Session 7: Autism Brain Tissue Panel-Progress and Future Strategies
Jane Pickett, Ph.D.
The Autism Society of America (ASA) Foundation and National Alliance for Autism Research (NAAR) are pleased to participate in this NIH/ACC conference on autism neuropathology. Brain tissue research has become an integral part of autism research and interest in studying donated brain tissue is increasing in other countries as well as in the U.S.
The Tissue Issue panel is an opportunity to explore various aspects of tissue research from the point of view of the investigator and look for ways to improve and coordinate research opportunities. Members of the panel expect that issues will come up throughout the conference as results of tissue research are discussed or investigators look to brain tissue to answer questions from other studies.
If we are to end up with a document at the end of the conference with recommendations to the NIH/ACC, it seems useful to begin by outlining some of the issues of brain tissue acquisition and research. Many of the issues relate to the operation of the Autism Tissue Program (ATP)1, launched in 1998 to: 1) promote national awareness of the importance of brain tissue donation for the purpose of autism biomedical research; 2) maintain a central database of registrants and available tissue; 3) act as a clearinghouse for the identification of existing tissue and fair and equitable distribution to investigators through a Tissue Advisory Board (TAB); and 4) inform the autism community of research progress and findings.
- Outreach and education: Target groups have been ASA chapters, advocacy organizations, physicians, educators, medical examiners, clinicians and researchers with populations of subjects or patients. Organ donor national programs like the Association of Organ Procurement Organizations, AOPO, and donor registry publicity promotes donation of everything but brain tissue in spite of increased mortality rates in autism2. The new Secretary of HHS, Tommy G. Thompson, recently announced plans to "launch a national campaign to raise awareness of organ donation in this country". The Health Resources and Services Administration (HRSA) will organize a national forum later this year on the potential of registries, the options available, and guidelines for registry development. Can we get brain tissue donation on the agenda? What about help to coordinate with the National Center for Research Resources? Are there legislative options?
- Acquisition and Tissue Protocols: Tissue processing protocols need to serve the researcher - that means that the Tissue Advisory Board needs input on a regular basis about current and future projects from scientists. Typically the Autism Tissue Program gets ME cases, all fixed tissue - otherwise tissue is half fixed, half frozen and sent to the banks. Given the fact that autism deaths are largely unexpected, how do we improve tissue quality? Reduce PMI?
- Repositories: We now have multiple repositories because of multiple NIH banks. Having 'regional' banks increased donations but would one recognized 'autism' bank work just as well, standardize tissue processing and make distribution easier? Should banks also be active research sites, train fellows, etc.?
- Donor information: The ADI-R is routinely done and a summary report written outlining past evaluation information on the donor and typical behaviors. These are saved as documents on file by case number. ADI-R raw data is put into the ISAAC web database at http://www.autismtools.org/. The family questionnaire includes autism subtyping questions about symptoms and co-morbid conditions. There is an interest in including the Family History Interview used by the CPEAs to provide more standardized information. What methods are currently in use for relating autism domain information from the ADI-R and other instruments to cell and molecular findings?
- Reporting requirements and research findings: Datasharing and databanking issues need to be addressed. What information (experimental findings) should we be gathering on cases and how should it be stored? Accessed? What about tissue already processed - the library concept for secondary research opportunities? How can we best support collaborations and maintain scientific independence and attract new investigators?
- Distribution: There are more requests for tissue all the time; some wanting whole brains for systematic histology or comprehensive genetics studies to answer autism questions. Recommendations on future directions of research from this conference is important input for the Tissue Advisory Board as well as public and private funding agencies.
- Post-mortem MRI: Stronger magnets present the possibility of high resolution; how do we weigh the benefits with the necessity of sectioning brains for the images? Who can judge the techniques? How many labs will image a given brain and what is the requirement of the investigator who does the imaging?
1The Autism Tissue Program (ATP) seeks to support and encourage the highest standard of autism spectrum disorders research, to ensure collaboration and cooperation at all levels, eliminate duplication of efforts, and assure that resources are used most efficiently. The website, www.brainbank.org, allows online registration and access to information by advocates and researchers. To date, there are over 2500 registrants, 26 brain donations and 17 concurrent neuropathology studies approved for tissue distribution by the TAB. Post-mortem MRI scans are routinely done at UC Davis and posted on ftp site there for access by investigators: brainshop.ucdavis.edu, login: anonymous; password: cns@@9.
