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2005 Progress Report: Clinical Sciences Project
EPA Grant Number: R829391C005Subproject: this is subproject number 005 , established and managed by the Center Director under grant R829391
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: CECEHDPR - University of Medicine and Dentistry of New Jersey Center for Childhood Neurotoxicology and Assessment
Center Director: Lambert, George H.
Title: Clinical Sciences Project
Investigators: Lambert, George H. , Johnson, William , Mars, Audrey , Moreno, Rosanne , Seshadri, Kapila
Current Investigators: Lambert, George H. , Carmody, Dennis , Johnson, William , Mars, Audrey , Moreno, Rosanne , Seshadri, Kapila
Institution: University of Medicine and Dentistry of New Jersey
Current Institution: University of Medicine and Dentistry of New Jersey
EPA Project Officer: Fields, Nigel
Project Period: November 1, 2001 through October 31, 2006
Project Period Covered by this Report: November 1, 2004 through October 31, 2005
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2001)
Research Category: Children's Health , Health Effects
Description:
Objective:The objective of this research project is to test the hypotheses that: (1) the regression of neurological function observed in some children with autistic spectrum disorder (ASD), which occurs at the time the children become more mobile, is caused by the exposure to high levels of neurotoxicants, reexposure to specific neurotoxicants, or unidentified neurotoxicants,or to caused by highly susceptible subjects specific genes or gene polymorphisms; (2) in children with ASD, high or unusual exposure to neurotoxicants alter regional brain growth or the combination of genes and environment; and (3) susceptibility to develop autism can be influenced by the child or mother’s genotype involved in protecting the developing human from chemical induced oxidative stress, regional brain growth, neurodevelopmental genes, or genes associated with autoimmune susceptibilities.
Progress Summary:Recruitment
In early June, less than 18 months into recruitment, there are 49 consents that have been sent out to parents that have been prescreened to meet the study criteria and have agreed to read the consent and most likely will join the study. Forty-five signed consents have been received. Of the 45 signed consents, 7 parents have been dropped out of the study because of illness in the child or family, divorce and movement of the child, or receiving chelation therapy.
Recruitment has come from The New Jersey Center for Outreach and Services for the Autism Community county facilitators; the State of New Jersey Early Intervention Program; Applied Behavior Analysis schools, including our partner, the Eden Family of Services; Douglass Developmental Disabilities Center; Princeton Child Development Institute; and developmental pediatricians in New York, New Jersey, and the Philadelphia area.
The original plans were to recruit 33 subjects per year or have 46 consents at this time. Therefore, we are about six consents behind, but at the current rate of six to eight consents per month, we will catch up to the planned recruitment phase this next 6 months. The final total number for the study is 100 recruited families, and this number will be reached before the beginning of Year 4 of the study. This will allow all the critical studies to be completed on all the subjects including the magnetic resonance imaging (MRI) and 4-year neurobehavioral assessment to be completed prior to the end of the study.
In regards to recruitment of minorities, we have more than 10 percent Hispanics, more than 10 percent minorities, and more than 12 percent female participation. Because of the entrance criteria of being diagnosed with ASD or pervasive developmental disorder prior to the age of 3 and the need that the family has not moved since 1 year prior to the conception of the child, the numbers of blacks reflect the fact that the average age of children who are black are diagnosed with ASD well after turning 4 years old; additionally, many families move prior to delivery or during the first few years of birth, excluding them from the study. A grant has been awarded to Dr. Ming to actively identify black children in Newark as soon as possible.
Study Visits
The study visits for neurobehavioral evaluation, neurological evaluation, physical exam, and biological assessment takes 2 and sometimes 3 days.
ADOS
To date, 32 of the 36 scheduled participants have been seen for initial behavioral assessment. All 32 children have met Autism Diagnostic Observation Schedule (ADOS) criteria to participate in the study.
Psychological Testing
To date, testing has been completed on 26 of the 32 children. Two children still are in the process and have to be scheduled for multiple visits because of fatigue and irritability and will be completed shortly. Three children have be scheduled later in the summer when they are at least 30 months old, which is the lower age limit.
Medical/Neurological Evaluation
To date 24 of 32 children have completed the history and physical examination. The remaining children are in the process of scheduling or finishing the examination. One child had café-au-lait spots and was referred for an MRI and other studies to rule out neurofibromatosis.
Characteristics of the Participants
There is a 28:4 male female ratio. Sixteen children met criteria for ASD, and 16 for autistic disorder (AD). Regression (including language and social) has been reported in 15 of 32 children. Analysis of psychological assessment data reveal that of the 26 children who have completed the full psychological battery, 17 have a score of 69 or below on the measure of cognitive functioning (Differential Ability Scales), 17 have a score of 69 or below on the measure of adaptive functioning (Vineland Adaptive Behavior Scales), and 14 have a cognitive and adaptive score which are commensurate with a score of 69 or below. Eleven of the 14 have a diagnosis of AD. Of the entire cohort, 24 of the 26 children have age scores of less than 2 years for assessment of visual motor functioning . All children are actually studied when they all are over the age of 2 years and 6 months. Mean age at entry into the study is 33 months of age.
