Susan Y Bookheimer - US grants

Autism is a pervasive development disorder characterized by profound deficits in many aspects of social communication. It is now widely accepted that the origins of autistic symptoms are genetic and are manifested in neurobiological dysfunction. Nonetheless, identifying the specific neuroanatomical underpinnings of autistic symptomatology has proved elusive. Most notably, answers to the causes of autistic symptoms are not to be found in macroscopic structural pathology. A promising alternative to structural explanations is offered by functional imaging, which can measure regional brain function as well as functional connectivity. Functional magnetic resonance imaging (fMRI) has recently emerged as a highly sensitive, non-invasive means of determining brain function in both normal and impaired populations. Functional MRI measures changes in deoxyhemoglobin levels resulting from local increases in cerebral blood flow, thus providing an indirect measure of focal brain activity associated with task performance. This project proposes using fMRI in high functioning autistic subjects while performing cognitive tasks that tap three primary deficits associated with autism: these are emotional responsiveness and empathy, perception and identification of facial emotions, and perception and attribution of affective prosody. The tasks are designed to isolate different levels of cognitive function essential to social communication: specifically, the effects of emotional arousal and responsiveness, perception of affective information, and the execution of utilization of affective information. Using newly established statistical techniques, the fMRI project will examine not only which brain areas respond to cognitive challenge in autistic vs. control subjects, but will also define the functional correlations between different cognitive processing regions for each population. This approach is geared toward testing the hypothesis that the primary deficits in autism are not structural, but are reflected in impaired functional connectivity between the analysis of affective information, and the dynamic utilization of that information in problems-solving tasks.

Determine the neural networks involved in three aspects of nonverbal and social communication: affective prosody, perception of facial expression, and response to emotionally laden scenes. We examine each category of cognitive task from three levels to address the following questions. a. Perceptual: is the basic apparatus for visual and auditory perception of emotional, versus non-emotional, sensory information intact? b. affective; does perception of affect produce appropriate emotional arousal as evidenced by activation of emotion-mediated brain centers in the limbic circuit? c. executive: are the neural networks involved . in utilizing and making judgments about perceived and experienced affect intact? 2. Determine differences in these neural networks in higher functioning autistic individuals, which are specific to autism, in comparison to a non-autistic, language impaired population, along the following dimensions: a. regional dvsfunction: do autistic and control subjects differ in their ability to activate key brain regions associated with the above levels of processing? b. functional connectivity: do autistic and control subjects differ in the functional connections between critical brain regions, and how do these regions interact during task performance? c. anatomical underpinnings of specific symptons: can we identify regional and functional connectivity differences associated with specific symptoms of autism?

The anatomic analysis of neuroimaging data sets has traditionally focused on the development of tools to extract or quantify features within the data that are obvious to casual visual inspection. This has resulted in an emphasis on percellating the brain on the basis of large scale macroscopic features. Such features are typically either bounded by abrupt changes in signal intensity (e.g., identification of the thalamus as distinct from the surrounding! white matter. or more generally. segmentation of tissue into gray matter, white matter and CSF), or are defined in terms of their gross morphometric characteristics (e.g., delineation of the boundaries of specific sulci or gyri). The importance and utility of tools to facilitate the analysis of macroscopic anatomic-dc features in neuroimaging data is clear, and the tools for such analyses are so mature that their existence and use is implicit throughout this proposal. The emphasis of this section will be the development of new tools tha t will allow us and our collaborators to push beyond the limits of macroscopic anatomy into the realm of features traditionally associated with microscopic anatomy. Although not necessarily obvious on casual visual inspection of the images, the latest generation of imaging technology has crossed resolution thresholds that allow brain images to be anatomically subdivided on the basis of features that are rooted in the microscopic realm. Tools that are based on a clear understanding of the associated microscopic anatomic fundamentals will allow optimal detection and analysis of these features. assuring that we will be able to take full advantage of each future incremental increase in image quality. Specific Aims 1. Develop methods for enhancing the laminar organization of the cortex so that it can be detected, quantified, and compared in MRI data sets both within and across subjects and during development or aging. Specific Aims Specific Aims 2. Develop general tools that can incorporate contextual information (e.g., texture or local orientation), prior anatomic expectations. or expert neuroanatomic guidance, to generate signals that are optimally sensitive to microscopic anatomic features. Specific Aims 3. S systematically ) explore anatomic resources to identify microscopic features expected to produce characteristic MRI signatures. Specific Aims 4. Anatomically validate the tools developed in this project using unique data sets including post-mortem cryornacrotome data of subjects who underwent antemortem MRI scanning.

The goal of this Project is to develop and implement novel, high resolution structural and functional MRI, to identify the earliest apparent brain changes in subjects at risk for developing AD. Specifically, we will examine young and older control subjects with and without the APOE-4 allele, and patients with MCI and mild AD, in a cross-sectional comparison of age-related changes in the brain, and in a 2-year longitudinal follow-up, using MRI acquisition and analysis tools recently developed in our laboratory. We will focus on changes in the structure and function in the hippocampus, where ample evidence indicates the pathological process leading to AD arises. Our aims cover 3 general goals: 1) to identify subtle changes in brain structure, particularly in entorhinal cortex and in anterior hippocampus, in at-risk and cognitively declining subjects 2) to identify abnormalities in functional activity in individual sub-regions of the nippocampal complex using different memory paradigms, and 3) to develop integrative models for determining the relationship between these functional and structural MRI markers and PET markers of amyloid burden (based on [18F]DDNP) and nippocampal 5HT1A receptor activity (based on [18F]MPPF PET). For structural MRI, we will acquire small voxel T1 weighted volumetric scans, on which we will conduct voxel-based parametric maps of longitudinal change in grey matter distribution, as well as grey-matter segmented region of interest analysis to be shared with the other projects. Additionally, we will collect very high in-plane resolution images of the hippocampus (.3 mm) to serve as a basis for studies of 1) gray matter thickness in entorhinal cortex, individual CA fields, subiculum and parahippocampal gyrus;2) sulcal variability maps, measuring small displacements in sulci secondary to subtle tissue loss;and 3) unfolded "flat maps" of the hippocampus to discriminate among subregions, in combination with 4) high resolution BOLD FMRI of the hippocampus during episodic encoding, retrieval, and novelty encoding paradigms. We will integrate these structural and functional imaging measures of regional nippocampal integrity with [18F]DDNP and [18F]MPPF maps to determine how amyloid burden relates to hippocampal morphometry and function, and how this relationship changes dynamically in genetically at-risk individuals. These studies will enable us to develop highly sensitive predictive formulas for identifying those most likely to show decline, and will help us to understand the pathophysiology of AD as it relates to neural loss and amyloidopathy.

