IACC Subcommittee for Basic and Translational Research Planning Group for Question 2 Conference Call - October 12, 2012
|Date:||Friday, October 12, 2012|
|Time:||3:00 p.m. to 4:00 p.m. Eastern|
|Agenda:||The planning group for Question 2 will discuss updates for the IACC Strategic Plan.|
|Place:||No in-person meeting; conference call only|
|Conference Call:||Dial: 877-951-7311
Access code: 7303505
|Contact Person:||Ms. Lina Perez
Office of Autism Research Coordination
National Institute of Mental Health, NIH
6001 Executive Boulevard, NSC, Room 6182A
Rockville, Maryland 20852
Phone: (301) 443-6040
|Please Note:||For call-in issues, dial *0 so that an operator may assist you.
Schedule subject to change.
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No in-person meeting; conference call only.
|3:00 p.m.||Roll Call and Opening Remarks
Walter Koroshetz, M.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Chair, Basic and Translational Research Question 2 Planning Group
Gemma Weiblinger – Designated Federal Official
National Institute of Mental Health (NIMH)
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The Interagency Autism Coordinating Committee (IACC) Subcommittee for Basic and Translational Research Strategic Plan Question 2 Planning Group convened a conference call on Friday, October 12, 2012.
In accordance with Public Law 92-463, the meeting was open to the public. Walter Koroshetz, M.D., Chair, presided.
Thomas Insel, M.D., Chair, IACC, National Institute of Mental Health (NIMH); Walter J. Koroshetz, M.D., Chair, National Institute of Neurological Disorders and Stroke (NINDS); Gemma Weiblinger, M.A., Designated Federal Official, (NIMH); David Amaral, Ph.D., University of California, Davis; Elizabeth Baden, Ph.D., Office of Autism Research Coordination (OARC), (NIMH;) Carlos Pardo-Villamizar, M.D., Johns Hopkins University; Kate Saylor, M.S., (NINDS) (assisting Walter Koroshetz)
Welcome and Discussion
Ms. Gemma Weiblinger welcomed participants to the teleconference on Question 2 of the Strategic Plan update (How can I understand what's happening?) Dr. Walter Koroshetz noted that during the previous call, the Group had identified subtopics under this question. Each subtopic was assigned to Group members. They submitted drafts that included the most important research items from the last year and new research gaps that they had identified. The purpose of this call was to discuss these draft sections to gain a sense of the major advances and the new gap areas.
Dr. Koroshetz began the discussion with his draft on "advances in understanding the molecular mechanisms of autism and clinical phenotypes." He reviewed several high-profile research articles on the underlying biological effects of genetic findings in autism. He also discussed research on transcriptome analysis of brain tissue. Dr. Koroshetz noted that several studies overlapped with the subtopics covered by Dr. Carlos Pardo-Villamizar. Dr. Pardo-Villamizar said that the work on the transcriptome analysis of brain tissue might belong in the molecular pathways topic, and also could be highlighted as part of the connection between the immune system and brain function. Dr. Koroshetz said that as the overall draft document was developed, they would combine these ideas.
Next the Group discussed the importance of postmortem samples for advancing autism research. It was noted that some recent work highlighted the importance of analyzing genetic changes in the autistic brain rather than in peripheral tissue. Dr. Thomas Insel said that it was important to emphasize the critical need for more and better tissue and standardized collections of tissue. This was an urgent need because research continued to show that there were gene expression differences in the brain that had not been seen in the blood, he said.1, 2 The increasing number of published papers in other areas suggested that the most important signals did not come from blood samples. The Group noted that this topic should be included as a new research gap.
Dr. Pardo-Villamizar discussed biomarkers and immunity. He said that there had been few publications on biomarkers in the last year. Many of the studies were limited due to small population sizes. These were unvalidated studies. However, there had been more progress on immunological factors, mainly in animal models. The most important and prominent contribution in the last year was the additional demonstration that microglia played a critical role in the building of the cortical organization and neuronal connectivity in the brain. Dr. Pardo-Villamizar said that the work of Beth Stevens, Ph.D., would be the most important to include.
Regarding adaptive immunity, Dr. Pardo-Vallamizar said that animal model work by Paul H. Patterson, Ph.D. – published recently in the Proceedings of the National Academy of Sciences – highlights the roles of maternal and environmental factors.3 The immunological activation in mothers that may influence the immunological outcome in the littermate or in the offspring4 was of particular interest. It was noted there was interest in the idea that the maternal environment and immunological challenge eventually may affect brain development and future behavior.
Dr. Pardo-Villamizar mentioned several other studies that should be considered for inclusion within this subtopic, such as passive transfer of maternal autoantibodies and behavioral abnormalities.5 It was noted that the assessment of the fetal immune system and the neonate immune system should be included as a research gap.
