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，慢性疲劳综合症的诊断是非常有争议的。因此，发现CFS特异性生物标志物，可以将该疾病与表型相似的精神疾病（如重度抑郁症（MDD））区分开来，可能会产生深远的影响，不仅对该疾病的普遍认知和管理方式，而且对开发客观诊断测试、确定新的治疗靶点，以及推进对CFS的科学理解。最近，利用先进的磁共振神经成像技术和标准化的临床评估，对15名CFS患者、15名MDD患者和13名健康对照者进行了临床评估，申请人发现了强有力的实验证据，包括与对照组相比，活组织中最丰富的抗氧化剂谷胱甘肽（GSH）平均缺失36%，脑脊液（CSF）乳酸增加，区域脑血流量（rCBF）减少。提示氧化应激升高是CFS的病理生理模型。然而，尽管这种氧化应激假说具有很高的前景和内在一致性，但其有效性和特异性仍然不确定，因为(a)该研究的基本发现尚未被复制，(b)与对照组相比，在重度抑郁症中发现了相同类型的异常。另一方面，由于比较揭示了CFS和MDD之间的趋势水平差异，研究人员假设有限的样本量，加上两种疾病固有的临床异质性，可能限制了他们的初步研究发现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，并尝试客观区分CFS和MDD -一个艰巨而持续的挑战-研究人员建议：(1)在更大的队列中复制

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.