Interdisciplinary Investigation of Biological Signatures of Autism Subtypes

Summary

Principal Investigator: D G Amaral
Affiliation: University of California
Country: USA
Abstract: DESCRIPTION (provided by applicant): This application, entitled, Interdisciplinary Investigation of Biological Signatures of Autism Subtypes is in response to RFA-MH-09-170 titled, Recovery Act Limited Competition: Research to Address the Heterogeneity of Autism Spectrum Disorders (R01). There is near universal agreement that there are multiple biological subtypes of autism and each of these types may have a quite distinct etiology. A major roadblock to understanding the causes of the different types of autism, and ultimately to identifying preventions or best treatments for each type, is that there is currently no way to distinguish and parse one type of autism from another at diagnosis. What is the best strategy to deal with the heterogeneity of ASD? This application proposes to study a very large cohort of children with autism spectrum disorders (ASD) using a multidisciplinary analytic approach in order to identify biological signatures that define distinct phenotypes of autism. The proposal is an extension of a pilot project initiated at the M.I.N.D Institute called the Autism Phenome Project (APP). One hundred sixty preschoolers with ASD and with typical development (TD) have already received full medical evaluation, medical record review, environmental exposure assessment;blood based genetic and immune profiling, structural magnetic resonance imaging, EEG based studies of auditory processing and comprehensive developmental and neuropsychological evaluations. We have established, therefore, that the intensive bio-behavioral studies proposed in this project are entirely feasible. Moreover, preliminary data from the APP have already highlighted at least three biological signatures of autism phenotypes. These include: (1) the presence of auto antibodies to GABAergic neurons which are observed in 21% of ASD children and 0% of TD (maternal antibodies and cytokine profiles are additional putative immune biosignatures);(2) abnormal auditory evoked potential responses (4 distinct response profiles have been observed) and (3) abnormal brain size (evidence is accumulating for both enlarged and small brains and frontal lobes). Having accomplished the pilot phase of this project and obtaining assurance that all procedures are feasible and well tolerated, we are ready to complete Phase 1 of this project. This will complete ongoing recruitment of 250 children with autism and 150 age-matched controls. This is a sufficiently large number to realistically expect to identify several subtypes of autism. All children will undergo the comprehensive multidisciplinary analyses described previously. Blood samples, DNA and RNA will be banked for future studies. We will establish a new data management and biostatistician group to organize and analyze data and transfer it to NDAR. Not only will this research program accomplish a unique, in depth analysis of a very large cohort of young children with autism and age-matched controls, but it will also provide the substrate for future longitudinal studies aimed at determining how early biological signatures of autism predict subsequent behavioral, biological and medical outcomes. It will also foster effective prevention and treatment research. PUBLIC HEALTH RELEVANCE: Autism is a neurodevelopment disorder that occurs in as many as 1 in 150 children and a major roadblock to preventing and more adequately treating autism is that there are many causes and many types. It is currently impossible to determine what type of autism a child has at diagnosis so in order to solve this problem;we will study the biology of a large number of children with autism to identify biological signatures of different types of autism. We already have strong evidence for at least an autoimmune type of autism and this research will lead to more effective efforts at preventing future cases of autism and treating existing children with autism.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder
    Christine Wu Nordahl
    The M I N D Institute, University of California at Davis, School of Medicine, Sacramento, CA 95817, USA
    Brain Behav Immun 30:61-5. 2013
  2. doi Myeloid dendritic cells frequencies are increased in children with autism spectrum disorder and associated with amygdala volume and repetitive behaviors
    Elizabeth Breece
    Department of Medical Microbiology and Immunology, University of California, Davis, USA
    Brain Behav Immun 31:69-75. 2013
  3. pmc Levels of soluble platelet endothelial cell adhesion molecule-1 and P-selectin are decreased in children with autism spectrum disorder
    Charity E Onore
    Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
    Biol Psychiatry 72:1020-5. 2012
  4. pmc Increased rate of amygdala growth in children aged 2 to 4 years with autism spectrum disorders: a longitudinal study
    Christine Wu Nordahl
    MIND Institute, University of California, Davis, School of Medicine, Sacramento, CA 95817, USA
    Arch Gen Psychiatry 69:53-61. 2012
  5. pmc Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders
    Christine Wu Nordahl
    Department of Psychiatry and Behavioral Sciences, Medical Investigation of Neurodevelopmental Disorders Institute, UC Davis School of Medicine, University of California, Sacramento, CA 95817, USA
    Proc Natl Acad Sci U S A 108:20195-200. 2011
  6. pmc The role of immune dysfunction in the pathophysiology of autism
    Charity Onore
    Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
    Brain Behav Immun 26:383-92. 2012
  7. pmc Detection of plasma autoantibodies to brain tissue in young children with and without autism spectrum disorders
    Christy C Rossi
    Department of Psychiatry and Behavioral Sciences, University of California, Davis, CA, United States
    Brain Behav Immun 25:1123-35. 2011
  8. pmc Brief report: symptom onset patterns and functional outcomes in young children with autism spectrum disorders
    Stacy Shumway
    Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892 1255, USA
    J Autism Dev Disord 41:1727-32. 2011
  9. pmc The promise and the pitfalls of autism research: an introductory note for new autism researchers
    David G Amaral
    Department of Psychiatry and Behavioral Sciences, The MIND Institute, University of California, Davis, Sacramento, CA 95817, USA
    Brain Res 1380:3-9. 2011

