Mesoscopic Biomarkers of Neurodegeneration and Inflammation with Diffusion MRI

项目总结 中枢神经系统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时候，每年花费超过5000亿美元。从病态上讲，白人 在中枢神经系统疾病中，物质(WM)通过神经炎性过程(胶质细胞增多症，星形胶质细胞增多症， 巨噬细胞浸润)、急性轴突串珠和神经退行性变过程(脱髓鞘、轴突 退化和丧失)。虽然轴突变性会导致不可逆转的残疾，但不同的 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 在人类体内解析这些并发过程的生物标记物。 我们的主要目标是区分和量化西医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，MS是一种慢性炎性和 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，该序列统一了我们的TE相关扩散成像 (Teddi)技术，具有自由梯度波形，将捕获时间减少到15分钟以内，并使用 Cramer-Rao下界最小化方法在轴突内外水分估算中的应用 分数、扩散系数和松弛时间，这些都是神经退行性变的建议标志 和炎症。然后，我们将在幻影和志愿者身上测试该协议的准确性和重复性。 在目标2中，我们将使用我们的方案来跟踪横断面和 对MS患者在疾病的不同阶段进行纵向观察，并识别所有参数的具体变化 随着疾病严重程度的增加。我们预计我们的神经退行性变相关参数将会更多 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 脑室弥散系数和松弛时间的变化，并与MS疾病进展相关。 在目标3中，我们将开发一个逼真的蒙特卡罗随机游动模拟框架，在WM几何中 从3D电子显微镜重建出来的。从头开始，我们将定量探索胶质细胞增多症的影响， 弥散和白质微结构标记物上正常外观白髓的珠状、脱髓鞘和轴突丢失。 总体而言，该项目将产生新的非侵入性临床可行的弥散磁共振标记灵敏和特异 扩散神经退行性变和炎症过程，这可能有助于更好地了解MS疾病 进展，并为有效管理患者和治疗开发开辟新的途径。这个 开发的用于评估WM微结构标记的MRI流水线将直接扩展到 MS，以帮助了解和量化其他神经系统疾病中的神经变性和炎症。

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.