Multiple sclerosis (MS) is a neurodegenerative inflammatory disease where an autoimmune response to components of the central nervous system leads to a loss of myelin and subsequent neurological deterioration. People with MS can develop primary or secondary progressive disease (PPMS, SPMS) and differentiation of the specific differences in the pathogenesis of these two courses, at the molecular level, is currently unclear. Recently, lipidomics studies using human biofluids, mainly plasma and cerebrospinal fluid, have highlighted a possible role for lipids in the initiation and progression of MS. However, there is a lack of lipidomics studies in MS on CNS tissues, such as normal-appearing white matter (NAWM), where local inflammation initially occurs. Herein, we developed an untargeted reverse phase ultra-performance liquid chromatography time of flight tandem mass spectrometry (RP-UPLC-TOF MS^E)-based workflow, in combination with multivariate and univariate statistical analysis, to assess significant differences in lipid profiles in brain NAWM from post-mortem cases of PPMS, SPMS and controls. Groups of eight control, nine PPMS and seven SPMS NAWM samples were used. Correlation analysis of the identified lipids by RP-UPLC-TOF MS^E was undertaken to remove those lipids that correlated with age, gender and post-mortem interval as confounding factors. We demonstrate that there is a significantly altered lipid profile of control cases compared with MS cases and that progressive disease, PPMS and SPMS, can be differentiated on the basis of the lipidome of NAWM with good sensitivity, specificity and prediction accuracy based on receiver operating characteristic (ROC) curve analysis. Metabolic pathway analysis revealed that the most altered lipid pathways between PPMS and SPMS were glycerophospholipid metabolism, glycerophosphatidyl inositol (GPI) anchor synthesis and linoleic acid metabolism. Further understanding of the impact of these lipid alterations described herein associated with progression will provide an increased understanding of the mechanisms underpinning progression and highlight possible new therapeutic targets.

中文翻译：

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正常出现的白色物质的脂质学UPLC-MS / MS谱可区分原发性和继发性进行性多发性硬化症。

多发性硬化症（MS）是一种神经退行性炎性疾病，其中对中枢神经系统成分的自身免疫反应导致髓磷脂的丧失和随后的神经功能恶化。MS患者可以发展为原发性或继发性进行性疾病（PPMS，SPMS），目前尚不清楚在分子水平上这两个过程的发病机理的具体差异。最近，使用人体生物流体（主要是血浆和脑脊髓液）进行的脂质组学研究突显了脂质在MS引发和进展中的可能作用。但是，在中枢神经系统组织（如正常出现的白质（NAWM））上，MS缺乏脂质组学研究，该组织最初发生局部炎症。在这里基于^E）的工作流程，结合多变量和单变量统计分析，以评估PPMS，SPMS和对照的死后病例在脑NAWM中脂质谱的显着差异。使用八个对照，九个PPMS和七个SPMS NAWM样品的组。RP-UPLC-TOF MS ^E对鉴定出的脂质的相关性分析进行了去除与年龄，性别和验尸间隔有关的脂质的混杂因素。我们证明，与MS病例相比，对照病例的脂质谱有显着改变，并且可以根据NAWM的脂质组来区分进行性疾病，PPMS和SPMS，并具有良好的敏感性，特异性和预测准确度（基于接受者的操作特征） （ROC）曲线分析。代谢途径分析显示，PPMS和SPMS之间改变最大的脂质途径是甘油磷脂代谢，甘油磷脂酰肌醇（GPI）锚合成和亚油酸代谢。