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疾病，常被误诊为精神疾病。因此，CFS的诊断是非常有争议的。CFS特异性生物标志物的发现，可以区分疾病与表型相似的精神疾病，如重度抑郁症（MDD），因此可能产生深远的影响，不仅对疾病的一般感知和管理，而且对客观诊断测试的发展，识别新的治疗靶点，以及推进CFS的科学理解。最近，申请人在15名CFS患者与15名MDD患者和13名健康对照中使用先进的磁共振神经成像技术和一系列标准化临床评估，发现了强有力的实验证据，包括活组织中最丰富的抗氧化剂谷胱甘肽（GSH）平均不足36%，脑室脑脊液（CSF）乳酸盐增加，与对照组相比，局部脑血流量（rCBF）减少，这表明氧化应激增加是CFS的病理生理学模型。然而，虽然非常有希望和内在一致性，CFS的氧化应激假说的有效性和特异性仍然不确定，因为（a）研究的基本结果尚未被复制，（B）与对照组相比，在MDD中发现了相同类型的异常。另一方面，通过比较揭示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，可能限制了他们的试点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局限性，并试图客观区分CFS和MDD -一个艰巨的和持续的挑战-研究人员建议：（1）在更大的队列中复制结果， 他们的初步神经影像学研究表明CFS的氧化应激假说;（2）通过测量所有受试者的血浆、尿液和CSF样本中几种已建立的氧化应激标志物来扩展模型的支持和证据基础;（3）将所得客观结果测量与所有受试者的总体健康和功能障碍的临床指标相关联;（4）尝试通过基于每种疾病独特的临床变量的分层或分型技术来降低CFS和MDD组中固有的临床异质性，然后比较所得亚组之间的结果测量。期望的是，这种方法将确定CFS和MDD患者的亚组，其中存在显著的结果测量差异，可以客观区分这两种疾病，从而将结果测量建立为真正的疾病生物标志物，并支持氧化应激作为CFS的有效和特定的病理生理学模型。

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.