Joseph Piven - US grants

Hereditary factors play a significant role in the etiology of autism. In addition to autism, abnormalities which are milder, but qualitatively similar to behaviors which define autism (i.e, particular personality, language and cognitive characteristics, and psychiatric disorders), have been shown to aggregate in relatives of autistic individuals. Clarification of the boundaries of phenotypic expression of the underlying genetic liability to autism is a critical preliminary step to further genetic analyses of this disorder. In addition, the finding that social deficits in the relatives of autistic probands, evident in measures of both personality and language, may be biologically-based and etiologically-related to particular cognitive disabilities and psychiatric disorders, is of importance beyond the significance these findings have for understanding the etiology of autism. This is an application for a Scientist Development Award for Clinicians. During the award period, the candidate proposes an organized program of training and supervised research. Training will focus on learning to assess and measure behaviors (i.e., language, personality and cognitive) hypothesized to define a "lesser variant" in autism and to develop a critical fund of knowledge in quantitative, medical and molecular genetics for examining the role of genetic factors in complex childhood neuropsychiatric disorders. The specific aims of the research portion of this award include: 1) estimation of the frequency of disorders that may be genetically associated with autism in first-degree relatives of autistic and Down syndrome probands and 2) definition of the characteristics of a "lesser variant" in autism for use in future genetic studies of this disorder by investigating the pattern of disorders among first-degree autism relatives. A variety of behavioral measures will be used to assess the first-degree relatives of autistic probands from multiple-incidence autism families and Down syndrome probands, in a case/control family study.

Hereditary factors play a significant role in the etiology of autism. In addition to autism, abnormalities which are milder, but qualitatively similar to behaviors which define autism (i.e., particular personality, language and cognitive characteristics, and psychiatric disorders), have been shown to aggregate in relatives of autistic individuals. Preliminary data indicate that these abnormalities may be more common and more severe in non-autistic first-degree relatives from Multiple- Incidence Autism Families (i.e., ascertained through two autistic probands) than in those ascertained through a single autistic proband, but the rate and severity of abnormalities in these two groups have not been previously compared. Clarification of the boundaries of phenotypic expression of the underlying genetic liability to autism is a critical preliminary step to further genetic analyses of this disorder. In this application, we propose to extend the research portion of the PI's Scientist Development Award for Clinicians by: 1) adding a third group of families ascertained from the population through a single autistic proband, an Autism Population Study Group (N=40), and 2) expanding the number of families in both the Multiple-Incidence Autism and Down syndrome (DS) groups from 25 to 30. The total number of families will be increased from 50 as proposed in the SDAL to 100. The aim of the SDAC, "A Family Study of Multiple-Incidence Autism Families," is: 1) to estimate the frequency of disorders that may be genetically associated with autism in first-degree relatives from Multiple-Incidence Autism and DS families and 2) to investigate the pattern of disorders among relatives that may define a lesser variant in autism. In addition to these aims, in this FIRST proposal we will compare the rate of abnormalities in first-degree relatives from: 1) Multiple- and Single-Incidence Autism Families and 2) the Autism Population and DS samples. Characteristics of the lesser variant determined from comparisons of Multiple-Incidence and DS families will then be applied to a genetic analysis of the Autism Population Sample. We also propose to study the genetic implications of elevated serotonin in autism. Previous studies suggest that peripheral serotonin may be associated with genetic liability for autism. We will further examine this association by: 1) comparing the serotonin levels in multiple- and single-incidence autistic probands and 2) exploring the relationship of serotonin levels to the presence of the lesser variant in families.

Hereditary factors play a significant role in the etiology of autism. In addition to autism, abnormalities which are milder, but qualitatively similar to behaviors which define autism (i.e, particular personality, language and cognitive characteristics, and psychiatric disorders), have been shown to aggregate in relatives of autistic individuals. Clarification of the boundaries of phenotypic expression of the underlying genetic liability to autism is a critical preliminary step to further genetic analyses of this disorder. In addition, the finding that social deficits in the relatives of autistic probands, evident in measures of both personality and language, may be biologically-based and etiologically-related to particular cognitive disabilities and psychiatric disorders, is of importance beyond the significance these findings have for understanding the etiology of autism. This is an application for a Scientist Development Award for Clinicians. During the award period, the candidate proposes an organized program of training and supervised research. Training will focus on learning to assess and measure behaviors (i.e., language, personality and cognitive) hypothesized to define a "lesser variant" in autism and to develop a critical fund of knowledge in quantitative, medical and molecular genetics for examining the role of genetic factors in complex childhood neuropsychiatric disorders. The specific aims of the research portion of this award include: 1) estimation of the frequency of disorders that may be genetically associated with autism in first-degree relatives of autistic and Down syndrome probands and 2) definition of the characteristics of a "lesser variant" in autism for use in future genetic studies of this disorder by investigating the pattern of disorders among first-degree autism relatives. A variety of behavioral measures will be used to assess the first-degree relatives of autistic probands from multiple-incidence autism families and Down syndrome probands, in a case/control family study.

This is an application for a Multi-Institutional Collaborative Research Project (MICRP) to conduct a genome search for genetic loci linked to the autism phenotype. This MICRP involves the collaboration of two independent sites: Tufts-New England Medical Center (PI:Susan Folstein) and The University of Iowa (PI: Joseph Piven). The PI's at these two sites have collaborated extensively over the past 8 years in genetic epidemiologic studies of autism. Preliminary data presented in this proposal replicate and expand on previous work by the PI's suggesting that a broader autism phenotype, which includes behavioral characteristics that are qualitatively similar to the defining features of autism, is genetically- related to autistic disorder. To maximize the likelihood of finding a significant linkage over a number of plausible genetic models we propose to employ both narrow and broad definitions of the autism phenotype. Specifically we plan to: 1) conduct a sib pair study of 150 autistic sib pairs; 2) conduct a linkage study of the broader, autism phenotype using 150 nuclear families ascertained through two autistic siblings; and, 3) conduct a linkage study of the broader autism phenotype using 50 moderate sized pedigrees ascertained through both autistic sib pairs and other (e.g., first cousin pairs) autistic relative pairs. Preliminary power analyses suggest excellent power to detect linkage under several possible models. The full collaboration of three data collection sites (Tufts, Iowa, Johns Hopkins) and two laboratory and data analytic sites (Tufts/Harvard and Iowa) will facilitate rapid data collection, genotyping and analysis, as well as provide sample sizes sufficient for an internal replication under some models. As a result of previous and ongoing studies by the PI's in Baltimore and Iowa an additional sample of 100 autistic probands, well characterized by standardized measures, is available for follow-up of significant findings of linkage by testing for allelic association and applicability of the findings to the general population.

