Brain injuries are a danger in many sports, but for none more than football and its most profitable enterprise, the National Football League. The NFL is spending hundreds of millions of dollars on a concussion-lawsuit settlement and has poured tens of millions into research on measuring and preventing head trauma.
That’s right, a protein called “NFL” may wind up helping the NFL address its most vexing medical problem.
“It's just a remarkable coincidence,” said Kevin Hrusovsky, chief executive of Quanterix, a company that has received $800,000 in grant money from the NFL through the league's “Head Health Challenge” partnership with GE. Quanterix's technology allows users to zero in on molecules with such precision that Hrusovsky likened it to “being able to see a grain of sand in 2,000 Olympic-size swimming pools.”
That is crucial, because only tiny amounts of the proteins, referred to as “biomarkers,” dribble across the blood-brain barrier from the cerebrospinal fluid around the brain, where they would be found in larger quantities. The ability to spot sub-concussion injuries is important because they often go undetected by conventional methods and yet are increasingly seen as major threats to long-term health.
The problem with simply sampling athletes' cerebrospinal fluid, of course, is that requires a lumbar puncture, or spinal tap, which is a lot to ask in the middle of a football game (or in any other time and place, for that matter). Pricking an athlete's finger for a blood test and getting the results 15 to 20 minutes later makes for a much more reasonable process, albeit one still a long way from implementation.
The NFL is in search of what Jeff Miller, the league's senior vice president of health and safety policy, described as a more “objective” test for traumatic brain injury (TBI). He said the motivation behind the program through which Quanterix won its grants “was to look for better ways to advance the science around diagnoses of concussion, because you know … that there is no objective test, that we rely upon experts in the field who do subjective assessments of players.”
Miller, who made news a year ago for being the first NFL official to publicly affirm a link between football and the neurodegenerative disease chronic traumatic encephalopathy, or CTE, praised the array of medical personnel and athletic trainers employed on sidelines and up in skyboxes for being “very good at diagnostics.” However, he added, “it is subjective, there is no easy test that you can tell whether a player or an athlete, or a member of our military, or a civilian, has suffered a concussion.”
In addition, current testing relies to some degree on athletes self-reporting their symptoms, and as one sports-concussions expert told The Post, “if someone is not willing or forthcoming, then you're going to be a little limited there.” Blood tests of biomarkers offer a potential means to avoid the conflicts of interest on the part of players, coaches or team physicians that can get in the way of proper medical treatment.
Jonathan Oliver, a professor of kinesiology at Texas Christian University, and his colleagues are studying the school's football team to measure neurofilament light (which is also sometimes rendered as “NF-L” and shall be referred to that way in this article to avoid confusion with the sports league.).
For a 2015 study, they took blood samples at specific periods and compared the results between starters, who could be expected to suffer the most damage, and non-starters. Samples were taken in the offseason, before any impacts, then right before two-a-day practices, right after two-a-days, and then every 14 to 21 days until the end of the season.
Oliver's team found that “our non-starters remained flat throughout the season,” but the starters' levels of NF-L showed a correlation with impacts, rising by the end of two-a-days, falling during the early portion of the season and “creeping back up” later in conference play. That pattern “is what you'd expect,” he said, “because they would get more playing time” as games became tougher and more meaningful.
For that study, Oliver deliberately excluded Horned Frogs (that's what TCU players are called) who had been diagnosed with concussions, because he wanted to “identify at what point players may get to a level that we're seeing elevations in this marker, NF-L, such that they match what somebody who has a concussion looks like.” That way, decisions about pulling players from games or prolonging their recovery periods could be at least partly informed by their blood tests, and possibly entirely so if the players in question weren’t showing — or, as too often happens, weren't reporting — any symptoms.
Even though a given player “may not be suffering from a concussion, the marker's indicating that, 'Hey, we may have a problem here,’” Oliver said. He noted that being able to look at one or more biomarkers could be all the more useful because “in football players in particular, there's a huge number that go unreported.”
Some players are worried that if they report concussions, they will be pulled from games, Oliver said. But, he pointed out, if an athlete suffers a concussion that goes untreated, then suffers another one, “the damage could be much greater.”
Hrusovsky agreed that, within the “culture” of football, a player is often “expected to be tough,” which can lead to a resistance to leaving the field “because of some subjective test.”
“If there's a more objective way to determine if that player has put himself at risk,” he added, the emerging science “could play a role in really helping change the culture of the game to make sure that athletes are protected.”
Of course, athletes from many more sports than football are at risk of TBI. Colleagues of Oliver's in Sweden published a 2014 study in which they enlisted 288 players from that country’s top hockey league. (Oliver also noted that the NFL/NF-L coincidence was largely wasted on his Swedish colleagues.)
That study showed a correlation between concussions and elevated levels of another protein, tau, which has been of great interest to scientists. Deposits of tau in the brain have played a key role in CTE diagnoses, and the protein’s link to concussions was bolstered by a recent study from the National Institutes of Health, which the agency said in a news release showed that “measuring tau levels could potentially be an unbiased tool to help prevent athletes from returning to action too soon and risking further neurological injury.”
