Validation of Diffusion Basis Spectrum Imaging of Neuroinflammation in Schizophrenia

精神分裂症神经炎症扩散基谱成像的验证

• 批准号: 10573475
• 负责人: DANIEL MAMAH
• 金额: $ 23.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10573475
• 关键词: Address; Adolescence; Alzheimer' s Disease; Anterior; Autopsy; Axon; Biological; Brain; Brain Diseases; Cellularity; Characteristics; Child; Complement; Corpus Callosum; Data; Delusions; Demyelinations; Development; Diffusion; Encephalitis; Etiology; Future; Genes; Genetic; Goals; Hallucinations; Hippocampus; Imaging Techniques; Inflammation; Inflammatory; Internal Capsule; Investigation; Limb structure; Longitudinal Studies; Magnetic Resonance Imaging; Major Histocompatibility Complex; Mediating; Methods; Microglia; Multiple Sclerosis; Nerve Degeneration; Pathogenesis; Patients; Persons; Phase; Positron-Emission Tomography; Prefrontal Cortex; Psychoses; Psychotic Disorders; Quality of life; Radiation; Radiation exposure; Risk; Risk Marker; Role; Sampling; Schizophrenia; Serum; Specificity; Temporal Lobe; Testing; Tissues; United States; United States National Institutes of Health; Validation; Variant; Water; Work; aged; axon injury; brain abnormalities; comparison control; complement system; cost; density; drug development; emerging adult; extracellular; functional decline; genome wide association study; genomic locus; gray matter; histological specimens; imaging biomarker; imaging modality; improved; improved outcome; in vivo; in vivo imaging; neuroimaging; neuroinflammation; neuropathology; new therapeutic target; novel; prevent; recruit; risk variant; schizophrenia risk; spectrograph; synaptic pruning; white matter

PROJECT SUMMARY Schizophrenia (SCZ) is a heterogeneous brain disorder typically characterized by delusions, hallucinations, and functional decline, with a typical first onset in late adolescence and early adulthood. Genetic, neuropathological, and neuroimaging studies have suggested a role of neuroinflammation in the etiology of SCZ, which is evident early in the course of illness. This suggests neuroinflammation may represent a SCZ risk marker and therefore facilitate early recognition and future drug development to improve outcomes. In vivo imaging methods for estimating neuroinflammation have been limited by radiation exposure, specificity, and cost. Our proposal aims to validate a novel non-invasive, new magnetic resonance imaging (MRI) technique called Diffusion Basis Spectrum Imaging (DBSI) to identify neuroinflammation in SCZ. DBSI can simultaneously detect and quantify neuroinflammation (increased cellularity) and white matter alterations (axonal injury/loss and demyelination) and has been previously validated in multiple sclerosis and Alzheimer's disease, but not in SCZ. We propose to test the overarching hypothesis that DBSI will identify neuroinflammation in histological samples from SCZ patients. To achieve this objective, we will obtain postmortem brain samples of 18–30-year-old SCZ patients and matched controls (n=20) from the NIH Neurobiobank and investigate the relationship of the DBSI cellularity subcomponent with tissue reactivity for the microglial marker, CD163, and the complement marker, C4 (Aim 1). We hypothesize a strong linear relationship between DBSI cellularity and selected gray and white matter regions. In addition, we will use DBSI in vivo to characterize the brains of 18–30-year-old SCZ patients and controls (n=30) and identify group differences in DBSI subcomponents (Aim 2). We hypothesize greater DBSI cellularity in SCZ brains compared to controls. In completing this work, we expect to identify non-invasive neuroinflammation and white matter integrity markers for SCZ. In the long term, this information would be used to improve the identification of those at risk for developing psychosis and facilitate the testing of new treatments.

项目摘要 精神分裂症（SCZ）是一种异质性脑障碍，其典型特征是妄想、幻觉和幻觉。 功能下降，典型的首次发病在青春期后期和成年早期。遗传的神经病理的 神经影像学研究表明，神经炎症在SCZ的病因学中起作用，这是显而易见的。 在疾病的早期。这表明神经炎症可能代表SCZ风险标志物，因此 促进早期识别和未来的药物开发，以改善结果。体内成像方法 估计神经炎症受到辐射暴露、特异性和成本的限制。我们的提案旨在 验证一种新的非侵入性磁共振成像（MRI）技术，称为扩散基础， 光谱成像（DBSI），以确定SCZ中的神经炎症。DBSI可以同时检测和定量 神经炎症（细胞增多）和白色物质改变（轴突损伤/缺失和脱髓鞘），以及 先前已在多发性硬化症和阿尔茨海默病中得到验证，但未在SCZ中得到验证。我们建议测试 DBSI将识别SCZ患者组织学样本中的神经炎症的总体假设。 为了实现这一目标，我们将获得18-30岁SCZ患者的死后脑样本，并将其与对照组进行匹配。 来自NIH Neurobiobank的对照（n=20），并研究DBSI细胞亚组分之间的关系。 具有对小胶质细胞标记物CD 163和补体标记物C4的组织反应性（Aim 1）。我们假设 DBSI细胞性与所选灰质和白色物质区域之间存在强线性关系。另外我们 将在体内使用DBSI来表征18-30岁SCZ患者和对照组（n=30）的大脑，并确定 DBSI子组件的组间差异（目标2）。我们假设在SCZ脑中DBSI细胞更多 与对照相比。在完成这项工作时，我们希望能够识别非侵入性神经炎症和白色 SCZ的物质完整性标记。从长远来看，这一信息将用于改进识别 那些有患精神病风险的人，并促进新疗法的测试。