Helping Make the Invisible, Visible: Plasma Biomarker Testing for the Evaluation of Traumatic Brain Injury

Although it does not receive as much attention as stroke, movement disorders, and multiple sclerosis, traumatic brain injury (TBI) has a high incidence and represents a significant public health burden. The Centers for Disease Control and Prevention (CDC) reported more than 200,000 TBI-related hospitalizations in 2020 and almost 70,000 TBI-related deaths in 2021.¹ Whether TBI is related to a car accident, a fall, or a blow to the head during a sporting event, the impact of brain injury is far-reaching with a range of impacts to health such as post-traumatic headache, mood disorders, cognitive impairment, seizures, and sleep and vision problems.² Understanding the impact of TBI on overall health underscores the need for quick, accurate, and accessible methods for TBI evaluation. But traditional protocols for TBI assessment have posed significant challenges in the clinical setting and have the potential to delay vital, time-sensitive treatment.³

This article provides an overview of the history of TBI evaluation, the development of plasma biomarker testing for the evaluation of TBIs, and ongoing initiatives to improve the care and outlook for individuals affected by brain injuries.

Current Evaluation of Potential Traumatic Brain Injury

Historically, evaluation of brain injury has involved documentation of the mechanism of injury sustained (blunt, nonpenetrating; penetrating; blast) as well as assessment of the effects of the injury on health, including neurologic effects such as consciousness and amnesia, which are assessed through the use of the Glasgow Coma Scale (GCS). The GCS was first published in 1974 and has been widely used since that time for evaluative purposes.⁴ To obtain a perfect score of 15 on the GCS, a patient needs to follow a command, such as making a fist, closing their eyes, speak spontaneously, and have their eyes open/tracking. These criteria are not always accurate in identifying all cases of TBI. For example, a lower score on the GCS is also associated with acute alcohol intoxication. Many variables can affect the GCS score, including the language ability of the patient, sociocultural factors, and behavioral issues, among other factors.^5-7

In addition to administering the GCS, physicians traditionally ask patients questions to assess potential memory impairment as part of their overall neurologic evaluation. This poses another obvious problem, as a patient with memory problems or amnesia may not realize they have memory problems or amnesia.

In addition to conducting a standard neurologic evaluation and obtaining a detailed patient history, clinicians will frequently order a CT scan to help identify evidence of hematomas, hemorrhage, contusions, skull fractures, and swelling. These scans are useful in some instances of TBI, as they can detect bleeding in the brain and skull fractures, but this imaging is usually negative in mild TBI even when injury has occurred.⁸ In addition, patients may feel uncomfortable or reluctant to receive a CT head scan because of concerns about exposure to radiation, the need to wait often prolonged periods of time to receive a head CT, and the added cost.

Current methods to evaluate brain injury have been useful to date, but there is clearly a need for additional objective measurements that would be helpful in the evaluation of brain injury and clinical decision-making.⁹

Development of Plasma Biomarker Testing for Evaluation of TBI

In 2014, responding to the complexity and shortcomings of existing methods of TBI evaluation and diagnosis, the United States Department of Defense (DoD) partnered with Abbott to develop TBI blood testing on a handheld platform to measure brain protein biomarkers within 15 minutes.¹⁰

Under this initiative, approximately 300 scientists worked together for 7 years developing an FDA cleared blood test that works on a portable, handheld device. This technology measures two different brain proteins that can be measured in the blood after a brain injury. The presence of these proteins (Glial Fibrillary Acidic Protein and Ubiquitin Carboxyl terminal Hydrolase L1) in plasma is indicative of injury.¹¹

Abbott’s i-STAT TBI Plasma Test

Abbott’s i-STAT TBI plasma test, developed to measure GFAP and UCH-L1 levels in plasma, received clearance from the Food and Drug Administration (FDA) in January 2021 (core was March 2023). Clearance was based on results from clinical trials, including the ALERT-TBI clinical trial (NCT01426919), which enrolled 2011 participants to investigate the efficacy of GFAP and UCH-L1 as plasma biomarkers predictive of traumatic intracranial injury. Results from this study demonstrated that GFAP and UCH-L1 were highly sensitive at predicting evidence of TBI and would have important clinical utility in helping to rule out the need for CT scans.¹²

Abbott’s i-STAT®TBI plasma test is available as a cartridge that can be used in the i-STAT Alinity handheld instrument (Figure 1). The test provides results in 15 minutes. The instrument analyzes blood plasma samples for the presence of GFAP and UCH-L1 at the picogram level—equivalent to the weight of DNA in 1 hummingbird cell.¹³

The key to these tests is the way that the concentrations of GFAP and UCH-L1 behave in plasma following brain injury. UCH-L1 levels peak right away after injury and then decrease over time, usually returning to baseline levels within 18 hours after injury. GFAP levels elevate immediately but peak later. 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.¹⁴

This TBI test is available in multiple settings on the i-STAT Alinity handheld instrument and as part of the Alinity Core Laboratory (Figure 2) which are available in hospitals across the United States and globally. When used in the emergency room (ER), the i-STAT TBI test can aid in rapid triage of patients, and the core lab platform would be essential in mass injury events, such as multi-car pile ups, which can be particularly burdensome for hospital systems. It is estimated that using the Abbott TBI plasma test can result in approximately 40% fewer CT scans in acute care settings, helping to free up valuable equipment and human resources in the hospital setting and helping patients avoid radiation exposure.¹⁵

Future Goals and the Importance of Prevention

The Abbott TBI test has been studied in multiple research studies to date, including those which have compared this test against other available assays.¹⁶ In addition, Abbott is currently researching a new form of the test using whole blood rather than plasma samples, which could expand the use of this test. The availability of this plasma biomarker test along with increasing recognition of the complex nature of TBI has led to a larger discussion in the medical community about how best to evaluate potential cases of TBI. Recommendations to include TBI blood tests have been put forth by various groups including American Congress of Rehabilitation Medicine (ACRM), The National Academies of Sciences, Engineering, and Medicine (NASEM), French guidelines, and Spanish consensus guidelines, with more on the way. The incorporation of regulatory cleared, objective testing into the evaluation of TBI is a very needed development that will affect clinicians and patients worldwide, helping to optimize the assessment of TBI, reduce unnecessary imaging testing, and reduce patient exposure to radiation.

The development of the Abbott TBI test along with discussions about optimal guidelines for the evaluation of TBI are part of a larger research and scientific efforts surrounding TBI, including work dedicated to addressing the post-TBI effects on health. The ultimate goal of this community is more timely, accurate assessment and treatment of this vulnerable patient group.

There are a variety of resources for clinicians to learn more about TBI research, including the International Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) initiative.