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Seeking the Holy Grail

Can Brain Scan Identify Signs of C.T.E.?

In breakthrough pilot study, UCLA researchers are first to find signs of disease in retired N.F.L. players.

Sports-related concussions and mild traumatic brain injuries have grabbed headlines in recent years, as the long-term damage they can cause becomes increasingly evident among both current and former athletes. 

Despite the potentially devastating consequences of traumatic brain injury and the large number of athletes playing contact sports who may be at risk, no method has been developed for detecting the tangled web of tau protein in the brain that are the telltale sign of chronic traumatic encephalopathy, or C.T.E.,  -  a degenerative condition associated with memory loss, confusion, progressive dementia, depression, suicidal behavior, personality changes, abnormal gait and tremors - while patients are alive. Up to now, the presence of the protein, which is also associated with Alzheimer's disease, could only be established posthumously by an autopsy. 

In a groundbreaking new study,1 UCLA researchers, using a type of brain-scan called PET (short for positron emission tomography), were able for the first time to identify the abnormal tau proteins in five retired National Football League players.  The distribution of tau in the retired players was consistent with the pattern found in autopsies of athletes diagnosed with C.T.E. after their deaths.

Study details 

Researchers recruited five former NFL players for the study, all 45 years of age or older, who had played a range of positions, including linebacker, quarterback, guard, center and defensive lineman, over careers ranging from 10 to 16 years.  Each had a history of one or more diagnosed concussions. Some were experiencing cognitive or mood symptoms.

The UCLA scientists gave the players intravenous injections of a chemical marker called FDDNP, which attaches to deposits of amyloid beta "plaques" and neurofibrillary tau "tangles," the hallmarks of Alzheimer's.  The players then underwent PET scans, a brain-imaging tool developed at UCLA used to assess neurological changes associated with Alzheimer's disease.

The researchers found that, compared to healthy men of comparable age, education, body mass index and family history of dementia, the NFL players had elevated levels of FDDNP in regions of the brains which control learning, memory, behavior, emotions, and other mental and physical functions. Those players who had experienced a greater number of concussions were found to have higher FDDNP levels, which "suggests a link between the players' history of head injury and FDDNP binding," the researchers wrote.

Each of the research volunteers also received a standard clinical assessment to gauge their degree of depression and cognitive ability. The players had more depressive symptoms than the healthy men, and generally scored lower on the test of cognitive ability. Three players had mild cognitive impairment, one had dementia, and another had normal cognitive function. 

"I hope that my participation in these kinds of studies will lead to a better understanding of the consequences of repeated head injury and new standards to protect players from sports concussions," said Wayne Clark, the player in the study who had normal cognitive function.    

PET scans showing tau protein in retired NFL players

"The FDDNP binding patterns in the players' scans were consistent with the tau deposit patterns that have been observed at autopsy in CTE cases," said study author Dr. Jorge R. Barrio, a professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA. 

Elevated levels of FDDNP have also been shown in studies to be associated with cognitive symptoms in normal aging, mild cognitive impairment and dementia, according to Barrio. The FDDNP signals appear to reflect a range of mental symptoms that have been observed in C.T.E. cases, he noted.

Although the FDDNP marker also binds to another abnormal brain protein called amyloid beta, previous autopsy studies have shown the amyloid plaques are observed in less than a third of CTE cases in retired football players, suggesting that the FDDNP signal in the players represents mostly tau deposits in the brain. 

Critical first step 

"Early detection of tau proteins may help us to understand what is happening sooner in the brains of these injured athletes," said lead study author Dr. Gary Small, UCLA's Parlow-Solomon Professor on Aging, professor of psychiatry and biobehavioral sciences at UCLA's Semel Institute for Neuroscience and Human Behavior, and director of the UCLA Longevity Center.  "Our findings may also guide us in developing strategies and interventions to protect those with early symptoms, rather than try to repair damage once it becomes extensive."