This is an application for an Independent Scientist Award (K02). During the award period the applicant plans to continue his research into the etiology and neurobiologic mechanisms in autism and to obtain additional training in cognitive neuroscience. The overall aim of this work is to elucidate the pathogenesis of autism through development of an integrated program of research involving family, molecular genetic and neuroimaging studies of autism and the broader autism phenotype. The aim of the family study is to explore the boundaries of the autism phenotype by examining a range of behavioral, cognitive, and biological characteristics in autistic probands and their relatives. The aim of the molecular genetic study is to conduct a genome search, using several different analytic strategies, to find genetic loci that contribute to the autism phenotype. Neuroimaging studies being conducted and proposed are aimed at examining anomalous patterns of growth and organization of the brain in individuals with autism and the broader autism phenotype through the study of abnormalities in brain size, shape and function. Career development activities in this application link directly to the research proposed and include training in: (1) the instrumentation and application of MRI, PET and fMRI; (2) training in behavioral neurology and neuropsychology; and (3) training in neuroanatomy and developmental neurobiology, as these areas related to the study of autism.

Autism is a severe neuropsychiatric disorder that affects young children with a disability that often continues throughout life. Because of the severe impairment and duration of this disorder, autism often confers a profound burden on autistic individuals, their families and society. Thus, research aimed at uncovering the pathogenesis of autism and potentially leading to rational approaches to prevention or treatment is of great importance. Our research team recently reported the presence of increased total brain volume (TBV) on MRI (including increased tissue and lateral ventricular volume) in autistic individuals. These findings are consistent with multiple reports of autistic individuals showing increased rates of macrocephaly (head circumference greater than or equal to 98th percentile) and post mortem studies showing increased brain weight and size. Head circumference studies by our group and others suggest that although enlarged head size may be present at birth, macrocephaly is not present until early childhood (age 4 years). Subsequent analyses of our MRI data suggest that cortical enlargement is the result of an increase in gray matter volume, further supporting our hypothesis that the increased rate of brain growth in autism occurs prior to age 5 years. Subsequent studies by our group and others have revealed a pattern of brain size and shape changes including: enlargement of the temporal, parietal and occipital (but not frontal) cortical lobes, that appears to be localized mostly to the right side of the brain; enlargement of the total cerebellar and caudate volume (proportionate to the increase in TBV); decreased size of some subregions of the corpus callosum; and, no change in size of the hippocampus. Clarification of the timing and pattern of brain growth and organization in autism will provide important insights into the pathogenesis and neural mechanisms underlying this disorder. Therefore we propose to conduct a longitudinal MRI study of the size and shape of the brain in autistic individuals and controls at 18-35 months of age with follow-up MRI brain scans of these same subjects after 24 months to examine the pattern of brain size and shape changes over time.

Autism is a severe neuropsychiatric disorder that affects young children with a disability that often continues throughout life. Because of the severe impairment and duration of this disorder, autism often confers a profound burden on autistic individuals, their families and society. Thus, research aimed at uncovering the pathogenesis of autism and potentially leading to rational approaches to prevention or treatment is of great importance. Our research team recently reported the presence of increased total brain volume (TBV) on MRI (including increased tissue and lateral ventricular volume) in autistic individuals. These findings are consistent with multiple reports of autistic individuals showing increased rates of macrocephaly (head circumference greater than or equal to 98th percentile) and post mortem studies showing increased brain weight and size. Head circumference studies by our group and others suggest that although enlarged head size may be present at birth, macrocephaly is not present until early childhood (age 4 years). Subsequent analyses of our MRI data suggest that cortical enlargement is the result of an increase in gray matter volume, further supporting our hypothesis that the increased rate of brain growth in autism occurs prior to age 5 years. Subsequent studies by our group and others have revealed a pattern of brain size and shape changes including: enlargement of the temporal, parietal and occipital (but not frontal) cortical lobes, that appears to be localized mostly to the right side of the brain; enlargement of the total cerebellar and caudate volume (proportionate to the increase in TBV); decreased size of some subregions of the corpus callosum; and, no change in size of the hippocampus. Clarification of the timing and pattern of brain growth and organization in autism will provide important insights into the pathogenesis and neural mechanisms underlying this disorder. Therefore we propose to conduct a longitudinal MRI study of the size and shape of the brain in autistic individuals and controls at 18-35 months of age with follow-up MRI brain scans of these same subjects after 24 months to examine the pattern of brain size and shape changes over time.

