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阳性症状（SCZ）中的作用已经确立，但越来越多的人认识到多巴胺可能只是不同病因的最终共同途径。一些证据指向神经炎症在SCZ发病机制中的作用。神经炎症也可能与脑萎缩有关，这在SCZ中是一致的发现。转运蛋白18Kd （TSPO）的正电子发射断层扫描（PET）是一种小胶质线粒体蛋白，为研究小胶质细胞活性（神经炎症的标志物）提供了一个机会。先前的研究使用[11C]-PK1195作为PET示踪剂，该示踪剂存在许多缺陷，且仅用于治疗的SCZ患者。然而，小胶质细胞激活/神经炎症在抗精神病性初发SCZ中的作用及其与脑萎缩和临床症状的关系尚未通过PET检查。重要的是，临床高风险（CHR）受试者的神经炎症检查从未进行过，这为早期干预和可能更好的结果提供了机会。因此，本研究旨在使用高分辨率（HRRT）扫描仪获得首个体内成像数据，通过测量三组个体（每组36人）的[18F]-FEPPA结合情况，研究SCZ相关疾病是否与神经炎症增加相关：抗精神病的初发SCZ患者、CHR和匹配的健康志愿者（HV）。[18F]-FEPPA是多伦多成瘾和心理健康中心（CAMH）开发的一种具有理想性能的新型放射性示踪剂。受试者将分别接受一次PET扫描和MRI扫描。主要目的是在控制基因型的情况下，检验各组（SCZ、CHR和HV）对海马和背外侧前额叶皮层（DLPFC） [18F]-FEPPA结合是否有显著影响。在事后分析中，我们假设与HV相比，抗精神病药物初发SCZ和CHR在海马和DLPFC中具有更高的[18F]-FEPPA结合。这项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放射配体，同时控制基因型。了解与小胶质细胞激活相关的神经生物学变化有可能确定SCZ和临床高风险患者的新治疗靶点（即减少神经炎症）。人们越来越认识到，早期识别和干预对改善预后至关重要

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.