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
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