Support Provided ByLearn More
Body + BrainBody & Brain

The Hazily Understood, Entirely Preventable Brain Disease

Our understanding of the chronic traumatic encephalopathy has rapidly advanced in the last decade, and the disease has been found in dozens of former NFL players. CTE, most neurologists now agree, is caused by repetitive head trauma and has been found in athletes from a variety of contact sports as well as soldiers exposed to blasts on the battlefield. Symptoms typically don't occur until decades after head trauma occurs and include cognitive loss and dementia, similar to Alzheimer's disease. Yet for all that is known about CTE, much remains unknown.

ByPhil McKennaNOVA NextNOVA Next
Contact sports like boxing have been linked to the development of CTE.

In a quiet cemetery in rural Virginia, a mystery lies buried underground. The cemetery is home to the body of Tamerlan Tsarnaev, the alleged mastermind of the Boston Marathon bombings that killed three people and injured more than 250 others on April 15, 2013.

Tsarnaev was motivated by extremist Islamic beliefs, according to reports from an interrogation by federal authorities of his younger brother, Dzhokhar, who says he was recruited by his older brother to help him carry out the attack. But what if there was another cause for his behavior? What if a poorly understood neurodegenerative disease, attributed to repeated blows to the head and linked to emotional instability and lack of impulse control, played a role in Tamerlan’s violent demeanor, if not the actual bombing?

Just after the attack, Robert Cantu, a co-director of the Center for the Study of Traumatic Encephalopathy at Boston University, and his colleague Robert Stern, also of Boston University, were careful to note that the deliberate, premeditated nature of the bombings made it unlikely that chronic traumatic encephalopathy, if Tsarnaev indeed had it, played a direct role in the bombings. Other incidents, however, including prior reports of physical abuse, outbursts at a local mosque leading up to the bombing, as well as suspected involvement in a triple homicide in 2011 were indicative of the disease, also known as CTE. The day after Tsarnaev died in a shootout with police, Cantu and Stern called for the examination of Tamerlan’s brain. “I hope to God they do the special testing,” Cantu told a reporter at the time.

“He was a boxer, and a good one too,” Cantu says. “He boxed for a number of years, and he could have had CTE on the basis of the brain injures he took as a result of his boxing,” he adds. “Some people that do the sudden flying-off-the-handle things sometimes to the point of killing are due to CTE.”

Michael Craig Miller, a psychiatrist at Harvard Medical School, agrees. “There was a violent act, a guy who had a history of having been a boxer, and there may have been violent activity in the past,” says Miller, who also called for testing. “That was enough it seemed to me to make him an interesting subject for study.”

Tsarnaev was buried in early May, and so far as we know, his brain was never tested for CTE. Had he been examined and found to have had the disease, it’s unclear what insights we would have gained into his psyche or what drove him to carry out such a horrific act. But the fact that such prominent researchers would even call to have his brain examined speaks volumes about the rapid increase in our understanding of a brain disease that was almost unheard of a decade ago and today remains only hazily understood.

“Punch Drunk”

In 1928 a medical examiner in Newark, New Jersey, noted an unusual condition common in prizefighters known as “punch drunk.” In an article published in the Journal of the American Medical Association , Dr. Harrison Martland notes, “fighters in whom the early symptoms are well recognized are said by the fans to be ‘cuckoo,’ ‘goofy,’… or ‘slug nutty.’ ”

For the next 70 years, our understanding of the disease, long thought to occur only in boxers, scarcely increased. A study published in 1969 found that 17% of former professional boxers who fought in the U.K. between 1929 and 1955 had the disease now known as CTE. But the figures were based only on individual’s symptoms; there was no way of knowing whether CTE or some other brain disease caused their mental decline.

Then in 2002, Dr. Bennet Omalu, a researcher at the University of Pittsburg found CTE in the brain of a deceased former professional football player. Since then, our understanding of the disease has rapidly advanced, and the disease has been found in dozens of former NFL players. CTE, most neurologists now agree, is caused by repetitive head trauma and has been found in athletes from a variety of contact sports as well as soldiers exposed to blasts on the battlefield.

