Abstract Down syndrome (DS), the most common genetic cause of intellectual disability, is associated with varying degrees of cognitive and behavioral impairments. Pharmacologic therapies and genetic modulators are emerging which, if administered early in conjunction with traditional therapies, show promise for improving developmental outcomes in children with DS. However, the stark absence of early neurodevelopment knowledge in DS hampers these efforts. The main goal of this proposal is to develop biomarkers as future targets for specific therapies based on careful characterization of early aberrant neurodevelopmental patterns. This study will be a combined effort with WU as the coordinating center and six other research groups: UNC, UW, CHOP, MNI, NYU, and University of Minnesota. These groups comprise the ACE-IBIS (Autism Center of Excellence Infant Brain Imaging Study) network, a well-established and experienced group that has been productively collaborating for 8 years on MRI imaging and behavioral characterization of infants at high risk for autism, healthy typical infants (TYP), and infants with Fragile X. The aims of this proposal are: 1) Define the longitudinal characteristics of early brain development in infants (3 to 24 months) with DS in comparison to TYP infants and infants with other developmental disabilities (ASD and Fragile X) using three different types of neuroimaging (MRI, DTI, rsfMRI); 2) Develop predictive models for developmental outcomes in infants with DS based on longitudinal structural or functional MRI characteristics; and 3) Characterize brain-behavior correlates with coordinated multimodal imaging in infancy characterizing the interrelationship between longitudinal network imaging parameters and cognitive, behavioral and neurodevelopmental outcomes using sophisticated multivariate support vector machine (SVM) analytic strategies. 120 infants with DS and 40 TYP control infants will be followed longitudinally from 3 to 24 months. MRI scans will be obtained during natural sleep and a series of well-validated developmental and behavioral assessments will be completed at each visit. This project will be the first to define the nature and timing of alterations in brain development in infants with DS. The proposed project addresses several key research recommendations from the “NICHD 2014-The NIH Research Plan on Down Syndrome.” The study aims match the recommendation for the quantitative characterization based on imaging of early brain development and the relationship of cognitive, behavioral and social development to early aberrant neurodevelopment in DS. This project will also address recommendations for investigation of comorbid ASD in DS, which could be as high as 5-10%. The IBIS network is uniquely qualified to examine early neurodevelopmental patterns, utilizing the ASD, TYP and FraX infant data sets to better characterize and examine specificity of DS early developmental patterns including ASD qualities and impairme...