Smaller Dentate Gyrus and CA2 and CA3 Volumes Are Associated with Kynurenine Metabolites in Collegiate Football Athletes

Abstract

An imbalance in kynurenine pathway metabolism is hypothesized to be associated with dysregulated glutamatergic neurotransmission, which has been proposed as a mechanism underlying the hippocampal volume loss observed in a variety of neurological disorders. Pre-clinical models suggest that the CA2-3 and dentate gyrus hippocampal subfields are particularly susceptible to excitotoxicity after experimental traumatic brain injury. We tested the hypothesis that smaller hippocampal volumes in collegiate football athletes with (n = 25) and without (n = 24) a concussion history would be most evident in the dentate gyrus and CA2-3 subfields relative to nonfootball healthy controls (n = 27). Further, we investigated whether the concentration of peripheral levels of kynurenine metabolites are altered in football athletes. Football athletes with and without a self-reported concussion history had smaller dentate gyrus ( p < 0.05, p < 0.10) and CA2-3 volumes ( p's < 0.05) relative to healthy controls. Football athletes with and without a concussion history had a trend toward lower ( p < 0.10) and significantly lower ( p < 0.05) kynurenine levels compared with healthy controls, while athletes with a concussion history had greater levels of quinolinic acid compared with athletes without a concussion history ( p < 0.05). Finally, plasma levels of 3-hydroxykynurenine inversely correlated with bilateral hippocampal volumes in football athletes with a concussion history ( p < 0.01), and left hippocampal volume was correlated with the ratio of kynurenic acid to quinolinic acid in football athletes without a concussion history ( p < 0.05). Our results raise the possibility that abnormalities of the kynurenine metabolic pathway constitute a mechanism for hippocampal volume differences in the context of sports-related brain injury.

Cumulative Effects of Prior Concussion and Primary Sport Participation on Brain Morphometry in Collegiate Athletes: A Study From the NCAA–DoD CARE Consortium

“…Rather, contact sport athletes with prior concussion had larger hippocampal volumes. Several previous studies in both retired and active athletes have reported smaller hippocampal volumes associated with more exposure or repeated concussion (16,18,22,23). Other studies, however, have reported no associations (13,19,20), while a recent study observed larger hippocampal volumes in current athletes with prior concussion relative to matched athletes without a history of prior concussion (47).…”

“…BSI-GSI, BESS, and SCAT scores were modeled using negative binomial distributions. For subcortical volumes, a priori analyses focused on bilateral thalamus, hippocampus, amygdala, and dorsal striatum (i.e., combined caudate and putamen) due to their vulnerability to brain injury (16,17,22,23,30). Linear mixed-effects (LME) models were fit to assess the effects of prior concussion, sport exposure, contact sport status, and the interaction between contact sport (yes or no) and exposure on structural measures, with visit modeled as a categorical variable to account for repeating scanning over time and participant modeled as a random effect.…”

“…There is emerging evidence to suggest that similar effects of prior concussion and contact sport participation on brain morphometry may be present in younger cohorts of active athletes, with evidence of smaller hippocampal volume and thinner cortex in contact sport athletes and mixed martial artists in relation to exposure variables, prior concussion, or baseline post-concussion symptoms (22)(23)(24)(25)(26). Nevertheless, the extent to which prior concussion and exposure to contact sport participation independently affect cortical and subcortical structure in young-adult, active athletes has not been definitively determined.…”

The kynurenine pathway: a finger in every pie

“…Specifically, we found that lower “neuroprotective indices”, i.e. the ratios of KynA/3HK and KynA/QA, were associated with reduced hippocampal volumes in individuals with MDD 48, 59 , concussed athletes with symptoms of depression 60 , and individuals with bipolar disorder (BD) 61 . Moreover, a follow-up study showed an inverse relationship between KynA/3HK and left hippocampal activity during the recall of autobiographical memories in depressed participants, indicating a link between kynurenine metabolism and hippocampal function 62 .…”

Neuropathology of mood disorders: do we see the stigmata of inflammation?

“… 59 , 60 In addition, the ratio of 3HK to KynA and/or QA to KynA in the serum was inversely correlated with hippocampal volume in both MDD and BD participants, as well as depressed football players with concussion, raising the possibility that neuroactive kynurenine metabolites may affect brain structure in the context of depression. 59 , 60 , 61 …”