ABSTRACT This project addresses a critical gap in the understanding of the mechanisms that underlie susceptibility for neurodevelopmental disability and reduced brain volume as measured via magnetic resonance imaging (MRI) in children. At the project’s core is the novel hypothesis that the expression of critical inflammation and stress response pathways in the placenta is associated with neurodevelopmental disability and altered brain structure later in life. To address this, we use a combined approach focusing on the placenta-brain axis that incorporates placental “-omics” data (gene expression), neonatal inflammatory biomarkers, neuroimaging measures, and neurodevelopmental disability data. This research focuses on cognitive and social impairment (including autism spectrum disorder; ASD) in an existing cohort of children born extremely prematurely (i.e., before 28 weeks’ gestation). A strength of this proposal is the unique and extensively characterized Extremely Low Gestation Age Newborn (ELGAN) Study. Since its initiation in 2001, the broad goal of the ELGAN Study has been to evaluate the relationship between perinatal inflammation and neurodevelopmental impairments among individuals born extremely premature. In the proposed project, we build on the success of the ELGAN Study by evaluating placental gene expression biomarkers of inflammation and stress response and neonatal blood and integrating these data with existing MRI-derived outcomes and neurodevelopmental disability of cognitive and social impairment. In the first year of the project, gene expression of selected inflammation and stress response pathways will be assayed and examined using data from archived specimens of placenta. Data analyses will begin in year 1, with an initial focus on establishing the relationships among placenta and reductions in MRI-derived brain structure measurements and neurodevelopmental impairment at age 10 and 15. Furthermore, moving into year 2 we will evaluate whether inflammation in the neonate mediates the relationship between the placenta gene expression and MRI-derived brain outcomes and ND at age 10 and age 15. Innovative aspects of this project include its longitudinal perspective and evaluation of placental mRNA gene expression patterns relative to alterations in MRI-derived brain measurements to study the placenta-brain axis. With the potential for public health impact, this research promises to inform the development of expanded therapies targeting molecular processes early in pregnancy to guide future etiological studies for the prevention and intervention of neurodevelopmental disability. A long term goal of this research will be to improve the quality of life for the more than 16,000 individuals who survive extremely preterm birth each year in the United States.

PROJECT NARRATIVE This project will identify biomarkers in the placenta that are associated with brain volume and neurodevelopmental impairments among individuals born extremely prematurely (<28 weeks gestation). The findings may inform the development of therapies to prevent or ameliorate cognitive disability in children.