Noninvasive Quantification of Axon Damage in EAE and MS

描述（由申请人提供）：MS是一种CNS慢性炎症性疾病，主要破坏髓鞘。几十年来，人们已经知道MS中也会发生轴突损失。原则上，炎症和脱髓鞘诱导的功能缺陷可能是可逆的。相反，一旦超过补偿阈值，轴突和神经元的损伤可能是不可逆的。因此，它已被广泛推测，轴突损失是病理相关的不可逆的神经功能缺损的MS。然而，轴突损失并不总是明显的病变，从患者受到严重影响。MS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，一种新的扩散张量成像（DTI）为基础的方法，用于无创检测中枢神经系统（CNS）的轴突损伤的白色物质将提出和评价使用MS的动物模型。翻译前验证将采用人类尸检CNS组织。由扩散张量成像导出的定向扩散率描述了平行于（AFDA-II，轴向扩散率）和垂直于（AFDA-I，径向扩散率）轴突束的水运动。我们以前提出并证实，在小鼠白色物质损伤模型中，减少的APDA-II与轴突损伤和功能障碍相关，增加的APDA-I-与髓鞘损伤相关。因此，MS患者或患有实验性自身免疫性脑脊髓炎（EAE）的小鼠CNS白色物质中的Euda-II的显著减少将提示轴突变性和不良的长期预后。为了检验我们的假设，将通过在两种小鼠品系中主动免疫来诱导EAE，以模拟进行性非缓解型MS（C57 BL/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功能缺损。这将在C57 BL/6小鼠中早期发生，反映了该模型的非缓解性质。在SJL小鼠中，早期轴突损伤将与神经功能缺损急性峰值后的不完全缓解相关，而轴突完整性将在完全缓解时保留。在这两种菌株中，轴突损伤的程度将与神经缺陷的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.