Real-World Experience Using Biomarker Testing for the Evaluation of Acute Traumatic Brain Injury

Traumatic brain injury (TBI) continues to impact a significant number of people with nearly 190 TBI-related deaths each day in the United States and 2.5 million related emergency department (ED) visits each year.¹ Although mortality related to TBI has been decreasing over the last decade, nearly one third of all injury-related deaths involve TBI. ED visits related to TBI have grown dramatically, partly owing to increases in an aging population, rising 53% between 2007 and 2013, according to data provided by the Centers for Disease Control and Prevention (CDC).¹ In addition to the major morbidity, mortality, and healthcare utilization consequences of TBI, there is a significant associated economic burden – roughly $80 billion dollars in all.²

Research initiatives, beginning with the NIH/NINDS Common Data Elements Initiative from the National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) and most recently in the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) clinical trial and related studies, have resulted in real progress in our understanding about the mechanisms of injuries associated with TBI as well as details about biomarkers, varying clinical courses, and outcomes. Studies have also underscored the heterogenous nature of brain injuries, and the challenges associated with the evaluation and treatment of individuals experiencing such injuries.³

Given the volume of ED visits associated with the evaluation of potential cases of TBI and the complexity and significance of brain injuries, there is the need for efficient, cost-effective methods for the evaluation of TBI.³

Current Evaluation of Suspected TBI

Whether the result of blunt, nonpenetrating forces or a penetrating injury, current evaluation of potential cases of TBI includes a standard assessment of the extent of injury, including level of consciousness, evidence of amnesia, and conducting the Glasgow Coma Scale (GCS). Depending on the results of these initial assessments, neuroimaging testing with CT may be recommended to provide additional details about lesion type, location, and volume that can assist the clinician in evaluating potential cases of TBI.⁴

Numerous studies have identified limitations with this current evaluative approach, including the lack of specificity of GCS/CT scans in predicting posttraumatic impairment. Admittedly, the GCS has great merit as an initial screening tool in the ED, but with respect to TBI, it does not fully take into account different injury types, different injury severities, and different injury locations. It may be challenging to perform the GCS in certain populations, such as those who may be intoxicated, in those with cognitive impairment, or in those presenting with behavioral issues, including agitation and underlying neuropsychiatric symptoms.^5,6

CT scans do provide valuable details about injuries to the brain involving brainstem compression, hemorrhages, hematomas, edema, and lesions. This imaging technique may miss finer injuries, however, such as smaller contusions as well as subarachnoid hemorrhage. In fact, researchers have estimated that up to 30% of individuals with mild TBI have intracranial pathologies that are undetectable by CT testing. This is a significant number of individuals who are potentially being underdiagnosed with TBI and all that entails in terms of subsequent suboptimal triage, lack of appropriate follow-up, and adverse health-related quality of life for affected patients.⁷

In contrast with CT tests, MRI scanning is more sensitive in detecting evidence of brain injury, including small cortical contusions and hemorrhagic diffuse axonal injury. MRI’s increased sensitivity can improve long-term outcomes in TBI, as demonstrated in a study by Yuh et al on the predictive value of MRI over 3 months. Unfortunately, implementation of large-scale MRI assessment for TBI is not feasible due to factors like costs, availability of equipment, patient acuity, and so forth.⁸

The Utility of Biomarkers in TBI Evaluation

As well as analyzing neuroimaging biomarkers of TBI, researchers have evaluated potential serum biomarkers of brain injury, including tau, ubiquitin C-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP). Much of this research was spearheaded by the US Department of Defense working with Abbott on scalable options for the evaluation and detection of markers of TBI.⁹ Study results demonstrated that two of these proteins, UCH-L1 and GFAP, were highly sensitive at predicting evidence of TBI and had important clinical utility in helping to rule out the need for CT scans. UCH-L1 and GFAP are in many ways ideal biomarkers for TBI not only because they can be detected in blood but because they provide insights into the timing of brain injuries. UCH-L1 is released into the bloodstream very quickly, peaks in approximately 6-8 hours, then returns to baseline levels in 12-18 hours. GFAP rises later, peaks in approximately 20 hours, and remains detectable for several days. These consistent concentrations of GFAP and UCH-L1 following brain injury allow for the evaluation of patients at variable times following injury, providing the widest diagnostic window possible—essential in real world scenarios in which a patient could present for evaluation immediately following trauma or some time thereafter.^10,11 After correlating levels of these proteins with TBI in individuals who had positive CT scans suggestive of TBI, researchers also found that serum UCH-L1 and GFAP levels correlated with MRI findings of TBI in those with negative CT scans. A recent study by TRACK-TBI researchers published in 2024 found that GFAP had favorable predictive value beyond the first 24 hours post-injury, including 3-, 5- and 14-days following injury.¹²

