Genetic/Congenital/Developmental Condition

Longitudinal assessment of asymptomatic congenital CMV infection in Minnesota infants identified by universal screening: what is risk of sequelae?

Principal Investigator:

Mark Schleiss, MD (Department of Pediatrics)

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Collaborators:

Jed Elison, PhD (Institute of Child Development), Igor Nestrasil, MD, PhD (Department of Pediatrics), Erin Osterholm, MD (Department of Pediatrics)

Abstract:

Symptomatic congenital CMV (cCMV) infections are commonly encountered in clinical practice, affecting approximately 0.65% of all newborns. Such infections - in symptomatic newborns - carry a substantial risk for long-term neurodevelopmental sequelae including developmental delay, mental retardation, seizure disorders, cerebral palsy, and sensorineural hearing loss. Nucleoside antiviral therapy is associated with only modest improvements in audiological and neurodevelopmental outcomes. It is much less clear how to manage infants identified with asymptomatic cCMV infection. These infants have in the past essentially escaped clinical recognition, precisely because these children are asymptomatic at birth, and there is no universal newborn cCMV screen. However, the landscape of cCMV screening is rapidly evolving, and there is increasing interest in implementation of universal cCMV screening programs.  In spite of recent progress, universal newborn screening for congenital CMV in many ways remains an area of scientific uncertainty. The optimal screening methodology remains uncertain. We don’t know if asymptomatic infants should undergo full laboratory and neuroimaging evaluations, or whether treatment of infants with asymptomatic congenital CMV with antivirals should be considered. Our proposal will conduct neurocognitive and neuroimaging studies in asymptomatic infants identified with congenital CMV infection in the context of a universal screening program to address these important areas of knowledge deficit. 

Longitudinal studies in MPS disorders: a multicenter study of the lysosomal disease network, longitudinal studies of brain structure and function in MPS disorders

Principal Investigator:

Chester B. Whitley, PhD, MD (Department of Pediatrics)

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Abstract:

The purpose of this study is to examine the changes in the central nervous system over time in patients with MPS I, II, IV, VI, and VII in both structure and function. We have determined that localization in the brain of abnormal cognitive and behavioral attributes varies by the type of MPS disorder. We will be examining how changes in the brain over time reflects the natural course of the disease or the effects of past or currently administered treatment such as hematopoietic cell transplant, systemic enzyme replacement or intrathecal enzyme replacement.

We hypothesize that specific and localized neuroimaging, neuropsychological and neurobehavioral findings and their relationship will be distinct for each MPS disorder. Further, without appropriate treatment, functions will decline and structure will change over time specific to each disease and stage of disease. We hypothesize that treatments such as ERT, HCT, HCT+ERT, and palliative and rehabilitation therapies, will differentially affect brain structure, functions and quality of life. Finally, we hypothesize that for each MPS type, variables such as age at first treatment, severity of disease, medical events related and unrelated to the disease, mutation, family and environmental factors, sensory abnormalities, and sociodemographic variables will influence brain functional and structural outcomes as well as quality-of-life.

Microstructural and functional MRI signatures of brain alterations in patients with mucopolysaccharidosis

Principal Investigator:

Igor Nestrasil, MD, PhD (Department of Pediatrics)

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Collaborators:

Julie Eisengart, Phd, LP (Department of Pediatrics)

Abstract:

We intend to employ a non-invasive technique using brain magnetic resonance imaging (MRI) along with analysis of microstructural and functional MRI signatures of these regions to measure and determine the alterations and their impact on clinical variability in mucopolysaccharidosis (MPS) patients. The study aims to identify the neuronal and functional signatures in MPS patients who have been scanned longitudinally. To accomplish this aim, we have established MRI parameters for detection of abnormalities in myelin content, microstructural integrity, and functional connectivity in the brain of MPS patients. The study also aims to determine the role of myelin abnormalities in cognitive deterioration in MPS subjects by relating comprehensive neurocognitive assessments to their respective MRI outcomes.

