Mike Webster played for 17 seasons in the National Football League (NFL). He was instrumental to the Pittsburgh Steelers’ four Super Bowl victories during his career. In 2002 he died of heart failure in the coronary care unit of Allegheny General Hospital at age 50. His medical history included serious neuropsychiatric problems beginning around the time he left the NFL. After Webster retired at age 38, his family watched him disintegrate into a tormented, wandering soul living out of his Chevrolet S-10 pickup truck. After his death, an astute neuropathologist at the University of Pittsburgh, Bennet Omalu, performed an autopsy on Webster and preserved regions of his brain for later microscopic analysis. When Omalu examined the specimens, he observed atrophy similar to that seen in Alzheimer’s disease patients—but in different areas of the brain. Omalu recognized the abnormalities as chronic traumatic encephalopathy (CTE), a form of brain deterioration previously reported in boxers and associated with the repeated traumatic brain injuries experienced in that sport. The 2005 report that Omalu published on Webster’s brain was the first known case of CTE in a professional NFL player. In the eight years since, the number of reports of the behavioral and cognitive changes experienced by NFL players has exploded. And the athletes themselves have taken notice. When Chicago Bears player Dave Duerson committed suicide in 2011, he shot himself in the chest and left a note requesting that his brain be donated to science. Analyses revealed that he, too, had developed CTE. The year of Duerson’s death, approximately 4,500 players sued the NFL for concealing information about the dangers of traumatic brain injuries. Last August the league agreed to an out-of-court settlement for $765 million. Since then, former players have launched new suits against the NFL, the National Collegiate Athletic Association (NCAA) and a helmet manufacturer, Riddell. The legal furor has been matched by a frenzy of activity on the scientific side. More than 100 NFL players and athletes from other sports have pledged their brains to the study of CTE. So far few of the mysteries of this disorder have been solved, but scientists have nonetheless gleaned compelling insights. Participating in contact sports and sustaining brain trauma raise a person’s risk of several forms of cognitive impairment and dementia, not only CTE. Yet the neuropathology of CTE is distinct, and its link to sports raises important questions regarding athletes’ safety. Science is progressing rapidly, and its message is clear: to preserve the game and its players, the culture of football must change. Brains under Fire Although CTE is most commonly associated with football, brain trauma is anything but rare. Annually in the U.S., traumatic brain injuries account for more than a million emergency room visits; an unknown number of brain injuries are treated outside the hospital or go unremarked. Head injuries from car accidents or, for military veterans, from explosive blasts take a toll, as do hits incurred in several sports, including hockey, soccer and martial arts. Yet the gut-wrenching stories of American football players who excelled on the field—only to face psychological difficulties off of it and to die in abrupt, often violent ways—have put this sport at the center of the CTE controversy. Cullen Finnerty, a former professional player, disappeared into the woods last May at age 30 before turning up dead two days later. Andre Waters, renowned as one of the NFL’s hardest hitters, committed suicide at age 44. Twenty-six-year-old Chris Henry, a wide receiver for the Cincinnati Bengals, fell off the back of a moving truck and died in 2009. When their brain tissue was later examined, all three athletes showed signs of CTE. Even more disturbing are the cases of young, nonprofessional players who developed CTE. Among them is a former captain of the University of Pennsylvania football team, 21-year-old Owen Thomas. In 2010 Thomas hanged himself in his off-campus apartment. According to his mother, he had never been diagnosed with a concussion. An examination of his brain nonetheless showed marks of the trauma-induced disease. Younger still was the 18-year-old multisport high school student who died from complications related to a brain injury on the field. The frontal cortex of his brain featured telltale protein buildups that also indicated a very early stage of CTE. Such cases have led parents to worry whether they should sign their kids up for youth football leagues—and if so, at what age. The controversies surrounding head injuries may be new to football, but the deleterious effects of multiple blows to the brain have been known anecdotally for almost a century. The first published report dates back to 1928, when pathologist Harrison S. Martland wrote of “punch drunk” boxers’ bizarre speech patterns, unsteady gait and progressive loss of cognitive function. He even drew a connection between traumatic encephalitis—an inflammation of the brain—and multiple head