Experimental brain scans of more than two dozen former N.F.L. players found that the men had abnormal levels of the protein linked to chronic traumatic encephalopathy, the degenerative brain disease associated with repeated hits to the head.
Using positron emission tomography, or PET, scans, the researchers found “elevated amounts of abnormal tau protein” in the parts of the brain associated with the disease, known as C.T.E., compared to men of similar age who had not played football.
The authors of the study and outside experts stressed that such tau imaging is far from a diagnostic test for C.T.E., which is likely years away and could include other markers, from blood and spinal fluid.
The results of the study, published in The New England Journal of Medicine on Wednesday, are considered preliminary, but constitute a first step toward developing a clinical test to determine the presence of C.T.E. in living players, as well as early signs and potential risk.
Thus far, pathologists have been able to confirm the diagnosis only posthumously, by identifying the tau signature in donated brains.
Previous studies had reported elevated levels of the tau signature in single cases. The new study is the first to compare the brains of a group of former players to a control group, using an imaging approach that specifically picks up tau and not other proteins in the brain.
“What makes this exciting is that it’s a great first step for imaging C.T.E. in the living, not just looking at single instances, but comparing averages and looking for patterns by comparing groups,” said Kevin Bieniek, director of the Biggs Institute Brain Bank Core at the University of Texas Health Science Center in San Antonio.
Dr. Bieniek was not involved in the study.
Over the past decade, the competition for research dollars to investigate C.T.E. has become fierce and political, with charges of exaggerated claims and interference by the N.F.L., which has produced scientific reports to rebut any link between the disease and repeated head trauma.
The group that develops the first useful clinical test stands to attract a surge of funding, not to mention potential commercial partnerships. At least one group, in California, has already formed a company to promote its own test.
The new study was led by Dr. Robert Stern of Boston University, which thus far has the largest collection of donated brains from former pro football players. He led a coalition of investigators at multiple centers who took brain images from 26 former pro players, aged 40 to 69, who had a variety of memory, mood and mental problems associated with C.T.E.
Those images showed marked elevation of tau proteins in the areas of the brain that display the tau signature when diagnosed post-mortem. The players’ tau signal in those areas was higher, on average, than the tau signal from a control group of men who had not played.
“We found, as well, that the amount of abnormal tau detected in these PET scans was associated with the number of years playing football,” Dr. Stern said.
His collaborators included brain scientists from the Mayo Clinic Arizona, Brigham and Women’s Hospital and Avid Radiopharmaceuticals. Avid makes a molecule, called a ligand, that binds to proteins, in this case in the brain. Avid’s ligand is the most studied of the so-called tau detectors, and the company helped finance the study.
Experts said the findings were encouraging, because any reliable marker for abnormal tau accumulation would allow doctors not only to identify people with C.T.E., but also to monitor progress from potential drug treatments.
But, these experts said, much more work is required to develop a reliable test for a disorder that is still not well understood. As in tests for people suffering from Alzheimer’s and other diseases that affect the brain, researchers have spent years trying to precisely refine the ligands that are ingested by patients before they receive PET scans and other imaging tests.
There are also many open questions about the tau protein that is a signature of C.T.E. Researchers are trying to determine whether the protein, which occurs naturally in the brain, accumulates faster in people who have received repeated head trauma, and how those accumulating levels are related to behaviors associated with C.T.E., which include not only memory deficits but also impulse control issues and symptoms of depression.
The new study found no correlation between the strength of the abnormal tau signature and the severity of cognitive and mood problems in the former players, though the sample was small.
The search for a test for C.T.E. in living patients has received intense scrutiny since the disease was first discovered in deceased professional football players 15 years ago.
The universe of professional players is relatively small — only about 2,000 active players and 20,000 retirees — and the Boston group’s work has been based on a sample of some of the worst cases. Many, perhaps most, pro football players do not develop disabling cognitive problems, and there are likely many other brain traumas that could potentially result in the C.T.E. tau signature.
Yet football is by far the country’s most popular sport, with more than a million high school students playing the tackle version of the game. The detection of C.T.E. in former pro players turned what was viewed as an occupational hazard into a public health debate. For years now, parents, coaches, school administrators, doctors and others have engaged in a dispute over whether children should be allowed to play collision sports.
Part of that dispute is trying to prove (or disprove) whether there is a direct link between exposure to repeated hits to the head absorbed in games like tackle football and the development of cognitive and neurological problems later in life.
Here, the science is emerging. Studies by Dr. Stern and other researchers, including in the paper just released, suggest that there is a dose response — the more hits to the head, the more likely you are to develop problems later.
But researchers have questioned studies that have showed a high percentage of deceased former football players found with C.T.E. They claimed that the research subjects were self-selected because the families of players who suspected they had brain disease were more likely to donate their brains to science.
Some researchers are looking at broader populations of people who have had traumatic brain injury, not just football players, to determine whether participation in collision sports, as opposed to genetics or other factors, is linked to the development of C.T.E.
“There’s a lot of lower-level head trauma out there that no one knows the consequence of,” said Dr. John Trojanowski, a research at the Perelman School of Medicine at the University of Pennsylvania, who plans to submit a research paper in the coming months on people who have suffered traumatic brain injury. “We are looking at people with traumatic brain injury, football players, rugby players, some people who fell off bikes.”
Even when tau is found in PET scans, many other questions remain.
“Identifying the tau is just a first step,” said Dr. Alexander Powers, associate professor of neurosurgery, pediatrics and orthopedics at Wake Forest School of Medicine. “Is tau increasing in the brain? And what is the rate? Does it steadily increase? Or rapidly, like cancer? And what are the factors that led to it?”
