Noninvasive Quantification of Axon Damage in EAE and MS

描述(申请人提供)：多发性硬化症是一种中枢神经系统的慢性炎症性疾病，主要损害髓鞘。几十年来，MS也会出现轴突丢失，从理论上讲，炎症和脱髓鞘导致的功能障碍可能是可逆的。相比之下，一旦超过补偿阈值，轴突和神经元的损害很可能是不可逆转的。因此，人们普遍推测轴突丢失是多发性硬化症患者不可逆神经损害的病理联系。然而，在受到严重影响的患者的皮损中，轴突丢失并不总是明显的。MS潜在机制的复杂性和异质性需要新的准临床标记物来更准确地诊断和更精确地治疗该病。在拟议的研究中，将提出一种基于扩散张量成像(DTI)的新方法，用于无创性检测中枢神经系统(CNS)白质中的轴突损伤，并将使用MS的动物模型进行评估。翻译前验证将使用人类尸检CNS组织。由扩散张量成像得到的方向扩散系数描述了水平行于(lambda-II，轴向扩散系数)和垂直于(lambda-I，径向扩散系数)轴突的运动。我们之前已经提出并验证了在白质损伤的小鼠模型中，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，在MS患者或实验性自身免疫性脑脊髓炎(EAE)小鼠中，中枢神经系统白质中lambda-II的显著降低将提示轴突变性和不良的长期预后。为了验证我们的假设，将在两个小鼠品系中通过主动免疫来诱导EAE，以模拟进展型、非缓解型多发性硬化症(C57BL/6小鼠)和复发-缓解型多发性硬化症(RRMS；SJL小鼠)。我们预测轴突损伤将与非缓解性神经缺陷相关。这将发生在C57BL/6小鼠的早期，反映了这种模型的非缓解性。在SJL小鼠中，早期轴突损伤将与神经缺陷急性达到顶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不变。在这两个菌株中，轴突损伤的程度将与神经功能缺陷急性峰值的持续时间密切相关-推测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.