Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Level 3, West Wing, Headley Way, Oxford, OX3 9DU, UK.
Department of Neurology, Medical University of Lodz, Lodz, Poland.
Acta Neuropathol Commun. 2017 Dec 6;5(1):95. doi: 10.1186/s40478-017-0495-8.
The overlapping clinical features of relapsing remitting multiple sclerosis (RRMS), aquaporin-4 (AQP4)-antibody (Ab) neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein (MOG)-Ab disease mean that detection of disease specific serum antibodies is the gold standard in diagnostics. However, antibody levels are not prognostic and may become undetectable after treatment or during remission. Therefore, there is still a need to discover antibody-independent biomarkers. We sought to discover whether plasma metabolic profiling could provide biomarkers of these three diseases and explore if the metabolic differences are independent of antibody titre. Plasma samples from 108 patients (34 RRMS, 54 AQP4-Ab NMOSD, and 20 MOG-Ab disease) were analysed by nuclear magnetic resonance spectroscopy followed by lipoprotein profiling. Orthogonal partial-least squares discriminatory analysis (OPLS-DA) was used to identify significant differences in the plasma metabolite concentrations and produce models (mathematical algorithms) capable of identifying these diseases. In all instances, the models were highly discriminatory, with a distinct metabolite pattern identified for each disease. In addition, OPLS-DA identified AQP4-Ab NMOSD patient samples with low/undetectable antibody levels with an accuracy of 92%. The AQP4-Ab NMOSD metabolic profile was characterised by decreased levels of scyllo-inositol and small high density lipoprotein particles along with an increase in large low density lipoprotein particles relative to both RRMS and MOG-Ab disease. RRMS plasma exhibited increased histidine and glucose, along with decreased lactate, alanine, and large high density lipoproteins while MOG-Ab disease plasma was defined by increases in formate and leucine coupled with decreased myo-inositol. Despite overlap in clinical measures in these three diseases, the distinct plasma metabolic patterns support their distinct serological profiles and confirm that these conditions are indeed different at a molecular level. The metabolites identified provide a molecular signature of each condition which is independent of antibody titre and EDSS, with potential use for disease monitoring and diagnosis.
复发缓解型多发性硬化症（RRMS）、水通道蛋白 4（AQP4）-抗体（Ab）视神经脊髓炎谱系障碍（NMOSD）和髓鞘少突胶质细胞糖蛋白（MOG）-Ab 病的临床表现重叠，这意味着检测疾病特异性血清抗体是诊断的金标准。然而，抗体水平与预后无关，并且在治疗后或缓解期可能无法检测到。因此，仍然需要发现抗体独立的生物标志物。我们试图发现血浆代谢组学是否可以为这三种疾病提供生物标志物，并探讨代谢差异是否独立于抗体滴度。通过核磁共振光谱分析对 108 名患者（34 名 RRMS、54 名 AQP4-Ab NMOSD 和 20 名 MOG-Ab 疾病）的血浆样本进行了分析，并进行了脂蛋白谱分析。正交偏最小二乘法判别分析（OPLS-DA）用于鉴定血浆代谢物浓度的显著差异，并产生能够识别这些疾病的模型（数学算法）。在所有情况下，这些模型都具有高度的辨别力，为每种疾病确定了独特的代谢物模式。此外，OPLS-DA 以 92%的准确率识别出 AQP4-Ab NMOSD 患者样本中抗体水平低/无法检测的情况。AQP4-Ab NMOSD 的代谢特征是 scyllo-肌醇和小高密度脂蛋白颗粒的水平降低，而大低密度脂蛋白颗粒的水平相对于 RRMS 和 MOG-Ab 疾病增加。RRMS 血浆表现出组氨酸和葡萄糖增加，同时乳酸、丙氨酸和大高密度脂蛋白减少，而 MOG-Ab 疾病血浆的特征是甲酸和亮氨酸增加，肌醇减少。尽管这三种疾病的临床指标存在重叠，但明显的血浆代谢模式支持其独特的血清学特征，并证实这些疾病在分子水平上确实不同。鉴定出的代谢物提供了每种疾病的分子特征，与抗体滴度和 EDSS 无关，具有用于疾病监测和诊断的潜力。
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