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Greater insight into the neurobiology underlying NDDs is critical to the development of successful treatments. Using a genetics\u2010first approach, we investigated the potential of advanced diffusion\u2010weighted 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\u2010shell DWI sequence optimized for neurite orientation density and dispersion imaging (NODDI) and diffusion kurtosis imaging (DKI). Region\u2010of\u2010interest and tract\u2010based analysis were conducted on subcortical regions and white matter tracts. Analysis of covariance, principal components, and linear discriminant analysis compared between three groups. 88 participants (<jats:italic>M<\/jats:italic><jats:sub>age<\/jats:sub>\u2009=\u20099.36, SD<jats:sub>age<\/jats:sub>\u2009=\u20092.61; 44 male) 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; estimated difference 0.044 [95% CI: \u22120.034, 0.053], <jats:italic>d<\/jats:italic>\u2009=\u20092.36), orientation dispersion index (ODI; estimate 0.018 [95% CI: 0.010, 0.026], <jats:italic>d<\/jats:italic>\u2009=\u20091.39), and mean kurtosis (MK; estimate 0.049 [95% CI: 0.025, 0.072], <jats:italic>d<\/jats:italic>\u2009=\u20091.39) were lower in NF1 compared with NS (all <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Reduced NDI was found in NF1 and NS compared with TD in all 39 white matter tracts investigated (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Reduced MK was found in a majority of the tracts in NF1 and NS relative to TD, while fewer differences in ODI were observed. The middle cerebellar peduncle showed lower NDI (estimate 0.038 [95% CI: 0.021, 0.056], <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) and MK (estimate 0.057 [95% CI: 0.026, 0.089], <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) in NF1 compared to NS. Multivariate analyses distinguished between groups using NDI, ODI, and MK measures. Principal components analysis confirmed that the clinical groups differ most from TD in white matter tract\u2010based NDI and MK, whereas ODI values appear similar across the groups. The subcortical regions showed several differences between NF1 and NS, to the extent that a linear discriminant analysis could classify participants with NF1 with an accuracy rate of 97%. Differences in neural microstructure were detected between NF1 and NS, particularly in subcortical regions and the middle cerebellar peduncle, in line with pre\u2010clinical evidence. Advanced DWI techniques detected subtle alterations not found in prior work using conventional diffusion tensor imaging.<\/jats:p>","DOI":"10.1002\/hbm.70087","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T12:29:36Z","timestamp":1734006576000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Elucidating Microstructural Alterations in Neurodevelopmental Disorders: Application of Advanced Diffusion\u2010Weighted Imaging in Children With Rasopathies"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5929-0651","authenticated-orcid":false,"given":"Julia R.","family":"Plank","sequence":"first","affiliation":[{"name":"Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences Stanford University  Palo Alto California 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Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences Stanford University  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamar","family":"Green","sequence":"additional","affiliation":[{"name":"Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences Stanford University  Palo Alto California 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