On playing fields across the country, nervous trainers stand on the sidelines, hoping none of their players will sustain a head injury. After years of denial, organizations such as the National Football League are finally beginning to recognize the dangers of concussion. Although awareness of the issue has increased enormously, diagnosis remains difficult, relying exclusively on players’ subjective reports of symptoms such as blurred vision, dizziness, headache and nausea.

At least two life sciences companies are now developing blood tests that can detect concussion more reliably and objectively, and a recent study suggests such tests may eventually be game-changers. “The biggest problem is that the clinical criteria for diagnosing concussion are very vague,” says Henrik Zetterberg, a professor of neurochemistry at the University of Gothenburg in Sweden. “If someone hits their head and doesn’t feel 100 percent well afterwards, that can fulfill the criteria—it’s not much stricter than that.” A blood test that diagnoses concussion accurately and reliably would, therefore, be a valuable aid to sports teams—and to medicine in general.

When someone bangs his or her head, rotational forces can damage long-projecting axons, the fibers that extend from neurons. That can cause proteins to leak out of brain cells, and the tests currently being developed are based on detecting tiny increases in the concentration of these proteins in blood samples.  One company working on such a test is the Lexington, Mass.–based start-up Quanterix, which develops ultrasensitive tests that can detect miniscule amounts of proteins in the blood, using antibodies that bind to specific molecules.

Zetterberg and his colleagues have been using Quanterix technology to measure some of these biomarkers in athletes. In 2013 they reported Olympic boxers have elevated blood plasma levels of a protein called tau. More recently they have shown tau levels are closely correlated with the duration of concussion symptoms in professional hockey players. The latest study, by researchers at the National Institutes of Health, measured tau protein concentrations in 46 college athletes and 37 healthy controls, and showed that players with elevated tau levels within six hours of a sports-related concussion experienced symptoms longer. Together, these results suggest blood tests could not only detect concussion more accurately but may also be used to predict a player’s recovery time, to ensure that they do not return to play prematurely.

Although dozens of concussion biomarkers have already been identified, the bigger challenge is developing antibody-based assays that are sensitive enough to detect tiny increases in protein concentrations. These markers are often elevated following an injury that damages neuronal fibers, says neurologist Beth McQuiston, medical director at global health care company Abbott. With funding from the U.S. Department of Defense, McQuiston and her colleagues are busy developing a blood test for two other concussion markers, UCH-L1 and GFAP, using an existing hand-held blood analysis device called the i-STAT. UCH-L1 is an enzyme that is abundant in neurons and is thought to be involved in the biochemical pathway that normally breaks down damaged and otherwise unwanted proteins whereas GFAP is a structural protein released from damaged neuron-supporting cells called astrocytes. Levels of both of these protein-based markers are substantially increased in patients with traumatic brain injury, even those with a normal brain scan, so they could indicate undetected microscopic injuries. “The DoD did [more than] a decade's worth of research looking at markers that would be useful for their soldiers, and they asked us to partner with them to make it available on the i-STAT platform,” McQuiston says. “We've developed the assay to a point where we can measure very low levels of these proteins successfully.”

The availability of objective measures such as these blood tests could help physicians diagnose and evaluate concussions quickly. Yet the handful of studies published to date all involve small numbers of participants, and their results are still preliminary, showing only that concussion is correlated with elevated levels of the identified markers, not caused by them.

Another recent study, by researchers at Western University in Ontario, showed a blood test that measures nearly 200 different metabolites could diagnose concussion in athletes with greater than 90 percent accuracy, and that the test remained this accurate when they whittled the number of markers down to 17. The study involved just 12 concussed and 17 nonconcussed athletes, however. It is still not clear which of the many identified biomarkers are the best indicators of injury.

McQuiston's team is involved in various ongoing collaborations with industry partners, academics, the military and sports organizations, which aim, among other things, to validate the efficacy of the blood tests in larger numbers of people and determine the best biomarkers. One of these partnerships is Track-TBI, a public-private partnership led by neurosurgeon Geoff Manley of the University of California, San Francisco, among the largest studies of concussion so far. The researchers are currently studying a group of 3,000 test participants, and hope to publish some of their results later this year.

Rather than being used alone, McQuiston envisions blood tests as part of a battery of tests that improve the diagnosis of concussion. “If you're looking at a health condition like chest pain, you’d use a number of different measures such as a blood test, electrocardiogram and a chest x-ray, along with the clinical presentation to paint a picture,” she says. “Likewise, we see blood tests as part of a multimodal assessment. Pulling different types of information together would allow for a better evaluation of the patient.” These larger studies may finally determine whether blood tests would be any more reliable in detecting concussion than the traditional method of asking an injured player, “How many fingers am I holding up?”

Meanwhile McQuiston believes efforts to raise awareness about concussions are crucial. “People know concussion is a bad thing, but the vast majority don’t know what the common signs and symptoms are,” she says, adding that most concussions occur as a result of falls in everyday situations. Tests that help physicians diagnose them reliably could therefore be applied far more widely than on playing fields and battlegrounds.

“We talk about how to evaluate and assess concussion as if it’s always going to happen no matter what, but many can be prevented by following proper techniques and wearing protective equipment,” McQuiston says. “We see a lot of concussions as a result of people falling from ladders or tripping on rugs and hitting their head. So if you’re going to climb a ladder, make sure it’s secure, and if you’re always tripping on that same rug, then get it fixed.”