ESPN reporters Mark Fainaru-Wada and Steve Fainaru are writing a book about football and brain injuries, to be published in 2013 by Crown Books, a division of Random House, and FRONTLINE is producing a documentary based on the reporters’ research. This article was produced as part of a collaboration with ESPN. League of Denial airs Oct. 8 on FRONTLINE.

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Researchers at Boston University have discovered 28 new cases of chronic brain damage in deceased football players — including 15 who played in the NFL — more than doubling the number of documented cases connecting football to long-term brain disease.

The NFL players include two Hall of Famers: running back Ollie Matson, who played 14 seasons in the 1950s and 1960s, and Colts tight end John Mackey, who played 10 seasons and once served as the head of the NFL players’ union. Both died last year after suffering from dementia.

The study examined brain tissue from 85 people with a history of repetitive head trauma, including military veterans, boxers and football and hockey players. Some of the cases had been previously reported. Sixty-eight were found to have chronic traumatic encephalopathy — a degenerative brain disorder linked to memory loss, depression and dementia.

According to the study, the BU researchers now have 50 confirmed cases of former football players with CTE — 33 who played in the NFL, one in the CFL, one semi-professionally, nine through college and six who played only through high school. That included Nathan Stiles, 17, who died of a subdural hematoma after a hit in a 2010 high school homecoming game in Spring Hill, Kan.

“The sheer volume of cases I think is going to just overwhelm anybody that wants to be in denial about the existence of this problem,” said Robert C. Cantu, a co-director of BU’s Center for the Study of Traumatic Encephalopathy and a senior adviser to the NFL on concussions.

Previously, CTE had been found in 18 of the 19 former NFL players whose brains were examined. The 15 new cases in the BU study mean that of the 34 brains of former NFL players that have been examined, 33 had the disease. Linemen made up 40 percent of those cases, supporting research that suggests repetitive head trauma occurring on every play — not concussions associated with violent collisions — may be the biggest risk. BU also reported CTE in four former NHL players.

The findings, published in the December issue of Brain, a medical journal affiliated with Oxford University, are certain to feed the growing debate about the risks of playing football and the work of the BU research team, which has gained international recognition while arguing that football-induced brain damage is indisputable and possibly widespread.

BU agreed to provide a copy of the study to ESPN’s Outside the Lines and FRONTLINE on the condition it not be released before publication.

At the International Consensus Conference on Concussion in Sport last month in Zurich, the BU researchers faced open skepticism from medical experts with the International Olympic Committee and FIFA, among others. Ann McKee, the neuropathologist who led the BU study, said the criticism felt like getting “stabbed, you know, swords through the heart.”

With few exceptions, critics acknowledge that CTE, which can only be diagnosed after death, is real. But some question whether BU has fueled unwarranted hysteria about the risks of playing football by overstating the significance of its findings. Some researchers question whether other factors besides head trauma may be behind the disease.

The BU research, which was funded in part by a $1 million gift from the NFL, has been limited to individual case studies of subjects who were significantly impaired before their deaths, making it impossible to measure the prevalence of CTE or establish conclusively that repetitive head trauma triggered the disease, according to some scientists.

Richard Ellenbogen, a Seattle neurosurgeon who chairs the NFL’s Head, Neck & Spine Committee, which helps set policy for the league, praised BU’s research but cautioned that there is not enough data to assess the risk of playing football.

“The only criticism I had and have always had, is that we need to do the science to figure out what the incidence of this is,” said Ellenbogen, who also attended the conference last month.

“For me it’s all about the kids,” Ellenbogen said. “Do we tell kids not to play sports any more? What we know from the (Centers for Disease Control) is kids are more likely to get hurt riding a bike or falling down while running. There’s nothing critical in saying that, I’m just putting it in perspective. What are the true risks?”

Chris Nowinski, a former Harvard football player and professional wrestler who serves as a co-director of the BU center, said Ellenbogen made a similar argument at the Zurich conference.

“I think that’s smoke and mirrors; I mean, it’s night and day,” Nowinski said. “If people having concussions riding a bike means that football is safe, it’s a silly piece of evidence. I’m surprised a doctor would lower himself to that because he must know it’s a silly argument, too.”

Lars Engebretsen, an orthopedic surgeon who is head of scientific activities for the IOC, said he was “one among several” people who raised questions about BU’s research in Zurich.

“All of us had read the papers that had been published on this issue,” he said, “and we were concerned that the data were a little bit, I wouldn’t say skewed, but we would like to see more data to see whether the data was representing the truth of the matter or not.”

Engebretsen said he thought there were “other possible reasons” that could explain CTE and questioned why the disease has not been seen in several other international sports.

Cantu said he believes the backlash stemmed from professional jealousy about the amount of media attention that McKee and the BU group have received.

“You know, scientists are human beings, they have the same range of emotions as anybody else,” said Cantu. “And I think that people are jealous of the amount of exposure that she’s gotten, and others are jealous of her being in the right place at the right time, to get all these brains to get to study this.”

