Research Projects: Phase II Projects

 

Informatics Core for the Collaborative Initiative on Fetal Alcohol Spectrum Disorders

William K. Barnett

The Informatics Core is part of the “Collaborative Initiative on Fetal Alcohol Spectrum Disorders” (CIFASD). The CIFASD will continue to coordinate basic, behavioral, and clinical investigators in a multidisciplinary, cross-cultural research project to better characterize, identify, treat, and provide interventions for FASD. It will involve the input and contributions from basic researchers, behavioral scientists, and clinical investigators using novel techniques and translational approaches to achieve results that would not otherwise be possible.

The Informatics Core will maintain and expand the CIFASD Central Repository, which will continue to be used to collect, maintain and distribute data generated by the various participants in the consortium. The Informatics Core will continue to be responsible for working with the other consortium participants to define data dictionaries to be used in standardizing data collection, enabling the transfer of data to and from the CIFASD Central Repository, consulting on how to establish local data management systems, providing both software tools and consulting to consortium participants, and producing reports about the accumulation of data in the CIFASD Central Repository.

The Informatics Core draws on a wealth of resources, experience, and expertise at Indiana University in information technology infrastructure and data management, The CIFASD Central Repository will continue to be maintained on Indiana University’s state-of-the-art central high-performance computing facilities and extended to make use of national cyberinfrastructure, taking advantage of both Indiana University’s strong commitment to institutional computing resources and to Indiana University’s participation in and contribution to national Grid computing projects. Resources that will be used to support the CIFASD Central Repository include supercomputers, an array of readily available database and statistical software, and a high-speed, secure, robust data archiving system capable of storing duplicate copies in multiple physical locations separated by more than fifty miles.

The Informatics Core will use these extraordinary computational resources to provide a single, highly secure, persistent repository for consortium participants to obtain the integrated, cross-cultural data that will enable the CIFASD to meet its goals of better understanding, treating, and lessening the incidence of FASD.

Spectrum of and Nutritional Risk Factors for FASD in Russia and Ukraine

Christina Chambers

Fetal Alcohol Spectrum Disorders (FASD), first described in the U.S. in 1973 by Jones and Smith, encompasses a pattern of structural abnormalities, growth deficiency, and neurobehavioral impairment that occurs in the offspring of women who consume moderate to heavy amounts of alcohol in pregnancy. FASD is thought to represent the leading known preventable causes of neurobehavioral impairment in the U.S. and perhaps throughout the world. The proposed study offers the opportunity within the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) consortium of projects to describe the spectrum of alcohol-related effects, to identify risk factors that are antecedent to pregnancy outcome, to test within-pregnancy interventions, and also to test methods that will allow for earlier identification of alcohol-related birth outcomes. Specifically, the proposed research will utilize a prospective cohort study design involving pregnant women and their offpsring recruited in Russia and Ukraine to address major gaps in knowledge about FASD by accomplishing the following specific aims: 1) to more fully delineate the complete range of expression of FASD in relation to specific quantities, patterns and gestational timing of alcohol exposure, and to evaluate the sensitivity of methods for earlier recognition of affected children; 2) to assess the contribution of maternal nutritional status in relation to physical and neurobehavioral outcomes associated with prenatal alcohol exposure, and to test the benefit of maternal second and third trimester supplementation with multinutrients with or without choline with respect to risk for FASD in the offpsring; and 3) in collaboration with other CIFASD investigators, to provide a well-characterized sample of mothers/children with and without prenatal exposure to alcohol for testing of alternative and earlier methods of identifying affected children, including prenatal ultrasound and post-natal 3D facial imaging. The proposed research has public health relevance from the standpoint of providing an improved estimate of the magnitude and scope of alcohol-related developmental problems in the context of specific quantities and patterns of prenatal alcohol exposure using standardized methods for assessment, and from the standpoint of developing and validating critically necessary clinical methods for improved and early recognition of affected children and testing the potential benefit of a reasonably applied prenatal intervention that may help ameliorate negative outcomes.

