Quantitative MRI distinguishes different leukodystrophies and correlates with clinical measures

Objectives: The leukodystrophy “vanishing white matter” (VWM) and “metachromatic leukodystrophy” (MLD) affect the brain's white matter, but have very different underlying pathology. We aim to determine whether quantitative MRI reflects known neuropathological differences and correlates with clinical scores in these leukodystrophies. Methods: VWM and MLD patients and controls were prospectively included between 2020 and 2023. Clinical scores were recorded. MRI at 3 T included multi-compartment relaxometry diffusion-informed myelin water imaging (MCR-DIMWI) and multi-echo T2-relaxation imaging with compressed sensing (METRICS) to determine myelin water fractions (MWF). Multi-shell diffusion-weighted data were used for diffusion tensor imaging measures and neurite orientation dispersion and density imaging (NODDI) analysis, which estimates neurite density index, orientation dispersion index, and free water fraction. As quantitative MRI measures are age-dependent, ratios between actual and age-expected MRI measures were calculated. We performed the multilevel analysis with subsequent post-hoc and correlation tests to assess differences between groups and clinico-radiological correlations. Results: Sixteen control (age range: 2.3–61.3 years, 8 male), 37 VWM (2.4–56.5 years, 20 male), and 14 MLD (2.2–41.7 years, 6 male) subjects were included. Neurite density index and MWF were lower in patients than in controls (p < 0.001). Free water fraction was highest in VWM (p = 0.01), but similar to controls in MLD (p = 0.99). Changes in diffusion tensor imaging measures relative to controls were generally more pronounced in VWM than in MLD. In both patient groups, MCR-DIMWI MWF correlated strongest with clinical measures. Conclusion: Quantitative MRI correlates to clinical measures and yields differential profiles in VWM and MLD, in line with differences in neuropathology. Key Points: Question Can quantitative MRI reflect known neuropathological differences and correlate with clinical scores for these leukodystrophies? Finding Quantitative MRI measures, e.g., MWF, neurite density index, and free water fraction differ between leukodystrophies and controls, in correspondence to known histological differences. Clinical relevance MRI techniques producing quantitative, biologically-specific, measures regarding the health of myelin and axons deliver more comprehensive information regarding pathological changes in leukodystrophies than current approaches, and are thus viable tools for monitoring patients and providing clinical trial outcome measures.