ABSTRACT Down syndrome (DS), the most common genetic cause of intellectual disability, accounts for ~30% of all moderate-to-severe IDD cases, with ~5,500 new individuals diagnosed with DS each year in the United States. DS is associated with varying degrees of cognitive impairment from infancy onward, yet progress has been very limited in understanding the relationships between neurodevelopment in DS and deficits in function. While clear structural brain differences and altered functional connectivity have been observed in DS at older ages, limited knowledge of infant brain development in DS hampers understanding of the relationship between brain differences and early delays, as well as the impact of disrupted development of neurocircuitry on later function. Infant brain imaging studies are needed to clarify mechanisms that could guide novel interventions during a highly plastic stage of neurodevelopment and to identify biomarkers that could inform the personalization of DS treatment and enhanced outcomes. In-depth characterization of DS-associated developmental differences in neural circuit structure and function is also key to evaluating a range of emerging pharmacologic therapies and genetic modulators that show promise for improving long-term function. To address these gaps, our team proposes to complete deep phenotyping and neuroimaging in a DS infant cohort in response to RFA-OD-24-003, which articulates the plan for multiple sites to collaboratively assemble a lifespan cohort of individuals with DS. Here we propose to leverage the Infant Brain Imaging Study Network (IBIS), a multisite, multidisciplinary team with >15 years’ experience in infant recruitment and collection of longitudinal behavioral and neuroimaging data in typically developing infants and infants with Autism spectrum disorder (ASD), DS, and Fragile X Syndrome. Our specific aims are: 1) To collect multimodal neuroimaging, including structural and functional MRI, as well as EEG, in a cohort of 100 infants with DS and 50 typically developing controls at ages 6, 12, and 24 months; 2) to perform concurrent, longitudinal deep phenotyping on these infants in key developmental domains of cognition and adaptive function, and 3) to collect data characterizing variation in early social communication in these infants that would advance early risk assessment for ASD, which occurs in ~15% of children with DS. Our team will leverage IBIS’ expertise in ASD-relevant phenotyping to include standardized clinical measures as well as dimensional research measures allowing more refined characterization of social attention and language. Data will be collected on medical comorbidities, sociodemographic information, and family environmental factors, along with biospecimens for future genetic analyses. Data will be accessible to the scientific community and allow novel analyses to characterize the nature and timing of altered neurodevelopment in DS, as well as establish a richly phenotyped cohort for future longitudinal studies elucidating relationships between infant brain and behavioral development and long-term outcomes.

NARRATIVE Down syndrome (DS) is the most common genetic cause of intellectual disability, yet progress has been very limited in understanding how early brain development in DS relates to long-term functional outcomes. In this project, the Infant Brain Imaging Study, a team with over 15 years’ of experience in infant neuroimaging, will collect comprehensive, state-of-the-art brain and behavioral data in infants with DS at ages 6, 12, and 24 months, with collection at five clinical sites across the U.S. These data will allow identification and tracking of early brain differences in DS and their relationships to behavior, which can help guide intervention research aimed at improving developmental outcomes.