Imaging inflammation in the whole body and brain of ME/CFS patients

ME/CFS 患者全身和大脑炎症的成像

• 批准号: 10312128
• 负责人: Michelle Louise James
• 金额: $ 23.53万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312128
• 关键词: Affect; Area; Arthralgia; Atrophic; Basal Ganglia; Biological Markers; Blood Tests; Body part; Bone Marrow; Brain; Brain imaging; Brain region; Brief Pain Inventory; Cell Lineage; Cells; Cerebellum; Chronic; Chronic Fatigue Syndrome; Clinical; Complex; Data; Detection; Development; Diagnosis; Diffuse; Diffusion Magnetic Resonance Imaging; Disease; Early Diagnosis; Enlargement of lymph nodes; Enzyme-Linked Immunosorbent Assay; Equipment and supply inventories; Exertion; Fatigue; Functional Magnetic Resonance Imaging; Functional disorder; Generations; Glial Fibrillary Acidic Protein; Headache; Herpesviridae; Herpesviridae Infections; Image; Imaging Device; Immune; Immune response; Immunomodulators; Impaired cognition; Infection; Inflammation; Innate Immune Response; Joints; Limbic System; Liquid substance; Liver; Location; Lymphatic System; Magnetic Resonance Imaging; Malaise; Measures; Medical; Memory Loss; Mental Depression; Methods; Microglia; Monitor; Muscle; Myalgia; Myelogenous; Myeloid Cell Activation; Neuraxis; Neuron-Specific Enolase; Normal Range; Organ; Pain; Pathogenesis; Patients; Pattern; Peripheral; Permeability; Persons; Plasma; Pontine structure; Positioning Attribute; Positron-Emission Tomography; Predisposition; Proteins; Questionnaires; Research Personnel; Role; Saliva; Salivary Glands; Severity of illness; Signal Transduction; Site; Sleep; Spleen; Staging; Symptoms; Techniques; Testing; Time; Tracer; United States; Viral; base; biomarker-driven; blood-brain barrier disruption; blood-brain barrier permeabilization; body position; cognitive function; cytokine; diagnostic accuracy; disabling symptom; economic cost; experimental study; imaging approach; imaging biomarker; immune activation; immunomodulatory strategy; improved; inflammatory marker; insight; lymph nodes; macrophage; monocyte; multimodality; neutrophil; novel; pathogen; peripheral blood; radiotracer; standard of care; theories; tomography; uptake; white matter change

Project Summary Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a highly debilitating disease affecting millions of people in the United States, yet very little is known about its underlying pathophysiology. The disease itself is exceedingly complex and characterized by variable clusters of incapacitating symptoms, including extreme fatigue, unrefreshing sleep, muscle pain, joint pain, headaches, and loss of memory or concentration. Preliminary theories suggest that an initial trigger, possibly viral, results in inflammation that chronically affects several parts the body, including the muscles, joints, lymphatic system, and central nervous system (CNS). Unfortunately, current standard of care techniques for diagnosing suspected ME/CFS (i.e., blood tests and structural brain imaging) do not provide direct measures of inflammation in the CNS or other organs and often afford results within normal range. Hence, there is a critical unmet need to develop more sensitive and specific tests that not only improve the accuracy of diagnosis but also provide a means to investigate specific immune responses and their role in the initiation and progression of ME/CFS in the brain and periphery of ME/CFS. Here, we propose for the first time to perform whole body position emission tomography (PET) imaging of ME/CFS patients using [11C]DPA-713, a highly sensitive and specific radiotracer for the translocator protein 18 kDa (TSPO). TSPO is an established imaging biomarker of inflammation that is predominately upregulated in activated innate immune cells including microglia in the CNS and other myeloid lineage cells (e.g., macrophages) in the periphery. We hypothesize that chronic, unresolved inflammation driven by innate immune cells underlies the central clinical problems of fatigue, pain, and cognitive dysfunction observed in ME/CFS. Our encouraging preliminary data shows increased [11C]DPA-713-PET signal in multiple brain regions of severe ME/CFS patients compared to healthy controls. We also demonstrate the feasibility of whole body PET/magnetic resonance (PET/MR) imaging using [11C]DPA-713. In this proposal, we will expand on this data by investigating the relationship between peripheral and central markers of inflammation, through the following aims: 1) Quantify [11C]DPA-713 uptake in the CNS and whole body of ME/CFS patients compared to healthy asymptomatic controls using PET/MRI, and 2) Correlate the extent and location of [11C]DPA-713-PET signal to clinical measures of disease severity and peripheral fluid-based biomarkers of inflammation and infection. Additionally, we will correlate PET findings with advanced multimodal MRI, including quantitative brain volumetry, diffusion tensor imaging, and quantitative susceptibility mapping (QSM). Completing these experiments will provide invaluable insights into the correspondence between myeloid cell activation in the CNS and whole body, with that of plasma cytokine signatures, herpesvirus shedding, blood brain barrier disruption, white matter changes, and disease severity in ME/CFS. Since [11C]DPA-713 is available for clinical use, this imaging tool has potential to immediately impact the way we study, monitor, and treat ME/CFS.

