In the OPTIMUM trial, researchers sought to determine disability, cognition, motor function, and multiple sclerosis (MS) fatigue in relation to baseline and change in brain volume (BV). Over the course of 108 weeks, patients were given either ponesimod (20 mg) or teriflunomide (14 mg). The relationships between the combined arms (n=1089) were explored. Normalized BV was measured at baseline, as well as at Week 60 (W60) and Week 108 (W108) as Percentage Brain Volume Change (PBVC). Expanded disability status scale (EDSS); Multiple Sclerosis Functional Composite (MSFC); Timed 25-Foot Walk (T25FW); 9-Hole Peg Test (9-HPT); Paced Auditory Serial Addition Test (PASAT-3) were among the clinical examinations. The Symbol Digit Modalities Test score (SDMT) was used to assess cognition, while the Fatigue Symptoms and Impact Questionnaire -RMS was used to assess MS-fatigue (FSIQ-RMS). All clinical measures at baseline (r range=-0.186 [T25FW] to 0.354 [MSFC], all p<0.001), W60 (r range=-0.150 [T25FW] to 0.321 [MSFC], all p<0.001), and W108 (r range=-0.176 [FSIQ-RMS] to 0.354 [MSFC], all p<0.001) were statistically significant. At W60 and W108, correlations between BV and MSFC were consistently stronger, while correlations between other clinical parameters and PBVC varied. PBVC remained strongly associated to MSFC (r=0.147 (p<0.001) and r=0.166 (p<0.001), EDSS (r=-0.114 (p=0.001) and r=-0.195 (p<0.001), SDMT (r=0.150 (p<0.001) and r=0.168, p<0.001), and 9-HPT (r=-0.105 (p=0.003) and r=-0.197 (p<0.001) at W60 and W108 W60 r=-0.102 (p=0.004), but not W108 r=-0.049 (p=0.190), showed a significant correlation with T25FW. W60 r=0.065 (p=0.066) had no significant correlation with PASAT-3, however W108 PASAT-3 r=0.100 (p<0.01) did. For FSIQ-RMS, W60 r=-0.002 (p=0.959) and W108 r=0.033 (p=0.428), no connection was identified. There were statistically significant associations between BV and clinical results measures of disability, cognition, motor function, and MS-fatigue; however, ambulation and MS-fatigue were not linked with the PBVC.