Symptoms typically don’t occur until decades after head trauma occurs and include cognitive loss and dementia, similar to Alzheimer’s disease. In fact, some neurologists don’t consider CTE to be a separate disease. A recent study of former, living NFL players suggests those with mild cognitive impairment may simply be suffering from the natural effects of aging. “They don’t have a different pattern of cognitive impairment than the routine clinical population,” says lead author Christopher Randolph, a neurologist at Loyola University in Maywood, Illinois. “It seems unlikely that there is a unique neurological syndrome in athletes who play contact sports.”

“Why do some people who play contact sports wind up with it and others don’t?”

Yet the study also found retired NFL players had a significantly higher incidence of impairment than the general population. Thirty-five percent showed signs of mild cognitive impairment as reported by their spouses, compared with prior studies that showed a prevalence of less than 5% for men of a similar age. Randolph says further tests are needed but concedes that repeated head trauma could diminish the “cerebral reserve,” or number of brain cells, in former players. “Repeated blows to the head could cause cell loss that over time adds up,” he says.

When looking at the brains of deceased players under the microscope, however, Cantu says CTE has a unique profile that is easily distinguished from Alzheimer’s and other neurological diseases. And, unlike Alzheimer’s, when the disease manifests itself in younger individuals, symptoms typically include depression, anxiety, suicidal thoughts, and aggressive behavior.

Yet for all that is known about CTE, much remains unknown. The only way to diagnose someone with the disease, for example, is to look at their brain after they are dead.

“There are tons of unanswered questions,” Cantu says. “We don’t know the incidence of it in those who play contact sports. We don’t know the associated risk factors. Obviously not everyone gets CTE. Why do some people who play contact sports wind up with it and others don’t?”

Support Provided ByLearn More

Nerve Center

Much of what we now know about the disease comes from the Edith Nourse Rogers Memorial Veterans Hospital, a sprawling suburban campus in Bedford, Massachusetts.

Following signs that say “Research Services,” I’m led to a nondescript brick building stocked full of brains. Slabs of white and grey matter—the brains of former NFL greats and muscle-bound Marines—sit on a lab bench in what appear to be ice cream pails. Brain shavings that look like pickled ginger lie stacked top to bottom in refrigerated display cases. Posters of particularly horrific brains, including one subjected to a frontal lobotomy, line the halls. Taking a seat, I struggle to keep my knees from bumping into a tray of carefully prepared brain tissue sandwiched between microscope slides that teeters on the edge of a desk.

My host, neuropathologist Ann McKee, apologizes for the smell, an overpowering bouquet of what I’m later told is frankincense and myrrh. “I used a new oil diffuser this morning, and it got a bit out of control,” she says sheepishly.

McKee, whose dark rimmed glasses contrast with her light blond hair, is the chief neuropathologist for the veterans’ medical center and, along with Robert Cantu, co-directs Boston University’s Center for the Study of Traumatic Encephalopathy. Her cheery personality and sparkling blue eyes belie decades spent peering through a microscope at the brains of dead people.

A cross section from a normal brain

McKee has diagnosed CTE in more than 90 individuals including soldiers, boxers, football players, wrestlers, hockey players, and one individual who engaged in “self-injurious head banging.”

The athletes whose brains she has examined range from professionals to kids who played high school sports. The youngest was only 17. When I ask her if this includes Tamerlan Tsarnaev, McKee pauses. She says she was contacted by “lawyers” asking if she would examine his brain but says she declined, not wanting to get caught up in a legal battle that could drag on for years. McKee says she doesn’t recall the lawyers’ names or who they represented. An attorney representing Tamerlan’s wife said no one from his team called for the testing, and the group of attorneys representing Tamerlan’s brother Dzhokhar declined comment.

McKee first started piecing together the pathology of CTE a decade ago while looking at the brains of individuals who had been diagnosed with Alzheimer’s disease. In the brain of a healthy person, neurons transmit electrical impulses through their long, threadlike axons. These axons are made up of microtubules that are held together by a scaffold of tau proteins. “In CTE, tau stops holding up the scaffolding and accumulates in an abnormal clump that we think is toxic to the cell.” McKee says. People with Alzheimer’s may also have concentrations of tau, but they are found in different parts of the brain and occur along with other proteins. “Look at this involvement of the frontal cortex” she says walking me through a slideshow on CTE. “You would never see this in other diseases.”

