Structural MRI signature of late- versus adult-onset multiple sclerosis: a multiparametric study

Background: Structural MRI differences between late-onset multiple sclerosis (LOMS; onset ≥ 50 years) and adult-onset MS (AOMS) patients remain incompletely characterized, particularly regarding tissue damage distribution and relationship with clinical and cognitive outcomes. Objectives: To compare the structural MRI profile of LOMS and AOMS patients within a multiparametric framework including age-matched healthy control (HC) groups, and to examine MRI-clinical associations. Methods: Forty LOMS patients, 195 sex- and disease duration (DD)-matched AOMS patients, and 175 age-matched HC (HC-LO = 50; HC-AO = 125) underwent 3 T MRI and clinical-cognitive assessment. Analyses included white matter (WM) lesion volume (T2-LV) and distribution, volumetric measures, tract-based spatial statistics, and voxel-based morphometry. Voxel-wise analyses assessed group differences and associations with DD, Expanded Disability Status Scale (EDSS), and Symbol Digit Modalities Test (SDMT) (p < 0.05, FWE-corrected). Results: Both MS groups showed higher T2-LV, widespread WM microstructural abnormalities. and lower total, gray matter (GM), and deep GM volumes than age-matched HC (pFDR ≤ 0.015). LOMS patients showed higher lesion frequency in the left superior longitudinal fasciculus (SLF) than AOMS patients (pFWE = 0.003). Onset category × disease status interaction revealed higher T2-LV (pFDR = 0.005) and more pronounced regional GM atrophy in motor-insular-subcortical regions in the LOMS versus AOMS groups (pFWE ≤ 0.040). In LOMS patients, longer DD correlated with higher lesion frequency in the left SLF and mean diffusivity in several WM tracts (pFWE < 0.05). In AOMS patients, higher EDSS and lower SDMT scores related to higher lesion frequency in commissural tracts and thalamic-hippocampal atrophy (pFWE ≤ 0.040). Conclusion: LOMS patients exhibit higher T2-hyperintense WM lesion burden and more pronounced regional GM atrophy than AOMS patients, despite similar DD and no detectable global GM differences, potentially reflecting combined MS-related damage and age-related processes shaping a more severe structural MRI profile.