Objective: To determine whether 24 weeks of high-intensity progressive aerobic exercise (PAE) affects brain MRI measures in people with multiple sclerosis (MS).

Methods: We conducted a randomized, controlled, phase 2 trial (with a crossover follow-up) including an exercise group (supervised PAE followed by self-guided physical activity) and a waitlist group (habitual lifestyle followed by supervised PAE). Mildly to severely impaired MS patients aged 18-65 years were randomized (1:1). The primary outcome was percentage brain volume change (PBVC) after 24 weeks, analyzed using the intention-to-treat principle.

Results: Eighty-six participants were recruited. PBVC did not change over the intervention period (mean between-group change +0.12%, 95% CI -0.27;0.51, p=0.55). In contrast, gray matter parenchymal fraction (+1.13 percentage points, 0.00;2.26, p=0.05; did not remain after Bonferroni correction), cardiorespiratory fitness (+3.5 mL O2/min/kg, 2.0;5.1, p<0.01), and annualized relapse rate (p<0.01) improved in the exercise group.

Conclusion: These findings do not support a neuroprotective effect of PAE in terms of total brain atrophy in people with MS. Oppositely, PAE-induced improvements in cardiorespiratory fitness was accompanied by a potential neuroprotective effect in terms of gray matter parenchymal fraction and a relapse rate of zero. While these exploratory findings cautiously support PAE as a potential adjunct disease-modifying treatment in MS, further investigations are warranted.

ClinicalTrials.gov identifier: NCT02661555

Level of evidence: This study provides level I evidence that 24 weeks of high-intensity PAE did not elicit disease-modifying effects in PBVC in people with MS. Exploratory analyses showed that PAE reduce relapse rate and may preserve gray matter brain volume.