Study the clues that a given gene could make the CTE worse

Researchers studying degenerative brain disease that has afflicted Aaron Hernandez and other football players have long been intrigued by a central mystery: why is chronic traumatic encephalopathy, or CTE, hitting some people more than other?

In an article published Saturday, a team from the Boston University School of Medicine identified a new clue in understanding an illness that raised worrying questions about the long-term risks of sports-related sports. contact.

Genes were suspected of playing a role in ETC, and the study is the first to suggest a specific culprit: a common variant of a gene known to TMEM106B.

The researchers examined the brain of a small group of people diagnosed after a death by CTE, which causes a series of cognitive and emotional disturbances and has been associated with repeated blows to the head. They found that people with variant TMEM106B were more likely to have severe illness and were 2.5 times more likely to develop dementia.

But to the researchers' surprise, having this variant of the gene did not make a person more likely to develop a CTE in the first place. This discovery "suggests that environmental exposure to repeated impacts on the head is the determining factor for contracting this disease," said Dr. Thor D. Stein, neuropathologist at VA Boston Healthcare System and one of the authors of the study.

Published in the journal Acta Neuropathologica
the results do not allow individuals to obtain a genetic test to assess their risk of TBI. As with Alzheimer's disease, it is likely that many genes affect susceptibility to CTE, and scientists are far from identifying them, said Stein.

But Dr. Merit E. Cudkowicz, head of the neurology department at Massachusetts General Hospital, said she was "pretty excited" to know where the study could lead.

"This is the beginning of the attempt to link genetic risk to the environment," said Cudkowicz, who did not participate in the research. In the distant future, she said, "We may be able to say," If you wear a particular set of genes, you may not be able to practice contact sports. "

More immediately, according to Stein and others, the study points the way forward for future research on the underlying mechanisms of CTE, which could someday lead to treatments.

"This opens a window to understanding some of the processes that may be at play," said Dr. Michael S. Jaffee, director of the department of traumatology, concussions and sports neurology at the University College of Medicine. of Florida. study. "It's a good start to broaden the conversation."

The study is "a small pilot project" and needs to be validated by a larger group of patients, but its findings "have important potential implications," says a joint email from Dr. Daniel T. Laskowitz of Duke University and of Ellen Bennett, professors in neurology. to study brain lesions The identification of a genetic risk factor could lead to a better understanding of the molecular mechanisms underlying the progression of the disease, which "could contribute to the development of new therapeutic strategies to help patients with this disease elusive, "said Duke researchers.

A devastating disease, CTE can cause memory loss, difficulty thinking, impulse control problems, aggression, anxiety and depression, and can progress to dementia. Although its frequency is unknown, the ETC has drawn public attention to reports that high-level athletes are victims and concerned about the risks of contact sports for young people.

Hernandez, the former Patriots star, proved to be one of the most serious cases of CTE among deceased athletes whose brains had been studied by BU researchers. His family sued the National Football League, accusing him of failing to protect himself from brain injuries that may have contributed to his suicide in 2017 while he was in prison for murder.

Earlier this year, UB researchers announced that ETC could begin earlier than expected, even among adolescents. This prompted the Concussion Legacy Foundation, a Boston-based nonprofit organization dedicated to the treatment and prevention of brain injury, to discourage parents from allowing their children to play football before the age of 14.

And on Friday, the foundation reported that 147 former colleges had diagnosed a CTE among former football players, including 26 with at least three former players who developed this disease, which can only be diagnosed after death .

Not all people who have experienced several head strokes develop the CTE And among those who do, the severity varies. These differences can be caused by lifestyle and environmental factors, or by genes.

At the beginning of the study, virtually nothing was known about the genetics of CTE, said Stein, an assistant professor of pathology and laboratory medicine at Boston University's School of Medicine.

But the researchers felt that TMEM106B may play a role because it has been linked to other degenerative brain diseases, including a form of dementia known as frontotemporal lobar degeneration.

The team selected 86 brains out of 271 from the brain bank offered by the CTE Center at Boston University. The researchers said the study group included the brains of some well-known athletes, but declined to name them.

Seeking a pool of similar people, the researchers limited their investigation to Caucasian football players diagnosed with CTE, but who did not have another brain disease.

They had two questions: Does this gene make a person more likely to develop a CTE? And does this affect the severity of the CTE for those who have it?

To answer the first question, they examined the database of another research group containing 376 people whose genes had been sequenced but had no neurological disease. And they discovered that these healthy people were just as likely to have the TMEM106B variant as the athletes who developed a CTE.

"This suggests that this genetic variation does not make you more likely to develop the disease," Stein said.

To answer the second question, the researchers isolated the TMEM106B gene from 86 brains. They also assessed the severity of the ETC by examining the brains using a microscope and examining the many questionnaires that friends and family members had completed about the symptoms of living brain donors.

And they found that people with variant TMEM106B were also much more likely to have serious illness and dementia.

"For those with CTE, having only one copy of the gene increases the risk of developing dementia by 2.5 times," Stein said. "Having two copies makes you five times more likely."

But this variant of the TMEM106B is very common: 60% of people wear it. It is therefore clear that many other factors influence the development of the ETC.

TMEM106B is thought to control the processes that break down and eliminate proteins in cells and is active in the inflammatory response of the brain to infections and wounds.

"If we can study this protein and try to understand more about what it does," Stein said, "we may be able to find ways to block or affect his action. have a treatment. "

Could this research allow people to determine, using a genetic test, whether they are sensitive to ETC? Not for a long time.

"Maybe later, when we have additional studies with more people, you will use this information to indicate your risk," said Stein. "This, in addition to many other genes, could indicate your risk of developing a serious illness if you are exposed to many repetitive injuries."

Felice J. Freyer can be contacted at [email protected]. Follow her on Twitter @felicejfreyer