The brain disease that the NFL has now acknowledged can be caused by playing football appears to be more widespread than originally thought, according to new scientific evidence that has alarmed some of the nation's top researchers.
The research, much of it published within the past year, includes brain bank studies that detected chronic traumatic encephalopathy, or CTE, in a large percentage of former high school football players and other athletes; scans that showed signs of the disease in NFL players decades after their retirement; animal models -- designed to replicate NFL-style head banging -- that suggest repetitive trauma can cause permanent brain damage; and a consensus statement issued by two dozen neuroscientists, who noted that CTE has "only been found in individuals who were exposed to brain trauma, typically multiple episodes."
Although many questions remain unanswered, the research appears not only to reinforce the connection between repetitive head trauma and CTE, but also suggests that the disease may be prevalent among people in the general population who played contact sports, not just former NFL players, whose diagnoses with CTE often dominate headlines.
"That's what keeps me up at night," Dr. Walter Koroshetz, director of the National Institute for Neurological Disorders and Stroke, said in a recent interview. "At least at this early stage, it seems to be much more common than anybody imagined. That's kind of what we've been afraid of for a while, and now we have data that it is more widespread. ... I think we have a significant problem that's getting bigger as we see how this pathology is more common."
Koroshetz cautioned that much still is unknown about CTE, including how common it is, when and why symptoms develop, and how the disease -- which is associated with depression, dementia and memory loss -- spreads inside the brain.
The findings come as the NFL, which for years downplayed the risks of concussions, is sending out contradictory signals about its views on the relationship between football and brain disease.
On Monday, Jeff Miller, the NFL's senior vice president for health and safety, acknowledged a link between football and CTE -- the first time the league has made such a connection. Miller's comments were even more surprising because they followed months of the NFL denying that the link had been established, downplaying the risks of playing football and going to extraordinary lengths to try to shape government research.
During Super Bowl week, the chief of the NFL subcommittee on long-term brain injury asserted that, in fact, there is no proven link between football and CTE. Commissioner Roger Goodell drew public criticism for comparing the risk of playing youth football to the risk of "sitting on the couch." At the same time, reports by Outside the Lines revealed how the NFL withdrew funding from a major CTE study last year because of objections to the principal investigator, a prominent Boston University researcher, even as the league doled out millions of dollars in research grants to league-affiliated doctors.
The conflicting statements leave the NFL in the awkward position of having two senior health officials, within weeks of each other, voicing diametrically opposing views on the central question of a growing public health crisis that is swirling around the sport.
Dr. Julian Bailes, a former Pittsburgh Steelers doctor and co-director of the NorthShore Neurological Institute in Evanston, Illinois, said he thinks it's dangerous for the NFL, given its influence, to continue to cast doubts on established CTE research.
"We can't let these scientific discussions be hijacked by people creating doubts about causation," said Bailes, who also is the medical director for Pop Warner football. "The only known cause we have thus far is repetitive cranial impact."
In an interview following Miller's comments, which were made in front of a roundtable discussion convened by the U.S. House of Representatives' Committee on Energy and Commerce, Bailes said: "It's good, important -- a positive development. It's hard to know if this is finally their admission or whether Jeff -- in the moment, in front of Congress -- told the truth, yes, and then they try to walk it back. Time will tell."
On Tuesday, a league spokesman issued two statements, the second of which said Miller's comments "accurately reflect the view of the NFL." In a legal filing later in the day, though, an NFL attorney cited a court finding that the "scientific community indisputably acknowledges that the causes of CTE remain unknown." The attorney also suggested that Miller's comments were not new, writing that the league had previously acknowledged "a potential association between CTE and certain football players."
Long established as a disease that afflicts boxers, steeplechase jumpers and others who face repetitive head trauma, CTE was first reported in a former NFL player, Steelers Hall of Fame center Mike Webster, in 2005. The disease is marked by an abnormal accumulation of tau, a protein that can destroy brain cells when CTE is triggered. It can only be diagnosed after death.
