Sports Medicine Research: In the Lab & In the Field: Blood Test Could Help Provide Information on Prolonged Concussion Recovery (Sports Med Res)
Monday, February 13, 2017

Blood Test Could Help Provide Information on Prolonged Concussion Recovery

Acute plasma tau relates to prolonged return to play after concussion

Gill J, Merchant-Borna K, Jeromin A, Livingston W, Bazarian J. Neurology. 2017; 88:1-8.

Take Home Message: Elevated plasma tau concentrations within 6 hours of sport-related concussion was associated with prolonged return to play.

Many clinical tools used to diagnose and return concussed athletes to play rely on patient-reported information. An objective predictor, such as a blood test for tau protein, would provide an unbiased tool to determine an athlete’s diagnosis, prognosis and readiness for return to play. Therefore, the authors evaluated NCAA Division I and III contact-sport athletes between 2009-2014 to determine changes in tau following concussion compared to preseason. The authors also compared tau changes after a sports-related concussion (43 athletes) to both an athletic control group (no concussion; 37 athletes) and a healthy, nonathletic, control group (21 participants). All athletes gave blood samples during pre-season. Athletes that sustained a sports-related concussion also gave blood samples within 6 hours of injury, and then 2, 3, and 7 days post injury. Athletes that sustained concussions were then grouped into long return to play (> 10 days) or short return to play (< 10 days). Healthy athletes had blood draws at the same time points as the concussion group, and nonathletic participants had blood draws at an unrelated time point. Thirty-nine percent of the athletes with concussion returned in less than 10 days. Females were nearly 6 times more likely to be in the prolonged return to play group (61%).  Both healthy and concussed athletes had higher mean tau during pre-season and all other times compared to nonathletic participants. The healthy athletes had higher mean tau concentrations compared to the concussed athletes at 24 and 72 hours. Athletes with long return to play had higher mean tau at 6 hours, 24 hours, and 72 hours post injury, after controlling for sex, compared to those with short return to play. The authors found that higher plasma tau 6 hours post-concussion was a good predictor of return to play in less than 10 days.

The authors presented that changes in tau from pre-season to 6 hours after a concussion was an accurate predictor of prolonged return to play following a concussion. Identifying biomarkers to better understand how an athlete may recover may protect athletes from neuronal damage, subsequent concussions, and sustaining further injuries (lower extremity injuries). Concussed athletes that took longer to recover typically had higher tau concentrations compared to those that took less than 10 days to recover. Therefore, the authors suggest that tau could be used as a prognostic biomarker. However, the mean tau levels at 24 and 72 hours were lower in the concussed athletes compared to the healthy athletes, which may suggest that physical activity can increase mean tau. This is supported by the finding that all athletes had higher levels of tau during pre-season compared with nonathletic participants. More research will need to be done to replicate and validate these findings in larger cohorts, while controlling for physical exertion. Currently, medical professionals should continue to use multiple clinical tests for concussion diagnosis and safe progression of athletes to play, and continue to be on the lookout for a reliable objective predictor such as a blood biomarker to use in his/her concussion protocol.

Questions for Discussion: Are biomarkers something you would be interested in implementing into your concussion protocol in the future? If not, what are your reservations?

Written by: Jane McDevitt, PhD
Reviewed by: Jeff Driban

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Gill, J., Merchant-Borna, K., Jeromin, A., Livingston, W., & Bazarian, J. (2017). Acute plasma tau relates to prolonged return to play after concussion Neurology, 88 (6), 595-602 DOI: 10.1212/WNL.0000000000003587

7 comments:

Nicholas Erdman said...

The findings of this article are very interesting and provide a direction for future research. However, I am concerned with the relatively small cohort of participants in each subgroup. The limited cohort allows a small number of participants to greatly affect the results of the study. I wonder why there wasn't a matched athletic and non-athletic control for each participant who suffered a concussion? This would have provided interesting analysis at each time point throughout the study!

While the spread of athletic participation between NCAA Division I and III should not affect the assessment on tau protein, it should be considered when analyzing the results. I would have enjoyed comparisons between Division I and Division III participants regarding tau protein at preseason and at all post-injury time points. Furthermore, sex differences between Division I and Division III participants would have been interesting to analyze and report!

I look forward to the future research of the tau protein biomarkers in the observed cohort. Given the findings of this study, I am interested to see research identifying the effects of exercise on tau protein concentration, which will make analysis post-concussion easier to interpret and generalize.

B_Green said...

An important thing to keep in mind when looking at prolonged recovery is that the cause is often multifactorial in nature. Many factors (age, sex, amnesia, signs/symptoms, biomarkers, etc) have been suggested as modifiers because of their potential to impact the recovery process. I would like to see more research that confirms suggested modifiers are indeed modifiers. Take sex for instance, this study reported females being nearly 6 times more likely to experience a prolonged recovery. Is the cause biological, psychological, or sociocultural? Are hormonal differences the culprit? Is there as great of a demand to return female athletes to participation as there is for males, especially at the Division I level?

I agree with the concluding statements...these results would mean more if tau levels in the concussed group would have remained lower at longer time points and further research is needed to validate these results.

Jane McDevitt said...

I agree with both comments. They did try and match as best as possible. They matched on both age and sex, and there were 2 separate control groups an active and non active to determine if there were Tau changes following a concussion compared to those concussed.

There were more women in the
long RTP group compared to the short RTP group,and the authors were able to statistically control for this difference
in the statistics models, and found that sex did not significantly contribute to these models.