Affect; Architecture; Archives; autism spectrum disorder; autistic Children; Autistic Disorder; base; Behavior Therapy; Behavioral; Brain; Brain region; Child; Childhood; Collaborations; Computer software; Data; Data Base Management; data management; data mining; Data Quality; Databases; desensitization; design; Development; Electronics; Enrollment; Ensure; Environment; experience; Experimental Designs; Feedback; follow-up; Foundations; Fright; Functional Imaging; Functional Magnetic Resonance Imaging; Genes; Genetic; genetic analysis; Genetic Risk; genetic risk factor; Goals; Head; Image; Image Analysis; image processing; Image Reconstructions; improved; Individual; Infant; Laboratories; Language Development; Magnetic Resonance Imaging; Magnetism; Medial; meetings; mirror neuron system; Motion; Neurobiology; Noise; Physiologic pulse; Positioning Attribute; Predisposition; Preparation; Principal Investigator; Protocols documentation; Recording of previous events; Recruitment Activity; Research; Research Infrastructure; Research Personnel; Resources; reward processing; Risperidone; Running; Scanning; Scientist; Services; Signal Transduction; simulation; social; software development; Solutions; Standardization; System; Techniques; Technology; Time; tool; Training; Training Programs; treatment response; Variant

[unreadable] DESCRIPTION (provided by applicant): This is a continuing renewal of our R01 previously titled "Functional MRl for Early Diagnosis of Alzheimer's Disease" (5 R01 AG013308-10). The proposed third grant cycle builds on recent findings from this project and new technologies we have developed for imaging hippocampal structure and function. Our data support the utility of combining genetic risk, structural and functional MRl to identify early manifestations of Alzheimer's disease (AD), and further suggest that brain changes may occur much earlier than previously thought in Apolipoprotein epsilon-4 (APOE-4) carriers. Recently, our group has developed new techniques in high-resolution functional MRl acquisition and analysis, and in mathematical modeling algorithms that identify structural MRl change in Alzheimer's disease subjects over very short time periods. In addition, our group has recently worked with positron emission tomography (PET) using [18F]MPPF imaging, a ligand that measures pyramidal cell density in the hippocampus (HC), entorhinal cortex and amygdala; our preliminary data show that [18F]MPPF binding is decreased in MCI and AD, and correlates with memory in healthy controls, suggesting its potential as an independent assessment of risk for AD. This grant proposes using a combination of four new imaging techniques, two structural (HC cortical thickness and HC radial atrophy), and two functional (FMRI and [18F]MPPF) in control subjects in the 40-80 range at-risk for AD and MCI patients, to determine if there are subtle longitudinal changes in HC structure and function similar to those seen in AD, in cognitively intact at-risk subjects in the late middle age to elderly range. We will recruit 60 younger (40-60) and 36 older (60+) controls, (50% of each with APOE-4), and 35 mild MCI subjects, and follow them for 21/2 years using these novel imaging measures and clinical assessments. Analyses will focus on modeling the rate of change of each measure alone and in combination, with the goal of identifying subjects at highest risk for developing AD. Diagnostic and neuropsychological evaluations will provide clinical corroboration that genotype, family history, and short-term brain changes predict cognitive decline. By combining these different measures of hippocampal structure and function, our primary goal is to develop an approach to identifying those at-risk who are more likely to develop AD, and to determine which of these novel imaging techniques provide the most optimal and independent predictors of future decline. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The research outlined in this application is devoted to a uniquely multi-disciplinary approach toward determining the bases, consequences, and mutability of social communication deficits in autism. Project I (Sigman) proposes a longitudinal study of over 300 infants at risk for autism based on their family history of having older siblings who are diagnosed with the autism syndrome. We will describe the developmental trajectories of subgroups of children who manifest varying patterns of symptoms ranging from full autism to the broader autism phenotype to non-affected siblings, thus developing the tools for earlier diagnosis and better determination of prognosis, an issue of critical importance to families. A unique feature of this research is that Project II (Geschwind) will use the same sample to investigate the extent to which the variability in the children's language gains is attributable to genetic factors that have previously been tied to the acquisition of language skills in children with autism. Project II improves upon earlier genetic studies in that genetic contributions to the trajectory of language acquisition can be investigated for the first time due to the availability of a broad range of phenotypic measures of language skills over the course of the children's early lives. Project III (Dapretto) examines the extent to which the social communication deficits in autism are due to specific neurophysiological patterns in brain systems, particularly to disorders of the mirror neuron and brain reward systems. Project III will examine the plasticity of the mirror neuron system in a sample of children who participated in a therapeutic intervention (Kasari) that succeeded in improving their communicative abilities, a path-breaking study to connect brain circuit activation with treatment outcome. Project IV (Kasari) will significantly extend our previous work demonstrating the remarkable consequences of successfully intervening with social communicative deficits of children with autism. Project IV investigates whether the treatment of very young children with autism can be carried out by parents rather than trained interventionists, thereby making such treatment more accessible. Project V (McCracken) researches the effects of risperidone on repetitive behaviors in children as well as the mediators of these effects by using fMRI to identify functional patterns that differentiate treated and non-treated children with autism. In summary, these projects represent a set of carefully interwoven designs, providing synergy by studying overlapping subject populations with complimentary methods that identify the nature and determinants of core deficits in autism. Information from these studies will lead to a better understanding of the relationships between these deficits in autism and their specific genetic risk factors and brain circuitry, as well as improved early diagnosis and treatment of autism. [unreadable] [unreadable] [unreadable]

