Blood Biomarkers for Brain Injury in Concussed Professional Ice Hockey Players

Abstract

IMPORTANCE Lack of objective biomarkers for brain damage hampers acute diagnosis and clinical decision making about return to play after sports-related concussion. OBJECTIVES To determine whether sports-related concussion is associated with elevated levels of blood biochemical markers of injury to the central nervous system and to assess whether plasma levels of these biomarkers predict return to play in professional ice hockey players with sports-related concussion. DESIGN, SETTING, AND PARTICIPANTS Multicenter prospective cohort study involving all 12 teams of the top professional ice hockey league in Sweden, the Swedish Hockey League. Two hundred eighty-eight professional ice hockey players from 12 teams contesting during the 2012-2013 season consented to participate. All players underwent clinical preseason baseline testing regarding concussion assessment measures. Forty-seven players from 2 of the 12 ice hockey teams underwent blood sampling prior to the start of the season. Thirty-five players had a concussion from September 13, 2012, to January 31, 2013; of these players, 28 underwent repeated blood sampling at 1, 12, 36, and 144 hours and when the players returned to play. MAIN OUTCOMES AND MEASURES Total tau, S-100 calcium-binding protein B, and neuron-specific enolase concentrations in plasma and serum were measured. RESULTS Concussed players had increased levels of the axonal injury biomarker total tau (median, 10.0 pg/mL; range, 2.0-102 pg/mL) compared with preseason values (median, 4.5 pg/mL; range, 0.06-22.7 pg/mL) (P < .001). The levels of the astroglial injury biomarker S-100 calcium-binding protein B were also increased in players with sports-related concussion (median, 0.075 μg/L; range, 0.037-0.24 μg/L) compared with preseason values (median, 0.045 μg/L; range, 0.005-0.45 μg/L) (P < .001). The highest biomarker concentrations of total tau and S-100 calcium-binding protein B were measured immediately after a concussion, and they decreased during rehabilitation. No significant changes were detected in the levels of neuron-specific enolase from preseason values (median, 6.5 μg/L; range, 3.45-18.0 μg/L) to postconcussion values (median, 6.1 μg/L; range, 3.6-12.8 μg/L) (P = .10). CONCLUSIONS AND RELEVANCE Sports-related concussion in professional ice hockey players is associated with acute axonal and astroglial injury. This can be monitored using blood biomarkers, which may be developed into clinical tools to guide sport physicians in the medical counseling of athletes in return-to-play decisions.

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“…Of note, previous studies have investigated the abovementioned markers in TBI patients and found evidence for increases in NFL, 53, 54 GFAP ,55 and Tau 56 concentrations, as well as decreased MBP ,57 in cerebral spinal fluid and/or serum. While serum and CSF were not analyzed in this study, RmTBI did affect expression of these markers in brain tissue in a similar manner.…”

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“…16,43 Upon reaching the brain, the proinflammatory signals interact with the resident brain immune system (eg, microglia and astrocyte populations), 3,9,27 causing a neuroinflammatory reaction and consequent neuronal dysfunction; this was shown in preclinical surgical models to affect CNS plasticity in brain regions relevant for higher cognitive functions. [1][2][3][4] We used plasma tau and NFL as markers of acute neuronal injury 39,40 on postoperative days 3 to 4 and at 3 months. The increase in plasma NFL concentrations with stable plasma tau concentrations over time suggests that no, or very limited, CNS neuronal injury occurred.…”

“…Another 10ml of arterial blood was sampled and directly centrifuged, and plasma was frozen for later analysis; the inflammatory molecules analyzed included interleukin-1b (IL-1b), IL-6, IL-8, IL-10, TNF-a, TNF-receptor 1 (TNF-R1), C-reactive protein (CRP), serum amyloid A (SAA), and brain injury markers neurofilament light chain (NFL) and tau. [38][39][40] For the ex vivo LPS challenge, triplicate blood samples were stimulated with LPS (Escherichia coli 0111:B4; Sigma, St Louis, MO; L2630) at a final concentration of 10ng/ml; as a control, phosphate-buffered saline was added to triplicate samples. Blood cultures were incubated on a rocking board at 378C, 5% CO 2 for 4 hours with 3mM adenosine triphosphate (Sigma, A2383) added for the last hour.…”

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“…Elevated serum and CSF levels of S100B have been observed in adult boxers after matches, and correlate positively with the number and severity of head impacts. 124,125 Increased serum S100B levels have also been observed in concussed professional ice hockey players, 126 with levels measured 1 h post-concussion predicting symptomatic recovery time. However, S100B levels were also raised after controlled play where no concussions occurred, indicating that this marker is not injury-specific.…”