Study of Down syndrome cortical development by MRI/DTI

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DESCRIPTION (provided by applicant): Down syndrome (DS) is the most common genetic form of mental retardation. One of the specific hallmarks of DS is anomalous cerebral cortical development. Studies have found cortical hypoplasia, abnormal lamination, reduced synaptogenesis, aberrant dendritic development, and a delay in myelination. These abnormalities lead to abnormal cortical organization and circuitry. Because of the lack of adequate DS tissue, it has been difficult to determine when abnormalities in cortical development first occur. Newer methods of brain imaging especially MRI have allowed studies of brain development to be done 3-dimensionally, without the invasiveness of histological methods. The present experiments will investigate development of the cortex during fetal development in DS compared to normal human development and also compare cortical formation and growth in DS with an animal model of DS, the segmental trisomy 16 mice (Ts65Dn). Many of the same chromosome 21 genes triplicated in DS are also triplicated in Ts65Dn and therefore Ts65Dn and DS share a common genetic abnormality. Using high resolution NM and the new method of resolving water diffusion in situ, diffusion tensor imaging (DTI) fiber bundle architecture and cortical organization will be resolved. We will characterize the volume of cortical regions, delineate the microstructure of the cortex and the architecture of major fiber bundles present during the fetal period. We have a unique collection of postmortem fetal DS brains (18-26 weeks gestation), a period of formation of future cortical organization. We will directly address the hypothesis that cortical volume and the size and shape of specific fiber bundles is abnormal in DS. In Aim 1, we will characterize the volume of cortical regions in fetal DS and Ts65Dn using MRI. In Aim 2, we will characterize cortical microstructure and fiber bundle architecture in DS and Ts65Dn using DTI. Thus we will not only characterize fetal development in DS and Ts65Dn, but also determine how similar they are. Defects during fetal neocortical development could lead to permanent cortical abnormalities responsible for cognitive deficits.