The ATP is co-sponsored by the Autism Society of America (ASA) Foundation, the M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute at UC Davis, and the National Alliance for Autism Research (NAAR). The ATP is the recipient of a supplemental grant (RO1 MH31862-21S1) to the Harvard Brain Tissue Resource Center from NIMH and NINDS and networks with the NICHD developmental brain and tissue centers at the University of Maryland and University of Miami and Miami's consortium bank in California.
Current Research Projects Supported By Atp Resources
"A Microscopic Study on the Neuroanatomical Abnormalities of Language-related Cortical Areas in Autistic Patients". Principal Investigator: Jorge Prieto, M.D., Ph.D., University de Miguel Hernandez, Spain.
"Post-Mortem Neuroanatomical Evaluation of the Amygdaloid Complex in Autism". Principal Investigator: David G. Amaral, Ph.D., University of California, Davis.
"Role of Connectivity in Autism (Synaptogenesis)". Principal Investigator: Karen Weidenheim, M.D., Albert Einstein School of Medicine, New York.
"Neurochemical Studies on Infantile Autism". Principal Investigator: Raju Pullarkat, Ph.D., Institute for Basic Research in Developmental Disabilities, Staten Island, New York.
"Further Identification of Differential Gene Expression in Autism Brain Tissue". PI: Jonathan Pevsner, Ph.D., Kennedy Krieger Institute and Johns Hopkins School of Medicine, Maryland.
"Molecular Characterization of the Autistic Brain". Principal Investigator: Lap Ho, Ph.D., Mt. Sinai School of Medicine, New York.
"Growth Factor Expression in Autism". Principal Investigator: Deborah Lee, M.D., Ph.D., Tulane University, New Orleans, Louisiana.
"Gene Expression Profiling of Autism: Alterations in Temporal Lobe Profiles". Principal Investigator: Scott Hemby, Ph.D., Emory University, Atlanta, Georgia.
"The Roles of Neuro-Regulatory Proteins Reelin and BCl-2 in Autism". Principal Investigator: S.H. Fatemi, M.D., Ph.D., University of Minnesota.
"Autism: developmental abnormalities in the cerebellum". Principal Investigator: Elizabeth Sajdel-Sulkowska, Ph.D., Harvard Medical School, Boston, Massachusetts.
"X Inactivation in Males and Females with Autism". Principal Investigator: Roger Stevenson, M.D., Greenwood Genetic Center, South Carolina.
"Structure of Cortical Layering, Cell Density, and Synaptic Spine Density in Individuals with Autism". Principal Investigator: Jeffrey Hutsler, Ph.D., University of Michigan, Ann Arbor, MI.
"Cholinergic Activities in Autism". Principal Investigators: Elaine Perry and Mandy Lee, Newcastle General Hospital, United Kingdom.
"Characterization of Genes Involved in the Etiology of Autism Spectrum Disorders". Principal Investigator: Jeanette Holden, Ph.D., Queen's University, Kingston, Ontario.
"Cell Adhesion Molecules in Cerebellum of Autistic Individuals". Principal Investigator: Omanand Koul, Ph.D., E. K. Shriver Center for Mental Retardation, Massachusetts.
"Cerebellar and Limbic System Research in Autism". Principal Investigator: Gene Blatt, Ph.D., Boston University School of Medicine, Massachusetts.
"Relating Autism to the Structure of Neocortical Minicolumns". Principal Investigator: Manuel Casanova, M.D., Medical College of Georgia.
2CAUSES of DEATH IN AUTISM. R.M. Shavelle,D.J. David J Strauss and J. Pickett. JADD (2001) in press.
The life expectancy of those with autism is of interest to parents, health professionals and service providers concerned with their lifetime needs. 13111 ambulatory Californians with autism were followed between 1983 and 1997. Observed numbers of cause-specific deaths were compared to numbers expected according to general population mortality rates. Standardized mortality rates (SMRs) were computed for each mental retardation level. Overall, children between the ages of 5 and 10 had the highest SMRs, especially girls with an SMR of 16.8. Further research is needed on why some causes are elevated, and on the male/female/age differences. Elevated death rates were observed for several causes, including seizures and accidents such as suffocation and drowning; elevated mortality due to respiratory disease was observed among persons with severe mental retardation. Overall, excess mortality was especially marked for persons with severe mental retardation, but life expectancy is reduced even for persons who are fully ambulatory and who have only mild mental retardation.
This study was supported by a generous donation by the East (San Francisco) Bay Autism Society of America Chapter.
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