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Quantitative T1 Mapping Indicates Elevated White Matter Myelin in Children With RASopathies
Julia R Plank1, Elveda Gozdas1, Jennifer Bruno1
1Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, Palo Alto, California.
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 previous 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/mitogen-activated protein kinase (RAS-MAPK) signaling pathway (RASopathies).
Methods:
We collected QT1, diffusion-weighted, and structural magnetic resonance imaging scans from 72 children (49 with RASopathies, 23 typically 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 component analysis captured cortical myelination patterns across 360 regions, followed by a multivariate analysis of variance (MANOVA). A support vector machine (SVM) identified the most discriminative features between groups.
Results:
Of 39 tracts, 34 were higher in MTV in children with RASopathies relative to TD children (false discovery rate-corrected p < .05), indicating widespread elevation in myelination. MANOVA revealed a group effect on cortical R1 (p = .002, η2 = 0.028), suggesting cortical myelination differences between the 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 that have shown 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.
