Brain atrophy in relapsing multiple sclerosis: relationship to relapses, EDSS, and treatment with interferon beta-Ia

Brain atrophy is a relevant surrogate marker of the disease process in mult iple sclerosis (MS) because it represents the net effect of various patholo gical processes leading to brain tissue loss. There are various approaches to quantifying central nervous system atrophy in MS. We have focused on a n ormalized measure of whole brain atrophy the brain parenchymal fraction (BP F). BPF is defined as the brain parenchymal volume, divided by the volume w ithin the surface of the brain. We applied this method to an MRI data set g enerated during a phase III clinical trial of interferon beta -1a (AVONEX). The purpose of the current study is to further explore clinical and MRI co rrelates of the BPF, particularly as they relate to relapse rate and Kurtzk e's Expanded Disability Status Score (EDSS); and to further explore the the rapeutic effects observed in interferon beta -1a recipients. Of all demogra phic and disease measures in the clinical trial data bose, T2 lesion volume most closely correlated with BPF in cross sectional studies, and was the b aseline factor most closely correlated with progressive brain atrophy in th e subsequent 2 years. We also observed that change in T2 lesion volume was the disease measure most closely correlated with change in BPF during 2 yea rs of observation. Of interest relapse number and EDSS change during 2 year s were only weekly correlated with BPF change during the some period Disabi lity progression, defined as sustained worsening of at least 1.0 EDSS point s from baseline, persisting at least 6 months, was associated with signific antly greeter brain atrophy progression. We observed a therapeutic effect o f interferon beta -1a in the second year of the clinical trial, and this be neficial effect was not accounted for by change in gadolinium enhanced lesi on volume, or by corticosteroid medication within 40 days of the final MRI scan. The BPF is on informative surrogate marker for destructive pathologic al processes in relaping MS patients, and is useful in demonstrating treatm ent effects in controlled clinical trials. The significance of progressive brain atrophy during relapsing MS will be assessed by measuring clinical an d MRI changes in prospective follow up studies.