Over the years McKee and her colleagues have shown how CTE affects young patients differently than older patients and doesn’t require full-blown concussions to negatively affect the brain.

A cross section from a brain with stage IV CTE

Of the 135 brains she’s examined for CTE thus far, McKee has found the disease in two-thirds of the cases. Of those that tested positive, 20% were suicides. The figures are probably a skewed representation of the disease; families are unlikely to donate the brain of a loved one unless they have a strong suspicion that the individual suffered from the disease. Still, it’s clear that something incredibly wrong has occurred in many of brains that end up under her microscope.

On the afternoon of my visit, she is looking at the brain of a 25-year-old former high school wrestler and college football player who recently took his own life. “Hanging, if I had to guess, based on what I’m seeing in his brain,” she says.

Projecting the image from her microscope onto an adjacent computer screen, she shows me brain tissue peppered with abnormal tau proteins. “You see all the red and brown things?” McKee asks. “The brown things are normal, red are tau, and he has a tremendous amount of it,” she says. “I’ve never seen this [so advanced] in someone so young. He’s only 25. He’s like a baby.”

For all of the advances she and others have made in our understanding of the disease, McKee is still tormented by the inability to diagnose CTE in living individuals. “It would have a huge impact on whether you let a person continue to play, whether an individual decided to retire from sports, and also in monitoring therapies,” McKee says. “Right now, even if you were to come up with a magic therapy, there is no way to see if it is doing any good.”

Scanning for CTE

The ability to detect CTE in the living may not be far off. Earlier this year researchers at UCLA described preliminary findings that were hailed at the time as the “holy grail” of CTE research. Using positron emission tomography (PET) scans, they looked at brains of five living, former NFL players who had histories of mood swings and cognitive decline. The retired players were injected with a radioactive compound that passes into the brain and binds to tau proteins, allowing for detection of irregular protein tangles during PET scans. In all five individuals, the compound lit up the scan in the amygdala, a region of the brain that processes memory and emotional reactions. (To see where the amygdala and other structures are located and how they appear in scans, explore NOVA’s mapping the brain web app .)

“The areas of brain where we saw high tau concentration were areas where tau had been identified in CTE at the time of autopsy,” says the study’s lead author, Gary Small. Protein buildups found by the group also correlated with individual’s exposure to head trauma. “The more concussions, the more tau they had in the brain.”

Arizona Cardinals quarterback Kevin Kolb is hit by Minnesota Vikings defensive tackle Kevin Williams and line backer Erin Henderson during a game in 2011.

Others were not convinced. “Beta amyloid [a protein associated with Alzheimer’s disease] as well as several other proteins would also show up positive,” Cantu says. “You need something specific for tau. Finding CTE in living individuals is hugely important and is being intensively studied, but unfortunately there is no solution yet.”

Now, a team at Boston University led by Robert Stern is testing a number of other approaches to see if they can detect CTE in the living. They will examine 100 former NFL players as well as 50 athletes who played non-contact sports such as swimming, rowing, or tennis. All participants will be subjected to a barrage of tests including blood and spinal fluid tests that look for concentrations of tau that may circulate outside the brain. They’ll also use an alphabet soup of scanning technologies—MRS, DTI, SWI—that measure the brain’s volume, structural integrity, and activity.

When the study was first conceived, the authors reasoned that if it was impossible to detect tau in a living brain, they would focus instead on other biomarkers that might correlate with the disease. Now, however, it seems direct measurements of the protein clusters may soon be possible by using molecules called ligands that bind to specific proteins in conjunction with PET scans. In January 2013, researchers with the pharmaceutical division of Siemens announced that they had developed a new chemical tracer that binds only to tau.

“The holy grail for a long time for all neurodegenerative disease—not just CTE—was to develop a ligand for PET scans for tau and only tau,” Stern says. “When we started the study there was no such thing, it was years away. But, lo and behold, now there is.”

