Imaging Microglial Activation in PTSD with PET

项目摘要 近9/10的美国人会在一生中遭受创伤，1/10的美国人会患上创伤后 应激障碍(PTSD)，其特征是威胁增加(例如，侵扰、焦虑唤醒)、丧失(例如， 快感缺乏、消极情绪)和神经认知(例如，语言学习、注意力)症状。具有以下特征的个人 创伤后应激障碍有更高的身体健康状况和功能损害，并伴有失落症状。 尤其是导致生活质量下降的原因。免疫系统负责维持健康， 这包括对身体(例如，病毒、伤害)和心理(例如，压力)侮辱做出反应，如 以及调节阿尔茨海默病等神经退行性疾病的进展。所有这些- 身体健康状况、心理困扰和神经退行性疾病--在 患有创伤后应激障碍的人比没有创伤后应激障碍的人。创伤后应激障碍患者存在外周免疫系统异常；然而， 已知的研究评估了神经免疫系统在创伤后应激障碍中的作用。在健康的免疫系统中， 中枢神经系统对侮辱或损伤的反应是通过激活小胶质细胞来调节的，小胶质细胞 执行维修功能。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， 就像在创伤后应激障碍患者身上发现的那样。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，如 [11C]因此，结合TSPO的PBR28可用于测量体内激活的小胶质细胞水平。在……里面 除了测量创伤后应激障碍患者(与对照组相比)激活的小胶质细胞水平外，我们还可以 通过注射一种有效的免疫激活剂--大肠杆菌脂多糖来挑战免疫系统 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内毒素- 诱导活化的小胶质细胞增加，伴随而来的外周炎症细胞因子的增加，以及 人类的相关情绪、焦虑和神经认知症状。在建议的研究中，我们会 系统评估[11C]PBR28评估的“神经炎症”与PET之间的关系， 以及80名创伤暴露者的威胁、丧失和神经认知症状的表现 创伤后应激障碍症状的全维谱。具体来说，我们将(1)确定个人是否 与创伤暴露的对照组相比，创伤后应激障碍患者激活的小胶质细胞水平更高；(2)使用一种新的 神经免疫“压力测试”以确定创伤后应激障碍患者是否存在神经免疫功能障碍 对全身注射内毒素的反应；以及(3)确定激活的小胶质细胞在介导 外周炎症标志物(如肿瘤坏死因子-α)与创伤相关症状的关系 创伤后应激障碍的潜在生物标志物。这项研究的结果将为新的、基于机制的和 与创伤后应激障碍及相关症状有关的可治疗神经免疫机制。

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.