Henrik Zetterberg, a professor of neurochemistry at the University of Gothenburg and University College London who helped lead the study of hockey players and has looked at boxers, said tau tends to increase quickly, within an hour, after a brain injury and “goes away rather quickly.” On the other hand, NF-L levels can remain elevated for seven to 14 days.
Zetterberg, who, like Oliver, has used Quanterix’s platform, posited that tau could be used to gauge the immediate severity of a brain injury, possibly helping make a decision about whether a player should be immediately returned to play, while an elevated NF-L level several days later could indicate that the player was at an “increased risk of having sustained or longer symptoms.” At that point, the player would be advised to get more rest.
What makes tau and NF-L, as well as some related proteins, such as S100-B and GFAP (glial fibrillary acidic protein), stand out is that they are not commonly found in organs other than the brain and central nervous system. They help form parts of axons, the long, slender arms that protrude from neurons and transmit information, performing countless essential functions.
Calling axons “the most vulnerable parts of the neurons,” Zetterberg said that “the most important injury mechanism in the concussion is” when they “break” and release contents into the brain, spinal fluid and, eventually, blood. Thus, if tau or NF-L is found in blood, it can be an indication that the brain has suffered axonal damage.
Zetterberg (no direct relation to the longtime Red Wings player of the same name, although he sometimes gets misdirected fan mail and passes it along to the Detroit star’s parents in northern Sweden) concurred with Oliver that NF-L appeared to be a better indicator of sub-concussive events. Such injuries, “over and over,” Oliver said, “can have a huge impact down the line.”
A tragic example of that cumulative impact became clear when former San Diego Chargers player Junior Seau committed suicide in 2012. An autopsy confirmed that his brain showed signs of CTE, even though his family said that the linebacker had never been formally diagnosed with a concussion. That was cited as an example of the effects of repeated sub-concussive trauma by Anthony Petraglia, a Rochester, N.Y.-based expert on sports-related brain injuries and co-author of “Handbook of Neurological Sports Medicine.”
Speaking by phone from an event that also featured Bennet Omalu, the doctor credited with uncovering the link between football and CTE, and Steve Tasker, a former Buffalo Bill who has acknowledged his own concussions but promotes the positive aspects of football, Petraglia described “the ability to develop serum markers” as the “holy grail” of concussion research.
However, while calling the research into proteins “a burgeoning field,” Petraglia urged “caution” about getting too far ahead of hard science, which is still in its very early stages. “It's going to be important not to overreact to some of this,” he said.
It might turn out that proteins such as NF-L could help make return-to-play decisions, but, Petraglia said, it may well be the case that proteins take longer to clear out of one athlete than another, mandating that each player have a well-defined baseline for comparison, and that specific levels deemed dangerous be rigorously calibrated. He also wondered what would happen if a player was “asymptomatic” but showed elevated levels of one or more proteins, creating an all-too-likely scenario in which the seemingly healthy athlete and his or her coach are at odds with medical personnel.
“Does that mean that we're going to hold people out just because of their biomarkers still being off?” Petraglia asked. “Is that going to be a dangerous thing, to send them back at that point?”
Another scenario posed by advancements in research is that the NFL could discover that, at any given moment in a season, a huge number of its players are showing elevated levels of key biomarkers, despite few of them displaying standard concussion symptoms. And what if, or when, some of those levels are shown to correlate with the onset of CTE?
In the meantime, the NFL will “go where the science goes,” Miller said of possibly administering blood tests on sidelines.
Much of the NFL’s funding has gone to imaging technologies, and although Zetterberg said that “you do not see much” with current scans, such as CT scans and MRI exams, he noted that there has been “quite a bit” of advancement in that field. “I think you'll find there's going to be a role for imaging in this, as well. It's not going to just be blood biomarkers,” Hrusovsky said.
One thing that is more certain is that we are still a long way from a reliable test for CTE in living patients (currently, diagnoses can be made only posthumously), whether that eventually can be done through blood tests, imaging, another technology or combinations thereof. But while acknowledging that CTE is “the scary monster at the end of the table,” Petraglia said that “we also need not forget that there is a lot of room” between injury and incurable neurodegenerative diseases.
“That's the area we need to be focusing on,” he said, because there are “many more people,” including athletes, military personnel and others, who “maybe don't go on to develop full-blown CTE, but they're dealing with chronic emotional issues, depression, anxiety, PTSD, maybe they're dealing with sleep issues or chronic headaches.
“And to the extent that is a result of repetitive head trauma,” Petraglia added, “well, could we have mitigated that, could we have gotten to a point where we say, 'Hey, we're at a point where we need to hold you back, so you don't head down this path'? I hope that at some point we're able to get there.”
If the NFL does reach that point, it may be because, unlikely as it sounds, NF-L helped it get there.