Mesoscopic Biomarkers of Neurodegeneration and Inflammation with Diffusion MRI

弥散 MRI 神经退行性变和炎症的细观生物标志物

• 批准号: 10251994
• 负责人: Els Fieremans
• 金额: $ 66.25万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251994
• 关键词: 3-Dimensional; Acute; Affect; Alzheimer' s Disease; American; Anatomy; Astrocytosis; Autoimmune Diseases; Axon; Biological Markers; Central Nervous System Diseases; Chronic; Clinical; Complex; Cuprizone; Demyelinations; Diffuse; Diffusion; Diffusion Magnetic Resonance Imaging; Dimensions; Disease; Disease Progression; Electron Microscopy; Fiber; Funding; Geometry; Gliosis; Human; Image; Imaging Techniques; Infiltration; Inflammation; Inflammatory; Injury; Intoxication; Lesion; Life; MRI Scans; Magnetic Resonance Imaging; Measures; Methods; Modeling; Molecular; Monitor; Monte Carlo Method; Motion; Multiple Sclerosis; Nerve Degeneration; Neurodegenerative Disorders; Noise; Pathologic; Pathologic Processes; Patients; Pilot Projects; Process; Prognostic Marker; Protocols documentation; Public Health; Relapse; Relaxation; Reproducibility; Roentgen Rays; Role; Rotation; Severity of illness; Signal Transduction; Specificity; Structure; Techniques; Testing; Therapeutic; Time; Translating; United States; Walking; Water; Weight; axonal degeneration; base; candidate marker; chronic inflammatory disease; computer framework; cost; disability; health economics; imaging modality; in vivo; insight; macrophage; mouse model; multiple sclerosis patient; nervous system disorder; neuroinflammation; novel; remyelination; simulation; soft tissue; therapy development; volunteer; white matter

PROJECT SUMMARY Diseases of the central nervous system (CNS) are a significant public health and economic problem, affecting one in three Americans at some point in life, and costing over $500 billion per year. Pathologically, the white matter (WM) is compromised in CNS disorders by neuro-inflammatory processes (gliosis, astrocytosis, macrophage infiltration), acute axonal beading, and neurodegenerative processes (demyelination, axonal degeneration and loss). While axonal degeneration results in irreversible disability, the roles of different inflammatory processes, and their interplay with neurodegeneration, are unknown, mainly due to the lack of biomarkers that parse these concurrent processes in vivo in humans. Our main objective is to distinguish and quantify neurodegenerative and inflammatory processes in WM with MRI, and evaluate them as prognostic markers for Multiple Sclerosis (MS), a chronic inflammatory and neurodegenerative disorder. In Aim 1, we will develop a fast T2-weighted dMRI sequence unifying our TE-dependent Diffusion Imaging (TEdDI) technique with free gradient wave forms reducing acquisition time to within 15 minutes, and employ Cramer-Rao lower bound minimization to find an optimal protocol for estimating intra- and extra-axonal water fractions, diffusion coefficients and relaxation times, which are the proposed markers of neurodegeneration and inflammation. We will then test the protocol's accuracy and reproducibility on phantoms and volunteers. In Aim 2, we will use our protocol to track neurodegeneration and inflammation both cross-sectionally and longitudinally on MS patients at different stages in the disease, and identify specific changes of all parameters with increasing disease severity. We expect that our neurodegeneration-related parameters will be more sensitive than lesion load and volumetrics in tracking disability. Furthermore, we will for the first time assess changes in compartmental diffusivities and relaxation times and relate them to MS disease progression. In Aim 3, we will develop a framework of realistic Monte Carlo random walk simulations in WM geometries reconstructed from 3d electron microscopy. Ab initio, we will quantitatively explore the effect of gliosis, beading, demyelination and axonal loss in normal-appearing WM on diffusion and WM microstructure markers. Overall, the project will yield novel non-invasive clinically feasible diffusion MRI markers sensitive and specific to diffuse neurodegeneration and inflammatory processes, that could help better understand MS disease progression and open new avenues for effective management of patients and therapy development. The developed MRI pipeline for estimating WM microstructure markers will be straightforwardly extendable beyond MS, to help understand and quantify neurodegeneration and inflammation in other neurological diseases.

项目概要 中枢神经系统（CNS）疾病是一个重大的公共卫生和经济问题，影响 三分之一的美国人在一生中的某个阶段花费了超过 5000 亿美元。病理上，白 中枢神经系统疾病中的物质（WM）受到神经炎症过程（神经胶质增生、星形细胞增多、 巨噬细胞浸润）、急性轴突成珠和神经退行性过程（脱髓鞘、轴突 退化和丧失）。虽然轴突变性会导致不可逆的残疾，但不同的作用 炎症过程及其与神经退行性变的相互作用尚不清楚，主要是由于缺乏 解析人类体内这些并发过程的生物标记。 我们的主要目标是区分和量化 WM 中的神经退行性和炎症过程 MRI，并评估它们作为多发性硬化症 (MS) 的预后标志物，多发性硬化症是一种慢性炎症和疾病 神经退行性疾病。 在目标 1 中，我们将开发一种快速 T2 加权 dMRI 序列，统一我们的 TE 依赖性扩散成像 (TEdDI) 技术具有自由梯度波形，可将采集时间缩短至 15 分钟内，并采用 Cramer-Rao 下限最小化找到估计轴突内和轴突外水的最佳方案 分数、扩散系数和弛豫时间，这些是神经变性的拟议标志 和炎症。然后，我们将在模型和志愿者上测试该协议的准确性和可重复性。 在目标 2 中，我们将使用我们的方案来跟踪神经退行性变和炎症的横截面和 对处于疾病不同阶段的多发性硬化症患者进行纵向研究，并确定所有参数的具体变化 随着疾病严重程度的增加。我们期望我们的神经退行性变相关参数会更多 在跟踪残疾方面比病变负荷和体积测量更敏感。此外，我们将首次评估 区室扩散率和弛豫时间的变化并将其与多发性硬化症疾病进展联系起来。 在目标 3 中，我们将开发 WM 几何中的真实蒙特卡洛随机游走模拟框架 从 3D 电子显微镜重建。从头开始，我们将定量探索神经胶质增生的影响， 扩散和 WM 微观结构标记上正常出现的 WM 中的珠状、脱髓鞘和轴突损失。 总体而言，该项目将产生新型非侵入性临床可行的扩散 MRI 标记物，敏感且特异 扩散神经退行性变和炎症过程，有助于更好地了解多发性硬化症 进展并为有效管理患者和治疗开发开辟新途径。这 开发的用于估计 WM 微观结构标记的 MRI 管道将可以直接扩展至 MS，帮助理解和量化其他神经系统疾病中的神经退行性变和炎症。