Neurobehavioral functioning in youth

Principal Investigator:

Christine Conelea, PhD (Department of Psychiatry)

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Collaborators:

Suma Jacob, MD, PhD (Department of Psychiatry)

Abstract:

Despite the recognition of high comorbidity rates and overlapping features among neurodevelopmental disorders, studies assessing neurocognitive functioning have typically only included youth within one diagnostic category (e.g., compare ASD vs. healthy controls). The current study will use a transdiagnostic approach to examine patterns of neurocognitive functioning in a sample of youth with a variety of neurodevelopmental disorders (ASD, OCD, ADHD, and tic disorders (TDs)). Identifying patterns of neurobehavioral functioning in a diagnostically heterogeneous sample has the potential to improve our ability to match youth to appropriate treatments and to inform development of new treatments.

Neurodevelopmental effects of fetal alcohol exposure (CIFASD)

Principal Investigator:

Jeff Wozniak, Ph.D., L.P. (Department of Psychiatry)

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Collaborators:

Bryon Mueller, Ph.D. (Psychiatry), Christopher Boys, Ph.D. (Department of Pediatrics), Kelvin Lim, M.D. (Department of Psychiatry)

Abstract:

The long-term aims of this research are to understand the neurobiological abnormalities that underlie cognitive and behavioral deficits in children with prenatal alcohol exposure. Prior research has clearly demonstrated that children with Fetal Alcohol Syndrome (FAS) have characteristic abnormalities in both the structure and function of their brains. Individuals with FAS have lower intellectual functioning, attention deficits, problems with memory/learning, and difficulties with organization/planning. Much less is known about brain structure and function in children who have a less severe diagnosis within the category of Fetal Alcohol Spectrum Disorder (FASD). This is the diagnostic term applied to those who have been exposed to alcohol prenatally and show some cognitive deficits but do not show all of the classic physical features of FAS (such as delayed growth and unusual facial features). We will use Magnetic Resonance Imaging (MRI) and neurocognitive tests to assess brain abnormalities in children with FASD compared to control participants.

Neuromodulation augmented cognitive remediation to improve executive dysfunction in fetal alcohol spectrum disorder

Principal Investigator:

Jeffrey R. Wozniak, Ph.D., L.P. (Department of Psychiatry)

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Collaborators:

Christopher J. Boys, Ph.D. (Department of Pediatrics), Kelvin Lim, MD (Department of Psychiatry)

Abstract:

Prenatal alcohol exposure (PAE) has profound detrimental effects on brain development and, as a result, has permanent consequences for cognition, learning, and behavior. Individuals with Fetal Alcohol Spectrum Disorders (FASD) commonly have a range of neurocognitive impairments that directly lead to practical problems with learning, attention, working memory, task planning/execution, and decision making, among other areas of functioning. Despite the profound public health burden posed by FASD, there have been very few treatment studies of any sort in this population. Our group conducted the first randomized controlled trials of the nutrient choline as a neurodevelopmental intervention in 2-5 year old children with FASD, in which we demonstrated effects on sequential memory.  For older children, a very different neurodevelopmental target is needed, and for this we have narrowed our focus to “plasticity” (the brain’s ability to adapt).  We propose to conduct a novel pilot study to examine the effects of cognitive remediation training augmented with tDCS in children and adolescents with FASD. Functional magnetic resonance imaging will be collected to provide preliminary data of brain circuitry changes created by this intervention.

Pilot study of administration of intravenous laronidase following allogeneic transplantation for Hurler Syndrome (MT2009-20)

Principal Investigator:

Paul J. Orchard, M.D. (Department of Pediatrics)

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Collaborators:

Weston Miller, MD (Pediatric Blood and Marrow Transplantation), Lynda Polgreen, MD (Pediatric Endocrinology), Jakub Tolar, MD, PhD (Pediatric Blood and Marrow Transplantation)

Abstract:

Hurler Syndrome or mucopolysaccharidosis type I (MPS I), is a rare, genetic, storage disease of early childhood in which the affected individual cannot breakdown long chains of sugar molecules called mucopolysaccharides due to a lack of the enzyme (α-L-iduronidase). As a result, there is a build-up of these molecules, leading to cellular and organ failure. The effects of Hurler Syndrome are multi-systemic and the natural history of this disease culminates in death during early childhood. Currently, hematopoietic cell transplant (HCT) is used to slow or halt the progressive course of the disease; however, individuals often continue to struggle with orthopedic, sensory, growth, and cognitive difficulties as they age. Enzyme replacement therapy (ERT) has been found to be helpful in other types of the mucopolysaccharidoses (such as type II) as well as the less severe form of MPS I (Hurler-Scheie and Scheie Syndromes), but it has yet to be tried in individuals with Hurler Syndrome post-HCT. This is a single center pilot study in which recombinant α-L-iduronidase (Laronidase) will be given weekly for two years in 10 patients with Hurler syndrome who have previously been treated with HCT.

