Imaging Neuroinflammation in Clinical high risk and Schizophrenia

描述(申请人提供)：虽然多巴胺在精神分裂症阳性症状(SCZ)中的作用已经得到证实，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。有几条证据表明神经炎症在SCZ的发病机制中发挥了作用。神经炎症也可能与脑萎缩有关，这是SCZ的一贯发现。转位蛋白18Kd(TSPO)是一种小胶质细胞线粒体蛋白，其正电子发射断层扫描(PET)为体内研究神经炎症标志物小胶质细胞的活性提供了机会。以前的研究使用[11C]-PK1195，一种存在许多缺陷的放射性示踪剂，作为PET放射性示踪剂，并且仅在治疗SCZ的患者中使用。然而，小胶质细胞激活/神经炎症在抗精神病药物朴素SCZ中的作用及其与脑萎缩和临床症状的关系尚未通过正电子发射计算机断层扫描进行检测。重要的是，临床高危(CHR)受试者的神经炎症检查，为早期干预和可能更好的结果提供了机会，从未进行过。因此，这项拟议的研究旨在利用高分辨率(HRRT)扫描仪获得第一个活体成像数据，通过测量三组人(每组36人)的[18F]-FEPPA结合来调查SCZ相关疾病是否与神经炎症增加相关：抗精神病药物幼稚的SCZ患者、CHR和匹配的健康志愿者(HV)。[18F]-FEPPA是多伦多成瘾与心理健康中心(CAMH)开发的一种具有理想性能的新型放射性示踪剂。受试者将被安排进行一次正电子发射计算机断层扫描和核磁共振扫描。主要目的是在控制基因的情况下，测试SCZ、CHR和HV组对海马和背外侧前额叶皮质(DLPFC)的[18F]-FEPPA结合是否有显著影响。在后组分析中，我们假设抗精神病药物naive SCZ和ChR在海马区和DLPFC中都有比HV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；在没有抗精神病药物混淆的情况下，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，神经炎症在SCZ的病理生理学中的作用。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和临床高危人群的新治疗靶点(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艾滋病的预后至关重要 SCZ.通过检测CHR和抗精神病药物单纯的SCZ，可以设想潜在的早期治疗，这些治疗可能对SCZ的最终结果产生重大影响，甚至推迟或中止其发生。

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.