Mesoscopic Biomarkers of Neurodegeneration with Diffusion MRI

描述(申请人提供)：中枢神经系统(CNS)疾病是一个重大的公共卫生和经济问题，几乎三分之一的美国人在一生中的某个时候受到影响，每年的费用超过5000亿美元。病理上，轴突的完整性 在大多数人类神经系统疾病或损伤中，包括多发性硬化症、脑白质营养不良、创伤性脑损伤，以及正常衰老和神经退行性疾病，如帕金森氏症、亨廷顿氏症、肌萎缩侧索硬化症和阿尔茨海默病，脑白质都受到损害。神经退行性变通过许多不同的过程发生，如急性轴突损伤、脱髓鞘、炎症、慢性轴突变性或轴突丧失，以及胶质细胞增生症。量化它们的程度，并区分这些不同的潜在退变过程，对于充分评估中枢神经系统疾病的进展和治疗尤为重要，但目前尚不可用。这项建议的主要目标是开发、验证和临床翻译MesoMRI，这是一个新提出的框架，通过识别中观尺度上的结构变化如何在扩散加权信号中表现出来，对不同的退变过程产生高特异性的扩散MRI指标。介观尺度是细胞组织结构的尺度，介于分子尺度和宏观MRI分辨率之间。我们的总体假设是，我们的脑组织完整性的新型介观生物标记物将针对体内神经变性的不同方面，包括脱髓鞘和轴突丢失。中观MRI框架的发展包括对微米尺度上轴突几何形状的作用以及水扩散指标对脱髓鞘、轴突丢失、损伤和其他病理变化的响应的定性理解和定量模拟。这涉及到将借鉴现代交通理论和统计物理的先进分析方法引入扩散磁共振成像的背景下。特别是，我们将首先开发和验证我们的白质束完整性指标，以及它们与单个白质纤维束中脱髓鞘程度和轴突丢失的关系。随后，我们将单个纤维束的介观建模扩展到整个白质，包括多个纤维方向和交叉的区域。这一扩展涉及到MesoFT的开发，这是一种新的介观建模和纤维跟踪范例，首次能够生成纤维的局部介观参数及其宏观连接图的自洽地图。我们将通过将MesoFT应用于回顾获得的阿尔茨海默病和多发性硬化症的临床病例来评估我们的技术开发在临床翻译方面的潜力。基于对临床上可行的标准扩散磁共振指标的充分解释，我们的框架将直接转化为临床，并将能够对神经系统疾病的疾病进展和治疗质量进行定量评估。

DESCRIPTION (provided by applicant): Diseases of the central nervous system (CNS) are a significant public health and economic problem, affecting nearly one in three Americans at some point in life, with a cost exceeding $500 billion per year. Pathologically, the axonal integrity in the brain white matter is compromised in most human neurological diseases or injuries, including multiple sclerosis, leukodystrophy, traumatic brain injury, as well as in normal aging and neurodegenerative diseases such as Parkinson's, Huntington's, amyotrophic lateral sclerosis, and Alzheimer's disease. Neurodegeneration occurs via a number of distinct processes, such as acute axonal injury, demyelination, inflammation, chronic axonal degeneration or axonal loss, and gliosis. Quantifying their degree, and distinguishing between these different underlying degenerative processes is particularly vital for adequate assessment of CNS disease progression and treatment, but currently not available. The main objective of this proposal is the development, validation and clinical translation of MesoMRI, a newly proposed framework that yields high specificity of diffusion MRI metrics to different degenerative processes by identifying how structural changes at the mesoscopic scale manifest themselves in the diffusion-weighted signal. The mesoscopic scale is the scale of cellular tissue architecture, intermediate between the molecular scale and the macroscopic MRI resolution. Our overall hypothesis is that our novel mesoscopic biomarkers of brain tissue integrity will be specific to different aspects of neurodegeneration in vivo, including demyelination and axonal loss. The development of the mesoscopic MRI framework involves qualitative understanding and quantitative modeling of the role of axonal geometry at the micrometer scale, and the response of water diffusion metrics to demyelination, axonal loss, injury, and other pathological changes. This involves bringing advanced analytical methods borrowed from modern transport theory and statistical physics into the context of diffusion MRI. In particular, we will first deveop and validate our white matter tract integrity metrics and the relation between them and the degree of demyelination and axonal loss in a single white matter fiber bundle. Subsequently, we will extend the mesoscopic modeling of a single fiber bundle onto the whole white matter, including regions of multiple fiber directions and crossings. This extension involves the development of MesoFT, a novel mesoscopic modeling and fiber tracking paradigm, able for the first time to produce self-consistent maps of both local mesoscopic parameters of fibers and their macroscopic connectivity maps. The potential of our technical developments for clinical translation will be evaluated by applying MesoFT to retrospectively acquired clinical cases of Alzheimer's disease and multiple sclerosis. Based on adequate interpretation of standard clinically feasible diffusion MRI metrics, our framework's translation into clinic will be straightforward, and will enable the quantitative assessment of disease progression and quality of treatment in neurological diseases.