McKee, in an interview with OTL & FRONTLINE, said some scientists in Zurich questioned the link between repetitive head trauma and CTE.

“One of the leaders of the conference was very pointed when he said, ‘I read your papers and frankly I think they’re very poor scientific evidence,'” McKee said. “It seemed like denial to me. I hadn’t really experienced denial for about four years.”

McKee compared the experience to one she had in 2009, when she presented her findings to members of the NFL’s since-disbanded Mild Traumatic Brain Injury Committee, which for more than a decade denied the connection between football and chronic brain damage.

“It was like déjà vu,” McKee said. “I agree we don’t know how big a problem this is, we don’t know what all the risks are. There’s a lot we don’t know, but I think we know enough to know that this is a problem.”

Kevin Guskiewicz, who serves on the NFL’s Head, Neck & Spine committee and also was in Zurich for the conference, said the issue of traumatic brain injuries is serious, but drawing a link from football to CTE exclusively from case studies was analogous to a track team blaming Nike for a rash of ankle injuries simply because the athletes wore that brand of shoe. Other factors need to be considered, he said.

“The vast majority of the neuroscience community does not believe that research has yet identified a causal relationship linking repetitive head trauma in football and CTE; I include myself in that,” said Guskiewicz, co-director of the Matthew Gfeller Sport-Related Traumatic Brain Injury Research Institute at the University of North Carolina.

The BU researchers say they have never drawn conclusions about the prevalence of CTE in football. Findings based exclusively on individual cases “will never establish the incidence or prevalence” of the disease but instead will lay the foundation for further research, the study states.

BU is drawing from a sample size that is “skewed beyond belief,” acknowledged Cantu, because the brains invariably come from subjects who were profoundly impaired.

At the same time, McKee, Cantu and others describe the growing body of cases as significant and ominous, particularly for the NFL.

Cantu cited another recent study that examined death certificates of former NFL players and concluded they were four times more likely to suffer from neurodegenerative diseases.

“So probably at the lowest level, the incidence of CTE is four times greater in NFL players than the population at large would lead you to expect,” Cantu said. “But that’s really the bottom of what it is. And where, how much higher than that it is, we really don’t know.”

Long-term brain damage was first documented in boxers in the 1920s. It was not seen in football players until 2005, when a Pittsburgh pathologist, Bennet Omalu, diagnosed late Hall of Fame Steelers center Mike Webster with CTE — a finding that was hotly contested by the NFL but is no longer disputed.

The data indicate that CTE advances both with exposure to head trauma and with age, according to the BU study. So typically, the longer a player spent in the NFL, the worse his case looked.

“We believe that this is a dose-related phenomenon — not just to concussions but total brain trauma,” said Cantu. “So clearly there’s a relation to how many hits you’ve taken, and that does correlate with how long you played.”

Cantu, a neurosurgeon and concussion expert, has voiced his opposition to tackle football for children younger than 14, an idea some skeptics consider alarmist and arbitrary.

The NFL’s $1 million research gift to BU in January 2010 acknowledged its right to conduct independent research, but the league also agreed to steer brains from former NFL players to the center’s brain bank, which is administered jointly with the Veterans Administration. The bank currently holds 135 brains from military veterans, athletes and other subjects. More than 600 athletes have pledged to donate their brains to BU after their deaths.

CTE occurs when repetitive head trauma produces abnormal proteins in the brain called “tau.” The proteins form neurofibrillary tangles that can effectively strangle brain cells. Under a microscope, with staining, the tangles look like dark brown splotches that can spread throughout the brain.

McKee described the study as “an attempt to look at the spectrum” of the disease: “What does it look like in the earliest stages. What does it look like as it gets more severe? How does it appear to progress throughout the nervous system and what does it look like in advanced disease?”

The study also for the first time identified four different stages of CTE. In Stage I, few tangles are evident, and symptoms range from headaches to short-term memory loss and depression. By Stage IV, according to the study, the tangles are widespread, and most subjects show signs of full-blown dementia, including “profound loss of attention and concentration, executive dysfunction, language difficulties, explosivity, aggressive tendencies, paranoia, depression” and difficulties walking and with depth perception.

According to the study, 31 of the 34 professional football players were found to have at least Stage III CTE, which is marked by memory loss and depression, among other symptoms. Dave Duerson, the former Chicago Bears safety who committed suicide last year by shooting himself in the chest, had Stage III CTE at the time of his death, according to McKee.

In addition to Matson and Mackey, other former players confirmed in the study to have CTE were Cookie Gilchrist, a former NFL and CFL linebacker who died of throat cancer last year; Ron Perryman, a former Boston College linebacker who died last year after suffering from Lou Gehrig’s Disease; and Eric Pelly, a former high school football and rugby player who died at 18 after suffering multiple concussions.

BU has previously identified several other NFL players with CTE, including John Grimsley, an All-Pro linebacker who played nine seasons with the Houston Oilers and Miami Dolphins, and Tom McHale, an offensive lineman who played nine seasons, primarily with Tampa Bay and Philadelphia. Other names have not been disclosed for privacy and scientific reasons.