Translational Studies of FASD Using a Sheep Model

Timothy A. Cudd

The main goals of this consortium are to identify sources of variation in fetal alcohol spectrum disorder (FASD) phenotypes (facial dysmorphology, structural brain damage and neurobehavioral functional deficits), to advance understanding of structure-function relationships, to improve diagnosis and early identification of FASD, and to develop early interventions that may limit adverse outcomes in at-risk pregnancies. Animal models are essential to those goals. This project proposes a novel sheep model that is especially well suited for experimental translational studies of FASD. In utero brain development in sheep matches human brain development relatively well, and prenatal binge alcohol exposure in sheep produces brain and behavioral effects consistent with FASD. There are two long-term objectives for this project. The first is to use the sheep model to compare the effects of binge-like alcohol exposure during the period of brain development comparable to that of the human first trimester (1st-trimester model) with similar binge-like exposure that extends over the stages of brain development encompassing all three human trimesters (3-trimester model). These studies evaluate phenotypic measures used in the diagnosis of fetal alcohol syndrome-growth, facial dysmorphology, and brain and behavioral development-using methods derived explicitly from and collaboratively linked directly to approaches applied in the human components of the consortium. These studies test the general hypothesis that more pervasive effects on brain and neurobehavioral development will result from binge exposure that continues after the first trimester. Aim 1 will evaluate growth, facial morphometry, and effects on in vivo brain regional volumes using structural magnetic resonance imaging. Aim 2 will assess neurobehavioral outcomes using eyeblink classical conditioning and spatial working memory. Aim 3 will assess neuroanatomical effects via neuronal counts in the cerebellum, hippocampal formation, and brainstem serotonin system. These studies are designed to inter-relate with and reciprocally inform four of the human projects [Facial Imaging (Foroud), Brain Imaging (Sowell), Neurobehavioral project (Mattson), and the Risk Factors/Nutrition project (Chambers)] and the two mouse basic science projects (Zhou; Sulik). The second objective (Aim 4) is to test the hypothesis that choline supplementation initiated periconceptually will attenuate the adverse effects of alcohol exposure in the 3-trimester sheep model. This study was designed with explicit and complementary collaboration with the choline-supplementation projects in rats [the basic science developmental project using rats (Thomas)] and in humans [Risk Factor/Nutrition project of Chambers/Keen]. This sheep model provides a unique opportunity to bridge the basic and clinical arms of the consortium more closely than has been achieved in the past.

3D Facial Imaging in FASD

Tatiana Foroud

During the past three years, members of the Facial Imaging Core have worked with the Consortium to apply novel methods to more effectively diagnose FAS using 3D images from an ethnically diverse sample. These data and their subsequent analyses were used to identify features which consistently and reliably distinguished individuals with a clinical diagnosis of FAS from controls. Based on the initial success of the ‘Facial Imaging Core’, we now propose an expanded series of aims to be part of a clinical project named ’3D Facial Imaging in FASD’. Subsequent work proposed in this study will build on the lessons learned in this first phase of research and utilize improved technology and sampling procedures to extend the diagnostic utility of these novel techniques to a wider range of individuals with prenatal alcohol exposure or FASD. In collaboration with several clinical projects, we will collect a longitudinal, multi-ethnic sample of individuals prenatally exposed to alcohol. This sample will allow us to reliably separate the effects of ethnic variation and developmental age from those due to alcohol exposure. We will also continue to work with the basic science projects to ensure that results in the different species (human, mouse, sheep) are used to inform analyses in each project. The overarching goals of this project are to: Goal 1: improve understanding of the dysmorphic features in FAS and FASD; Goal 2: enhance the capability for definitive diagnosis of FAS and the broader spectrum of FASD at different stages of the lifespan; and Goal 3: establish whether there is a relationship between FAS and FASD dysmorphic features and the specific underlying impairments in brain function.

