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）是一种异质性脑疾病，通常以妄想，幻觉和 功能下降，典型的青少年和成年初发作。遗传，神经病理学， 神经影像学研究表明，神经炎症在SCZ病因中的作用，这证明了这一点 在疾病的早期。这表明神经炎症可能代表SCZ风险标记，因此 促进早期认可和未来的药物开发以改善预后。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。我们的建议目标 验证一种新型的非侵入性，新的磁共振成像（MRI）技术称为扩散基础 频谱成像（DBSI）以鉴定SCZ中的神经炎症。 DBSI可以轻松检测和量化 神经炎症（细胞增加）和白质的改变（轴突损伤/丧失和脱髓鞘）和 先前已在多发性硬化症和阿尔茨海默氏病中得到了验证，但在SCZ中没有得到验证。我们建议测试 DBSI将确定SCZ患者组织学样本中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患者的验尸脑样本并匹配 来自NIH Neurobiobank的对照（n = 20），并研究了DBSI细胞子组件的关系 与小胶质标记的组织反应性CD163和补体标记物C4（AIM 1）。我们假设 DBSI细胞与选定的灰色和白质区域之间的线性关系很强。另外，我们 将使用DBSI在体内表征18-30岁的SCZ患者和对照组的大脑（n = 30），并识别 DBSI亚组件的组差异（AIM 2）。我们假设SCZ大脑中的DBSI细胞更大 与对照组相比。在完成这项工作时，我们希望确定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，这些信息将用于改善 患有精神病的风险的人并促进了新疗法的测试。