisions;6) determining risk for long-term impairment;and 7) helping to reduce exposure to ionizing radiation. Moreover, from a research perspective, biomarkers could provide clinical trial outcome measures that are quick and cost-effective and help to identify long awaited drug therapies. Unique to this proposal is the assessment of biokinetic properties of the individual biomarkers that will provide insight into their temporal profiles and half-lives. Three novel serum-based assays will be assessed in this protocol as will two already commercially available assays.
Specific Aim 1 will assess the diagnostic utility of these five candidate biomarkers in MMTBI patients by examining relationships between levels of specific biomarkers in blood and injury severity, intracranial abnormalities on CT scan, and need for neurosurgical intervention.
Specific Aim 2 will assess the prognostic utility of candidate biomarkers by examining the relationship between levels of specific biomarkers, their biokinetic parameters, complications and long-term neuropsychosocial outcome.
Specific Aim 3 will prospectively validate in a separate group of patients a diagnostic/prognostic panel of biomarkers measured in blood selected on the basis of data from Specific Aim 1 and 2. The results of this study could provide a blood test that could be used immediately after injury to diagnose and treat patients with TBI. Ultimately, we hope this proposal will provide physicians and researchers the tools they need to improve patient care and long-term outcome in patients with TBI.

Public Health Relevance

Despite many years of research, there are no blood tests commercially available to diagnose a brain injury. The proposed study will work to develop a blood test (biomarkers, or substances that are not normally present in our blood but are released from the brain after it has been damaged) that doctors could use to diagnose and treat patients after they have suffered a brain injury. These biomarkers could tell us how serious a head injury is through taking a simple blood test, and thus, would revolutionize and improve the care of patients with brain trauma by helping doctors identify injuries earlier, determine if patients need a CT Scan of the head, determine if patients need brain surgery, determine if patients can return safely home or to work or to playing sports, and if patients will have complications from their injury. It would also help researchers to test new treatments for brain injury that could help patients recover and have a better quality of life.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Hicks, Ramona R
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Orlando Regional Healthcare System, Inc.
United States
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Papa, Linda; Mittal, Manoj K; Ramirez, Jose et al. (2017) Neuronal Biomarker Ubiquitin C-Terminal Hydrolase Detects Traumatic Intracranial Lesions on Computed Tomography in Children and Youth with Mild Traumatic Brain Injury. J Neurotrauma 34:2132-2140
Papa, Linda; Brophy, Gretchen M; Welch, Robert D et al. (2016) Time Course and Diagnostic Accuracy of Glial and Neuronal Blood Biomarkers GFAP and UCH-L1 in a Large Cohort of Trauma Patients With and Without Mild Traumatic Brain Injury. JAMA Neurol 73:551-60
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Papa, Linda; Mittal, Manoj K; Ramirez, Jose et al. (2016) In Children and Youth with Mild and Moderate Traumatic Brain Injury, Glial Fibrillary Acidic Protein Out-Performs S100? in Detecting Traumatic Intracranial Lesions on Computed Tomography. J Neurotrauma 33:58-64
Papa, Linda; Ramia, Michelle M; Edwards, Damyan et al. (2015) Systematic review of clinical studies examining biomarkers of brain injury in athletes after sports-related concussion. J Neurotrauma 32:661-73
Papa, Linda; Zonfrillo, Mark R; Ramirez, Jose et al. (2015) Performance of Glial Fibrillary Acidic Protein in Detecting Traumatic Intracranial Lesions on Computed Tomography in Children and Youth With Mild Head Trauma. Acad Emerg Med 22:1274-82
Papa, Linda; Silvestri, Salvatore; Brophy, Gretchen M et al. (2014) GFAP out-performs S100? in detecting traumatic intracranial lesions on computed tomography in trauma patients with mild traumatic brain injury and those with extracranial lesions. J Neurotrauma 31:1815-22
Papa, Linda; Lewis, Lawrence M; Silvestri, Salvatore et al. (2012) Serum levels of ubiquitin C-terminal hydrolase distinguish mild traumatic brain injury from trauma controls and are elevated in mild and moderate traumatic brain injury patients with intracranial lesions and neurosurgical intervention. J Trauma Acute Care Surg 72:1335-44
Papa, Linda; Stiell, Ian G; Clement, Catherine M et al. (2012) Performance of the Canadian CT Head Rule and the New Orleans Criteria for predicting any traumatic intracranial injury on computed tomography in a United States Level I trauma center. Acad Emerg Med 19:2-10
Papa, Linda; Lewis, Lawrence M; Falk, Jay L et al. (2012) Elevated levels of serum glial fibrillary acidic protein breakdown products in mild and moderate traumatic brain injury are associated with intracranial lesions and neurosurgical intervention. Ann Emerg Med 59:471-83

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