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a continuing renewal of our R01 previously titled "Functional MRl for Early Diagnosis of Alzheimer's Disease" (5 R01 AG013308-10). The proposed third grant cycle builds on recent findings from this project and new technologies we have developed for imaging hippocampal structure and function. Our data support the utility of combining genetic risk, structural and functional MRl to identify early manifestations of Alzheimer's disease (AD), and further suggest that brain changes may occur much earlier than previously thought in Apolipoprotein epsilon-4 (APOE-4) carriers. Recently, our group has developed new techniques in high-resolution functional MRl acquisition and analysis, and in mathematical modeling algorithms that identify structural MRl change in Alzheimer's disease subjects over very short time periods. In addition, our group has recently worked with positron emission tomography (PET) using [18F]MPPF imaging, a ligand that measures pyramidal cell density in the hippocampus (HC), entorhinal cortex and amygdala;our preliminary data show that [18F]MPPF binding is decreased in MCI and AD, and correlates with memory in healthy controls, suggesting its potential as an independent assessment of risk for AD. This grant proposes using a combination of four new imaging techniques, two structural (HC cortical thickness and HC radial atrophy), and two functional (FMRI and [18F]MPPF) in control subjects in the 40-80 range at-risk for AD and MCI patients, to determine if there are subtle longitudinal changes in HC structure and function similar to those seen in AD, in cognitively intact at-risk subjects in the late middle age to elderly range. We will recruit 60 younger (40-60) and 36 older (60+) controls, (50% of each with APOE-4), and 35 mild MCI subjects, and follow them for 21/2 years using these novel imaging measures and clinical assessments. Analyses will focus on modeling the rate of change of each measure alone and in combination, with the goal of identifying subjects at highest risk for developing AD. Diagnostic and neuropsychological evaluations will provide clinical corroboration that genotype, family history, and short-term brain changes predict cognitive decline. By combining these different measures of hippocampal structure and function, our primary goal is to develop an approach to identifying those at-risk who are more likely to develop AD, and to determine which of these novel imaging techniques provide the most optimal and independent predictors of future decline.

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).

A major advance in the study of the brain has been the discovery of specific regions that play a critical role in memory. These regions include the medial temporal lobe, which includes several different interconnected structures. With support from the National Science Foundation, Dr. Barbara Knowlton and colleagues at UCLA will use functional magnetic resonance imaging to discover the different roles of these regions in human memory, and how they work together to support the rich, detailed memories of our experiences that define us as people. Much of the work is motivated by theories of human memory that state that one medial temporal lobe region, the CA3 region of the hippocampus, is very important for the creation of distinct memories for events, and allows us to keep memories for similar events from blending together. Dr. Knowlton and her research team will test the idea that activity in the CA3 during learning is directly related to how robust and long-lasting memories will be. The experiments will also compare brain activity when people learn information by trying to think about what is unique about each item to brain activity when people learn information by concentrating on what is similar across items. The research hypothesis is that there will be more activation in the CA3 region in the first kind of learning because the brain will be forming distinctive memories. Additionally, the research will test the idea that the same pattern of activity that occurs in the medial temporal lobe when an item is learned will be repeated when that same item is later remembered.

These experiments will provide important new information about how neural circuits form human memories, and thus will be the source of insights into how memory can be improved. Furthermore, this proposal will train graduate students in high resolution and cortical unfolding techniques, which can be applied to other areas of cognitive neuroscience.

DESCRIPTION (provided by applicant): Autism is a tremendously heterogeneous disorder with complex genetic and neural underpinnings. This grant aims to understand variability in the autism phenotype by examining links between known genetic risk factors for autism and brain structure and function. We will recruit 80 children with autism and 40 controls who will undergo a comprehensive phenotyping assessment, high field structural MRI, and functional MRI using three tasks that differentiate typically developing children from those with autism, and which tap into core deficits seen in ASD. Our study will focus on five autism risk polymorphisms and one known genetic syndrome, 22q11deletiion with the goal of identifying structural and functional brain abnormalities that are linked to autism risk polymorphisms, and in turn to link these neural anomalies to variations in the autism phenotype. We hope to develop profiles of imaging phenotypes in autism that will help identify valid autism subtypes based on brain structure and function, and link these phenotypes to their genetic origins, thereby moving towards a more crystallized conceptualization of ASD. PUBLIC HEALTH RELEVANCE: This grant aims to examine the effects of 5 replicated autism risk genes on brain structure and function, using functional and structural MRI. The goal is to try to understand the neural basis of behavioral variations in autism by drawing connections from genes to brain to behavior. We will examine 5 autism risk genes and one known genetic syndrome, 22q11deltion, where there are high rates of autism, and identify brain regions and systems associated with these genes, relating them to variations in the autism phenotype.

PROJECT SUMMARY (See instructions): As the nucleus of the UCLA Autism Center of Excellence (UCLA ACE), the Administrative and Data Management Core (Core A) aims to provide a administrative structure that optimizes the functions of the ACE Center as a whole by setting scientific goals, overseeing project success, and providing centralized infrastructure and resources for data management and sharing. Core A will ensure that administration of the Projects and Cores is done efficiently and cost-effectively to promote timely completion of research objectives with high quality control. The Core A Director, Dr. Susan Bookheimer, has served as ACE PI the past four years, and will work closely with Dr. Dan Geschwind, the Director of the UCLA Center for Autism Research and Treatment (CART). Data management, sharing through NDAR, and comprehensive statistical support will be provided by a Data Management Unit co-directed by Dr. Catherine Sugar, Director of the Semel Institute Biostatistics Core, and Dr. Giovanni Coppola, Director of Informatics. The core is supported by Senior Center Administrator Kathy Suzuki, and Director of Operations and Outreach, Dr. Candace Wilkinson, who provide oversight of daily operations and advise the Director and Co-Director of progress and needs. Primary Core responsibilities are: 1) To maintain an organizational framework under an Executive Committee to establish scientific priorities, facilitate collaboration, and ensure we achieve Center goals, with input from an internal and external advisory board; 2) To provide Data Management and analytical/statistical support through the Data Management Unit to project scientists and other core directors within the Center; Capture, archive, protect, analyze, and share data and monitor database activities including quality assurance data checking, other quality controls and transfer of data to the National Database for Autism Research (NDAR) to facilitate data sharing; 3) To deliver Administrative Support and oversight for the center projects and cores, including financial management, monitoring core utilization, overseeing Human subjects protection, and providing centralized resources for meeting subject recruitment goals and monitoring equitable recruitment.

