Supplementary Material for: Magnetic Resonance Spectroscopy following Mild Traumatic Brain Injury: A Systematic Review and Meta-Analysis on the Potential to Detect Posttraumatic Neurodegeneration

Introduction: Traumatic brain injury (TBI) is the most relevant external risk factor for dementia and a major global health burden. Mild TBI (mTBI) contributes to up to 90% of all TBIs, and the classification “mild” often misrepresents the patient’s burden who suffer from neuropsychiatric long-term sequelae. Magnetic resonance spectroscopy (MRS) allows in vivo detection of compromised brain metabolism although it is not routinely used after TBI. Objective: Thus, we performed a systematic review and meta-analysis to elucidate if MRS has the potential to identify changes in brain metabolism in adult patients after a single mTBI with a negative routine brain scan (CCT and/or MRI scan) compared to aged- and sex-matched healthy controls (HC) during the acute or subacute postinjury phase (≤90 days after mTBI). Methods: A comprehensive literature search was conducted from the first edition of electronic databases until January 31, 2020. Group analyses were performed per metabolite using a random-effects model. Results: Four and 2 out of 5,417 articles met the inclusion criteria for the meta-analysis and systematic review, respectively. For the meta-analysis, 50 mTBI patients and 51 HC with a mean age of 31 and 30 years, respectively, were scanned using N-acetyl-aspartate (NAA), a marker for neuronal integrity. Glutamate (Glu), a marker for disturbed brain metabolism, choline (Cho), a marker for increased cell membrane turnover, and creatine (Cr) were used in 2 out of the 4 included articles. Regions of interests were the frontal lobe, the white matter around 1 cm above the lateral ventricles, or the whole brain. NAA was decreased in patients compared to HC with an effect size (ES) of –0.49 (95% CI –1.08 to 0.09), primarily measured in the frontal lobe. Glu was increased in the white matter in 22 mTBI patients compared to 22 HC (ES 0.79; 95% CI 0.17–1.41). Cho was decreased in 31 mTBI patients compared to 31 HC (ES –0.31; 95% CI –0.81 to 0.19). Cr was contradictory and, therefore, potentially not suitable as a reference marker after mTBI. Conclusions: MRS pinpoints changes in posttraumatic brain metabolism that correlate with cognitive dysfunction and, thus, might possibly help to detect mTBI patients at risk for unfavorable outcome or posttraumatic neurodegeneration early.引言：创伤性脑损伤（Traumatic brain injury, TBI）是引发痴呆最关键的外部风险因素，亦是一项重大的全球健康负担。轻度创伤性脑损伤（mild TBI, mTBI）占所有TBI病例的90%，但“轻度”这一分类往往无法准确反映存在长期神经精神后遗症患者的实际病痛负担。磁共振波谱（Magnetic resonance spectroscopy, MRS）可实现体内脑代谢受损状态的无创检测，尽管目前创伤性脑损伤术后并未常规开展该项检查。 研究目的：为此，本研究开展了一项系统综述与荟萃分析，旨在明确：在伤后急性或亚急性阶段（轻度创伤性脑损伤后≤90天），对于常规颅脑扫描（计算机断层扫描CCT和/或磁共振MRI扫描）结果为阴性的成年单发轻度创伤性脑损伤患者，磁共振波谱是否能够识别其与年龄、性别匹配的健康对照（healthy controls, HC）之间的脑代谢差异。 研究方法：本研究于2020年1月31日前，全面检索了各电子数据库自建库以来的相关文献。采用随机效应模型针对每种代谢物进行组间统计分析。 研究结果：在5417篇检索文献中，分别有4篇和2篇文献符合荟萃分析与系统综述的纳入标准。本次荟萃分析共纳入50例轻度创伤性脑损伤患者与51例健康对照，平均年龄分别为31岁与30岁，所有受试者均接受了N-乙酰天门冬氨酸（N-acetyl-aspartate, NAA）的扫描检测——该物质是神经元完整性的特异性标志物。纳入的4篇文献中有2篇同时检测了谷氨酸（Glutamate, Glu，脑代谢紊乱标志物）、胆碱（choline, Cho，细胞膜转运增加标志物）与肌酸（creatine, Cr）。感兴趣区域包括额叶、侧脑室上方约1cm处的白质，或全脑。与健康对照相比，患者的NAA水平降低，效应量（effect size, ES）为–0.49（95%置信区间CI：–1.08至0.09），该结果主要基于额叶区域的检测。在22例轻度创伤性脑损伤患者与22例健康对照的白质检测中，谷氨酸水平升高（效应量0.79；95%置信区间CI：0.17至1.41）。31例轻度创伤性脑损伤患者与31例健康对照的胆碱水平降低（效应量–0.31；95%置信区间CI：–0.81至0.19）。肌酸的检测结果存在矛盾，因此其或不适用于轻度创伤性脑损伤后的参考代谢标志物。 研究结论：磁共振波谱可精准定位创伤后脑代谢的特征性变化，该变化与认知功能障碍密切相关，因此或可帮助早期识别存在不良预后或创伤后神经退行性变风险的轻度创伤性脑损伤患者。