Imaging Microglial Activation in PTSD with PET

使用 PET 对 PTSD 中的小胶质细胞激活进行成像

• 批准号: 9309643
• 负责人: Kelly P Cosgrove
• 金额: $ 83.75万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9309643
• 关键词: Alzheimer' s Disease; American; Amygdaloid structure; Anhedonia; Anxiety; Arousal; Attention; Binding; Blood - brain barrier anatomy; Brain; Brain imaging; Clinical; Clinical assessments; Data; Diagnosis; Dimensions; Endotoxins; Escherichia coli; Functional disorder; Health; Hippocampus (Brain); Hormones; Human; Hydrocortisone; Image; Immune; Immune system; Impaired cognition; Individual; Inflammation; Inflammatory; Injury; Lead; Lipopolysaccharides; Measures; Mediating; Mediator of activation protein; Microglia; Moods; Nerve Degeneration; Neuraxis; Neurocognitive; Neurodegenerative Disorders; Neuroimmune; Neuroimmune system; Neuroimmunomodulation; Neuronal Dysfunction; Pathology; Peripheral; Pharmacology; Play; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Proteins; Psychopathology; Public Health; Quality of life; Role; Severities; Stress; Stress Tests; Symptoms; Syndrome; TNF gene; Trauma; Ventral Striatum; Verbal Learning; Virus; anxiety symptoms; anxious; base; blood-based biomarker; cytokine; frontal lobe; functional disability; in vivo; inflammatory marker; insight; mood symptom; negative affect; neuroinflammation; novel; physical conditioning; potential biomarker; pre-clinical; psychologic; psychological distress; radiotracer; reduce symptoms; repaired; response; stressor; symptomatology; targeted treatment

Project Summary Nearly 9 in 10 Americans will be exposed to trauma in their lifetime and 1 in 10 will develop post-traumatic stress disorder (PTSD), which is characterized by elevated threat (e.g., intrusions, anxious arousal), loss (e.g., anhedonia, negative affect) and neurocognitive (e.g., verbal learning, attention) symptoms. Individuals with PTSD have elevated rates of physical health conditions, as well as functional impairment, with loss symptoms in particular contributing to decreased quality of life. The immune system is responsible for maintaining health, which includes mounting a response to physical (e.g., virus, injury) and psychological (e.g., stress) insults, as well as modulating the progression of neurodegenerative disorders such as Alzheimer’s disease. All of these - physical health conditions, psychological distress, and neurodegenerative disorders - are more prevalent in individuals with than without PTSD. There are peripheral immune system abnormalities in PTSD; however, no known study has evaluated the role of the neuroimmune system in PTSD. In the healthy immune system, the response of the central nervous system to an insult or damage is mediated by the activation of microglia, which carry out repair functions. However, excessive activation can lead to neuronal dysfunction and damage through the release of inflammatory cytokines and stress hormones, and may contribute to neurodegeneration, such as that found in individuals with PTSD. When microglia are activated, there is a robust increase in the expression of translocator protein (TSPO). Positron emission tomography (PET) radiotracers such as [11C]PBR28, which bind to TSPO, can therefore be used to measure levels of activated microglia in vivo. In addition to measuring levels of activated microglia in individuals with PTSD (vs. controls), we can also challenge the immune system by administering E. Coli lipopolysaccharide (LPS), a potent immune activator and measure increases in activated microglia within subject. We have recently demonstrated robust LPS- induced increases in activated microglia, and concomitant increases in peripheral inflammatory cytokines, and associated mood, anxiety, and neurocognitive symptoms in humans. In the proposed study, we will systematically evaluate the relationship between “neuroinflammation”, as assessed with [11C]PBR28 and PET, and the expression of threat, loss, and neurocognitive symptoms in 80 trauma-exposed individuals presenting with the full dimensional spectrum of PTSD symptoms. Specifically, we will (1) determine whether individuals with PTSD have higher levels of activated microglia compared to trauma-exposed controls; (2) use a novel neuroimmune “stress test” to determine whether individuals with PTSD have a dysfunctional neuroimmune response to systemic administration of LPS; and (3) determine the role of activated microglia in mediating the relationship between peripheral inflammatory markers (e.g., TNF-α), and trauma-related symptoms to discover potential biomarkers of PTSD. Results of this study will yield insight into novel, mechanism-based, and treatable neuroimmune mechanisms implicated in PTSD and related syndromes.

项目摘要 十分之一的美国人将在一生中遭受创伤，十分之十将发生创伤后发展 应激障碍（PTSD）的特征是威胁升高（例如，入侵，焦虑唤醒），损失（例如， Anhedonia，负面影响）和神经认知（例如，口头学习，注意）符号。有个人 PTSD的身体健康状况和功能障碍的率升高 特别有助于改善生活质量。免疫系统负责维持健康， 其中包括安装对身体（例如病毒，损伤）和心理（例如压力）感染的反应 以及调节神经退行性疾病的进展，例如阿尔茨海默氏病。所有这些 - 身体健康状况，心理困扰和神经退行性疾病 - 更为普遍 比没有PTSD的人。 PTSD中存在外周免疫系统异常。但是，不 已知的研究评估了神经免疫系统在PTSD中的作用。在健康的免疫系统中， 中枢神经系统对损伤或损害的反应是由小胶质细胞的激活介导的，而小胶质细胞的激活 执行维修功能。但是，过量激活会导致神经元功能障碍和损害 通过释放炎症性细胞因子和应激激素，并可能有助于神经变性， 例如在PTSD的个体中发现的。当小胶质细胞激活时， 转运蛋白（TSPO）的表达。正电子发射断层扫描（PET）放射性示例，例如 [11C]与TSPO结合的PBR28可用于测量体内活化的小胶质细胞水平。 除了测量PTSD患者（与对照组）中激活的小胶质细胞的水平，我们还可以 通过管理大肠杆菌脂多糖（LPS）来挑战免疫系统，这是潜在的免疫活性剂 并测量受试者中活化的小胶质细胞的增加。我们最近证明了强大的LPS- 诱导的小胶质细胞升高，外周炎性细胞因子和外周炎症的增加和增加 相关的情绪，动画和人类的神经认知症状。在拟议的研究中，我们将 通过[11C] PBR28和PET评估，系统地评估“神经炎症”之间的关系 以及80个暴露的人的威胁，丧失和神经认知症状的表达 具有PTSD症状的完整维度。具体来说，我们将（1）确定个人是否 与暴露创伤的对照相比，PTSD具有更高的活化小胶质细胞。 （2）使用小说 神经免疫性“压力测试”，以确定PTSD的个体是否患有功能失调的神经免疫性 对系统施用LP的反应； （3）确定活化的小胶质细胞在介导的作用 周围炎症标记（例如TNF-α）和与创伤相关的符号之间的关系以发现 PTSD的潜在生物标志物。这项研究的结果将深入了解新颖的，基于机制的和 在PTSD和相关综合征中实施的可治疗神经免疫机制。