Research at Boston University

Anatomy of

By Cassandra Nelson

Part of what makes chronic traumatic encephalopathy, or CTE, so devastating is its invisibility. A degenerative brain disease that is closely related to Alzheimer’s, CTE is caused by repeated head trauma and is known to affect professional boxers, football and hockey players, and now, veterans of the wars in Iraq and Afghanistan.

Because damage to neurons occurs at a cellular level, it has proven difficult for researchers to detect the disease in living individuals and to develop treatment options. As a result, CTE’s effect on patients and their families can be baffling as well as brutal, as symptoms of dementia—including memory loss, aggression, confusion, and depression—appear years or even decades after trauma, but well before normal, age-related decline could be expected to occur.

These challenges only lend an added urgency to the work being done at the Center for the Study of Traumatic Encephalopathy, which is led by codirectors Robert Cantu, clinical professor of neurosurgery; Ann McKee, professor of neurology and pathology; and Chris Nowinski, cofounder and executive director of the Sports Legacy Institute and himself a former professional wrestler. The center’s early findings garnered national attention for CTE from the media and politicians in 2009, prompting a series of Congressional hearings about head injuries in the National Football League, and leading to rule changes and an improved approach to treating concussions in the NFL. We sat down with McKee to talk about how far understanding of CTE has come in recent years, and the way forward.

The Brain Bank is at the heart of the center’s research. How does that work?

MCKEE: We started the Brain Bank in 2008, to collect and study postmortem human brain and spinal cord tissue in order to better understand the effects of trauma on the human nervous system. Athletes, and family members of deceased athletes, can choose to donate tissue. It has grown to be the world’s largest collection of its kind. We also have a small number of veterans’ brains in the Brain Bank, but those are harder to find. We have a grassroots network within the athletic community, and we don’t yet have that infrastructure with veterans and military families.

Is it frustrating for families to receive a definitive diagnosis only after the fact, after their loved one has died?

MCKEE: It’s a very hard disease to study, not least because we can’t do anything for CTE right now. But just letting family members know that there is a disease process, that there is something structural in the brain that was causing the problem is, believe it or not, comforting. With CTE, we’re talking about microscopic structural damage. You can’t see it easily on any scan, because you would need such high resolution, but it’s still a structural injury.

“I feel a sense of urgency. We need to be able to detect CTE first, and then to do something about it.”

There is relief, in other words, in being able to identify this structural damage and give it a name.

MCKEE: When you name it, you can know that, no, you’re not going insane, and no, this isn’t because you have a weak constitution. It’s a subtle disease, and not easily detected at first. The usual story is that someone’s life has spiraled out of control—they’ve alienated their family, they’ve lost their friends or their job. And it just gets worse and worse. That’s a terrible set of symptoms to present, especially when you’re young, and you don’t really know what’s going on and no one else knows either.

So I think it does change things to receive that diagnosis, even postmortem. I’ve had so many people say to me that I gave them back their brother or their dad or their husband. They will have experienced this person who became someone they didn’t even know—who became addicted to drugs, or started acting in aggressive or horrible ways—and to realize that that behavior wasn’t willful, that it wasn’t really them, makes these relatives feel so much better. Instead of being angry at the person affected, for instance, they can think, “Wow, they were strong, they were really fighting a tough disease.”

I had a woman come in—there have been a few, but this particular woman was young, in her thirties—and she wanted to look at the brain of her dad who was an NFL football player. Afterwards, she started to cry and she said, “I now understand my dad. I thought he didn’t love me, I thought he didn’t care about me. But now I see that he had this disease that interfered with his ability to emote and to understand.” It was immensely touching.

What steps are you taking toward developing a diagnostic for living patients?

MCKEE: You can’t fix a problem until you understand a problem. So we need to start with a thorough understanding of what the disease looks like, how it plays out.

