Serum SNTF Increases in Concussed Professional Ice Hockey Players and Relates to the Severity of Postconcussion Symptoms

Abstract

Biomarkers for diffuse axonal injury could have utilities for the acute diagnosis and clinical care of concussion, including those related to sports. The calpain-derived αII-spectrin N-terminal fragment (SNTF) accumulates in axons after traumatic injury and increases in human blood after mild traumatic brain injury (mTBI) in relation to white matter abnormalities and persistent cognitive dysfunction. However, SNTF has never been evaluated as a biomarker for sports-related concussion. Here, we conducted longitudinal analysis of serum SNTF in professional ice hockey players, 28 of whom had a concussion, along with 45 players evaluated during the preseason, 17 of whom were also tested after a concussion-free training game. Compared with preseason levels, serum SNTF increased at 1 h after concussion and remained significantly elevated from 12 h to 6 days, before declining to preseason baseline. In contrast, serum SNTF levels were unchanged after training. In 8 players, postconcussion symptoms resolved within a few days, and in these cases serum SNTF levels were at baseline. On the other hand, for the 20 players withheld from play for 6 days or longer, serum SNTF levels rose from 1 h to 6 days postconcussion, and at 12-36 h differed significantly from the less-severe concussions (p=0.004). Serum SNTF exhibited diagnostic accuracy for concussion, especially so with delayed return to play (area under the curve=0.87). Multi-variate analyses of serum SNTF and tau improved the diagnostic accuracy, the relationship with the delay in return to play, and the temporal window beyond tau alone. These results provide evidence that blood SNTF, a biomarker for axonal injury after mTBI, may be useful for diagnosis and prognosis of sports-related concussion, as well as for guiding neurobiologically informed decisions on return to play.

Keywords: calpain; diffuse axonal injury; mild traumatic brain injury; sports concussion; tau.

FIG. 1.

Sustained increase in serum SNTF concentrations in professional ice hockey players after concussion, but not concussion-free training. SNTF levels were measured in serum during the preseason (n=45) or serially after an in-game concussion (n=28), or before and after a training game (n=17). The mean serum SNTF levels (±standard error of the mean) were elevated at 1, 12, 36, and 144 h postconcussion, compared with the mean preseason baseline concentration, and the increases at the latter three time points were statistically significant (two-tailed t-test; *p<0.03; **p<0.002). At the time of return to play (RTP) after a period of rest, SNTF levels returned to their preseason baseline. In contrast to the pronounced effects of concussion, SNTF was unchanged 1 or 12 h after concussion-free training (p≥0.87). SNTF, calpain-derived αII-spectrin N-terminal fragment.

FIG. 2.

Serum levels of SNTF after concussion are related to serum tau, but not S100β. The mean serum SNTF concentration at 12 and 36 h postconcussion is linearly related to the serum tau concentration measured at 1 h postconcussion (A), but not to the serum level of S100β at 1 h (B). For measures of either SNTF or tau at all other time points, the correlation between the two markers is less strong (data not shown). Levels of each marker are represented in units (see Methods for more details). SNTF, calpain-derived αII-spectrin N-terminal fragment.

FIG. 3.

Diagnostic accuracy of serum SNTF and tau assessed by receiver operator characteristics AUC analyses. (A) Serum SNTF levels at 36 h postconcussion versus preseason levels. (B) Serum tau levels at 1 h postconcussion versus preseason levels. (C) Serum SNTF levels at 36 h for concussions with return to play ≥6 days versus preseason levels. (D) Mean serum SNTF levels at 12–36 h for concussions with return to play ≥6 days versus preseason levels. SNTF, calpain-derived αII-spectrin N-terminal fragment; AUC, area under the curve; CI, confidence interval.