Blood Protein Cutoffs Help Clinicians Identify Brain Injury That CT Scans Miss

Clinician-scientists at the University of Pittsburgh School of Medicine and collaborating institutions have reported clinical cutoffs for two brain-associated proteins detected in blood after head injury, a step they hope will sharpen the identification and triage of patients with traumatic brain injury whose diagnoses might otherwise be missed. The findings, published in the Journal of Neurosurgery by a multi-institutional research team led by Pitt neurosurgery clinician-scientists, define concentration thresholds for the proteins glial fibrillary acidic protein, known as GFAP, and ubiquitin c-terminal hydrolase-L1, known as UCH-L1, that may help clinicians decide which patients with brain injury need escalated care and which can be safely sent home. The work is aimed at expanding the use of blood-based biomarker testing for traumatic brain injury, a condition that remains difficult to confirm objectively in many emergency department patients.

The scale of the problem is substantial. Approximately 2.8 million people experience a traumatic brain injury each year in the United States, and the condition carries significant mortality, morbidity and long-term disability. Shawn Eagle, Ph.D., assistant professor in Pitt’s Department of Neurological Surgery and lead author of the study, noted that the outlook for many patients seen after head trauma remains grim. “There are amazingly poor long-term outcome rates for people with a TBI who get seen in the emergency department,” Eagle said. His team’s central concern is that a large share of these poor outcomes may stem not from the injuries themselves but from failures in identification, meaning patients who would benefit from specialized follow-up never receive it.

The new cutoffs emerge from TRACK-TBI, a federally funded, multi-center, longitudinal study designed to give physicians better tools to diagnose brain injuries and support their patients. Pitt’s Neurotrauma Clinical Trials Center, directed by David Okonkwo, M.D., Ph.D., professor of neurological surgery at Pitt and director of neurotrauma at UPMC, and co-led by Ava Puccio, R.N., Ph.D., associate professor of neurological surgery at Pitt, collects data and biospecimens from patients with traumatic brain injury presenting at the emergency department and serves as the primary biorepository for the study. That infrastructure allowed the researchers to compare blood protein levels against the imaging findings that currently drive clinical decisions in patients with Glasgow Coma Scale scores of 13 to 15, the mild end of the injury spectrum.

Previous findings from TRACK-TBI underline the stakes of accurate identification. More than 50 percent of participants in the study who had a mild brain injury were found to have functional limitations at one year after their injury. Eagle suspects that a major driver of these poor long-term outcomes is that patients are not being properly identified in the first place. “Prior to this research, in the absence of a positive CT scan, there was no objective way to identify if you had a brain injury,” Eagle said. In other words, for the many patients whose head computed tomography scans come back negative, clinicians have lacked a measurable, biological signal to confirm that an injury occurred at all.

For a patient presenting with a traumatic brain injury, a head CT scan is generally the first-line evaluation tool. CT scans are inexpensive and widely available, and they can quickly identify acute injuries, which makes them well suited to the time pressures of emergency care. But the technology has a documented blind spot. Approximately 25 percent of patients have intracranial pathologies that CT scans miss. “We’re sending people home with a negative CT scan, but 1 in 4 have an abnormality visible on MRI indicating that they should have specialized follow-up care,” Eagle said. That gap between what CT detects and what is actually present in the brain is precisely the population the new biomarker cutoffs are designed to reach.

Magnetic resonance imaging offers a more sensitive and detailed look at brain tissue and can capture injuries that a head CT may miss, which explains why so many patients with normal CT scans continue to have symptoms. However, MRI scans are slow, costly and inappropriate for patient triage in an emergency setting, so they cannot serve as a practical first filter for the thousands of head injury patients who pass through emergency departments. A blood test measuring the two proteins released from the brain after injury offers an alternative pathway. In 15 minutes, clinicians can use the test to rule out unnecessary imaging in patients with mild traumatic brain injury, reserving advanced imaging and specialized care for those whose biomarker levels indicate genuine concern.

The conceptual twist in the new study involved reversing the usual logic of the test. “We were curious about how the test would perform if you flipped it on its head,” Eagle said. “What level could you be pretty certain that someone does have a bleed in their head versus certainty that they don’t?” Rather than using the biomarkers only to exclude injury, as earlier applications did, the researchers asked whether specific concentration levels could actively confirm the presence of intracranial pathology. The clinical cutoffs reported in the Journal of Neurosurgery represent the answer: threshold values for the two proteins that distinguish between patients with mild traumatic brain injury who had positive CT scans and those with negative CT scans, and, importantly, between patients who had negative CT scans but positive MRI results and patients whose CT and MRI scans were both negative.

The biology of the two proteins explains why they behave differently as diagnostic signals. Within 24 hours of traumatic brain injury, the researchers found that the level of GFAP in the blood could be used to differentiate patients with acute brain injury from those with no evidence of pathology on neuroimaging. GFAP is released from glial cells in the brain and shows a rapid acute spike between 4 and 20 hours after injury, followed by a slow decline over the days that follow, a time course that makes it well matched to the window in which emergency department patients are evaluated. In contrast, UCH-L1, a protein released from neurons, showed less ability to distinguish between the different groups tested in this study, making GFAP the stronger of the two markers for the classifications the team examined.

A practical advance increases the feasibility of moving these cutoffs into routine care. A point-of-care, whole-blood version of the test is now available, meaning it can be performed at the bedside rather than requiring that samples be sent to a laboratory for processing. That distinction matters in emergency settings, where triage decisions must be made quickly and where delays in laboratory turnaround could erase the advantage the biomarkers provide. “We’re working to incorporate this test into the daily clinical practice in the ED,” Eagle said. He expects that increased adoption will lead to broader uses for the test, and he is actively exploring whether blood biomarkers could help predict long-term outcomes for patients following traumatic brain injury, extending the technology from diagnosis into prognosis.

The study, titled “Clinical cutoffs for plasma biomarkers to identify intracranial pathology in traumatic brain injury patients with Glasgow Coma Scale scores 13 to 15: a TRACK-TBI study,” was published with a digital object identifier of 10.3171/2026.3.JNS252691, and additional authors are listed in the Journal of Neurosurgery article. Funding was provided by the Department of Defense through multiple awards, including W81XWH-13-1-0441, W81XWH-14-2-0176, W81XWH-18-2-0042 and W81XWH-15-9-0001, and by the National Institute of Neurological Disorders and Stroke through grants U01NS086090, U01NS1365885 and RC2NS069409. The reported conflict-of-interest disclosures include grants and consulting fees from diagnostic companies and federal funders to several co-authors, declared in the journal article. For now, the cutoffs give emergency clinicians something they have not had before: a rapid, measurable blood signal that, alongside CT, can identify intracranial pathology in injured patients whose scans alone would have sent them home.

Subject of Research: Clinical blood biomarker cutoffs for identifying intracranial pathology in traumatic brain injury

Article Title: Blood test can help clinicians better identify brain injury severity in patients

Article References: Blood test can help clinicians better identify brain injury severity in patients. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: traumatic brain injury, GFAP, UCH-L1, blood biomarkers, emergency department triage, head CT scan, MRI, TRACK-TBI, University of Pittsburgh, Journal of Neurosurgery, point-of-care testing, mild TBI