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

项目摘要： 将精神分裂症（SCZ）与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）系统在疾病的病理生理学中起着关键作用。早期大麻 使用大麻会使患SCZ的风险增加近两倍，使大麻成为SCZ的一个重要风险因素。 [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）和临床高风险状态， 在FEP之前，迫切需要确定新的预防和治疗靶点。 脂肪酸酰胺水解酶（FAAH）是负责eCB代谢的酶， 大麻素（AEA）设定eCB的基调，严格调节大脑水平。在人类中，戏剧性的 SCZ和首次发作的脑脊液（CSF）中检测到AEA升高（高达8倍） 精神病（FEP）[91，92]，重要的是在精神分裂症[136]中，表明存在改变的eCB 在SCZ病程早期，包括其高风险状态，代谢（FAAH降低）。然而，没有研究 已经研究了FAAH，eCB守门酶，在体内脑中FEP或EEP，及其与ECB的关系。 与行为和认知的关系目前尚不清楚。 我们的团队已经合成了[11 C]CURB，并展示了其优异的性能，用于选择性和可靠性。 FAAH的PET脑成像[172]。我们还确定了[11 C]CURB的安全性、验证和剂量测定 以及其可重复的可量化性[177，179]。因此，我们建议的总体目标是利用 [11 C]CURB使用PET和高分辨率研究断层扫描仪对eCB酶FAAH进行成像 150名参与者（n=50名FEP， 将纳入n=50例患者和n=50例HV），以检验我们的假设。本研究将帮助我们了解a） 在疾病的早期过程中是否存在FAAH的变化（FEP<HV <HV），B）探索 首次发现大脑FAAH在行为和认知中的作用。我们相信这项研究将提供新颖的 治疗目标（即FAAH调节eCB），以治疗或甚至延迟或中止向SCZ的过渡， 那些处于危险之中的人。 我们在FEP、NH 4和HV中的初步[11 C]CURB数据表明AEA减少的第一个证据 在疾病过程的早期代谢（减少脑FAAH）与我们的假设一致 (FEP<CHR<HV），并且与我们在（治疗的）SCZ患者中的初步数据一致。 PI和她的同事在执行复杂分子PET方面拥有相当多的记录 FEP和SPECT受试者的影像学研究[65，181 -184]。高分辨率PET扫描仪， 特征放射性示踪剂和基础设施的神经生物学研究中的神经元和FEP是新的 该项目的各个方面将为未来的药理学研究提供基础。 在CHR中，对FEP的干预措施侧重于eCB治疗FEP，甚至预防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.