The North Carolina Mental Retardation and Developmental Disability Research Center (MRRC) is a diverse and coordinated program to advance knowledge concerning the etiology and treatment of mental retardation. The causes of mental retardation and developmental disabilities are multiple. The few hundred suspected or identified represent only a fraction of the total number of causes. Many moderate to severe conditions of mental retardation have biological causes identifiable with currently available technology; however, biological causes of the majority of less severe mental retardation are presently unknown. The boundary between biological and psychosocial factors in mental retardation is becoming less distinct, not only because progress in biological sciences has led to the identification of more causes, but more importantly because there is increasing awareness of the importance of the interactive influence of psychological events of biology and of biological processes on psychological consequences. This broad-based approach remains the guiding principle of the MRRC. Thus, our research programs encompass the broadest range of concepts, disciplines and methodologies, from social and behavioral sciences to fundamental molecular genetics and developmental neurobiology. While preserving this diversity, we focus much of our work on eight major areas on research emphasis: (1) early intervention effectiveness and processes, (2) family processes and interventions, (3) language, cognitive, and social processes, (4) neurohormones and maternal behavior, (5) brain development: molecular genetics, biochemistry, toxicology and pathology, (6) neurogenetic disorders including fragile X syndrome, (7) neurotransmitter pharmacology and brain function, and (8) interaction of the immune system and the brain. MRRC researchers represent diverse disciplines and university departments. The majority of MRRC research projects are conducted in two university Centers: The Neuroscience Center (UNCNC, Kunihiko Suzuki, Interim Director) and the Frank Porter Graham Child Development Center (FPG, Don Bailey, Director). The MRRC operates as an integrated program to establish an optimal interdisciplinary environment by providing an Administrative ore and four scientific core units: Information Technology (Richard Mailman, Director), Design and Statistical Computing (Market Burchinal, Director), Observational Methods (Maria Boccia, Director) and Morphology- Pathology (Kinuko Suzuki, Director). These research efforts are augmented by existing training programs in mental retardation and related fields, a State-supported Genetic Counseling Program, and a visiting lecturer seminar series. The UNC-Chapel Hill and the State of North Carolina provide extensive support to the MRRC. By efficiently coordinating specialized core support services and by providing a common administrative framework to these diverse research programs, the MRRC achieves a cost- effective means for conducting research that seeks eventual understanding, treatment, and prevention of mental retardation and developmental disabilities.

DESCRIPTION: (Adapted from the applicant's Description) This application requests support for a postdoctoral training program to develop researchers with expertise in both the biological basis and clinical manifestations of neurodevelopmental disorders, in order to enable them to better relate across disciplines and maximize potential for understanding the pathogenesis and treatment of these disorders. In the past, training program in behavioral science, neuroscience, and molecular genetics have led to dramatic gains in our understanding of the pathogenesis of neurodevelopmental disorders. The proposed training plan provides a variety of opportunities, including (1) mentored research training in specific methods, disorders, and underlying pathogenetic mechanisms; (2) a range of didactic experiences (such as courses, seminars, and lectures) that integrate the study of clinical disorders, normal developmental processes, mechanisms of disease and research methods; and, (3) clinical exposures to complement previous levels of clinical experience. Twelve to 15 Ph.D. or M.D. level trainees will participate in two to three year training over the five-year course of this program.

CORE ABSTRACT NOT AVAILABLE

[unreadable] DESCRIPTION (provided by applicant): Fragile X (FRAX) is the most common known inherited cause of neurodevelopmental disability, resulting from a disruption in expression of the fragile X mental retardation 1 gene (FMRI). Associated with increased risk for a particular profile of cognitive deficits (including mental retardation) and a number of aberrant behaviors (including attentional dysfunction, hyperactivity, perseveration, stereotypies, hyperarousal and social deficits), this life long condition results in considerable impairment to individuals and confers a substantial burden on families and society. A series of cross-sectional neuroimaging studies of older children and adults, from our collaborative group of investigators, demonstrate an association between reduced FMR1 function and a pattern of brain abnormalities in the frontal, striatal, parietal, cerebellar and temporal lobe (hippocampus and superior temporal gyrus) regions. Further, these brain abnormalities are associated with selected cognitive and behavioral abnormalities that are characteristic of FRAX (e.g., enlarged caudate and stereotyped behavior and hyperactivity). In this Collaborative R01, between Stanford (PI: Allan Reiss) and UNC-Duke (PI: Joe Piven), we propose to conduct a longitudinal MM study of 60 FRAX, 60 developmentally-delayed (DD) and 30 typically-developing (TYP) males at age 18-42 months and again 24 months later at age 42-66 months. The overarching aim of this application is to examine the trajectory of gene, brain and behavior relationships, from a developmental perspective, beginning at the earliest ages that it is feasible to undertake such a study (in the three proposed study groups). We believe that this study requires a collaborative effort to: (1) insure a sufficient sample size for study and, (2) to combine a wide range of necessary and complementary expertise and experience. We have assembled a unique team of investigators, experienced in longitudinal behavioral studies of very young children with FRAX, neuroimaging of FRAX and autism, multi-site neuroimaging studies and advanced methods of image processing, that we believe is ideally suited to conduct this study. FRAX offers an important model for understanding the developmental relationships between a complex pattern of cognitive and behavioral abnormalities, brain structure and function, and gene function. Further study of this model system is likely to provide important insights into the pathogenesis and treatment of FRAX and other developmental disorders and abnormalities of behavior and cognition.

DESCRIPTION (provided by applicant): For over 15 years our research team and others have taken Kanner's original observations about personality features characteristic of some parents of autistic individuals and developed definitions of, and standardized measures for, a broader autism phenotype. The broad autism phenotype (BAP) is thought to represent the phenotypic expression of the genetic liability to autism in non-autistic relatives of autistic probands, and is defined by characteristics that are milder but qualitatively similar to the defining features of autism. This work has potential importance for 1) teasing apart the gene-behavior relationships in autism, 2) understanding brain-behavior relationships in autism and, 3) providing additional qualitative and quantitative information on the range and nature of the phenotypic expression of autism genes, which may augment our ability to find those genes. While autism and the BAP are defined by particular behavioral characteristics, they are clinically and etiologically heterogeneous, and are the end result of a range of underlying neuropsychological, neural and genetic mechanisms. In this project we propose to examine the relatives of autistic and Down syndrome probands on selected neuropsychological measures of social cognition, central coherence and executive function, three principal cognitive frameworks proposed as theories to explain the neuropsychological basis of autism. These neuropsychological characteristics will be examined in relationship to our clinically-based measures of the BAP, in order to both elucidate the neuropsychological basis of the BAP and to provide efficient, valid and reliable measures for future studies of the BAP. Autism and OS relatives will be compared in these three neuropsychological domains, to a unique sample of individuals with focal brain lesions in the amygdala, orbital-frontal cortex and right somatosensory cortex, drawn from a brain injury registry at the University of Iowa, to provide insights into the neural basis of the behavioral and neuropsychological characteristics of autism and the BAP. Finally, patterns of co-occurrence of these characteristics will be examined in individuals and families. This study will complement ongoing studies of the same neuropsychological characteristics in autistic probands. This project brings together a unique group of experienced researchers with complementary expertise in family-genetic (Piven) and neuropsychological studies of autism (Happ[unreadable]), and in the neural basis of social cognition (Adolphs), to study the neuropsychological basis of the broad autism phenotype.

