Are the Promises of Concussion Blood Tests Getting Ahead of the Science?

In 2002, Dr. Kevin Guskiewicz from the University of North Carolina (now a member of the NFL's Head, Neck, and Spine Committee and the NCAA's Concussion Committee) said, "concussion is a difficult injury to diagnose." WebMD, which most parents across the country use to evaluate head injuries that occur during football games where no certified sideline evaluation staff is available, plainly states "It is not always easy to know if someone has a concussion." Sports medicine doctors—but rarely head trauma experts—are often quoted saying similar things about the ambiguous nature of concussions.

This sentiment was echoed by the Boston Globe's Ben Volin in a recent article about Quanterix, a medical technology company that specializes in blood-based biomarkers, which has received $800,000 from the NFL to develop a blood-based concussion test. "Doctors can diagnose a broken foot or torn ACL moments after it happens, and now a company based in the Boston area says it has the technology to do essentially the same for concussions with a simple finger prick. Within 20 minutes, a blood analysis could let the player know if he suffered a concussion and when he can return to play." Likewise, a recent Wall Street Journal video segment asked rhetorically, "Now imagine how helpful it would be to detect the onset of concussion just moments after injury to make an objective determination about whether that athlete should return to play?" Their guest to discuss this: Quanterix CEO Kevin Hrusovsky.

At first glance, this would be a groundbreaking technological achievement that would change the way head trauma is managed, from youth sports to the pros alike, ending the perceived subjectivity of concussion detection. The NFL likely agrees, as they have donated $2.4 million through the NFL Head Health Challenge to three different teams researching blood-based biomarkers (Quanterix, Banyan Labs, and researchers at the University of Montana). Kevin Hrusovsky, the CEO of Quanterix and a successful pharmaceutical executive, told me he envisions within two years "a point of care device that could be carted out to sidelines and to be used right at the sideline to determine, at that moment, whether someone has had a concussion or not."

This whole narrative—that concussions are difficult to detect and expensive blood tests will fix that—is a beneficial one for a sport with plummeting youth participation rates due to parental concerns about the sport's long-term health effects, as well as the businesses trying to capitalize on potential solutions. But it's not at all clear blood tests are a solution to this problem, or that the efficacy of sideline tests is even a problem to begin with.

Dr. Douglas Smith, Director of the Center for Brain Injury and Repair and Professor of Neurosurgery at the University of Pennsylvania who has been working full-time in neurosurgery for the last 18 years and published over 170 reports on head trauma, jokes with people that, "in most cases, I think even my dog can detect concussions."

Blood biomarkers are promising in many ways for head trauma research and long-term, return-to-play decision making. But to parse exactly what this technology can and can't do for player health, it's important to understand head trauma as best as current science allows, and to see what we still have to learn.

Part of a standard sideline concussion test requires tracking the movement of a finger with your eyes. This is an incredibly rigorous test requiring dozens of microscopic steps and minuscule signals transmitted throughout your brain. Even the slightest malfunction would cause you to fail the test. The system must be in perfect working order.

Although there are many steps outside the brain, let's focus on what happens as it relates to brain trauma. The necessary signals for the eye tracking test are transmitted in your brain's white matter, which is made up in large part by axons, long tubes that stretch from one cell to another. You are thinking and processing these words right now because sodium crosses a sodium channel from the outside of the axons to the inside, causing a momentary spark. The number of these sparks are regulated by the sodium channel, which controls how much sodium gets in, like a flapper in a toilet tank.

Despite its precision, this system is remarkably difficult to disrupt. Even getting your head cut off likely leaves humans in an odd disembodied state with electrical brain function for a few seconds. There is only one known way to make this electrical system instantaneously break, and we see it every fall Sunday on television and every Friday night at your local high school.

Many researchers believe that, in a traumatic brain injury, that flapper stays open. Just like when your toilet flapper is open and it won't flush, sodium rushes into the channels, preventing more sparks from being made. The entire system malfunctions, either in the form of being knocked out cold, not creating memories, or even just being dazed and confused. As you try and track the finger, the sparks won't be triggered as quickly, and your eye movement will lag. The same will happen when you try and balance on one leg. You have a concussion.