injuries. Subsequent postmortem analyses of boxers characterized the changes in more detail and introduced the term “chronic traumatic encephalopathy.” Nowadays CTE refers to a constellation of brain changes, some of which can be seen with the naked eye during an autopsy. A CTE-afflicted brain weighs less than a healthy one, with atrophy visible across numerous areas. Two of the brain’s four ventricles—cavities filled with cerebrospinal fluid—appear enlarged. Under the microscope, the brain is peppered with tangles of a protein called tau that clump irregularly around blood vessels and inside brain cells. Sometimes other proteins also accumulate—namely, beta amyloid (implicated in Alzheimer’s) and TDP-43 (a major factor in amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease). The brain degeneration can only be observed postmortem, yet certain behavioral changes might signal its presence in a living person. Symptoms include memory impairment, erratic behavior, depression and problems with impulse control; suicidal behavior also appears to be endemic. Also telling is a 2007 study of more than 2,500 retired NFL players. The scientists found that cognitive impairment, memory problems and depression rose in step with the number of concussions a player had endured. Yet questions remain as to whether the same disorder that left younger players psychologically crippled also explains the cognitive decline that seems to manifest only decades after some players have retired. Researchers recently concluded that CTE afflicts people in one of two ways. In one cohort, aged 20 to 40, the disease progresses rapidly and instigates major changes to behavior and mood, which can lead to suicide. For an older cohort, roughly between the ages of 50 and 70, cognitive impairment is more notable, with dementia as a common end point. The afflictions of this older cohort appear more acute than the mild cognitive decline often seen in the aging brain, as neurologist Christopher Randolph of Loyola University Medical Center and his colleagues observed in a study published in 2013. They administered a questionnaire to the spouses of 513 retired NFL players with a mean age of 64 years. When asked whether the athletes exhibited significant cognitive impairment, 35 percent of the spouses said yes. In the general population of men under age 75, the figure is less than 5 percent. A Shaken Brain The core question is how a history of head hits can trigger the brain’s disintegration. The most widely accepted theory builds on the observation that rotational forces, in which the brain twists to one side, seem to deal the most damage. The brain floats in its skull mostly unattached, buoyed by cerebrospinal fluid, a colorless liquid that cushions the brain and spine. After a hit, the brain deforms. If shaken hard enough, and especially if the brain twists, parts of neurons can stretch and even shear. The twisting motion tears open axons, the long, slim fibers that connect one neuron to another neuron (or to a muscle or organ). With the axon’s outer protective sheath ripped open, the thin filaments inside start to unravel. These filaments, called microtubules, allow cargo to travel from the nucleus to target cells. When the microtubules are damaged, molecules of glutamate leak from the cell. The cell also releases several proteins: tau (a structural element that helps to hold together microtubules), amyloid precursor protein and TDP-43. The dispersal of these molecules signals nearby cells that damage has occurred, triggering an immune and inflammatory response. Part of that reaction involves the release of a protein called S100B, which plays an important role in generating and repairing axons, among other things [see box]. What exactly these molecules do once released and how long they linger in the brain are critical open questions. Notably, we know that tau and amyloid precursor protein are critical constituents in Alzheimer’s. When a microtubule disintegrates, tau comes loose and can aggregate into unruly tangles. An abundance of tau is a hallmark of Alzheimer’s (among other forms of dementia), although whether these tangles cause the disease’s devastating effects or are a mere by-product remains unknown. The breakdown of amyloid precursor protein, for its part, can lead to the buildup of amyloid plaques, which constitute another major sign of Alzheimer’s. A crucial shortcoming in CTE research is that we have no way of identifying axonal damage in a living brain. To this end, S100B, one of the proteins released in response to a damaged axon, has recently come under closer scrutiny by researchers. After a traumatic brain injury, molecules of S100B can leak across the blood-brain barrier, which typically seals off the brain from any contaminants circulating in the bloodstream. Testing a player’s blood for levels of S100B could offer a quick read on the athlete’s brain health after an injury. Looking Ahead Only a small percentage of athletes experience profound changes in personality and cognition, and one of scientists’ most pressing