White matter microstructure in school-age children with down syndrome

Abstract

Down syndrome (DS) is the most common genetic cause of intellectual disability, but our understanding of white matter microstructure in children with DS remains limited. Previous studies have reported reductions in white matter integrity, but nearly all studies to date have been conducted in adults or relied solely on diffusion tensor imaging (DTI), which lacks the ability to disentangle underlying properties of white matter organization. This study examined white matter microstructural differences in 7- to 12-year-old children with DS (n = 23), autism (n = 27), and typical development (n = 50) using DTI as well as High Angular Resolution Diffusion Imaging, and Neurite Orientation and Dispersion Imaging. There was a spatially specific pattern of results that showed a dissociation between intra- and inter-hemispheric pathways. Intra-hemispheric pathways (e.g., inferior fronto-occipital fasciculus, superior longitudinal fasciculus) exhibited reduced organization and structural integrity. Inter-hemispheric pathways (e.g., corpus callosum projections) and motor pathways (e.g., corticospinal tract) showed denser neurite packing and lower neurite dispersion. The current findings provide early insight into white matter development in school-aged children with DS and have the potential to further elucidate microstructural differences and inform more targeted clinical trials than what has previously been observed through DTI models alone.

Keywords: Axonal density; Diffusion imaging; Down syndrome; Fiber pathways; Neurite dispersion; White matter development.

Fig. 1

Fiber tractography of the intra-hemispheric tracts examined. Not shown; corticothalamic superior, which is the sum of corticothalamic parietal and motor. ILF = inferior longitudinal fasciculus, IFOF = inferior fronto-occipital fasciculus, CST = corticospinal tract, SLF = superior longitudinal fasciculus.

Fig. 2

Segmentation of the corpus callosum. Body of the corpus callosum (left) is composed of premotor, motor, and parietal segments.

Fig. 3

Group differences in white matter microstructure. Intra-hemispheric tracts, such as the IFOF and SLF II, show a pattern of lower GFA and higher ODI, in children with DS compared to autism and TD, potentially indicative of lower structural integrity and neurite organization. Inter-hemispheric tracts, such as the splenium and tapetum, had a pattern of higher GFA, lower ODI (not shown here, available in Supplementary Figure 3), and higher NDI in DS, suggesting lower dispersion and denser axonal packing. Motor tracts such as the CST and motor segment of the corticothalamic projection appear distinct from this intra- and inter-hemispheric pattern in the brain, with higher GFA and ODI, potentially indicating less complex neurite fanning compared to autism and TD. IFOF = inferior fronto-occipital fasciculus, SLF = superior longitudinal fasciculus, CST = corticospinal tract. GFA= generalized fractional anisotropy, ODI = orientation dispersion index, NDI = neurite density index.