Imaging Alterations in Endocannabinoid Metabolism in Clinical High Risk and First Episode Psychosis

项目总结： 将精神分裂症(SCZ)和大麻联系起来的强有力的流行病学证据表明 内源性大麻素(ECB)系统在该病的病理生理学中起着关键作用。早期大麻 吸食大麻会使患SCZ的风险增加近两倍，使大麻成为SCZ的强烈风险因素 [59，60]，通过未知的分子机制起作用。了解早期的神经病理学 SCZ的病程，如首发精神病(FEP)和临床高危状态(CHR) 在FEP之前，迫切需要为预防和治疗确定新的治疗靶点。 脂肪酸酰胺水解酶(FAAH)是一种负责ECB代谢的酶，如 阿南达胺(AEA)为欧洲央行定下了基调，严格调控大脑水平。在人类身上，戏剧性的 在SCZ和首发病例的脑脊液(CSF)中检测到AEA升高(高达8倍) 精神病(FEP)[91，92]，重要的是在CHR[136]，这表明存在改变的ECB 新陈代谢(FAAH降低)在SCZ的早期，包括其高风险状态。然而，没有一项研究 已经研究了欧洲央行守门酶FAAH在FEP或CHR大脑中的活体作用及其相互关系 与行为和认知的关系目前尚不清楚。 我们的团队合成了[11C]抑制物，并展示了其选择性和可靠性的优异性能 FAAH的PET脑成像[172]。我们还建立了[11C]路缘的安全性、有效性和剂量学 以及其可再现性[177,179]。因此，我们提案的总体目标是使用 [11C]使用高分辨率研究断层扫描仪使用正电子发射计算机断层扫描技术对欧洲央行酶FAAH进行成像 (HRRT)在无抗精神病药物的FEP和CHR患者中。150名参与者(n=50名FEP， N=50chr和n=50HV)将被包括在内以检验我们的假设。这项研究将帮助我们了解) FAAH在病程早期是否有变化(FEP&lt；CHR&lt；HV)，b)探讨 首次研究了大脑FAAH在行为和认知中的作用。我们相信这项研究将为我们提供新的 治疗靶点(即调节ECB的FAAH)治疗，甚至可能推迟或中止向SCZ的转变 那些处于危险中的人。 我们在FEP、CHR和HV中的初步[11C]抑制数据表明AEA减少的第一个证据 病程早期的代谢(脑FAAH降低)与我们的假设一致 (FEP&lt；Chr&lt；HV)，与我们在(治疗)SCZ患者中的初步数据一致。 PI和她的同事在进行复杂分子PET方面有相当多的记录 FEP和CHR受试者的影像研究[65,181-184]。高分辨率的PET扫描仪，嗯 CHR和FEP的特征放射性示踪剂和神经生物学研究的基础设施是新的 该项目的各个方面将为未来的药理学研究提供基本的基础 对CHR和FEP的干预主要集中在ECB治疗FEP，甚至预防CHR的SCZ。

Project Summary: Strong epidemiological evidence linking schizophrenia (SCZ) and cannabis suggests that the endocannabinoid (eCB) system plays a key role in the pathophysiology of the disease. Early cannabis use increases the risk of developing SCZ by almost twofold, making cannabis a strong risk factor for SCZ [59,60], acting through an unknown molecular mechanism. Understanding the neuropathology of the early course of SCZ such as First Episode Psychosis (FEP) and the state of clinical high risk (CHR) that precedes FEP is critically needed to identify new therapeutic targets for prevention and treatment. Fatty acid amide hydrolase (FAAH) is the enzyme responsible for the metabolism of eCBs such as anandamide (AEA) setting the tone of the eCB, tightly regulating brain levels. In humans, dramatic elevations (up to eightfold) of AEA were detected in cerebrospinal fluid (CSF) of SCZ and first episode psychosis (FEP) [91,92], and importantly in CHR [136], suggesting the presence of altered eCB metabolism (reduced FAAH) early in the course of SCZ, including its high risk states. However, no study has investigated FAAH, the eCB gatekeeping enzyme, in-vivo in brain in FEP or CHR, and its relationship with behavior and cognition is currently unknown. Our team has synthesized [11C]CURB and demonstrated its excellent properties for selective and reliable PET brain imaging of FAAH [172]. We also established the safety, validation and dosimetry of [11C]CURB as well as its reproducible quantifiability [177,179]. Thus, the overall aim of our proposal is to use [11C]CURB to image the eCB enzyme FAAH using PET with a high-resolution research tomograph (HRRT) in antipsychotic-free patients with FEP and CHR. One hundred and fifty participants (n=50 FEP, n=50 CHR and n=50 HV) will be included to test our hypothesis. This study will help us understand a) whether there are changes in FAAH in the early course of disease (FEP<CHR<HV), b) explore for the first time the role of brain FAAH in behavior and cognition. We believe this study will provide novel treatment targets (i.e. FAAH to regulate eCBs) to treat or perhaps even delay or abort transition to SCZ in those at risk. Our preliminary [11C]CURB data in FEP, CHR and HV suggest the first evidence of reduced AEA metabolism (reduced brain FAAH) early in the course of disease consistent with our hypothesis (FEP<CHR<HV), and congruent with our preliminary data in (treated) SCZ patients. The PI and her colleagues have a considerable track record of performing complex molecular PET imaging studies in FEP and CHR subjects [65,181-184]. The high resolution PET scanner, well characterized radiotracer and the infrastructure for neurobiological research in CHR and FEP are novel aspects of the project that will provide a fundamental basis for future studies of pharmacologic interventions in CHR and FEP focused on eCB to treat FEP or even prevent SCZ in CHR.