Test selection and clinical integration of blood-based biomarkers for mild traumatic brain injury

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 15^1. 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 pack^7,8.

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.

References

1. Maas AIR, Menon DK, Manley GT, et al. Traumatic brain injury: progress and challenges in prevention, clinical care, and research. Lancet Neurol. Nov 2022;21(11):1004-1060. doi:10.1016/S1474-4422(22)00309-X 
2. Powell JM, Ferraro JV, Dikmen SS, Temkin NR, Bell KR. Accuracy of mild traumatic brain injury diagnosis. Arch Phys Med Rehabil. Aug 2008;89(8):1550-5. doi:10.1016/j.apmr.2007.12.035 
3. Isokuortti H, Iverson GL, Silverberg ND, et al. Characterizing the type and location of intracranial abnormalities in mild traumatic brain injury. J Neurosurg. Dec 1 2018;129(6):1588-1597. doi:10.3171/2017.7.JNS17615 
4. Bazarian JJ, Biberthaler P, Welch RD, et al. Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study. Lancet Neurol. Sep 2018;17(9):782-789. doi:10.1016/S1474-4422(18)30231-X 
5. FDA. DEN170045 EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR Banyan Brain Trauma Indicator, DECISION MEMORANDUM 2017; 
6. FDA. K201778 Premarket Notification for i-STAT TBI Plasma cartridge with the i-STAT Alinity System 510(k) 2021; 
7. FDA. K232669 Summary of Safety and Effectiveness for Abbott Laboratories TBI Assessment Test. 2023; 
8. FDA. K223602 Summary of Safety and Effectiveness for Abbott Laboratories TBI Assessment Test. 2023;
9. FDA. K240279 SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY for VIDAS TBI (GFAP, UCH-L1) 2024; 
10. FDA. K234143 SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY for i-STAT TBI Cartridge with the i-STAT Alinity System. 2024; 
11. DOD. VA/DOD Clinical Practice Guidelines: Management and Rehabilitation of Post-Acute Mild Traumatic Brain Injury (mTBI) (2021). 2021; 
12. Jagoda AS, Bazarian JJ, Bruns JJ, Jr., et al. Clinical policy: neuroimaging and decisionmaking in adult mild traumatic brain injury in the acute setting. Ann Emerg Med. Dec 2008;52(6):714-48. doi:10.1016/j.annemergmed.2008.08.021 
13. Papa L, Ladde JG, O'Brien JF, et al. Evaluation of Glial and Neuronal Blood Biomarkers Compared With Clinical Decision Rules in Assessing the Need for Computed Tomography in Patients With Mild Traumatic Brain Injury. JAMA Netw Open. Mar 1 2022;5(3):e221302. doi:10.1001/jamanetworkopen.2022.1302 
14. Silverberg ND, Iverson GL, members ABISIGMTTF, et al. The American Congress of Rehabilitation Medicine Diagnostic Criteria for Mild Traumatic Brain Injury. Arch Phys Med Rehabil. Aug 2023;104(8):1343-1355. doi:10.1016/j.apmr.2023.03.036 
15. FACS. Best Practices Guidelines on the Management of Traumatic Brain Injury. 2024; 
16. Kobeissy F, Arja RD, Munoz JC, et al. The game changer: UCH-L1 and GFAP-based blood test as the first marketed in vitro diagnostic test for mild traumatic brain injury. Expert Rev Mol Diagn. Jan-Feb 2024;24(1-2):67-77. doi:10.1080/14737159.2024.2306876 
17. Chayoua W, Visser K, de Koning ME, et al. Evaluation of Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 Using a Rapid Point of Care Test for Predicting Head Computed Tomography Lesions After Mild Traumatic Brain Injury in a Dutch Multi-Center Cohort. J Neurotrauma. Jul 2024;41(13-14):e1630-e1640. doi:10.1089/neu.2023.0491 
18. Papa L, Brophy GM, Welch RD, et al. 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. May 1 2016;73(5):551-60. doi:10.1001/jamaneurol.2016.0039