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

精神分裂症的神经炎症：综合 PET 和高场敏感性

• 批准号: 8768059
• 负责人: Konasale M Prasad
• 金额: $ 16.92万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768059
• 关键词: Acetamides; Acute-Phase Proteins; Adverse effects; Affect; Affinity; Anisotropy; Anti-Inflammatory Agents; Anti-inflammatory; Antipsychotic Agents; Apoptosis; Autoantibodies; Autoimmune Diseases; Autopsy; Axon; Behavior; Benzodiazepine Receptor; Binding; Biological Markers; Biological Response Modifiers; Brain; C-reactive protein; Cells; Cerebrum; Chronic; Clinical; Cognitive; Cognitive deficits; Data; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disease remission; Dopamine; Dorsal; Drug Targeting; Forcep; Functional disorder; Funding; Genes; Glutamates; Gray unit of radiation dose; Head; Health Care Costs; Hippocampus (Brain); Image; Immune; Impaired cognition; Inferior; Inflammation; Inflammatory; Interleukin-6; Iron; Kinetics; Ligands; Literature; Magnetic Resonance Imaging; Major Histocompatibility Complex; Measures; Meta-Analysis; Metabolic syndrome; Methods; Microglia; Minor; Mitochondria; Modeling; Molecular Target; Monitor; Nerve; Neuraxis; Neurobehavioral Manifestations; Neurobiology; Neuroglia; Neuronal Plasticity; Neurons; Neurotransmitters; Noise; Norepinephrine; Pathway interactions; Peripheral; Pharmaceutical Preparations; Positron-Emission Tomography; Predisposition; Prefrontal Cortex; Proteins; Psychopathology; Psychotic Disorders; Radial; Recovery; Regulation; Resolution; Risk; Schizophrenia; Secondary to; Serotonin; Severities; Signal Transduction; Social Functioning; Symptoms; System; Testing; Therapeutic; Time; United States National Institutes of Health; Variant; Weight; arteriole; clinically significant; cost; cytokine; density; design; diabetes risk; diffusion anisotropy; disability; functional outcomes; genome wide association study; improved; in vivo; indexing; inflammatory marker; innovation; lipophilicity; macrophage; neuroimaging; neuroinflammation; neuron development; neurotransmission; novel; novel therapeutics; peripheral blood; psychotic symptoms; public health relevance; radioligand; receptor; social; therapy design; therapy development; uptake; venule; water diffusion; white matter

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.

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物未能长期显着改善 术语“社会/功能结果”。因此，迫切需要表征替代病理生理学模型来设计新的治疗方法。过去 5 年来越来越多的证据表明，神经炎症可能成为病理生理学研究和新疗法开发的卓有成效的目标。神经炎症在 SZ 的病理生理学中被认为不重要。新出现的证据强烈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，例如在神经元和神经胶质细胞上表达的细胞因子通过多巴胺、血清素、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。这些神经递质的异常与 SZ 的病理生理学有关。同样，从神经末梢分泌的神经递质调节免疫细胞活动，支持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有意义的替代病理生理学模型。尽管现有文献提供了关于神经炎症的充足提示性数据，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关于 SZ 和健康对照 (HC) 神经炎症的收敛初步体内多模式神经影像数据，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) 使用高度特异性放射性配体 ([11C]PBR28]) 与激活的小胶质细胞/巨噬细胞线粒体中称为易位蛋白 18 kDa (TSPO) 的受体结合，收集有关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）磁化率加权成像 (SWI) 可靠地捕获脑微血管系统（小静脉/小动脉，以及称为树枝化的小静脉/小动脉分支）和局部铁的变化 由于活化的小胶质细胞/巨噬细胞的积累而产生的含量。我们预测，与 HC 相比，SZ 受试者的 [11C]PBR28 结合增加、小静脉/小动脉和树枝化密度增加以及局部铁水平增加，特别是在前额叶皮层和海马体中（目标 1）。我们还将测试 [11C]PBR28 结合、静脉密度、树枝化和局部铁水平是否相互相关（目标 2）。我们将探讨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（探索性目标）。这种关于神经炎症的体内汇聚证据可以进一步评估生物标志物表征，针对 SZ 受试者使用抗炎药物，寻找与 SZ 相关的特定免疫途径，并开发针对已识别途径的新药物。