Neuroinflammation in Schizophrenia: An Integrated PET and High-Field Susceptibili

描述（由申请人提供）：精神分裂症（SZ）的病理生理学研究和治疗开发主要集中在调节神经递质。目前可用的影响神经递质的抗精神病药未能显著改善长期 长期的社会/功能结果。因此，迫切需要表征替代病理生理学模型以设计新颖的治疗方法。在过去的50年里，越来越多的证据表明，神经炎症可能是卓有成效的病理生理学研究和新的治疗开发的目标。神经炎症在SZ的病理生理学中被认为不重要。新出现的证据有力地表明免疫系统和中枢神经系统之间的相互调节。免疫介质，例如在神经元和神经胶质上表达的细胞因子，通过多巴胺、5-羟色胺、谷氨酸和去甲肾上腺素调节神经元发育、程序性细胞死亡、神经元信号转导、神经可塑性和神经传递。这些神经递质的缺失与SZ的病理生理学有关。同样地，从神经末梢分泌的神经递质调节免疫细胞活性，支持两个明显不同的系统之间的复杂的相互关系。因此，对神经炎症的系统研究将为新的治疗设计提供有意义的替代病理生理学模型。虽然现存文献提供了大量关于神经炎症的提示性数据，但缺乏神经炎症及其临床和神经生物学相关性的直接体内证据。该提案旨在系统地收集SZ和健康对照（HC）神经炎症的两个不同方面（即活化的炎症细胞和微血管变化）的收敛初步体内多模态神经成像数据。正电子发射断层扫描（PET）使用高度特异性的放射性配体（[11 C] PBR 28]），与激活的小胶质细胞/巨噬细胞线粒体中称为转运蛋白18 kDa（TSPO）的受体结合，收集激活的免疫细胞的体内数据。同时获得高分辨率（32通道头部线圈，灵敏度提高4倍），高场（7特斯拉）磁敏感加权成像（SWI）可靠地捕获脑微血管（小静脉/小动脉和称为树枝状的静脉/小动脉分支）和局部铁的变化 由于活化的小胶质细胞/巨噬细胞的积累，我们预测与HC相比，SZ受试者的[11 C] PBR 28结合增加，小静脉/小动脉和分支密度增加，局部铁水平增加，特别是在前额叶皮层和海马中（目的1）。我们还将测试[11 C] PBR 28结合、静脉密度、分支和局部铁水平是否彼此相关（目的2）。我们将探索这些神经炎症指标是否与大脑连接、认知障碍和精神病理学相关（探索性目的）。可以进一步评价关于神经炎症的这种会聚的体内证据的生物标志物表征，靶向SZ受试者的抗炎药物，发现与SZ相关的特异性免疫途径，并开发靶向所鉴定途径的新药。

DESCRIPTION (provided by applicant): Pathophysiological studies and treatment development in schizophrenia (SZ) have mainly focused on modulating neurotransmitters. Currently available antipsychotics that affect neurotransmitters fail to significantly improve long term social/functional outcomes. Therefore, there is an urgent need to characterize alternative pathophysiological models to design novel treatments. Mounting evidence over the last 5 decades suggest that neuroinflammation may be fruitfully targeted for pathophysiological studies and novel treatment development. Neuroinflammation was relegated to be unimportant in the pathophysiology of SZ. Emerging evidence strongly suggest reciprocal regulation between the immune and the central nervous systems. Immune mediators, e.g. cytokines that are expressed on neurons and glia modulate neuronal development, programmed cell death, neuronal signal transduction, neuroplasticity and neurotransmission through dopamine, serotonin, glutamate, and norepinephrine. Abnormalities of these neurotransmitters are implicated in the pathophysiology of SZ. Likewise, neurotransmitters secreted from nerve terminals modulate immune cell activity supporting an intricate reciprocal relationship between the two apparently disparate systems. Hence, systematic studies on neuroinflammation would provide a meaningful alternative pathophysiological model for novel treatment designs. Although extant literature provides ample suggestive data on neuroinflammation, there is a paucity of direct in vivo evidence of neuroinflammation and its clinical and neurobiological correlates. This proposal aims to systematically gather convergent preliminary in vivo multimodal neuroimaging data on neuroinflammation in SZ and healthy controls (HC) on two distinct aspects of neuroinflammation, namely activated inflammatory cells and microvascular changes. Positron Emission Tomography (PET) using highly specific radioligand ([11C]PBR28]) that binds to a receptor called the Translocator Protein 18 kDa (TSPO) in the mitochondria of activated microglia/ macrophage collects in vivo data on activated immune cells. Concurrently obtaining high-resolution (32-channel head coil that improves sensitivity by 4 times), high-field (7 Tesla) susceptibility weighted imaging (SWI) reliably captures changes in cerebral microvasculature (small venules/arterioles, and branching of venules/arterioles called arborizations) and local iron content due to accumulation of activated microglia/macrophages. We predict an increased [11C]PBR28 binding, increased density of venules/arterioles and arborizations, and local iron levels among SZ subjects compared to HC, specifically in the prefrontal cortex and hippocampus (aim 1). We will also test if the [11C]PBR28 binding, venluar density, arborizations and local iron levels are correlated with each other (aim 2). We will explore if these neuroinflammatory measures will correlate with brain connectivity, cognitive impairments and psychopathology (exploratory aim). Such convergent in vivo evidence on neuroinflammation could be further evaluated for biomarker characterization, targeting SZ subjects for anti-inflammatory drugs, finding specific immune pathways relevant for SZ and developing novel drugs that target identified pathways.