CORE ABSTRACT NOT AVAILABLE

DESCRIPTION (provided by applicant): For over 15 years our research team and others have taken Kanner?s original observations about personality features characteristic of some parents of autistic individuals and developed definitions of, and standardized measures for, a broader autism phenotype. The broad autism phenotype (BAP) is thought to represent the phenotypic expression of the genetic liability to autism in non-autistic relatives of autistic probands, and is defined by characteristics that are milder but qualitatively similar to the defining features of autism. This work has potential importance for 1) teasing apart the gene-behavior relationships in autism, 2) understanding brain-behavior relationships in autism and, 3) providing additional qualitative and quantitative information on the range and nature of the phenotypic expression of autism genes, which may augment our ability to find those genes. While autism and the BAP are defined by particular behavioral characteristics, they are clinically and etiologically heterogeneous, and are the end result of a range of underlying neuropsychological, neural and genetic mechanisms. In this project we propose to examine the relatives of autistic and Down syndrome probands on selected neuropsychological measures of social cognition, central coherence and executive function, three principal cognitive frameworks proposed as theories to explain the neuropsychological basis of autism. These neuropsychological characteristics will be examined in relationship to our clinically-based measures of the BAP, in order to both elucidate the neuropsychological basis of the BAP and to provide efficient, valid and reliable measures for future studies of the BAP. Autism and OS relatives will be compared in these three neuropsychological domains, to a unique sample of individuals with focal brain lesions in the amygdala, orbital-frontal cortex and right somatosensory cortex, drawn from a brain injury registry at the University of Iowa, to provide insights into the neural basis of the behavioral and neuropsychological characteristics of autism and the BAP. Finally, patterns of co-occurrence of these characteristics will be examined in individuals and families. This study will complement ongoing studies of the same neuropsychological characteristics in autistic probands. This project brings together a unique group of experienced researchers with complementary expertise in family-genetic (Piven) and neuropsychological studies of autism (Happe), and in the neural basis of social cognition (Adolphs), to study the neuropsychological basis of the broad autism phenotype.

DESCRIPTION (provided by applicant): The goal of this application is to identify and characterize autism susceptibility loci and genes. While numerous linked chromosomal regions of interest have been identified in autism, the traditional approaches to finding disease genes within those regions have encountered unforeseen difficulties. First, these linked regions tend to be large and difficult to narrow, thus the number of candidate genes can be overwhelming. Second, the genes we are looking for are likely to be genes of small effect with types of variability that may be difficult to detect using traditional gene screening methods. Countering these difficulties, however, are a number of significant recent technological advances. Foremost is the ready availability of draft and finished genomic sequence providing the raw material for gene discovery that in the past took months and years to generate. Genome analysis tools and annotation databases are rapidly accelerating our ability to delineate genomic structure and accurately describe a gene's pattern of expression, function, and potential relevance to the disease of interest. Lastly, we are increasingly able to identify functional domains within genes that may be more likely to harbor disease-causing mutations. Our application, therefore, attempts to skirt the obstacles while focusing on the advances. First, we streamline the gene examination process with sophisticated computational bioinformatics technology that automatically identifies, delineates, and extracts expression information for genes in linked regions of interest. Prioritized genes are then screened in multiple autism DNA samples using our high-throughput sequencing and genotyping capabilities, with a preferential focus on protein functional domains. We will also identify and refine linked regions of interest by extending our innovative research on the Broader Autism Phenotype. Laboratory resources that will support this project include 1) a prominent, highperformance computer laboratory dedicated to genomic research; 2) a molecular laboratory with dedicated genotyping and sequencing facilities that has extensive expertise and a track record of success in disease gene discovery; 3) a premier statistical genetics research center; and 4) a wealth of well characterized clinical resources.

[unreadable] DESCRIPTION (provided by applicant): This application requests funds for a five-year continuation of the fragile X syndrome (FXS) Research Center, the focus of which is on family adaptation to FXS. Thirteen investigators from eleven disciplines (anthropology, developmental psychology, educational psychology, clinical psychology, forensic medicine, social work, law, medical genetics, special education, speech and hearing sciences, and psychiatry), based at the Mental Retardation and Developmental Disabilities Research Centers at the University of North Carolina at Chapel Hill, the University of Kansas, and University of Wisconsin - Madison, as well as in partnership with RTI International, are collaborating on an integrated and longitudinal set of studies: Project I: Maternal Responsivity and the Development of Children with FXS; Project II: Adaptations of Families of Adolescents and Adults with FXS; and Project III: Family Adaptation to Newborn Screening for FXS. The projects are supported by one existing MRDDRC core (Design and Statistical Computing) as well as two new cores (Administrative and Ethnographic and Qualitative Methods). Center investigators will collect data using a range of methods, including biologic samples, direct observation, speech samples, daily diaries, surveys, and semi-structured interviews. A range of mixed methods will be used to analyze these data. [unreadable] [unreadable] [unreadable]

