Biomarkers Pave the Way for Concussion Blood Test

A new study has identified at least two blood biomarkers that could be used to diagnose concussion.

"At present, concussion is diagnosed clinically by observed signs and self-reported subjective symptoms. The challenge we face is the lack of an objective marker of concussion," lead author Michael McCrea, PhD, told Medscape Medical News.

"If we could combine subjective clinical symptoms and objective physiological markers, that would give the greatest predictive ability," he said.

McCrea, who is codirector of the Center for Neurotrauma Research at the Medical College of Wisconsin, Milwaukee, said the current work is the largest study of biomarkers in sports-related concussion ever conducted, with two control groups. Pre-injury baseline measures in concussed individuals are available, and blood samples were taken at multiple time points.

"Our current results are a great start towards the development of a blood test for concussion," he commented. "The results are positive and suggest strong support for the utility of some of these biomarkers, but our results are not enough on their own to turn the tide and form a test for widespread clinical use given the resources that that would require."

He says a future blood test for concussion would probably need to include several different biomarkers.

"We believe no single biomarker will be the answer, but rather a panel of best-performing biomarkers will be needed. We have identified two biomarkers that could potentially be included in such a panel in this study, but we need to find others, maybe from other areas of brain injury mechanisms," McCrea added.

"Our current results will help in the design of future research studies, but they also pave the way for the prospect of clinical utility," he said.

The study was published online January 24 in JAMA Network Open.

'Important, Timely, and Clinically Relevant'

An accompanying editorial describes the study as "important, timely, and clinically relevant."

In their article, McCrea and colleagues note that, during the past decade, several candidate biomarkers have emerged as potential diagnostic markers of traumatic brain injury. Sports-related concussion represents the most subtle and mild form of traumatic brain injury, and consequently, diagnosis is often challenging because of the need to rely on subjective self-reported symptoms that are not specific to mild traumatic brain injury, they add.

The current study is one of many being conducted as part of the CARE Consortium, a large-scale effort funded by the US Department of Defense (DOD) and the National Collegiate Athletic Association (NCAA), to understand more about concussion and recovery in soldiers and athletes.

"This includes understanding about the effects of concussion symptoms such as headache and cognitive deficits, and how long it takes for these to resolve, and a new great frontier — the effects on brain structure and function and the time course of neurobiological injury," McCrea said.

The current study investigated levels of four blood biomarkers in 264 collegiate varsity athletes with acute sports-related concussion and compared these with preseason baseline levels in the same individuals. The blood biomarker levels were also compared with two closely matched athlete control groups without concussion, which included 138 contact sport controls and 102 noncontact sport controls.

Results showed that the group of athletes with concussion had significant elevation of three biomarkers — glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), and tau — at the acute time point (6-24 hours after injury) compared with preseason baseline levels.

"This suggests potential utility and relevance in sports-related concussion," McCrea said.

The combination of two of the biomarkers, GFAP and UCH-L1, were found to be useful for differentiating athletes with concussion from contact sport controls, with an area under the curve (AUC) of 0.71.

"An AUC of 0.71 shows a reasonable ability to differentiate between concussion and nonconcussion," McCrea explained. "But to maximize clinical certainty, we would like to find an optimal set of biomarkers that would produce an AUC of 0.9. That would be a test that would outperform most clinical measures."

Elevations in the acute post-injury time point were most evident in GFAP and UCH-L1, two biomarkers recently granted clearance by the US Food and Drug Administration for clinical use in identifying the presence of underlying intracranial injury after more severe traumatic brain injury.

Useful for Triaging Patients

GFAP remained elevated in athletes with concussion up to 24-48 hours after injury; and levels of both GFAP and neurofilament light chain (NF-L) were even more elevated for several days in athletes with more serious concussions, as indicated by loss of consciousness or post-traumatic amnesia.

Researchers note that the potential role of blood biomarkers in sports-related concussion is accentuated by the fact that neuroimaging study results are normal in most athletes with acute concussion.

They also point out that most of the biomarkers tested showed a dose–response in terms of severity of traumatic brain injury, which they say could be particularly valuable when triaging patients in critical care settings.

They note that the goal of biomarkers should not be to replace signs and symptoms in the clinical diagnosis of concussion but rather to augment clinical specificity and confidence with more objective indicators of brain injury.

"I believe biomarkers will prove to have great value but they will never replace skilled clinicians and sports trainers evaluating injured athletes," McCrea added.

In their editorial, Jeffrey Bazarian, MD, University of Rochester Medical School, New York, Frederick Korley, MD, PhD, University of Michigan Medical School, Ann Arbor, and Rebekah Mannix, MD, Boston Children's Hospital, Massachusetts, note that the symptoms of concussion are nonspecific and highly prevalent in the general population.

"As such, the accurate and timely diagnosis of concussion is a challenge for many clinicians. This challenge is amplified in the setting of sports-related concussion in which head injuries are under-reported and often unrecognized," they write.

They point out that in the current study, some of the biomarkers remained elevated after symptoms had resolved and athletes had been cleared for return to play, suggesting persistent increased molecular risk to the stressors associated with full sport participation.

"These findings indicate the need for future research investigating the significance of incomplete molecular recovery associated with functional outcomes and subsequent neurologic heath in athletes in contact sports returning to full sport participation," they add.

The editorialists conclude that it remains to be seen whether these biomarkers can contribute to individual decisions on return to play, and that it will be important to quantify their prognostic accuracy at each post-injury time point to help inform whether they may be used for predicting outcomes as well as aiding in the diagnosis of concussion.

McCrea has reported receiving grants from the US DOD and NCAA during the conduct of the study and research funding from the National Institute of Neurological Disorders and Stroke, Centers for Disease Control and Prevention, and National Football League outside the submitted work. Bazarian has reported serving on a scientific advisory board for Abbott Laboratories outside the submitted work.

JAMA Netw Open. Published online January 24, 2020. Full text, Editorial

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