Specificity and Validity of Oxidative Stress Model of Chronic Fatigue Syndrome

描述(申请人提供)：慢性疲劳综合征(CFS)是一种复杂的多系统障碍，经常被误诊为精神疾病。因此，CFS的诊断极具争议性。因此，发现CFS特异的生物标志物，可以将这种疾病与表型相似的精神疾病，如严重抑郁障碍(MDD)区分开来，可能会产生深远的影响，不仅对于如何普遍认识和管理这种疾病，而且对于开发客观的诊断测试，确定新的治疗靶点，以及促进对CFS的科学理解都有深远的影响。最近，申请者利用先进的磁共振神经成像技术和标准化的临床评估组合，在15名CFS患者、15名MDD患者和13名健康对照组中发现了强有力的实验证据，包括活组织中含量最丰富的抗氧化剂谷胱甘肽(GSH)平均缺乏36%，脑室脑脊液(CSF)乳酸增加，局部脑血流量(RCBF)减少，这表明氧化应激是CFS的病理生理模型。然而，尽管这一氧化应激假说在本质上是非常有希望和一致的，但对于CFS的有效性和特异性仍然不确定，因为(A)这项研究的基本发现尚未被重复，以及(B)与对照组相比，MDD被发现了相同类型的异常。另一方面，通过比较发现CFS和MDD之间的趋势水平差异，研究人员假设，有限的样本量，加上这两种疾病固有的临床异质性，可能限制了他们的先导研究检测两种疾病之间潜在差异的能力。因此，为了解决这一潜在的限制，并试图客观区分CFS和MDD--这是一项艰巨而持续的挑战--研究人员建议：(1)在更大的队列中复制以下结果 他们的先导性神经成像研究提出了CFS的氧化应激假说；(2)通过测量所有受试者血浆、尿液和脑脊液样本中几个公认的氧化应激标志物，扩大了对该模型的支持和证据基础；(3)将得出的客观结果指标与所有受试者的总体健康和功能残疾的临床指标相关联；(4)试图通过基于每个疾病特有的临床变量的分层或分型技术，降低CFS和MDD组固有的临床异质性，然后比较结果亚组之间的结果指标。人们期望这种方法将识别CFS和MDD患者亚组之间存在显著差异的结果指标，从而能够客观地区分这两种疾病，从而将结果指标确立为真正的疾病生物标记物，并支持氧化应激作为CFS的有效和特异的病理生理模型。

DESCRIPTION (provided by applicant): Chronic fatigue syndrome (CFS) is a complex multi-system disorder, which is often misdiagnosed as a psychiatric illness. As a result, the diagnosis of CFS is highly controversial. Discovery of CFS-specific biomarkers that can differentiate the disorder from phenotypically similar psychiatric conditions, such as major depressive disorder (MDD), could thus have a profound impact, not only for how the disorder is generally perceived and managed, but also for the development of objective diagnostic tests, for identification of new therapeutic targets, as well as for advancing scientific understanding of CFS. Recently, using advanced magnetic resonance neuroimaging techniques and a standardized battery of clinical assessments in 15 patients with CFS with those in 15 patients with MDD and in 13 healthy controls, the applicants discovered strong experimental evidence, including a mean deficit of 36% in the most abundant antioxidant in living tissue, glutathione (GSH), increased ventricular cerebrospinal fluid (CSF) lactate, and decreased regional cerebral blood flow (rCBF) compared to controls, which suggested increased oxidative stress as a pathophysiological model of CFS. However, while highly promising and intrinsically consistent, both the validity and the specificity of this oxidative stress hypothesis for CFS remain uncertain, as (a) the essential findings of the study have yet to be replicated, and (b) the same types of abnormalities were found in MDD compared to controls. On the other hand, with comparisons revealing trend-level differences between CFS and MDD, the investigators hypothesized that limited sample size, coupled with the inherent clinical heterogeneity of the two disorders, likely limited the power of their pilot study to detect potential differences between the two disorders. Therefore, to address this potential limitation and to attempt objective differentiation of CFS and MDD - a daunting and continuing challenge - the investigators propose: (1) to replicate in larger cohorts the results of their pilot neuroimaging study that suggested the oxidative stress hypothesis of CFS; (2) to extend the support and evidence base for the model through measurements of several established markers of oxidative stress in plasma, urine and CSF samples from all the subjects; (3) to correlate the resulting objective outcome measures with clinical indices of overall health and functional disability in all subjects; and (4) to attempt to decrease the inherent clinical heterogeneity in both the CFS and MDD groups through stratification or subtyping techniques based on clinical variables that are unique to each disorder, and then to compare the outcome measures between the resulting subgroups. The expectation is that this approach would identify subgroups of CFS and MDD patients between which significant differences in outcome measures exist that can enable objective differentiation of the two disorders, thereby establishing the outcome measures as bona fide diseases biomarkers, and supporting oxidative stress as a valid and specific pathophysiological model for CFS.