By Karishma Parikh, MD, and Barry Kosofsky, MD, PhD

Dr. Parikh is Pediatric Resident at SUNY Downstate Medical Center, New York.

Dr. Kosofsky is Professor of Pediatrics and Professor of Neurology and Neuroscience at Weill Cornell Medical College.

Dr. Parikh and Dr. Kosofsky report no financial relationships relevant to this field of study.

SYNOPSIS: In this case-controlled study, PET scanning reflective of microglial activation and diffusion-tensor imaging assessing white matter integrity was performed on 14 National Football League players (four current, 10 retired) and compared to 16 matched controls, suggesting significant ongoing localized brain injury and repair along with subtle white matter changes in professional football players.

SOURCE: 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; Nov 28. doi: 10.1001/jamaneurol.2016.3764. [Epub ahead of print].

There has been tremendous clinical and public interest in identifying the long-term consequences of concussion on brain structure and function, and the possible relationship between repetitive concussive or sub-concussive head injury in contributing to the subsequent development of chronic traumatic encephalopathy (CTE). To address this question, Coughlin et al pioneered the use of high-resolution positron-emission tomographic (PET) imaging using a second-generation TPSO-targeted radiotracer, [11C]DPA-713, an indirect reflection of microglial activation, serving as a functional biomarker of ongoing brain injury and repair following concussion. Using this in vivo brain imaging approach, they found TPSO to be persistently activated in multiple temporal lobe and adjacent brain regions, despite a mean of seven years since the last self-reported concussion. Using diffusion tensor imaging (DTI) and structural MRI imaging, they additionally identified subtle alterations in white matter integrity in former NFL players compared to matched control participants.

Four active NFL players along with 10 former NFL players (defined as stopping play within the last 12 years) were recruited for this study, along with 16 control men matched for age, education, and body mass index. In addition to PET imaging and MRI, a board-certified psychiatrist performed clinical and neuropsychological testing on all participants.

There was no significant difference in clinical and demographic characteristics nor in neuropsychological performance between the NFL players and control participants.

For brain PET analysis, 12 regions of interest were selected for study: right and left hippocampus, parahippocampus, entorhinal cortex, amygdala, temporal pole, and supramarginal gyrus. FreeSurfer, an automated morphometric image analysis pipeline, was used to quantitate total cortical gray matter and total intracranial volume, data used to determine the total distribution volume (Vt) of TPSO for each of these areas, using a two-way ANOVA, with cohort (NFL players vs. controls) and genetic group (polymorphisms coding for high vs. low TPSO binding affinities) as independent fixed factors.

DTI data were analyzed utilizing an automated white matter segmentation and 3D analytic pipeline calculating both fractional anisotropy (FA) and mean diffusivity (MD) values. They studied eight predefined long cortical-subcortical white matter projection pathways hypothesized to be vulnerable to inertial brain injury: the right and left anterior, superior, and posterior corona radiata, and posterior thalamic radiation. Statistical analyses for both the morphometric and diffusion tensor data utilized a Bonferroni correction.

Participants assessed and analyzed on T1-weighted brain MRI showed no structural abnormalities and no between-group volumetric abnormalities. The Vt of TPSO was significantly elevated in the 12 NFL players as compared with 11 control participants in eight of the 12 areas analyzed, including the left and right hippocampus, left entorhinal cortex, left and right parahippocampal cortex, left and right supramarginal gyrus, and left temporal pole. There was no effect of age, race, ethnicity, body mass index, or years of education affecting these between-group differences in Vt of cortical gray matter. Among the NFL players, there was no significant difference in Vt of cortical gray matter seen between the active and former players, nor was there an effect of years in the NFL, number of NFL games played, or number, age of first, or years since last self-reported concussion.

In NFL players, DTI analyses revealed a lower FA, a potential indicator for decreased white matter integrity, in only one of the eight areas analyzed: the right posterior thalamic radiation. MD values, often found to demonstrate the inverse relationship of FA values, were higher in NFL players in only one of the eight areas analyzed: the left anterior corona radiata.

COMMENTARY

This study identifies the value of in vivo high resolution PET imaging utilizing a novel radiotracer, [11C]DPA-713, to indirectly demonstrate evidence for the persistent activation of microglia in the brains of NFL players as compared with controls. In these same subjects, DTI revealed minimal between-group differences, and neither morphometric nor neuropsychologic measures distinguished the two groups. This study provides a proof of principle for research identifying the role of microglia in activating responses in the brain following injury and during recovery, and the application of this method to study the long-term effects of concussion. Regarding the former, although PET imaging with [11C]DPA-713 is an indirect measure of microglial activation following TBI, the results reported confirm data from preclinical studies suggesting significant and ongoing changes mediated by microglial activation occur for months to years following concussive brain injury. Although it will be essential to clarify whether such changes in microglial activation are adaptive or maladaptive, this method may provide an essential starting point for clinico-neuroanatomic correlations. Regarding the latter, if validated, this method may be useful as an early functional biomarker of significant traumatic brain injury, which may be evident in the absence of structural changes, or neuropsychologic deficits. Such validation will require larger, well-controlled, longitudinal analyses, which if confirmed, could set the stage for therapeutic trials to try to prevent some of the long-term consequences of traumatic brain injury, potentially including CTE in NFL players.