DESCRIPTION (provided by applicant): This is a renewal application for the UCLA Autism Center of Excellence. The primary focus of the UCLA ACE renewal is to understand the relationship between aberrant brain development and core deficits in autism by identifying mechanisms relating genes to brain structure/function and brain to behavior, and to develop effective interventions based on basic experimental and clinical research findings that will change outcomes in autism. In five interdependent projects and cores, our center builds on our expertise in autism genetics, multimodal brain imaging, early detection and analysis of core autism features, and experience in implementing randomized control trials of novel interventions that target these core symptoms. In this renewal application, projects focus on defining longitudinal trajectories of brain and behavioral development in infants with multiple risks for autism (Proj I); infants and toddlers with early signs of autism (Project II), nonverbal school age children with autism (Proj III), and higher functioning children/ adolescents (Project IV), using a shared set of imaging, neurophysiological and neurobehavioral biomarkers, as well as genetic risk and expression analysis (Proj V) in longitudinal studies. This center is focused on understanding both early and later trajectories of emerging and developing functional connectivity and behavioral change in relation to variation in autism phenotypes, defining how genetic risks mediate both imaging and behavioral phenotypes, and altering trajectories through two separate treatments focused on core deficits in ASD, one targeted developing joint attention and social orientation in infants, and one focused on improving language nonverbal children with augmentative pharmacological intervention. Four cores support the scientific goals: an Administrative Core, facilitating scientific progress and providing data management/statistics support; a Diagnostic and Phenotyping Core; a Neuroimaging/Neurophysiology core, and a Research Education and Outreach core. The UCLA ACE benefits from our years of working together as a team. We present a highly integrated center with multiple collaborations across levels of analysis to further a strongly translational research strategy aimed at changing outcomes in children with autism spectrum disorders. RELEVANCE: This is a renewal application for the UCLA Autism Center of Excellence. The UCLA Autism Center of Excellence is dedicated to identifying the causes of autism, discovering how risk factors translate into abnormal brain development, developing and validating novel interventions, and targeting the core deficits to change trajectories and outcomes in individuals with autism spectrum disorder.

Core C, the Neuroimaging/Neurophysiolgy Core, provides comprehensive services for acquisition, analysis, and integration of brain biomarker data from EEG, MRI, and eye tracking studies. There is a critical need to develop brain biomarkers of autism that are relevant across age ranges and severity level, and that are sensitive for detecting early brain abnormalities, developmental trajectories, and response to treatment. Each of the five Projects in the center will utilize services, resources and expertise provided by Core C to address specific aims and Center themes more generally. The Core will provide four main functions: 1) Subject preparation and desensitization; 2) implementing a common set of tasks across projects and modalities; 3) data acquisition, and 4) data analysis and integration with projects to address specific aims and facilitate cross-project collaborations. By centralizing these modalities within the same core we can provide a common set of measures, acquired consistently across subjects and methods, allowing us to integrate data in cross- project collaborations. Common tasks will address core themes including language acquisition, implicit (statistic) learning, and social attention. We have access to outstanding infrastructure and equipment resources for acquiring the core measures proposed: these are structural MRI, Diffusion Tensor Imaging (DTI) resting state MRI, functional MRI activation. Resting and activation EEG, eye tracking and pupillometry. The Core provides a team of experts in acquisition and analysis of these data. Further, the core will support several novel approaches to data analysis and integration including graph theoretical approaches to understand brain connectivity networks applied across modalities, and machine learning analytic approaches for predicting outcomes, groups, or phenotypic characteristics. Working in tandem with the statistics unit, the Core personnel will work with project and core investigators to integrate neuroimaging and neurophysiology findings with project-specific data to address both project aims and the ACE central themes.

Project Summary The goal of this application is to examine the relationship between threat- and reward-related neural circuitries and symptom dimensions of anxiety and depression during the transition from adolescence to adulthood. This project is in line with the Research Domain Criteria?s (RDoC) objective of identifying new strategies for psychiatric classification based on observable dimensions and their corresponding neural circuitries. We have identified a tri-level model of symptom dimensions that includes a broad factor (General Distress) common to all anxiety and depressive symptoms, as well as factors of intermediate breadth (Fears, Anhedonia-Apprehension) that are more distinctive to subsets of anxious and depressive symptoms. Existing research highlights dysregulation of a ?threat-related? neural circuit encompassing the amygdala and subgenual portion of the anterior cingulate cortex in both anxiety and depression. Distinctions between anxiety and depression may be present in a ?reward-related? neural circuit encompassing the ventral striatum and orbitofrontal cortex, which appears elevated in anxiety but reduced in depression. By studying both reward- and threat-related brain function, we will address RDoC constructs of Positive Valence (reward sensitivity) as well as Negative Valence (threat sensitivity). We will prospectively examine whether neural profiles predict the course of symptoms, and conversely, whether symptom courses covary with changes in neural activation over 36 months. Taking a vulnerability-stress perspective, we will test whether life-stress moderates the prospective associations between neural profiles and symptom trajectories. In addition, we will evaluate whether neural data possess predictive value above and beyond other indices of threat and reward sensitivity, including self- report, behavioral, and physiological measures. Results are expected to a) enhance our understanding of threat- and reward-related dysregulation in anxiety and depression, b) identify intermediate neural phenotypes that are not limited to existing diagnostic criteria, c) facilitate more targeted pharmacological and neurofeedback based treatments, d) contribute to a classification system for anxiety and depression that is informed by contemporary science, and e) evaluate the precision with which neural data can cross-sectionally and longitudinally classify individuals into empirically established symptom and impairment profiles. To achieve these aims, we will use self-report measures of threat and reward sensitivity to select 18 to 19 year olds who represent the full range on each dimension. Symptoms, impairment, and life stress will be assessed at baseline, 12-months, 24 months, and 36 months, and fMRI scanning of threat- and reward-related brain function will occur at baseline and 36 months. Participants will be recruited from local communities at two sites, UCLA (n=125) and Northwestern University (n=125) when they are 18 to 19 years old.

DESCRIPTION: Provided by Applicant: This application is for continued support of the administrative and research cores of the UCLA Intellectual and Developmental Disabilities Research Center (IDDRC). This IDDRC provides a comprehensive multidisciplinary research program in the field of intellectual and developmental disabilities. Importantly, the research investigations carried out by the Center Investigators encompass 23 of the 31 IDD research priorities listed in the current P30 RFA. This Center maintains and sharpens its focus on discovering ways to prevent and treat IDD, and to improve the quality of life for intellectual and developmentally disabled individuals, by fostering research innovation into the pathophysiological mechanisms of developmental disorders in animal models and also by patient-based research through interdisciplinary interactions among investigators. Newly emerging areas of excellence at the IDDRC, which extensively combine studies of human IDD and animal models, include studies of fragile X syndrome, autism spectrum disorders, pediatric brain tumors, and pediatric epilepsy. To serve these and other areas of excellence, the cores have been reorganized to provide much greater support for translational research while expanding cutting edge technology for the basic sciences. The eight cores are: (A) Administration and Communication, (B1) Neurogenomics and Bioinformatics and (B2) Epigenetics, (C) Stem Cells, (D) Cell Biology and Cellular Imaging, (E) Animal Models, (F) Electrophysiological Assessment, and (G) Translational Core for Human Phenotyping and Imaging. These cores are strengthened by the expertise of the increased number of IDDRC faculty involved with the cores, and the increased synergy among them. The mission of the Center is to provide an environment promoting the highest level of research in IDD by providing investigators open access to cutting edge and efficient core services in the IDDRC. The Center also organizes seminars, mini-symposia, an annual retreat, and core-based workshops to foster cohesive scientific discourse and collaboration. The Center assigns high priority to the support of talented young investigators and the training of pre- and postdoctoral fellows in a variety of disciplines related to its goals. The Center's mission is facilitated by strong ties with faculty in more than ten departments and institutes at UCLA excelling in neuroscience, genetics, human and animal imaging, nanotechnology, molecular biology, psychology, psychiatry, neurology, neurosurgery, pathology, pharmacology, pediatrics, education, and anthropology. The Center has recently begun interactions with a new IDD program at the University of Southern California, and it has increased interactions with national and international IDD researchers to share resources and knowledge to accelerate research breakthroughs and their translation.

