Abstract
Neurodevelopmental disorders (NDDs) can severely impact functioning yet effective treatments are limited. Greater insight into the neurobiology underlying NDDs is critical to the development of successful treatments. Using a genetics-first approach, we investigated the potential of advanced diffusion-weighted imaging (DWI) techniques to characterize the neural microstructure unique to neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). In this prospective study, children with NF1, NS, and typical developing (TD) were scanned using a multi-shell DWI sequence optimized for neurite orientation density and dispersion imaging (NODDI) and diffusion kurtosis imaging (DKI). Region-of-interest and tract-based analysis were conducted on subcortical regions and white matter tracts. Analysis of covariance, principal components, and linear discriminant analysis compared between groups. 88 participants were included: 31 NS, 25 NF1, and 32 TD. Subcortical regions differed between NF1 and NS, particularly in the thalamus where the neurite density index (NDI), orientation dispersion index (ODI), and mean kurtosis (MK) were lower in NF1 compared to NS (p < .001). The middle cerebellar peduncle showed lower NDI and MK in NF1 compared to NS (both p < .001). Multivariate analyses distinguished between groups using NDI, ODI, and MK measures. Differences in neural microstructure were detected between neurofibromatosis type 1 and Noonan syndrome, particularly in subcortical regions and the middle cerebellar peduncle, in line with pre-clinical evidence. Advanced DWI techniques detected subtle alterations not found in prior work using conventional diffusion tensor imaging.