DESCRIPTION [provided by applicant]: The University of North Carolina Mental Retardation and Developmental Disabilities Research Center (MRDDRC) is an integrated, multidisciplinary program to support and promote research relevant to understanding the pathogenesis and treatment/prevention of neurodevelopmental disorders. The University of North Carolina MRDDRC is the focal point for research and research training relevant to mental retardation and developmental disabilities on the University of North Carolina campus. This Center currently supports 40 investigators and 76 research projects (72 PHS) covering 32 of the 33 areas listed in the RFA for MRDD Research Centers, and representing a substantial increase over the last application. This broad-based research program is well integrated around an expanded portfolio of bio-behavioral research projects on neurodevelopmental disorders such as autism, fragile X syndrome, neurofibromatosis and Turner syndrome, highlighted by the recent funding of an NIH Studies to Advance Autism Research and Treatment (STAART) Center. This expansion of bio-behavioral studies serves to integrate longstanding programs in basic biological and behavioral research relevant to mental retardation and developmental disabilities. Over the last five-year granting period the University of North Carolina MRDDRC has made substantial progress including (1) appointment of a new Director; (2) establishment of the MRDDRC within a new, independent University Center, "The University of North Carolina Neurodevelopmental Disorders Research Center (NDRC)", with a mission fully consistent with that of the MRDDRC, (3) expansion of focus on bio-behavioral research and the integration of basic biological and behavioral studies; (4) establishment of an NIH (T32) Postdoctoral Research Training Program in Neurodevelopmental Disorders; and, (5) development of four new (proposed) research cores including The Developmental Neuroimaging Core (human in vivo neuroimaging and multiphoton/confocal microscopy), The Behavior Measurement Core (supporting both mouse behavioral phenotyping and specialized consultation on the measurement of selected human behaviors); the Microarray Gene Expression Core; and, the Subject Registry Core. Substantial modifications are also proposed for the Data Management and Statistical Analysis Core. These five research cores provide cutting-edge, high-quality and cost-effective support to this integrated, multidisciplinary program of MRDD research.

[unreadable] DESCRIPTION (provided by applicant): Autism is a severe neurodevelopmental disorder defined by social and communication deficits and ritualistic-repetitive behaviors. Encouraged by reports of a high heritability and a sibling risk ratio > 50, a substantial number of linkage and positional cloning studies have now been conducted. Employing primarily the affected sib pair paradigm, these studies have met with limited success, generally identifying modest linkage signals covering broad genomic regions that include very large numbers of candidate disease genes. The common responses to this dilemma (to increase sample sizes and marker densities) have met with numerous practical and theoretical obstacles. In this application, we instead propose a strategy using multigenerational, extended pedigrees with multiple individuals affected with autism, as well as milder but qualitatively similar, genetically-related phenotypes (endophenotypes) in non-autistic relatives. Linkage studies in extended pedigrees are recognized to have substantially more power than those employing affected sib pairs and have been successful in other complex disorders (1). Although large pedigrees in autism are rare, through our work over the past 10 years, and through collaboration with colleagues, we have identified 20 potential extended, multigenerational pedigrees in the U.S. and Canada. In this application, we propose a detailed phenotypic study (including measurement of quantitative and qualitative neuropsychological and behavioral characteristics in autistic individuals and their non-autistic relatives) of twelve of these pedigrees as part of a whole genome linkage study of autism and related phenotypes. These twelve pedigrees will include approximately 60 individuals with autistic disorder and 60 individuals with the broad autism phenotype. We have previously demonstrated that incorporating additional phenotypic information substantially increases power to detect linkage. In this application, we also propose novel analytic strategies, developed by our research team, expressly to allow efficient and flexible incorporation of the phenotypic measures proposed here, including joint linkage analysis of dichotomous and quantitative traits. [unreadable] [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This application for an Autism Centers of Excellence (ACE) Network is a collaborative effort by investigators at four clinical sites: University of North Carolina (UNC), University of Washington (UW), Washington University (WU), and Yale University; and one data coordinating center (DCC) at the Montreal Neurological Institute (MNI) to conduct a longitudinal MRI/DTI and behavioral study of infants at high risk for autism (i.e., siblings of autistic individuals) at 6, 12, and 24 months of age. Multiple lines of converging evidence (from MRI, post-mortem, and head circumference studies) document brain enlargement in autism. MRI studies have revealed generalized enlargement in cerebral cortical gray and white matter, and selected subcortical structures as early as two years of age. Longitudinal head circumference studies suggest the onset of brain overgrowth beginning in the latter part of the first year of life. Data from behavioral studies of infant siblings of autistic individuals (infant siblings who are therefore at high risk for developing an autism spectrum disorder, or ASD) suggest that some of the defining features of this condition are not present at six months of age (e.g., social deficits) and have their first appearance by 12 months. New imaging methods are available that now provide highly detailed MRI data and are well suited for rapid scanning of very young children. The investigators' MRI research team has developed image processing tools specifically designed for highly efficient, reliable, and valid processing of MRI data from birth to two years of age. New behavioral assessment tools (the AOSI and FYI), recently developed by investigators on this application, now enable the efficient screening and detection, at 12 months, of infants who are likely to meet criteria for autism at age two. In this application they propose to employ these new methods to conduct a longitudinal MRI/DTI study of six months old infant sibs of autistic individuals, with follow-up at 12 and 24 months of age. This study will provide important, new information about the trajectory of early postnatal brain overgrowth (regions, tissues, structures, and fiber tracts), as measured on MRI and DTI, and its potential relationship to clinical features. It has the potential to provide insights into developmental brain and behavioral phenotypes, as well as neurobiological mechanisms, that will inform other levels of analysis (e.g., molecular biological studies of this period), during what appears to be a critical period of development in the pathogenesis of autism. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): For over 15 years, our research team has taken Kanner's original observations about behavioral features characteristic of some parents of autistic individuals and developed standardized, valid, and reliable clinical measures to define what is now referred to as the Broad Autism Phenotype (BAP). The BAP is thought to represent the phenotypic expression of the underlying genetic liability to autism in non-autistic relatives of autistic individuals and is defined by characteristics that are milder but qualitatively similar to the defining features of autism. In our current UNC STAART Autism Research Center, we have identified abnormalities of social cognition (on tasks linked in previous studies to specific brain regions in the neural circuitry of social cognition) that occur more commonly in 'autism parents' with the social behavioral characteristics of the BAP (i.e., aloof personality) than in either 'autism parents' without aloof personality or community controls. We have developed fMRI paradigms that identify abnormalities in key components of the neural circuitry of social cognition in autism (amygdala, superior temporal sulcus, and fusiform gyrus) and developed a novel approach for probing the complex processing of social information from faces - the Bubbles Method that allows us to integrate simultaneous measurement of eye tracking data, skin conductance response, and BOLD responses on fMRI to isolate which features of the face drive behavioral, autonomic, and neural discrimination of social information from faces. In this revised application, we propose to use fMRI, neuropsychological, behavioral, and psychophysiological measures to characterize the neural circuitry of abnormal social cognition in parents of autistic individuals and to elucidate the stage of information processing at which dysfunctional social cognition arises in the BAP. This application is a collaboration of three investigators with a track record of collaboration and complementary experience in autism and the BAP (J. Piven at UNC), fMRI of social cognition (G. McCarthy at Duke), and novel approaches to elucidating the neural basis of social cognition (R. Adolphs at Caltech). Study of the behavioral and neural mechanisms underlying the social behavioral component of the BAP, as proposed in this application, will provide important new insights into the forme fruste of the autism brain and behavioral phenotype for use in future genetics, brain, and behavioral studies of autism and the BAP. [unreadable] [unreadable] [unreadable]

