Central nervous system inflammatory demyelinating diseases present overlapping clinical features but diverge fundamentally in underlying pathophysiological mechanisms. Historically, neurologists regarded multiple sclerosis as the archetype of progressive neurodegeneration. In contrast, researchers considered antibody-mediated disorders, such as myelin oligodendrocyte glycoprotein antibody-associated disease and aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder, primarily attack-dependent pathologies. However, mapping long-term structural volume changes across these distinct entities remained challenging. A multicenter investigation by the Magnetic Resonance Imaging in Multiple Sclerosis network now provides critical clarity. By analyzing longitudinal brain atrophy trajectories across diverse cohorts, this landmark study demonstrates that neuroaxonal loss in MOGAD couples tightly to inflammatory activity and lesion dynamics rather than chronic, smoldering neurodegeneration.

Deciphering Brain Atrophy Trajectories Across Demyelinating Disorders

Understanding structural tissue loss requires separating generalized neurodegeneration from focal inflammatory injury. Multiple sclerosis drives widespread axonal damage across the white matter and cerebral cortex. Consequently, patients with multiple sclerosis display steady, diffuse whole-brain volume loss that progresses independently of clinical relapses. Conversely, clinicians have long debated whether antibody-mediated conditions cause silent parenchymal loss during periods of remission. Because MOGAD and AQP4-positive NMOSD exhibit distinct immunological cascades, their downstream neurodegenerative footprints should logically differ. Aquaporin-4 astrocytopathy produces severe, complement-mediated astrocytic lysis that centers primarily on the spinal cord and optic nerves. In contrast, MOGAD triggers transient oligodendrogliopathy with marked inflammatory edema and significant capacity for tissue remyelination. Therefore, evaluating regional and global volume changes over extended follow-up reveals how distinct immune pathways reshape brain structure over time.

Methodological Framework of the Multicenter MAGNIMS Cohort

To quantify these dynamics, researchers gathered retrospective longitudinal data across 15 international specialized centers within the MAGNIMS network. The investigative team analyzed 489 participants, comprising 98 patients with multiple sclerosis, 72 with MOGAD, 41 with AQP4-positive NMOSD, and 278 healthy controls. Furthermore, investigators implemented rigorous inclusion parameters to avoid confounding acute post-inflammatory fluctuations. Eligible patients were at least 18 years old and had undergone two or more brain MRI scans on the same scanner at least six months apart. Crucially, all follow-up imaging occurred at least three months after any acute attack to mitigate the confounding impact of transient vasogenic edema and pseudoatrophy. The team performed automated white matter lesion segmentation and calculated longitudinal brain volumes on lesion-filled T1-weighted images using Sequence Adaptive Multimodal SEGmentation. Finally, linear mixed-effects models adjusted for age, sex, baseline volume, and scanning center to ensure robust volumetric estimates.

Distinct Volumetric Profiles in MS, MOGAD, and AQP4-Positive NMOSD

The statistical analyses demonstrated clear, disease-specific patterns of parenchymal loss across the study groups. Healthy controls maintained relatively stable brain volumes throughout observation. Compared with healthy controls, patients with multiple sclerosis exhibited accelerated global brain atrophy, losing approximately two cubic centimeters of brain parenchyma per year. In contrast, patients with MOGAD did not display generalized whole-brain atrophy. Instead, they demonstrated selective cerebral white matter volume reduction alongside significant enlargement of the lateral and third ventricles. Meanwhile, individuals with AQP4-positive NMOSD showed preserved global brain volumes but developed isolated, significant volumetric reduction in the globus pallidus. These divergent neuroimaging patterns indicate that tissue loss does not follow a universal degenerative pathway across demyelinating disorders. Instead, each condition produces a signature pattern of tissue remodeling reflecting its unique immunopathology.

