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A Marker of Brain Inflammation Is Found Higher in Young NFL Players Than Controls

Hurley, Dan

doi: 10.1097/01.NT.0000512097.79797.df
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Positron emission tomographic technology detected higher than average levels of translocator protein 18 kD, a protein related to brain inflammation in 14 current or recently retired National Football League players than in 16 controls.

Positron emission tomographic (PET) technology detected higher than average levels of a protein related to brain inflammation in 14 current or recently retired National Football League (NFL) players than in 16 controls, according to a study published online November 28, 2016, in JAMA Neurology.

The study offers a possible mechanism for how repeated head trauma may eventually lead to neuropsychological deficits, and a means to visualize the damage before it leads to clinically significant outcomes.

An editorial accompanying the paper called the new imaging technology “a potential in vivo biomarker” and said it may offer “a window of opportunity for anti-inflammatory intervention.”

However, leading sports neurologists told Neurology Today that the findings fall far short of proof that the technique offers a biomarker of long-term damage, a view the first author of the paper said she agreed with.

“This imaging technique is not yet ready for clinical applications,” said Jennifer M. Coughlin, MD, assistant professor of psychiatry and behavioral sciences at the Johns Hopkins School of Medicine. “The findings show there's an inflammatory component of brain injury associated with NFL play. We can use this brain imaging technique to visualize and quantify a marker of that inflammation. We have much work to be done in exploring whether this technique provides a marker for higher risk of neuropsychiatric problems down the road.”

While many other studies have used magnetic resonance imaging (MRI) to visualize structural changes to the brain following repeated head impacts, no means of imaging brain inflammation has been available until now.

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In hopes of finding such a technique, Dr. Coughlin and colleagues radio-tagged translocator protein 18 kDa (TSPO), believed to be associated with activation of microglia, the resident immune cells of the central nervous system. (Although found throughout the body, TSPO has been identified as having a role in many inflammatory processes.)

The cross-sectional study compared four active and 10 recently retired NFL players and 16 controls matched for age, sex, education and body mass index. The mean age of the players and controls was 31.3 (with a range of 6.1 years) and 27.6 (4.9 years), respectively. Players reported a mean of seven years (with a range of one to 21 years) since their last self-reported concussion.

Among the 12 players and 11 controls in whom the TSPO results were available, the NFL players showed significantly higher total levels in eight of the 12 brain regions examined (p<0.004). Limited change in white matter fractional anisotropy and mean diffusivity was also observed in 13 players compared with 15 controls.

No difference was seen between the two groups, however, in regional brain volumes or in neuropsychological performance, suggesting that if the TSPO signal is meaningful, it could be a marker of later onset of neuropsychological symptoms.

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The accompanying editorial described the use of TSPO imaging as an exciting and potentially important new way to connect the causal chain from head injury to long-term cognitive damage.

“Quantification of TSPO binding presents a novel and exciting way to assess neuroinflammation temporally and spatially in patients with TBI,” stated the editorial, coauthored by Jonathan P. Godbout, PhD, associate professor, and Kristina G. Witcher, a doctoral candidate, in the department of neuroscience at Ohio State University.

“The finding that there is evidence of increased inflammation in the absence of significant mental health and white matter integrity differences suggests that increased TSPO expression in glia is present prior to the development of issues in physical or mental health,” they wrote. “Overall, these data provide in vivo evidence linking concussive brain injuries sustained during football play to persistent glia-mediated inflammation.”

The findings, they wrote, support the view “that PET-based imaging methods can be used to assess brain injury and brain inflammation in vivo. Moreover, this study supports the idea that PET-based imaging can be used to detect brain inflammation in current players prior to the development any significant health problems. Thus, PET detection of TSPO may serve as a biomarker for early detection of brain inflammation. This is an important advancement.”

In an interview with Neurology Today, Dr. Coughlin took a more measured view of the findings. “Inflammation in the brain is not necessarily a bad thing,” she said. “The TSPO signal could simply be showing that the brain is trying to repair itself through an ongoing inflammatory process. It's going to take a much larger, longer study to determine whether the inflammation we're seeing in these relatively young players ultimately leads to clinically meaningful adverse outcomes.”



The strength of the technique, she said, is that it offers a way to answer that question. “Up until now, we had no real way to probe for brain changes in living athletes, to see whether there was any signal that could be linked to onset of later symptoms,” Dr. Coughlin said. “What this technique allows us to do in the living brain is to follow what we believe to be a marker of brain injury.”

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Neurologists who specialize in the treatment and study of sports-related head injuries said that while they see the potential for the technique, for now its value remains unproven.

“Particularly with the small number of people involved, we're not sure what these changes are indicating as far as actual brain health over the course of a lifetime,” said Jeffrey S. Kutcher, MD, FAAN, who left the University of Michigan in January to become national director of the Sport Neurology Clinic at the CORE Institute.

Dr. Kutcher said his greatest concern is that athletes might think the findings of heightened TSPO levels could mean they are doomed to dementia or other adverse outcomes.

“From my own clinical experience and speaking to colleagues around the country and around the world,” he said, “many people show up to our clinics with concerns they attribute to repeated concussions, but may be due to the same causes that non-athletes have. Causality is assumed. Patients give up. It ultimately ends up hurting people.”

Anthony Alessi, MD, FAAN, associate clinical professor of neurology and orthopedics and director of the UConn NeuroSport Program at the University of Connecticut, took a similarly skeptical view of the study's significance.

“Everyone is looking for the one test that will tell us if someone is going to have long-term neuropsychological effects from repeated head trauma,” he said, adding that the study authors “could be absolutely right, and 20 years from now, this will be the test. But it's 14 patients. All they're saying is, ‘Here's a new idea.’”

TBI clinical specialist and neuroimaging expert Christopher T. Whitlow, MD, PhD, MHA, associate professor and chief of neuroradiology at Wake Forest School of Medicine, agreed that the findings need to be interpreted with caution, but said that PET imaging of TSPO might well prove useful.

“I do think the study is provocative in that it proposes a mechanism for the kinds of changes that people are worried about in NFL football players, like chronic traumatic encephalopathy,” Dr. Whitlow said. “Many physicians and scientists certainly believe that neuroinflammation may play a role. Here the authors are providing a novel tool to measure that inflammation in the brains of football players, before clinical effects are evident. Whether or not these findings can be generalized to all players involved in contact sports, and whether TSPO serves as a biomarker of future cognitive impairment or neurodegenerative change, remains to be proved. But the approach and results definitely offer an interesting beginning to a new research direction that may yield important biomarkers and targets for intervention that are sorely needed.”

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•. Coughlin JM, Wang Y, Minn I, et al. Imaging of glial cell activation and white matter integrity in brains of active and recently retired National Football League players JAMA Neurol 2016; Epub 2016 Nov 28.
    •. Witcher KG, Godbout JP. Can sustained glia-mediated brain inflammation after repeated concussive brain injury be detected in vivo JAMA Neurol 2016; Epub 2016 Nov 28.
      •. Moran LM, Babikian T, Del Piero L, et al. The UCLA Study of Predictors of Cognitive Functioning Following Moderate/Severe Pediatric Traumatic Brain Injury J Int Neuropsychol Soc 2016;22(5):512–519.
        •. Bahrami N, Sharma D, Rosenthal S, et al. Subconcussive head impact exposure and white matter tract changes over a single season of youth football Radiology 2016;281(3):919–926.
          © 2017 American Academy of Neurology