MRI and Functional MRI
Each child is scheduled to have an MRI and Functional MRI after the age of 4. All MRIs of this study will be compared to the MRIs that presently are being conducted in a multi-center National Institute of Child Health and Human Development (NICHD) study of normal children from age 3 months to adolescence. It is expected there will be 30 subjects’ MRIs in our age range to compare. We have set up a collaborative agreement with the NICHD lead institution and investigators. Our MRIs will be conducted and analyzed in the exact same manner that they are being conducted in the NICHD study to allow for comparison analysis. We will use the exact same software for analysis and both groups will share their data with each other. Dr. Almli is a lead NICHD investigator and recently has been appointed to our External Advisory Board.
In additional to the structural MRI, we also are doing functional MRIs of voice recognitions, using names and numbers familiar to the children. The children appear to have significantly more brain activation when numbers are used rather than names. This can be seen in the MRIs of various regions of the brain. This appears to confirm some observations that children with autism appear to recognize numbers better than names. In addition, as described last year, we are adding tests of theory of mind and self-awareness at the time of the MRIs. These new tests, developed by Dr. Lewis of our Center, should be particularly useful in evaluating children with autism. Clearly with only a few studies conducted to date these results are very preliminary but also very exciting.
Biologic Samples
The collection of blood, urine, and hair samples have gone as expected to a degree. There are the occasional children from whom we cannot get all the blood we want because of small veins and healthy amounts of subcutaneous tissue hiding the small veins. This has not been a serious problem, and the sample to which we give the least amount of priority is the blood sample for VOCs.
As discussed, the hair samples have not been a problem, with the rare exception of the boy with very short hair cut. Because of technical issues in running the initial hair samples in the exposure laboratory project, however, almost the entire cohort studied to date will have to have another sample taken to obtain for sensitive and accurate analysis. This particularly is important, as there are some anecdotal reports of children with autism having lower than expected hair mercury values.
The urine samples have been the most problematic. Most of the younger children are not toilet trained, and we need 50 ml of urine for the analysis. The subjects aggressively remove any bag for urine collection and the diaper would not appear to give us enough sample, so we are waiting until the children are slightly over the age of 3 when they are being toilet trained and urine collection can be obtained by the mother.
As expected, there are no blood, urine, or hair samples that have had alarming levels of heavy metals, VOCs, or pesticides. We have not had the opportunity, however, to separate the subjects according to regression versus nonregression to see if the children with regression have higher levels of specific environmental chemicals as stated in the hypothesis. Genetic analyses are underway and are too few at this stage to make any significant comment; however, a preliminary report from Dr. Johnson’s laboratory, using our samples and samples of other cohorts of autistic children, indicates that a polymorphism of glutathione transferase is expressed at higher than expected frequency. This report is under review at this time.
Additional Studies To Be Conducted on the Biological Samples
The following additional chemicals are to be analyzed in the urine samples: phthalates and phthalate metabolites, including di(2-ethylhexyl) phthalate metabolites and phenols. Perfluorinated chemicals (perfluorooctane sulfonate, perfluorooctanoic acid,, etc.) will be measured in the serum. These are some of the chemicals that SAR modeling indicates are similar to thalidomide, and these have been rising in children over the last few decades. These all will be sent to the Centers for Disease Control and Prevention (CDC) for analysis. In addition, Dr. Ming will study the oxidative metabolite concentration in the urine of the children. Preliminary studies indicate that the children with autism have a different pattern.
Summary
There are many exciting preliminary studies of not only environmental chemicals, but of exposure to new chemicals, regional brain growth, gene environmental interaction, computational toxicology, and so forth. The study was written 4 years ago and with the advances of genes and analysis of chemicals in the urine and blood (CDC), with the comparison with autism phenotype including history of regression, the clinical study appears primed for many interesting conclusions and new avenues of research.
Future Activities:The investigators did not report any future activities.
Journal Articles:No journal articles submitted with this report: View all 9 publications for this subproject
Supplemental Keywords:children’s health, disease and cumulative effects, ecological risk assessment, environmental chemistry, health risk assessment, risk assessments, susceptibility/sensitive population/genetic susceptibility, toxicology, genetic susceptibility, assessment of exposure, assessment technology, autism, behavioral assessment, behavioral deficits, childhood learning, children, developmental disorders, developmental effects, environmental health hazard, environmental toxicant, exposure assessment, gene-environment interaction, neurodevelopmental, neurological development, neuropathological damage, neurotoxic, neurotoxicity, outreach and education, public health,
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ENVIRONMENTAL MANAGEMENT, Scientific Discipline, Health, RFA, Susceptibility/Sensitive Population/Genetic Susceptibility, Risk Assessment, Biology, Risk Assessments, genetic susceptability, Health Risk Assessment, Children's Health, Environmental Chemistry, exposure assessment, public health, neurological development, neuropathological damage, autism, developmental disorders, developmental effects, assessment of exposure, outreach and education, gene-environment interaction, neurotoxic, children, childhood learning, behavioral deficits, assessment technology, environmental health hazard
Progress and Final Reports:
2004 Progress Report
Original Abstract
2006 Progress Report
Main Center Abstract and Reports:
R829391 CECEHDPR - University of Medicine and Dentistry of New Jersey Center for Childhood Neurotoxicology and Assessment
Subprojects under this Center:
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R829391C001 Neurotoxicant Effects on Cell Cycle Regulation of Neurogenesis
R829391C002 Adhesion and Repulsion Molecules in Developmental Neurotoxic Injury
R829391C003 Disruption of Ontogenic Development of Cognitive and Sensory Motor Skills
R829391C004 Exposure Assessment and Intervention Project (EAIP)
R829391C005 Clinical Sciences Project