Cognitive and structural brain changes in ofatumumab-treated multiple sclerosis: A longitudinal study

Anti-CD20 therapies control inflammatory activity in multiple sclerosis (MS), but their effects on neurodegeneration and cognition in real-world settings remain uncertain. We conducted a longitudinal observational study of relapsing MS (RMS) patients treated with ofatumumab. Cognitive performance was assessed using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS), with processing speed as the primary outcome, and Magnetic Resonance Imaging (MRI) measures included thalamic volume, deep gray matter (DGM) volume, and cortical thickness (CTh). Longitudinal changes and structure-cognition associations were analyzed using linear mixed-effects models. Eighty-five RMS patients treated with ofatumumab (mean age 37.9 ± 9.9 years; 69.4% female; 222 MRI scans) were included. Brain atrophy persisted but attenuated beyond 12 months: whole-brain volume -0.15% to -0.09%; DGM -1.01% to -0.36%; thalamus -0.94% to -0.77%; CTh -1.67% to -0.62% (all p for slope changes >0.05). Cognitive performance increased (Symbol Digit Modalities Test, SDMT +3.79 points/year, 95% CI 1.35 to 6.23; p= 0.003), with increases in verbal and visuospatial memory (Brief Visuospatial Memory Test-Revised and California Verbal Learning Test-Second Edition, p< 0.05). No global longitudinal structure-cognition association was observed. In subgroups, thalamic atrophy was associated with SDMT decline in patients with Expanded Disability Status Scale ≥3 (β= -54.31; p= 0.013), and DGM atrophy with cognitive worsening in patients with baseline SDMT z-score ≤ -1 (β= -55.91; p= 0.012). In ofatumumab-treated relapsing MS, neurodegeneration persists but slows over time while cognition may be preserved, and structural-functional coupling emerges only in vulnerable patients.