In January, we published a paper in Brain: A Journal of Neurology that was a compilation of our experiences with the Brain Bank. Because the collection of brains continues to grow, it was hard to know when to stop examining new samples and write up our results. But back in July or so last year, I felt that I had seen enough cases of what I would call pure CTE to be confident about what to expect. It was a somewhat arbitrary number (I remember thinking, “Oh, maybe just one more case…”), but when we got to 68 cases, it seemed to crystallize. I felt convinced that we had enough data to make a real statement about what this disease is. The results kept following a pattern.

In that paper, we tracked the progression of the disease through the brain and described the features of the disease pathologically. We divided it into four stages—early, mild, moderate, and severe. With 68 samples, it was by far the biggest series that has yet been done on CTE. It’s three or four times larger than any previous series. In a lot of ways it was the definitive paper on the pathology of this disorder.

Could these stages eventually be used as a diagnostic—a way of determining whether someone is at the early, or moderate, or severe stage of the disorder?

MCKEE: Yes, absolutely, that’s the thinking. We are also looking for a biomarker for the disease, a way of measuring whether CTE is present in an individual. Right now we are doing that here at the VA Hospital with veterans of Iraq and Afghanistan, looking in particular at their tau proteins and at their CSF, that is, their cerebrospinal fluid. There’s an MRI [magnetic resonance imaging] technique called diffusion tensor imaging, or DTI, that assesses fiber tracks in the brain’s white matter, and we’re looking at that too. Bob Stern [professor of neurology and neurosurgery] currently has a large study looking at retired athletes, using both CSF analysis and imaging techniques. In each case, the goal is to find an in vivo diagnostic.

“For people living with suspected CTE, a better understanding of the disorder can also change how they look at themselves. They can realize that they’re struggling with a disease and of course they can’t completely master it, but they’re doing amazingly well with all these difficulties.”

Is this process the same in both athletes and veterans, regardless of the source of head trauma?

MCKEE: Yes. Last year Lee Goldstein [associate professor of psychiatry, neurology, ophthalmology, pathology & laboratory medicine, and biomedical engineering] and I published a paper in Science Translational Medicine on the effects of blast injuries on three Iraq and Afghanistan vets and one vet with concussive injury. We showed that the changes in their brains after those injuries are very similar to what athletes develop after sports exposures.

So there are a lot of similarities between the two, and I’m sure that when we have more samples of veterans, we’re going to find differences too. We don’t have the numbers right now to make those determinations. But in general, football tends to produce much more homogeneous injuries. There are variations on it, but they’re mostly doing the same thing. Whereas military injuries can be very heterogeneous—they can be car accidents, falls, concussions, blasts, mortar rounds. It tends to be more of a mixed pathology in the military injuries, and on top of that, a lot of people in the military are athletes, so they might be parachute jumping or playing football on the weekend. They have lots of exposures, not necessarily all neatly defined.

Another crucial aspect of your paper with Goldstein was the animal model you developed.

MCKEE: Lee had developed an animal model of blast injury, which was the first time anyone had published on that subject. He was able to produce a blast injury that didn’t kill the mice. Afterwards, they woke up out of the anesthesia and were able to eat and acted normally. When you looked at the brain with scans it was completely normal, yet you could see some real differences when the mice were tested behaviorally. In many ways, the experiment really mimicked what we thought was happening to soldiers who were exposed to IEDs [improvised explosive devices].

When we looked at the mice brains neuropathologically, under a microscope, we were able to find some very distinct changes—changes that were similar to what we see in human beings. So we’re hoping to really expand on that mouse model.

The model also revealed new insights into the cause of blast injuries.

MCKEE: Yes, the blast model demonstrated that it’s the blast winds that create the injury, not the blast wave. Everyone thought that it was the wave of the blast, but it’s actually the winds that follow the blast and cause the head to sort of ricochet around. Lee calls it the “bobblehead effect.” It’s almost like multiple concussions are occurring at a very high speed—a fraction of a millisecond. Both the head and the brain are just whipping around.

Could a helmet help reduce this ricochet effect?

