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.

项目摘要 中枢神经系统（CNS）的疾病是一个重大的公共卫生和经济问题，影响 在人生的某个时候，三分之一的美国人，每年耗资超过5000亿美元。从病理上，白色 物质（WM）在中枢神经系统疾病中受到神经炎症过程（神经胶质，星形细胞增多症， 巨噬细胞浸润），急性轴突珠和神经退行性过程（脱髓鞘，轴突 退化和损失）。轴突变性导致不可逆的残疾，但不同的作用 炎症过程及其与神经变性的相互作用是未知的，这主要是由于缺乏 在人类中解析这些并发过程的生物标志物。 我们的主要目的是区分和量化WM中的神经退行性和炎症过程 MRI，并将其评估为多发性硬化症（MS）的预后标记，一种慢性炎症和 神经退行性疾病。 在AIM 1中，我们将开发一个快速的T2加权DMRI序列，统一我们的TE依赖性扩散成像 （TEDDI）具有自由梯度波形形式的技术，将获取时间减少到15分钟之内，并采用 CRAMER-RAO下限最小化，以找到用于估计内和轴外水的最佳方案 馏分，扩散系数和放松时间，这是提出的神经退行性标记 和炎症。然后，我们将测试协议对幻影和志愿者的准确性和可重复性。 在AIM 2中，我们将使用我们的方案在横截面和 在疾病的不同阶段对MS患者的纵向纵向，并确定所有参数的特定变化 随着疾病严重程度的增加。我们希望我们的神经变性相关参数将更多 在跟踪残疾方面比病变负荷和体积敏感。此外，我们将首次评估 隔室扩散性和放松时间的变化，并将其与MS疾病进展相关联。 在AIM 3中，我们将在WM几何形式中开发一个现实的蒙特卡洛随机步行模拟框架 从3D电子显微镜重建。从头开始，我们将定量探索神经胶质的影响， 在扩散和WM微观结构标记上，正常的WM的串珠，脱髓鞘和轴突损失。 总体而言，该项目将产生新型的非侵入性临床可行扩散MRI标记敏感和特异性 为了扩散神经变性和炎症过程，可以帮助更好地理解MS疾病 进展和开放的新途径，用于有效管理患者和治疗的发展。这 开发的MRI管道用于估计WM微结构标记将是直接扩展的 MS，帮助理解和量化其他神经系统疾病中的神经退行性变化和炎症。