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Prospective study of the effects of sport-related concussion on serum kynurenine pathway metabolites
Brain, Behavior, and Immunity ( IF 8.8 ) Pub Date : 2020-07-01 , DOI: 10.1016/j.bbi.2020.03.002
Timothy B Meier 1 , Morgan E Nitta 2 , T Kent Teague 3 , Lindsay D Nelson 4 , Michael A McCrea 4 , Jonathan Savitz 5
Affiliation  

Reports of neurodegenerative and psychiatric disease in former athletes have increased public concern about the acute and chronic effects of sport-related concussions (SRC). The biological factors underlying individual differences in the psychiatric sequalae of SRC and their role in potential long-term negative outcomes have not been determined. One understudied biological consequence of the known inflammatory response to concussion is the activation of a key immunoregulatory pathway, the kynurenine pathway (KP). Activation of the KP produces several neuroactive metabolites that have been associated with psychiatric and neurodegenerative diseases. We tested the hypothesis that SRC results in an elevation of serum KP metabolites with neurotoxic properties (quinolinic acid [QuinA], 3-hydroxykynurenine [3HK]) together with a reduction in the neuroprotective metabolite kynurenic acid (KynA), and that these metabolites would predict post-concussion psychological symptoms. Additionally, because brain injury is thought to prime the immune system, a secondary goal was to test the hypothesis that athletes with acute SRC and a history of prior SRC would have elevated neurotoxic relative to neuroprotective KP metabolites compared to athletes that were concussed for the first time. High school and collegiate football players (N=1,136) were enrolled at a preseason baseline visit that included clinical testing and blood specimen collection. Athletes that suffered a SRC (N=59) completed follow-up visits within 6-hours (early-acute), at 24-48 hours (late-acute) and at 8, 15, and 45 days post-injury. Uninjured contact sport (CC; N=54) and non-contact sport athletes completed similar visits and served as controls (NCC; N=30). SRC athletes had significantly elevated psychological symptoms, assessed using the Brief Symptom Inventory-18 (BSI), acutely following injury relative to both control groups. There was a group-by-visit interaction on the ratio of KynA to 3HK in serum, a neuroprotective index, with elevated KynA/3HK in athletes with SRC at the early-acute visit relative to later visits. Importantly, athletes with greater elevation in this neuroprotective index at the early-acute visit reported fewer depressive symptoms at the late-acute visit. Finally, SRC athletes with prior concussion had significantly lower serum KynA/QuinA at all visits compared to SRC athletes with no prior concussion, an effect driven by elevated QuinA in SRC athletes with prior concussion. These results suggest that early-acute activation of the KynA branch of the KP may protect against the development of depressive symptoms following concussion. Furthermore, they highlight the potential of serum QuinA as a biomarker for repetitive head injury and provide insight into possible mechanisms linking prior concussion with subsequent injury.

中文翻译:

运动相关脑震荡对血清犬尿氨酸通路代谢产物影响的前瞻性研究

前运动员神经退行性疾病和精神疾病的报告增加了公众对运动相关脑震荡 (SRC) 的急性和慢性影响的关注。SRC 精神病后遗症的个体差异背后的生物学因素及其在潜在长期负面结果中的作用尚未确定。已知的脑震荡炎症反应的一个未充分研究的生物学后果是关键免疫调节途径犬尿氨酸途径 (KP) 的激活。KP 的激活会产生几种与精神疾病和神经退行性疾病有关的神经活性代谢物。我们检验了 SRC 导致具有神经毒性的血清 KP 代谢物(喹啉酸 [QuinA]、3-羟基犬尿氨酸 [3HK]) 以及神经保护代谢物犬尿氨酸 (KynA) 的减少,并且这些代谢物可以预测脑震荡后的心理症状。此外,由于脑损伤被认为可以启动免疫系统,因此次要目标是检验以下假设:与第一次脑震荡的运动员相比,患有急性 SRC 和既往 SRC 病史的运动员相对于神经保护性 KP 代谢物的神经毒性升高时间。高中和大学橄榄球运动员 (N=1,136) 参加了季前基线访问,包括临床测试和血液样本采集。遭受 SRC 的运动员 (N=59) 在受伤后 6 小时(早期急性期)、24-48 小时(晚期急性期)和 8、15 和 45 天后完成了随访。无伤身体接触运动(CC;N=54) 和非接触运动运动员完成了类似的访问并作为对照 (NCC; N=30)。SRC 运动员的心理症状显着升高,使用简要症状量表-18 (BSI) 评估,与两个对照组相比,在受伤后急性。血清中 KynA 与 3HK 的比率(一种神经保护指数)存在逐组交互作用,SRC 运动员的 KynA/3HK 在早期急性访视时相对于后期访视时升高。重要的是,在早期急性访视时该神经保护指数更高的运动员在晚期急性访视时报告的抑郁症状较少。最后,与没有先前脑震荡的 SRC 运动员相比,先前有脑震荡的 SRC 运动员在所有访问中的血清 KynA/QuinA 都显着降低,这是由先前有脑震荡的 SRC 运动员的 QuinA 升高所驱动的。这些结果表明,KP 的 KynA 分支的早期急性激活可以防止脑震荡后抑郁症状的发展。此外,他们强调了血清 QuinA 作为重复性头部损伤的生物标志物的潜力,并提供了对将先前脑震荡与随后损伤联系起来的可能机制的见解。
更新日期:2020-07-01
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