Finding a Biomarker of Concussion
Finding a biomarker has been the holy grail of concussion research. Without an accurate biomarker we are left with using subjective symptoms and relatively weak objective tests of the functional response to concussion as our means for diagnosing and determining recovery.
Recently McCrea et al found that a combination of biomarkers in acutely concussed college athletes was significantly different from their baseline levels and different from non-concussed controls. When the reductions in GFAP, UCH-L1, and tau were combined in the analysis, they appeared to provide a sensitive indicator of injury. Finding a combination of biomarkers has been long-suspected as the most likely approach to finding a sensitive biological indicator of concussion.
Association of Blood Biomarkers With Acute Sport-Related Concussion in Collegiate Athletes: Findings From the NCAA and Department of Defense CARE Consortium
IMPORTANCE There is potential scientific and clinical value in validation of objective biomarkers for sport-related concussion (SRC).
OBJECTIVE To investigate the association of acute-phase blood biomarker levels with SRC in collegiate athletes.
DESIGN, SETTING, AND PARTICIPANTS This multicenter, prospective, case-control study was conducted by the National Collegiate Athletic Association (NCAA) and the US Department of Defense Concussion Assessment, Research, and Education (CARE) Consortium from February 20, 2015, to May 31, 2018, at 6 CARE Advanced Research Core sites. A total of 504 collegiate athletes with concussion, contact sport control athletes, and non–contact sport control athletes completed clinical testing and blood collection at preseason baseline, the acute postinjury period, 24 to 48 hours after injury, the point of reporting being asymptomatic, and 7 days after return to play. Data analysis was conducted from March 1 to November 30, 2019.
MAIN OUTCOMES AND MEASURES Glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light chain, and tau were quantified using the Quanterix Simoa multiplex assay. Clinical outcome measures included the Sport Concussion Assessment Tool–Third Edition (SCAT-3) symptom evaluation, Standardized Assessment of Concussion, Balance Error Scoring System, and Brief Symptom Inventory 18. RESULTS A total of 264 athletes with concussion (mean [SD] age, 19.08 [1.24] years; 211 [79.9%] male), 138 contact sport controls (mean [SD] age, 19.03 [1.27] years; 107 [77.5%] male), and 102 non–contact sport controls (mean [SD] age, 19.39 [1.25] years; 82 [80.4%] male) were included in the study. Athletes with concussion had significant elevation in GFAP (mean difference, 0.430 pg/mL; 95%CI, 0.339-0.521 pg/mL; P < .001), UCH-L1 (mean difference, 0.449 pg/mL; 95%CI, 0.167-0.732 pg/mL; P < .001), and tau levels (mean difference, 0.221 pg/mL; 95%CI, 0.046-0.396 pg/mL; P = .004) at the acute postinjury time point compared with preseason baseline. Longitudinally, a significant interaction (group Å~ visit) was found for GFAP (F7,1507.36 = 16.18, P < .001), UCH-L1 (F7,1153.09 = 5.71, P < .001), and tau (F7,1480.55 = 6.81, P < .001); the interaction for neurofilament light chain was not significant (F7,1506.90 = 1.33, P = .23). The area under the curve for the combination of GFAP and UCH-L1 in differentiating athletes with concussion from contact sport controls at the acute postinjury period was 0.71 (95%CI, 0.64-0.78; P < .001); the acute postinjury area under the curve for all 4 biomarkers combined was 0.72 (95%CI, 0.65-0.79; P < .001). Beyond SCAT-3 symptom score, GFAP at the acute postinjury time point was associated with the classification of athletes with concussion from contact controls (β = 12.298; 95%CI, 2.776-54.481; P = .001) and non–contact sport controls (β = 5.438; 95%CI, 1.676-17.645; P = .005). Athletes with concussion with loss of consciousness or posttraumatic amnesia had significantly higher levels of GFAP than athletes with concussion with neither loss of consciousness nor posttraumatic amnesia at the acute postinjury time point (mean difference, 0.583 pg/mL; 95%CI, 0.369-0.797 pg/mL; P < .001).
CONCLUSIONS AND RELEVANCE The results suggest that blood biomarkers can be used as research tools to inform the underlying pathophysiological mechanism of concussion and provide additional support for future studies to optimize and validate biomarkers for potential clinical use in SRC.
Citation: McCrea, M., Broglio, S. P., McAllister, T. W., Gill, J., Giza, C. C., Huber, D. L., Harezlak, J., Cameron, K. L., Houston, M. N., McGinty, G., Jackson, J. C., Guskiewicz, K., Mihalik, J., Brooks, M. A., Duma, S., Rowson, S., Nelson, L. D., Pasquina, P., Meier, T. B., … DiFiori, J. (2020). Association of Blood Biomarkers With Acute Sport-Related Concussion in Collegiate Athletes: Findings From the NCAA and Department of Defense CARE Consortium. JAMA Network Open, 3(1), e1919771. https://doi.org/10.1001/jamanetworkopen.2019.19771
Notes: GFAP: Glial fibrillary acidic protein GFAP is thought to help to maintain astrocyte mechanical strength as well as the shape of cells. Astrocytes provide physical and metabolic support for neurons, detoxification, guidance during migration, regulation of energy metabolism, electrical insulation (for unmyelinated axons), transport of blood-borne material to the neuron, and reaction to injury.
UCH-L1: Ubiquitin C-terminal hydrolase-L1: UCH-L1 is an enzyme that is abundantly present in all neurons. Reductions have been noted in neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Reductions may signal neuron degeneration.
Tau: Tau is a family of proteins that have roles in maintaining the stability of microtubules in axons and are abundant in the neurons of the central nervous system. Excessive tau has been associated with CTE.