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。 基于松弛的磁共振成像(MRI)在揭示宏观组织异常方面是敏感的 在大脑中，它们对多发性硬化症病变的病理基础没有特异性，对预后的预测有限。 角色。这些方法对MS白质病变(WM)、定性MS病变在白质(WM) 临床核磁共振已证实大脑皮层病变较为困难。高级扩散磁共振成像(DMRI)技术可提供 MS定量敏感性对提高对轴突和树突损伤的认识的潜力 标测(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和可靠的全脑成像生物标记物，用于早期 诊断多发性硬化症，监测病情进展。我们已经开发出了整个小鼠大脑的dMRI和 QSM方法在25微米各向同性分辨率下使用3D欠采样采集和非线性重建。 我们最新的研究结果表明，术后1d，胼胝体QSM显著降低(更具抗磁性) 用药2周。我们的假设是，将新的dMRI和QSM技术结合在一起 高空间分辨率通过检测多发性硬化症的 整个大脑的铁调节失调、脱髓鞘和轴突损伤的进展。在这 建议，我们将在体内和体外进行核磁共振成像，以量化整个大脑脱髓鞘，铁 使用Thy-1 YFP-16转基因小鼠并给予铜比林的调节失调和轴突损伤。QSM 从基本扩散张量成像(DTI)模型到高级轴突定位的价值和dMRI结果 弥散和密度成像(NODI)模型和扩散峰度成像(DKI)模型将在 不同的计时点(目标1)。目前，直接将MRI表现与组织学相关联仍然具有挑战性，因为 由于水的扩散、松弛和磁性而产生的有限空间分辨率和各种图像对比度 敏感度特征。3D MRI定量映射将与整个大脑进行对比验证 在每个时间点进行光片显微镜(LSM)检查。基于成像的生物标记物将由体素观察- 基于MRI与LSM的比较。3D联合注册比较也将帮助我们从根本上 了解磁共振图像对比度的来源和特性(目标2)。高分辨率多维大脑 每个时间点的地图集将在WaxholmSpace和Allen Brain Mouse Atlas上生成和共享 不同空间分辨率，从25微米到200微米各向同性分辨率(目标3)。这个项目是预期的 为提高MRI诊断多发性硬化症的特异性和了解其复杂性提供新的见解 这种疾病的发病机制。