• April 18, 2014

A Brain Gone Bad

Researchers clear the fog of chronic head trauma

5942-Helmet

Kelvin Ma for The Chronicle Review

The first thing Patient 53 saw as he walked in was a red football helmet. A groan rattled through his vending-machine-sized frame. "The last thing I want to see," he said, "is a football helmet.."

It was the heavy plastic variant from his playing days, in the 1980s, as an offensive lineman in the National Football League, one of four helmets lined up on the front desk of the Center for the Study of Traumatic Encephalopathy. Tucked into the seventh floor of the Boston University School of Medicine, the center had welcomed 52 retired football players like him over the past six months, each racked by a single question: Had their brains gone bad?

Two years before, when he entered his mid-50s, Patient 53 fell into a fog, and he hadn't come back since. He was dizzy and tired and frazzled. He'd visited more than a dozen doctors. None helped much. He'd seen the news, seen former teammates struggle. The suicides. He knew doctors had found a degenerative brain disease—chronic traumatic encephalopathy, or CTE, as it's known—in a number of deceased former football players. But none could say if he had it. There was no way to know; it could be diagnosed only by cutting the brain open, they told him.

So when Patient 53 heard that these Boston researchers, the same pioneers who had found the disease in those dead pros, were recruiting former players to help them diagnose CTE in the living, he signed up immediately. So did several hundred of his peers.

This is a problem you've heard about. Over the past decade, CTE, a disease once thought limited to a few boxers and labeled dismissively as "punch-drunk syndrome," has blown up as a medical and cultural phenomenon. 60 Minutes investigated it. Prime-time courtroom dramas have filmed scripts on it. Worry is widespread: Is it a threat only to the thousands of current and former NFL players? What about the more than 60,000 active players in college football? The 1.1 million children playing in high school? The two million veterans of the wars in Iraq and Afghanistan?

Concerned parents flood the five-year-old BU center with questions; because the symptoms—anxiety, depression, confusion—are widespread, and far from exclusive, it's easy to jump to self-diagnosis. "Everybody wants to know if they have this disease," one researcher told me. "Then everyone wants a treatment." What they don't want to know is how little the scientists know.

"We don't have any clue about the rest of the disease—the hows, the whys. Anything really about it, except what it looks like," says Robert A. Stern, the BU neurology professor leading the detection study, which began last year and is the first such study financed by the National Institutes of Health. CTE is closely related to Alzheimer's disease. (Only in the past year have most scientists accepted it as a separate condition.) Do genetics play a role? Can lifestyle help cause it? "Is it specific to the type and frequencies of hits, or the amount of rest between hits?" Stern asks. "When they start, when they stop? The total duration? We don't know any of that."

To answer any of those questions—to figure out why some football players get CTE and some don't, or even how prevalent it is—they first need to be able to diagnose it.

"All we know is that one variable seems to make it happen in some people," Stern says.

It's a very simple variable: being hit, repeatedly.

Patient 53 has had that variable. A lot of that variable. On the condition of anonymity, he agreed that I could shadow him through his tests. And now he was here, around 8 in the morning, greeted by Stern. Balding and bubbly, the professor, who also directs clinical research at BU's Alzheimer's Disease Center, is an exuberant football fan, and he warmed up Patient 53 with some talk about the former player's bad back. That's the type of injury 53 had known to expect when he played. But not the brain stuff. Is that what was wrong with him?

"Now I wish I had never played. Well, some I do, some I don't," 53 told Stern. "I'm hoping you can help."

"That's why we're so glad you're here," Stern said. "We're the people who know the most. And we're hopeful."

Dressed in loose, old blue jeans and a teal pullover zipped to the throat, Patient 53 loomed over Stern and Christine Baugh, the study's research coordinator, who would guide him through the next two days. They would make a fine study in contrasts: 53 was large, his beard patchy, nose thick, breathing heavy. Just a few years out of Harvard University, where she studied the history of neuroscience, Baugh was very much a former rower—tall, thin. Her father had played professional football for a couple of years, so she has a vested interest in the disease and an easy way of talking with former pros. She's sharp, too, which was good, because as they settled into a conference room across the hallway, 53 would show that he'd lost little wit to his mental fog.