"It's shocking that you have the lights on," Dr. Smith told me. "It's like a symphony working at 100 meters per second. Each process along a tract is computationally manipulated and sent on to the next tract. Essentially, the signal is passed along like a baton, but modified at each step so when it completes the loop, it drives eye muscles to move your eyes back and forth to track and do the test." This system's resilience underscores just how damaging head trauma is and how unprepared our bodies are to cope with it on a regular basis.

In order to turn the lights back on, the axons need to get the sodium out. To do this, your brain enlists calcium. Too much calcium in your axons brings in enzymes called proteases that chew up your axons and other proteins from the inside out like little Pac Men. One of the proteins calcium chews up is spectrin, whose fragment, SNTF, is what Dr. Smith's blood tests detect.

A growing body of research suggests that head trauma opens the blood brain barrier, and that the more severe the trauma, the greater the degree to which it is opened. This is what allows tiny amounts of tracers to enter the bloodstream. (Researchers currently don't fully grasp the ramifications of the blood brain barrier being breached. It could prove helpful from an immune defense perspective, but scientists have always thought the barrier served a very important function.)

This year, Dr. Smith co-authored a study in the Journal of Neurotrauma measuring SNTF levels in Swedish hockey players. His team found SNTF elevated in concussed players one hour after the injury, remaining elevated anywhere from 12 hours to six days after the injury. SNTF restored to baseline levels correlated well with concussion symptoms subsiding, as measured by traditional concussion protocols. The study explained, "Serum SNTF exhibited diagnostic accuracy for concussion, especially so with delayed return to play." A 2014 study in JAMA Neurology co-authored by Quanterix researchers had similar results.

But different companies and researchers test for different biomarkers, which is why the gaps in our understanding of head trauma are so important. Some test for tau, the most publicized of the proteins which also comes from axons—further evidence that the underlying cause for head trauma is diffuse axonal injury (DAI). Others test for UCHL-1, GFAP, and still more look at (the coincidentally-named) NF-L. All these biomarkers potentially signal different things, and researchers don't quite know exactly what. After all, on its most fundamental level, we don't even know for sure what head trauma does to the body. So how can we know what each biomarker tells us?

It's possible that each biomarker signals a different element of brain trauma—short term versus long term effects, different symptoms within both—and a battery of them could provide a more complete picture of the exact nature of the injury. GFAP could signal brain bleeding, a very serious condition which often needs to be treated surgically. UCHL-1 could be specific to neural damage. NF-L, which is more abundant in deeper brain layers and the spinal cord, may signal more profound structural damage. Researchers simply don't know.

This (finally) gets us to the most immediate question regarding sideline blood tests: is this something technology can even do? Protein tracers take time to enter the bloodstream. This whole process—the sodium getting flushed from the axons by calcium, which chews up the proteins that then have to cross the blood brain barrier—is not instantaneous. We're not sure how long it takes, but some researchers like Dr. Smith believe it takes at least an hour. The idea that a concussed player can get up, walk to the sideline, get his finger pricked, and have results back within minutes is simply not supported by the science at this time. "As such, for the foreseeable future," Dr. Smith wrote to me after we spoke, "it is difficult to imagine that there would be sufficient brain protein accumulation in the blood to permit a 'sideline' test moments after head impact." (Hrusovsky disputes this, telling me "Today, our research has demonstrated that we can detect a concussion 45 minutes after impact, although we are currently in the process of validating the technology's ability to detect these levels just 20 minutes after impact. The barrier to testing athletes quicker has been due to the transporting of samples to a laboratory with our technology, which is why we are focused on developing a point-of-care device.")

Even if Hrusovsky's team eventually gets the technology sorted out, it's not clear exactly what problem this is solving. Dr. Henry Feuer, a member of the NFL's Head Neck and Spine Committee and a longtime team physician for the Indianapolis Colts, defended the traditional sideline test in Wired, saying, "Players who have suffered a concussion are going to have a very difficult time closing their eyes and maintaining balance on one leg. We're still not there in having a test that's close to foolproof. But it's much better than what was being done in the past."

While a member of the NFL's Head Neck and Spine Committee has obvious incentives to tout the sideline test's effectiveness, common sense backs him up. A quick perusal of the NFL's current sideline test shows several areas a player could conceivably falsify—reporting symptoms such as headache, dizziness, and word recall that appears to feature the same words every time—but many others they cannot—factual questions about where they are, the state of the game, who scored last, pupil reaction, motor issues, and confusion—if the test is properly administered.

