Grantee Research Project Results
2017 Progress Report: An MRI Study of the Effects of Prenatal and Early Childhood PAH Exposure on Brain Maturation and Its Mediating Influences on Adverse Adolescent Outcomes
EPA Grant Number: R836154C003Subproject: this is subproject number 003 , established and managed by the Center Director under grant R836154
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: The Columbia Center for Children’s Environmental Health
Center Director: Perera, Frederica P.
Title: An MRI Study of the Effects of Prenatal and Early Childhood PAH Exposure on Brain Maturation and Its Mediating Influences on Adverse Adolescent Outcomes
Investigators: Peterson, Bradley S
Institution: University of Southern California
EPA Project Officer: Callan, Richard
Project Period: September 1, 2015 through August 31, 2019 (Extended to August 31, 2020)
Project Period Covered by this Report: May 1, 2016 through May 1,2017
RFA: Children's Environmental Health and Disease Prevention Research Centers (2014) RFA Text | Recipients Lists
Research Category: Children's Health , Endocrine Disruptors , Human Health
Objective:
Aim 1: We will assess the effects of prenatal and early childhood postnatal exposure to PAH (hereafter, “early PAH exposure”) on the structure, function, and metabolism of self-regulatory systems (frontal, parietal, and mesial temporal cortices, and subcortical nuclei) in the brains of 350 cohort children who have undergone MRI scanning at 9-12 years of age.
Aim 2: We will assess whether PAH-related brain disturbances at 9-12 years of age (identified in Aim 1) mediate the association between prenatal PAH exposure and adverse CEBA outcomes at 15-17 years.
Aim 3: We will acquire anatomical MRI scans at 15-17 years in 350 children with previous imaging at 9-12 years to assess how prenatal and early childhood exposures to PAH alter the trajectory of brain development throughout adolescence, and whether such alterations predict CEBA problems.
Aim 4 (integrative): All 3 projects in this P50 share a common cohort in which we will explore how prenatal PAH exposure dysregulates neurodevelopment (project 1) and physical growth (project 2) via its mediational effects on the brain (project 3).
Progress Summary:
We have made great progress in processing all of the Magnetic Resonance Imaging (MRI) data, including processing of anatomical data, task-based fMRI and Arterial Spin Labeling (ASL) perfusion data, Diffusion Tensor Imaging (DTI) data, and Magnetic Resonance Spectroscopy (MRS) data. Integration with demographic, behavioral, and cognitive data is complete. Currently, we are integrating the data with measures of growth and obesity. Also, statistical analyses are underway for ASL perfusion data, and are nearly complete for the DTI and MRS data sets. Mediation analyses, which are both labor-intensive and computationally demanding, are underway for DTI and MRS data. Moreover, the quality of anatomical brain images acquired thus far is superb, both from the perspective of scanner performance and the presence of minimal motion artifact.
For the DTI findings, we correlated the total air-borne prenatal PAH levels with FA (fractional anisotropy) and ADC (average diffusion coefficient, or mean diffusivity) values across the brain in 252 of our participants at ages 9-12. We detected significant positive correlations of prenatal PAH exposure with FA measures within white matter of the internal capsule and corpus callosum and ADC measures white matter of the frontal cortex and optic radiations, as well as in the gray matter of the caudate nucleus. As FA is an index of the degree of tissue organization in the brain, particularly within white matter tracts, the positive correlations indicate that higher prenatal exposures to PAH are associated with pathological and proportionally greater degrees of white matter tissue organization in deep white matter tracts of the brain bilaterally. The anterior and posterior limbs of the internal capsule (ALIC and PLIC, respectively) interconnect frontal and parietal cortices with the basal ganglia nuclei in cortical-subcortical loops that support attention and impulse control. The corpus callosum (CC) interconnects homotopic regions across the two cerebral hemispheres.
These findings, combined with our prior anatomical findings of reduced white matter volumes in the left cerebral hemisphere, suggest that smaller white matter volumes are associated with a pathologically greater density and organization of white matter tissue in those exposed to higher prenatal PAH levels. This greater density or organization of white matter could derive from several different cellular features of white matter, including smaller and more densely packed axons, more glial cells or myelin, or reduced extracellular space and its fluids. Mean diffusivity measures additionally implicate organizational and cellular alterations in the caudate, superficial frontal white matter, and optic radiations.
For the MRS data, the findings were similar for NAA, choline, and creatine, and therefore, we show here only findings for NAA, which include greater prenatal exposure to PAH associated with reduced NAA (purple color coding) primarily in posterior cingulate cortex but also midbody and dorsal anterior cingulate cortex, dorsal white matter, and the basal ganglia and thalamus. The cingulate gyrus is a vitally important structure for executive functioning, and the basal ganglia and thalamus are important for attention and impulse control.
Future Activities:
In the next reporting period, we will continue follow-up of the cohort members as they reach ages 16-18 years and we expect to complete 144 follow-up visits. The next reporting period will focus, in part, on intensive MRI and behavioral data collection from study participants. Recruitment and data collection will follow the approaches described in our grant application. We will process data from each participant as it is collected. Our original proposal called for follow-up and data collection from 100 subjects in year one, two and three of the project and from 50 participants in year four. As a result of the challenges we experienced in developing a single MRI scan protocol that acquires both brain and abdominal images on our 3T MRI scanner, the launch of participant recruitment and data collection was delayed. We anticipate beginning data collection in June of 2016, and thus, expect to collect data from 30 participants in year 1 of the project. In years 2 and 3, we plan to complete recruitment at data collection for 135 participants to bring us back on schedule by year 4 of the project.
Furthermore, in the following year, we will complete statistical analysis for DTI, MRS, and anatomical data, including mediation analyses. Findings will be interpreted and, based on those interpretations, manuscripts will be prepared and submitted for publication. The manuscript reporting DTI and MRS findings is in preparation.
Supplemental Keywords:
PAH, MRI, prenatal exposure, brain, adolescent outcomesRelevant Websites:
http://ccceh.org/ Exit Exit
Progress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R836154 The Columbia Center for Children’s Environmental Health Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R836154C001 The Impact of PAH Exposure on Adolescent Neurodevelopment: Disruption of Self-Regulatory Processes
R836154C002 The Impact of PAH Exposure on Childhood Growth Trajectories and Visceral Adipose Tissue
R836154C003 An MRI Study of the Effects of Prenatal and Early Childhood PAH Exposure on Brain Maturation and Its Mediating Influences on Adverse Adolescent Outcomes
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.