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A. OBJECTIVE The Administrative Core provides overall leadership, management and direction for the Center and coordinates the various components of the Center leading to an integrated, cohesive organization. Specifically, the Administrative Core has the following objectives: Strategic Planning: The Director and the Executive Committee are responsible for major decisions regarding the research direction of the DDRC. These decisions are informed by consultation with the Internal and National Advisory Boards. Over the last five years the Executive Committee has had a major role in evaluating and shaping the core modifications put in place in the last competitive application and described elsewhere in this application. Strategic planning efforts have also included the integration of the DDRC with the new Carolina Institute. Over the next five years the DDRC Administrative Core will interact with the planning and administrative efforts of the Carolina Institute. Plans are underway to form a National Advisory Board for the Institute in the spring of 2008. This Advisory Board will make recommendations about all aspects of the Institute - including clinical services, education, research and the interaction of all three of these components. The DDRC Leadership will be in close contact with this National Advisory Committee as well as the leadership of the Institute and its components, in planning integration and development of this new organization. It is anticipated that initially components of the Institute (the DDRC, CDL, TEACCH, FSN) will continue with independent administrative infrastructures but over the next five years integration of these administrative efforts will be explored. Thus the DDRC Leadership will continue to have an important role in strategic planning for the Center. Management: The Core coordinates all DDRC activities and sets policies that govern the Center. The Director manages day-to-day operations and assists the Core Directors in order to insure the efficient administration of their units. This goal is accomplished together with the Executive Committee, which, along with the Director, comprise the senior management of the Center. The Executive Committee is responsible for such decisions as admission of new investigators and projects, services to be provided through the Research Cores, dissemination of information from the Center to the public and to other investigators and general operating policies of the Center. The Executive Committee meets regularly throughout the academic year. Communication/Education: The Administrative Core coordinates regular business and educational meetings for Center Investigators through the annual business lunch, monthly Investigator Forum, and annual DDRC Research Symposium. In addition there are regular communications available by mail, list serve and through our Center website (www.NDRC.unc.edu). These and other activities by the Administrative Core serve to promote contact and collaboration among investigators. The Administrative Core will continue to interact with AUCD and the AUCD website. Ms. Iris Greene, Program Assistant, will be responsible for interfacing with the AUCD administrative offices to maintain the AUCD website. With the establishment of the Carolina Institute there will be substantially more opportunities for dissemination of information and education to practitioners as well as the general public. As described elsewhere in this application, the TEACCH Program and UNC CDL have extensive clinical training programs in autism and other neurodevelopmental disabilities, at all levels of clinical care. Both have well-developed educational programs for service providers as well as the community, including the joint fall conference put on annually by TEACCH and the Autism Society of North Carolina and the Annual May Meeting put on by TEACCH for clinicians and researchers from within and outside of North Carolina. Also, the TEACCH, DDRC, CDL and FSN websites will be integrated to provide a more comprehensive overview of efforts in research, education and service in MRDD to the public, providers and other researchers. Quality Assurance: The Director and Executive Committee are responsible for oversight of the quality of the Research Cores through regular, informal review as well as a more formal annual Committee Review and User Survey. The Director is responsible for advising and guiding Core Directors in the cost effective, state-of-theart, quality operation of all Research Cores, as discussed in each respective Core Section. These issues come up ad hoc in regular Executive Committee meetings as well as the more format spring review of each core (prior to the submission of the non-competitive renewal). Each Core has established an Advisory Group to review all aspects of their service, including quality control. Quality assurance is also established in our periodic site visits by the National Advisory Board (last joint on-site review took place in the fall of 2006). Advocacy: A major goal of the DDRC is to raise the visibility of MRDD research at UNC and increase the allocation of resources and money to this end, at UNC and in the local community. The Center has enjoyed considerable success in this regard with the establishment of the Carolina Institute, including building a new 17,000 sq ft building for clinical services and clinical training in MRDD (to house the CDL) adjacent to the existing 13,000 sq ft Autism Center, which houses several DDRC autism clinical research efforts, the Chapel Hill TEACCH Clinic and the TEACCH Administrative offices. Additional success can be seen in the large number of new investigators joining the Center (described elsewhere). The UNC School of Medicine is committed to seeking state funds for all aspects of the Carolina Institute efforts and has put forward a proposal from the Institute for substantial state funding with the annual overall request from the University. In addition, as noted above, advocacy is a strong component of the new partners of the DDRC within the Carolina Institute - the CDL, TEACCH Program and the FSN. The DDRC will join together with these groups in advocating to raise the level of visibility of MRDD research in the UNC and surrounding community.

