MECHANISMS OF NEURODEGENERATION AND STRATEGIES FOR NEUROPROTECTION IN MS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 多发性硬化症（MS）研究的一个基本目标是阐明细胞和分子途径， 参与调解永久性残疾。临床、影像学和病理学研究表明， 残疾可由急性临床恶化和疾病的慢性进展阶段引起。 我们研究的基本假设是，MS中的永久性残疾，无论其阶段如何， 疾病，是轴突受损的结果。在此，我们计划定义细胞和分子机制， MS中的轴突损伤，开发残疾的成像生物标志物，从而测试合理的神经保护和 神经修复策略 将MS的神经保护和神经修复策略从实验室转化为床边的主要目标是 开发髓鞘和轴突完整性的替代指标，可用于II期临床试验，以筛选 初步疗效。钆增强病变作为炎症替代标志物在II/III期临床试验中的应用 免疫调节药物的III期临床试验现已被广泛接受。尽管如此，即使没有明显的 炎症，临床残疾进展。这被认为是由于轴突变性介导的结果， 众多下游因素。 放射学研究已经证明了远距离沃勒变性的证据 以及在活动性炎性脱髓鞘后数月至数年的萎缩。的相关性 残疾和常规测量，如T1体积（钆后）、T2体积和萎缩或T1黑色 洞只是适度的（在各种研究中相关系数在0.3和0.6之间），大概是因为所有 这些措施缺乏永久性脑组织病理学的特异性。磁共振研究进展 成像（MRI），例如磁化传递成像（MTI），质子磁共振波谱（1H-MRS）， 和扩散张量成像（DTI）提供了更敏感和具体的措施，潜在的结构， 病理非常需要开发和优化这些措施，以便能够非侵入性地 量化MS患者脱髓鞘和轴突变性的程度。 我们将致力于发展DTI和MTI，以便对沿着白质的病理进行定量测量 束，然后可以用作潜在的神经保护和 神经修复剂DTI提供了白质束的方向性和完整性的信息，包括 轴突和髓磷脂的信息。MTI已被证明与轴突密度和髓鞘 完整性，因此可能与跟踪通过区域的轴突的局部和远处变化有关。 受损的髓鞘，以及髓鞘修复的措施。纤维跟踪软件允许三维 在一个实施例中，该方法可以用于重建感兴趣区域（ROI）远端和近端或两个或更多个ROI之间的特定路径。 以这种方式，然后可以在本地和远程站点处获取多种类型的定量信息， 急性炎症性损伤此外，我们可以询问重建的通路， 时间在病人身上。由于所有的MR图像都是共配准的，我们可以比较DTI和MTI束特异性 信息，这可以提高我们辨别沿着轨迹的不同病理的能力。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A fundamental objective in multiple sclerosis (MS) research is to elucidate the cellular and molecular pathways that are involved in mediating permanent disability. Clinical, radiographic, and pathological studies suggest that disability can ensue both from acute clinical exacerbations and during the chronic progressive stages of the disease. The underlying hypothesis in our research is that permanent disability in MS, regardless of the stage of the disease, is a result of damage to the axon. Herein, we plan to define the cellular and molecular mechanisms of axonal injury in MS, develop imaging biomarkers of disability, and thereby test rational neuroprotective and neuroreparative strategies. A major goal in translating neuroprotective and neuroreparative strategies for MS from the bench to the bedside is to develop surrogate measures of myelin and axon integrity that can be used in phase II clinical trials to screen for preliminary efficacy. The utility of gadolinium-enhancing lesions as a surrogate marker of inflammation in phase II/ III trials of immunomodulatory drugs is now well accepted. Nonetheless, even in the absence of apparent inflammation, clinical disability progresses. This is thought to occur as a result of axon degeneration mediated by numerous downstream factors. Radiological studies have demonstrated evidence of distant Wallerian degeneration and atrophy that ensue months to years after active inflammatory demyelination. The correlation between disability and conventional measures such as T1 volume (post-gadolinium), T2 volume, and atrophy or T1 black holes is only modest (correlation coefficients between 0.3 and 0.6 in a variety of studies), presumably because all of these measures lack specificity for permanent brain tissue pathology. Recent advances in magnetic resonance imaging (MRI) such as magnetization transfer imaging (MTI), proton magnetic resonance spectroscopy (1H-MRS), and diffusion tensor imaging (DTI) offer promise as more sensitive and specific measures of underlying structural pathology. There is a great need to develop and optimize these measures so as to be able to non-invasively quantify the extent of demyelination and axon degeneration in MS patients. We will focus on developing DTI and MTI to allow quantitative measurement of pathology along white-matter tracts, which can then be used as outcome measures for clinical trials of potential neuroprotective and neuroreparative agents. DTI gives information on the directionality and integrity of white-matter tracts, containing both axonal and myelin information. MTI has been shown to be associated with both axon density and myelin integrity, and therefore may be relevant to tracking local and distant changes in axons that pass through areas of damaged myelin, as well as a measure of myelin repair. Fiber-tracking software allows the 3 dimensional reconstruction of specific pathways distal and proximal to a region of interest (ROI) or between two or more ROIs. In this way, multiple types of quantitative information can then be acquired both locally and at distant sites from an acute inflammatory lesion. Moreover, we can interrogate the reconstructed pathways to measure changes over time in an individual patient. Since all of the MR images are coregistered we can compare DTI and MTI tract specific information, which may improve our ability to discern different pathologies along the trajectories.