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.

摘要 多发性硬化症（MS）是一种以自身免疫性炎症为特征的异质性神经系统疾病 再加上脱髓鞘和最终的神经变性，影响到全球200多万人。 基于弛豫的磁共振成像（MRI）在揭示宏观组织异常方面是敏感的 在脑中，它们对MS病变的病理基质不是特异性的，并且具有有限的预后 作用这些方法对白色物质（WM）中的MS病变敏感，对MS病变的表征在脑白质中敏感。 临床MRI已经证明大脑皮层是困难的。先进的弥散MRI（dMRI）技术提供了 提高对MS中轴突和树突损伤的理解的潜力。定量易感性 磁共振成像（QSM）作为一种新的MRI技术，已被证明与髓鞘和 铁含量我们的长期目标是开发特异性且可靠的全脑成像生物标志物，用于早期诊断 MS的诊断和监测疾病进展。我们已经开发了整个小鼠大脑的dMRI， 使用3D欠采样采集和非线性重建的25 µm各向同性分辨率的QSM方法。 我们最近的研究结果表明，胼胝体的QSM显着降低（更多的抗磁性）后， 2周铜腙给药。我们的假设是，结合新的dMRI和QSM技术， 高空间分辨率提供了强大的和定量的基于成像的MS生物标志物， 铁失调、脱髓鞘和轴突损伤在整个脑中的进展。在这 建议，我们将进行体内和体外MRI，以量化全脑脱髓鞘，铁 使用Thy-1 YFP-16转基因小鼠和铜腙给药，观察到了神经元功能失调和轴突损伤。的QSM 从基本扩散张量成像（DTI）模型到高级神经突定向的值和dMRI结果 弥散和密度成像（NODDI）模型和弥散峰度成像（DKI）模型将在 不同的时间点（目标1）。目前，直接将MRI结果与组织学相关联仍然具有挑战性， 有限的空间分辨率和各种图像对比度来自水扩散，弛豫，和磁 敏感性特征将针对全脑验证3D MRI定量映射 光片显微镜（LSM）在每个时间点。将通过体素观察基于成像的生物标志物- MRI和LSM之间的比较。3D共配准比较还将帮助我们从根本上 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 每个时间点的图谱将在Waxholm空间和艾伦脑小鼠图谱中生成和共享 以不同的空间分辨率，从25微米到200微米的各向同性分辨率（目标3）。该项目预计 提供新的见解，以提高MRI诊断MS的特异性，并了解复杂的 疾病的机制。