Baugh was explaining the study's spinal tap. It's a normal point of anxiety, a reason they've had a hard time getting subjects for a control group. (They desperately need volunteers: former professional or college athletes in sports like baseball or rowing who haven't been hit in the head. When I visited, in March, only three such volunteers had gone through the study.) The same fluid in the spine also surrounds the brain, she explained. In CTE, a protein called tau congregates in fibrous tangles inside the brain's neurons. It's one of the mechanisms seen in other degenerative brain diseases, like Alzheimer's, for which spinal taps have recently proved promising in diagnosis. They might find similar spinal biomarkers for CTE, though that's far from certain.

But there are possible side effects, she noted. "The other thing that can happen is what's called a spinal headache," she said. "We do a couple things to try and minimize that. We use a special needle, and we also have you lay down afterward, both of which have actually been shown to help."

"What did you call it?" Patient 53 said. "The what headache?"

"Spinal headache."

"Oh, great."

"I know. We really try to minimize the headaches. We know you guys have all too many of those."

They went through permissions—53 donning his steel-framed glasses to read the documents—and descriptions of the rest of the tests: physical, blood sample, neurological exam, EEG, psychiatric interview, medical history, cognitive test, and, on Day 2, a couple of hours in an MRI machine. A spiral of white-plastic brains hung on the wall, its pattern reminiscent of a meditation labyrinth. Don't worry, Baugh assured Patient 53, if anything health-related arises, they'd let him know right away. But much of this work won't yield any diagnostic results until the study is done, she said.

"When do you anticipate everything will be done?" he asked.

"Everybody should be fully through the study in about a year's time."

"From now?"

"From now."

Christine Baugh and Patient 53 eased their way up a flight of stairs—given his chronic back injuries, he doesn't walk so much as grind—to the center's clinical-research unit, a quiet floor mocked up like a standard hospital, nurse's station and all. Patient 53 would spend most of his day here in a drab beige room, paintings of white and blue potted flowers on the wall, attended by a cast of efficient caretakers.

First came a dark-haired, middle-aged nurse—a real pro in blue scrubs and white coat, with a Boston accent—to take blood and vitals. She needed three tablespoons of blood, some to see if the spinal tap could go forward, and the rest for genetic tests. The researchers theorize that the most common genetic risk factor for Alzheimer's could play a similar role in CTE. If it does, it wouldn't be the cause of CTE but another indication that genes play a role in why the results of brain injury vary so much.

Between tests, Patient 53 encompassed a gray padded chair, his arms dangling close to the floor. He delighted over the day's strange vocab, the "Johnny top" hospital gown, and a scale branded Detecto. Then the neurologist, Samuel Frank, an associate professor, swept in, young-featured and wearing olive pants and a blue-and-white-checked shirt.

Before the spinal tap, he ran 53 through physical tests: tracking Frank's fingers, clenching hands, tapping toes. "Do you get much sleep?" he asked at one point. "I don't sleep much," 53 said. "Not very well." Then there was the drunk-driving test, putting one foot in front of the other. "Can you take a few steps way up on your tiptoes?" Frank asked. 53 grimaced. "My calves don't work," he said. Long, quiet pauses punctuated the conversation as Frank tapped records into a black tablet. Eventually he started poking 53's feet with a safety pin, to little response. 53 had suffered bad frostbite during one game, he explained. His feet were gray for months.

The neurological tests ended with 53 standing on a four-inch-thick blue mat, balancing on one foot. Baugh timed him with an iPhone. He barely had his foot off the floor before he tipped forward. "This is depressing," 53 said.

"This is hard for anybody," Baugh quickly protested.

"You did fine," Frank said.

"No, I didn't," 53 said with a sad laugh. "But that's OK."

