Imaging Neuroinflammation in Clinical high risk and Schizophrenia

描述（由申请人提供）：虽然多巴胺在精神分裂症（SCZ）阳性症状中的作用已得到充分证实，但人们越来越认识到多巴胺可能只是不同病因因素的最终共同途径。一些证据表明神经炎症在SCZ发病机制中的作用。神经炎症也可能与脑萎缩相关，这是SCZ中的一致发现。转运蛋白18 Kd（TSPO），一种小胶质细胞线粒体蛋白的正电子发射断层扫描（PET）提供了一个机会，研究小胶质细胞的活动，神经炎症的标志物，在体内。以前的研究使用[11 C]-PK 1195，这是一种放射性示踪剂，作为PET放射性示踪剂存在许多缺陷，并且仅用于接受治疗的SCZ患者。然而，小胶质细胞活化/神经炎症在抗精神病药初治SCZ中的作用，其与脑萎缩和临床症状的关系尚未使用PET进行研究。重要的是，在临床高风险（CNS）受试者中检查神经炎症，这为早期干预和可能更好的结果提供了机会，但从未进行过。因此，所提出的研究旨在使用高分辨率（HRRT）扫描仪获得第一个体内成像数据，以通过测量三组个体（每组36人）中的[18 F]-FEPPA结合来研究SCZ相关疾病是否与神经炎症增加相关：抗精神病药初治SCZ患者，健康志愿者（HV）。[18 F]-FEPPA是一种新型放射性示踪剂，具有理想的特性，由多伦多成瘾和精神健康中心（CAMH）开发。将安排受试者各接受一次PET扫描和一次MRI扫描。主要目的是测试组（SCZ、HVM和HV）对海马和背外侧前额叶皮层（DLPFC）中的[18 F]-FEPPA结合是否有显著影响，同时控制基因型。在事后分析中，我们假设与HV相比，抗精神病药物初治SCZ和抗精神病药物治疗组在海马和DLPFC中的[18 F]-FEPPA结合率更高。本研究解决了精神分裂症研究中的一个相关问题;神经炎症在SCZ病理生理学中的作用，没有抗精神病药物的混淆，使用最先进的成像技术和第二代TSPO放射性配体，同时控制基因型。了解与小胶质细胞活化相关的神经生物学变化有可能在SCZ和临床高风险疾病中确定新的治疗靶点（即减少神经炎症）。越来越多的人认识到，早期识别和干预对于改善 SCZ。通过检查未接受过抗精神病药物治疗的SCZ，可以设想潜在的早期治疗，这些治疗可能对SCZ的最终结局产生重大影响，甚至延迟或中止其发生。

DESCRIPTION (provided by applicant): While the role of dopamine in positive symptoms of schizophrenia (SCZ) is well established, it is increasingly recognized that dopamine may only be a final common pathway of different etiological factors. Several lines of evidence point towards a role for neuroinflammation in the pathogenesis of SCZ. Neuroinflammation is also possibly related to brain atrophy, which is a consistent finding in SCZ. Positron emission tomography (PET) of translocator protein 18Kd (TSPO), a microglial mitochondrial protein provides an opportunity to study microglia activity, a marker of neuroinflammation, in-vivo. Previous studies used [11C]-PK1195, a radiotracer with many deficiencies as a PET radiotracer, and only in treated patients with SCZ. However, the role of microglia activation/neuroinflammation in antipsychotic naive SCZ, its relation to brain atrophy and clinical symptoms has not been examined using PET. Importantly, examination of neuroinflammation in Clinical high risk (CHR) subjects, which provides an opportunity for early intervention and possibly better outcome, has never been undertaken. Thus, the proposed study aims to obtain first in-vivo imaging data using a high-resolution (HRRT) scanner to investigate whether SCZ related disorders are associated with increased neuroinflammation by measuring [18F]-FEPPA binding in three groups of individuals (36 in each): antipsychotic naive SCZ patients, CHR and matched healthy volunteers (HV). [18F]-FEPPA is a novel radiotracer with desirable properties developed at Centre for addiction and mental health (CAMH), Toronto. Subjects will be scheduled for one PET scan and MRI scan each. The main objective is to test whether there is a significant effect of group (SCZ, CHR and HV) on [18F]-FEPPA binding in hippocampus and dorsolateral prefrontal cortex (DLPFC), while controlling for genotype. On Post-hoc analysis, we hypothesize that both antipsychotic naive SCZ and CHR will have higher [18F]-FEPPA binding in hippocampus and DLPFC, as compared to HV. This study addresses a relevant question in schizophrenia research; the role of neuroinflammation in the pathophysiology of SCZ, without the confound of antipsychotic medications, using state of the art imaging technology and second generation TSPO radioligands while controlling for genotype. Understanding the neurobiological changes associated with microglia activation has the potential to identify novel treatment targets (i.e. decrease neuroinflammation) in SCZ and in those at clinical high risk for the disease. There is increasing recognition that early identification and intervention is critical for better outcome in SCZ. By examining CHR and antipsychotic naive SCZ, potential early treatments can be conceived that could have significant impact on final outcome of SCZ, and even delay or abort its occurrence.