ID #868 p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 12.0px ‘Times New Roman’; color: #000000 White matter differences in children with NF1 on MEK inhibition versus untreated children with NF1

Introduction MEK inhibition (MEKi) has demonstrated efficacy in treating plexiform neurofibromas and low-grade glioma in children with neurofibromatosis type 1 (NF1). However, its effects on white matter development remain poorly understood. Given the role of the RAS-MAPK pathway in myelination and the presence of known white matter abnormalities in NF1, understanding how MEKi impacts developmental white matter trajectories is critical. This study examined longitudinal changes in white matter microstructure in children with NF1 receiving MEKi therapy compared to untreated NF1 controls. Methods Fourteen children with NF1 receiving MEKi aged 1.3-12.8 years (mean = 5.8 years) and thirteen untreated controls aged 4.1-16.5 years (mean = 10.3 years) underwent diffusion MRI at 3T (25 directions, b = 1000 s/mm2). Automated white matter tract (WMT) segmentation was used to extract fractional anisotropy (FA) from eight major WMTs. Linear mixed-effects models examined group differences (MEKi/non-MEKi) in longitudinal FA change after controlling for age at first scan. Statistical significance was set at p < 0.05 (uncorrected). Results Compared to untreated NF1 patients, children receiving MEKi demonstrated significantly greater increases in FA over time in two of eight tracts: the corticospinal tract and inferior fronto-occipital fasciculus [p = 0.032 and p = 0.040, respectively). The remaining 6 tracts showed similar trends without reaching significance. Conclusion MEKi is associated with greater longitudinal increases in white matter microstructural organization in select tracts involved in motor and cognitive function in children with NF1. These findings suggest MEK inhibition may positively impact white matter organization, with potential implications for neurodevelopmental outcomes. Larger, prospective longitudinal studies with extended follow-up are needed to determine whether these microstructural changes are associated with functional outcomes in this population.