"Providing a non-invasive method for early detection is a critical first step in developing interventions to prevent symptom onset and progression in CTE," said Small.  "Early recognition and identification of those at high risk would allow clinicians to develop strategies and interventions to protect those with early symptoms rather than attempt to repair damage once it becomes extensive," he said.

"It is the holy grail of CTE research to be able to identify those who are suffering from the syndrome early, while they're still alive. Discovering the effects of prior brain trauma earlier opens up possibilities for symptom treatment and prevention," said study co-author Dr. Julian Bailes, director of the Brain Injury Research Institute and the Bennett Tarkington Chairman of the Department of Neurosurgery at NorthShore University HealthSystem based in Evanston, Illinois.  "For the first time, it opens the possibility we can intervene and stop the inexorable decline" of those with C.T.E., Bailes said in an interview with the New York Times 

Study of C.T.E. in infancy 

While research into CTE and the long-term effects of mild traumatic brain injuries such as sports-related concussions has been picking up momentum, it is still in its infancy.  It may take years for scientists and doctors to find out the role concussive and repetitive sub-concussive hits have in patients who develop the disease, as opposed to other factors, such as genetic predisposition and other health conditions.   

Because the group studied was so small, Small said that the results of their pilot study should be interpreted with caution. Larger follow-up studies will be needed, he said, to determine the impact and usefulness of detecting these tau proteins early.  But given the large number of people at risk for mild traumatic brain injury - not just athletes but military personnel, auto accident victims and others - a means of testing what is happening in the brain during the early stages of C.T.E. could potentially have a considerable impact on public health.  

"There are a lot of variables to consider, with regard to the size of the sample and the extent of the injuries the five players suffererd," says Rosemarie Scolaro Moser, PhD, MomsTEAM's expert sports concussion neuropsychologist.  But let's be clear: the UCLA study is a great, great breakthrough."

"Right now, you can't conclude that all NFL players have Alzheimer's or plaques and tangles (indicating C.T.E.). You can only say it's a remarkable study that allows us to see neuro-markers while people are still living, and it will stir on bigger studies," Moser says. 

"If indeed [the test] is sensitive and specific enough for tau, it would be extremely exciting and hugely important, but this was only five players," said Robert Cantu, MD, of Emerson Hospital in Concord, Mass., co-director of Boston University's Center for the Study of Traumatic Encephalopathy, and MomsTEAM's concussion expert emeritus, in an interview with the online publication, MedPage Today. 

That researchers have thus far only studied what effectively amounts to a self-selected group of patients, mostly former professional football players and other pro athletes and soldiers, with significant symptoms of C.T.E. makes it difficult, however, to assess and quantify the risk of the disease, and how prevalent it is in the general population, without larger studies tracking patients over a long period of time.

"We have to look more broadly and deeply at this," said Dr. Geoffrey Manley, a professor of neurosurgery at the University of California, San Francisco, in an interview with the Times. "We have too many one-offs. There's little that substitutes for following these people for years. We are right at the very beginning of this." 

Game changer? 

So, is the a study a game-changer? Will it change attitudes? Moser doesn't know.  

We can only be certain of this: Football players are at a higher risk for CTE, and it's always going to be up to them to determine whether they want to incur that risk. And if studies on active NFL players show a higher occurrence of CTE, "then that changes the game," Moser asserts.

"But that's very different from (the impact on minors)," she adds. "Hopefully, we can construct a game so that we don't have contact risks - that skill development, culture changes, attitude changes mean that we're not grooming 8-year-olds to be pros." 

1. Small Gw, Kepe V, Siddarth P, Ercoli LM, et. al.  PET Scanning of Brain Tau in Retired National Football League Players: Preliminary Findings.  Am J Geriatr Psychiatry 2013;21:138-144. 

Sources: MedPage Today, David Geffen UCLA Medical School and UCLA Health Sciences Media Relations, New York Times.

Video and photograph courtesy of UCLA Health Sciences. 

Posted January 24, 2013.  Revised to include Dr. Moser's comments on January 28, 2013