ANALYSIS OF THE AXONAL DEGENERATION FOLLOWING INFLAMMATORY DEMYELINATION IN MULT

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。将多发性硬化症的神经保护和神经修复策略从实验室转化为床边的一个主要目标是开发髓磷脂和轴突完整性的替代措施，可用于II期临床试验，以筛选初步疗效。在免疫调节药物的II/III期试验中，钆增强病变作为炎症的替代标志物现已被广泛接受。然而，即使没有明显的炎症，临床残疾也会进展。这被认为是由许多下游因素介导的轴突变性的结果。放射学研究表明，在活动性炎性脱髓鞘发生数月至数年后，会出现远端沃勒氏变性和萎缩（230）。残疾与T1体积（钆后）、T2体积、萎缩或T1黑洞等常规测量方法之间的相关性并不高（在各种研究中相关系数在0.3和0.6之间），可能是因为所有这些测量方法都缺乏永久性脑组织病理的特异性。磁共振成像（MRI）的最新进展，如磁化转移成像（MTI）、质子磁共振波谱（1H-MRS）和扩散张量成像（DTI），为潜在的结构病理提供了更敏感和更具体的测量方法。有很大的需要发展和优化这些措施，以便能够无创量化MS患者脱髓鞘和轴突变性的程度。我们正专注于开发DTI和MTI，以允许沿着白质束进行病理定量测量，然后可以将其用作潜在神经保护和神经修复药物临床试验的结果测量。DTI提供了白质束的方向性和完整性信息。MTI已被证明与轴突密度和髓鞘完整性有关，因此可能与追踪经过受损髓鞘区域的轴突的局部和远处变化以及髓鞘修复的测量有关。纤维跟踪软件允许三维重建的特定路径远端和近端到感兴趣的区域（ROI）或两个或更多的ROI之间。通过这种方式，可以从急性炎症病变的局部和远处获得多种类型的定量信息。此外，我们可以询问重建的路径，以测量个体患者随时间的变化。由于所有的MR图像都是共同注册的，我们可以比较DTI和MTI通道的特定信息，这可能会提高我们辨别不同病理的能力。该项目的目的是基于以下概念：(1)急性炎性脱髓鞘MS斑块内部和远处都有显著的轴突损伤；(2)轴突完整性的进行性改变发生在慢性脱髓鞘环境中，并解释了疾病的致残进展阶段。我们假设：(1)分数各向异性（FA）主要反映轴突完整性的破坏，而磁化传递比（MTR）主要反映髓磷脂完整性的变化；(2) MS患者白质束损伤的程度和持续时间，通过FA和MTR测量，将对相关通路的功能损伤具有同步和预测有效性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 (230). 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 are focusing 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. 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. The aims of this project are based on the notions that: (1) there is significant axon damage both within and distant from the acute inflammatory demyelinating MS plaque; and (2) progressive changes in axon integrity occur in the chronically demyelinated setting and account for the disabling progressive stages of the disease. We hypothesize that: (1) fractional anisotropy (FA) predominantly reflects disruption of the integrity of axons whereas the magnetization transfer ratio (MTR) predominantly reflects changes in myelin integrity; and (2) the extent and duration of white-matter tract damage in MS patients, as measured by FA and MTR will have concurrent and predictive validity for functional impairment related to the involved pathways.