2005 — 2009 |
Hessl, David R |
K23Activity Code Description: To provide support for the career development of investigators who have made a commitment of focus their research endeavors on patient-oriented research. This mechanism provides support for a 3 year minimum up to 5 year period of supervised study and research for clinically trained professionals who have the potential to develop into productive, clinical investigators. |
Genetics and Physiology of Social Anxiety in Fragile X @ University of California Davis
DESCRIPTION (provided by applicant): The aim of this application is to develop the candidate's knowledge and skills in patient-oriented clinical research in the domain of neurodevelopmental disorders. Toward this aim, he will complete a program including formal coursework, mentored training, and a research project on the molecular genetics and psychophysiology of social anxiety in children with fragile X syndrome and the fragile X premutation. The research project includes measurement of biobehavioral markers of autonomic and amygdala function, fragile X mental retardation 1 (FMR1) mRNA and gene expression, and behavioral measures in children with fragile X and matched comparison samples of children with idiopathic developmental disability and typical development. The primary underlying hypothesis of the project is that the FMR1 mutation causes over-responsiveness of the amygdala to social stimuli, leading to symptoms of social anxiety and avoidance that are hallmark behavioral features of the fragile X behavioral phenotype. The study will also investigate whether this mechanism of increased anxiety contributes to autistic behaviors, particularly deficits in reciprocal social behavior, in children with fragile X. The candidate's ultimate goals are to become a clinical researcher able to compete for independent grant support, and to conduct high quality studies that will directly lead to improvement in the lives of individuals with fragile X, as well as to contribute to a better understanding of the genetic and physiological mechanisms underlying emotional and behavioral disturbance in children with neurodevelopmental disorders. By the end of the award period, the candidate will become a recognized clinical researcher in the area of neurodevelopmental disorders, and will receive funding to conduct research as an independent investigator.
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0.958 |
2007 — 2011 |
Hessl, David R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Limbic System Function in Carriers of the Fragile X Premutation @ University of California At Davis
DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) results from a trinucleotide repeat expansion (full mutation;>200 CGG repeats) in the in the 5'untranslated region of the fragile X mental retardation 1 gene (FMR1) located at Xq27.3, leading to a reduction or absence of the gene's protein product, the FMR1 protein (FMRP), ultimately causing cognitive and behavioral impairments that are characteristic of the syndrome. Individuals with the FMR1 premutation (55-200 CGG repeats) are at risk for transmission of the gene in its expanded full mutation form in subsequent generations. Until recently, these "carriers" were believed to be clinically unaffected. However, following a period of scientific debate and controversy over this topic, recent evidence has emerged demonstrating that a proportion of these individuals have significant social, emotional, and cognitive problems, even autism and mental retardation in the most affected patients (Cornish, et al., 2005;Franke, et al., 1998;Goodlin-Jones, Tassone, Gane, &Hagerman, 2004;R. J. Hagerman &Hagerman, 2002;Johnston, et al., 2001;Moore, Daly, Schmitz, et al., 2004;Moore, Daly, Tassone, et al., 2004;Tassone, Hagerman, Taylor, Mills, et al., 2000). These deficits have previously been attributed to a mild deficit of FMRP that can occur in premutation carriers, especially those with higher CGG repeat alleles. In addition, we have discovered that male and rare female carriers are at significant risk for a neurodegenerative disease in later adulthood primarily characterized by intention tremor and gait ataxia called Fragile X-Associated Tremor Ataxia Syndrome (FXTAS, R. J. Hagerman, et al., 2001;Jacquemont, et al., 2003). This disease is not seen in FXS and has a different molecular mechanism involving, we believe, a toxic gain of function effect of abnormal elevation of FMR1 mRNA. This proposal does not involve FXTAS patients but rather younger men and women with the premutation who demonstrate psychiatric disturbances and are at risk for later neurodegeneration (Hessl, et al., 2005). The limbic region, especially the hippocampus and amygdala, appear to be especially impacted by increased CGG repeat size and the abnormal elevation of FMR1 mRNA (Abitbol, et al., 1993;Greco, et al., 2002;Jdkdld, et al., 1997;Moore, Daly, Tassone, et al., 2004) and we therefore focus on this region in the present study. This research will elucidate gene-brain-behavior associations related to the premutation that may provide insight into other disorders involving memory, social-emotional dysfunction, and the broader autism phenotype. The potential relevance of this work is significant given that the premutation occurs in an estimated 1 in 251 to 813 males and 1 in 113 to 259 females (Dombrowski, et al., 2002;Rousseau, Rouillard, Morel, Khandjian, &Morgan, 1995;Toledano-Alhadef, et al., 2001). PUBLIC HEALTH RELEVANCE: This research examines whether fragile X premutation carriers have emotional, social, or memory problems due to alterations in the structure or function of the limbic system of the brain. The premutation of the FMR1 gene is relatively common, affecting approximately 1 in 150 to 1 in 800 individuals. This research will help to clarify links between genes, brain, and behavior within this condition that may have implications for understanding of these types of mechanisms in other more common neuropsychiatric conditions.
