By David Epstein
March 07, 2013
A study found that a simple blood test may be able to determine damage from head trauma in active players.
/Cal Sport Media

While the central focus of brain injury in football has rested squarely on concussions, a burgeoning body of scientific work suggests that the repetitive, sub-concussive hits that occur every play may be at least as deleterious to the brains of players. Increasing the insidiousness of the problem, that damage has been maddeningly difficult to detect until a former football player displays severe behavioral and neurocognitive impairments, or dies and has his brain dissected.

A study published Wednesday in the journal PLOS ONE adds new evidence highlighting the importance of sub-concussive hits, and could help lead to a quick and cheap blood test to check for signs of damage in active players. The study, led by Jeffrey J. Bazarian of the University of Rochester and Nicola Marchi and Damir Janigro of the Cleveland Clinic, found that college football players who took more shots to the head in games had higher levels in their blood streams of a particular protein that is indicative of brain injury.

The researchers tested players from Baldwin Wallace University, John Carroll University and the University of Rochester before and after games, and found elevated concentrations of the S100B protein in the blood of players who experienced the most hits. S100B is thought to aid in the functioning of neurons early in life, and it is present only in the brain. The so-called "blood-brain barrier" separates the brain from the blood stream, keeping brain proteins in and potentially harmful materials out. The fact that S100B was showing up in the blood of players after games "means the barrier was open," Marchi says. The primary concern is not the S100B itself, but the body's immune response to the sudden presence of a particular protein that should not exist in the blood stream. The body reacts to S100B in the blood as a foreign invader and releases auto-antibodies to attack it. The antibodies can then leak into the brain through the weakened blood-brain barrier where they are thought to attack brain tissue. Four out of 27 players who had pre- and in-season blood tests showed signs of an autoimmune response to elevated S100B levels.

The finding is important in two ways. First, none of the players with elevated S100B in their blood had suffered a concussion, so sub-concussive hits were apparently all it took to undermine the integrity of the blood-brain barrier. (S100B blood tests are already used outside of sports, and as a standard procedure in a few emergency rooms in Germany for diagnosing brain trauma.) A growing body of work suggests that the accumulation of smaller hits, those that do not result in concussions, might be as important or more so to the damage done to a player's brain. Many, if not most, of the brains that have shown evidence of the now infamous chronic traumatic encephalopathy (CTE) have come from former NFL lineman, who almost never suffer concussions and are impacted very little by football's rule changes. Researchers in the Purdue Neurotrauma Group -- who have found transient neurocognitive deficits in high school players who take large numbers of small hits but are not concussed -- have begun recommending that football coaches monitor head hits the way a baseball mangers thinks of pitch counts, with strict weekly limits. (The new study was blinded so that researchers doing the blood testing did not know the hit tallies of the players, but Marchi says he is now aware that offensive and defensive linemen generally displayed the highest elevation in S100B.)

Second, the work could be a step toward real-time blood testing for the damage imposed by sub-concussive hits. In 2010, the U.S. Army, in partnership with the Alachua, Fla.-based company Banyan Biomarkers, announced that 34 patients had been accurately diagnosed with traumatic brain injury via a blood test for other proteins (SBDP145 and SBDP120) that seep through the blood-brain barrier after damage. The Army data focused principally on mild to severe injury, so the new S100B study -- though it is small and requires repetition -- might help create blood testing technology to detect mild brain trauma quickly and perhaps for as little as $40. "This is really our ultimate goal," Marchi says. "In theory, you can finger prick an individual and within three or five minutes you can have a response. This seems feasible for S100B, so in an ideal world we would like to develop a particular device for quick measurement of S100B. Having a device could be of great help on the field, in the locker room. This is basically for detection of an acute event."

The study also used diffusion tensor imaging (DTI) -- which shows the flow patterns of water over the brain to detect damage to cerebral white matter -- to show that the presence of S100B antibodies was correlated with apparent brain tissue damage. (Neuroimaging with DTI has shown increasing promise as a means to detect brain damage early in football players.)

Aside from developing real time tests for brain damage, though, the urgent need is to study what doctors call the "dose response" relationship between hits and brain trouble. That is the connection between the number and force of hits and the specific damage to the brain. As Kevin Guskiewicz, a neuroscientist, athletic trainer and director of North Carolina's Center for the Study of Retired Athletes, recently told SI: "That's been neglected." Some recent work by Guskiewicz and colleagues at North Carolina found that college football players who sustained about 1,000 sub-concussive hits over a season did not display impairment on tests of balance and cognitive performance after the season, and the Purdue Neurotrauma Group found that cognitive performance in high school players who took large numbers of hits was impaired at times during the season, but returned to normal after the season. The question, then, is when the impairment becomes permanent.

An intriguing but speculative aspect of the new S100B study is the possibility that a lingering autoimmune response might have a role in explaining why severe cognitive impairment shows up years after players stop playing. "Every time the immune system sees something that is different," Marchi says, "if this elevation in blood is repeated over time, in five years, or 10 years, then an autoimmune response could mount and maybe this could contribute to the long term cognitive decline."

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