How is concussion injury currently diagnosed?

A: Concussion injury—the mild form of traumatic brain injury (mTBI)—accounts for the majority of TBI cases, but is also the most difficult type of TBI to diagnose. The clinical tools currently used to assess TBI include the Glasgow Coma Scale (GCS), neuroimaging modalities, and serum biomarkers. GCS is an observational tool used to rate eye, verbal, and motor function responses of patients with suspected TBI, but oftentimes this tool misses mTBI because these patients tend to have responses on par with a healthy person’s. Frustratingly, confirmation with cranial computed tomography (CCT) isn’t always reliable either, as negative CCT scans (i.e., showing no detectable lesions) are also common in patients with mTBI. This lack of reliable diagnostic methods has spurred efforts to find brain-specific serum biomarkers for concussion.

What are the most promising blood biomarkers for concussion?

Most concussion biomarker tests are immunoassays that measure brain-derived proteins produced predominantly by neuronal cell bodies, astroglial cells, axons, or myelin sheath. Following a head injury, these proteins enter the bloodstream more readily, which increases their levels above baseline within minutes to hours. Some of the most well-studied protein biomarkers for concussion injury are glial fibrillary acidic protein (GFAP); ubiquitin C-terminal hydrolase-L1 (UCH-L1); calcium-binding protein S100, beta isoform (S100β); myelin basic protein; neuron-specific enolase; and prostaglandin D synthase.

Of these, only GFAP and UCH-L1 test kits from a single manufacturer have received Food and Drug Administration approval for in vitro diagnostic use in the U.S. Internationally, other test markers such as S100β also have been approved for diagnostic use.

What are the benefits and challenges associated with concussion biomarker tests?

Potential benefits of serum biomarkers for assessment of concussion injury include minimally invasive sample collection, faster turnaround time of test results, and cost savings from ruling out the need for expensive imaging tests like CCT.

However, there are many barriers to implementing these biomarkers in routine testing. These barriers include low market availability of approved test kits and lack of standardization across platforms, as well as challenges with achieving the analytical sensitivity needed to reliably detect very low serum concentrations of these biomarkers in healthy/non-concussed populations.

Currently, the clinical use of these biomarkers is also limited to ruling out concussion. This is because concussion biomarkers generally have excellent diagnostic sensitivity (i.e., a low false negative rate), but poor specificity compared to CCT, the accepted gold standard reference test. As a result, patients with positive biomarker test results must undergo a confirmatory CCT scan to eliminate false positives.

Could serum biomarker tests eventually improve concussion diagnosis?

Improving the reliability of positive test results for mTBI is an important goal. So far, investigators have found some success in this arena when combining results from multiple biomarkers to improve diagnostic or predictive outcome measures.

Another possible way to achieve this would be to establish reliable baseline concentrations of concussion biomarkers in healthy individuals using tests that reliably measure the very low blood concentrations typically observed in the general population. To establish a baseline, every at-risk individual (for example, military personnel, athletes in contact sports) would receive prescreen testing when in a healthy state. A serial sampling strategy could then be used to compare an individual’s initial result to that from a sample drawn after suspected concussion injury, similar to how high-sensitivity troponin assays are used to detect cardiac injury. In order to apply this approach to mTBI patients, researchers in the field would also have to collectively determine a critical difference/reference change value that indicates a positive change. This value could be based on clinical outcome studies, biological variation estimates, expert consensus, or some combination of these.

Paul R. Johnson, PhD, DABCC, is an associate professor of clinical laboratory science at Upstate Medical University in Syracuse, New York. +Email: johnspau@upstate.edu