New Blood-Based Markers May Be Capable of Guiding Post-Concussion Return-to-Play Decisions

Several recent studies indicate progress in the search to find blood-based biomarkers associated with concussions. Forty-nine states have passed so called return-to-play (RTP) laws requiring better management of head injuries in student athletes, including requiring clearance by a medical professional before resumption of regular activity. Yet a definitive biomarker demonstrating safe RTP remains elusive, and these decisions are made based on subjective clinical evaluations and the absence of self-reported symptoms by the athlete. “Establishing a serum marker of injury and recovery would assist bedside clinicians . . . bringing this highly prevalent diagnosis in line with other common conditions, such as abdominal pain and fever, in which laboratory studies are routinely combined with clinical predictors to allow clinicians to stratify patients by risk,” writes lead author Rebekah Mannix, M.D., from Boston Children’s Hospital in Massachusetts, in a study published online ahead of print on Feb. 4 in the Journal of Neurotrauma. CSF Protein Measurable in Blood For the first time, an ultrasensitive diagnostic platform has been able to detect total tau (T-tau), a highly specific cerebrospinal fluid protein in blood, and correlate these blood measurements to a concussive diagnosis and readiness for RTP, according to another study published March 13 in JAMA Neurology. The Simoa platform (Quanterix; Lexington, Mass.), a single molecule array technology, was used by researchers in Sweden to study sports-related head injuries. Neuronal proteins, like T-tau, have concentrations in peripheral circulation below the detection limit of conventional tests, the company says, but the Simoa platform offers a 3,000-fold improvement in sensitivity compared to available tests. The ability to measure low-abundance biomarkers of brain function in a simple blood test may provide new insights for diagnosis, monitoring, and treatment of other neurological and neurodegenerative conditions. From Sept. 13, 2012, to Jan. 31, 2013, 35 Swedish Hockey League players suffered a concussion, of whom 28 had repeated blood sampling (four times in the 144 hours after injury and at RTP). Post-concussion levels of three markers (T-tau, S-100 calcium-binding protein B, and neuron-specific enolase) were compared to baseline measurements taken in the preseason. The study found that T-tau is significantly elevated following mild to severe concussion and remains elevated, compared to preseason levels, for at least six days post-concussion. Concussed players had significantly elevated levels of the axonal injury biomarker T-tau (difference in median levels, 5.5 pg/mL) following injury compared to baseline measurements. In the first hour following the injury, concentrations were highest, but the level of T-tau one hour after injury was not able to significantly differentiate between concussion severity categories. However, there were trends toward higher concentrations in players who had symptoms lasting for more than 10 days or had loss of consciousness (both indicators of more severe injury). T-tau concentrations immediately after injury did predict the number of days it took for the concussion symptoms to resolve and the players to have safe RTP. Additionally, high T-tau levels 144 hours after concussion correlated with persistence of post-concussive symptoms. Glial Fibrillary Acidic Protein Another serum biomarker—glial fibrillary acidic protein (GFAP)—shows promise in aiding in the diagnosis and prognosis in pediatric concussion cases, according to a small study published in the Journal of Neurotrauma. GFAP has previously been shown to correlate with markers of injury severity in adult patients. In the present study, the researchers examined 13 children and young adults (11 years to 21 years of age) presenting to the emergency department (ED) within 24 hours of concussion. Initial serum samples were obtained in the ED, and follow-up samples were collected within 24 hours to 72 hours of injury. Samples were tested using the GFAP assay (Banyan Biomarkers; Alachua, Fla.), a sandwich electro chemiluminescent immunoassay. For the assay, the lower limit of detection was 0.008 ng/ml. Laboratory personnel performing the tests were blinded to clinical data. The researchers found that the mean initial GFAP level was 0.12 ng/ml. Initial GFAP levels were significantly associated with the burden of symptoms both initially and at follow-up, up to one month after injury. However, GFAP levels at follow-up did not correlate with symptom burden. While hopeful that GFAP could offer an objective measure of injury and recovery after pediatric concussion, the authors caution that it is “likely that no single biomarker, but rather a combination of biomarkers and other clinical variables, will offer the best [concussive] diagnostic and prognostic utility.” Takeaway: This research furthers a trend to improve diagnosis of brain injury through objective measures in a practice area notoriously based on subjective measures. While further validation is necessary, clinicians are eager for a biomarker that can guide RTP decisions. Side Box: New Study Suggests Molecular Products in Urine Reflect Brain Injury Development of diagnostics based on brain injury urinary signatures using either combinatorial quantitative models or pattern-recognition methods may serve a role in addressing the need for incorporating a great number of markers representing the multifactorial nature of brain injury, according to a study published March 27 in the Journal of Neurotrauma. Researchers from Virginia Commonwealth University (Richmond, Va.) analyzed urine specimens from head trauma subjects admitted for acute brain injury rehabilitation, as well as nontraumatized matched controls. They utilized an innovative data-independent mass spectrometry approach for molecular quantification of small metabolic byproducts across osmolarity-normalized samples. They found that human urine contains 10,929 reproducible traumatic brain injury discriminant measures of pathobiological relevance and diagnostic potential, representing a diverse class of molecular products. “These results support further development of pattern-based urinary metabolite diagnostics and theragnostics to assess rehabilitation readiness and efficacy of intervention applicable broadly to brain injuries from traumatic, ischemic, and hemorrhagic insults,” conclude the authors.