THE AUTISM TISSUE PROGRAM - AN ESSENTIAL RESOURCE TO FIND THE CAUSES OF AUTISM
Connie Frenzel, MS, RN
Jane Pickett, PhD
Autism Tissue Program
Princeton, New Jersey, USA
Contact: Denise Soto
Email: dsoto@autismspeaks.org
Date First Published: April 2, 2007
Date Last Updated: April 2, 2007
While autism is known to be a neurological disorder affecting the functioning of the brain, relatively little is known about how the brain works on a cellular and molecular level. Brain research is needed which allows for the causes of autism to be better identified and better treatments to be developed. Brain tissue donation is a valuable contribution to mental health research. It enables scientists to investigate how the normal brain works, and how the brain is disturbed when it is affected by autism and autism spectrum disorders. Investigating brain tissue enables scientists to better understand the biochemical, structural and genetic mechanisms of brain cell development and maturation, as well as discover interactions between genetic and environmental triggers which may have occurred during gestation or after birth.
The Autism Tissue Program (ATP) was established in 1998 to help educate the public on the importance of brain tissue donation, and to facilitate donations through partnering brain banks. Because of the ATP, more than 120 families have donated autistic brain tissue to the program, 60 independent research projects have been launched worldwide, and 41 studies have been published utilizing ATP brain tissue. So far, over 20,000 people have registered to donate with the Autism Tissue Program, either directly through ATP or through the Iowa Donor Registry. In Iowa, brain donation is listed as an option on their online state donor registry. Without the national campaign conducted by ATP to encourage brain donation, this would not have been possible.
Since its inauguration in 1998, ATP has been the only program dedicated to increasing the availability of postmortem brain tissue for autism research and reducing the duplication of outreach efforts between research organizations to ensure efficient use of autistic brain tissue. Each donation is included in up to 20 research projects so that this precious resource is used responsibly and effectively.
What We Have Learned From Brain Tissue
Specific neurotransmitters tied to disease:
Gene Blatt and his lab at the Laboratory of Autism Neuroscience Research at Boston University have been studying altered communication of cells which use GABA as their main chemical of communication. GABA is a neurotransmitter (brain chemical) that “turns off” brain cells and appears to be produced at abnormal levels in the cerebellum of autistic patients. The GABA system acts as a type of filtering system. One study demonstrated that there are fewer than expected numbers of receptors for GABA in the cerebellum of autistic patients—further demonstrating a dysregulation of GABA activity in autism. On the other hand, new research from the Blatt lab has shown that in the hippocampus, an area of the brain which helps form memories, GABA containing cells are more densely packed. This suggests that the hippocampus and the cerebellum may be vulnerable to a disruption in circuits due to impaired communication between these areas and other parts of the brain.
"As we begin to understand the GABA system as it relates to the neurological underpinnings of autism, we may advance toward new therapies," says Michael Cuccaro, PhD, who is another autism researcher at Duke. Andy Shih, Chief Science Officer of Autism Speaks, states “One hope is that research into the role of GABA will lead to medications that can lessen or prevent many of the symptoms of autism in a subgroup of people with the disorder.”
These findings are important because changes in GABA transmission are the targets of many pharmacological treatments for autism and epilepsy. Specific anti-epileptic medications already focus on the GABA system. A better understanding of how GABA neurons are organized and function in the autistic brain will lead to better pharmacological therapies for autism. Furthermore, these functional studies have implications for current and future treatments and suggest that altered communication between nerve cells is the result of impaired signaling of this neurotransmitter.
Changes in cell number in brain regions important for social behavior:
Using computer-aided counting methods, David Amaral, Research Director at the UC Davis M.I.N.D. Institute, and Cynthia Mills Schumann, a researcher at UC Davis, counted and measured neurons in the amygdala of autistic and normal postmortem brains. The amygdala is an area of the brain that is associated with emotions, memory, and fear-related responses. They found significantly fewer neurons in the lateral nucleus of the amygdala in the brains of people with autism. This groundbreaking study was funded by Autism Speaks using brain tissue provided by the Autism Tissue Program. Published in the Journal of Neuroscience, it expanded upon previous studies which found that the amygdala of young adolescents with autism spectrum disorders was larger than that of normal individuals of the same age. The results of this study may explain why individuals with autism often respond with fear to faces and in social settings. Earlier studies of the amygdala were hampered because many postmortem brains available for research were from individuals who had autism and epilepsy, a condition known to cause pathology of the amygdala.
“Back when these studies were conducted, it wasn’t easy to acquire the brain of a deceased person who had only autism,” Amaral explained. “We are fortunate now to have the Autism Tissue Program. With their help, we were able to analyze more than double the number of previously examined postmortem brains, none of which had seizure disorders or any major neurological disorder other than autism.”
Markers for oxidative stress may indicate immune dysfunction
Dr. Diana Vargas and her colleagues at Johns Hopkins University have found elevated markers for oxidative stress in the frontal cortex and cerebellum, which may stem from inflammation in the brain. Oxidative stress is a biochemical process that, when not regulated properly, can lead to nerve cell dysfunction and sometimes cell death. Because the frontal cortex is responsible for higher cortical functions such as impulse control, as well as planning and executing complex behavior, dysfunction in this brain region has direct implication for individuals with autism.