goals is to determine who is most at risk. The fact that not all players succumb to CTE suggests that given time, the brain can repair damaged areas. Repeated blows within some critical window seem to prime the brain for CTE: they either amplify existing injuries or prolong the recovery, or both. A subsequent hit could rev up the inflammatory processes already at work, potentially setting off toxic cascades. Assuming future research pans out, a timely blood test for S100B might let team physicians monitor the extent of damage caused by a head hit and thus determine whether it is safe for a player to return to the field. The test might even serve as a simple, if crude, way of tracking players’ risk of developing CTE game by game. Another promising advance could turn brain imaging into a diagnostic tool by monitoring the presence of tau in a living person. A new radioactive tracer can bind to tau, exposing it in brain scans produced by positron-emission tomography. In a 2013 pilot study led by psychiatrist Gary Small of the University of California, Los Angeles, five retired NFL players with CTE symptoms underwent brain scans after being injected with the new tracer. The resulting images showed significantly higher levels of tau than the control subjects had. Though preliminary, this approach opens up the possibility of early detection, a significant first step before clinicians can begin delivering therapy. As for treatment, the NFL Alumni Association is working with a company called Neuralstem to develop drugs that might combat the symptoms of CTE. Neuralstem’s proposed intervention targets atrophy in the hippocampus, a memory center of the brain. By introducing neural stem cells into the hippocampus, the thinking goes, we can stimulate new neurons to grow, replacing the lost brain cells and potentially restoring memory or at least halting the deterioration. In studies using human neural stem cells grown in culture, the company’s drug, called NSI-189, was shown to stimulate the development of new neurons in the hippocampus. Yet these are early days—the drug is undergoing safety testing in two dozen patients and is, at best, years away from showing up on pharmacy shelves. Protection for Players The biggest gains, at least in the short term, will come not from drugs but from changes in how players protect themselves and how the game is played. Several measures can encourage teams at all levels and ages to adopt safer standards and help to prevent the spread of CTE. During a game, referees should penalize players who make reckless tackles or who wear protective equipment improperly, such as leaving helmet chinstraps unbuckled. Although well-fitted helmets are important, they are unlikely to protect the brain from rotational forces. Thus, it falls to coaches to teach players proper tackling and hitting, as well as self-protection. The NFL has begun promoting a playing technique called Heads Up tackling, which it has deemed safer than the existing style of taking down opponents [see “A Safe Way to Tackle?”]. At the college level, coaches need to recognize the risks of full-contact practice and keep head impacts during training to a minimum. Trainers, too, have a role. They should emphasize neck-strengthening exercises as a way of buttressing the head against the rotational forces of a hit. Several studies, including some that used dummies to simulate the collision mechanics in concussions, have found that the stiffness of the neck influences the degree of head rotation and displacement in a concussion and that building up the muscles of the neck can protect some players. One suggestion from several research groups is to have players wear helmets equipped with sensors that can monitor collisions. These commercially available sensors send their data to a computer system on the sidelines that tracks the number and intensity of hits players receive during a practice or game. The technology does not prevent brain trauma so much as allow team personnel to monitor players and pull them off the field should their impact data cross some threshold considered unsafe. Although we do not yet know how long the brain needs to recover after a hit, we can say that a player with blurry vision, balance problems or confusion is at greater risk of getting clobbered a second time. The collision data collected by the sensors can help coaches and trainers decide whether an athlete should continue playing after an impact, even in the absence of any outward signs of instability. Modifying practices to cut back on concussions—not just in football but also in hockey, soccer and boxing, to name a few—need not deprive competitive athletics of their entertainment value. All sports involve some element of risk, yet engaging in team physical activity also promotes a healthy lifestyle. Just as seat belts reduced the number of road deaths without having to ban cars, so, too, can safer habits and standards spare athletes without overhauling their sports. As the many fallen athletes remind us, the risks are far too great to ignore.
