Application of Advanced Quantitative Methods to Schizophrenia Research

先进定量方法在精神分裂症研究中的应用

基本信息

批准号：
10541252
负责人：
ANDREW J DWORK
金额：
$ 45.25万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541252
关键词：
3-Dimensional Academy Age Anisotropy Antibodies Architecture Area Arts Autopsy Axon Biochemical Biochemistry Brain Cerebrum Cessation of life Characteristics Clinical Collaborations Collection Confocal Microscopy Consensus DNA Methylation Data Data Set Deformity Dependence Diagnosis Diagnostic Diameter Diffusion Magnetic Resonance Imaging Dimensions Electron Microscope Electron Microscopy Electrons Evaluation Face Fiber Forensic Medicine Genetic Transcription Heavy Metals Histologic Histology Image Image Analysis Immunofluorescence Immunologic Immunohistochemistry Individual Interviewer Knowledge Label Left Macedonia Machine Learning Magnetic Resonance Imaging Major Depressive Disorder Measurement Measures Mental disorders Messenger RNA Methodology Methods Microscopy Modeling Molecular Morphologic artifacts Multiomic Data Myelin Myelin Sheath National Institute of Mental Health Neurofibrillary Tangles Neurofilament Proteins New York Oligodendroglia Online Systems Optic Nerve Paraffin Pathologist Persons Pharmaceutical Preparations Phosphorylation Probability Procedures Process Property Proteins Proteomics Protocols documentation Psychiatrist Psychologist Recording of previous events Reporting Research Research Personnel Resolution Schizophrenia Science Shotguns Silver Staining Space Perception Stains Structural defect Structure Techniques Testing Thick Time Tissues Toxicology Training Transcript Universities Variant Visualization cognitive function cohort data archive data fusion deep neural network design diffusion anisotropy glial activation high resolution imaging histological studies imaging study innovation instrument interest microscopic imaging multidimensional data network models neuropathology novel precursor cell psychologic reconstruction sex symposium tool two photon microscopy two-photon water diffusion white matter

项目摘要

PROJECT SUMMARY Abnormalities of white matter are important in schizophrenia. A preponderance of studies have found decreased levels of transcripts for myelin-related proteins in autopsy brains. Some have found a decrease in the proteins themselves, and some have not. Hundreds of diffusion tensor imaging (DTI) studies have found reduced fractional anisotropy (FA) in the brains of many people with schizophrenia (SCH). Prefrontal white matter is among the areas usually involved. Decreased FA is interpreted as disruption of normal architecture. However, postmortem examination has failed to identify characteristic abnormalities, suggesting that abnormalities causing diminished FA are subtle, and that postmortem examinations have not used the right tools to find them. We have therefore been developing, as part of a FIC/NIMH collaboration with the Macedonian Academy of Sciences and Arts, two new methods to characterize white matter at high resolution. The first is a machine learning protocol to measure axonal diameters and myelin sheath thickness in electron microscope (EM) images of prefrontal white matter, recognizing and avoiding artifacts in EM of autopsy tissue. This will enable us to measure thousands of fibers in EM images, from individuals with SCH, major depressive disorder (MDD), or no psychiatric illness (NPI). The second method, suggested by the DTI findings, is to analyze the spatial orientation of the axons themselves. We will use 3-dimensional (3D) reconstructions of high-resolution images of the axons themselves, identified by Bielschowsky silver stain or immunohistochemistry for phosphorylated neurofilament protein. To obtain high- resolution images of Bielschowsky stains, we will take advantage of the recent observation by Dr. Mark Sonders, co-investigator on this project, that these and other heavy metal stains luminesce under 2-photon infrared excitation. This technique yields clear images of individual axons that can be traced and measured in 3 dimensions. We will perform these procedures on sections from existing paraffin blocks that comprise a complete left prefrontal coronal section from 36 triads containing 1 case each of SCH, MDD, or NPI, matched for sex and age. These brains were included in earlier studies that yielded data on protein composition, mRNA for myelin- related proteins, DNA methylation, microglial activation, and semiquantitative myelin histology. In a third, exploratory aim, we will employ graphical models in three multi-omics data fusion approaches to combine different types of high-dimensional data, including those produced by Aims 1 and 2, with known structural properties of axons and myelin in white matter, in order to build a model or detect novel dependencies of what is disturbed in schizophrenia. We expect that novel techniques for data fusion will reveal associations based on multidimensional correlations that could not be detected by modeling the single-domain datasets separately.

项目概要白质异常在精神分裂症中很重要。大量研究发现尸检大脑中髓磷脂相关蛋白的转录水平降低。有些人发现减少了蛋白质本身，有些则没有。数百项扩散张量成像 (DTI) 研究发现，许多精神分裂症（SCH）患者大脑中存在分数各向异性（FA）。前额叶白质是在通常涉及的领域中。 FA 降低被解释为正常结构的破坏。然而，尸检未能发现特征性异常，这表明异常导致 FA 的减少是微妙的，事后检查没有使用正确的工具来发现它们。我们有因此，作为 FIC/NIMH 与马其顿科学院合作的一部分，我们一直在开发 Arts，两种以高分辨率表征白质的新方法。第一个是机器学习协议测量前额白电子显微镜 (EM) 图像中的轴突直径和髓鞘厚度物质，识别并避免尸检组织电镜中的伪影。这将使我们能够测量数千个 EM 图像中的纤维，来自患有 SCH、重度抑郁症 (MDD) 或无精神疾病 (NPI) 的个体。 DTI 研究结果建议的第二种方法是分析轴突本身的空间方向。我们将使用轴突本身的高分辨率图像的 3 维 (3D) 重建，由 Bielschowsky 银染色或免疫组织化学检测磷酸化神经丝蛋白。为了获得高 Bielschowsky 染色剂的分辨率图像，我们将利用 Mark Sonders 博士最近的观察，该项目的联合研究员，这些和其他重金属污渍在 2 光子红外下发光励磁。该技术可生成单个轴突的清晰图像，可在 3 年内进行追踪和测量方面。我们将在现有石蜡块的部分上执行这些程序，这些石蜡块构成完整的石蜡块。左前额叶冠状切片来自 36 个三联体，其中 SCH、MDD 或 NPI 各有 1 个病例，性别和性别相匹配年龄。这些大脑被纳入早期的研究中，这些研究产生了有关蛋白质组成、髓磷脂 mRNA 的数据。相关蛋白质、DNA 甲基化、小胶质细胞激活和半定量髓磷脂组织学。在第三个中，为了探索性的目标，我们将在三种多组学数据融合方法中采用图形模型来结合不同类型的高维数据，包括目标 1 和 2 产生的具有已知结构的数据白质中轴突和髓磷脂的特性，以便建立模型或检测什么的新依赖性精神分裂症受到干扰。我们期望数据融合的新技术将揭示基于通过单独对单域数据集建模无法检测到多维相关性。