Neuroinflammation and brain atrophy in former NFL players: An in vivo multimodal imaging pilot study

Abstract

There are growing concerns about potential delayed, neuropsychiatric consequences (e.g, cognitive decline, mood or anxiety disorders) of sports-related traumatic brain injury (TBI). Autopsy studies of brains from a limited number of former athletes have described characteristic, pathologic changes of chronic traumatic encephalopathy (CTE) leading to questions about the relationship between these pathologic and the neuropsychiatric disturbances seen in former athletes. Research in this area will depend on in vivo methods that characterize molecular changes in the brain, linking CTE and other sports-related pathologies with delayed emergence of neuropsychiatric symptoms. In this pilot project we studied former National Football League (NFL) players using new neuroimaging techniques and clinical measures of cognitive functioning. We hypothesized that former NFL players would show molecular and structural changes in medial temporal and parietal lobe structures as well as specific cognitive deficits, namely those of verbal learning and memory. We observed a significant increase in binding of [(11)C]DPA-713 to the translocator protein (TSPO), a marker of brain injury and repair, in several brain regions, such as the supramarginal gyrus and right amygdala, in 9 former NFL players compared to 9 age-matched, healthy controls. We also observed significant atrophy of the right hippocampus. Finally, we report that these same former players had varied performance on a test of verbal learning and memory, suggesting that these molecular and pathologic changes may play a role in cognitive decline. These results suggest that localized brain injury and repair, indicated by increased [(11)C]DPA-713 binding to TSPO, may be linked to history of NFL play. [(11)C]DPA-713 PET is a promising new tool that can be used in future study design to examine further the relationship between TSPO expression in brain injury and repair, selective regional brain atrophy, and the potential link to deficits in verbal learning and memory after NFL play.

Keywords: Microglia; Mild traumatic brain injury; Molecular neuroimaging; Neuroinflammation; Translocator protein.

Fig. 1

Individuals of C/C genotype demonstrate increased binding of [¹¹C]DPA-713 over those with C/T genotype. When compared with individuals of the same genotype (blue = C/C; black = C/T) the former NFL Players (NFL) had higher binding of [¹¹C]DPA-713 than Elderly Healthy Controls (EHC) across all regions tested. Statistical significance (P -values) of the effect of NFL play on regional [¹¹C]DPA-713 V_T were generated using linear mixed model analysis with P < 0.05 indicated with *. Results meeting more stringent threshold of significance (accounting for multiple comparisons) where P < 0.004 are indicated with **. V_T = Total distribution volume within the region labeled. Data given as mean ± standard deviation (SD).

Fig. 2

Former NFL players demonstrate increased binding of [¹¹C]DPA-713, reported as total distribution volume (V_T) across many brain regions compared to binding of [¹¹C]DPA-713 in the brains of elderly healthy controls. Parametric [¹¹C]DPA-713 V_T images from one former NFL player and one age- and rs6971 genotype-matched healthy individual are presented for comparison.

Fig. 3

Regional V_T normalized by the overall cortical gray matter V_T, defined as _GMV_T, was generated for each of the 12 regions of interest. Regional [¹¹C]DPA-713 _GMV_T in former NFL players (NFL) compared to _GMV_T of Elderly Healthy Controls (EHC) revealed little difference in binding between the two groups except for in the right supramarginal gyrus, where _GMV_T was greatly increased in former NFL players (mean ± SD: 1.13 ± 0.03) over that of EHCs (1.07 ± 0.06).