Monitoring brain atrophy during the course of MS

描述：本提案的总体目标是：1）检验假设 脑萎缩将被证明是疾病的一个有用的替代标志 MS的病理学和进展，以及2）确定组织病理学 由不同对比机制定义的MRI病变的相关性。 申请人有4个具体目标：1）确定的速度和模式 有趣的是，与流行的观点相反， 他们假设（基于初步数据）， 比较他们的萎缩指标，脑实质分数，BPF，在5 RRMS患者和2例SPMS患者），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的假设 他们将在这里测试的是，早期萎缩是由大脑补偿的， 冗余，但预测以后的残疾和转换为SP MS; 3） 确定萎缩与炎症的关系（由CSF WBC计数定义 和Gd增强）和MRI病变定义的其他对比机制， 常见用途包括T2 WLV、T1 WLV、MTRLV和NAWM中的MTR。假设是 测试的是：a）炎症预示萎缩，和B）T1 LV、MTRLV和 NAWM中的MTR与萎缩的相关性优于T2 LV;以及4）确定 MRI病变的组织病理学相关性由不同的 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将对应于轴突损失。 为了实现前三个目标，申请人建议研究两组 患者A组为III期患者的回顾性研究 1992年至1995年进行的IFN-α试验。申请人仅指85名 安慰剂患者在原始应用程序中。然而，在其补充 他们暗示了分析治疗患者的明显好处 为了验证他们的代理人的能力， 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T1 W扫描，5 mm切片。B组是 包括60例MS患者（RR组20例，SP组20例，RR组20例，SP组20例）， 1992年，谁将重新进入目前的议定书，以获得长期 随访信息）和30名正常对照受试者。B组患者将 使用新协议（T2 W FSE FLAIR、T2 W FSE、T1 W +/-Gd SE和MTR）进行扫描 (PDW 3D GE +/- MT脉冲）。 为了实现第四个目标，申请人与以下机构建立了合作关系： 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， 在死后原位的大脑，在MRI兼容的切片盒中重新扫描它们， 预定义的标记切片位置，然后变换和配准图像

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