Blood Biomarkers May Predict Concussion Recovery

Michelle E. Grady

July 11, 2019

Levels of serum inflammatory markers may be useful in identifying which athletes are more likely to require a longer recovery time after a sport-related concussion (SRC), new research shows.

Results of a prospective study examining inflammatory markers in high school and college football players shows two serum biomarkers, interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1RA), were notably elevated and significantly differentiated athletes with and without concussion.

In addition, post-concussion IL-6 levels were significantly associated with the duration of concussion symptoms. 

"With so many people sustaining concussions and a sizeable number of them having prolonged symptoms and recovery, any tools we can develop to help determine who would be at greater risk of problems would be very beneficial, so these results are a crucial first step," principal investigator Timothy B. Meier, PhD, Medical College of Wisconsin in Milwaukee, said in a press release.

The study was published online July 3 in Neurology.

Two Candidate Biomarkers

Meier told Medscape Medical News that previous animal research and some clinical studies indicate there is an increase in particular inflammatory biomarkers within 24 hours of traumatic brain injury (TBI), and this led to the team's interest exploring this further.

"Very limited work has been done with a decently sized sample of athletes with concussion," he said.

The investigators' selection of specific inflammatory markers was based on previous studies of concussion. In addition to IL-6 and IL-1RA, these included IL 10, IL-1β, C-reactive protein (CRP), tumor necrosis factor (TNF) and interferon-γ (IFN-γ).

However, Meier noted there are numerous other inflammatory markers currently under investigation in traumatic brain injury.

A total of 857 high school and college football players were enrolled in the study. Of these, 41 concussed athletes and 43 matched control athletes who did not sustain a concussion during football season met the study's inclusion criteria.

All athletes underwent blood testing at the start of the football season. Those with concussions had blood tests within 6 hours after their concussion and again at 24 to 48 hours post-injury. Concussed athletes also had blood samples drawn 8, 15, and 45 days later. The control group had blood testing at similar times for comparison purposes.

Investigators found that of the seven biomarkers, two of them — IL-6 and IL-1RA — were both elevated 6 hours after concussion and significantly discriminated between study participants with and without concussion (IL-6 area under receiver operating characteristic curve [AUC], 0.79; 95% confidence interval [CI], 0.65 - 0.92; IL-1RA AUC, 0.79; 95% CI, 0.67 - 0.90).

For IL-6, levels at study outset were 0.44 picograms per milliliter (pg/mL) in participants who subsequently sustained a concussion and 0.40 pg/mL for those who did not.

At 6 hours after injury, those with concussions had IL-6 levels of 1.01 pg/mL, compared to levels of 0.39 at a similar time for those without concussion.

This elevation is a meaningful increase when compared with athletes who did not sustain a concussion, said Meier.

Longer Recovery

In addition, athletes with higher levels of IL-6 six hours after the injury were more likely to take longer to recover from their symptoms. Overall, those with concussion had symptoms for an average of 8.9 days. Eight of the 17 athletes with concussion and high IL-6 levels at 6 hours after injury still had symptoms 8 days later.

These findings, said Meier, suggest the increase in IL-6 levels in these athletes "in this really early time frame could predict recovery."

The investigators note that the potential limitations of the study include the fact that the number of athletes with concussion may be too small to determine the accuracy of inflammatory markers as biomarkers. The study also included only male high school and college athletes, so the results may not apply to female or younger athletes.

"Practically, we need a lot more research before this has any real world implications," said Meier. "This is the first proof of concept and certainly it would need to be replicated in a different sample of athletes."

If the findings are replicated, the investigators will need to make sure these potential blood biomarkers provide additional information beyond clinical measures, said Meier.

"We have to show that this marker has some added value, because right now the most predictive factor for prolonged symptoms is how severe the initial symptoms are," he said. "There are obviously concerns around relying on self-reported symptoms from athletes because they tend to underreport their symptoms as their report dictates when they return to play."

The researchers also plan to investigate the combined diagnostic and prognostic potential of blood biomarkers to capture multiple aspects of the neurometabolic cascade, as well as the relationship with other potential biomarkers, including neuroimaging metrics.

"Most immediately, we're interested to see if these inflammatory markers add anything or complement some of the markers more specific to brain injury that others have been interested in. One of the issues with inflammatory markers in terms of diagnostic biomarkers is they are not specific to brain injury. I think the next question for us is how these nonspecific inflammation markers are relating to other markers that we think are a little more specific to brain injury," said Meier.

The team is also conducting ongoing research comparing inflammatory and other blood markers to non-football athletes as a secondary control group in order to account for the potential effects of repetitive blows to the head that occur in football players without diagnosed concussion.

"Eventually, these results may help us better understand the relationship between injury and inflammation and potentially lead to new treatments," Meier said.

The study was supported by the Department of Defense Broad Agency Announcement for Extramural Medical Research, the National Institute of Neurological Disorders and Stroke, the National Institute of General Medical Sciences, the National Institute of Mental Health, and the National Center for Advancing Translational Sciences. The investigators have disclosed no relevant financial relationships.

Neurology. Published online July 3, 2019. Abstract

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