Immunological changes have been observed in the blood and other tissues of individuals with autism, but the effects on the brain have not been clear. These results suggest that an inflammatory mechanism controlled by the immune system may have damaging effects to brain tissue. Further research on what causes these changes in the immune system and how it can be controlled effectively and safely will lead to better treatments.
Where Are We Going -- New Studies Using New Technologies
A new ground breaking technology is being used by Dr. Philip Schwartz at Children's Hospital of Orange County (CHOC) to study neurodevelopmental disorders with autism as the current focus. This innovative technology utilizes neural progenitor cells found in the post-mortem brain. These cells are then inserted into growth medium and grown in tissue culture dishes. The cells will mature into various types of brain cells in the laboratory. Dr. Schwartz will distribute these cells to scientists for studies to understand the autistic brain. The widespread availability of this ‘open source’ of brain neural progenitor cells will speed progress in the field. Previously, scientists have been unable to study living cells from autistic brain tissue, therefore this study is the first of its kind which will provide scientists resources to better understand how the development of the brain cell in those affected with autism is altered. Dr. Schwarz quotes: “When examining a cell line, if we understand what happened and when, how and where the cells started to change, then we will have the answer to the underlying cause, such as excessive protein levels, gene mutations or chemical environmental triggers.’’
Collaboration and Data Sharing Accelerate Research
Collaboration and data sharing among scientists is critical to accelerating research and unlocking the mysteries of this puzzling disorder. The Autism Tissue Program provides and maintains an important centralized resource for the scientific community for sharing data as well as promoting data driven research. The ATP Informatics Portal, a web-accessible database, can be found at www.atpportal.org. This information network is critical for managing the donation registrants as well as providing important information on the autism donor cases and combined autism, autism relatives, and control donors. Without this information on the donor and the family, scientists would not be able to pinpoint the nature of the neurobiology with the function. Information is partially obtained from the ADI-R (Autism Diagnostic Interview) and other research questionnaires which are administered by the ATP Clinical Coordinator with donor families. This information is essential for researchers who are studying subtypes of autism and linking behavioral dysfunctions with specific neurological impairments. This sort of analysis will bring science even farther in determining what causes this devastating disorder.
Future Studies on the Horizon
Further studies are planned by Dr. Amaral and colleagues at the MIND Institute to follow up on the recent evidence of pathology in the amygdala in a person with autism. “We need to look at other brain regions to find out if the cell loss is idiosyncratic to the amygdala or a more general phenomenon,” Amaral states. “We’re in the very early stages of understanding autism and its neurological pathologies. It’s clearly a process with many steps, and at least we are now one step further." Said Cynthia Mills Schumann, "One possibility is that there are always fewer neurons in the amygdala of people with autism. Another possibility is that a degenerative process occurs later in life and leads to neuron loss. More studies are needed to refine our findings.”
The General Public and the Autism Community Are Essential
We are excited to collaborate with the Interactive Autism Network. Both IAN and ATP hope to create partnerships between researchers and parents/families, to help parents understand the research process, to educate them about current research projects, and to interpret current research results. We hope to partner with families and ask families who want to be involved to register as a potential brain donor in the event of death. This is a national campaign against a mystifying disorder. By working with advocates in Autism Speaks chapters, ASA chapters, other autism organizations, autism centers, schools, clinics, organ procurement organizations, and with medical examiners, we hope to notify potential donors and their families of the importance of brain tissue donations and provide support to families having to make such difficult decisions.
How to Donate or Register
Complete information and secure online registration for future donation is available on the ATP website, http://www.autismstissueprogram.org. The hotline at 1-877-333-0999 may also be contacted for further information or materials regarding the program. This program, which links families, brain tissue donors, and autism researchers, is based on hope, commitment and trust. We welcome IAN’s support in helping to provide scientists with this precious research tissue which has the significant potential to change the course of autism research and treatment.
References
Blatt, G.J., Thevarkunnel, S., Antzoulatos, E., Van Sluytman, G., Bauman, M.L,, Kempber, T.L. (2006) Decreased GABA-A receptor density in the anterior cingulated cortex in autism. International Society for Autism Research, Montreal, CA. PS2.1
Lawrence, Y.A.,, Kemper, T.L., Bauman, M.L. and Blatt, G.J. (2006) Density of parvalbumin, calbindin-D28K and calretinin immunoreactive interneurons in the hippocampus in autism. International Society for Autism Research, Montreal, CA. PS2.2.
Schumann, C.M., & Amaral, D.G. (2006). Stereological analysis of amygdale neuron number in autism. Journal of Neuroscience, 26, 7674-7679.
Simms, M.L., Kaplan, H.B., Kemper, T.L., Bauman, M.L., & Blatt, G.J. (2006). Neuronal cell packing density and cell size in the anterior cingulate cortex of the autistic brain. International Society for Autism Research, Montreal, CA. PS2.4.
Thevarkunnel, S., Antzoulatos, T., Gibbs, T.T., Marcon, R.G, Bauman, M.L., Kemper, T.L., & Blatt, G.J. (2006). Altered GABA-A receptor binding in the posterolateral cerebellar hemisphere in autism. International Society for Autism Research, Montreal, CA. PS2.5.
