The focus of this project is the use of magnetic resonance imaging (MRI) to understand the pathophysiology of multiple sclerosis (MS) and to determine whether disease activity is altered by treatment with interferon beta 1b (IFNB-1b), insulin-like growth factors, and altered peptide ligand. In the IFNB-1b treatment trial, 33 multiple sclerosis (MS) patients were followed for a minimum of 36 months with the following observations: (1) The majority of patients treated with IFNB- 1b show an immediate decrease in the number of blood brain-barrier openings (enhancing lesions). This effect of IFNB-1b is not sustained, however, and after approximately 24 months of treatment, there is a slow increase in enhancing lesions. (2) Cumulative white matter disease or white matter lesion load (WMLL) was reduced by approximately 15 percent after 6 months of treatment. The WMLL started to drift up toward baseline at 18 months despite the relatively low number of new lesions. (3) Cerebral atrophy, which occurs at a rate of about 1 to 2 percent per year in untreated MS patients, is slowed by IFNB-1b during a period of 36 months. Magnetization transfer (MT) imaging, which is sensitive to the amount of bound and free water in the white matter and indirectly reflects myelination, was also used to evaluate these patients. MT region of interest (MTR) analysis of individual enhancing or non-enhancing lesions reveals that there is no difference in the pattern of MS lesion recovery when a lesion either develops during the natural history of the disease or after receiving INFB-1b. However, there appears to be a faster improvement in the MTR recovery toward baseline when enhancing lesions occur in association with a clinical exacerbation requiring treatment with intravenous steroids. These results indicate that closure of the blood-brain barrier with steroids is associated with a decrease in the ratio of free to bound water within an MS lesion that is detected as a change in MTR. Seven patients have completed each of the open-labeled baseline versus treatment trials in which two primary outcome measures are change in the frequency of contrast-enhancing lesions. For the seven patients enrolled in the recombinant insulin-like growth factor 1 trial, which stimulates oligodendrocyte proliferation and close of the blood-brain barrier, the trial is expected to close in the year 2000. This trial will include both clinical safety and MRI extended followup of all patients for at least 6 to 12 months after completion of the 6 months of treatment. The second phase II open-labeled baseline versus treatment trial is using altered peptide ligand, which is thought to interfere with binding of T cells to antigen-presenting cells and induce tolerance in MS patients. MS patients are continuing to be recruited at a second lower dose to further evaluate the pharmacological mechanism of action for this agent in the treatment of MS.
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