? DESCRIPTION (provided by applicant): Adolescence is a critical neurodevelopmental period associated with dramatic increases in rates of substance use (SU). Identifying the pathways to SU and its effects on child and adolescent development is critically important, as the effects of substance use during ongoing maturation likely have long-lasting effects on brain function and behavioral, health, and psychological outcomes. This Research Project Site application from the University of Southern California/Children's Hospital Los Angeles and UCLA is in response to RFA-DA-15-015 as part of the ABCD-USA Consortium (8/13), to prospectively determine the neurodevelopmental and behavioral predictors and consequences of SU on children and adolescents. A representative community sample of 850 9-10 year olds enriched for high-risk characteristics will be recruited, contributing to the sample of 11,111 to be collected from 11 hubs across the ABCD-USA Consortium. All participants will undergo a comprehensive baseline assessment, including state-of-the-art brain imaging, comprehensive neuropsychological testing, bioassays, mobile monitoring and careful assessment of SU, environment, psychopathological symptoms, and social functioning every 2 years. Interim annual interviews and quarterly web-based assessments will provide refined temporal resolution of behaviors, development, and life events with minimal participant burden. These Consortium-wide data obtained during the course of this project will elucidate: 1) the effects of SU patterns on the adolescent brain; 2) the effects of SU on behavioral and health outcomes; 3) the bidirectional relationship between psychopathology and SU patterns; 4) the effects of individual genetic, behavioral, neurobiological, and environmental differences on risk profiles and SU outcomes; and 5) the gateway interactions between use of different substances. Elements Unique to This Site: Our Research Project focuses on the mediating or moderating effects of 1) pubertal hormones and sex differences, 2) socioeconomic (SES) factors, and 3) prenatal exposure (PE) to drugs of abuse on SU and other psychopathologies. These three factors are known to influence timing and trajectories of neurodevelopment, and have been linked to SU, but are seldom studied in tandem in neurodevelopmental studies of typically developing children. In this proposal, in conjunction with the larger ABCD-USA consortium, we are in a unique position to investigate the extent that SES and PE individually or interactively perturb the timing or outcomes of maturation of frontolimbic circuits important in reward processing and decision making, and, how pubertal changes (independent of age) may correspond with the onset of SU and co-occurring psychopathology within the context of the developmental environment. In Y03, we will focus on studying cross-sectional relationships between brain structure and function and puberty, SES and PE prior to onset of SU, and in subsequent years, we will focus on longitudinal studies from onset of SU and SU disorder progression, and precursors or consequences of SU on brain structure and function in Y6-Y10.

? DESCRIPTION (provided by applicant): The major technological and analytical advances in human brain imaging achieved as part of the Human Connectome Projects (HCP) enable examination of structural and functional brain connectivity at unprecedented levels of spatial and temporal resolution. This information is proving invaluable for enhancing our understanding of normative variation in young adult brain connectivity. It is now timely to use the tools and analytical approaches developed by the HCP to understand how structural and functional wiring of the brain changes during the aging process. Using state-of-the art HCP imaging approaches will allow investigators to push our currently limited understanding of normative brain aging to new levels. We propose an effort involving a consortium of five sites (Massachusetts General Hospital, University of California at Los Angeles, University of Minnesota, Washington University in St. Louis, and Oxford University), with extensive complementary expertise in human brain imaging and aging and including many investigators associated with the original adult and pilot lifespan HCP efforts. This synergistic integration of advances from the MGH and WU-MINN-OXFORD HCPs with cutting-edge expertise in aging provides an unprecedented opportunity to advance our understanding of the normative changes in human brain connectivity with aging. Aim 1 will be to optimize existing HCP Lifespan Pilot project protocols to respect practical constraints in studying adults over a wide age range, including the very old (80+ years). Aim 2 will be to collect high quality neuroimaging, behavioral, and other datasets on 1200 individuals in the age range of 36 - 100+ years, using matched protocols across sites. This will enable robust cross-sectional analyses of age-related changes in network properties including metrics of connectivity, network integrity, response properties during tasks, and behavior. Aim 3 will be to collect and analyze longitudinal data on a subset of 300 individuals in three understudied and scientifically interesting groups: ages 36-44 (when late maturational and early aging processes may co-occur); ages 45-59 (perimenopausal, when rapid hormonal changes can affect cognition and the brain); and ages 80 - 100+ (the `very old', whose brains may reflect a `healthy survivor' state). The information gained relating to these important periods will enhance our understanding of how important phenomena such as hormonal changes affect the brain and will provide insights into factors that enable cognitively intact function into advanced aging. Aim 4 will capitalize on our success in sharing data in the Human Connectome Project (HCP), and will use these established tools, platforms, and procedures to make this data publicly available through the Connectome Coordination Facility.

