Abstract
Down syndrome (DS), resulting from Trisomy 21, is the most prevalent chromosomal disorder and a leading cause of intellectual disability. Despite the significant impact of Trisomy 21 on brain development, research on white matter (WM) microstructure in infants with DS remains limited. While widespread reductions in WM integrity have been identified in children and young adults with DS, no study has examined WM microstructure in infancy. This study investigates early WM microstructure in infants with DS using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI). Forty-nine infants with DS (28 [57.14%] female) and 36 control (18 [48.65%] female) infants were scanned at 6 months of age. Infants with DS showed significant reductions in fractional anisotropy and neurite density index across multiple association tracts, particularly in the inferior fronto-occipital fasciculus and superior longitudinal fasciculus II, consistent with reduced structural integrity and neurite density. Increased radial diffusivity was observed in these tracts, a feature associated with disrupted myelination. In the inferior fronto-occipital fasciculus, superior longitudinal fasciculus II, and uncinate fasciculus, an elevated orientation dispersion index suggested increased neurite dispersion and fanning in infants with DS. These findings reveal widespread WM developmental alterations in DS, providing new insights into the early neurodevelopment of DS, which may inform timing of early therapeutic interventions.