Characterization of Whole Brain Demyelination and Axon Damage Using High-resolution Magnetic Resonance Imaging

使用高分辨率磁共振成像表征全脑脱髓鞘和轴突损伤

基本信息

批准号：
10626948
负责人：
Nian Wang
金额：
$ 39.63万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626948
关键词：
3-Dimensional Acute Affect Anatomy Animal Model Atlases Autoimmune Axon Brain Brain imaging Central Nervous System Diseases Cerebral cortex Characteristics Clinical Complex Corpus Callosum Coupled Cuprizone Databases Demyelinations Dendrites Development Diagnosis Diffusion Diffusion Magnetic Resonance Imaging Dimensions Disease Disease Progression Early Diagnosis Early treatment Exhibits External Capsule Functional disorder Goals Histology Human Image Imaging Techniques Immunohistochemistry Inflammation Process Investigation Iron Knowledge Lesion Light Magnetic Resonance Imaging Magnetism Maps Measures Methods Microscopic Microscopy Modeling Monitor Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Nerve Degeneration Neurites Neurodegenerative Disorders Neurons Non-Invasive Detection Oligodendroglia Outcome Pathologic Pathology Persons Predisposition Process Property Protocols documentation Relaxation Resolution Rodent Role Sampling Site Specificity Structure Symptoms Techniques Technology Testing Time Tissues Transgenic Mice anterior commissure autoimmune inflammation axon injury biophysical model brain magnetic resonance imaging chronic demyelination clinical application connectome contrast imaging density disease diagnosis early detection biomarkers gray matter image archival system imaging biomarker imaging modality improved in vivo indexing insight interest meter microscopic imaging mouse model nervous system disorder novel prognostic quantitative imaging reconstruction remyelination tractography water diffusion white matter

项目摘要

Abstract Multiple sclerosis (MS) is a heterogeneous neurological disorder characterized by autoimmune inflammation coupled to demyelination and eventual neurodegeneration, affecting more than 2 million people worldwide. Relaxation-based magnetic resonance imaging (MRI) is sensitive in revealing macroscopic tissue abnormalities in the brain, they are not specific to the pathological substrate of the MS lesion and have a limited prognostic role. These methods are sensitive to the MS lesions in white matter (WM), characterization of MS lesions in the cerebral cortex has been proven to be difficult by clinical MRI. Advanced diffusion MRI (dMRI) techniques offer the potential to improve the understanding of axon and dendrites damage in MS. Quantitative susceptibility mapping (QSM), as a novel MRI technique, has been demonstrated to show high correlations with myelin and iron content. Our long-term goal is to develop specific and reliable whole brain imaging biomarkers for early diagnosis of MS and monitoring the disease progression. We have developed the whole mouse brain dMRI and QSM methods at 25 µm isotropic resolution using 3D under sampling acquisition and nonlinear reconstruction. Our recent results have showed that QSM of corpus callosum decreases significantly (more diamagnetic) after 2 weeks cuprizone administration. Our hypothesis is that combining novel dMRI and QSM technologies at high spatial resolution affords robust and quantitative imaging-based biomarkers of MS by detecting the progression of iron dysregulation, demyelination, and axon damage through the whole brain. In this proposal, we will perform both in vivo and ex vivo MRI to quantify the whole brain demyelination, iron dysregulation, and axon damage using Thy-1 YFP-16 transgenic mice with cuprizone administration. The QSM values and dMRI outcomes from basic diffusion tensor imaging (DTI) model to the advanced neurite orientation dispersion and density imaging (NODDI) model and diffusion kurtosis imaging (DKI) model will be measured at different timing points (Aim 1). Currently, directly correlating MRI findings to histology is still challenging due to the limited spatial resolution and various image contrasts derived from water diffusion, relaxation, and magnetic susceptibility characteristics. The 3D MRI quantitative mappings will be validated against with the whole brain light sheet microscopy (LSM) at each timing point. The imaging-based biomarkers will be observed by the voxel- based comparison between MRI and LSM. The 3D co-registration comparison will also help us to fundamentally understand the origin of MR image contrasts and properties (Aim 2). The high-resolution multidimensional brain atlas at each timing point will be generated and shared at both Waxholm space and Allen Brain Mouse Atlas space at different spatial resolution, from 25 µm to 200 µm isotropic resolution (Aim 3). This project is expected to provide novel insights to improve the specificity of MRI for the diagnosis of MS and understand the complex mechanism of the disease.

抽象的多发性硬化症 (MS) 是一种异质性神经系统疾病，其特征为自身免疫性炎症加上脱髓鞘和最终的神经退行性变，影响了全世界超过 200 万人。基于松弛的磁共振成像（MRI）对于揭示宏观组织异常非常敏感在大脑中，它们对多发性硬化症病变的病理基础并不具有特异性，并且预后有限这些方法对白质（WM）中的MS病变敏感，表征MS中的病变。临床 MRI 已证明大脑皮层是困难的。提高对 MS 中轴突和树突损伤的理解的潜力。映射（QSM）作为一种新型 MRI 技术，已被证明与髓磷脂和我们的长期目标是为早期开发特异性且可靠的全脑成像生物标志物。诊断多发性硬化症并监测疾病进展我们开发了全小鼠大脑 dMRI 和使用 3D 采样采集和非线性重建实现 25 µm 各向同性分辨率的 QSM 方法。我们最近的结果表明，胼胝体的 QSM 显着降低（更具抗磁性）我们的假设是，将新颖的 dMRI 和 QSM 技术结合起来，进行 2 周的铜宗给药。高空间分辨率通过检测 MS 提供稳健且定量的基于成像的生物标志物整个大脑的铁失调、脱髓鞘和轴突损伤的进展。建议，我们将进行体内和离体 MRI 来量化全脑脱髓鞘、铁使用铜宗给药的 Thy-1 YFP-16 转基因小鼠的失调和轴突损伤。从基本弥散张量成像 (DTI) 模型到高级神经突定向的值和 dMRI 结果色散和密度成像（NODDI）模型和扩散峰度成像（DKI）模型将在目前，由于以下原因，将 MRI 结果与组织学直接关联起来仍然具有挑战性。有限的空间分辨率和由水扩散、弛豫和磁力产生的各种图像对比度 3D MRI 定量映射将针对整个大脑进行验证。体素将在每个时间点观察基于成像的生物标记物。基于 MRI 和 LSM 的比较也将从根本上帮助我们。了解 MR 图像对比度和属性的起源（目标 2）高分辨率多维大脑。每个时间点的图集将在 Waxholm 空间和 Allen Brain Mouse Atlas 上生成和共享空间分辨率从 25 µm 到 200 µm 各向同性分辨率（目标 3）。提供新颖的见解，以提高 MRI 对 MS 诊断的特异性并了解复杂的情况疾病机制。