The longitudinal cerebrospinal fluid metabolomic profile of amyotrophic lateral sclerosis

Neurochemical biomarkers are urgently sought in ALS. Metabolomic analysis of cerebrospinal fluid (CSF) using proton nuclear magnetic resonance (¹H-NMR) spectroscopy is a highly sensitive method capable of revealing nervous system cellular pathology. The ¹H-NMR CSF metabolomic signature of ALS was sought in a longitudinal cohort. Six-monthly serial collection was performed in ALS patients across a range of clinical sub-types (<i>n = </i>41) for up to two years, and in healthy controls at a single time-point (<i>n = </i>14). A multivariate statistical approach, partial least squares discriminant analysis, was used to determine differences between the NMR spectra from patients and controls. Significantly predictive models were found using those patients with at least one year's interval between recruitment and the second sample. Glucose, lactate, citric acid and, unexpectedly, ethanol were the discriminating metabolites elevated in ALS. It is concluded that ¹H-NMR captured the CSF metabolomic signature associated with derangements in cellular energy utilization connected with ALS, and was most prominent in comparisons using patients with longer disease duration. The specific metabolites identified support the concept of a hypercatabolic state, possibly involving mitochondrial dysfunction specifically. Endogenous ethanol in the CSF may be an unrecognized novel marker of neuronal tissue injury in ALS.

肌萎缩侧索硬化症（Amyotrophic Lateral Sclerosis, ALS）亟需发掘特异性神经化学生物标志物。利用质子核磁共振（proton nuclear magnetic resonance, ¹H-NMR）波谱技术对脑脊液（cerebrospinal fluid, CSF）开展代谢组学分析，是一种可揭示神经系统细胞病理状态的高灵敏度方法。本研究在纵向队列中探寻ALS的¹H-NMR CSF代谢组学特征：针对41例涵盖不同临床亚型的ALS患者，开展了长达两年的每六个月一次的连续样本采集；同时对14名健康对照者仅采集单次样本。采用偏最小二乘判别分析（partial least squares discriminant analysis, PLS-DA）这一多变量统计方法，对比患者与健康对照者的核磁共振波谱差异。结果显示，在招募后至少间隔一年采集第二次样本的患者亚组中，可获得具有显著预测效能的模型。葡萄糖、乳酸、柠檬酸以及意外发现的乙醇，是ALS患者体内水平升高的差异代谢物。研究结论表明，¹H-NMR可捕捉到与ALS相关的细胞能量利用紊乱相关的CSF代谢组学特征，且在疾病病程更长的患者亚组对比中该特征最为显著。本研究鉴定出的特异性代谢物，支持ALS存在高分解代谢状态的观点，且该状态可能特异性地与线粒体功能障碍相关。脑脊液中的内源性乙醇，或可成为ALS神经元组织损伤的一种未被认知的新型生物标志物。