Evaluation of developing lesions with a combined approach of Magnetic Resonance Imaging, Magnetic Resonance Elastography and histopathology in an animal model of multiple sclerosis.

多发性硬化(MS)是最常见的神经炎症性疾病。它会导致中枢神经系统的脱髓鞘、轴突和神经元损伤，导致受影响的人相当大的损害。多发性硬化症是一种免疫介导的疾病，存在于遗传易感人群中。然而，其病因和发病机制尚不清楚。磁共振成像(MRI)已成为诊断和监测MS的最重要的临床旁工具，然而，传统的MRI参数缺乏特异性，与临床病程相关性较差。此外，它们几乎不允许就潜在的病理得出结论，而且预后价值有限。因此，需要新的体内参数来改善这种情况。拟议的项目专注于在非常早期阶段检测多发性硬化症患者大脑中的炎症灶。实验性自身免疫性脑炎(EAE)小鼠模型将被用来测试是否可以描述早期的神经炎性变化。常规MRI将与一种特殊的动脉自旋标记(ASL)技术相结合，从而能够量化血管的渗透性，并与磁共振弹性成像(MRE)相结合。磁共振成像提供非侵入性和活体组织生物力学特性的定量信息。这些特性是通过分析在感兴趣器官中机械诱导的低频剪切波的传播而获得的。最后，影像参数将与专注于炎症、髓鞘和细胞外基质的组织病理学分析相关联。MS和EAE的病变发展分别包括自体反应性T细胞在大脑中的流入，进一步的免疫细胞的招募和激活，导致脱髓鞘和轴突和神经元的损伤。这些过程干扰了脑实质的正常几何网络，这使得它们可以通过磁共振机械地检测到。在急性炎症期间，一些介质被释放，导致血脑屏障(BBB)的破坏。这可以用一种新的ASL方法来研究。它提供了关于毛细血管转移时间的信息，这是一个反映血脑屏障完整性变化的参数，因为它与毛细血管功能有关。为了促进免疫细胞的流入和使病变发展的位置可预测，将使用聚焦超声在预定的区域逐渐打开血脑屏障。总之，该项目结合了对血脑屏障完整性的评估和多发性硬化症的EAE模型中的生物力学特性的评估，以潜在地找到能够预测病变发展的生物标志物。这种生物标记物有可能显著改善多发性硬化症患者的管理。早期炎症活动的无创性识别首先可以帮助MS的诊断，其次可以改善何时开始或修改治疗的决策，第三可以帮助预测病程。

Multiple Sclerosis (MS) is the most common neuroinflammatory disease. It leads to demyelination, axonal and neuronal damage in the central nervous system resulting in considerable impairment of those affected. MS is an immune-mediated disorder in genetically susceptible individuals. However, cause and pathogenesis are still unknown. Magnetic Resonance Imaging (MRI) has emerged as most important paraclinical tool to diagnose and monitor MS. However, conventional MRI-parameters lack specificity and correlate only poorly with the clinical course. Additionally, they hardly allow conclusions to be drawn with regard to the underlying pathology and the prognostic value is limited. Hence, novel in vivo parameters are needed to improve this situation.The proposed project focuses on the detection of inflammatory foci in the brain of MS patients in a very early stage. The experimental autoimmune encephalitis (EAE) mouse model will be used to test whether early neuroinflammatory changes can be depicted. Conventional MRI will be combined with a special arterial spin labeling (ASL) technique allowing for the quantification of vessel permeability and with Magnetic Resonance Elastography (MRE). MRE provides quantitative information on the biomechanical properties of a tissue non-invasively and in vivo. These properties are acquired by analyzing the propagation of low-frequency shear waves, which are mechanically elicited in the organ of interest. Finally, imaging parameters will be correlated to histopathological analyses focusing on inflammation, myelin and the extracellular matrix.Lesion development in MS and EAE respectively comprises the influx of autoreactive T-cells in the brain, recruitment and activation of further immune cells leading to demyelination and damage of axons and neurons. These processes interfere with the normal geometrical network of the brain parenchyma, which renders them mechanically detectable with MRE.During acute inflammation, some mediators are released leading to a disruption of the blood brain barrier (BBB). This can be investigated with a novel ASL method. It renders information on the capillary transfer time, a parameter reflecting changes in the integrity of the BBB as it is linked to capillary function.In order to facilitate influx of immune cells and to make the site of lesion development predictable, the BBB will be gradually opened in a predefined area using focused ultrasound. In summary, the project combines the evaluation of BBB integrity and the assessment of biomechanical properties in the EAE-model of MS to potentially find a biomarker able to predict the development of lesions. Such a biomarker has the potential to significantly improve the management of MS-patients. The non-invasive identification of early inflammatory activity could firstly facilitate the diagnosis of MS, secondly improve decision-making when a treatment should be initiated or modified and thirdly could help to predict the disease course.