After Webster retired at age 38, his family watched him disintegrate into a tormented, wandering soul living out of his Chevrolet S-10 pickup truck. After his death, an astute neuropathologist at the University of Pittsburgh, Bennet Omalu, performed an autopsy on Webster and preserved regions of his brain for later microscopic analysis.
When Omalu examined the specimens, he observed atrophy similar to that seen in Alzheimer’s disease patients—but in different areas of the brain. Omalu recognized the abnormalities as chronic traumatic encephalopathy (CTE), a form of brain deterioration previously reported in boxers and associated with the repeated traumatic brain injuries experienced in that sport. The 2005 report that Omalu published on Webster’s brain was the first known case of CTE in a professional NFL player.
In the eight years since, the number of reports of the behavioral and cognitive changes experienced by NFL players has exploded. And the athletes themselves have taken notice. When Chicago Bears player Dave Duerson committed suicide in 2011, he shot himself in the chest and left a note requesting that his brain be donated to science. Analyses revealed that he, too, had developed CTE. The year of Duerson’s death, approximately 4,500 players sued the NFL for concealing information about the dangers of traumatic brain injuries. Last August the league agreed to an out-of-court settlement for $765 million. Since then, former players have launched new suits against the NFL, the National Collegiate Athletic Association (NCAA) and a helmet manufacturer, Riddell.
The legal furor has been matched by a frenzy of activity on the scientific side. More than 100 NFL players and athletes from other sports have pledged their brains to the study of CTE. So far few of the mysteries of this disorder have been solved, but scientists have nonetheless gleaned compelling insights. Participating in contact sports and sustaining brain trauma raise a person’s risk of several forms of cognitive impairment and dementia, not only CTE. Yet the neuropathology of CTE is distinct, and its link to sports raises important questions regarding athletes’ safety. Science is progressing rapidly, and its message is clear: to preserve the game and its players, the culture of football must change.
Brains under Fire Although CTE is most commonly associated with football, brain trauma is anything but rare. Annually in the U.S., traumatic brain injuries account for more than a million emergency room visits; an unknown number of brain injuries are treated outside the hospital or go unremarked. Head injuries from car accidents or, for military veterans, from explosive blasts take a toll, as do hits incurred in several sports, including hockey, soccer and martial arts. Yet the gut-wrenching stories of American football players who excelled on the field—only to face psychological difficulties off of it and to die in abrupt, often violent ways—have put this sport at the center of the CTE controversy. Cullen Finnerty, a former professional player, disappeared into the woods last May at age 30 before turning up dead two days later. Andre Waters, renowned as one of the NFL’s hardest hitters, committed suicide at age 44. Twenty-six-year-old Chris Henry, a wide receiver for the Cincinnati Bengals, fell off the back of a moving truck and died in 2009. When their brain tissue was later examined, all three athletes showed signs of CTE.
Even more disturbing are the cases of young, nonprofessional players who developed CTE. Among them is a former captain of the University of Pennsylvania football team, 21-year-old Owen Thomas. In 2010 Thomas hanged himself in his off-campus apartment. According to his mother, he had never been diagnosed with a concussion. An examination of his brain nonetheless showed marks of the trauma-induced disease. Younger still was the 18-year-old multisport high school student who died from complications related to a brain injury on the field. The frontal cortex of his brain featured telltale protein buildups that also indicated a very early stage of CTE. Such cases have led parents to worry whether they should sign their kids up for youth football leagues—and if so, at what age.
The controversies surrounding head injuries may be new to football, but the deleterious effects of multiple blows to the brain have been known anecdotally for almost a century. The first published report dates back to 1928, when pathologist Harrison S. Martland wrote of “punch drunk” boxers’ bizarre speech patterns, unsteady gait and progressive loss of cognitive function. He even drew a connection between traumatic encephalitis—an inflammation of the brain—and multiple head injuries. Subsequent postmortem analyses of boxers characterized the changes in more detail and introduced the term “chronic traumatic encephalopathy.”
