Institute of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
PLoS One. 2011 Apr 4;6(4):e17947. doi: 10.1371/journal.pone.0017947.
BACKGROUND/AIM: The changes in the cerebrospinal fluid (CSF) metabolome associated with the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) are poorly understood and earlier smaller studies have shown conflicting results. The metabolomic methodology is suitable for screening large cohorts of samples. Global metabolomics can be used for detecting changes of metabolite concentrations in samples of fluids such as CSF.
Using gas chromatography coupled to mass spectrometry (GC/TOFMS) and multivariate statistical modeling, we simultaneously studied the metabolome signature of ∼120 small metabolites in the CSF of patients with ALS, stratified according to hereditary disposition and clinical subtypes of ALS in relation to controls.
The study is the first to report data validated over two sub-sets of ALS vs. control patients for a large set of metabolites analyzed by GC/TOFMS. We find that patients with sporadic amyotrophic lateral sclerosis (SALS) have a heterogeneous metabolite signature in the cerebrospinal fluid, in some patients being almost identical to controls. However, familial amyotrophic lateral sclerosis (FALS) without superoxide dismutase-1 gene (SOD1) mutation is less heterogeneous than SALS. The metabolome of the cerebrospinal fluid of 17 ALS patients with a SOD1 gene mutation was found to form a separate homogeneous group. Analysis of metabolites revealed that glutamate and glutamine were reduced, in particular in patients with a familial predisposition. There are significant differences in the metabolite profile and composition among patients with FALS, SALS and patients carrying a mutation in the SOD1 gene suggesting that the neurodegenerative process in different subtypes of ALS may be partially dissimilar.
CONCLUSIONS/SIGNIFICANCE: Patients with a genetic predisposition to amyotrophic lateral sclerosis have a more distinct and homogeneous signature than patients with a sporadic disease.
背景/目的：与致命神经退行性疾病肌萎缩侧索硬化症（ALS）相关的脑脊液（CSF）代谢组学变化尚不清楚，早期的一些较小研究结果存在矛盾。代谢组学方法适用于筛选大量样本。全局代谢组学可用于检测 CSF 等体液样本中代谢物浓度的变化。
使用气相色谱-飞行时间质谱联用（GC/TOFMS）和多变量统计建模，我们同时研究了 ALS 患者 CSF 中约 120 种小分子代谢物的代谢组学特征，根据遗传倾向和 ALS 的临床亚型对患者进行分层，并与对照组进行比较。
该研究首次报告了通过 GC/TOFMS 分析的大量代谢物的数据集，在两个 ALS 与对照组患者子集上验证的数据。我们发现，散发性肌萎缩侧索硬化症（SALS）患者的脑脊液代谢物特征存在异质性，有些患者与对照组几乎相同。然而，无超氧化物歧化酶-1 基因突变的家族性肌萎缩侧索硬化症（FALS）比 SALS 异质性更小。我们发现，17 名携带 SOD1 基因突变的 ALS 患者的脑脊液代谢组形成了一个单独的同质组。代谢物分析表明，谷氨酸和谷氨酰胺减少，尤其是在有家族易感性的患者中。FALS、SALS 和携带 SOD1 基因突变的患者之间的代谢物谱和组成存在显著差异，这表明不同亚型的 ALS 中神经退行性过程可能部分不同。
结论/意义：具有肌萎缩侧索硬化症遗传易感性的患者比散发性疾病患者具有更明显和更同质的特征。
