Abstract Down syndrome (DS), or trisomy 21, is the most common chromosomal disorder in newborns (about 1 in every 700 babies in the United States). Associated with numerous impairments, the cognitive deficits constitute one of the most notable features in DS, having problems with learning, memory, and speech/language throughout life. Abnormal brain development in DS begins in utero. It is critical to be aware of an altered initial brain anatomy in DS for better predicting what aspects of brain function will likely preferentially/precociously deteriorate, which would allow for potentially earlier/better prevention and treatment. A comprehensive knowledge of the early morphological/fiber pathway development in DS is still lacking. An earlier phase of this project was funded as an R21. This retrospective study, based on routine clinical MRI, successfully identified early brain abnormalities in DS. The Brodmann’s Area 3b (primary somatosensory) in the parietal lobe showed abnormally increased cortical thickness/volume, starting from birth in DS, which could explain sensory perceptual deficits. In contrast, abnormal measures in the temporal lobe (superior temporal gyrus; language function) were not found at birth but became significant with age. Our findings suggest that our approach has a great potential for identifying common early MRI-based brain malformations in DS. In addition, our data showed decreased pathways between the VZ/SVZ and the temporal lobe in DS infants, suggesting that our HARDI tractography could be useful for detecting early fiber abnormalities, including postnatal migration streams, in regions where morphological measures tend to miss early signs of pathology. In this proposal, we plan to confirm these findings using ex vivo MRI with significantly higher spatial resolution as well as polarization sensitive optical coherence tomography (PSOCT) which provides micron-level spatial resolution.