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

• 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
• 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

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）是一种以自身免疫性注射为特征的异质性神经系统疾病 加上脱髓鞘和最终的神经变性，影响了全球超过200万人。 基于松弛的磁共振成像（MRI）在揭示宏观组织异常方面很敏感 在大脑中，它们不是特定于MS病变的病理底物，并且预后有限 角色。这些方法对白质（WM）中的MS病变很敏感，MS病变的表征 通过临床MRI证明，大脑皮层已被证明很困难。高级扩散MRI（DMRI）技术提供 提高对MS中轴突和树突损伤的理解的潜力。定量敏感性 作为一种新颖的MRI技术，映射（QSM）已被证明与髓磷脂和 铁含量。我们的长期目标是为早期开发特定可靠的整个脑成像生物标志物 诊断MS并监测疾病进展。我们已经开发了整个小鼠脑DMRI，并且 在25 µM各向同性分辨率下使用3D采样采集和非线性重建的QSM方法。 我们最近的结果表明，在 2周的库酮给药。我们的假设是将新颖的DMRI和QSM技术相结合 高空间分辨率通过检测 铁失调，脱髓鞘和轴突通过整个大脑的损害的进展。在这个 提案，我们将同时执行体内和离体MRI来量化整个脑脱髓鞘，铁 使用THY-1 YFP-16转基因小鼠使用cuprizone给药，功能障碍和轴突损伤。 QSM 从基本扩散张量成像（DTI）模型到高级神经元化的值和DMRI结果 分散和密度成像（NODDI）模型和扩散峰度成像（DKI）模型将在 不同的时序点（目标1）。目前，由于 有限的空间分辨率和来自水扩散，松弛和磁性的各种图像对比度 敏感性特征。 3D MRI定量映射将与整个大脑进行验证 每个时间点的轻度显微镜（LSM）。基于成像的生物标志物将由体素观察到 基于MRI和LSM之间的比较。 3D共同注册比较也将帮助我们从根本上 了解MR图像对比和属性的起源（AIM 2）。高分辨率多维大脑 在Waxholm空间和Allen Brain Mouse Atlas都将生成和共享每个时刻的地图集 不同空间分辨率的空间，从25 µm到200 µm各向同性分辨率（AIM 3）。期望这个项目 提供新颖的见解以提高MRI的特异性以诊断MS并了解复合物 疾病的机制。