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

项目概要 - 项目 1 肌痛性脑脊髓炎/慢性疲劳综合症（ME/CFS）是一种复杂且医学上无法解释的疾病， 其特点是严重且令人衰弱的疲劳，且休息无法缓解，并且出现一系列症状， 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。对于这种疾病没有经过科学验证的测试，也没有被广泛接受 治疗，导致临床医生在评估患者长期、 无法解释的、令人衰弱的身心疲劳。发现 ME/CFS 特异性生物标志物 增进我们对疾病及其致病机制的了解，将疾病与疾病区分开来 因此，目前迫切需要解决重叠或共病诊断并确定潜在的治疗目标 以及未满足的研究和公共卫生需求。当前 ME/CFS 这一部分的总体目标 合作研究中心（CRC）（U54）拨款提案将开始通过使用来填补这一知识空白 先进的神经影像技术来测试并验证 ME/CFS 的病理生理学模型，该模型假设 氧化应激和神经炎症，以及可能的继发性线粒体功能障碍，是 该疾病的发病机制相互交织。具体来说，本研究的目的是：(a) 使用质子 磁共振波谱 (1H MRS) 测量体内谷胱甘肽 (GSH) 的水平——最 中枢神经系统中丰富的抗氧化剂——作为氧化应激的标志； (b) 使用 1H MRS 来 测量体内乳酸和 N-乙酰天冬氨酸 (NAA) 的大脑水平，作为线粒体功能障碍的标志； (c) 使用 31P MRS 测量体内 ATP、磷酸肌酸 (PCr) 和无机磷酸盐 (Pi) 的脑水平 作为线粒体功能障碍的补充指标； (d)使用体内脑11C-(R)-PK11195正电子 发射断层扫描（PET）测量配体的结合潜力作为神经炎症的标志物； (f) 测量神经炎症和氧化应激的循环标志物，以证实所提出的建议 神经影像生物标志物。确保疾病的影响而不是队列的影响 调查后，所有拟议的神经影像扫描和血液样本分析都将在之前和之后进行 心肺运动测试 (CPET) 引发症状后，已知会引发劳累后症状 ME/CFS 患者的不适（PEM）。如果成功完成，拟议的研究将有可能 为 ME/CFS 的神经生物学机制和基础提供新的线索，以推进我们的研究 了解疾病，并建立 ME/CFS 特异性生物标志物以区分该疾病与 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.