Measuring neuroinflammation in chronic fatigue syndrome with whole-brain magnetic resonance spectroscopy

项目摘要/摘要 在这个R01项目中，我们将测试磁共振光谱成像(MRSI)技术，以评估 神经炎症的几个标记物遍布整个大脑。我们将利用这项技术来调查 不明原因的肌痛性脑脊髓炎/慢性疲劳综合征(ME/CFS)的病理生理学 以深度疲劳为特征的病因学，不能通过休息来缓解。缺乏关于ME/CFS的信息 病理生理学对特效性和非特异性治疗方法的发展构成了重大障碍。 对这种疾病很有效。我们假设ME/CFS是大脑低水平炎症的结果。 小胶质细胞和星形胶质细胞的慢性激活刺激相互作用的促炎因子的释放 神经元会引起疲劳、疼痛敏感、认知和情绪紊乱的症状。MRSI可能是 能够通过显示肌醇、胆碱、乳酸、大脑温度、 低N-乙酰天冬氨酸与小胶质细胞异常激活有关。在这五年中 R01研究，我们将分别进行三项研究。研究1检查了90名患有ME/CFS的女性，年龄为30岁- 和体重指数匹配的健康对照组。神经炎性标志物将在体素上逐个进行评估- 整个大脑的体素基础，产生大约4,000个灰质和白色的评估 物质和脑脊液。我们假设神经炎性标志物将在 ME/CFS组的多个脑区。研究2采用“好日子，坏日子”的纵向设计 探讨神经炎性标志物与症状严重程度波动的相关性 我/CFS。我们假设，疲劳严重程度越高的天数将与更高的 神经炎性标志物。在研究3中，我们将使用正电子发射断层扫描来验证mrsi扫描。 小胶质细胞活化标志物18F-DPA-714的PET分析。我们预计将在MRSI中看到空间重叠 以及神经炎症的PET指示物。支持这三个假设将表明ME/CFS是 与脑部炎症有关。这项测试将允许安全和廉价的纵向评估 正电子发射断层扫描(PET)或腰椎穿刺术不可能出现的神经炎症 脑脊液。因为我们收集了每个体素中的全部可用光谱，所以我们还将拥有 首个ME/CFS的全脑代谢数据。MRS数据可用于量化其他感兴趣的标记 对于ME/CFS研究人员，如谷氨酸和谷氨酰胺。因此，我们将提供整个数据集 交给其他研究人员进行二次分析。最终，我们希望这种非侵入性扫描技术将有助于 在ME/CFS的诊断、治疗决策和新疗法的开发方面。

PROJECT SUMMARY/ABSTRACT In this R01 project, we will test a magnetic resonance spectroscopic imaging (MRSI) technique to assess several markers of neuroinflammation across the entire brain. We will use the technique to investigate the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a condition of unknown etiology that is characterized by profound fatigue not alleviated by rest. The lack of information on ME/CFS pathophysiology has posed a substantial obstacle to the development of treatments that are specific and effective for the disorder. We hypothesize that ME/CFS is the result of low-level inflammation in the brain. Chronic activation of microglia and astrocytes provokes the release of proinflammatory agents that interact with neurons to cause symptoms of fatigue, pain sensitivity, and cognitive and mood disruption. MRSI may be able to detect that neuroinflammation by showing elevated myo-inositol, choline, lactate, brain temperature, and lower N-acetylaspartate that have been associated with abnormal microglia activation. In this five-year R01 study, we will conduct three separate studies. Study #1 examines 90 women with ME/CFS and 30 age- and body mass index-matched healthy controls. Neuroinflammatory markers will be assessed on a voxel-by- voxel basis throughout the entire brain, yielding approximately 4,000 assessments in gray matter, white matter, and cerebrospinal fluid. We hypothesize that the neuroinflammatory markers will be elevated in several brain regions in the ME/CFS group. Study #2 uses a “good-day, bad-day” longitudinal design to examine correlation between neuroinflammatory markers and symptom severity fluctuations in 20 women with ME/CFS. We hypothesize that the higher fatigue severity days will be associated with higher levels of neuroinflammatory markers. In Study #3, we will validate the MRSI scan with positron emission tomography (PET) analysis of 18F-DPA-714, a marker of activated microglia. We expect to see spatial overlap in MRSI and PET indicators of neuroinflammation. Support for these three hypotheses would show that ME/CFS is associated with brain inflammation. This test would allow for safe and inexpensive longitudinal assessment of neuroinflammation that is not possible with positron emission tomography (PET) or lumbar puncture measures of cerebrospinal fluid. Because we collect the entire available spectrum in each voxel, we will also have the first whole-brain metabolic data in ME/CFS. The MRS data can be used to quantify other markers of interest to ME/CFS researchers, such as glutamate and glutamine. We will therefore make the entire dataset available to other researchers for secondary analyses. Ultimately, we hope this non-invasive scanning technique will aid in ME/CFS diagnosis, treatment decisions, and the development of new treatments.