Alan S. Brown - US grants

[unreadable] DESCRIPTION (provided by applicant): In this proposed career development award, I aim to build upon the work of my previous career award. Funded by that award, I examined the relation between prenatal insults and adult schizophrenia spectrum disorders (SSD) in three birth cohorts, and identified several novel associations. In the current award I will extend this work in several ways. First, I will investigate whether early developmental exposures are associated with an increased risk of SSD. Second, I will assess whether early developmental exposures are associated with structural and functional brain abnormalities in patients with SSD. Third, I will examine the relation of genetic vulnerability to early developmental insult in SSD. To achieve this objective I will receive further training in neuroimaging, genetic epidemiology, and other research areas from distinguished experts. This will include direct supervision, formal coursework, readings, and seminars. The research arm of the award will utilize prospectively acquired data on prenatal viral infection and other early developmental insults in two birth cohorts in which I have completed follow-up studies for schizophrenia. Unlike previous studies, serologic analysis will be used to document prenatal viral exposures and cytokine elevations in relation to the risk of schizophrenia. Subjects in these cohorts will receive neuroimaging assessments, including volumetric magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS), and a comprehensive neuropsychological test battery. A summary measure of early developmental insult will then be examined in relation to specific structural and functional brain abnormalities detected by the above methodologies. In the genetics section of the proposal, I will test models of gene-environment interaction. [unreadable] [unreadable]

DESCRIPTION: (Adapted from applicant's abstract) This study will investigate the relation of early developmental insult (EDI) to adult brain disturbance among cases of schizophrenia and schizophrenia spectrum disorder (SSD). The study represents a collaborative effort between epidemiologists and clinical neuroscientists, in which advanced neuroimaging and neuropsychological approaches are brought to bear on a large birth cohort with extensive early developmental exposure data. The proposal study builds upon two unique investigations, the Child Health and Development Study (CHDS) and one of its extensions, the Prenatal Determinants of Schizophrenia (PDS) Study. The CHDS was based on a cohort of 19,044 live births during 1959-1966 in the Oakland Hospital of the Kaiser Foundation Health Plan (KFHP). Using cases already diagnosed in the PDS study, and cases to be diagnosed in the present study, we expect that 100-11O cases and 100-110 matched controls will be assessed for all the proposed adult brain disturbances. Specifically, the applicants aim to: 1) Compare case of SSD with matched controls from the PDS study with respect to adult brain disturbances indicative of early development insult. The applicants hypothesize that associations will be demonstrated between SSD and adult brain disturbances in the following dimensions: neuroanatomical, neurochemical, and neuropsychological; 2) Examine, among cases of SSD, associations between EDI and adult brain disturbances; and 3) For those adult brain disturbances that show a relation to ED! in Aim 2, the applicants will then examine evidence for whether familial liability to SSD contributes to EDI, leading to the above adult brain abnormalities in SSD cases. This study has several notable strengths, which include: extensive prospectively collected data on EDT and prenatal sera for analysis of additional early developmental exposures; research-based diagnoses; good control of bias; a representative sample of control subjects; more refined and extensive brain measures; good statistical power; and the ability to analyze causal pathways. Important implications of this study are to provide evidence of pathogenic mechanisms by which ED! might lead to SSD, lend validation for the neurodevelopment hypothesis of schizophrenia, and elucidate underpinnings of the diverse brain disturbances found in patients with SSD.

This study will examine the relation of prenatal influenza and pro-inflammatory cytokines to the risk of schizophrenia and other schizophrenia spectrum disorders (SSD), using serologic methods to document the exposures of interest. The proposed study builds upon a unique investigation, the Prenatal Determinants of Schizophrenia (PDS) Study, a follow-up of SSD in a large birth cohort. This study has many strengths, including a large and representative sample of births, and a rich array of prospectively collected data on developmental antecedents. In the present proposal, we seek to capitalize on an additional and unique resource of this birth cohort--archived maternal serum specimens that were drawn during the pregnancies of cohort members. These samples have been stored frozen since the time that they were acquired, and are available for analysis. This resource will permit us to examine for the first time serologically documented prenatal infection, a plausible risk factor for SSD. Specifically, we shall: 1) Examine the relation between serologically documented prenatal influenza infection during mid-gestation and risk of SSD. We hypothesize that there will be a higher rate of seroconversion to influenza in prenatal sera of SSD cases as compared to matched controls. For this purpose, we shall document seroconversion for influenza antibody in prenatal sera of 100 SSD cases and 400 matched controls from the PDS birth cohort, compare the proportions with seroconversion for influenza between the two groups, and compute odds ratios with confidence intervals using methods appropriate for matched data; 2) Examine the relation between serologically documented maternal pro-inflammatory cytokines in the etiology of SSD. This will represent an important first step toward investigating other prenatal infections in the etiology of SSD. We hypothesize that there will be increased levels of four specific cytokines-- interleukin 1-beta (IL-1-beta), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF- alpha)--during mid-gestation among mothers of SSD, as compared to control, offspring. For this purpose, we shall quantify levels of these cytokines in 100 SSD cases and their respective matched controls, and compare these levels between the groups.