Dr. Ann McKee, a Boston University neuropathologist, has diagnosed 176 CTE cases over the past five years, including 90 out of 94 former NFL players whose brains were examined; 45 out of 55 college players; and six out of 26 high school players. During Monday's Congressional panel, McKee warned: "It cannot be rare. In fact, I think we are going to be surprised at how common it is" in football players.
In late 2013, McKee received a $6 million grant from the National Institutes of Health to define the principal characteristics of CTE. The funding came from a $30 million "unrestricted gift" the NFL gave the NIH in 2012. She assembled seven neuropathologists for a blind study to identify tissue from several brain diseases and to determine whether CTE could be distinguished from disorders such as Alzheimer's disease and progressive supranuclear palsy. The researchers gathered in Boston to compare their findings. The neuropathologists agreed on more than 90 percent of the CTE cases, some of which involved former NFL players.
The study produced a "consensus definition" of CTE and, for the first time, defined it as a distinct neurodegenerative disease.
"It's overwhelming that this is occurring in professional players; we're just seeing it over and over," McKee said in an interview.
Armed with the new definition, researchers at the Mayo Clinic searched for signs of CTE among the 7,000 brains that are preserved at the clinic's Jacksonville, Florida, location.
Kevin Bieniek, a postdoctoral research fellow in the Mayo Clinic's Department of Neuroscience, initially narrowed the number to a more manageable 1,800 in an effort to limit his sample to people who participated in contact sports. Bieniek then spent months combing through medical records, obituaries and other resources.
He identified 66 brains of people who had played contact sports -- primarily high school and college football, but also boxing, rugby, wrestling and soccer. The researchers also examined the brains of 198 control subjects who had not been exposed to contact sports. They found signs of CTE in the brains of 21 people who played contact sports -- almost one in three. They found no signs of CTE in the brains of the people who had not played contact sports.
"I was surprised," said Bieniek, who published his findings with his adviser, Dr. Dennis Dickson, one of the nation's leading experts in neurodegenerative diseases. "There is a pretty strong link between repetitive head trauma and CTE."
Bieniek cautioned he studied a low number of cases but said the absence of CTE in the control group had implications beyond the NFL. "I think our study is very telling for the general population, because so many individuals play a contact sport in high school," Bieniek said.
Once a scientific backwater, concussion research has exploded in recent years in response to health concerns that began in the NFL and trickled down to the nation's youth leagues, spreading to other sports.
Over the past 3½ years, the NFL has donated more than $100 million for scores of research studies, giving the league significant influence over science that could have a direct bearing on its bottom line, Outside the Lines reported last month. In addition to funding McKee's CTE study, the league, through the NIH, donated $6 million to Dr. Wayne Gordon, a prominent brain researcher at Mount Sinai Hospital in New York City, to study whether a single moderate-to-severe brain injury can lead to CTE.
"We want the facts to help us develop better solutions. And that's why we're advancing medical research, to let the science go where the science goes," Jill Pike, an NFL spokeswoman, wrote in an email to Outside the Lines. "We are grateful to have the resources to fund such important work and a platform to continue to drive awareness around the issue of concussions and brain injury and the importance of player health and safety more broadly."
The NFL declined requests by Outside the Lines to interview Goodell, Miller or other league officials about their views on current research.
Until Monday, the NFL had never acknowledged that football can lead to long-term brain disease. In December 2009, league vice president Greg Aiello told the New York Times, "It's quite obvious from the medical research that's been done that concussions can lead to long-term problems." He did not, however, acknowledge that playing football could lead to those issues. When pressed by Congress and in interviews about football being a cause of brain disease, Goodell has avoided taking a position, repeating that the league will let the medical community decide.
Before the Super Bowl, Dr. Mitch Berger, who leads the league's subcommittee on former players and long-term effects of brain and spine injury, was asked several times if he believes the link between football and CTE has been established. Berger, a former defensive end at Harvard, replied finally: "No."
That response produced an outcry among many researchers who have studied the relationship between repetitive head trauma and CTE.