Dr. David Amaral reviewed research on brain structure using MRI, which was an area of active research. One trend was to look for potential early alterations in the brains of children with autism compared with their nonaffected siblings. Dr. Amaral said that new imaging techniques were allowing researchers to look at the integration of many brain regions at the same time – large networks of fiber connections – that were associated with the diagnostic features of autism. Investigators also were using imaging with larger sample sizes, in order to define neural phenotypes. Some work in this area indicated that one of the common features of altered morphology of autism is precocious brain growth,6, 7 said Dr. Amaral.
In terms of neuropathology, it was noted that in one study brains of individuals with autism had an increased number of neurons and also an increased brain weight compared with control brains.8 However, other research had shown no difference in the numbers of neurons in the frontal lobes of individuals with autism. The Group agreed that this topic should be considered a gap area because of conflicting data on neuron growth. Importantly, it was noted that without adequate tissue to replicate these studies and conduct additional ones with larger sample sizes, it would be difficult to gain clarity on the cellular pathology of autism.
Dr. Amaral also discussed clinical subtypes of ASD. Recent work has supported the existence of a phenotype with a regressive trajectory that appeared to take place at about the end of the second year. This autistic phenotype needed to be better understood, he said. The Group also discussed several studies on macrocephaly and neuron count. Comorbid developmental delay appeared to be decreasing with time, and would an important topic to include in the draft as well.
Dr. Dennis Choi described research on ASD and concurrent epilepsy, a ketoacid dehydrogenase kinase mutation, protocadherin proteins. There was also mention of research on the overlap of ASD and gastrointestinal (GI) disturbances, and also changes in sleep architecture in children with autism. Dr. Insel noted that one of the objectives in the Strategic Plan addressed underlying biological mechanisms of co-occurring conditions.
Dr. Koroshetz discussed neurocircuitry (based on Dr. Kevin Pelphrey's synopsis of important recent research). He mentioned research on disruption in synchronized activity across circuits for social information and processing, and eye tracking and clinical outcomes.9 In terms of sex differences, recent research indicated that the diagnosis of ASD was less common in women and girls in the absence of additional intellectual or behavioral problems.10 Studies of females with ASD were needed to analyze genes, brains, and behavior. The Group also noted that there was a lack of longitudinal studies of brain function. In particular, it was suggested that a paper on the use of induced pluripotent stem cells to determine phenotypes of Timothy syndrome should be highlighted, 11 as it signaled a new direction for the screening of novel therapeutics.
Dr. Insel noted that it would be helpful to quantify the number of publications in a subtopic whenever possible. He outlined the next steps in the process – how comments and changes would be incorporated into the document.
The call was adjourned.
I hereby certify that this meeting summary is accurate and complete.
/Susan Daniels/ November 16, 2012
Susan A. Daniels, Ph.D.
Executive Secretary, Interagency Autism Coordinating Committee
1 Sullivan PF1, Fan C, Perou CM. Evaluating the comparability of gene expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet. 2006 Apr 5;141B(3):261-8. [PMID: 16526044]
2 Rollins B1, Martin MV, Morgan L et al. Analysis of whole genome biomarker expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet. 2010 Jun 5;153B(4):919-36. [PMID: 20127885]
3 Hsiao EY, McBride SW, Chow J et al. Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12776-81. [PMID: 22802640]
4 Malkova NV, Yu CZ, Hsiao EY et al. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun. 2012 May;26(4):607-16. [PMID: 22310922]
5 Braunschweig D, Golub MS, Koenig CM et al. Maternal autism-associated IgG antibodies delay development and produce anxiety in a mouse gestational transfer model. J Neuroimmunol. 2012 Nov 15;252(1-2):56-65. [PMID: 22951357]
6 Chawarska K, Campbell D, Chen L et al. Early generalized overgrowth in boys with autism. Arch Gen Psychiatry. 2011 Oct;68(10):1021-31. [PMID: 21969460]
7 Hazlett HC, Poe MD, Gerig G et al. Early brain overgrowth in autism associated with an increase in cortical surface area before age 2 years. Arch Gen Psychiatry. 2011 May;68(5):467-76. [PMID: 21536976]
8 Courchesne E, Mouton PR, Calhoun ME et al. Neuron number and size in prefrontal cortex of children with autism. JAMA. 2011 Nov 9;306(18):2001-10. [PMID: 22068992]
9 Elsabbagh M, Mercure E, Hudry K, Chandler S et al. Infant neural sensitivity to dynamic eye gaze is associated with later emerging autism. Curr Biol. 2012 Feb 21;22(4):338-42. [PMID: 22285033]
10 Dworzynski K, Ronald A, Bolton P et al. How different are girls and boys above and below the diagnostic threshold for autism spectrum disorders? J Am Acad Child Adolesc Psychiatry. 2012 Aug;51(8):788-97. [PMID: 22840550]
11 Pasca SP, Portmann T, Voineagu I et al. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med. 2011 Nov 27;17:1657-62. doi: 10.1038/nm.2576 [PMID: 22120178]
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- Meeting Transcript (PDF - 76 KB)