Bennet Omalu was the first pathologist in the world to detect CTE in a former football player.
The year was 2002, and the player was former Steelers center Mike Webster, who had died of a heart attack at the age of 50.
Dr. Omalu was a young pathologist working for former Allegheny County Coroner Cyril H. Wecht. As a Nigerian native, he knew very little about American football, except that it was a brutal head-banging sport. Given the reports he had heard about Webster's erratic behavior before his death, he figured the autopsy might show visible evidence of brain damage.
"When I opened up his skull on autopsy, I expected his brain to be all shriveled and small, but lord God almighty, his brain looked normal," he recalled in an interview this year. "It actually confused me more. I thought that means I'm wrong."
Still, with the Webster family's permission, he had a lab prepare the brain for microscopic examination, and weeks later, in his Pittsburgh apartment, he finally looked at the slides. "I pulled out the first slide, and I was munching on an apple, and I thought 'They've made a mistake. This should be the brain of another person.' I looked again and I thought, 'Aha!' "
What he saw were smudges and tangles of tau deposits in the brain, similar to those that would be seen in Alzheimer's disease, but without the accompanying plaques of beta amyloid protein also seen in Alzheimer's. He later named the disorder chronic traumatic encephalopathy, which simply means a long-developing brain injury.
Around the same time, another pathologist, Ann McKee, was amazed at a brain she was examining in her lab outside Boston.
Dr. McKee, now co-director of the Center for Traumatic Encephalopathy at Boston University, had already studied more than 1,500 brains of Alzheimer's patients, and she knew this one was different. "It was this extraordinary case, florid tauopathy of the likes I had never seen," she said, referring to the harmful form of the protein tau. The brain belonged to a former world-champion boxer, she recalled in an interview last year.
We all have tau in our brains. Normally, it makes up part of the skeleton of our brain cells. But in Alzheimer's disease, CTE and some other conditions, the tau becomes damaged and forms tangles and clumps. There is some evidence that this toxic form of the protein can then infect nearby cells, hastening its spread through the brain.
Mysteries of the Mind: About this series
Over the course of this year, the Pittsburgh Post-Gazette is looking deeply at five brain disorders that affect millions of people: schizophrenia, athletes' brain injuries, autism, depression and phobias. In this second segment of the series, we examine a disorder that causes mood changes, dementia and may even trigger suicides in some former athletes and soldiers -- chronic traumatic encephalopathy, or CTE. It is the latest of our "Mysteries of the Mind."
Sunday's story: The tragedy of CTE: a brain disease that afflicts athletes
Coming Tuesday: Mike Webster's brain damage was the beginning of a saga that has led to a massive lawsuit against the National Football League.
Researchers like Drs. Omalu and McKee knew that the tau they were seeing in CTE was not Alzheimer's because it was showing up in different parts of the brain and advancing with a different pattern.
In Webster's brain, Dr. Omalu said, there was no distorted tau in his hippocampus -- a seahorse-shaped structure lower in the brain that is critical for memory formation and is usually heavily damaged in Alzheimer's disease.
Dr. McKee, who has now examined scores of CTE brains, said the damaged tau shows up first in the frontal lobes of the brain, particularly in the sulci -- the deep valleys in the folds of the brain -- and spreads outward from there.
In a study published in the journal Brain late last year, Dr. McKee and her colleagues examined 85 brains of athletes, soldiers and others who had experienced repetitive brain injuries and found CTE in 80 percent of them.
Of the 35 who had played professional football, ranging in age from their 20s to their 90s, all but one had signs of CTE, and seven -- or 20 percent -- had died of suicide, gunshot wounds or overdoses.
Most of the former football players with CTE were in their 40s and older, although three were in their 20s and 30s.
The brains had been donated by families, many of them concerned by psychological changes they had seen in their loved ones, and were not part of a randomized study.
"We try to get everybody. We have a very low threshold," she said. "But the fact is you're much more likely to donate if you're concerned."
Looking at CTE after someone has died, however, is less than ideal for understanding how it develops.
"Somebody once said that looking at these pathology endpoints is like walking through a cemetery and looking at the gravestones and trying to figure out what happened in a community," said D. Martin Watterson, a brain researcher at Northwestern University.
Developing new tests
Gary Small, a psychiatrist at the University of California at Los Angeles, hopes to change that with a new test that uses a radioactively tagged tracer to detect tau deposits in living brains.