Dysmorphology Core

Kenneth L. Jones

Since 1973 when the specific pattern of malformation referred to as the Fetal Alcohol Syndrome (FAS) was first delineated, it has become clear that prenatal alcohol exposure is associated with a broad spectrum of structural anomalies as well as neurobehavioral deficits now referred to as the Fetal Alcohol Spectrum Disorder (FASD). However, the full range of structural anomalies in children prenatally exposed to alcohol is unknown and the incidence of specific anomalies or clusters of anomalies associated with specific patterns of prenatal alcohol consumption are poorly understood. Over the previous three years of the Consortium, the Dysmorphology Core has established a standard comprehensive protocol for physical evaluation of children in order to assure consistency in identification of the broad spectrum of features that constitute FASD at all sites. We propose to continue to support these activities throughout the renewal period in children during the first year of life at Consortium sites in prospective studies in Moscow Region, Russia, and Rivne, Ukraine as well as in older children in retrospective studies in Los Angeles, CA, San Diego, CA, Albuquerque, NM, the Northern Plains states, Atlanta, GA, and Cape Town, South Africa. Identification of large numbers of children at various ages with FAS as well as those with some features of the disorder but not enough to presently qualify them for that diagnosis (FASD), each of whom has received a standardized clinical examination, as well as neurobehavioral evaluation, neuroimaging studies, 3D photographs and, in the prospective studies, prenatal ultrasound studies, will provide the opportunity to address hypotheses regarding the relationship between FASD-related structural defects identified through the standard physical examination with complementary diagnostic methods that are being tested in other Consortium projects. The specific aims of this project are to assure consistency as well as accuracy in recognition of FASD at all CIFASD project sites where children are being evaluated; to delineate the full range of structural anomalies in children prenatally exposed to alcohol in order to determine the boundaries that encompass FASD in prospective as well as retrospective studies involved in the Consortium; to identify specific structural features or clusters of features that are predictive of or correlated with deficits in neurobehavioral development across developmental ages spanning from infancy to adolescence; to correlate the specific structural features or clusters of features identified on the CIFASD standard physical examination with alternative or complementary methods that are being tested in other CIFASD projects; and to better understand the extent to which structural features of FASD are related to specific defects in the development of the brain.

A Multisite Neurobehavioral Assessment of Fetal Alcohol Spectrum Disorders

Sarah Mattson

This application is part of the competitive renewal for the “Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD)” (Notice RFA-AA-03-004) to continue and expand the current multidisciplinary CIFASD. This RFA calls for, in part, research aimed at “improved diagnosis” and “enhanced understanding of the domains of neurobehavioral impairment” of fetal alcohol spectrum disorders (FASD). Although 30 years of research have identified myriad deficits in individuals with FASD, most neuropsychological studies are plagued by the question of global dysfunction vs. a pattern of relative sparing and impaired function. Delineation of a neuropsychological profile has been the subject of much recent debate. Limited research, including the current CIFASD consortium, has examined if prenatal alcohol exposure results in general dysfunction or a more specific neurobehavioral profile of strengths and weaknesses. The primary aim of this project is to determine whether a neurobehavioral phenotype exists in children with fetal alcohol syndrome, whether the same phenotype exists in children with FASD who lack facial dysmorphology, and whether the phenotype can be used for differential diagnosis. Secondary aims, involving collaboration with other CIFASD projects and cores, are to determine the relationship between brain dysmorphology, facial dysmorphology, and neurobehavioral function. These aims are in keeping with the overall aims of the CIFASD, including enhanced understanding of the neurobehavioral phenotype and establishment of standardized diagnostic criteria and methods of assessment of FASD. A standard neurobehavioral protocol will be administered to four groups of children at six sites and will address the functional domains of executive function, working memory, verbal function, and psychological symptomatology. In addition to children with FASD and non-exposed controls, children with low IQ scores or ADHD will be included as contrast samples. Using this heterogeneous sample and multivariate statistical methods, neurobehavioral profile specific to FASD will be sought. In addition, participants will be assessed using methodology prescribed by the Dysmorphology Core and the facial and brain imaging projects of the CIFASD. Data from three broad domains (neurobehavior, dysmorphology, and brain morphology and function) will be analyzed both separately and together to address the main aim of the CIFASD: improving the diagnostic criteria for FASD. This project is directly relevant to public health concerns surrounding the effects of heavy prenatal alcohol exposure, improving diagnosis of alcohol-affected individuals, and defining the profile of neurobehavioral effects that are specific to FASD. Improved identification and delineation of these features will ultimately lead to improved treatment.