The Mechanistic Impact of Relapses and Lesion Accrual in MOGAD

The most compelling findings emerge from the granular subgroup analysis within the MOGAD cohort. Among patients with MOGAD, disease phenotype markedly influenced ventricular expansion rates. Specifically, relapsing MOGAD patients, who constituted 62.5% of the MOGAD group, exhibited significantly greater third ventricular enlargement than patients with multiple sclerosis. Even more strikingly, patients with MOGAD who developed new MRI lesions during follow-up showed pronounced expansion of both the lateral and third ventricles. Their ventricular enlargement significantly outpaced that observed in healthy controls, multiple sclerosis patients, and NMOSD cohorts. Conversely, patients with monophasic MOGAD and those without new lesions demonstrated stable volumetric measurements over time. Consequently, these findings confirm that brain atrophy in MOGAD represents an event-driven consequence of inflammatory lesion accrual rather than an unremitting, autonomous neurodegenerative cascade.

Clinical Translation and Differential Diagnosis in Practice

These volumetric distinctions provide actionable diagnostic and therapeutic guidance for clinicians managing demyelinating diseases. When assessing patients with uncertain serologies, diffuse global brain volume loss strongly supports multiple sclerosis over antibody-mediated diseases. Furthermore, the event-dependent nature of tissue loss in MOGAD carries vital therapeutic implications. Because neuroaxonal injury in MOGAD tracks directly with clinical relapses and subclinical lesion accrual, preventing acute inflammatory attacks represents the most effective strategy to preserve brain parenchyma. Clinicians should maintain rigorous radiological surveillance even during clinical stability. If routine MRI surveillance detects new inflammatory lesions, physicians must promptly re-evaluate immunotherapy regimens to prevent cumulative brain tissue loss. Although retrospective designs and scanner heterogeneity present inherent challenges, these robust data offer reassuring evidence that timely, effective disease control directly prevents irreversible structural brain atrophy in MOGAD.

Frequently Asked Questions

How does brain atrophy in MOGAD differ fundamentally from multiple sclerosis?

Multiple sclerosis produces continuous, diffuse global brain atrophy driven by chronic neurodegeneration and microglial activation that persists outside relapses. In contrast, MOGAD causes selective white matter loss and ventricular enlargement that occurs almost exclusively secondary to acute inflammatory attacks and active lesion formation. Without active inflammatory relapses, MOGAD patients generally maintain stable longitudinal brain parenchymal volumes.

Why is ventricular enlargement clinically meaningful in patients with MOGAD?

Ventricular enlargement serves as a sensitive, indirect marker of central white matter loss and periventricular tissue contraction following inflammatory damage. In MOGAD, third and lateral ventricular expansion accelerates sharply among individuals who develop new white matter lesions or recurrent attacks. Consequently, longitudinal ventricular tracking provides clinicians with an objective imaging biomarker to evaluate cumulative structural damage over time.

How should clinicians monitor disease activity to prevent volume loss in MOGAD?

Clinicians should implement structured clinical assessments combined with scheduled, standardized brain and spinal MRI evaluations outside acute relapse windows. Detecting silent lesion accrual or subclinical disease activity is essential because each inflammatory episode drives irreversible tissue destruction. Promptly escalating maintenance immunotherapy upon detecting active lesions helps protect patients from cumulative ventricular enlargement and permanent neuroaxonal injury.

Disclaimer: This content is for informational and educational purposes only. It should not be used as a substitute for professional medical advice, diagnosis, or treatment. Refer to the latest local and national guidelines for clinical practice.

References

1. Cortese R et al. Differential Trajectories of Brain Atrophy in Multiple Sclerosis, MOGAD, and AQP4 + NMOSD: The Role of Disease Activity in MOGAD. Neurology. 2026 Nov 24. doi: 10.1212/WNL.0000000000218673. PMID: 42900856.
2. Cortese R, Prados F, Tur C, et al. Differentiating Multiple Sclerosis From AQP4-Neuromyelitis Optica Spectrum Disorder and MOG-Antibody Disease With Imaging. Neurology. 2023;100(3):e308-e323. doi:10.1212/WNL.0000000000201465.
3. Lorefice L, Cortese R. Brain and spinal cord atrophy in NMOSD and MOGAD: Current evidence and future perspectives. Mult Scler Relat Disord. 2024;85:105559. doi:10.1016/j.msard.2024.105559.
4. Banwell B, Bennett JL, Marignier R, et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neurol. 2023;22(3):268-282. doi:10.1016/S1474-4422(22)00431-8.