Oxidative Stress and Neuroinflammation: Co-conspirators in ME/CFS Pathophysiology

项目摘要-项目1 肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）是一种复杂的医学上无法解释的疾病， 其特征在于不能通过休息来改善的严重和使人衰弱的疲劳，以及一系列症状， 包括肌肉骨骼疼痛、喉咙痛、头痛、注意力不集中和短期记忆力受损，以及 睡眠障碍目前还没有科学有效的测试方法来检测这种疾病，也没有被广泛接受的方法。 治疗，导致临床医生在评估长期， 无法解释的身心疲惫发现ME/CFS特异性生物标志物， 提高我们对疾病及其致病机制的认识，区分疾病与 重叠或共病诊断，并确定潜在的治疗目标，因此，目前是一个紧迫的 未满足的研究和公共卫生需求。目前多边环境部粮安委这一部分的总体目标是： 合作研究中心（CRCs）（U 54）拨款提案将开始填补这一知识空白， 先进的神经影像学技术，以测试，然后验证ME/CFS的病理生理模型，假设 氧化应激和神经炎症，可能还有继发性线粒体功能障碍， 在疾病的发病机制中相互交织的机制。具体而言，本研究旨在：（a）使用质子 磁共振波谱（1H MRS）来测量体内大脑谷胱甘肽（GSH）水平--最 中枢神经系统中丰富的抗氧化剂-作为氧化应激的标志物;（B）使用1H MRS， 测量作为线粒体功能障碍标志物的乳酸和N-乙酰天冬氨酸（NAA）的体内脑水平; (c)用31 P MRS测量活体脑内ATP、磷酸肌酸（PCr）和无机磷酸盐（Pi）水平 作为线粒体功能障碍的补充指标;（d）使用体内脑11 C-（R）-PK 11195正电子 发射断层扫描（PET）以测量作为神经炎症标志物的配体的结合潜力; 和（f）测量神经炎症和氧化应激的循环标志物以证实所提出的 神经影像学生物标志物。为了确保疾病的影响而不是队列的影响， 研究，所有拟议的神经影像学扫描和血液样本分析将在之前进行， 在心肺运动试验（CPET）的症状激发后， ME/CFS患者中的不适（PEM）。如果成功完成，拟议的研究将有可能 揭示了ME/CFS的神经生物学机制和基础，以推进我们的 了解疾病，并建立ME/CFS特异性生物标志物，用于区分疾病与 重叠或共病诊断，并确定潜在的治疗目标。

PROJECT SUMMARY- PROJECT 1 Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and medically unexplained illness, characterized by severe and debilitating fatigue that is not ameliorated by rest, and a constellation of symptoms, including musculoskeletal pain, sore throat, headaches, impaired concentration and short-term memory, and sleep disturbances. There are no scientifically validated tests for the illness, nor are there widely accepted therapies, leading to a great deal of uncertainty among clinicians when evaluating patients with prolonged, unexplained, and debilitating psycho-physical fatigue. Discovery of ME/CFS-specific biomarkers that can advance our understanding of the illness and its pathogenic mechanisms, differentiate the disorder from overlapping or comorbid diagnoses, and identify potential treatment targets is, therefore, currently a pressing and unmet research and public health need. The overall objective of this component of the present ME/CFS Collaborative Research Centers (CRCs) (U54) grant proposal is to begin filling this knowledge gap by using advanced neuroimaging techniques to test and then validate a pathophysiological model of ME/CFS which posits that oxidative stress and neuroinflammation and, possibly, a secondary mitochondrial dysfunction, are intertwined mechanisms in the etiopathogenesis of the disorder. Specifically, this study will aim to: (a) use proton magnetic resonance spectroscopy (1H MRS) to measure in vivo brain levels of glutathione (GSH) -- the most abundant antioxidant in the central nervous system – as a marker of oxidative stress; (b) use 1H MRS to measure in vivo brain levels of lactate and N-acetylaspartate (NAA) as markers of mitochondrial dysfunction; (c) use 31P MRS to measure in vivo brain levels of ATP, creatine phosphate (PCr) and inorganic phosphate (Pi) as complementary indices of mitochondrial dysfunction; (d) use in vivo brain 11C-(R)-PK11195 positron emission tomography (PET) to measure the binding potential of the ligand as a marker of neuroinflammation; and (f) measure circulating markers of neuroinflammation and oxidative stress for corroborating the proposed neuroimaging biomarkers. To ensure that the effects of the disease rather than those of the cohorts will be investigated, all the proposed neuroimaging scans and blood samples assays will be performed before and following symptom provocation with cardiopulmonary exercise tests (CPET), known to trigger post-exertional malaise (PEM) in ME/CFS patients. If successfully completed, the proposed research will have the potential to shed new light onto the neurobiological mechanisms and underpinnings of ME/CFS to advance our understanding of the illness, and establish ME/CFS-specific biomarkers for differentiating the disorder from overlapping or comorbid diagnoses, and identifying potential treatment targets.