Imaging of Glial Cell Activation and White Matter Integrity in Brains of Active and Recently Retired National Football League Players

Abstract

Importance: Microglia, the resident immune cells of the central nervous system, play an important role in the brain's response to injury and neurodegenerative processes. It has been proposed that prolonged microglial activation occurs after single and repeated traumatic brain injury, possibly through sports-related concussive and subconcussive injuries. Limited in vivo brain imaging studies months to years after individuals experience a single moderate to severe traumatic brain injury suggest widespread persistent microglial activation, but there has been little study of persistent glial cell activity in brains of athletes with sports-related traumatic brain injury.

Objective: To measure translocator protein 18 kDa (TSPO), a marker of activated glial cell response, in a cohort of National Football League (NFL) players and control participants, and to report measures of white matter integrity.

Design, setting, and participants: This cross-sectional, case-control study included young active (n = 4) or former (n = 10) NFL players recruited from across the United States, and 16 age-, sex-, highest educational level-, and body mass index-matched control participants. This study was conducted at an academic research institution in Baltimore, Maryland, from January 29, 2015, to February 18, 2016.

Main outcomes and measures: Positron emission tomography-based regional measures of TSPO using [11C]DPA-713, diffusion tensor imaging measures of regional white matter integrity, regional volumes on structural magnetic resonance imaging, and neuropsychological performance.

Results: The mean (SD) ages of the 14 NFL participants and 16 control participants were 31.3 (6.1) years and 27.6 (4.9) years, respectively. Players reported a mean (SD) of 7.0 (6.4) years (range, 1-21 years) since the last self-reported concussion. Using [11C]DPA-713 positron emission tomographic data from 12 active or former NFL players and 11 matched control participants, the NFL players showed higher total distribution volume in 8 of the 12 brain regions examined (P < .004). We also observed limited change in white matter fractional anisotropy and mean diffusivity in 13 players compared with 15 control participants. In contrast, these young players did not differ from control participants in regional brain volumes or in neuropsychological performance.

Conclusions and relevance: The results suggest that localized brain injury and repair, indicated by higher TSPO signal and white matter changes, may be associated with NFL play. Further study is needed to confirm these findings and to determine whether TSPO signal and white matter changes in young NFL athletes are related to later onset of neuropsychiatric symptoms.

Figure 1. Scatter Plots of Regional Total Distribution Volume Values in Active and Recently Retired National Football League (NFL) Players and Control Individuals Injected With [¹¹C]DPA-713

Individual total distribution volume data from NFL and control cohorts are shown along with mean (SD) values. Using 2-way analysis of variance with genetic group (C/C vs C/T) and cohort (NFL vs control) as independent fixed factors, regional total distribution volume values in 8 of the 6 right and left side regions (12 total regions) were significantly higher than those of control participants. The threshold for significance after accounting for multiple comparisons was P < .06/12 = .004. ^aP < .004. ^bP < .001.

Figure 2. Former National Football League (NFL) Players Demonstrate Higher Binding of [¹¹C]DPA-713 Across Many Brain Regions Compared With the Brains of Age-, Sex-, Education-, and Body Mass Index-Matched Control Individuals

A, Mean parametric [¹¹C]DPA-713 total distribution volume (V_T) images displayed in groups of 3 views (left to right: axial, sagittal, and coronal) from 6 controls (left 3 views) and 5 NFL players (right 3 views) with C/T rs6971 genotype are presented. B, Mean parametric [¹¹C]DPA-713 V_T images from 5 controls (left 3 views) and 7 NFL players (right 3 views) with C/C rs6971 genotype are presented.