Collaborative Initiative on Fetal Alcohol Spectrum Disorders Administrative Core

Edward P. Riley

This is a competitive renewal application for the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) in response to RFA-AA-07-004. It is a multidisciplinary project with several goals, one of which is to provide diagnostic criteria for the range of outcomes following prenatal alcohol exposure using physical, behavioral, and brain measures. Improved diagnosis includes empirically determining criteria for both the diagnosis of Fetal Alcohol Syndrome (FAS) and other Alcohol Related Birth Defects (ARBD). Another goal is to test specific interventions and possible mechanisms for ethanol-induced damage with the hope of designing new, empirically based interventions. A third, general goal is to translate basic science findings to clinical investigations and practice, while also informing basic science projects of clinician needs. The CIFASD consists of three core resource projects (Administrative, Informatics, and Dysmorphology) and two major research components. The Basic Science and Clinical Components consist of four and five projects, respectively. The Administrative Core provides the organizational framework for the CIFASD and supports the Steering Committee of each component and the External Science Advisory Board in the management and review of the various projects.

The Specific Aims of the Administrative Core are:

  1. Provide scientific and administrative leadership and oversight, ensuring that CIFASD investigators adhere to its goals and mission, as well as assisting and coordinating interactions between the various projects. It functions as the main liaison to NIAAA regarding the CIFASD.
  2. Facilitate communication between the various projects by maintaining the CIFASD web site, scheduling monthly conference calls, convening the biannual meetings of the Steering Committees, and preparing and distributing annual progress reports.
  3. Provide assistance with data collection and distribution by working with the Informatics Core. Work with the Informatics Core to develop online interactive capacity among CIFASD investigators, and make most of these databases available to outside, interested scientists.
  4. Assist the Science Advisory Board and the Steering Committees in their annual evaluations of progress for each of the projects and the two major components. In conjunction with the Steering Committees, it will establish annual priorities and deal with issues related to allocation of resources.
  5. Administer the Developmental Projects of the CIFASD.

Mapping the Brain, the Face and Neurocognitive Function in FASD

Elizabeth Sowell

This new application is part of the competitive renewal for the “Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD)”. One of the overall goals of the entire CIFASD during this renewal period is to determine if innovative techniques can be used to identify brain alterations, neurobehavioral deficits and facial characteristics and relationships between these variables to help define prenatal alcohol spectrum disorders (FASD). To help address this overarching question, we will use quantitative brain mapping techniques with high-resolution structural and functional MRI collected both cross-sectionally and longitudinally from 80 FASD children evaluated across 3 multi-cultural data collection sites (San Diego, Los Angeles and Cape Town, South Africa). While this brain imaging project can independently achieve some of the goals of the CIFASD by identifying brain structural and functional abnormalities across the broad spectrum of FASD, critically this funding opportunity will allow the assessment of relationships between the brain, neurocognitive deficits and facial dysmorphology through our active collaborations with the neurobehavioral project (Mattson PI), the facial imaging project (Foroud PI), and the dysmorphology core (Jones PI). Controlled animal studies are essential to determine timing and dosages of prenatal alcohol that result in FASD, but human imaging studies are essential to corroborate anatomical findings across species. Through our association with the UCLA Laboratory of Neuro Imaging, we have access to state-of-the-art brain mapping tools that allow the morphological evaluation of any brain structure that can be identified with MRI. Thus, we are in a unique position to allow findings in animal studies to drive hypothesis-based analyses in the human imaging data. The proposed longitudinal project will highlight how an integrated approach relating neurobehavioral, functional and structural brain imaging data, and measures of facial morphology might yield important new insights on the complex nature of brain-behavior interactions and how they are altered by prenatal alcohol exposure. To our knowledge, this will be the first study to undertake such challenges, and participation in the CIFASD is essential to address our specific aims. Ultimately, as part of the CIFASD, this project will enhance the capability for definitive FASD diagnoses that, in turn, will help clinicians manage and treat neurobehavioral deficits and associated secondary disabilities.

