Blood Test May Flag Concussion but Sex, Race Influence Results

Damian McNamara

November 20, 2018

Serum biomarkers may aid in the diagnosis of sports-related concussion (SRC) but sex and race need to be considered in order to accurately interpret and effectively manage such patients, new research suggests. 

Results from a three-part study examining seven concussion-related biomarkers in a large group of college athletes before and after concussion showed that female athletes had higher levels of one particular biomarker, while male athletes had higher levels of two other biomarkers. In addition, black athletes had higher levels of one biomarker set while white athletes had higher levels of a different set of biomarkers.

"The sex and race differences were pretty strong, particularly for a handful of the biomarkers studied," principal investigator Breton Michael Asken, MS, ATC, a clinical psychology doctoral student specializing in neuropsychology in the Department of Clinical and Health Psychology at the University of Florida in Gainesville, told Medscape Medical News.

"Clinicians should have healthy skepticism about biomarker research that reaches conclusions without appropriately considering these factors," added Asken, who is also a clinical psychology resident on internship at the Clinical Psychology Training Programs at Brown University: A Consortium of the Providence VA Medical Center, Lifespan, and Care New England.  

The three papers from the Concussion Biomarkers Assessed in Collegiate Student Athletes (BASICS) were published online November 7 in the journal Neurology.

Filling a Research Gap

In the first report, investigators assessed "normal" levels of biomarkers and sought to identify factors that influence them.

The second study examined whether head-impact exposure history can explain differences in biomarker levels and how the biomarkers line up with clinical data.

The third study evaluated acute biomarker changes, whether they align with clinically diagnosed concussion, and whether diagnostic accuracy improves by accounting for factors identified in the first two studies.

Building on blood biomarker research performed in emergency departments, investigators are now exploring their use in SRCs. However, to date, no biomarkers have been validated for clinical SRC detection in the United States.

Authors of a recent systematic review identified some gaps in the literature and called for greater inclusion of females and athletes playing sports other than football; participant enrollment prior to injury; and consideration of head- impact history in future SRC biomarker studies.

These unknowns, combined with a poor understanding of normal variation in biomarker concentrations, prompted Asken and colleagues to learn more.  

Racial, Sex Differences

In the first study, the investigators examined 415 University of Florida varsity athletes, including 256 men and 159 women. There were 238 football players, 18 players from men's basketball, 18 players from women's basketball, 70 athletes from women's lacrosse, and 71 players from women's soccer.

Blood samples were collected between 2011 and 2017 outside of each athlete’s competitive sports season as a baseline measure. The investigators assessed seven biomarkers but restricted some of their analysis to four, with detectable and quantifiable concentrations in all participants. These included Aß-amyloid peptide 42 (Aß42), total tau, S100B and UCH-L1.

Mean age was 19 years (range, 19 to 23). Race analyses only included participants classified as white (n = 244) or black (n = 156) because only a small number of people were outside these groups. Seven participants were of another race, and eight were missing race data.

Men had higher baseline concentrations of UCH-L1 (F1,347.4 = 54.926; P < .001; d = 0.75) and S100B (F1,371.0 = 31.030; P < .001; d = 0.56). Women had higher baseline CNPase levels (F1,403 = 16.250; P < .001; d = 0.43).

Black participants had higher baseline levels of UCH-L1 (F1,386 = 34.242; P < .001; d = 0.61) and S100B (F1,384 = 104.910; P < .001; d = 1.1) compared with white participants.

Conversely, white participants had higher baseline levels of Aβ42 (F1,362.4 = 7.909; P = .005; d = 0.28) and CNPase (F1,389 = 18.991; P < .001; d = 0.46).

"The neurobiological basis for the observed differences in baseline serum biomarker levels between black and white participants is not known," the researchers noted.

There was no effect of race or sex on baseline total tau concentrations.

Important Research Implications

The researchers also performed test-retest reliability analyses on a subset of 31 of the female athletes. These women voluntarily provided two blood samples approximately 6 months apart. However, none of the four biomarker levels decreased or increased enough to validate reliability for clinical testing.

Asked if there would be any benefit to screening for biomarkers at regular intervals over time in athletes, Asken replied, "From a research standpoint, absolutely. It would also, however, require long-term follow-up to see if screenings actually inform risk for neurologic changes throughout the lifespan.

"Before any of this can happen, though, we need to know more about what’s normal, what things impact normal, and maybe most importantly, if these tests are reliable. Our preliminary findings raised concerns about reliability; if a test isn’t reliable, there are significant limitations to its ultimate utility," he added.

Despite these concerns, "this study provided an important contribution to the blood biomarker literature in systematically describing variability in ‘normal’ peripheral expression of concussion-related biomarkers in human serum," the authors noted.

"We aren’t at the point of individualizing biomarker assessments. The bird’s-eye view of these findings shows that, at a minimum, sex and race must be considered when researching these biomarkers moving forward," said Asken.

The authors emphasized the importance of replicating their findings "given the novelty of this research area."

In terms of future research, Asken said reliance on a single biomarker is also probably far less preferable than utilizing biomarker panels, but each biomarker must be sufficiently studied before knowing which biomarkers should be included in the panel. 

"Ultimately, the elephant in the room is trying to reconcile when a biomarker panel is ‘abnormal’ but, clinically, the individual looks perfectly fine.  Neurodegenerative disease research is facing these same challenges currently. This is where we need to get more creative with how we apply these biomarkers and integrate them with clinical assessment tools," he said.

No Holy Grail

In an accompanying editorial, Erin D. Bigler, PhD, of the Department of Psychology and Neuroscience at Brigham Young University in Provo, Utah, and Ellen Deibert, MD, of the Department of Neurology at Drexel University College of Medicine in York, Pennsylvania, applaud the researchers' "systematic approach" to concussion biomarker research.  

They also note that this research laid out in three separate papers is the "most comprehensive of this kind of SRC biomarker studies. These studies have addressed many important study design issues along with answering some basic questions about several serum biomarkers in SRC." 

However, while the study "does provide Class III evidence that some serum biomarkers are elevated or higher than controls after SRC, their diagnostic accuracy depends on which reference group method is used and [amount of] time post-injury."

This research, they note, provides "ample direction" for future concussion biomarkers studies.

However, they add, "ultimately, because of the complexities of concussion, the serum biomarker in and of itself cannot be the Holy Grail, but instead another tool in guiding the clinical management of concussion and return-to-play decisions."


The study was primarily supported by a grant from the Head Health Initiative, a collaboration between GE and the NFL, Banyan Biomarkers, Inc., and the U.S. Army Medical Research and Materiel Command (USAMRMC). The University of Florida owns stock in Banyan, the sponsor of the study. Asken received partial support (hourly) from Banyan for data collection and analysis.

Bigler has received travel funding/speaker honoraria from the National Academy of Neuropsychology; serves on the editorial board of Neuropsychology; receives publishing royalties from Oxford University Press; has given expert testimony; and has received research support from USAMRMC (the views and opinions expressed in this article are those of the author and do not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred). Deibert reports no disclosures.

Neurology. Published online November 7, 2018.

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