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）的病理生理研究和治疗发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不能长期显著改善