Noninvasive Quantification of Axon Damage in EAE and MS

MS是一种中枢神经系统慢性炎症性疾病，主要损害髓鞘。它有 早在几十年前就已经知道，MS中也会发生轴突丧失。原则上，由 炎症和脱髓鞘可能是可逆的。相比之下，对轴突和神经元的损害可能会 一旦超过赔偿门槛，将不再可逆。因此，人们普遍猜测， 轴突丢失是多发性硬化患者不可逆神经损害的病理相关因素，然而，轴突丢失是 在受严重影响的患者的皮损中并不总是明显。的复杂性和异构性 MS的潜在机制需要新的准临床标记物来进行更准确的诊断和更多 精准的疾病治疗管理。在拟议的研究中，一种新的扩散张量成像 基于DTI的中枢神经系统白质轴突损伤非侵入性检测方法 问题将使用MS的动物模型进行呈现和评估，翻译前验证将使用 人体尸检中枢神经系统组织。 由扩散张量成像得到的定向扩散系数描述了平行于 (K，轴向扩散率)和垂直于(A，I，径向扩散率)轴索。我们之前已经提出过 并证实了Xy减少与轴突损伤和功能障碍有关，而增加的^是 在白质损伤的小鼠模型中与髓鞘损伤相关。因此，大幅减少油墨\\ 在MS患者或实验性自身免疫性脑脊髓炎(EAE)小鼠的中枢神经系统白质中 提示轴突变性，远期预后不佳。 为了验证我们的假设，将通过主动免疫在两个品系的小鼠中诱导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。这将在早期发生。 在C57BL/6小鼠体内，反映了该模型的非缓解性。在SJL小鼠中，早期轴突损伤将与 神经功能缺失急性达到顶峰后不完全缓解，而轴突完整性将 保留全部减刑。在两种菌株中，轴突损伤的程度将与持续时间密切相关。 神经功能缺失的急性高峰--可能是由急性炎症反应引起的。

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 (k\\, axial diffusivity) and perpendicular to (A,i, radial diffusivity) axonal tracts. We have previously proposed and validated that decreasedXy is associated with axonal injury and dysfunction, and increased^ is associated with myelin injury in mouse models of white matter injury. Therefore, a significant reduction inK\\ 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.