EMERGING MARKETS

Blood-Based Concussion Diagnostic Tests

There is a great need for better tools to diagnose concussion. Currently, there is no single marker of panel of markers in widespread clinical use and diagnosis remains based on clinical judgment. But as evidenced by the recent flurry of publications and commercial partnerships, blood-based concussion testing may soon be a clinical reality, possibly even at the site of injury.

Clinical Barriers to Testing
Until recently, many researchers doubted that it would be possible to develop a blood-based test for concussion, given the risk that the blood-brain barrier would prevent movement of candidate markers from the brain to the blood. However, recent research shows that some markers, including metabolites and proteins, are present in the blood. The challenge is that candidate markers are often present only in low concentrations and can be difficult to detect, especially following mild injury.

Current State of Concussion Testing
G2 surveyed recent publications and industry announcements to assess the current state of concussion testing. Here is a rundown of what we learned.

Metabolomics Profiling
Metabolomics profiling is a promising new method of diagnosing concussion which may be amenable to point-of-care testing in the near future.

One source of evidence of the method’s effectiveness is a study published in the December 2016 issue of Metabolomics finding that a panel of metabolites can identify concussions in athletes with more than 90 percent accuracy.

Plasma was obtained from 12 concussed and 17 non-concussed adolescent male ice hockey players. Controls were age-, sex- and activity-matched. Initially, the plasma was assayed for 174 metabolites with proton nuclear magnetic resonance and direct injection liquid chromatography tandem mass spectrometry.

The researchers found that using principal component analysis (PCA) of the leading 10 components, each containing 9 metabolites, could account for 82 percent of the variance between the groups. This differentiation relied heavily on changes in glycerophospholipids, which accounted for 50 percent of the variance between concussed and non-concussed athletes. It is "unclear" which metabolite changes are the result of injured cells, metabolic processes or a combination of both, the authors note.

The number of metabolites required to achieve the 92 percent diagnostic accuracy was minimized from 174 to 17 metabolites. Using receiver operating characteristic analyses the panel generated an area under the curve of 0.91, indicating "excellent concussion diagnostic potential," the authors say.

"The attraction of metabolomics lies with the concept that metabolites fall downstream of genetic, transcriptomic, proteomic and environmental variation, thus providing an integrated and dynamic measure of a medical condition," write the authors led by Mark Daley, from Western University in Canada.

Markers of Recovery
Just as there is a lack of a reliable marker to diagnose concussion, there is also no objective measure to determine recovery and an athlete’s readiness to return to play. However, measuring the blood protein tau just hours after injury may provide objective clinical information to inform decision-making about predicted recovery times and safe return to play, according to a study published online in Neurology on Jan. 6.

Athletes who return to play before full recovery and those receiving multiple concussions are at increased risk for long-term neurological complications. Most athletes see their post-concussive symptoms disappear within 10 days, but in some, the symptoms become chronic.

Tau is made by neurons and is known to get stuck in plaques in the brains of people with Alzheimer’s and chronic traumatic encephalopathy, the neurodegenerative disease linked to the premature death of football players. Previous research also showed tau to be marker of neuronal injury following severe brain injuries.

Researchers from the National Institute of Nursing Research and Quanterix (Lexington, Mass.) measured tau levels using an ultrasensitive immunoassay after a sports-related concussion in 46 athletes (soccer, football, basketball, hockey, and lacrosse), as well as in 37 teammate without concussions and a group of 21 healthy, non-athletes. Sampling occurred at six hours, 24 hours, 72 hours, and 7 days post-concussion. Concussed athletes were grouped by the length of time until their return to play (RTP; long = more than 10 days, n = 23 and short = less than 10 days, n = 18).

Concussed athletes who needed a longer amount of recovery time before RTP had significantly higher tau concentrations at six, 24, and 72-hours postconcussion, compared to athletes with shorter RTP. These findings were consistent in in both male and female athletes, as well as across sports type. Receiver operator characteristic analyses showed that higher plasma tau 6 hours post concussion was a significant predictor of RTP with an area under the curve 0.81.

"In the future, this research may help to develop a reliable and fast clinical lab test that can identify athletes at higher risk for chronic post-concussion symptoms," said NINR director Patricia A. Grady Ph.D., R.N., in a statement.

The study utilized Simoa, a highly sensitive, fully automated immunoassay platform (Quanterix). The company reports they plan on launching a clinical trial with the National Football League this year. In the meantime, they are working on shrinking the platform to permit sideline testing. Ultimately, they say, the goal is to get the test sensitive enough to have a tau result within 15 minutes of the injury.

Key Market Players for Concussion Tests

A number of other companies are carrying out clinical trials and regulatory submissions for blood-based concussion tests. Such companies include:

Banyan Biomarkers: San Diego-based Banyan Biomarker’s research is focused on ubiquitin C-terminal hydrolase L1, which is found in brain neurons, and glial fibrillary acidic protein (GFAP) found in specialized glial cells in the central nervous system called astrocytes. The company has partnered with several diagnostics firms including Abbott, Philips, BioMérieux, and Quanterix to develop a handheld test for traumatic brain injury. It says that a test based on these proteins could reduce the need for CT scans to evaluate concussion.

Abbott: Abbott says it is currently developing a blood-based concussion test to detect specific proteins associated brain injury. The test will be available on Abbott’s i-STAT analyzer, a handheld device used by the military to perform a broad range of common blood tests. Initial test development began in 2014 with funding from the U.S. Department of Defense. The test will reportedly first be available in India while U.S. trials are underway.

Takeaway: As research continues to identify reliable tests to diagnose concussion, early blood-based concussion tests are beginning to enter the commercial market.

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