? DESCRIPTION (provided by applicant): The major technological and analytical advances in human brain imaging achieved as part of the Human Connectome Projects (HCP) enable examination of structural and functional brain connectivity at unprecedented levels of spatial and temporal resolution. This information is proving crucial to our understanding of normative variation in adult brain connectivity. It is now timely to use the tools and analytical approaches developed by the HCP to understand how structural and functional wiring of the brain develops. Using state-of-the art HCP imaging approaches will allow investigators to push our currently limited understanding of normative brain development to new levels. This knowledge will critically inform prevention and intervention efforts targeting well known public health concerns (e.g., neurological and psychiatric disorders, poverty). The majority of developmental connectivity studies to date have used fairly coarse resolution, have not been multi-modal in nature, and few studies have used comparable methods to assess individuals across a sufficiently wide age range to truly capture developmental processes (e.g., early childhood through adolescence). Here we propose a consortium of five sites (Harvard, Oxford, UCLA, University of Minnesota, Washington University), with extensive complimentary expertise in brain imaging and neural development, including many of the investigators from the adult and pilot lifespan HCP efforts. Our synergistic integration of advances from the HARVARD-MGH and WU-MINN-OXFORD HCPs with cutting edge expertise in child and adolescent brain development will enable major advances in our understanding of the normative development of human brain connectivity. The resultant unique resource will provide rich, multimodal data on several biological and cognitive constructs that are of critical importance to health and well-being across this age range and allow a wide range of investigators in the community to gain new insights about brain development and connectivity. Aim 1 will be to optimize existing HCP Lifespan Pilot project protocols on the widely available Prisma platform to respect practical constraints in studying healthy children and adolescents over a wide age range and will also collect a matched set of data on the original Skyra and proposed Prisma HCP protocols to serve as a linchpin between the past and present efforts. Aim 2 will be to collect 1500 high quality neuroimaging and associated behavioral datasets on healthy children and adolescents in the age range of 5-21, using matched protocols across sites, enabling robust characterization of age-related changes in network properties including connectivity, network integrity, response properties during tasks, and behavior. Aim 3 will be to collect and analyze longitudinal subsamples, task, and phenotypic measures that constitute intensive sub-studies of inflection points of health-relevant behavioral changes within specific developmental phases. Aim 4 will capitalize on our success in sharing data in the HCP, and use established tools, platforms and procedures to make all data publically available through the Connectome Coordinating Facility (CCF).

DESCRIPTION (provided by applicant): The goal of this application is to examine the relationship between threat- and reward-related neural circuitries and symptom dimensions of anxiety and depression during the transition from adolescence to adulthood. This project is in line with the Research Domain Criteria's (RDoC) objective of identifying new strategies for psychiatric classification based on observable dimensions and their corresponding neural circuitries. We have identified a tri-level model of symptom dimensions that includes a broad factor (General Distress) common to all anxiety and depressive symptoms, as well as factors of intermediate breadth (Fears, Anhedonia-Apprehension) that are more distinctive to subsets of anxious and depressive symptoms. Existing research highlights dysregulation of a threat-related neural circuit encompassing the amygdala and subgenual portion of the anterior cingulate cortex in both anxiety and depression. Distinctions between anxiety and depression may be present in a reward-related neural circuit encompassing the ventral striatum and orbitofrontal cortex, which appears elevated in anxiety but reduced in depression. By studying both reward- and threat-related brain function, we will address RDoC constructs of Positive Valence (reward sensitivity) as well as Negative Valence (threat sensitivity). We will prospectively examine whether neural profiles predict the course of symptoms, and conversely, whether symptom courses covary with changes in neural activation over 36 months. Taking a vulnerability-stress perspective, we will test whether life-stress moderates the prospective associations between neural profiles and symptom trajectories. In addition, we will evaluate whether neural data possess predictive value above and beyond other indices of threat and reward sensitivity, including self- report, behavioral, and physiological measures. Results are expected to a) enhance our understanding of threat- and reward-related dysregulation in anxiety and depression, b) identify intermediate neural phenotypes that are not limited to existing diagnostic criteria, c) facilitate more targeted pharmacological and neurofeedback based treatments, d) contribute to a classification system for anxiety and depression that is informed by contemporary science, and e) evaluate the precision with which neural data can cross-sectionally and longitudinally classify individuals into empirically established symptom and impairment profiles. To achieve these aims, we will use self-report measures of threat and reward sensitivity to select 18 to 19 year olds who represent the full range on each dimension. Symptoms, impairment, and life stress will be assessed at baseline, 12-months, 24 months, and 36 months, and fMRI scanning of threat- and reward-related brain function will occur at baseline and 36 months. Participants will be recruited from local communities at two sites, UCLA (n=125) and Northwestern University (n=125) when they are 18 to 19 years old.

CORE A: Abstract The primary aim of the Administration, Education and Outreach core (Core A) of the UC-TRaN is to provide scientific leadership, oversee and evaluate core services, and provide an essential centralized infrastructure that will support the Center's global mission to create an optimal environment for performing excellent and impactful translational research in IDDs. The Core will serve to build a strong collaborative IDD research group, fostering opportunities to bring together basic scientists and clinical researchers. The Core will effectively serve as a liaison for dialogue on priorities and dissemination of research findings, and to funding agencies, and provide a rich and supportive training milieu in translational developmental neuroscience research. The Core will serve as the administrative hub for scientific integration and resource oversight. It will coordinate and oversee research activities, fiscal and resource management, grant management, providing support services for all components of the UC-TRaN research program. The Core will develop new data resources and innovative research opportunities with partner organizations, including establishment and implementation of a West Coast IDDRC consortium. This will include developing a rare IDD patient registry, implementing a visiting scholars program, developing cross-IDDRC educational and resource sharing opportunities. More specifically, the Administrative Core will serve as the centralized infrastructure base for: Furthering Scientific Progress: Through interactions between the leadership group (directors and Executive Committee) and advisory groups (Internal and External Advisory Boards; UC- TRaN Steering Committee. Core Utilization, oversight, quality assessment and financial management, Administrative and Logistical functions, and Liaison activities.

? DESCRIPTION (provided by applicant): This submission is a new application for the UCLA IDDRC, entitled UCLA Center for Translational Research in Neurodevelopment (UC-TRaN). The fundamental purpose of our Center is to provide an optimal environment for performing outstanding research into the causes, mechanisms, and treatments of intellectual and developmental disorders. The new leadership model in the center emphasizes collaborations among Center investigators, core personnel, and community partners, with support for research spanning basic research and clinical practice. Our aims are 1) to create cutting edge and cost effective infrastructure resources in facilities and personnel for IDD investigators; 2) to provide integrated services within cores that support research from multidisciplinary teams and multiple levels of analysis; 3) to promote interactions between cores and among research investigators to promote collaborative, multidisciplinary and translational research, and 4) to create educational and outreach opportunities within the center, in collaboration with a West Coast Consortium of IDDRCs and community partners. We propose five interacting cores: 1) Administration, Education and Outreach; 2) Genetics, Genomics and BioInformatics, which performs genetic analysis, sequencing, expression, and provides Big Data resources; 3) Cells, Circuits and Systems analysis, supporting electrophysiology, human iPSC and cerebral organoid culture development, and optogenetics; 4) Structural and Functional Visualization, which provides access to and analysis of imaging tools from miniaturized microscopes through animal and human MRI; and 5) Clinical Translation, supporting clinical trial development, recruitment, phenotyping across species, and collecting biosamples. The Center proposes an exciting model research project, Neurophysiological biomarkers of cognition in Dup15 syndrome: From mouse models to patients. Dup15q11.2-13.1 is associated with marked cognitive impairment and other symptoms of developmental delay. The study examines a novel EEG biomarker in a cohort of children with Dup15q and in two separate mouse models of Dup15q syndrome, one defined by an overexpression of a single gene, UBE3A, and the other from a full duplication of the region. In the animal model the project will test three mechanism-based pharmacologic treatments: d-serine, rapamycin, and a GABA-A ?5 receptor subunit inverse agonist, to determine whether these treatments change cell activation patterns and behavior. Together, the project and cores support our primary goal of optimizing outcomes of individuals with intellectual and developmental disabilities by promoting outstanding translational research.