Tau is not controlled hormonally; it is stimulated via enzymes to phosphorylate or to stop phosphorylating and via isoforms (genetic predisposition to stabilization). However, I agree I think hormones do play a role in the recovery of a concussion, but this study did not focus on proteins that are regulated hormonally.

There is just as big of a demand in ensuring females are safely returned to play at all levels. Many may focus on males because it is easier to recruit concussions from this sports since the team is so much larger then others 50 players compared to 20 players.

Landon Lempke said...

My comments and concerns are similar to that of the comment Nick mentioned. Limited sample sizes in this study are a limitation and results should be taken cautiously. Furthermore, I think that the use of short (<10 days) and long (>10 days) for a cut off of return to play times is not exactly a fair cutoff. We know that in general 90% of concussed athletes will be able to return to play within 10-14 days, but that is not always the case. Prolonged recovery, or long term recovery, I don't believe should be identified by being immediately after 10 days. This however might be a matter of personal opinion.

Additionally, they researchers controlled for age and sex but did not mention if any attempt was made to match for physical activity. They did have a control athletic group, but to group all athletics into one category and assume equal fitness level in all sports is not a safe assumption especially if physical activity levels tends to alter tau protein levels. Table 1 in the publication shows a breakdown of the sports, but again not controlling for physical activity/fitness levels is a limitation of the study.

Finally, although the researchers found statistical differences in their results, I believe Figure 1a and 2a show that we can't be confident that there truly is. There appears to be significant overlap in confidence intervals. There is also a significant lack of data points at 6 hours post injury which could skew the results.

To talk upon the discussion question, I believe blood draws and examining biomarkers is something I would be hesitant to include in the future for concussion protocols. Currently there limited and somewhat controversial research that suggests biomarkers are accurate diagnostic and prognostic tools to use. Until there is large consensus over the validity and clinical utility of the use of biomarkers, I believe they shall need to stay away from clinical practice.

A question for you: If biomarkers/blood examinations are found to be valid for concussion use, who and how do you see these exams being funded?

Jane McDevitt said...

Landon,
I agree with your point on prolonged recovery. I feel the normal means I see in return to play times in the literature as well as in clinical practice are returning after 2 weeks. So 10 or more days does not seem like a valid cut off for prolonged recovery. I also agree a much larger cohort would need to be done, and because this protein is released with any inflammation there needs to be a more specifically matched group in regards to activity level and intensity.

I think if we consider the way the athletic training profession is moving I do not see why athletic trainers would not be able to draw the small amount of blood necessary to provide this sample for examination. However, the storage and examination of the blood sample is still difficult and pricey. It is becoming more affordable to send away and obtain the sample scores; however, I have no answers to how much or how this would be funded. I believe we are still years away before this should be budgeted in but I think it is worth discussions about what other clinicians are thinking and doing. The easiest way this would get covered is if this test was covered by the athlete's health care provider. However, I wouldnt even begin to speak on how or what that paperwork would look like.

Catherine Hess said...

These findings are very interesting and indicative of the direction that concussion assessments may be going. I really value how the biomarker concept is completely objective and cannot be clouded by the intentions of the athlete to mask symptom. Additionally, this concept of biomarkers could provide information that would prevent premature return to play and the negative consequences associated. This study provides vital information about one component to look at – elevated tau 6 hours post-concussion. Ultimately, elevated tau protein levels meant longer than 10 days for RTP. This is very useful information, clinically, because it could help to identify athletes in need of further attention or care because they are on track for a longer recovery. However, 10 days is not a typical number that I have witnessed clinically for athletes returning from a concussion. This makes me wonder the value of this cut off for short-term versus long-term recovery. It would be very interesting to look at other markers beyond just tau to determine any possible correlations. I would be interested in looking at the role that physical activity has on elevated tau versus just a concussion without physical activity. Additionally, with the differences at baseline between the athletic and non-athletic groups, is this something that could be applied to the non-athletic population? Would different baseline values and ranges have to be established based on physical activity since it does have an influence on tau levels? Lastly, I feel as though this would be tricky to implement clinically in a fool proof manner because of how individualized every concussion is. If a certain number of days is provided to the athlete as a reference to when they will return and they fall beyond that, it makes for a frustrating situation for both the athlete and clinician. This is where policies and procedures for institutions come in handy with determining just how situations are managed.
There is definitely a strong need for more research in this area utilizing bigger cohorts. I would be very interested in using biomarkers clinically once they have been further established. I would be very curious to see how the findings of this study fair as more research is done or even just looking at whether or not the values that were found as significant hold true in every situation – I feel as though there are always exceptions to the rules. Also, this would be tricky to carry out clinically because ATCs aren’t able to draw blood, meaning we would have to outsource this task which could cost a substantial amount of money. Additionally, I feel it would be challenging to get them at the particular time points that have been found as valuable. As of right now, just seems like a lot of red tape and obstacles, but as the research progresses, so too will the clinical applicability.


Jane McDevitt said...

Catherine,
I think you bring up a really interesting point on baseline range. One of the problmes with tau is that it is eleveated after activity, and that could range given numerous factors. I think one place to start to see the range is maybe identify different types of practices long vs short, skill vs intense and maybe try and calculate some sort of baseline range per athlete. That would be very time consuming and expensive but may be able to determine what part of the elevation is coming from physical activity and what part is coming from the concussion injury. I am anxious to see how these progresses and what other biomarkers may come about.

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