项目摘要 肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）是一种影响数百万人的高度衰弱性疾病 的人在美国，但很少有人知道其潜在的病理生理学。疾病本身就是 非常复杂，以各种各样的失能症状为特征，包括极端的 疲劳、睡眠不佳、肌肉疼痛、关节疼痛、头痛、记忆力减退或注意力不集中。初步 理论认为，最初的触发因素，可能是病毒，导致炎症，慢性影响几个部位 身体，包括肌肉、关节、淋巴系统和中枢神经系统（CNS）。不幸的是， 用于诊断疑似ME/CFS的当前护理技术标准（即，血液测试和大脑结构 成像）不能提供CNS或其他器官中炎症的直接测量， 在正常范围内。因此，开发更敏感和更具体的检测方法是一个关键的未满足的需求， 不仅提高了诊断的准确性，而且还提供了一种研究特异性免疫反应的手段， 它们在ME/CFS的脑和外周中的ME/CFS的起始和进展中的作用。 在这里，我们首次提出进行全身位置发射断层扫描（PET）成像， ME/CFS患者使用[11 C]DPA-713，一种高灵敏度和特异性的转运蛋白18放射性示踪剂 kDa（TSPO）。TSPO是一种已确立的炎症成像生物标志物，其主要在炎症中上调。 活化的先天免疫细胞包括CNS中的小胶质细胞和其它骨髓谱系细胞（例如，巨噬细胞） 在外围。我们假设先天免疫细胞驱动的慢性未解决的炎症 是ME/CFS中观察到的疲劳、疼痛和认知功能障碍的中心临床问题的基础。 我们令人鼓舞的初步数据显示，在重度脑梗死患者的多个脑区，[11 C]DPA-713-PET信号增加。 ME/CFS患者与健康对照组相比。我们还证明了全身PET/磁共振成像的可行性。 使用[11 C]DPA-713进行PET/MR成像。在本提案中，我们将通过调查来扩展这些数据， 外周和中枢炎症标志物之间的关系，通过以下目的：1）量化 与健康无症状相比，ME/CFS患者CNS和全身的[11 C]DPA-713摄取 使用PET/MRI的对照，以及2）将[11 C]DPA-713-PET信号的范围和位置与临床 疾病严重程度的测量以及炎症和感染的基于外周液的生物标志物。此外，本发明还 我们将把PET结果与先进的多模式MRI相关联，包括定量脑容量测定、弥散 张量成像和定量磁化率绘图（QSM）。 完成这些实验将提供宝贵的见解，骨髓细胞之间的对应关系， CNS和全身的激活，以及血浆细胞因子特征、疱疹病毒脱落、血脑 屏障破坏、白色改变和ME/CFS的疾病严重程度。由于[11 C]DPA-713可用于 临床使用，这种成像工具有可能立即影响我们研究，监测和治疗ME/CFS的方式。