A concussion diagnosis is hard to define with injuries not appearing on routine brain scans and no definitive diagnostic test available. It is usually identified based on symptoms and, in athletes, comparison with baseline testing. However, concussion symptoms tend to be non-specific, unreliable, and easily influenced by emotions.
A new study used urine samples from college athletes to determine whether an individual has sustained a concussion and allowed the researchers to understand the biological effects of a concussion diagnosis.
“Athletes usually want to go back to their sport, so lots of times they say, ‘I feel great, doc,’ putting themselves at risk should they sustain a second brain injury,” said William Meehan, MD, a physician in the Division of Sports Medicine at Boston Children’s Hospital and director of The Micheli Center for Sports Injury Prevention. “But we’ve also had a lot of kids coming in worried, saying, ‘I’m not doing so well in school and I play soccer. Could it be a concussion?’ It would be great if a test could just tell us yes or no.”
Rebekah Mannix, MD, MPH, in Boston Children’s Division of Emergency Medicine, says 40% to 60% of concussions are missed in the acute setting, where more visible injuries tend to get the attention. “Concussion can be very subtle. But there are lots of reasons to want to diagnose concussion acutely — it can facilitate recovery, prevent kids from going back to sports too quickly, and avoid second-impact syndrome. We are always looking for objective markers of injury.”
The new research can be found in the January 11 issue of Neurology.
Finding biomarkers for a concussion diagnosis
The study was founded when David Howell, PhD, a postdoctoral fellow with Meehan, spoke at Boston Children’s Hospital about a study of concussion diagnosis they were beginning in collegiate athletes. Marsha Moses, PhD, director of the Vascular Biology Program at Boston Children’s approached Howell afterwards. “My lab works in the urinary biomarker space,” she said. “We should talk.”
“In many illnesses, markers of physical and biological damage find their way into the bloodstream, and can often be found in the urine,” Moses said. “Urine testing can be done early and often and is inexpensive compared to other types of tests.”
A dialogue quickly started up. “We had the study population, and Marsha’s lab brought the scientific expertise of urine biomarker discovery and validation,” said Howell, who is now at the University of Colorado.
Until the COVID-19 pandemic, Moses and her team attended annual preseason evaluations at a local college. They consented to the athletes and collected and froze their urine samples according to protocols established in the Moses Lab. Athletes who sustained a concussion diagnosis (diagnosed by a sports medicine physician) provided a repeat urine sample within seven days, then again one, three, six, and 12 months after injury.
“As concussions occur, we wait for those samples to come in,” said Cassandra Daisy of the Moses Lab, co-first author on the study with Howell and fellow Moses Lab member Speros Varinos. “Our population allows us to closely match athletes with and without concussion in terms of age and sex.”
The team gathered enough samples to compare the urine profiles of 95 athletes: 48 individuals who sustained concussions and 47 controls. To measure proteins, the researchers used mass spectroscopy in collaboration with John Froehlich, PhD, and Richard Lee, MD, in Boston Children’s Department of Urology, as well as enzyme-linked immunosorbent assays (ELISAs).
Of 71 proteins that differed significantly between the two groups, two stood out as the most predictive of concussion: IGF-1 and the IGF-binding protein 5 (IGFBP5), both found at significantly lower levels post-concussion. They appeared to be involved in brain injury repair, finding that the body may retain them after a concussion diagnosis rather than excrete them. Used together and added to gait evaluations, the proteins distinguished between athletes with and without a concussion diagnosis with high reliability.
Whilst the other proteins were less predictive, many were quite interesting scientifically and could help in understanding the biological effects of a concussion diagnosis.
“We were surprised by what we didn’t find,” added Daisy. “Known markers of severe brain injury didn’t differ between the athletes with concussion and controls. Concussion appears to be very different.”
Testing biomarkers
With the biomarkers for concussion in hand, the team aims to validate its proof-of-principle study through clinical trials in different populations, such as a broader college athlete population, adolescents playing sports, and people with non-sport-related concussions. Eventually, the goal is to develop a test that could be available at the point of care and even at the time of injury.
“As with COVID-19, if you have symptoms but aren’t sure of the cause, it would be ideal to have a test to diagnose a concussion or rule it out,” says Howell.
