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

描述(申请人提供)：精神分裂症(SZ)的病理生理学研究和治疗进展主要集中在调节神经递质上。目前可用的影响神经递质的抗精神病药物未能显著改善Long 术语社会/功能结果。因此，迫切需要确定可供选择的病理生理模型，以设计新的治疗方法。在过去的50年里，越来越多的证据表明，神经炎症可能是病理生理学研究和新的治疗开发的有效靶点。神经炎症在SZ的病理生理学中被认为是不重要的。新出现的证据有力地表明，免疫系统和中枢神经系统之间存在相互调节。免疫介质，如细胞因子，表达在神经元和胶质细胞上，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、细胞程序性死亡、神经元信号转导、神经可塑性和神经传递。这些神经递质的异常与SZ的病理生理有关。同样，神经末梢分泌的神经递质调节免疫细胞活动，支持这两个明显不同的系统之间复杂的相互关系。因此，对神经炎症的系统研究将为新的治疗设计提供一个有意义的替代病理生理学模型。虽然现有的文献提供了大量关于神经炎症的提示性数据，但很少有直接的体内证据表明神经炎症及其临床和神经生物学的相关性。这项建议旨在系统地收集关于SZ和健康对照组(HC)神经炎症的初步体内多模式神经成像数据，这些数据涉及神经炎症的两个不同方面，即激活的炎症细胞和微血管变化。正电子发射断层扫描(PET)使用高度特异的放射性配基([11C]PBR28])，与激活的小胶质细胞/巨噬细胞线粒体中称为转位蛋白18 kDa(TSPO)的受体结合，收集体内激活的免疫细胞的数据。同时获得高分辨率(32通道磁头线圈，将灵敏度提高4倍)，高场(7特斯拉)磁化率加权成像(SWI)可靠地捕获脑微血管(小静脉/小动脉，以及称为树枝的小静脉/小动脉的分支)和局部铁的变化 这是由于激活的小胶质细胞/巨噬细胞积聚所致。我们预测，与HC相比，SZ受试者的[11C]PBR28结合量增加，小静脉/小动脉和树枝密度增加，局部铁水平增加，特别是在前额叶皮质和海马区(目标1)。我们还将测试[11C]PBR28结合、静脉密度、树枝形成和局部铁水平是否相互关联(目标2)。我们将探索这些神经炎性措施是否与大脑连接、认知障碍和精神病理学相关(探索性目的)。这些关于神经炎症的体内证据可以进一步评估生物标记物的特征，针对SZ患者的抗炎药物，寻找与SZ相关的特定免疫途径，并开发针对已确定途径的新药。

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.