This application seeks to renew our highly productive and interdisciplinary UCLA Autism Center of Excellence (ACE III). Over the last decade, our group has made significant advances in the field, identifying risk genes, candidate brain based biomarkers of treatment response and early risk markers of Autism Spectrum Disorder (ASD) beginning in the first few weeks of life. We developed new interventions for toddlers with social communication delays, identified an intervention with the most robust effects on repetitive behaviors to date, and we showed how genetic risk influences brain structure and function in ASD. Most unique and impactful is our Center's integration of genetics, early biomarkers and behavioral assays with intervention In parallel with growing awareness in the field, we recognize the profound clinical and genetic heterogeneity in ASD, which poses a significant challenge to identifying diagnostic biomarkers and to developing effective interventions that target individual profiles. In order to move from a ?one size fits all? to a ?precision medicine? approach, we must better understand the biological and clinical basis of this heterogeneity. Our ACE application takes a multidisciplinary, integrative approach to study the relationship between genetic, neural and phenotypic heterogeneity in ASD, to determine whether this heterogeneity reflects unique biological mechanisms underlying autism, and to identify predictors of developmental trajectories and treatment outcome. In four interacting projects, we will focus on three areas of heterogeneity that our work suggests has unique neural, genetic and behavioral signatures: sensorimotor processing social attention/motivation, and social communication/language. Project I aims to determine how differences in genetic risk for autism (familial risk, 22q11deletion, and Tuberous Sclerosis Complex (TSC) affect early brain development, neuroimaging and EEG biomarkers in the first year of life and identifying predictors of ASD diagnosis at age 3; P. II examines heterogeneity in treatment response using a SMART design, 3-phase adaptive treatment intervention for very young children at risk for ASD; P. III uses MRI in youth with ASD to determine how behavioral phenotypes and genetic risk differentially affect brain activation, structural and functional connectivity. P. IV conducts a proof-of- mechanism pharmacological trial aimed to increase social interest and social reward responsivity with the dopamine precursor L-DOPA in adolescents and young adults enrolled in a social skills intervention.. All projects examine these target phenotypes using at least one biological marker, in addition to standardized and observational tests. This will allow us to integrate biomarkers, genetics and behavior across projects and across ages. A well-established core infrastructure centralizes diagnostics, genetics, imaging, and EEG acquisition, with a common database built for cross project and core collaboration, and outstanding, specialized statistical support. A new Dissemination, Outreach and Education Core centralizes recruitment, and strengthens our community ties and educational program to maximize scientific and community impact.

Abstract Adolescent Brain Cognitive Development (ABCD) is the largest long-term study of brain development and child health in the United States. The ABCD Research Consortium consists of 21 research sites across the country, a Coordinating Center, and a Data Analysis and Informatics Resource Center. In its first five years, under RFA- DA-15-015, ABCD enrolled a diverse sample of 11,878 9-10 year olds from across the consortium, and will track their biological and behavioral development through adolescence into young adulthood. All participants received a comprehensive baseline assessment, including state-of-the-art brain imaging, neuropsychological testing, bioassays, careful assessment of substance use, mental health, physical health, and culture and environment. A similar detailed assessment recurs every 2 years. Interim in-person annual interviews and mid-year telephone or mobile app assessments provide refined temporal resolution of developmental changes and life events that occur over time with minimal burden to participating youth and parents. Intensive efforts are made to keep the vast majority of participants involved with the study through adolescence and beyond, and retention rates thus far are very high. Neuroimaging has expanded our understanding of brain development from childhood into adulthood. Using this and other cutting-edge technologies, ABCD can determine how different kinds of youth experiences (such as sports, school involvement, extracurricular activities, videogames, social media, unhealthy sleep patterns, and vaping) interact with each other and with a child?s changing biology to affect brain development and social, behavioral, academic, health, and other outcomes. Data, securely and privately shared with the scientific community, will enable investigators to: (1) describe individual developmental pathways in terms of neural, cognitive, emotional, and academic functioning, and influencing factors; (2) develop national standards of healthy brain development; (3) investigate the roles and interaction of genes and the environment on development; (4) examine how physical activity, sleep, screen time, sports injuries (including traumatic brain injuries), and other experiences influence brain development; (5) determine and replicate factors that influence mental health from childhood to young adulthood; (6) characterize relationships between mental health and substance use; and (7) specify how use of substances such as cannabis, alcohol, tobacco, and caffeine affects developmental outcomes, and how neural, cognitive, emotional, and environmental factors influence the risk for adolescent substance use.

This proposal requests 5 years of additional funding for the UCLA Intellectual and Developmental Disabilities Research Center (IDDRC). For over 40 years, our mission has been to provide an optimal environment for conducting multidisciplinary research into the mechanisms underlying intellectual and developmental disabilities (IDDs), to translate these findings into effective treatments for IDDs, and disseminate these findings to the scientific community and the public. This submission expands on the translational focus that we began 5 years ago with an added emphasis on human research and clinical trials, and closer ties to the community. Each of the 5 cores are structured to facilitate interdisciplinary collaborations, following four thematic goals: 1) providing state of the art infrastructure for IDD related research; 2) encourage innovation by supporting technical development and providing financial incentives for new projects; 3) promote integration across disciplines, by encouraging interdisciplinary research among faculty and between cores; and 4) to disseminate advances in technology to other scientists, train new IDD investigators, and convey findings to the scientific community and stakeholders in community outreach efforts. We propose 5 interacting cores: A: Administration and Dissemination, which oversees core functions and usage, assures quality and accountability, and promotes outreach and dissemination; B: Clinical Translation, supporting clinical trials, recruitment, diagnosis and deep phenotyping, and biosample collection; C: Genetics, Genomics and BioInformatics, which performs genetic analysis, sequencing, expression, and provides resources for planning and executing analysis of genomics data; D: Cells, Circuits and Systems, supporting human iPSC and 3-dimensional organoid development, in- and ex- vivo electrophysiology and optogenetics; and E: Structural and Functional Visualization, which provides training, access, and analysis services for in vitro microscopy, mini-cameras for in vivo visualization, animal and human structural and functional MRI and spectroscopy. Our model research project focuses on mechanisms underlying sleep impairments in two IDDs, building on new findings from our last submission: a near absence of slow-wave sleep in Dup15q syndrome. We will examine mechanisms underlying sleep impairments in Dup15q and Rett's Syndrome using a multidisciplinary approach that includes a clinical component, animal models, and brain organoid model using patient-derived IPSCs, to elucidate how mechanisms underlying altered sleep physiology lead to cognitive dysfunction. Results from this project will directly inform next steps for developing interventions that may modulate sleep and, in turn, neurodevelopment in IDDs.

