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Original Investigation |

Blood Biomarkers for Brain Injury in Concussed Professional Ice Hockey Players

Pashtun Shahim, MD1; Yelverton Tegner, MD, PhD2; David H. Wilson, PhD3; Jeffrey Randall, PhD3; Tobias Skillbäck, MD1; David Pazooki, MD, PhD4; Birgitta Kallberg, BSc5; Kaj Blennow, MD, PhD1; Henrik Zetterberg, MD, PhD1,6
[+] Author Affiliations
1Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden
2Division of Medical Sciences, Department of Health Sciences, Luleå University of Technology, Luleå, Sweden
3Quanterix Corp, Lexington, Massachusetts
4Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
5Clinical Chemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
6Reta Lila Weston Laboratories, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, England
JAMA Neurol. 2014;71(6):684-692. doi:10.1001/jamaneurol.2014.367.
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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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Figure 1.
Preseason and Postconcussion Levels of Total Tau (T-tau), S-100 Calcium-Binding Protein B (S-100B), and Neuron-Specific Enolase (NSE)

A, Plasma T-tau was higher in postconcussion samples (all times) compared with preseason samples. There were no significant changes in the serum levels of S-100B (B) and NSE (C) after concussion compared with preseason samples. Horizontal lines indicate medians.

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Figure 2.
Total Tau (T-tau), S-100 Calcium-Binding Protein B (S-100B), and Neuron-Specific Enolase (NSE) Measured at Selected Times in Concussed Hockey Players

A, Concentrations of T-tau peaked during the first hour after concussion. The levels declined significantly (P < .001) during the first 12-hour period. Further declines in T-tau between 12 and 144 hours were not statistically significant (P = .15). Concentrations of T-tau remained elevated 144 hours after concussion compared with preseason levels (P = .002). B, Similar to T-tau, the levels of S-100B peaked during the first hour after concussion and declined during the first 12-hour period (P < .001). C, Concentrations of NSE remained unchanged over time after concussion. RTP indicates return to play.

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Figure 3.
Biomarker Concentration Time Course Profile in Concussed Hockey Players

The spline curves represent the concentration time course of total tau (T-tau) (A), S-100 calcium-binding protein B (S-100B) (B), and neuron-specific enolase (NSE) (C) in relation to preconcussion levels, estimated on the basis of preseason values from 2 complete teams, from 1 hour after concussion until players return to unrestricted competition. The vertical lines represent the time of brain injury.

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Figure 4.
Biomarker Concentrations in Relation to Severity of Brain Injury

Total tau (T-tau) (A), S-100 calcium-binding protein B (S-100B) (B), and neuron-specific enolase (NSE) (C) concentrations 1 hour after concussion are shown in relation to concussion severity. Values are presented as means; error bars indicate standard error of mean; and PCS indicates postconcussive symptoms. Concentrations of T-tau (D), S-100B (E), and NSE (F) 1 hour after concussion are shown in relation to resolution of PCS and return to play. One player returned to play 69 days after concussion. Another resigned owing to persistent PCS and was entered as more than 90 days in the graph.

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Figure 5.
Diagnostic Accuracy of the Biomarkers

Area under the receiver operating characteristic curve (AUC) for total tau (T-tau), S-100 calcium-binding protein B (S-100B), and neuron-specific enolase (NSE) concentrations 1 hour after concussion vs biomarker concentrations after a friendly game (A) and 1 hour (B) and 144 hours (C) after concussion in players with persistent postconcussive symptoms for more than 6 days vs biomarker concentrations after a friendly game.

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