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0.958 |
2013 — 2021 |
Hessl, David R Rivera, Susan M (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Trajectories and Markers of Neurodegeneration in Fragile X Premutation Carriers @ University of California At Davis
DESCRIPTION (provided by applicant): Carriers of the fragile X (FMR1) premutation have been shown to exhibit mild cognitive impairments and increased risk for psychiatric problems. Furthermore, they are at risk for developing a neurodegenerative disease, fragile X-associated tremor ataxia syndrome (FXTAS), characterized by neurological manifestations of progressive gait ataxia, intention tremor, Parkinsonism, dementia, autonomic dysfunction, and peripheral neuropathy. Neuropathological features of FXTAS include whole brain atrophy, ventricular enlargement, white matter disease, and neuronal and astrocytic intranuclear inclusion formation and neuropsychiatric symptoms include depression, anxiety, and executive dysfunction. The hypothesized molecular genetic pathogenic mechanism of FXTAS is toxic gain-of-function of FMR1 mRNA. The disease has a variable and age-related penetrance, affecting 75% of male premutation carriers by the eighth decade of life. While the features of FXTAS have been well-described, it is not known why some carriers become affected and others do not, and the variable rate of progression and risk factors associated with disease onset are poorly understood. In the first 5 years of this program of research (Limbic System Function in Carriers of the Fragile X Premutation), alongside other collaborative studies at our center, we have demonstrated that abnormal elevation of FMR1 mRNA is associated with reduced hippocampus, amygdala, and frontal lobe function, which in turn are correlated with psychological symptoms and social deficits, impaired memory recall and working memory in male premutation carriers at risk for FXTAS. Our other studies have shown brain white matter deterioration with age, reduced brain stem and increased ventricular volume, and high rates of mood and anxiety disorders in adult carriers without FXTAS compared to controls with normal FMR1 alleles. This work has provided important clues about potential genetic, brain and neuropsychological risk factors for disease progression, however no prospective longitudinal studies have been completed that provide critical data required to identify risk or protective factors for FXTAS. For the current project, we will examine the trajectory of key neuropsychological and neurological factors in adult male carriers of the FMR1 premutation between the ages of 40 and 69, in comparison to male controls without the premutation, using a longitudinal design. We will examine how several FMR1 molecular measures play a role in mediating the rate of progression of these key factors. The results of the study will provide critical information about the early markers of neurodegeneration that will aid in identification o patients most in need of preventive care and treatment as these interventions become available, and it may identify important measures to track response to interventions in the future.