In a February study of five former National Football League players and five control subjects, the positron emission tomography, or PET, scans showed that the former NFL players had higher levels of deposits in subsurface brain regions and the amygdala, an almond shaped structure that governs emotions like fear and anger.
The UCLA tracer attaches to both tau and beta amyloid proteins, which are found together in Alzheimer's disease, but Dr. Small said the pattern of deposits is different than in Alzheimer's.
The study is too small to draw definitive conclusions, but he hopes to study a much larger group as soon as he can arrange funding.
Even in his small sample, one player who showed significant levels of tau protein, former NFL quarterback Wayne Clark, was not experiencing the mood changes and thinking problems of the other retired players.
So why do some players who get repeated head injuries not develop CTE deposits, or why would others have the damaged protein but not experience symptoms?
One possibility is a genetic vulnerability to the disorder, say several researchers.
Robert Mahley, a scientist at the Gladstone Institutes, affiliated with the University of California at San Francisco, said one candidate is a gene for a certain type of cholesterol transporter, known as APOE4.
Research already has shown that people who inherit the APOE4 gene variant have a much higher risk of getting Alzheimer's disease, he said, and that those with the variant who suffer a serious head injury have a twentyfold greater risk of getting Alzheimer's later. It's also a risk factor for multiple sclerosis, another neurological ailment.
Dr. Mahley suspects that former athletes who get CTE may have the same vulnerability, although more research is needed to prove that. In the Boston University autopsy studies, for instance, about 40 percent of the former professional football players had at least one version of the APOE4 gene.
Work in the Gladstone labs has shown a direct connection between APOE4 and the damaged tau that shows up in Alzheimer's and CTE. The APOE4 protein has one amino acid that is different than the typical version, out of a string of 299 amino acids. That single change causes the head and tail of the protein to curl toward each other, and the brain, recognizing that isn't normal, produces enzymes that clip off a piece of the protein's tail.
That stray piece can float through brain cells and cause damage, he said, changing tau into the distorted form that clumps together in the brain.
Soldiers who have suffered blast injuries also are vulnerable to CTE, scientists say.
Lee Goldstein, a psychiatrist at Boston University, has shown in experiments with mice that a single blast wave can create tau deposits in the brains of the animals that look just like those in CTE.
The wind that follows an explosion, Dr. Goldstein said, can reach 330 to 350 mph. These blasts end up "whipping the head around like a bobblehead." By analyzing the mice with high-speed photography, his team could show that "it causes shearing forces in the brain, just like if you were to take a bowl of Jell-O and rapidly twist it."
That shearing motion, acting on the spindly axons that carry signals in the brain, causes tau to fall off, "and it damages the surrounding blood vessels, which causes chronic inflammation, which we think leads to the tau around the blood vessels," he said.
In a more recent blast experiment at the University of Pittsburgh, rats whose heads were held still did not show the tau deposits. But even those animals showed subtle changes in gene expression in the brain that mimicked the pattern seen in Alzheimer's disease, said lead investigator Patrick Kochanek, director of Pitt's Safar Center for Resuscitation Research.
Dr. Goldstein said his group is the first one to show a direct mechanical cause of tau deposits in the brain, and he believes the blast effect is equivalent to several smaller blows that athletes would get playing football, hockey or other contact sports.
While some might question how good a model mice are for human head injuries, another Boston researcher says they have distinct advantages.
William Meehan, a concussion expert and Harvard University pediatrics professor, said one of the arguments that skeptics have made about head injury complaints in football, hockey and other sports is that players may have abused steroids or growth hormones or might be making false complaints.
"But mice don't malinger, they don't take steroids, they're not on growth hormones," Dr. Meehan said, so experimental results aren't confounded by any of that.
His work with mice has shown that a series of mild concussions has profound effects on the rodents when they try to navigate a water maze afterward.
The maze is filled halfway with water and contains hidden platforms underneath, with markers to help the mice remember where the platform is. If the mice can swim to the platform, they are dried off and get a food reward.
The concussed rodents took much longer to find the platform than mice without head injuries. "Mice that sustained five concussions, even a year after the last injury, still had learning and memory problems," he said.
While Dr. Meehan doesn't study CTE directly, it makes sense to him that it could result from a series of milder head injuries.