Stern’s group recently received funding from the U.S. Department of Defense to use the compound in their ongoing study to see if they can diagnose CTE in living patients using PET scans. “Not only will we hopefully be able to measure tau directly, but because of all the other measures we use we will hopefully be able to distinguish between different individuals or subgroups who may or may not have CTE, but may have problems due to changes in the white matter of their brain from repetitive brain trauma.” Stern says. “This is unbelievably exciting.”

“By understanding disease process and progression, we hope to find ways to mitigate the disease.”

While Stern and his colleagues are beginning their search for tau and other biomarkers, another study involving more than 300 active boxers and mixed martial artists is already yielding intriguing results. Using brain scans similar to those used in the Boston University study, researchers at the Lou Ruvo Center for Brain Health in Las Vegas are tracking changes in brain volume, connectivity, and structural integrity of active fighters over a four-year period. According to study director and Cleveland Clinic neurologist Charles Bernick, “We wanted to see if we can use brain scans to detect markers that are occurring and accumulating and can they be predictive of progressive decline over time.”

After just one year of testing, the answer seems to be yes. “The more pro fights a fighter had, the more relationship there is to lower volumes in the brain,” Bernick says. “You actually see shrinkage, particularly in the thalamus,” a portion of the brain that, among other functions, relays motor and sensory signals to other regions.

The group obtained similar results for connectivity and neural networks. Bernick says he suspects the changes they are observing precede the buildup of tau proteins and the onset of CTE symptoms. “By understanding disease process and progression, we hope to find ways to mitigate the disease, either through medication or a reduction of exposure,” Bernick says.

Safer Sports

A number of things have already been done to make contact sports safer for those who play them. In the NFL, independent neurologists now diagnose concussions from the sidelines and penalties are given for players who intentionally strike opponents with their head. In boxing, championship fights are now 12 rounds instead of 15, and fights are stopped sooner than in the past if either opponent showing signs of significant impairment.

Cantu, however, says more needs to be done, especially in youth leagues. “I don’t believe youths should be banging their heads. They should play sports but in a different way.” For example, he says kids playing youth soccer shouldn’t be allowed to head the ball.

“No head trauma is good head trauma.”

Changes are occurring. USA Hockey, the governing body of youth ice hockey in the United States, recently raised the minimum age for checking, or legal physical contact, between players from 11 to 13.

Despite some of the horrific cases she has seen, McKee cautions parents not to overreact. “A single, isolated concussion, well managed, has never been associated with CTE,” she says. “Several concussions over time—each well treated—have never led to CTE. It’s repeated trauma over and over and the length of exposure that is important.”

Still, with so many unknowns related to the disease, Cantu can’t help but worry. “No head trauma is good head trauma,” he says. “It doesn’t need to be as severe as a concussion. And the more you get, the greater the chance for developing CTE.”

Receive emails about upcoming NOVA programs and related content, as well as featured reporting about current events through a science lens.

Photo credits: kwdesigns/Flickr (CC-BY-NC) , Ann McKee, and Eric Miller/Reuters/Corbis


Bernick, Charles, and Sarah Banks. 2013. "What boxing tells us about repetitive head trauma and the brain." Alzheimer’s Research & Therapy 5(23). DOI: 10.1186/alzrt177

Martland, Harrison S. 1928. "Punch Drunk." JAMA 91(15): 1103-1107. DOI: 10.1001/jama.1928.02700150029009

McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC. 2013. "The spectrum of disease in chronic traumatic encephalopathy." Brain 136(1): 43-64. DOI: 10.1093/brain/aws307 .

Small, Gary W., Vladimir Kepe, Prabha Siddarth, Linda M. Ercoli, David A. Merrill, Natacha Donoghue, Susan Y. Bookheimer, Jacqueline Martinez, Bennet Omalu, Julian Bailes. 2013. "PET Scanning of Brain Tau in Retired National Football League Players: Preliminary Finding." The American Journal of Geriatric Psychiatry 21 (2): 138-144. DOI: 10.1016/j.jagp.2012.11.019 .

Funding for NOVA Next is provided by the Eleanor and Howard Morgan Family Foundation.

National corporate funding for NOVA is provided by Draper. Major funding for NOVA is provided by the David H. Koch Fund for Science, the Corporation for Public Broadcasting, and PBS viewers. Additional funding is provided by the NOVA Science Trust.