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

## TL;DR

This study shows that brain volume decreases and skull thickness increases in metachromatic leukodystrophy and multiple sclerosis, which may affect how brain atrophy is measured.

## Contribution

The study reveals that skull morphology adapts to brain atrophy in neurological diseases, challenging the assumption of stable intracranial volume.

## Key findings

- Intracranial volume decreases over time in both MLD and MS patients.
- Skull thickness increases in MLD and MS, and is inversely related to ICV loss.
- Using ICV as a normalization factor may underestimate brain atrophy in these conditions.

## Abstract

•ICV decreases over time in patients with metachromatic leukodystrophy and people with MS.•Skull thickness increases over time in patients with metachromatic leukodystrophy and people with MS.•Increased skull thickness and decreased ICV are inversely related in MLD and MS, but not in controls.•Skull morphology is not stable and may adapt to brain atrophy.•Using normalized volumes may underestimate atrophy.

ICV decreases over time in patients with metachromatic leukodystrophy and people with MS.

Skull thickness increases over time in patients with metachromatic leukodystrophy and people with MS.

Increased skull thickness and decreased ICV are inversely related in MLD and MS, but not in controls.

Skull morphology is not stable and may adapt to brain atrophy.

Using normalized volumes may underestimate atrophy.

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.