"I think every single concussion leaves a lasting effect on the brain. But if someone gets one concussion in sport, you're going to recover so much it will not be noticeable," he said. "But if you accumulate them over and over and over again, that small amount will add up and start to have a cumulative effect."
Punch drunk syndrome
CTE was first detected in boxers in the late 1920s by New Jersey pathologist Harrison Martland, who noticed some boxers having balance, memory and speech problems.
He dubbed the condition "punch drunk syndrome."
Dr. Meehan noted that when Martland examined boxers for the syndrome, "he didn't see it in skilled boxers who outscore you with points and dodge your punches. He saw it in sluggers, who kind of wade in, and they don't tend to get a lot of concussions per se, because if you get concussions a lot in boxing, you lose reaction speed and your career's over."
In a similar way, said Robert Cantu, a neurosurgeon at Boston University, the preliminary evidence suggests that the football players most susceptible to CTE may not be the ones who have spectacular high-speed collisions, but linemen and linebackers, "who on every play are banging their heads and may be experiencing subconcussive blows."
But Robert Harbaugh, chairman of neurosurgery at Penn State University and a member of the NFL's Head, Neck and Spine Committee, said head collisions by themselves may not be enough to cause CTE.
So far, he said, studies haven't shown a "dose-response curve," where players with the most head injuries are the most likely to get dementia. Clouding the issue is the fact that NFL players seem to be at higher risk for getting Alzheimer's disease, he said.
One area he thinks might be relevant to look at is sleep apnea, in which people stop breathing briefly during sleep, often several times a night. People who are heavier have a higher incidence of sleep apnea, and studies have shown it is a risk factor for getting Alzheimer's.
"NFL players tend to be large people, and I suspect there is an increase in sleep apnea" among them, which can raise blood pressure and lower brain oxygen levels, Dr. Harbaugh said.
How to treat it?
While there is no effective treatment for CTE, there are several experimental therapies that show promise.
In Boston, Dr. Meehan is working with Margaret Naeser of the VA Boston Healthcare System on shining red light through the skull as a method of healing brain injuries.
The research, which just received a grant from the American Medical Society for Sports Medicine, is based on studies of mice that received experimental concussions and showed improvement in their brain function after the light therapy.
Experiments are underway now at the Boston VA with soldiers who have had head injuries and at Boston Children's Hospital with children who have had persistent concussion symptoms. Doctors attach several LED clusters to their scalps, and the light shines through the skulls and penetrates about 1 centimeter into the brain.
Dr. Meehan believes the light helps stimulate the production of a vital energy source known as adenosine triphosphate, or ATP, which is needed to restore the chemical balance of brain cells after injury.
In Philadelphia, University of Pennsylvania professor John Trojanowski also has used mice to show that an experimental drug owned by Bristol-Myers Squibb halts the progression of tau degeneration in the rodents' brains and actually improves their thinking ability.
The treatments might hold out hope for both Alzheimer's disease patients and victims of CTE, he said.
"We have shown that preventing this loss of tau function will correct this functional loss and reverse [tau] tangle pathology," Dr. Trojanowski said. "And we're interested in working with others to see if this will be of benefit to football players or soldiers with blast injuries, as well as to develop a better understanding of traumatic brain injury."
In Chicago, University of Chicago neurosurgeon Julian Bailes has suggested that fish oil supplements might be able to lessen damage from brain injuries.
Doctors at nearby Northwestern University have identified an experimental treatment that reduces inflammation in the brain, which some researchers think is an underlying problem in many brain diseases.
Mr. Watterson, the Northwestern brain researcher, said that when the brain is injured, it produces substances called cytokines that create inflammation and can eventually damage the connections between neurons and even kill them. A substance known as MW151 was able to suppress the inflammation in mice subjected to head trauma.
Northwestern sold the rights to the drug to a commercial company for development, he said, but because developing new drugs for human use is so expensive and time-consuming, "companies are risk averse and the government is risk averse and so there is not much funding for this. But the public outcry over sports and military head injuries may increase funding."
Even if treatments are not available for years, though, Boston University's Dr. McKee said she thinks there would be tremendous value in having an effective brain imaging method to pick up signs of CTE early on.
At least that way, she said, athletes could make decisions about whether to keep playing. "If it were me," she said, "I would not go back and play in the NFL if I had those little deposits in my brain."
Mark Roth: firstname.lastname@example.org or 412-263-1130. First Published May 13, 2013 4:00 AM