Quantitative T1 mapping indicates elevated white matter myelin in children with RASopathies

Evidence suggests pathological roles of myelination in neurodevelopmental disorders, but our understanding is limited. We investigated quantitative T1 mapping (QT1) as a clinically feasible tool for measuring myelination in children with neurodevelopmental disorders of the RAS-MAPK signaling pathway (RASopathies).

We collected QT1, diffusion-weighted, and structural MRI scans from 72 children (49 RASopathies, 23 typical developing (TD)). QT1 measures of myelin content included the macromolecular tissue volume (MTV) in white matter and R1 (1/T1 relaxation) of the cortex. For white matter, we assessed between-groups differences across 39 tracts. For cortical R1, we used principal components analysis to reduce dimensionality and capture myelination patterns across 360 regions. A multivariate ANOVA assessed differences across principal components. Finally, a support vector machine (SVM) identified the most discriminative features between TD and RASopathies.

Thirty-four of 39 tracts were higher in MTV in RASopathies relative to TD (p_FDR <.05), indicating widespread elevation in myelination. Our MANOVA revealed a group effect on cortical R1 (p=.002, η² =.028), suggesting cortical myelination differences between-groups. SVM yielded an accuracy of 87% and identified cognitive and cortical R1 features as the most discriminant between-groups.

We found widespread elevated myelin in white matter tracts and region-dependent patterns of cortical myelination in children with RASopathies. QT1 enabled us to leverage preclinical models showing oligodendrocyte dysfunction to uncover the myelination pattern in vivo in the developing human brain. Using QT1, myelin represents a promising treatment target that can be identified and monitored in neurodevelopmental disorders, offering significant potential for advancing current therapeutic strategies.