Frank and the nurse readied him for the spinal tap. He was the tallest patient they had tested, though not the heaviest; he hadn't shrunk like some of his post-steroid peers—53 never took steroids, he said—and carried his gut well. Still, Frank said, they should start with the long needle. 53 sat on the side of a bed, leaning facedown on two pillows stacked on a rollaway food tray. "You should have the documentary Spinal Tap playing when you do this," he said, his voice muffled. He paused: "The mockumentary."

Frank streaked red-brown iodine on 53's spine and pressed the needle, thin, about a half-inch long, into 53's back, searching for a route between two vertebrae. In Alzheimer's patients, the researchers have seen a large increase of tau in the spinal fluid, possibly because of nerve destruction. They wanted to see if the same held for CTE—far from a given—and how it might be detected early on. The needle resembled a dipstick, its interior sliding out to show whether Frank had tapped the spinal fluid.

"You in there yet?" 53 asked, after some time had passed. Not yet. "We have a little bit more tissue to go through than normal," Frank said.

As Frank continued to explore, there was a knock on the door, and Robert Stern, the study's leader, appeared. "Perfect timing," Frank said.

"No matter what my schedule is, I walk in just as he's doing this!" Stern said. "How's it going?" he asked Patient 53.

"You always ask that just as we're doing this," Frank said. "What are they supposed to say? 'Oh, it's great'?"

"Are you coming out the other side or what?" 53 asked, in good humor. They had to try a different spot, it turned out; Frank couldn't get between the bones. Stern chatted with 53 about Lou Gehrig's disease; one variant of it seems related to CTE, caused by repetitive blows to the head.

"It's nasty," 53 said.

"It's really nasty, really nasty," Stern said.

Frank started again. Soon enough he struck fluid.

"I've got maple syrup coming out of me," 53 said.

"This is much less viscous," Frank said. "It's quite literally like water. Water with a few extra proteins. That's what we're looking for."

The nurse walked around the bed to show 53 his fluid, now in vials.

"That's what your brain floats around in," Baugh said.

"I guess it's good it's clear, right?" 53 said.

Patient 53's day was far from over. After Frank, Stern, and the nurse left, Baugh had him lie down. She scrubbed his face, then stuck on circular white electrodes for the electroencephalogram, which would measure the electrical activity of his brain in a resting state. The room was still, though 53 fidgeted, drawn to chat with Baugh. She dimmed the lights. The clock ticked, ticked again.

He got no spinal headache, thankfully, and a late breakfast soon arrived: sausage, eggs, banana, apple. "I had never had a spinal tap, so I was a little nervous about that," 53 said. "But that wasn't bad." His back is such a problem, he continued. He was due for surgery soon, a three-tiered fusion. "I'm not necessarily in pain. But walking is very uncomfortable. It's like getting stabbed."

Patient 53 started playing contact football when he was 14 years old. His dad didn't allow him to play tackle before then. "Smart man," he said. He was a tight end in high school, playing basketball (center, of course) and heaving a shot put. His size and smarts made him an offensive lineman by college, the burly yet agile players responsible for defending the quarterback and opening holes for the running back. It's an unheralded position—one that can record thousands of light blows to the head. And blows that are not so light.

We were still in the exam room. Patient 53 had spent a couple of hours speaking confidentially with a psychiatrist. Then Baugh returned to learn about his past: sports, injuries, medical history, drug use. He'd taken off his pullover and absently curled his left hand into a fist, wrapped under his beige T-shirt.

"Next I'm going to ask you some questions about concussions."

"What?" 53 said.

"Next I'm going to ask you some questions about—"

He laughed. "It's a bad joke."

53 believes he suffered 30 to 50 concussions during his playing career. A lot of dings. A lot of stars. "Man, that's a lot of football, isn't it?" he said. Only once did he black out. (It's a misconception that concussions require a loss of consciousness.) "I remember putting my pads on, and I remember a nurse waking me up," he said. "With a bad headache." That was in college, and would have been in practice, he said. He rarely left games after his other concussions; there were smelling salts, after all. More than once he approached the wrong huddle, only to have his teammates drag him back across the field.

