Introduction: Down syndrome (DS), arising from Trisomy 21, is the most common genetic condition associated with intellectual disability. While smaller total brain volumes have been consistently observed in DS, no longitudinal neuroimaging studies have examined volumetric brain development in DS during infancy, a period of rapid neural growth when interventions may have the greatest impact. Method: High-resolution T1- and T2-weighted images were acquired during natural sleep in a multisite longitudinal cohort of 44 infants with DS and 39 control infants without DS at ages 6 and 12 months. Neuroimaging data were harmonized to reduce batch effects, and a novel deep-learning, repeated-measures segmentation approach was applied to optimize neuroanatomical segmentations. Total intracranial volume (ICV) and bilateral absolute subcortical volumes (amygdala, caudate, hippocampus, pallidum, putamen, thalamus) were first directly compared in infants with and without DS at 6 and 12 months. Hierarchical linear modeling (HLM) evaluated longitudinal group differences for each structure, accounting for sex, gestational age, and laterality. Subcortical group differences estimated by HLM were also compared to group differences in total ICV. Results: ICV in infants with DS was lower than controls at 6 months (12.6%; p<.001) and 12 months (16.3%; p<.001). Subcortical structures displayed a range of lower volumes (6.9%-13.1%; p's<.003) in infants with DS, although the caudate and putamen were exceptions. Caudate volumes were on average lower in DS but not significantly different from controls, while putamen volumes were on average higher in DS but not significantly different from controls, except for the right putamen, which was significantly larger (5.3%; p=.018) at 6 months. In HLM, ICV and all subcortical structures showed slower growth in DS from 6 to 12 months, except for the amygdala and putamen, which displayed similar growth rates to controls. DS-associated reductions in subcortical volumes were similar in magnitude to ICV, although 12-month caudate and 6- and 12-month putamen volumes were enlarged relative to ICV. Conclusion: Infants with DS exhibited substantially reduced ICV and widespread reductions in subcortical volumes and growth from 6-12 months. Across a range of volumetric differences, findings were most distinct in the basal ganglia, for which volume reductions were attenuated in the caudate, while the putamen was uniquely enlarged with comparable growth to controls. These observations support early regional specificity in the neural impact of Trisomy 21 and underscore the utility of infant neuroimaging to inform biologically based interventions and clinical trial readiness in DS.
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