A New Model to Identify Preterm Neonates at High-Risk for Cognitive Impairments and School Readiness

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Project Summary/Abstract Children born very preterm (VPT; <32 weeks’ gestation) face a disproportionate burden of neurodevelopmental impairments (NDI). Impairments in the subdomains of mathematics, reading, and behavior are the most common NDI, affecting 25-50% of VPT children. These abilities are critical to school readiness and success at work. In the first cycle of this grant, we assembled the largest North American cohort of VPT infants and performed advanced brain MRI at term corrected age (CA) with longitudinal neurodevelopmental assessments. We demonstrated the clinical importance of diffuse white matter abnormality (DWMA) and multiple other novel MRI biomarkers to enhance prediction of short-term NDI at 2 or 3 years CA. During this second funding cycle, our unique cohort will reach the critical early school ages of 5 to 7 years, when higher-order cognitive abilities in math and reading, emotional self-regulation, and behavior become more apparent and accurately testable. The ability to accurately predict these functions several years earlier could enable early interventions. Assessment of the dynamic trajectories of NDI in VPT children and their modifiable environmental and biologic causes can also accelerate the development of targeted neuroprotective interventions during these critical early years when neuroplasticity is at its peak. The overall objectives of this proposal are to map the early childhood trajectory of brain structural and functional changes and develop early and accurate prognostic models of school readiness. Our rationale is that elucidation of the long-term impact of DWMA, identification of the trajectory and mediators of NDI changes, and robust prognostic models of school readiness will enable novel early intervention trials in targeted VPT infants. To achieve our goals, we will perform morphometric, diffusion, and functional MRI at age 5 and comprehensive developmental testing at 5 and 7 years CA in our cohort of VPT children and a matched group of term-control children. To advance this highly impactful area of research, we propose the following three specific aims: (1) Determine the impact of DWMA at term CA on brain development and functional impairments at age 5; (2) Model individual trajectories of NDI and identify the mediators of neurodevelopmental changes between 3 and 7 years CA; and (3) Develop early prognostic models of school readiness. For the first aim we will correlate objectively quantified DWMA volume at term CA with brain structural and functional connectivity derived from advanced MRI and with higher-order cognitive functions, both at 5 years CA. Under Aim 2, we will plot individual trajectories of neurodevelopmental scores and identify the mediators of trajectory change between 3 and 7 years CA. For the third aim, we will apply the rich collection of clinical, biologic, and neurodevelopmental data collected between birth and 3 years CA to predict our three measures of school readiness at 5 and 7 years CA. This study will provide U.S. population-based prevalence data about the long-term adverse neuroanatomic and functional consequences of VPT birth, identify mediators of NDI change, and facilitate early prediction of school readiness to enable targeted EI and novel randomized clinical trials for VPT children.