Repetitive brain trauma (RBT) from participating in American football is a growing concern, with an estimated 0.41 concussions sustained per game in the National Football League [1] These repeated instances of traumatic brain injury place NFL players and other athletes participating in contact sports at risk for chronic traumatic encephalopathy (CTE), a neurodegenerative disorder characterized by accumulation of hyperphosphorylated tau. Despite the fact that all confirmed cases of CTE have had exposure to RBT, not all athletes exposed to RBT develop CTE [2]. The present study assesses the effect of degree of exposure to RBT among NFL athletes on alteration of brain metabolites reflective of traumatic brain injury. While all NFL players are at risk for RBT and concussion, the degree of risk depends strongly on the position played. Linemen have been shown to sustain the highest number of head impacts in a typical season yet are still at lower risk for concussion than players in skill positions such as running and defensive backs who typically sustain a smaller number of high-severity impacts. [1,3] We hypothesized the existence of observable neurometabolite differences between two groups of former professional football players known to be at different risks for concussion.

45 retired NFL players and 15 professional athletes (n=15, age 57+8) in non-contact sports and without a history of concussions who served as controls were recruited and scanned using magnetic resonance spectroscopy (MRS) at 3T (PRESS, TR/TR: 2000/30). Scans acquired metabolite concentrations from four brain regions of interest: anterior cingulate gyrus (ACG), posterior cingulate gyrus (PCG), and parietal white matter (PWM) as shown in Figure 1. Spectra were frequency corrected and brain concentrations of N-acetylaspartate (NAA), glutamate (Glu), creatine (Cr), glutathione (GSH), phosphocholine (PCh), and myo-inositol (mI) were measured using LCmodel. Neuropsychological evaluations were conducted for all study participants, and information was obtained related to years and position played in the NFL. Subjects were grouped according to relative risk profiles for concussion by position played in the NFL [1,4]. Offensive linemen, defensive linemen, and linebackers formed a “moderate risk” group (n=22, age 57+7) while running backs, defensive backs, and tight ends were placed in a “high risk” group (n=23, age 57+6) due to the documented differences in concussions and impact severity between these groups of players. Student t-tests were used to assess differences in metabolite concentrations between the groups.Within the PCG, the moderate-risk group showed a higher concentration of Glu and Cr when compared with controls; however, the high-risk group exhibited a significantly lower Glu concentration (p=0.008) and Cr concentration (p=0.04) in the PCG than the moderate-risk group. While other locations showed similar trends, the differences were significant only in the PCG. There were also no other significant differences between other metabolites when comparing the moderate and high risk groups or between controls and the athletes. Increased glutamate has been shown in acute traumatic brain injury and also previously reported in a smaller cohort of retired NFL players [5]. As shown in Figure 3, when glutamate levels are plotted based on player position and concussion burden described for each position [4], Glu exhibited a sharp increase followed by a linear decline with increasing concussion burden by player position. One potential mechanism for this change may be due to the excitoxicity model of Glu where Glu levels rise with concussion burden to the point whereby it begins to damage brain cells thus reducing Glu levels with more concussions. Creatine changes have also been observed in previous brain injury studies reflective of reduced cerebral energetics [5]. These changes appear to worsen with the concussion burden. Further exploration of currently undefined repetitive head injury exposure metrics as well as longitudinal studies will help to determine the primary determinant that may relate to the development of CTE.Position played in the NFL dictates the frequency and severity of head impacts and concussions sustained over the course of a career. By grouping NFL players according to concussion risk, we were able to demonstrate significant changes in Glu and Cr for those NFL players at highest risk for concussion during their careers.