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）领域亟需发掘有效的神经化学生物标志物。采用质子核磁共振（proton nuclear magnetic resonance, ¹H-NMR）光谱技术对脑脊液（cerebrospinal fluid, CSF）进行代谢组学分析，是一种高灵敏度方法，可用于揭示神经系统细胞病理状态。本研究针对ALS患者的¹H-NMR CSF代谢组学特征展开纵向队列研究：研究纳入多种临床亚型的ALS患者（n=41），每6个月进行一次连续样本采集，最长随访时长达2年；健康对照组仅在单个时间点采集样本（n=14）。研究采用偏最小二乘判别分析（partial least squares discriminant analysis）这一多变量统计方法，对比分析患者与健康对照的核磁共振光谱差异。结果显示，仅在招募与第二次样本采集间隔至少1年的患者队列中，可构建出具有显著预测效能的模型。在ALS患者中，葡萄糖、乳酸、柠檬酸以及意外发现的乙醇为区分患者与健康对照的差异代谢物，且在患者体内表达水平显著升高。研究表明，¹H-NMR技术可捕捉到与ALS相关的细胞能量利用紊乱相关的脑脊液代谢组学特征，且该特征在疾病病程更长的患者队列对比中最为显著。本次鉴定出的特异性代谢物支持ALS存在高分解代谢状态的假说，该状态可能特异性涉及线粒体功能异常。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。