Further, a sideline blood test would be subject to the very same self-reporting conundrums and reliance on trained medical professionals that result in people arguing concussions are difficult to detect now. Nor is it clear whether blood tests will detect football's biggest elephant in the room, subconcussive hits, or the routine bangs exhibited on every football play, which often don't result in traditional concussion symptoms.

"Sideline tests are by and large pretty good," Dr. Smith told me, recalling his "my dog could detect a concussion" joke. "Besides, you should be somewhat conservative. If someone looks like they got 'dinged' then you wouldn't send them back in anyways. A positive blood test really shouldn't change your decision on the fact that they look like they took a big hit."

This isn't to say blood biomarkers are useless; far from it. Most obviously, they could prove useful on the back end of return-to-play decision making. Currently, the NFL puts its players through a concussion protocol that gradually elevates their cognitive and physical strains until they're ready to play. This is a process that truly does involve subjectivity. Much of it is reliant on players reporting their mental and physical wellness, which appears to be a severely flawed system; a majority of players on the injury report for concussions don't miss a game. A blood test could alleviate much of this subjectivity.

Further, Hrusovsky hopes a blood test could help change the culture in football. "I have had many athletes tell me, pro level alumni from NFL, tell me, you know, if I get my bell rung and I don't go back in, I might get looked at as maybe not being tough. But if there's an objective test that tells me that my bell's been rung and I'm taking on a very serious health implication by continuing, maybe it has a shot at changing the culture of the game."

Critically, other biomarkers could test for long term damage. Axons behave like Silly Putty. If you stretch an axon slowly and gradually, it will expand while maintaining its continuity. (This is why you don't get a brain injury, from say, plopping down in your chair or shaking your head, despite so much press about the "slosh" effect.) But if you rip it apart, it'll break, and a growing consensus of experts believe this rapid break occurs as a result of brain injuries, otherwise known as diffuse axonal injury or DAI. If your head experiences abrupt rotational acceleration or impact—in less than 50 milliseconds, or about the time a single frame is shown during a standard movie—axons behave stiffly, like ripped apart silly putty.

In addition, all that built-up calcium has harmful effects. Inside the axons are train tracks to carry information called microtubules, which transport some of the proteins mentioned above. All that calcium rushing in to restore the system back to normal breaks microtubules, and all the cargo (proteins) gets dumped on the site, causing the axons to swell like a balloon. If this happens too often, the axons can burst, and they'll never get put back together.

So not only can the blood tests help determine when an athlete can return to play, but maybe if they should ever return to play. "If I see SNTF or tau proteins in the blood, I know axons are dead which means that's permanent," Dr. Smith told me. "Think about it like an airplane has four engines. You're up in the air and one breaks down, you're still flying, but how many more engines do you want to lose?"

To Dr. Smith, the potential benefits of a working blood biomarker are even bigger than that. Currently, head trauma treatment is incredibly difficult to research. Approximately four out of every five head trauma victims quickly return to a normal life. The remaining patients won't be able to go to work or school and have their lives derailed as a result of their injury. Currently, researchers have no way of knowing whether any given patient will be the 80 percent or the 20 percent until the first few days and weeks pass. This makes researching potential remedies, therapies, or treatments nearly impossible, since 80 percent of your potential population will get better on their own regardless. A blood test telling you whether someone will be in the 80 percent or the 20 percent would change all that.

Quanterix and Banyan are certainly aware of these possibilities and are poised to cash in. Hrusovsky envisions a future where perhaps four or five biomarkers are used to get a full picture of any given patient. Banyan is currently conducting a large study with University of Florida athletes in both contact and noncontact sports to determine the efficacy of its markers, primarily UCHL-1, during the 2015-16 season. It hopes to have the data by 2017.

In the meantime, Hrusovsky, who described himself to me as an entrepreneur, is preparing a crossover round of funding to try and raise $40 million, and is mulling over an IPO next year.

Perhaps blood tests will prove useful in ways researchers didn't initially envision. In Dr. Smith's Swedish hockey players study, he stumbled upon a potentially disturbing finding. Several of the players in the study had elevated SNTF levels in their preseason baseline blood tests. "It's anecdotal, but in our view, the test is sensitive, and that should not be in the blood unless there's brain injury." They don't know what this finding means yet. More research is needed.