Magnetic Resonance and Diffusion Tensor Imaging of a Mouse FASD Model

Kathleen K. Sulik

Fetal Alcohol Spectrum Disorders (FASD), significant components of which are Central Nervous System (CNS) and craniofacial abnormalities, are a major public health problem. While eliminating FASD is the ultimate goal for both clinical and basic FASD research, we recognize that in the near future, adverse effects from prenatal ethanol exposure will persist. To better diagnose and treat affected individuals, a more complete understanding of the full spectrum of the ethanol-induced abnormalities is needed. The proposed investigations are designed to integrate with those of other consortium members in meeting this need. For this work, both high resolution Magnetic Resonance Imaging (MRI), which can provide 29 micron (or less) isotropic scans and subsequent accurate 3-D reconstructions and segmental analyses, and Diffusion Tensor Imaging (DTI), which allows CNS fiber tract analyses, will be applied to the study of an FASD mouse model. Previous research utilizing this model has established critical exposure times that yield facial and CNS abnormalities that are consistent with full-blown Fetal Alcohol Syndrome, as well as other components of FASD. The proposed studies will employ this model and both acute and chronic ethanol treatment paradigms to test the overall hypothesis that in mice, ethanol induces structural abnormalities of the brain and face that are consistent with and informative for those in human FASD. To this end, utilizing MRI and DTI as high throughput screening platforms, we propose to address the following specific aims : 1) to provide comprehensive documentation and discovery of the ethanol-induced CNS dysmorphology that results from prenatal ethanol exposure at embryonic and early fetal stages of development; 2) to define the facial dysmorphology that results from prenatal ethanol exposure during embryonic and/or early fetal stages and to relate their character and severity to accompanying abnormaities of the brain; and 3) to identify regions other than the brain or face that may serve as diagnostic indicators of prenatal ethanol exposure. The results of the proposed studies will be compared to those of corresponding investigations by other consortium members. It is expected that the structural abnormalities of the brain and face that are induced by ethanol in mice will reflect the pattern of defects observed in children with FASD, will inform human diagnostic tests, and will provide new information that will be helpful in reducing the incidence of FASD.

Mouse Model Neuro-Facial Dysmorphology: Translational and Treatment Studies

Feng C. Zhou

Fetal alcohol syndrome (FAS) occurs in children born to women who drink alcohol heavily during pregnancy and is one of the leading non-hereditary causes of mental retardation in the Western World. It is estimated that the prevalence of FAS in the general U.S. population is between 0.5 and 2.0 per 1,000 births, while the undiagnosed population with variable facial and brain dysmorphology described as fetal alcohol spectrum disorder (FASD) is estimated to be 10 times higher. The difficulty in the diagnosis of FASD involves misdiagnosis due to the presence or absence of the typical facial dysmorphology in association with brain dysfunction. Accurate diagnosis is further complicated by the lack of information about the contribution of dose, frequency, and timing of alcohol exposure during pregnancy to variation in facial dysmorphology. In this project, a mouse model that models human consumption and is known to produce FAS-like features resulting from prenatal alcohol exposure, will be used to test the effects of differences in dose and timing of alcohol exposure on face and brain development. A combination of 3D imaging that includes Micro-video and micro-resonance imaging (MRI) will be used to capture the detailed facial structure, micro-computational tomography (Micro-CT) to capture the underlying facial bone, MRI for detailed brain dimensions, and diffusion tensor imaging (DTI) for nerve fiber tracks in the fetal period. A novel computational program will be compiled to detect features specifically as function of alcohol exposure. The association and dissociation of facial and brain dysmorphology as a function of dose and timing of alcohol exposure will be analyzed to better inform the diagnosis of FAS/ FASD. These studies will be a collaboration sharing resources and methods and will be performed across both Basic and Clinical Science components in consortium effort. To date there is no cure for FAS/FASD, which is a life long ordeal from the birth. Experimental tests, using the above model and setting, of trophic peptides which have been known to prevent neurodegeneration in trials for Alzheimer Disease and protect cell death in embryonic stage, have been partially tested in the embryonic period to show protection against the alcohol-induced retardation. The new studies will test whether the trophic peptides can prevent alcohol-induced brain and facial dysmorphology as well as behavioral impairment known to occur in FAS.

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