ADMIN CORE- ABSTRACT The primary aim of the Administration, Education and Dissemination Core (Core A) of the UCLA IDDRC is to support the overall mission of the Center by providing scientific leadership, oversight and evaluation of core services, and an efficient centralized infrastructure, to create an environment that is optimized for conducting outstanding research into Intellectual and Developmental Disabilities. The Core is divided into three main functional units: Scientific Leadership, Education and Dissemination, and Administrative Support. With input from an integrated Scientific Advisory Board, the Executive Committee of the Core will set the scientific priorities of the Center, conceptualize and help develop new research directions and provide opportunities for a multidisciplinary group of investigators to interact. The leadership team will set priorities for Core funding and utilization, evaluate cost effectiveness and core quality. The Core will support trainees and early stage investigators by creating a wide range of educational opportunities within the university, emphasizing translational research, and in partnership with the other West Coast IDDRCs, develop technical workshops and research symposia to provide excellent training in translational research. The core will organize mechanisms for dissemination of research findings to the broad community, and will emphasize minority outreach, and will build ties with stakeholders and advocacy groups. Finally, the Core will serve as the administrative hub for scientific support and resource oversight. It will coordinate and oversee core utilization, quality assessment and cost efficiency, liaison activities, and provide financial management, administrative and logistical functions for faculty and students.

ABSTRACT For patients with mild cognitive impairment (MCI) and Alzheimer?s Disease (AD) there are few effective treatments for memory enhancement. Strategies that directly manipulate neural activity are promising but currently have serious limitations. Deep brain stimulation (DBS) of the entorhinal cortex (ERc), a part of the brain important for memory, in a small sample of patients has been shown to improve memory, but DBS is highly invasive and requires neurosurgery. Other neuromodulation techniques that do not require surgery are limited in that they target only surface brain structures. In MCI and AD, it is the deep brain structures, including the ERc and the hippocampus (HC) that are most affected. Low intensity focused ultrasound pulsation (LIFUP) uses acoustic energy waves with frequencies higher than humans can hear to penetrate the skull to effect specifically targeted deep brain regions. Therefore, LIFUP could be targeted at the deep brain structures critical for episodic memory formation, the same regions that are affected in MCI and AD. We are the first to do just this and our preliminary data shows that LIFUP: increases perfusion of the ERc; increased functional connectivity of the ERc/HC memory network and may improve behavioral memory performance. Our LIFUP set-up is safe to use inside a magnetic resonance imaging (MRI) machine which allows for simultaneous brain modulation and real- time measurement of the modulation using MRI. We will use each participant?s structural brain MRI to aim LIFUP at the ERc. This will allow us to directly test the effects of LIFUP on activity in the ERc, in other brain regions connected to the ERc (e.g. HC), as well as on blood flow in the HC and other brain areas important for memory. Applying this to patients with MCI, we will try to determine the dose, booster effect and duration of LIFUP effects on brain and blood flow, structure and function, determine whether these LIFUP-related changes improve memory in this population and evaluate the effect of LIFUP on blood-based biomarkers of AD-related neurodegeneration. Understanding how the parameters of LIFUP dose and booster session effect the impact and duration of LIFUP on brain, biomarker and memory performance will be a significant step towards constructing a comprehensive clinical trial. The ability to change the activity and blood flow of brain regions by targeting them with LIFUP would be an important step towards developing a non-invasive memory prosthetic that would make a very significant contribution to AD treatment.

ABSTRACT FOR OVERVIEW The Aging Adult Brain Connectome (AABC) leverages the existing infrastructure developed by the Human Connectome Project for Aging (HCP-A) by obtaining longitudinal follow-up data (neuroimaging, cognitive testing, and blood) using a standardized protocol from a well characterized cohort of over 1,000 healthy individuals to generate within-participant brain trajectories for up to 10 years. At initial recruitment, individuals enrolled in the HCP-A were generally physically and cognitively healthy but over time some will develop preclinical AD or early cognitive changes due to AD or ADRD. The AABC is comprised of four Projects: Project 1 examine the effects of stress and allostatic load, including inflammation, during the early adult period. Project 2 examines the effects of lifestyle behaviors on the trajectory of cognitive and brain changes during the mid adult period. Project 3 examine the effects of menopause transition/vasomotor symptoms during the mid adult period. Project 4 exam- ine the clinical and neural indicators of resiliency and resistance to AD and ADRD in the later decades of adult- hood. The AABC also consists of 4 Cores: The Administration Core (AC) will provide essential core and site leadership to carry out the scientific mission of the AABC. The diversity recruitment and retention unit (DRRU) will be located within this core and will ensure that the AABC continues to recruit and retain an adequate distri- bution of races that is currently seen in the US. The Integrated Data Acquisition Core (IDAC) provides expertise and personnel from each site to acquire high quality neuroimaging, deep phenotyping of non-imaging data, and biosamples from each site.The Informatics, Data Analysis, and Statistics Core (IDASC) will house project imag- ing data using the IntraDB database, will perform quality control of raw and analyzed data, will develop and run cross-sectional and longitudinal pipelines to produce multi-modal imaging data phenotypes for each project, will provide dimension-reduced summaries, will impute missing data; and will develop and run statistical models for each project. The IDASC will also be responsible for data sharing with the general public. The Genetics and Multi-omics Specimens Core (GMSC) will provide genetic information on participants evaluated through the AABC who have been characterized using a uniform protocol. Multi-omic data and AD biomarker data will be generated by the GMSC.