Abbott’s TBI Biomarker Blood Tests

Based on favorable findings from a variety of studies including the ALERT-TBI clinical trial (NCT01426919), the Food and Drug Administration (FDA) cleared Abbott’s i-STAT TBI test cartridge first for the evaluation of plasma samples in clinical laboratory settings for the presence of UCH-L1 and GFAP in January 2021, followed by clearance for evaluation of whole blood samples at the point-of-care/patient’s bedside in April 2024.^11,13 Abbott also received FDA clearance for the first commercially available lab-based blood test in March 2023, which provides healthcare facilities with multiple options their clinicians can utilize to help assess concussions.

Abbott’s i-STAT TBI test cartridge can be used on the i-STAT Alinity System handheld instrument and provides results in 15 minutes. The instrument analyzes whole blood samples for the presence of GFAP and UCH-L1 at the picogram level to assist in determining the need for a head CT and can be conducted at point-of-care up to 24 hours following injury in adults aged 18 years and older.¹⁴

Abbott’s Alinity i Immunoassay System provides a reliable result in 18 minutes to help clinicians quickly assess concussion and triage patients. Similar to the i-STAT TBI test, it measures the same two biomarkers in the blood and for those with negative results, it rules out the need for a CT scan and can eliminate wait time at the hospital. The Alinity i Immunoassay System previously received European Union clearance and has been available in markets outside the U.S. since 2021. The Alinity i Immunoassay System is also FDA cleared and available in the U.S. since July 2023.

Real-World Experience of Using Blood Based Biomarkers in Practice

Although the recently cleared Abbott i-STAT TBI test cartridge has only been in use for a few months, before using the test in practice, it’s important to consider patient selection criteria and how the test can be integrated within current evaluative processes.

The optimal use of Abbott’s TBI biomarker blood tests is in conjunction with a standard initial assessment of potential head injury along with GCS scoring. It is a helpful test to rule out the need for CT imaging for patients whose results are not elevated. When used for this purpose, the test has the potential to help free up valuable resources in ED and imaging departments and save patients from having an unnecessary CT scan. And with the i-STAT TBI test cartridge specifically, being able to perform the test at the patient’s bedside and provide results in 15 minutes can help expedite the overall assessment process. It’s important to note that an individual could have elevated test results but have a normal head CT scan. Furthermore, the Abbott tests are useful to assess intoxicated patients.

In addition, in the future there may be utility for neurologists to monitor GFAP/UCH-L1 levels after the acute phase of TBI to determine lingering effects of TBI on the brain.¹⁵

Future Directions

The field of biomarker testing for TBI is evolving but answering additional questions can be beneficial to our understanding. Questions like:

• Could elevated GFAP levels be associated with specific types of brain injuries and/or with injuries affecting specific brain regions?
• What is the role of biomarker testing beyond the initial injury window, and what are the downstream physiologic effects of brain injuries on immunity?
• What is the role of other potential biomarkers, including C reactive protein, in TBI?¹⁶
• And finally, could GFAP be a potential biomarker in assessing other neurologic conditions, including Alzheimer disease and NMOSD?¹⁵

Conclusion

Biomarker testing for UCH-L1 and GFAP using the Abbott TBI blood biomarker tests incorporated into the standard evaluation process for cases of potential mild TBI has a strong evidence base, can save valuable financial, medical personnel, and equipment resources, and can improve patient health, helping to spare patients from unnecessary testing. Protocols need to be updated to ensure that biomarker testing is included in decision-making algorithms.