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0.958 |
2014 — 2021 |
Hessl, David R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
A Cognitive Test Battery For Intellectual Disabilities @ University of California At Davis
Abstract The basic science and preclinical studies of intellectual and developmental disabilities (IDDs) have outpaced the development and validation of tools to measure treatment response in human clinical trials. While an ever-increasing number of targeted treatments documented to normalize neurobiological and behavioral phenotypes in animal models are advanced for experimental evaluation in humans with IDDs, limitations of outcome measures and lack of consensus among investigators have been major barriers to progress in the translational pipeline. In fact, it has been argued that true benefits of experimental treatments have been missed in some so-called ?failed trials? due to lack of sensitivity to change in the outcome measures for the disorder of interest, and/or susceptibility to large placebo effects that obscure these potentially real changes. For the past 5 years we have made substantial progress validating the National Institutes of Health Toolbox Cognitive Battery (NIHTB-CB) for use as a set of outcome measures for individuals with IDDs and have generated solid psychometric evidence of its utility for a high proportion of individuals with mental ages at or above 5 years. Despite these important advances, our work has also highlighted critical knowledge gaps, and potential solutions. First, some of the established NIHTB-CB tests were not feasible or lacked acceptable psychometric properties for more severely affected or very young individuals with IDD ? subgroups that remain critical targets for intervention ? and the battery does not cover important domains which can be measured very early in development. Second, while cross- sectional data is available from the battery?s normative sample, longitudinal trajectories of NIHTB-CB test scores among people with IDD are not available. And third, despite evidence of sensitivity to developmental changes, there are currently no data to demonstrate that the NIHTB-CB is sensitive to treatment-related change. For the current project we will a) optimize the NIHTB-CB for lower functioning individuals with moderate and severe IDD, b) complete development and validation of new NIHTB-CB tests to fill critical gaps in cognitive constructs not currently assessed, including Concept Formation and Numeracy, c) extend understanding of developmental changes in the NIHTB- CB tests using expanded longitudinal observations in children and youth with IDD, and d) examine the preliminary sensitivity of the NIHTB-CB to detect treatment-related cognitive changes utilizing a randomized, double-blind placebo-controlled stimulant (methylphenidate extended release liquid) trial in children and adolescents with IDD + ADHD. It is anticipated that successful fulfillment of these knowledge gaps will result in a scalable and standardized cognitive battery suitable for widespread use in the field and consideration for FDA registration.
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0.958 |
2021 |
Hessl, David R |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Development of An Ecological Momentary Assessment Outcome Measure For Down Syndrome Clinical Trials @ University of California At Davis
Abstract There is a growing translational research effort to understand the brain mechanisms of dysfunction in neurodevelopmental disorders including Down syndrome (DS) and other conditions that cause intellectual and developmental disability (IDD). Targeted treatments under development, often supported by animal studies, have the potential to normalize, or at least substantially mitigate, the neurobiological, cognitive, and behavioral problems associated with DS. However, several controlled clinical trials focused on DS and other IDDs (such as fragile X syndrome) in the past decade have been completed with limited success. Although the medications may actually be ineffective or inadequately provide clinical benefit, other explanations for trial failures include limited brain plasticity in the adults or adolescents studied, robust placebo effects that may obscure true benefits of active drug, and outcome measures that are inadequately sensitive to changes occurring in daily life. Optimization of ecologically valid, reliable and sensitive outcome measures for these conditions will facilitate the evaluation and identification of effective and clinically meaningful interventions. Executive dysfunction (ED), spanning processes and behaviors of planning and goal-directed behavior, cognitive flexibility, working memory, inhibitory control, and several forms of attention, has been emphasized by NIH DS working groups and other investigators as a key domain to target in trials. ED is a key component of the cognitive phenotype of DS, is predictive of limitations in adaptive functioning, and may be associated with risk for later dementia in this population. The primary aim of this project is to refine and develop the preliminary feasibility, reliability and validity of a smartphone-based electronic Ecological Momentary Assessment (eEMA) tool (iBehavior) for caregiver and teacher ratings of behaviors associated with ED in the daily lives (home and classroom environments) of children and adolescents with DS and IDD. The second aim of the project is to utilize the tool in the context of an already planned and funded (R01HD076189) double-blind placebo- controlled crossover trial of extended release methylphenidate in children and adolescents with DS and other forms of IDD with comorbid ADHD. This aim will determine iBehavior?s sensitivity to treatment and relative susceptibility to placebo effects compared to other rating scales and cognitive tests. The empirical validation of an eEMA app appropriate for use as an outcome measure in future DS trials will provide a technologically novel method for use in the home and classroom setting that has the potential to detect treatment-related changes in daily life, changes that may not be adequately captured by laboratory tests or retrospective caregiver questionnaires and interviews.
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0.958 |