Scientific Experts

  • D G Amaral
  • Stacy Shumway
  • Christine Wu Nordahl
  • Paul Ashwood
  • Sally J Rogers
  • Sally Rogers
  • Elizabeth Breece
  • JUDY A VAN DE WATER
  • Charity Onore
  • Charity E Onore
  • Sally Ozonoff
  • Aaron Lee
  • Judy Van de Water
  • Michael H Buonocore
  • Christy C Rossi
  • Brian Paciotti
  • Daniel Braunschweig
  • Ana Maria Iosif
  • Gregory S Young
  • Tony Simon
  • Milo Careaga
  • Xiaowei Yang
  • Robert Scholz
  • Deana D Li
  • Lou Ann Barnett
  • Nicholas Lange
  • Tony J Simon

Detail Information

Publications10

  1. pmc Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder
    Christine Wu Nordahl
    The M I N D Institute, University of California at Davis, School of Medicine, Sacramento, CA 95817, USA
    Brain Behav Immun 30:61-5. 2013
    ..These results suggest that maternal autoantibodies associated with autism spectrum disorder may impact brain development leading to abnormal enlargement...
  2. doi Myeloid dendritic cells frequencies are increased in children with autism spectrum disorder and associated with amygdala volume and repetitive behaviors
    Elizabeth Breece
    Department of Medical Microbiology and Immunology, University of California, Davis, USA
    Brain Behav Immun 31:69-75. 2013
    ..These data further implicate innate immune cells in the complex pathophysiology of ASD...
  3. pmc Levels of soluble platelet endothelial cell adhesion molecule-1 and P-selectin are decreased in children with autism spectrum disorder
    Charity E Onore
    Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
    Biol Psychiatry 72:1020-5. 2012
    ..Findings of immune dysfunction in ASD include increases in inflammatory cytokines, chemokines, and microglial activity in brain tissue and cerebrospinal fluid, as well as abnormal peripheral immune cell function...
  4. pmc Increased rate of amygdala growth in children aged 2 to 4 years with autism spectrum disorders: a longitudinal study
    Christine Wu Nordahl
    MIND Institute, University of California, Davis, School of Medicine, Sacramento, CA 95817, USA
    Arch Gen Psychiatry 69:53-61. 2012
    ..Precocious amygdala enlargement is commonly observed in young children with autism. However, the age at which abnormal amygdala enlargement begins and the relative growth trajectories of the amygdala and total brain remain unclear...
  5. pmc Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders
    Christine Wu Nordahl
    Department of Psychiatry and Behavioral Sciences, Medical Investigation of Neurodevelopmental Disorders Institute, UC Davis School of Medicine, University of California, Sacramento, CA 95817, USA
    Proc Natl Acad Sci U S A 108:20195-200. 2011
    ..For boys with regressive autism, divergence in brain size occurs well before loss of skills is commonly reported. Thus, rapid head growth may be a risk factor for regressive autism...
  6. pmc The role of immune dysfunction in the pathophysiology of autism
    Charity Onore
    Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
    Brain Behav Immun 26:383-92. 2012
    ....
  7. pmc Detection of plasma autoantibodies to brain tissue in young children with and without autism spectrum disorders
    Christy C Rossi
    Department of Psychiatry and Behavioral Sciences, University of California, Davis, CA, United States
    Brain Behav Immun 25:1123-35. 2011
    ..Children whose plasma was immunoreactive with neuronal cell bodies scored higher on multiple CBCL scales. These studies indicate that additional research into the genesis and prevalence of brain-directed autoantibodies is warranted...
  8. pmc Brief report: symptom onset patterns and functional outcomes in young children with autism spectrum disorders
    Stacy Shumway
    Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892 1255, USA
    J Autism Dev Disord 41:1727-32. 2011
    ..Findings indicate that current functioning does not differ according to onset pattern, calling into question the use of onset categorizations for prognostic purposes in children with ASD...
  9. pmc The promise and the pitfalls of autism research: an introductory note for new autism researchers
    David G Amaral
    Department of Psychiatry and Behavioral Sciences, The MIND Institute, University of California, Davis, Sacramento, CA 95817, USA
    Brain Res 1380:3-9. 2011
    ..This short article provides a brief overview of some of the achievements and some of the difficulties in conducting autism research...