Nowadays CTE refers to a constellation of brain changes, some of which can be seen with the naked eye during an autopsy. A CTE-afflicted brain weighs less than a healthy one, with atrophy visible across numerous areas. Two of the brain’s four ventricles—cavities filled with cerebrospinal fluid—appear enlarged. Under the microscope, the brain is peppered with tangles of a protein called tau that clump irregularly around blood vessels and inside brain cells. Sometimes other proteins also accumulate—namely, beta amyloid (implicated in Alzheimer’s) and TDP-43 (a major factor in amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease).
The brain degeneration can only be observed postmortem, yet certain behavioral changes might signal its presence in a living person. Symptoms include memory impairment, erratic behavior, depression and problems with impulse control; suicidal behavior also appears to be endemic. Also telling is a 2007 study of more than 2,500 retired NFL players. The scientists found that cognitive impairment, memory problems and depression rose in step with the number of concussions a player had endured.
Yet questions remain as to whether the same disorder that left younger players psychologically crippled also explains the cognitive decline that seems to manifest only decades after some players have retired. Researchers recently concluded that CTE afflicts people in one of two ways. In one cohort, aged 20 to 40, the disease progresses rapidly and instigates major changes to behavior and mood, which can lead to suicide. For an older cohort, roughly between the ages of 50 and 70, cognitive impairment is more notable, with dementia as a common end point.
The afflictions of this older cohort appear more acute than the mild cognitive decline often seen in the aging brain, as neurologist Christopher Randolph of Loyola University Medical Center and his colleagues observed in a study published in 2013. They administered a questionnaire to the spouses of 513 retired NFL players with a mean age of 64 years. When asked whether the athletes exhibited significant cognitive impairment, 35 percent of the spouses said yes. In the general population of men under age 75, the figure is less than 5 percent.
A Shaken Brain The core question is how a history of head hits can trigger the brain’s disintegration. The most widely accepted theory builds on the observation that rotational forces, in which the brain twists to one side, seem to deal the most damage.
The brain floats in its skull mostly unattached, buoyed by cerebrospinal fluid, a colorless liquid that cushions the brain and spine. After a hit, the brain deforms. If shaken hard enough, and especially if the brain twists, parts of neurons can stretch and even shear. The twisting motion tears open axons, the long, slim fibers that connect one neuron to another neuron (or to a muscle or organ).
With the axon’s outer protective sheath ripped open, the thin filaments inside start to unravel. These filaments, called microtubules, allow cargo to travel from the nucleus to target cells. When the microtubules are damaged, molecules of glutamate leak from the cell. The cell also releases several proteins: tau (a structural element that helps to hold together microtubules), amyloid precursor protein and TDP-43. The dispersal of these molecules signals nearby cells that damage has occurred, triggering an immune and inflammatory response. Part of that reaction involves the release of a protein called S100B, which plays an important role in generating and repairing axons, among other things [see box].
What exactly these molecules do once released and how long they linger in the brain are critical open questions. Notably, we know that tau and amyloid precursor protein are critical constituents in Alzheimer’s. When a microtubule disintegrates, tau comes loose and can aggregate into unruly tangles. An abundance of tau is a hallmark of Alzheimer’s (among other forms of dementia), although whether these tangles cause the disease’s devastating effects or are a mere by-product remains unknown. The breakdown of amyloid precursor protein, for its part, can lead to the buildup of amyloid plaques, which constitute another major sign of Alzheimer’s.
A crucial shortcoming in CTE research is that we have no way of identifying axonal damage in a living brain. To this end, S100B, one of the proteins released in response to a damaged axon, has recently come under closer scrutiny by researchers. After a traumatic brain injury, molecules of S100B can leak across the blood-brain barrier, which typically seals off the brain from any contaminants circulating in the bloodstream. Testing a player’s blood for levels of S100B could offer a quick read on the athlete’s brain health after an injury.
