Differential Trajectories of Brain Atrophy in Multiple Sclerosis, MOGAD, and AQP4 + NMOSD: The Role of Disease Activity in MOGAD.

BACKGROUND AND

OBJECTIVES

Multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD) are inflammatory demyelinating disorders with distinct mechanisms of tissue injury. MS is characterized by diffuse neurodegeneration, whereas damage in antibody-mediated diseases is considered attack related. In MOGAD, the relationship between disease activity and brain atrophy remains unclear. We aimed to compare longitudinal trajectories of global and regional brain atrophy across MS, MOGAD, and AQP4 + NMOSD and investigate whether atrophy in MOGAD is associated with disease course and lesion dynamics.

METHODS

In this retrospective multicenter Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) study, patients fulfilling the following criteria were enrolled: (1) age 18 years or older, (2) MS/MOGAD/AQP4 + NMOSD diagnosis, (3) ≥2 same-scanner brain MRIs ≥6 months apart and ≥3 months postattack, (4) concurrent Expanded Disability Status Scale, and (5) disease course information. White matter lesions were segmented using the Lesion Segmentation Toolbox. Longitudinal brain volumes were quantified on lesion-filled T1-weighted images using Sequence Adaptive Multimodal SEGmentation (SAMSEG) with a within-subject template approach. In MOGAD, lesion dynamics were classified as stable/new lesions/lesion resolution. Linear mixed-effects models adjusted for age, sex, baseline volume, and center estimated atrophy rates.

RESULTS

Overall, 489 participants from 15 centers were included (98 MS [mean age 39.79 years, 68.37% female], 72 MOGAD [42.14 years, 66.67%], 41 AQP4 + NMOSD [51.25 years, 87.80%], and 278 healthy controls [42.94 years, 61.87%]). The mean follow-up was MS: 2.44 ± 1.55 years, MOGAD: 2.57 ± 1.85, and AQP4 + NMOSD: 3.22 ± 2.42. Compared with controls, MS showed accelerated global brain atrophy (β = -2.027 cm3 per year, 95% CI -3.430 to -0.623). MOGAD demonstrated white matter volume loss (β = -0.989, 95% CI -1.889 to -0.090) and ventricular enlargement (lateral: β = 0.219, 95% CI 0.089-0.350; third ventricle: β = 0.009, 95% CI 0.003-0.015). AQP4 + NMOSD showed pallidal volume reduction (β = -0.008, 95% CI -0.014 to -0.001). Within MOGAD, relapsing patients (62.5%) exhibited greater third ventricular expansion than MS (β = 0.009, 95% CI 0.001-0.017). MOGAD with new lesions (22.22%) had greater ventricular enlargement than controls (lateral: β = 0.359, 95% CI 0.147-0.572; third ventricle: β = 0.016, 95% CI 0.006-0.025), MS, and AQP4 + NMOSD.

DISCUSSION: Each inflammatory demyelinating disease exhibits a characteristic pattern of brain atrophy. In MOGAD, neuroaxonal loss seems associated with inflammatory activity and lesion accrual, supporting an event-driven pattern of tissue injury rather than diffuse neurodegeneration. Limitations include small NMOSD sample, heterogeneous follow-up, and potential scanner-related variability.