Academy of Diagnostics & Laboratory Medicine - Scientific Short
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Mild traumatic brain injury (mTBI) accounts for over 90% of all TBI cases and is defined by a Glasgow Coma Scale (GCS) score between 13 and 151. Yet, nearly half of these cases are inaccurately diagnosed2. With an estimated 69 million cases worldwide each year, there remains a significant gap in the diagnosis and treatment of mTBI1 .
Computed tomography (CT) is a commonly used tool for diagnosing mTBI, but fewer than 20% of patients actually have an identifiable intracranial abnormality on CT3. Many patients undergo unnecessary CT scans, which increase radiation exposure, burden the healthcare system, and lead to longer wait times and treatment delays.
While no blood-based biomarkers can directly diagnose TBI, several FDA-cleared laboratory tests are now available to help reduce unnecessary CT scans. This article compares these tests and discusses how they are addressed in clinical guidelines to help laboratory professionals decide which tests may be appropriate for their own settings.
All currently FDA-cleared TBI assays measure two proteins—glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1)—which are associated with astrocyte activation and neuronal damage following brain trauma. When both GFAP and UCH-L1 are not elevated, this is typically associated with the absence of acute intracranial lesions on head CT, suggesting that imaging may not be necessary. Studies have shown that using these tests could reduce the number of CT scans by up to 40%4. Despite their potential, these biomarker tests must be used in conjunction with other clinical information. They are intended for patients aged 18 or older with suspected mild TBI (GCS 13–15), and blood samples must be collected within 12 hours of injury—except for one test that allows up to 24 hours.
The first test to receive FDA authorization was the Banyan Brain Trauma Indicator in 2017 through the de novo premarket review pathway, which used a chemiluminescent ELISA to measure GFAP and UCH-L15. Although this test was never marketed due to its long turnaround time and lack of automation, it served as the predicate for subsequent FDA-cleared tests.
Following this, the GFAP and UCH-L1 plasma test was cleared for use on Abbott’s handheld i-STAT Alinity device. It provided faster results (about 15 minutes) and required a small sample volume (20 µL)6. The technology used electrochemical detection instead of chemiluminescence and tested serum instead of plasma. However, this version was not approved for point-of-care use and was limited to core labs. In 2023, Abbott received FDA clearance to run the GFAP and UCH-L1 test on its Alinity i and ARCHITECT platforms. These automated systems returned to using chemiluminescent detection and offered kits with 100 tests per pack7,8.
In 2024, bioMérieux received FDA clearance for its VIDAS TBI test, which also measures GFAP and UCH-L1 using enzyme-linked fluorescent detection. Unlike Abbott’s platforms, which support both plasma and serum, the VIDAS test uses serum only and has a longer time to result (about 40 minutes)9. Also in 2024, a new i-STAT Alinity TBI cartridge was cleared for use with venous whole blood collected in EDTA tubes10. This version finally received approval for point-of-care testing, making it more suitable for emergency departments. It also extended the sample collection window to within 24 hours of injury10.
Despite the availability of these tests, recent guidelines from organizations like the Department of Defense11, and the American College of Emergency Physicians12 do not yet recommend the use of blood biomarkers for diagnosing mTBI, citing limited evidence. Instead, they continue to endorse validated clinical decision rules such as the Canadian CT Head Rule (CCHR), New Orleans Criteria (NOC), and NEXUS II, which rely on risk factors like age, mechanism of injury, loss of consciousness, amnesia, vomiting, neurological deficits, and signs of skull fracture to guide CT use.
However, clinician surveys show dissatisfaction with these decision rules, as some rely on subjective clinical judgment and lack standardization, and studies have shown they may have suboptimal sensitivity and specificity. As a result, 86% of clinicians express strong interest in blood-based testing as a more objective alternative13. As validation studies continue to support the utility of blood-based tests, in 2023, the American Congress of Rehabilitation Medicine (ACRM) began recommending the use of elevated blood biomarkers to help triage patients for CT imaging and potentially identify mTBI even when CT findings are negative14. The 2024 FACS guidelines went further, stating that GFAP and UCH-L1 levels may help estimate the severity of underlying brain injury15.
Even though all currently FDA-cleared TBI tests have high sensitivity—typically over 95%—their specificity remains low (around 30% to 42%)16. As a result, they are better suited for ruling out rather than ruling in injury. Additionally, some studies have questioned the added value of UCH-L1 when combined with GFAP. While UCH-L1 was originally included to improve sensitivity, recent data suggest that GFAP alone may outperform the combination in certain settings17. GFAP and UCH-L1 levels can vary significantly based on factors such as age and systemic injuries, yet the currently approved cut-off values are not stratified accordingly18.
In summary, while current blood-based biomarker tests for mTBI offer promising tools for triage and CT reduction, their clinical adoption will depend on continued validation, refined cutoff strategies, and alignment with evolving guidelines.