Looking Ahead Only a small percentage of athletes experience profound changes in personality and cognition, and one of scientists’ most pressing goals is to determine who is most at risk. The fact that not all players succumb to CTE suggests that given time, the brain can repair damaged areas. Repeated blows within some critical window seem to prime the brain for CTE: they either amplify existing injuries or prolong the recovery, or both. A subsequent hit could rev up the inflammatory processes already at work, potentially setting off toxic cascades. Assuming future research pans out, a timely blood test for S100B might let team physicians monitor the extent of damage caused by a head hit and thus determine whether it is safe for a player to return to the field. The test might even serve as a simple, if crude, way of tracking players’ risk of developing CTE game by game.
Another promising advance could turn brain imaging into a diagnostic tool by monitoring the presence of tau in a living person. A new radioactive tracer can bind to tau, exposing it in brain scans produced by positron-emission tomography. In a 2013 pilot study led by psychiatrist Gary Small of the University of California, Los Angeles, five retired NFL players with CTE symptoms underwent brain scans after being injected with the new tracer. The resulting images showed significantly higher levels of tau than the control subjects had. Though preliminary, this approach opens up the possibility of early detection, a significant first step before clinicians can begin delivering therapy.
As for treatment, the NFL Alumni Association is working with a company called Neuralstem to develop drugs that might combat the symptoms of CTE. Neuralstem’s proposed intervention targets atrophy in the hippocampus, a memory center of the brain. By introducing neural stem cells into the hippocampus, the thinking goes, we can stimulate new neurons to grow, replacing the lost brain cells and potentially restoring memory or at least halting the deterioration. In studies using human neural stem cells grown in culture, the company’s drug, called NSI-189, was shown to stimulate the development of new neurons in the hippocampus. Yet these are early days—the drug is undergoing safety testing in two dozen patients and is, at best, years away from showing up on pharmacy shelves.
Protection for Players The biggest gains, at least in the short term, will come not from drugs but from changes in how players protect themselves and how the game is played. Several measures can encourage teams at all levels and ages to adopt safer standards and help to prevent the spread of CTE.
During a game, referees should penalize players who make reckless tackles or who wear protective equipment improperly, such as leaving helmet chinstraps unbuckled. Although well-fitted helmets are important, they are unlikely to protect the brain from rotational forces. Thus, it falls to coaches to teach players proper tackling and hitting, as well as self-protection. The NFL has begun promoting a playing technique called Heads Up tackling, which it has deemed safer than the existing style of taking down opponents [see “A Safe Way to Tackle?”]. At the college level, coaches need to recognize the risks of full-contact practice and keep head impacts during training to a minimum.
Trainers, too, have a role. They should emphasize neck-strengthening exercises as a way of buttressing the head against the rotational forces of a hit. Several studies, including some that used dummies to simulate the collision mechanics in concussions, have found that the stiffness of the neck influences the degree of head rotation and displacement in a concussion and that building up the muscles of the neck can protect some players.
One suggestion from several research groups is to have players wear helmets equipped with sensors that can monitor collisions. These commercially available sensors send their data to a computer system on the sidelines that tracks the number and intensity of hits players receive during a practice or game. The technology does not prevent brain trauma so much as allow team personnel to monitor players and pull them off the field should their impact data cross some threshold considered unsafe. Although we do not yet know how long the brain needs to recover after a hit, we can say that a player with blurry vision, balance problems or confusion is at greater risk of getting clobbered a second time. The collision data collected by the sensors can help coaches and trainers decide whether an athlete should continue playing after an impact, even in the absence of any outward signs of instability.
Modifying practices to cut back on concussions—not just in football but also in hockey, soccer and boxing, to name a few—need not deprive competitive athletics of their entertainment value. All sports involve some element of risk, yet engaging in team physical activity also promotes a healthy lifestyle. Just as seat belts reduced the number of road deaths without having to ban cars, so, too, can safer habits and standards spare athletes without overhauling their sports. As the many fallen athletes remind us, the risks are far too great to ignore.
