Imaging Microglial Activation in PTSD with PET

项目摘要 近十分之九的美国人在一生中会受到创伤，十分之一的人会发展为创伤后 应激障碍（PTSD），其特征在于升高的威胁（例如，侵入，焦虑唤醒），损失（例如， 快感缺乏、负面情绪）和神经认知（例如，语言学习、注意力）症状。人士 创伤后应激障碍有较高的身体健康状况，以及功能障碍，与损失的症状 特别是导致生活质量下降。免疫系统负责维持健康， 其包括安装对物理的响应（例如，病毒，损伤）和心理（例如，压力）侮辱，如 以及调节神经退行性疾病如阿尔茨海默病的进展。所有这些- 身体健康状况、心理困扰和神经退行性疾病--在 与没有PTSD的人相比。PTSD患者存在外周免疫系统异常;然而， 一项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由小胶质细胞的激活介导， 执行修复功能。然而，过度激活会导致神经元功能障碍和损伤 通过释放炎性细胞因子和应激激素，并可能导致神经变性， 例如在患有创伤后应激障碍的个体中发现的。当小胶质细胞被激活时， 转运蛋白（TSPO）的表达。正电子发射断层扫描（PET）放射性示踪剂，例如 [11 C] PBR 28与TSPO结合，因此可用于测量体内活化小胶质细胞的水平。在 除了测量PTSD患者（与对照组相比）中激活的小胶质细胞水平外，我们还可以 通过施用E.大肠杆菌脂多糖（LPS），一种有效的免疫激活剂 并测量受试者体内激活的小胶质细胞的增加。我们最近展示了强大的LPS- 诱导活化的小胶质细胞增加，并伴随外周炎性细胞因子增加， 相关的情绪、焦虑和神经认知症状。在拟议的研究中，我们将 系统地评价“神经炎症”之间的关系，如[11 C] PBR 28和PET评估， 以及80名创伤暴露者的威胁、丧失和神经认知症状的表达， 创伤后应激障碍症状的全维度谱具体而言，我们将（1）确定个人是否 与创伤暴露对照组相比，PTSD患者有更高水平的活化小胶质细胞;（2）使用新的 神经免疫“压力测试”，以确定PTSD患者是否有功能失调的神经免疫系统。 对全身给予LPS的反应;和（3）确定活化的小胶质细胞在介导LPS的作用中的作用。 外周炎性标志物（例如，TNF-α）和创伤相关症状，以发现 创伤后应激障碍的潜在生物标志物这项研究的结果将深入了解新的，基于机制的， 创伤后应激障碍和相关综合征的神经免疫机制。

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.