Noninvasive Quantification of Axon Damage in EAE and MS

描述（由申请人提供）：MS是一种慢性中枢神经系统炎症性疾病，原发性髓鞘破坏。几十年来，人们已经知道多发性硬化症也会发生轴突损失。原则上，炎症和脱髓鞘引起的功能缺陷可能是可逆的。相反，一旦超过补偿阈值，对轴突和神经元的损伤可能是不可逆的。因此，人们普遍推测轴突丧失是ms中不可逆神经损伤的病理相关性。然而，轴突丧失在严重患者的病变中并不总是明显的。多发性硬化症潜在机制的复杂性和异质性需要新的准临床标志物来更准确地诊断和更精确地治疗该疾病。在拟议的研究中，一种新的基于弥散张量成像（DTI）的无创检测中枢神经系统（CNS）白质轴突损伤的方法将被提出，并使用ms动物模型进行评估，预翻译验证将采用人体尸检CNS组织。由扩散张量成像导出的定向扩散系数描述了平行于轴突束（λ - ii，轴向扩散系数）和垂直于轴突束（λ - i，径向扩散系数）的水运动。我们之前提出并验证了在小鼠白质损伤模型中，lambda-II的减少与轴突损伤和功能障碍有关，而lambda-I-的增加与髓鞘损伤有关。因此，MS患者或实验性自身免疫性脑脊髓炎（EAE）小鼠中枢神经系统白质中lambda-II的显著减少将提示轴突变性和不良的长期预后。为了验证我们的假设，我们将在两种小鼠株中通过主动免疫诱导EAE，以模拟进行性非缓解型MS （C57BL/6小鼠）和复发缓解型MS （RRMS； SJL小鼠）。我们预测轴突损伤将与非缓解性神经缺陷相关。这将在C57BL/6小鼠早期发生，反映出该模型的非缓解性。在SJL小鼠中，早期轴突损伤将与神经功能缺损急性高峰后的不完全缓解相关，而轴突完整性将在完全缓解时保持。在这两种毒株中，轴突损伤的程度将与神经功能缺陷急性高峰的持续时间密切相关——可能是由急性炎症反应引起的。

DESCRIPTION (provided by applicant): MS is a chronic inflammatory disease of the CNS with primary destruction of myelin sheaths. It has been known for decades that axonal loss also occurs in MS. In principle, the functional deficit induced by inflammation and demyelination may be reversible. In contrast, the damage to axons and neurons is likely to be irreversible once the threshold of compensation is exceeded. Thus, it has been widely speculated that axonal loss is the pathologic correlate of irreversible neurological impairment in MS. However, axonal loss is not always evident in lesions from patients who are severely affected. The complexity and heterogeneity of the underlying mechanisms of MS require new para-clinical markers for more accurate diagnosis and more precise therapeutic management of the disease. In the proposed studies, a new diffusion tensor imaging (DTI) based method for noninvasive detection of axonal damage in central nervous system (CNS) white matter will be presented and evaluated using animal models of MS. Pre-translational validation will employ human autopsy CNS tissues. The directional diffusivities derived by diffusion tensor imaging describe water movement parallel to (lambda-II, axial diffusivity) and perpendicular to (lambda-I, radial diffusivity) axonal tracts. We have previously proposed and validated that decreased lambda-II is associated with axonal injury and dysfunction, and increased lambda-I- is associated with myelin injury in mouse models of white matter injury. Therefore, a significant reduction in lambda-II in CNS white matter in MS patients or in mice with experimental autoimmune encephalomyelitis (EAE) will be suggestive of axonal degeneration and a poor long-term prognosis. To test our hypothesis, EAE will be induced by active immunization in two mouse strains to mimic progressive, non-remitting forms of MS (C57BL/6 mice) and relapsing-remitting MS (RRMS; SJL mice). We predict that axonal damage will be associated with non-remitting neurological defects. This will occur early in C57BL/6 mice reflecting this model's non-remitting nature. In SJL mice, early axonal damage will correlate with incomplete remission following acute peaking of neurological deficits, whereas axonal integrity will be retained with full remissions. In both strains, the extent of axonal damage will closely relate to the duration of the acute peaking of neurological deficits - presumably caused by acute inflammatory responses.