Acute Plasma Tau Predicts Prolonged Return to Play After Concussion

Among collegiate athletes, elevated plasma tau concentrations within six hours after a sport-related concussion predict a prolonged recovery, according to research published online ahead of print January 6 in Neurology. This finding suggests that tau levels may help to determine when athletes should return to play. Variability of tau concentrations across athletes and the effect of physical exertion on plasma tau may complicate the use of the biomarker for concussion management, however.

Approximately 3.8 million sport-related concussions occur each year in the United States, but no biomarkers are known to predict recovery and an athlete’s readiness to return to play. Postconcussive symptoms typically resolve within 10 days in about half of collegiate athletes, but symptoms are chronic in a subset of patients. Shahim et al found that plasma tau elevations predicted a return to play of more than 10 days in professional ice hockey players in Sweden.

Diagnosing Sport-Related Concussion

Jessica Gill, RN, PhD, an investigator with the National Institute of Nursing Research at the NIH, and colleagues conducted a study to determine whether changes in plasma tau after sport-related concussion relate to return to play in men and women collegiate athletes. The researchers included students with concussion, as well as athlete and nonathlete controls. The athletes participated in various National Collegiate Athletic Association (NCAA) division I and III contact sports (ie, football, soccer, basketball, hockey, and lacrosse).

Jessica Gill, RN, PhD

Between 2009 and 2014, 632 athletes underwent plasma sampling and cognitive testing prior to the sports seasons and were followed prospectively for a diagnosis of sport-related concussion. Sport-related concussions were witnessed by an on-field certified athletic trainer and met the Sport Concussion Assessment Tool 2 definition of concussion.Investigators collected blood samples from athletes with concussion and athlete controls at six hours, 24 hours, 72 hours, and seven days after a concussion. Nonathlete controls had blood draws at an unrelated time point. Investigators measured total tau using an ultrasensitive immunoassay.

Return to play for each athlete was determined by athletic trainers or team physicians. They followed NCAA guidelines, which recommend that athletes be asymptomatic at rest and as they progressively resume activity before returning to play.

A total of 46 athletes were diagnosed with a sport-related concussion. Concussions occurred between 19 days and 218 days after baseline assessments (mean, 92.3 days). Thirty-seven athletes without concussion served as athlete controls. Athletes with and without concussion did not differ significantly in sport played, history of sport-related concussion, or other demographic features. A control group of 21 healthy nonathletes was demographically similar to the athlete groups.Return to play information was available for 41 of the athletes with concussion. Athletes who took more than 10 days to recover were considered to have a long return to play (23 athletes). Those who recovered in less than 10 days had a short return to play (18 athletes). The mean return to play duration was 21.68 days (range, two days to 263 days). Five athletes had a return to play duration of 30 days or more. Approximately 39% returned to play in less than 10 days. There were no significant differences in sport played or history of concussion among those with long return to play versus short return to play. Women made up 61% of the long return to play group and 28% of the short return to play group.

Tau Measurements

Compared with nonathletes, athletes had significantly higher mean tau concentrations at baseline and all other time points. The longitudinal pattern of tau differed significantly between athletes with and without concussion. Athletes with concussion had significantly lower mean total tau at 24 hours (6.06 pg/mL vs 7.89 pg/mL) and 72 hours (5.19 pg/mL vs 6.94 pg/mL), compared with athlete controls.

Athletes with a long return to play had higher tau concentrations overall, after controlling for sex, than those with a short return to play. The differences were statistically significant at six hours (10.98 pg/mL vs 7.02 pg/mL), 24 hours (7.19 pg/mL vs 4.08 pg/mL), and 72 hours (6.29 pg/mL vs 3.94 pg/mL).

Mean change in tau from baseline also significantly differed between the return to play groups. Athletes with long return to play had a mean increase of 2.26 pg/mL at six hours postconcussion, compared with a mean reduction of 1.19 pg/mL in the short return to play group, after controlling for sex. Area under the curve (AUC) analyses revealed that higher total tau six hours post concussion and change in tau from baseline to six hours post concussion predicted long return to play (AUC of 0.81 and 0.80, respectively). Higher total tau at 72 hours postconcussion also was a significant predictor of long return to play (AUC, 0.82).

“These findings suggest that changes in total tau within six hours of a sport-related concussion may provide vital information about return to play decisions, and may serve to mitigate the negative consequences of returning to play prematurely,” Dr. Gill and colleagues said. Preclinical models link insufficient recovery time from a mild traumatic brain injury (mTBI) to greater neuropathology following a subsequent mTBI, including pathology that overlaps with that of chronic traumatic encephalopathy.

Lower levels of tau in athletes with concussion, compared with athletes without concussion, at 24 hours and 72 hours “may be due to the effects of physical exertion on tau,” the researchers said. Limitations of the study include the relatively small sample size within subanalyses of long and short return to play.

More Research Is Needed

“While normally measured in CSF, tau measured in blood could provide the opportunity to assess neurologic injury shortly after concussion, as well as facilitate monitoring of recovery over time,” said Barbara B. Bendlin, PhD, Associate Professor of Medicine and Public Health at the University of Wisconsin–Madison, and Michael Makdissi, MBBS, PhD, research fellow at the Florey Institute of Neuroscience and Mental Health and Adjunct Associate Professor of Rehabilitation, Nutrition, and Sport at the La Trobe Sport and Exercise Medicine Research Centre in Australia, in an accompanying editorial.

However, differences in plasma tau levels between athletes and nonathletes; lower plasma tau levels at 24 hours and 72 hours post concussion in athletes with concussion, compared with nonconcussed teammates; variability across players; and fluctuations in plasma tau levels over time in general may complicate the use of the biomarker in concussion management. In addition, tau in plasma may reflect CNS and peripheral nervous system origins.

“This study and others conducted in the sports setting open the door for further evaluation and possible future implementation of blood-based biomarkers for evaluation of concussion,” they said. “Nevertheless, more work is needed before blood-based biomarkers can be used for management of sport-related concussion.”

—Jake Remaly

Suggested Reading

Bendlin BB, Makdissi M. Blood-based biomarkers for evaluating sport-related concussion: Back in the game. Neurology. 2017 Jan 6 [Epub ahead of print].

Gill J, Merchant-Borna K, Jeromin A, et al. Acute plasma tau relates to prolonged return to play after concussion. Neurology. 2017 Jan 6 [Epub ahead of print].

Shahim P, Tegner Y, Wilson DH, et al. Blood biomarkers for brain injury in concussed professional ice hockey players. JAMA Neurol. 2014;71(6):684-692.