BACKGROUND: Aquaporin-4 antibody positive (AQP4+) neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are two distinct antibody-mediated neuroinflammatory diseases. Diffusion Tensor Imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI) are advanced diffusion-weighted MRI models providing quantitative metrics sensitive to cerebral microstructural changes. This study aims to differentiate brain tissue damage in NMOSD and MOGAD from controls and investigate its association with clinical disability, using NODDI and DTI-derived measures, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity. METHODS: This study included 31 AQP4+ NMOSD, 21 MOGAD patients and 45 healthy controls. Clinical information included disease duration, Expanded Disability Status Scale (EDSS), Timed 25 Foot Walk test (T25FW), Nine-Hole Peg Test (9HPT), Symbol Digit Modalities Test (SDMT) and monocular 100 % high contrast visual acuity (HCVA). All participants underwent MRI scanning with multi-shell diffusion-weighted imaging, T2w fluid-attenuated inversion recovery and T1w magnetization prepared-rapid acquisition gradient echo sequences to obtain manually segmented T2-hyperintense white matter lesions (WML) and normal-appearing brain tissue (NABT) masks, including white matter (NAWM), cortical and deep gray matter (NACGM, NADGM). DTI and NODDI metrics were compared between groups using region-of-interest (ROI) analysis and tract-based spatial statistics. Tissue-weighted means were obtained for the NODDI metrics (weighted neurite density index, wNDI
weighted orientation dispersion index, wODI). Group differences in ROI analyses were assessed using age and sex adjusted linear regression models, followed by post-hoc comparisons with estimated marginal means. Stepwise multivariable linear regression models were used to evaluate the association between MRI biomarkers and clinical outcomes. RESULTS: NMOSD patients had higher T2 lesion volume (1120.5 mm CONCLUSION: NODDI and DTI measures are sensitive to pathological alterations in myelin and axon integrity, as water diffusion is less restricted in demyelinated tissue. Compared to MOGAD, patients with NMOSD tend to exhibit more extensive chronic white matter damage, demyelination or axonal injury. NODDI demonstrates greater sensitivity and specificity to alterations in NACGM compared to DTI. Given their association with clinical disability, NODDI metrics appear to be valuable neuroimaging biomarkers for assessing microstructural damage in clinical research.