He turned and looked at me. "Stupid (expletive) sport," he said.

Though Baugh was asking about concussions, chronic traumatic encephalopathy is not tied just to concussions. This is a point of wide and understandable confusion; until recently, Stern and his team thought it was all about concussions. Now they know that the disease is linked to the hundreds of "subconcussive" blows the brain suffers, the collective scrapes and bruises it takes from the skull. "It's somehow the total load of hitting your head," Stern told me earlier. "Something about that in some people puts into motion this cascade of events in the brain that eventually leads to this overall disease course."

The mechanisms aren't known. The researchers suspect that tau spreads in a way similar to Creutzfeldt-Jakob disease and related disorders, in which defective proteins, called prions, beget more defective proteins. There's also a neuroinflammation hypothesis, but nothing the researchers are ready to unveil. The center has found CTE in the brains of 34 of the 35 deceased players it's examined, but that's a highly selective sample, given that most of those donated brains came from players known to have had the disease's symptoms. Stern has also recently noted that CTE has two stages: one that causes changes in behavior and mood, and the other, later in life, that causes cognitive problems and leads to dementia. (That paper is not yet published.) Why does that happen? He doesn't know.

Patient 53 had a lot of history to go over. He'd done his share of partying in his day. Lots of beer, lots of pot, some cocaine, all of it social. Big nights on the town, usually after the game and at Thursday dinners. The trainers would stuff them with aspirin, and with other pills in unlabeled white envelopes. He took speed, too, in his last couple of seasons, when he was slowing. He still hates his old coach. He's wrestled with depression since his retirement, lost loved ones in what has become an isolated life. He has mood swings. But today was a pretty good day. A young, smart woman was interested in what he had to say. Everyone laughed at his jokes.

Near the end of the history-taking, Stern appeared again. Another test still loomed today, a cognitive exam that I couldn't watch, because an observer could easily disrupt the results. Tomorrow, 53 would go for his brain scans.

"I've seen every doctor there is. Been through every kind of test," he said.

"We just need the right one, then," Stern said.

"Well, I don't know. I hope we can find one."

"We will. We will."

The second day was a bad day.

Patient 53 had woken exhausted from the long day at BU and a delivery dinner of bad Chinese food. He hadn't slept well. We were in the basement of Brigham and Women's Hospital, not far from Fenway Park, as he prepared for the two hours he would spend in the MRI machine. A photo of the Eiffel Tower at dusk, a dim gaslight in the foreground, hung on the wall. "I just don't feel very good," 53 said. Today wasn't unusual. "This is what I deal with."

Hovering nearby, dressed in a charcoal suit, was Alexander Lin, a clinical spectroscopist at the hospital. A lead investigator in the CTE study's MRI work, along with Martha Shenton, director of the psychiatry neuroimaging lab at Harvard Medical School, Lin had initially worked more on severe brain trauma—the kind of damage that results in comas—but became interested in mild brain damage when he saw one patient, a 14-year-old girl, who had suffered a concussion in soccer and couldn't return to school for months. He met Shenton and Stern at a meeting, and their collaboration took off from there.

Lin escorted 53 to an eggshell-blue Siemens MRI machine, its extra-wide bore typically used for pregnant women. 53 eased onto its bed, ginger about his back and worried about his heart arrhythmia. He held a stress ball: Squeeze it, Lin told him, and its trigger would have them rush in. 53 had asked for soothing music to be played; Ravel's "Pavane pour une infante défunte" jockeyed with the MRI's whine. Lin lowered an enhancing coil on 53's face. It looked like a storm trooper's mask.

"This is called a football helmet," Lin said.

"Yeah, that's an irony, isn't it?" 53 said.

Lin hustled into the control room, where ghostly slices of 53's brain popped onto the multiplex of monitors. Lin's assistant flipped through the images with a mouse's scroll wheel. A protein like tau is invisible in these images; a brain carrying its tangles will look just like any other. But Lin and Shenton hope that their advanced techniques can begin to reveal, somehow, whether a brain is suffering from CTE.

