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

Background: Evidence suggests a pathological role of myelination in neurodevelopmental disorders with links to cognitive difficulties, but in vivo assessment remains challenging. Quantitative T1 mapping (QT1) has been used in prior clinical studies (e.g., of multiple sclerosis) and shows promise for reliable measurement of myelin alterations. We investigated QT1 for measuring myelination in children with neurodevelopmental disorders of the RAS-MAPK signaling pathway (RASopathies).

Methods: We collected QT1, diffusion-weighted, and structural MRI scans from 72 children (49 RASopathies, 23 typical developing (TD)). QT1 myelin content measures included white matter macromolecular tissue volume (MTV) and cortical R1 (1/T1 relaxation). Group differences were assessed across 39 white matter tracts. Principal components analysis captured cortical myelination patterns across 360 regions, followed by a MANOVA. A support vector machine (SVM) identified the most discriminative features between-groups.

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

Conclusions: We found widespread elevated white matter tract myelin and region-dependent cortical myelination patterns in children with RASopathies. Leveraging preclinical models showing oligodendrocyte dysfunction, QT1 revealed precocious myelination. Further work is needed to explore relationships with cognition. QT1 is a promising tool for identification and monitoring of myelin as a treatment target in neurodevelopmental disorders, offering significant potential for advancing current therapeutic strategies.