Pilot study of gait in mucopolysaccharidoses

Principal Investigator:

Igor Nestrasil, PhD (Department of Pediatrics)

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Collaborators:

Elsa Shapiro, PhD (Department of Pediatrics), John Anderson, M.D., Ph.D. (Department of Otolaryngology), Christopher Fuller (Department of Otolaryngology), Lynda Polgreen. M.D. (Department of Pediatrics)

Abstract:

Preservation of mobility is an emerging clinical challenge and is the main primary endpoint evaluated perpetually in clinical trials. The ability to obtain objective outcome measures, which are accurate as well as responsive and relevant to change in disease burden, is a crucial condition for the evaluation of both disease severity and treatment efficacy. We plan to develop a gait evaluation technique, which will provide an efficient non-invasive gait assessment that is reliable, and accurate. In this project, we will be examining gait difficulties in mucopolysaccharidoses (MPS). MPS are group of lysosomal storage disorders (LSDs) caused by specific enzyme deficiency. Impaired mobility is a symptom very frequently seen in MPS and has a significant impact on quality of life and functional abilities. The 6 minute walk test, which has been historically used in other MPS studies, depends on endurance, and motivation. Kinematic gait analysis, which we plan to employ will not depend on either and will yield quantitative data. We will also collect control data from healthy pediatric population. It bears a tremendous potential for future applications of the method. We plan to establish reference values which can be readily used to evaluate gait impairment in other disorders, e.g. rheumatoid arthritis, cerebral palsy, and can be used in related clinical studies. We expect that kinematic gait analysis as a robust quantitative tool holds a strong potential to replace fatiguing, strenuous, and mostly endurance measuring walk tests in future clinical trials.

Rett Syndrome: health and behavioral analyses

Principal Investigator:

Frank Symons, PhD (Department of Educational Psychology)

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Abstract:

Most widely available assessments of sensory processing and cognitive functioning rely on the participant’s ability to respond verbally or motorically to instructions or sensory stimuli. Individuals with Rett syndrome, as well as some other genetic syndromes, present with verbal and motoric deficits that make the administration of such assessments difficult or even impossible. Therefore, the development of novel or adapted methods for assessing cognitive functioning in this population is necessary. The primary aim of this protocol is to develop and test a modified Mullen Scales of Early Learning (MSEL) developmental test for populations with language and motor limitations. We will do so by implementing an adapted administration protocol and incorporating eye-tracking technology. The preservation of visual attention and eye gaze communication in individuals with Rett syndrome makes this population amenable to study using eye tracking paradigms. Integration of an eye tracker with a 128-channel EEG system, permits co-registration of eye position with the moment-by-moment transactions that take place in the brain, allowing for a passive assessment of cortical function.

Screening for profiles of risk associated with ASD and other emerging atypical phenotypes

Principal Investigator:

Jed Elison, PhD (Institute of Child Development)

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Collaborators:

Suma Jacob, MD, PhD (Department of Psychiatry), Amy Esler, PhD, LP (Department of Pediatrics), Jason Wolff, PhD (Department of Educational Psychology)

Abstract:

There is a great need for improved screening approaches and improved implementation of screening procedures to identify children who will need early intervention for ASD. New screening approaches are needed to capture the heterogeneity of the disorder(s), which includes identifying children who are likely to access services in the community even though they may not meet strict research criteria for an autism spectrum diagnosis.

In the current application, we propose to test a new screening approach that we refer to as pheno-screening.  We ask parents to complete online versions of standardized questionnaires that are designed to capture individual differences in highly dimensional traits relevant to the early emergence of clinically impairing behaviors that constitute ASD. We use data driven approaches to derive clusters or latent classes of children that represent a continuum of risk. Next, based on a given cluster’s profile, we invite children into the laboratory for direct phenotypic assessment that also includes measurement of biomarkers hypothesized to help us parse the heterogeneity of behavioral profiles encapsulated by an ASD diagnosis.  Improved screening procedures promise to advance early identification, and improved characterization of biomarkers associated with risk promises to advance new interventions designed to target specific mechanisms associated with behavioral symptomatology.

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