Monitoring brain atrophy during the course of MS

描述：本提案的总体目标是：1)检验假设 脑萎缩将被证明是一种有用的疾病替代标志 MS的病理和进展，以及2)确定组织病理学 不同对比剂机制定义的MRI病变的相关性。 申请者有4个具体目标：1)确定 有趣的是，与普遍认为的大脑萎缩相反， 他们假设(基于初步数据)，疾病会随着时间的推移而“耗尽” 比较他们对萎缩的测量，脑实质分数，BPF，在5 RRMS患者和2名SPMS患者)的萎缩率将 随着病程的增加而加速；2)确定 萎缩到残疾进展和转化为SP MS的假说 他们在这里测试的是，早期的萎缩是由大脑补偿的 冗余，但预测以后会出现故障并转换到SP MS；3)到 确定萎缩与炎症的关系(通过脑脊液白细胞计数来定义 和Gd增强)和MRI中由其他对比剂机制定义的病变 NAWM中常用的有T2WLV、T1WLV、MTRLV和MTR。假设是 测试结果是：a)炎症预示萎缩，b)T1LV、MTRLV和 NAWM的MTR将比T2LV与萎缩的相关性更好；以及4)确定 不同类型MRI病变的组织病理学相关性研究 上面的对比机制。这里要检验的假设是T2病变 在病理上是非特异性的，但低MTR将对应于 脱髓鞘和低T1与轴突丢失相对应。 为了实现前三个目标，申请者建议学习两组 病人。A组为III期患者的回顾性研究 1992年至1995年间进行的干扰素-(-1a)试验。申请者仅指85% 安慰剂在患者中的原始应用。不过，在他们的补充质询中 材料他们暗示了分析治疗患者的明显益处。 也是为了验证他们的代孕母亲的能力 基于现有数据的治疗效果。这些患者只有 常规双自旋回波和T1W扫描，层厚5 mm。B组将是 包括60例MS患者(20例RR，20例SP，A组20例RR 1992年，谁将重新加入目前的议定书，以获得长期 随访资料)和30名正常对照组。B组患者会 使用新协议(T2W FSE FLAIR、T2W FSE、T1W+/-Gd SE和MTR)进行扫描 (PDW 3D GE+/-MT脉冲)。 为了实现第四个目标，申请者与 CCF器官采购计划和病理学、放射学、 和BME，并开发了一种基于立体定位的方法，在这种方法中，他们扫描 大脑原位尸检，在与MRI兼容的切片盒中重新扫描 预定义、标记切片位置，然后转换和配准图像

DESCRIPTION: The overall goals of this proposal are: 1) to test the hypothesis that brain atrophy will prove to be a useful surrogate marker of disease pathology and progression in MS, and 2) to determine the histopathological correlates of MRI lesions defined by different contrast mechanisms. The applicants have 4 specific aims: 1) To determine the rate & pattern of brain atrophy in MS. Interestingly and contrary to popular belief that the disease "burns out" over time, they hypothesize (based on preliminary data comparing their measure of atrophy, the brain parenchymal fraction, BPF, in 5 patients with RRMS and 2 patients with SPMS) that the rate of atrophy will accelerate with increasing disease duration; 2) To determine the relationship of atrophy to disability progression and conversion to SP MS. The hypothesis they would test here is that early atrophy is compensated for by cerebral redundancy, but predicts later disability and conversion to SP MS; 3) To determine the relationship of atrophy to inflammation (defined by CSF WBC count and Gd enhancement) and MRI lesions defined by other contrast mechanisms in common use including T2WLV, T1WLV, MTRLV and MTR in NAWM. The hypotheses to be tested are: a) that inflammation predicts atrophy, and b) that T1LV, MTRLV and MTR in NAWM will correlate better than T2LV with atrophy; and 4) To determine the histopathological correlates of MRI lesions defined by the different contrast mechanisms above. The hypothesis to be tested here is that T2 lesions are pathologically nonspecific but that low MTR will correspond to demyelination and low T1 will correspond to axonal loss. To accomplish the first 3 aims, the applicants propose to study two groups of patients. Group A would be a retrospective study of patients in the phase III IFN-(-1a trial between 1992 and 1995. The applicants refer only to the 85 placebo patients in the original application. However, in their supplementary materials they allude to the obvious benefits of analyzing the treated patients as well in order to validate the ability of their surrogate to demonstrate therapeutic efficacy based on existing data. These patients had only conventional dual spin echo and T1W scans with 5 mm slices. Group B would be comprised of 60 MS patients (20 RR, 20 SP, 20 patients from Group A who were RR in 1992 who would be re-entered in the current protocol to obtain long term follow-up information) and 30 normal control subjects. Group b patients would be scanned with a new protocol (T2W FSE FLAIR, T2W FSE, T1W+/-Gd SE, and MTR (PDW 3D GE +/- MT pulse). To accomplish the 4th aim the applicants have established collaborations with the CCF organ procurement program and the departments of pathology, radiology, and BME and have developed a stereotaxically-based approach in which they scan brains in situ post-mortem, rescan them in a MRI-compatible slicing box with predefined, marked slice locations, and then transform and register the images