MCKEE: Lee also experimented with stabilizing the mouse’s head on the body, and he found that it really mitigated the effects of the blast. So that does potentially translate to helmet technology. If you could stabilize the helmet onto the torso, you might really limit the extent of blast injuries. The problem is that when you do that, you have to deal with limited peripheral vision. As I understand it, the military is developing these pneumatic collars that come up when a blast occurs. They would be activated just when they’re needed, so you would get a kind of virtual rigidity. And if you look at NASCAR helmets, they are already fixed to the shoulders.

Are there other ways to reduce one’s chances of developing CTE?

MCKEE: For now, preventative care is the best approach, but it’s one that’s a little easier with athletes than with soldiers. The military is going to encounter these blast exposures almost no matter what. At the center, Chris Nowinski is working to educate athletes about the importance of keeping your head out of the game, of avoiding head contact when you can, and of being aware of what a concussion is and managing concussions properly when they occur. The theory is that a well-managed concussion does not lead to an increased risk of CTE. It’s when there is injury upon injury upon injury, to an unrecovered nervous system—that’s what seems to stimulate this disease.

How long does it take for the nervous system to recover?

MCKEE: It’s individualized for every person. Resting your nervous system means coming out of the game, getting evaluated by a medical professional, and being monitored both cognitively and physically for symptoms. There’s a gradual return to activity, while continuing to monitor symptoms. If symptoms reappear, you pull back. Some people recover in a couple of days, some people in a couple of weeks. For others, it takes much longer.

Do we know what accounts for this difference?

MCKEE: No. Some people seem to be more susceptible to concussions, so there is likely some genetic predisposition to the injury. But we would need huge numbers of samples, in the thousands at least, to develop genetic marker studies. And that’s going to require detection in living people. It would take 10 years to get up to the thousands with the autopsy series.

Women and small children tend to be more susceptible than men—one hypothesis is that they have weaker neck strength—but if you play contact sports long enough, everyone is susceptible. When I was growing up, football was a fall sport. Now they practice all year long and they’re playing all year long, so it’s basically continual. If you start out at nine years old, by the time you’re 21, you’ve got a lot of years behind you. And if you’re a good player, and you’re playing football every play—that’s a substantial exposure by the time you’re retiring.

“We’re dealing with two demographics that are very tough and very stoic. They’re 10 feet tall and bulletproof.”

Is it difficult to convince athletes and veterans to allow time for recovery?

MCKEE: It can be. We’re dealing with two demographics that are very tough and very stoic. They’re 10 feet tall and bulletproof, or however the saying goes. They really don’t want to admit that they have any problems. A successful athlete is one who plays through pain. And when you talk to people in the military, they just want to get back and help their unit. So you have to overcome that barrier.

Awareness of the disease has made a difference, though. I think the Congressional hearings were really the beginning of public awareness about CTE. It has changed how coaches think, and has stimulated research funding, including $1 million gift from the NFL to our lab. We still have a long way to go, but I’m encouraged by the amount of money that the NFL and NFL Players Association have given to further research on CTE. They gave $100 million to Harvard and $30 million to NIH. The Department of Defense has put up $62 million to study the chronic effects of neurotrauma. That’s almost $200 million right there.

Given the long-term scale of the center’s goals, what motivates you on a day-to-day basis?

MCKEE: What I feel right now is an exceptional obligation to the young athletes and the young veterans who might be developing this disorder. I feel a sense of urgency. We need to be able to detect CTE first, and then to do something about it. We need to be able to take care of them. And maybe there isn’t going to be a magic potion, or a pill—there are plenty of diseases that we don’t have cures for, or even treatments. Alzheimer’s is one of them. So maybe it’s going to be supportive care, and rehab, and similar strategies. But we do need to be able to address these individuals who are just lost and whose families are really desperate.

At the very least, we would be able to help people understand the road they have to walk down, and give them the chance to do it with their eyes open and their heads held high.

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