Lin's scans came first. He's an expert in MR spectroscopy, a discipline that focuses not on the brain's structure but on its chemical signatures. "People can barely pronounce it, let alone spell it," he said. "So we call it the virtual biopsy." After controlling for all the water in the brain—"shimming," they call it—Lin can measure how much, say, glutamate, a neurotransmitter, or N-acetylaspartate, a molecule found in adult neurons, is found in the brain, in injured and healthy populations. Such comparisons can be diagnostic: They can predict if a patient will come out of a coma, and Lin suspects that an increase in glutamate could be involved in CTE's origins.

53's scans lasted at least 10 minutes at a time; periodically Lin called through the intercom, checking in, to supportive groans in response. ("Next scan will be 12 minutes. You're doing great!") The virtual biopsy was targeting the posterior cingulate, a neural clump near the brain's back. In total, the team would look at the abundance of 20 molecules. After a minute, a colorful bar chart popped up. "There's the spectrum," Lin said.

Halfway through, 53 took a break, walking to the outpatient locker room. He was groggy, his voice quiet. Did he sleep during the scan? "In and out," he said. "It was loud." "This part is going to be a little louder," warned the research assistant walking with him. They returned to the MRI's bed, and he got back in.

Martha Shenton's scan used a technique called diffusion tensor imaging—an imposing term, unless you think of ink and paper. Drip black ink on a paper without fibers, and it spreads in a perfect circle; drip the same on fibrous paper, and the ink follows those channels. Looking at the shape of the ink's spread can tell you about those fibers. The same is true for water and the brain's nerve fibers, called axons, along with some of its other structures. But creating the conditions for diffusion calls for a pulsing magnetic field from the MRI machine. A loud pulsing magnetic field.

It was the day's toughest scan, lasting 18 minutes. As the magnet got going, it warbled like a house-sized songbird. "The table's shaking in there," one technician said. "This is hard-core," Lin said. The classical music was drowned out.

The intercom crackled.

"It's like one of those hotel massage beds," 53 said.

Lin, Shenton, and Stern hope that 53's MRI scans will soon be rendered, in some ways, obsolete. Over the past year, two research groups have finally developed a molecule that will pass through to the brain and bind to tau, allowing the protein to be seen in PET scans, rather than merely inferred, as it might be from the MRI.

"This is probably the most exciting thing in the entire field," Stern told me earlier that week. "Not just in CTE but in the whole of neuro­degenerative diseases." One of those research groups, then based at Siemens (and now owned by Eli Lilly and Company), reported the successful use of the tracer in human beings this year, to little fanfare, in the Journal of Alzheimer's Disease. The group's grant proposal to use the tracer is pending with the Defense Department, which is concerned about the legacy of subconcussive blows for former soldiers. "This is going to be worse than Agent Orange," Shenton told me that morning.

But for now, there are only the MRI scans, which for 53 went on for slightly over two hours. When they were done, he walked back to the locker room to change. It had been a rough two days. It took all he had. He was glad to do the tests, he said, even if it turned out he didn't have CTE.

The next week, Stern would go through his combined records and give him a call to talk about his general health. But there would be no diagnosis of CTE. Not yet. Like the 52 patients before him, and the 47 after, he won't know for years, although Stern, the study's leader, is hopeful—if they can get more volunteers for controls. He had told me that with enough resources, an accurate diagnosis was five years away. A cure? Decades.

A clear diagnosis couldn't come soon enough.

"It's not fun," 53 said as he shrugged on his pullover. "Whatever it is that's going on, it's not fun."

Back in street clothes, Patient 53 found Christine Baugh, who had been in the waiting room all day, tapping on a laptop. She greeted him, a friendly face from a better day, and they ambled down the hospital's wide white hallway, toward the elevators, the airport, and the cloudy day beyond.

Paul Voosen is a senior reporter at The Chronicle.

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