Validating diffusion MRI biomarkers of inflammation and axon pathologies in EAE

公共卫生。如果申请得到资助，这一描述将成为公开信息。因此， 不包括专有/机密信息。不要超过所提供的空间。 我们先前证明了扩散张量成像(DTI)能够成功地检测轴突和髓鞘损伤。 通过降低轴向扩散系数(平行于白质束)和增加径向扩散系数(#61534；)， 在中枢神经系统(CNS)疾病的动物模型中 受伤。在最初的计划项目资助期，我们确定了混杂因素，例如 炎症和组织丢失，导致对DTI检测到的轴突病理的误解。因此，我们 发展了一种新的基于扩散的光谱成像(DBSI)来检测、区分和量化 炎症和轴突/髓鞘损伤(Wang等人)。2011年)。 在这个PPG更新中，体内DBSI将被用来记录炎症、轴突损伤和 小鼠EAE视神经和脊髓白质束脱髓鞘与神经病学的关系 减损。DBSI确定的病理将与免疫组织化学(IHC)相关联 EAE病程以验证DBSI损伤标志物。功能障碍将与个体相关 和/或由DBSI和IHC确定的轴突病理的组合，以确定哪种最佳 与临床损伤相对应。 为探讨DBSI作为临床试验终点的应用，FTY720治疗对患者功能的影响 EAE的损害将与DBSI确定的视神经和脊髓轴突病理相关 并经IHC确认。此外，我们将同时使用DBSI和广泛报道的锰 增强MRI可同时评估对照组和对照组的视神经顺行轴突传输率。 EAE小鼠确定轴突运输功能障碍与DBSI测定轴突的关系 病理学。这将使我们有机会描述视神经的炎症或轴突损伤 神经是功能缺陷的基础，并确定轴突运输在视神经炎中的作用。如果轴突 运输缺陷很早就出现并持续存在(正如我们的初步数据所表明的那样)，这可能是一种潜在的 治疗靶点。

public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. We previously demonstrated that diffusion tensor imaging (DTI) successfully detects axon and myelin injury through decreased axial diffusivity (λ║, parallel to the white-matter tract) and increased radial diffusivity (λ, perpendicular to the white-matter tract) in animal models of central nervous system (CNS) diseases and injuries. During the initial Program Project funding period, we identified confounding factors, such as inflammation and tissue loss, causing misinterpretation of DTI-detected axonal pathologies. Thus, we developed a novel diffusion basis spectrum imaging (DBSI) to detect, differentiate, and quantify the extent of inflammation, and axon/myelin injury (Wang et al. 2011). In this PPG renewal, in vivo DBSI will be used to document the evolution of inflammation, axonal injury, and demyelination in optic nerve and spinal cord white-matter tracts in murine EAE, correlating with neurological impairment. DBSI-determined pathologies will be correlated with immunohistochemistry (IHC) during the course of EAE to validate DBSI injury markers. Functional impairment will be correlated with individual and/or combinations of axonal pathologies determined by DBSI and IHC to ascertain which best corresponds to clinical impairments. To explore the use of DBSI as an endpoint for clinical trials, the effect of FTY720 treatment on functional impairment in EAE will be correlated with DBSI-determined axonal pathologies in optic nerve and spinal cord tracts and confirmed by IHC. In addition, we will use both DBSI and the widely-reported manganese enhanced MRI to concomitantly assess the anterograde axonal transport rate of optic nerve in control vs. EAE mice to determine the relationship between axonal transport dysfunction and DBSI-determined axonal pathologies. This would allow an opportunity to delineate whether inflammation or axonal injury of optic nerve underlies functional deficits and to define the role of axonal transport in optic neuritis. If axonal transport defects occur early and persist (as suggested by our preliminary data), this may be a potential therapeutic target.