Quantifying Demyelination and Axonal Loss with Diffusion MRI

描述(申请人提供)：中枢神经系统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。脱髓鞘和轴突丢失是大多数人类神经系统疾病/损伤的共同病理特征，包括多发性硬化症(MS)、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(AD)。轴突丢失被认为是永久性残疾的原因，而脱髓鞘已被证明是一个可逆的过程。然而，人们通常不清楚个别患者存在多大程度的脱髓鞘和轴突丢失，以及给定的治疗药物是否成功地改变了这些神经变性过程。因此，脱髓鞘和轴突丢失的定量、非侵入性生物标志物将提高诊断的准确性，它们对于监测治疗反应和有效的患者管理是必不可少的。我们的主要目标是用MRI来量化轴突的丢失和脱髓鞘。我们最近引入了一个白质模型，它允许通过扩散峰度成像(DKI)测量的白质中的非高斯扩散信号的直接物理解释，扩散张量成像(DTI)在临床上是可行的扩展。分析 使用该模型可获得特定的脑白质微结构完整性指标，例如轴突内和轴突外扩散系数、轴突含水率(AWF)和轴突外间隙的曲折度(？)。我们的模型表明，1)曲度与髓鞘厚度密切相关，2)AWF与轴突密度密切相关。我们已经从分析和数字上证实了这些发现。此外，我们已经证明，在MS和AD患者中测量AWF和曲度与这些患者的预期病理是一致的。这项研究的主要目标是对我们模型的预测进行组织学验证，并初步评估AWF在监测疾病进展和恢复方面的实用性和曲折性。我们将使用Cuprizones小鼠脱髓鞘和轴突丢失的模型来测试以下两个特定目的：1)确定体内DKI估计的曲线度和AWF与组织病理学测量的髓鞘厚度和轴突密度之间的关系；2)确定Cuprizones中毒和恢复期曲线度和AWF的纵向变化。如果成功，该项目将建立一种新的非侵入性白质变性评估方法，基于MRI测量的曲折度和AWF作为脱髓鞘和轴突丢失的客观定量生物标志物，将显著改进药物发现和患者管理。

DESCRIPTION (provided by applicant): Diseases of the central nervous system 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. Both demyelination and axonal loss are common pathological features of most human neurological diseases/injuries including multiple sclerosis (MS), leukodystrophy, traumatic brain injury, as well as of normal aging and neurodegenerative diseases such as Parkinson's, Huntington's, amyotrophic lateral sclerosis, and Alzheimer's disease (AD). Axonal loss is considered the cause of permanent disability, while demyelination has been shown to be a reversible process. However, it is often unclear what degrees of demyelination and axonal loss are present in individual patients, and whether these neurodegenerative processes are successfully modified by a given therapeutic agent. Hence, quantitative, noninvasive biomarkers of both demyelination and axonal loss would improve accuracy of diagnosis, and they are essential for monitoring treatment response and effective patient management. Quantifying axonal loss and demyelination with MRI is our main objective. We recently introduced a white matter model that allows a direct physical interpretation of the non-Gaussian diffusion signal in white matter as measured with diffusional kurtosis imaging (DKI), a clinically feasible extension of diffusion tensor imaging (DTI). Analysis with this model yields specific white matter microstructural integrity metrics such as the intra- and extra-axonal diffusivities, the axonal water fraction (AWF) and tortuosity (¿) of the extra-axonal space. Our modeling suggests that 1) the tortuosity ¿ correlates strongly with the thickness of the myelin sheath, and 2) AWF correlates strongly with the axonal density. We have confirmed these findings both analytically and numerically. In addition, we have demonstrated that measurements of AWF and tortuosity ¿ in MS and AD patients are compatible with the expected pathology in these patients. The main goals of this study are the histological validation of the prediction of our model, and preliminary evaluation of the utility o AWF and the tortuosity ¿ in monitoring disease progression and recovery. We will use the cuprizone mouse model of demyelination and axonal loss to test the following two specific aims: 1) To determine the relationship between the tortuosity ¿ and AWF estimated with in vivo DKI and the myelin thickness and axonal density measured by histopathology, and 2) To determine the longitudinal changes of tortuosity ¿ and AWF during cuprizone intoxication and recovery period. If successful, this project will establish a novel noninvasive method for assessment of white matter degeneration that will significantly improve drug discovery and patient management, based on the MRI- measured tortuosity ¿ and AWF as objective quantitative biomarkers for demyelination and axonal loss.