DESCRIPTION (provided by applicant): Virtually nothing is known about older adults (> 50 years of age) with an Autism Spectrum Disorder (ASD). With the aging of the U.S. population and recent recognition of the high prevalence of ASD, it is likely that in the near future, older adults with ASD will impose a tremendous burden on the healthcare system and society. In Aim 1 of this pilot, exploratory study, we propose to access the National Core Indicators database in North Carolina, to systematically examine rates of medical/behavioral problems, level of function, support and service utilization in, perhaps the most vulnerable older individuals with ASD,~ 100 older adults with ASD and intellectual disability (ID), in comparison to ~ 1000 non-ASD, older adults with ID. Whereas Aim 1 casts a broad but shallow net, in Aim 2, we propose a much more detailed examination of behavioral patterns and diagnoses, medical conditions, level of function, support, access to care and quality of life in 40 older adults with ASD in comparison to 40 non-ASD older adult controls. The overarching aim of this study is to obtain preliminary data for a future comprehensive study of older adults with ASD, informing future clinical practice, policy and training.

DESCRIPTION (provided by applicant): The University of North Carolina Intellectual and Developmental Disabilities Research Center (IDDRC) is an interdisciplinary program with the overarching goal of supporting and promoting research relevant to understanding the pathogenesis and treatment of neurodevelopmental disorders. The UNC IDDRC is a critical component of the new Carolina Institute for Developmental Disabilities (CIDD), which is the focal point for clinical services, research, and training relevant to intellectual and developmenta disabilities (IDDs) on the UNC campus. The UNC IDDRC currently supports 39 investigators from 16 University departments, and includes 67 externally-funded research projects. The broad-based research program of this IDDRC is integrated around 3 themes: (1) Autism and Related Neurodevelopmental Disorders; (2) Brain and Behavior Development; and, (3) Early Detection/Intervention. The UNC IDDRC is a highly collaborative program highlighted by the presence of several NIH-funded, interdisciplinary research centers/programs. This application seeks support for: (1) an Administrative Core; (2) three research cores - a Clinical Translational Core, which includes the Research Participant Registry and Brain Measurement Laboratory; a Preclinical Core, which includes the Mouse Behavioral Phenotyping, Brain Imaging Analysis, and Confocal/Multiphoton Microscopy Labs; and the Bioinformatics/Biostatistics Core; and (3) a preclinical/clinical research project entitled Neural Circuit Regulation of Social Reward Motivation potentially providing important new information related to novel therapeutic targets for normalizing social behavior in individuals with ASD. The three proposed research cores provide cutting-edge, high-quality and cost effective support for this integrated, multidisciplinar, translational program of IDD-relevant research. Overall, this Center has had a major impact on developmental disabilities research and scientific training at the University of North Carolina, and renewal would allow us to continue our support of the truly exceptional program of IDD research conducted at UNC.

Project Summary This application is in response to the RFA-MH-16-160, entitled ?Lifespan Human Connectome Project (HCP): Baby Connectome?. Investigators at The University of North Carolina at Chapel Hill (UNC) and The University of Minnesota (UMN) will join forces to accomplish the goals outlined by this RFA. The team at UNC has over 10 years of experience in recruiting and imaging typically developing and at-risk children, scanning over 1000 children from birth to five years1-40. Well established infrastructure at the Biomedical Research Imaging Center (BRIC) at UNC and Center for Magnetic Resonance Research (CMRR) at UMN are in place to recruit and retain pediatric subjects and facilitate the coordination of pediatric imaging studies. Our past and ongoing studies for imaging children (birth ? five years of age) without sedation have achieved an overall success rate of 81% and attrition rate of 29.3%. Our track record demonstrates that we possess the critical and essential components to successfully conduct longitudinal pediatric imaging studies focusing on early brain development, a critically-important aspect of this RFA. Our ability to recruit, retain, and image non-sedated, typically developing children is further strengthened by our image analysis team, which has developed novel image analysis tools specifically for early brain development. The expertise at UNC is complementary to and strengthened by the expertise of the team at UMN. The CMRR at UMN has been one of the leading groups in the HCP project and has developed novel MR imaging approaches to dramatically shorten data acquisition time. Furthermore, the team at UMN has extensive experience in behavioral and cognitive studies of early child development. Together, our combined team is well positioned to accomplish the goals of this RFA. To this end, a total of 500 typically developing children between birth and five years of age will be recruited across two data collection sites in a sequential cohort, accelerated longitudinal study design. The participants are divided into two main groups, longitudinal (n=285) and cross-sectional (n=215) groups, respectively. This hybrid longitudinal and cross-sectional design enables detailed characterization of early brain development from both brain structural/functional using MRI and behavioral aspects using behavioral assessments. All of the acquired images and behavioral assessments will undergo extensive quality assurance and control processes to ensure that high quality data is obtained and transferred to the Central Connectome Facility at Washington University. In addition, we will integrate novel image analysis tools, developed by our team onto the existing HCP pipelines.

Project Summary This application is a competing continuation of an Autism Center of Excellence (ACE) Network grant now entitled, `A Longitudinal Brain and Behavior Study of Autism from Infancy through School Age`. Prior funding has supported a prospective, longitudinal study that has collected high quality brain imaging and behavior assessments in children at high- and low- familial risk (HR, LR) for an autism spectrum disorder (ASD), at 2-4 time points (including 3, 6, 9, 12, 15 and 24 months) with 36 month diagnostic re-assessment for autism. This project has been successful in producing 50 manuscripts either published/in press (#35) or under review (#15); and generated 21 external funding opportunities, leveraging this network and expanding the scope of this work. The overarching goal of this ACE Network competing continuation is to continue to follow a unique cohort of 300 HR and 100 LR children into school age (7-10 years) with detailed brain and behavior assessments. School age is a time when academic and social functioning are critically important for future success and a time when HR children are prone to manifest comorbid psychiatric disorders, difficulties with peer relationships, and learning problems which can be assessed more extensively and with greater detail than at earlier ages. Work from this network has revealed that: (1) early brain imaging features are detectable by 6 months of age, well before ASD diagnosis is possible, in those who go on to have an ASD diagnosis at 24 months; (2) autism-specific brain and behavior features change substantially from 6-24 months of age, as autism unfolds; and, (3) brain features in the first year of life are associated with later ASD behaviors and accurately predict individual ASD diagnosis at 24 months. The proposed work extends this solid foundation. In this proposal we aim to: (1) characterize school- age clinical outcomes of HR children and determine early predictors of those clinical outcomes from brain imaging and behavioral features we have already identified from 3-36 months; (2) characterize brain and brain- behavior trajectories in HR-ASD from infancy through school-age and identify the timing of ASD-related brain changes; and (3) empirically derive and validate novel subgroups within the HR group based on brain and behavior trajectories from infancy through school age, incorporating data from molecular genetics and environmental exposures. The potential impact of this study includes: (1) early identification (< 3 years) of children who are more likely to develop school-age (7-10 years) clinical problems, increasing the potential for early intervention; (2) informing intervention studies by identifying age-specific brain targets, biomarkers of treatment efficacy, and targets for pre-clinical, cross-species studies to inform drug development; and,(3) identifying empirically-derived and biologically-meaningful subgroups, based on brain and behavior trajectories from infancy to school age, that could be used to support development of individualized interventions.

