Despite the marked increase in scientific attention to concussion and mild traumatic brain injury (TBI) in the past decade, the diagnosis and assessment of a concussion remain largely based on subjective symptom reporting. 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 sport-related concussion (SRC), in which head injuries are underreported and often unrecognized.1 The identification of an accurate and objective marker of TBI would be useful for improving identification of concussion and making critical return-to-play (RTP) decisions.2
Although many previous studies of brain biomarkers have focused on their value for identifying potentially life-threatening intracranial hemorrhage on head computed tomography scans,3 considerably fewer have examined their value for differentiating individuals with concussion from those without.4 The major challenges to performing these diagnostic biomarkers studies are ensuring that all participants have clinically defined concussion and that they are compared with appropriately matched controls.
These challenges were addressed in the study by McCrea et al,5 who used a prospective case-control design to investigate the association of SRC with 4 serum markers associated with TBI: glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light chain (NF-L), and total tau. In a sample of 264 collegiate athletes with concussion who were compared with 138 individuals who played contact sports and did not have concussion and 102 individuals who did not play contact sports or have concussion as controls, McCrea et al5 identified significant increases in the acute postinjury period in GFAP, UCH-L1, and tau levels, but not NF-L levels, in athletes with concussion compared with preseason baseline levels and both control groups.
Among athletes with concussion, GFAP levels remained elevated compared with baseline at all other measured postinjury points: 24 to 48 hours (median, 41.25 hours after injury), asymptomatic (median, 6.96 days), and 7 days after RTP (median, 21.41 days). Compared with baseline measurements, athletes with concussions also had significantly increased NF-L levels at 7 days after RTP, and NF-L was the only biomarker that was significantly elevated at this time point in a more severely injured subgroup of athletes with loss of consciousness (LOC) or posttraumatic amnesia (PTA). Additionally, increased GFAP level was independently associated with the classification of athletes with concussion vs both control groups after adjusting for postconcussive symptoms determined using the Sport Concussion Assessment Tool–Third Edition.5 This is a particularly noteworthy finding, suggesting that it may be possible to diagnose SRC with the help of biomarkers and independently of self-reported symptoms, which are notoriously unreliable. Further studies are needed to determine whether GFAP improves the discriminative ability of the Sport Concussion Assessment Tool for distinguishing between individuals with concussion and those without.
While the investigation of these 4 biomarkers is not novel, the rigorous approach in the largest athlete cohort to date, to our knowledge, makes the study by McCrea et al5 important, timely, and clinically relevant. An important strength of this study was the ability to measure preinjury and serial, longitudinal, postinjury biomarker levels in the same individuals. Unfortunately, by not performing a more thorough analysis of individual-level changes in biomarker levels from baseline to each time point, the authors did not take full advantage of their study design. A detailed analysis of absolute and relative changes in biomarker levels between baseline and the acute postinjury period would have provided insights into the amount of change in biomarker levels that may be relevant for clinical decision-making. Findings from a 2014 study6 suggest that this analytical approach improves classification accuracy between individuals with concussion vs those without. The group analysis of biomarker changes from before injury to the acute postinjury period among athletes with concussion may be biased by missing data, since only 100 of 264 athletes with concussion (38%) contributed samples at the acute postinjury time point. Although athletes who contributed samples at the acute postinjury time point had acute clinical severity (estimated by Sport Concussion Assessment Tool scores) similar to those who did not contribute samples, this is no guarantee that the distribution of biomarker values in these 2 groups would be similar.
While the study by McCrea et al5 provides evidence that these 4 biomarkers, particularly GFAP, are elevated in the acute period after concussion, it is not clear how soon after injury these elevations can be detected. Acute samples were acquired a median of 3.42 hours after injury, with the lower end of the interquartile range being 1.52 hours. This is relevant because the most critical RTP decisions are often made in the minutes after a suspicious head hit, typically on the sideline of an athletic contest. The diagnostic utility of biomarkers acquired at later time points, at which point the clinical diagnosis may have already been determined, might be less impactful.
Although the biomarkers used in the study by McCrea et al5 were associated with a modest ability to distinguish individuals with concussion from control groups without concussion, the longitudinal trajectories of these biomarkers yielded important insights into SRC. Biomarker values among athletes with concussion with LOC or PTA were higher than among those without LOC or PTA, suggesting that these alterations in mental state at the time of injury may represent a more severe form of SRC. That marker values remained elevated at 7 days after RTP compared with baseline values further suggests incomplete molecular recovery in these athletes with more severe concussion. Incomplete molecular recovery at RTP may not be confined to athletes with LOC or PTA. Among all athletes with concussion, McCrea et al5 reported significant increases in UCH-L1 and tau levels at the asymptomatic to 7-day post-RTP time points, suggesting persistent increased molecular risk to the stressors associated with full sport participation, potentially including subconcussive head impacts. A similar post-RTP increase in biomarkers has also been reported by Shahim et al.7 These findings indicate the need for future research investigating the significance of incomplete molecular recovery associated with functional outcomes and subsequent neurologic health of athletes in contact sports returning to full sport participation.
In summary, the study by McCrea et al5 advances our knowledge of the associations of SRC with biochemical markers associated with TBI. It remains to be seen whether these biomarkers can contribute to individual RTP decisions. As McCrea et al5 point out, it will be important to quantify the prognostic accuracy associated with these biomarkers measured at each postinjury time point. This will help inform whether these biomarkers may be used for prognosticating outcomes from concussion, in addition to aiding in diagnosing concussion.
Published: January 24, 2020. doi:10.1001/jamanetworkopen.2019.19799
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Bazarian JJ et al. JAMA Network Open.
Corresponding Author: Jeffrey J. Bazarian, MD, MPH, Department of Emergency Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY 14642 (email@example.com).
Conflict of Interest Disclosures: Dr Bazarian reported serving on a scientific advisory board for Abbott Laboratories outside the submitted work. No other disclosures were reported.
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Bazarian JJ, Korley F, Mannix R. Biomarkers May Provide Unique Insights Into Neurological Effects Associated With Sport-Related Concussions. JAMA Netw Open. 2020;3(1):e1919799. doi:10.1001/jamanetworkopen.2019.19799
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