Imaging Biomarker Flags Brain Inflammation in NFL Players

Pauline Anderson

December 02, 2016

Active or recently retired National Football League (NFL) players with a history of concussion have higher levels of an inflammatory marker in the brain compared with nonplayers, although there are no significant differences in cognition or widespread differences in white matter integrity, a new study has found.

The players had significantly increased expression of the translocator protein 18kDa (TSPO) in various brain regions on positron emission tomography (PET).

Normally expressed at low levels in brain tissue, TSPO is increased in expression by activated microglia. Microglia are resident immune cells of the central nervous system.

The results of the study, published online November 28 in JAMA Neurology, suggest that increased TSPO expression in glia may precede the development of mental or physical disorders. And as the study used the radiotracer [11C] DPA-713 with PET imaging, the findings also support using PET-based imaging to assess brain injury and brain inflammation in vivo.

"TSPO PET enables us to measure the activity of microglia, which are involved in neuroinflammation, directly in the brains of affected patients," Martin G. Pomper, MD, PhD, Henry N. Wagner Jr. Professor of Radiology, Johns Hopkins University, Baltimore, Maryland, told Medscape Medical News.

The study included 14 NFL players (4 active and 10 recently retired), mean age of 31.3 years, and 16 controls matched for age, sex, education, and body mass index (BMI). The retired players ended their professional career not more than 12 years before study participation.

Concussion History

All players had sustained at least one concussion (some had had several). They reported a mean of 7.0 years since their last concussion. None of the controls had experienced a concussion.

Of the 14 players, 1 scored a 14 on the Hamilton Depression Rating Scale, consistent with moderate depressive symptoms. All others were without depressive symptoms.

Neuropsychological test scores did not differ between the 13 players and 13 controls with available data.

The researchers also found no evidence of structural abnormalities on MRI and no significant between-group differences on volumetric analyses.

Age, race/ethnicity, BMI and years of education had no significant effect on PET radiotracer binding (total distribution volume) in gray matter.

But the PET tracer imaging showed that values between 12 NFL players and 11 controls differed significantly in the left and right hippocampus, left entorhinal cortex, left and right parahippocampal cortex, left and right supramarginal gyrus, and left temporal pole.

Among players, there was no effect of actively playing (vs being a former player), duration of retirement, number of years playing in the NFL, number of games played, number of concussions, age at first concussion, or years since last concussion.

An earlier study by the same researchers had similar findings in older players. But Dr Pomper wanted to study younger players who were closer to actual play because, he said, "findings in older players might have been confounded by having cerebrovascular disease, which you tend to get when you're older."

The collective results from this and the previous study "suggest potential vulnerability of the supramarginal gyrus to injury from TBI [traumatic brain injury] in football that warrants further investigation," write the authors.

The higher TSPO signal found in the left temporal pole and mesial temporal lobe structures of young NFL players compared with controls "provides in vivo evidence of hypothesized vulnerability of these regions to biomechanical forces occurred through sports-related TBI," they said.

Diffusion tensor imaging data were available for 13 NFL players and 15 controls. Functional anisotropy values were significantly lower in the right posterior thalamic radiation of NFL players compared with controls. Mean diffusivity values in the left anterior corona radiata were significantly higher in the NFL players than in controls.

The radiotracer "enables you to measure something objectively in the brain, so you will be able to basically put a number on what's going on in terms of inflammation," commented Dr Pomper.

"It could also be a predictive biomarker," he added. The study participants were relatively young with little neuropsychological impairment.

"The individuals who have positive scans could be those who are primed in the future to develop neuropsychological findings."

A longitudinal study, which could be the next step for this research team, "could show what sort of changes happen over time," said Dr Pomper.

He noted that such a study would illustrate injury but also repair, as microglia can also be reparative.

"The bottom line is that this procedure gives you a quantitative measure; it could be a prognostic marker; and it could be an early marker for later development for neuropsychological problems."

This technique could potentially be used for therapeutic monitoring, said Dr Pomper. "In other words, one could scan patients at baseline, give them an anti-inflammatory therapy, and then follow them using this imaging test to see if they no longer have elevated microglial activation, which could indicate that the therapy is working."

However, various anti-inflammatory treatments have been tried in other neuropsychiatric disorders that are characterized by elevated TSPO levels "without really too much effect," said Dr Pomper.

"Safe and effective therapy, perhaps used earlier in the cascade of events that follow TBI, is badly needed."

Important Advancement

The study was accompanied by an editorial from Kristina G. Witcher, BA, and Jonathan P. Godbout, PhD, Department of Neuroscience, Center for Brain and Spinal Cord Repair, The Ohio State University Wexner Medical Center, Columbus.

According to their editorial, this new study is "relevant" because it supports the conclusion that PET-based imaging can be used to assess brain injury and brain inflammation in vivo and supports the idea that PET-based imaging can be used to detect brain inflammation in current players before the development of any significant health problems.

"Thus, PET detection of TSPO may serve as a biomarker for early detection of brain inflammation," which is "an important advancement," they said. However, longitudinal studies are required to determine whether increased TSPO binding in the brain is predictive of later onset of neuropsychiatric symptoms.

With a potential in vivo biomarker for early detection of inflammatory-related glial changes, "one can test whether therapeutic interventions reverse or attenuate brain inflammation," they write.

As neuropsychiatric complications and neurodegenerative diseases develop later in life, "there is a window of opportunity for anti-inflammatory intervention if TSPO is predictive of TBI-related complications."

This study was supported by the National Association for Research on Schizophrenia and Depression, the Alexander Wilson Schweizer Fellowship, a grant from the National Institute of Environmental Health Sciences, and GE/NFL Head Health Challenge I. Dr Pomper and the editorial writers have disclosed no relevant financial relationships.

JAMA Neurol. Published online November 28, 2016. Abstract, Editorial

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