ABSTRACT The overarching goal of this proposal is to lower the age of detection in autism to early infancy, making presymptomatic (i.e., before the emergence of ASD-specific behavioral features) intervention feasible. Infants with an older autistic sibling have up to a 20% risk of developing autism spectrum disorder (ASD). Prospective high familial risk (HR) infant sibling studies have shown that the defining behaviors of ASD do not emerge until the latter part of the first year and into the second year of life. Therefore, the vast majority of affected children are diagnosed after age 2. No behavioral markers in the first year of life have yet been identified that can predict later ASD diagnosis with sufficient accuracy (i.e., positive predictive value: PPV ? 80%) to justify presymptomatic intervention. We recently published two independent approaches that use brain imaging in the first year of life to predict which HR infants will be diagnosed with ASD at 2 years of age. Specifically, structural MRI (sMRI) at 6 and 12 months of age, and resting state functional connectivity MRI (fcMRI) at 6 months of age independently predicted later ASD diagnosis in HR infants with over 80% PPV. Our preliminary data show that a third MRI approach, using regions of CSF volume and cortical shape at 6 months of age can also accurately predict later ASD diagnosis. If we replicate and extend these findings, we will be able to identify individual infants at ?ultra-high risk? (80% chance) of developing ASD, rather than being limited to group-level risk (20% chance), where we do not know who will later be affected. This R01 application aims to move our initial findings toward a clinical test for ASD in HR infants in the first year of life. Aim 1 will validate our previous findings in a new, independent sample of HR infants, extend our methods to a new MRI platform, and examine whether fcMRI and/or sMRI, with and without behavioral information, during the presymptomatic period in infancy, accurately predict ASD diagnosis at 24 months of age. Aim 2 will move beyond predicting categorical diagnosis to predicting dimensional, clinically-relevant characteristics for individual infants. Specific dimensional targets include expressive language level, social responsiveness, initiation of joint attention, and repetitive behavior. Validating and extending our findings on presymptomatic prediction of ASD in a new sample, on a different MRI scanner, and with dimensional developmental characteristics are critical next steps for moving the field forward toward (a) the development of a clinically-useful, presymptomatic test for identifying ultra-high risk infants who would benefit from very early intervention in infancy, (b) efficient studies of presymptomatic intervention strategies in individuals at ultra-high risk, and (c) the development of future presymptomatic tests for use in the general (not just HR) population.

Project Summary/Abstract Many individuals with monogenic and idiopathic forms of autism spectrum disorder (ASD) exhibit larger brain volumes early in life. Cortical surface area hyper-expansion from 6 to 12 months of age precedes brain volume overgrowth from 12-24 months and predicts ASD diagnosis at 24 months of age. The underlying cellular and molecular mechanisms leading to this idiopathic ASD biomarker are unknown. Induced pluripotent stem cells (iPSCs) are an excellent model system to study cellular and molecular mechanisms regulating cortical surface area because they allow generation of neocortical neural progenitor cells and their neuronal progeny directly from well-characterized patients and controls. iPSC-derived neural cells also allow for cell-type specific measurements of gene regulation and gene expression, biological processes critical to inter-individual variability in post-natal cortical surface area and brain size. In this proposal, we will study molecular phenotypes in iPSC-derived neural progenitors and neurons from extensively phenotyped participants of the largest longitudinal neuroimaging study of infants at high risk for autism. Individuals selected for participation in this proposal have previously undergone (1) longitudinal neuroimaging at 6, 12, and 24 months of age, (2) extensive behavioral assessments, as well as (3) rare and common variant genotyping. We will leverage this unique, deeply characterized clinical sample to relate individual in vitro measures of neocortical proliferation and neurogenesis to in vivo measures of infant brain structure and ASD severity. First, we will generate iPSCs, differentiated neocortical progenitors, and neurons from individuals with ASD (n=5) and matched controls (n=5) who have been deeply phenotyped since infancy. Then, we will identify molecular signatures of ASD- associated cortical brain overgrowth during neural progenitor proliferation and neurogenesis using multiple high-throughput genomic methods. Finally, we will relate in vitro signatures of neural development to in vivo measures of infant brain structure and behavior. An important advantage of our study is that we are able to not only identify gene modules and regulatory elements associated with risk for ASD, but we are also able to evaluate if those genes and regulatory elements can predict in vivo cortical surface area trajectories during infant development that precede the subsequent emergence of autistic behavior. This represents a unique opportunity as no similar cohort exists that phenotyped infants from high risk families and acquired cortical surface area phenotypes (both cross-sectional and longitudinal) during the first two years of life, the period when symptoms of autism are first emerging. Data and analyses generated in this proposal will lead to well- defined cellular and molecular mechanisms during neocortical neurogenesis associated with cortical surface area overgrowth in autism. These mechanisms can directly address questions of molecular convergence prior to symptom onset and can serve as a basis for therapeutic development in idiopathic autism.