DESCRIPTION (provided by applicant): The proposed application is for a 5 year competing renewal of a K02 award. The current award has allowed the candidate to develop and complete many studies on the relationship between novel prenatal exposures and risk of schizophrenia, using rigorous methodologic approaches in a large birth cohort. These findings included the first serologic evidence that several prenatal infections and immune markers increased the vulnerability to schizophrenia. In the present application, the candidate seeks to extend his ongoing theme of research on the epidemiology of prenatal factors and adult psychopathology in new and important directions. The research aims include: 1) examining the specificity of prenatal factors that have been associated previously with schizophrenia by investigating their relationship with bipolar disorder;2) investigating whether specific prenatal micronutrients [vitamin B12, iron (ferritin), vitamin A (retinol)] are associated with an increased risk of adult schizophrenia;3) examining the interplay between genetic polymorphisms and prenatal nutrients in the etiology of schizophrenia. The career development plan will provide the candidate with the necessary expertise to address questions that represent the confluence of his existing skill set and the following three training activities necessary to carry out the proposed research objectives. The areas of training include: 1) research in the neurobiology and pathogenesis of bipolar disorder;2) nutrition;3) genetics. These activities will include periodic discussions with experts in their respective fields, formal coursework, seminars, and scientific meetings, and didactic readings. The research plan will also serve as a vehicle by which the candidate will further his ability to practically apply his new knowledge base to the above research objectives. The proposed work has important implications for the investigator's ongoing career development in the identification of new prenatal factors for schizophrenia and bipolar disorder, and the discovery of putative susceptibility genes that interact with these exposures.

DESCRIPTION (provided by applicant): In this proposal, which is a renewal of a previously funded award, we will investigate maternal environmental factors during pregnancy and risk of childhood autism in the offspring from a national birth cohort in Finland (the Finnish Prenatal Study of Autism, FiPS-A). No previous study of autism has ever examined the proposed prenatal factors by maternal biomarkers and their relationship to perinatal complications and growth velocity of the child's head circumference during infancy. The putative risk factors include environmental toxins (including PCBs and insecticides) and infections (influenza and Chlamydia trachomatis). We aim to address these questions in pregnancies of a large sample of autism cases and matched controls using maternal serum samples that were drawn and stored in nearly all pregnancies in Finland over the course of the study. The children with autism and their matched controls have been identified from detailed databases that contain diagnoses on nearly all cases of autism in Finland. These subjects have been linked to the maternal serum samples and to other registries including data on perinatal complications. In this study, the maternal serum samples of autism cases and of matched controls will be analyzed for these environmental factors, and their occurrence during pregnancy will be compared between the cases and controls. We shall also test whether these maternal environmental factors during pregnancy are related to a select number of other pregnancy and birth complications and to abnormalities in the velocity of head circumference during infancy. This research has the potential to result in a better understanding of potential risk factors for autism and of convergen, as well as divergent, developmental pathways that lead to the illness. Since the risk factors investigated in this study are relatively common in the population, their discovery may lead to prevention of cases of autism by straightforward public measures in pregnant women, including reduction of exposure to environmental contaminants, and prevention of infections, such as influenza and sexually transmitted diseases during pregnancy. These studies could also result in an improved understanding of the mechanisms by which prenatal insults alter postnatal brain development in autism and, along with other measures, potentially target infants at high risk for the disorder for intervention. In summary, the proposed work builds on an existing national birth cohort, and is anticipated to have considerable impact on an emerging and potentially transformative area of research epidemiology and clinical/basic neuroscience, as well as lead to improvements in current public health policy recommendations for care during pregnancy.

In this proposal, we seek to evaluate common and distinct prenatal risk factors between autism spectrum disorders (ASD) and two other psychiatric disorders, schizophrenia (SZ) and attention deficit hyperactivity disorder (ADHD). We will examine relationships between maternal persistent organic pollutants (POPs) and SZ and ADHD in offspring to provide a basis for comparison for our ongoing study of POPs and ASD. We shall also compare putative associations between low maternal levels of micronutrients (vitamin B12 and vitamin D) and ASD with observed relationships of these exposures in SZ and ADHD. This study will be conducted in the national birth cohort of the Finnish Prenatal Studies (FiPS), the largest seroepidemiologic investigations of prenatal exposures in psychiatric disorders. The study draws upon the Finnish Maternity Cohort (FMC), which consists of over 1.5 million pregnancies in Finland from 1983 to the present. Maternal serum samples were obtained from each gravida during pregnancy, and are archived in one freezer at a single site and the comprehensive national psychiatric registries contain validated diagnoses of ASD, SZ, and ADHD throughout the country. No previous study has ever examined the proposed prenatal factors using maternal biomarkers for these outcomes within a single investigation. We aim to address these questions in pregnancies of large samples of cases of ASD, these other disorders, and their matched controls, using biomarker assays of these maternal serum samples and large databases on demographic and perinatal factors. The study is based on a nested case-control design. The serum samples will be analyzed for these environmental factors, their occurrence during pregnancy will be compared between the cases and controls, and we shall also compare associations with exposures between disorders to determine if there are common or distinct risk factors. We shall also assess interactive and mediating relationships between risk factors for ASD (including sex and perinatal events), as well as SZ and ADHD. This research has the potential to result in a better understanding of potential risk factors for ASD, and the specificity of putative associations to other psychiatric disorders. Since the risk factors investigated in this study are relatively common in the population, their discovery may lead to prevention of cases of ASD, SZ, and ADHD by straightforward public measures in pregnant women, including reduction of exposure to environmental contaminants, and supplementation with vitamins during pregnancy. This study may also have implications for improving our understanding of pathogenic mechanisms by which prenatal insults alter brain development in ASD and other psychiatric disorders. In summary, the proposed work builds on an existing national birth cohort, and is anticipated to have considerable impact on an emerging and potentially transformative area of research epidemiology and clinical/basic neuroscience, as well as lead to improvements in current public health policy recommendations for care during pregnancy.