"I don't know what Kool-Aid he's been drinking," Gordon said in a recent interview. "I know Mitch, and he's a very decent man. He's a great neurosurgeon. But how can you make a statement like that? It doesn't add up. He may not like it, but to say that the evidence isn't there, well, the evidence is pretty strong, and nobody has come out to refute that evidence."
Gordon, who helped develop the consensus definition of CTE, compared Berger's position to people "who don't believe in climate change."
Berger did not respond to interview requests before or after Miller's comments.
Asked about Berger's comments by Illinois Rep. Jan Schakowsky at the congressional session, Miller replied: "Well, I'm not going to speak for Dr. Berger."
Several days before Monday's roundtable, Outside the Lines asked Pike, the NFL spokeswoman, what the league believes about the relationship between football and CTE. She referred Outside the Lines to a 2012 consensus statement issued following the Fourth International Conference on Concussion in Sports, held in Zurich, Switzerland. In a section on CTE, the authors wrote that the "cause and effect relationship has not as yet been demonstrated between CTE and concussions or exposure to contact sports."
Dr. Uzma Samadani, a Minneapolis neurosurgeon who works as an unaffiliated sideline consultant to the NFL, said she believes the league has been correct in its prior statements that no firm connection has been established between football-related head trauma and CTE -- at least among youths.
"We know that repetitive trauma causes CTE," Samadani said. "We've seen that in boxers. ... I don't necessarily believe that football at the amateur level is sufficient to cause repetitive brain injury that can result in CTE."
Samadani, whose recent book, "The Football Decision," addresses how parents should weigh the risks of contact sports, said until researchers are able to study football players over time, including issues such a genetics and substance abuse, it will be impossible to assert whether head trauma is the main cause of CTE in football. Koroshetz, who oversees brain research for the NIH, said that much is still unknown about CTE. "I think we are challenged by the pathology because we don't yet understand the clinical significance: What, if anything, are the symptoms?" he said. "Does the pathology progress or can it remain stable over years?"
Many researchers, in fact, have long moved on from the question of whether CTE is caused by repetitive head trauma. They instead are trying to determine the process that occurs inside the brain after those hits occur.
At the Roskamp Institute in Sarasota, Florida, researchers are using mice to try to show how the buildup of tau protein may occur in response to blows to the head. After a single hit or even five hits over a short period of time, the researchers did not see any persistent effects on tau in the brains of the mice.
The researchers then developed a new chronic injury model, striking the mice twice a week over a period of three months, an approach intended to mimic sports-related head trauma and referred to internally as "the NFL model." The researchers, after the mice were euthanized, studied their brains and saw persistent changes in tau, months after the injury, consistent with some of the changes that have been seen in former NFL players with CTE.
"It does change the pathology for the worse," said Dr. Fiona Crawford, president and CEO of the Roskamp Institute and director of its Traumatic Brain Injury Research Program. "What we do really has opened my eyes, and it's quite scary."
Crawford acknowledged that experiments on mice may not be directly relevant to humans.
Researchers at the Johns Hopkins University School of Medicine used new imaging techniques to examine nine former NFL players whose ages ranged from 57 to 74. They also examined nine control patients with no previous exposure to head trauma. The researchers were looking for changes in a "translocator protein" that tends to concentrate in areas of the brain that are inflamed or damaged.
What they found was ominous: The control patients showed no evidence of damage. The group of former NFL players -- years after they played -- had evidence of injury in several regions of the brain. One region -- the hippocampus, which plays a role in memory -- had shrunk in the players, possibly because of previous injury.
"I remind myself it was a pilot study: nine former NFL players and nine healthy controls," said Dr. Jennifer Coughlin, who led the study. "You really need a much larger study."
Funding came in part from the Head Health Challenge, a research partnership between the NFL and General Electric. The Johns Hopkins researchers received $300,000 -- one of 16 awards given out in the first round of the competition.
The researchers applied for the final round, which awarded $500,000 to each of six groups. Hopkins was not selected.
Producer Michael Ehrlich of ESPN's Digital Original Video Unit and ESPN NHL reporter Pierre LeBrun contributed to this report.