Longitudinal MRI-based changes in intracranial volume and skull thickness observed in both metachromatic leukodystrophy and multiple sclerosis.

Abstract

Intracranial volume (ICV) is often used as normalization factor in volumetrics and considered to be stable in young adults. We noticed thick skulls on MRI scans of leukodystrophy patients, suggesting potentially changing skull morphology. In this study we aimed to quantify skull thickness and ICV in metachromatic leukodystrophy (MLD) patients and people with multiple sclerosis (pwMS). We retrospectively analyzed single-center cross-sectional and longitudinal MRI scans. Skull thickness and ICV were determined using automated segmentation techniques. Participants included MLD (n = 32, 11 male, scans = 136, median age first scan = 14.1 [IQR 7.9-25.7] years), MS (n = 232, 78 male, median age first scan = 47.3 [IQR 39.6-55.4] years, scans = 431), and controls (n = 139, 67 male, median age first scan = 30.7 [IQR 10.7-48.9] years, scans = 283). Both ICV and skull thickness showed natural growth in young controls. In young MLD participants, ICV decreased (-18.8 ± 22.4 mL/year, p < 0.001). Above age 20, ICV and skull thickness remained stable in controls. In comparison to controls, we observed ICV loss in MLD participants (-4.01 ± 8.29 mL/year, p < 0.001) and in pwMS (-2.99 ± 2.69 mL/year, p < 0.001), as well as skull thickening (MLD: 0.16 ± 0.14 mm/year, p < 0.001, pwMS: 0.04 ± 0.09 mm/year, p = 0.009). In adult patient groups, negative correlations were found between ICV and skull thickness (MLD: -19.24 mL/mm, p < 0.001, pwMS: -11.56 mL/mm, p < 0.001), but not in controls (p = 0.11). Despite limitations due to scanner variations, segmentation reliability and absence of validation against ground truth, these findings demonstrate a reduction in ICV in pathologies, already in young adulthood. Although the observed changes are small, they may lead to underestimations of atrophy when using ICV as a normalization factor.