Dynamics of pseudo-atrophy in RRMS reveals predominant gray matter compartmentalization

OBJECTIVE: To assess the dynamics of "pseudo-atrophy," the accelerated brain volume loss observed after initiation of anti-inflammatory therapies, in patients with multiple sclerosis (MS).METHODS: Monthly magnetic resonance imaging (MRI) data of patients from the IMPROVE clinical study (NCT00441103) comparing relapsing-remitting MS patients treated with interferon beta-1a (IFNbeta-1a) for 40weeks versus those receiving placebo (16weeks) and then IFNbeta-1a (24weeks) were used to assess percentage of gray (PGMVC) and white matter (PWMVC) volume changes. Comparisons of PGMVC and PWMVC slopes were performed with a mixed effect linear model. In the IFNbeta-1a-treated arm, a quadratic term was included in the model to evaluate the plateauing effect over 40weeks.RESULTS: Up to week 16, PGMVC was -0.14% per month in the placebo and -0.27% per month in treated patients (P<0.001). Over the same period, the decrease in PWMVC was -0.067% per month in the placebo and -0.116% per month in treated patients (P=0.27). Similar changes were found in the group originally randomized to placebo when starting IFNbeta-1a treatment (week 16-40, reliability analysis). In the originally treated group, over 40weeks, the decrease in PGMVC showed a significant (P<0.001) quadratic component, indicating a plateauing at week 20.INTERPRETATION: Findings reported here add new insights into the complex mechanisms of pseudo-atrophy and its relation to the compartmentalized inflammation occurring in the GM of MS patients. Ongoing and forthcoming clinical trials including MRI-derived GM volume loss as an outcome measure need to account for potentially significant GM volume changes as part of the initial treatment effect. © 2021 The Authors.