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

项目总结/摘要 在这个R 01项目中，我们将测试磁共振光谱成像（MRSI）技术，以评估 整个大脑的神经炎症的几个标志物。我们将使用该技术来调查 肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）的病理生理学， 以休息不能缓解的极度疲劳为特征的病因学。缺乏关于ME/CFS的信息 病理生理学已经对开发特异性的治疗造成了实质性的障碍， 有效治疗疾病。我们假设ME/CFS是大脑中低水平炎症的结果。 小胶质细胞和星形胶质细胞的慢性激活引起促炎因子的释放， 与神经元接触，导致疲劳、疼痛敏感、认知和情绪紊乱的症状。MRSI可能是 能够通过显示升高的肌醇，胆碱，乳酸，脑温， 和较低的N-乙酰天冬氨酸，这与异常的小胶质细胞激活有关。在这五年中， R 01研究，我们将进行三项单独的研究。研究#1检查了90名ME/CFS女性和30名年龄- 和体重指数匹配的健康对照组。神经炎症标志物将在体素上评估， 在整个大脑中的体素基础上，产生大约4，000个灰质评估，白色 物质和脑脊液。我们假设，神经炎症标志物将升高， ME/CFS组的几个脑区。研究#2使用“好日子，坏日子”纵向设计， 检查20名患有神经炎性疾病的妇女的神经炎性标志物和症状严重程度波动之间的相关性。 ME/CFS。我们假设，疲劳严重程度越高， 神经炎症标志物。在研究#3中，我们将使用正电子发射断层扫描验证MRSI扫描 (PET)18F-DPA-714（活化的小胶质细胞的标志物）的分析。我们希望在MRSI中看到空间重叠 和神经炎症的PET指标。支持这三个假设将表明，ME/CFS是 与脑部炎症有关该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）或腰椎穿刺测量不可能出现的神经炎症 脑脊髓液因为我们收集了每个体素中的整个可用光谱，所以我们还将获得 ME/CFS中的第一个全脑代谢数据。MRS数据可用于量化其他感兴趣的标志物 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 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能帮助 ME/CFS诊断，治疗决策和新治疗方法的开发。

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.