Posted by Autism Speaks staffers Simon Wallace, Ph.D., director of scientific development for Europe; Dana Marnane, vice president of awareness and events; and Daniel Lightfoot, Ph.D., director of the Autism Tissue Program
Over the last week, we visited three European countries to explore partnerships with researchers and autism organizations. In particular we’ve been discussing Autism Speaks’ efforts in the areas of awareness, communication, our Global Autism Public Health (GAPH) initiative and the Autism Tissue Program (ATP).
Pulling our suitcases behind us, our first stop was in Stockholm, Sweden, where we met with Prof. Sven Bölte, of the Karolinska Institute for Neurodevelopmental Disorders, to discuss establishing an autism brain bank in Sweden.
As highlighted in a recent Nature article, one of the best ways for scientists to understand how autism affects brain development is by looking directly at the tissue. Just as diabetes researchers must study the pancreas, scientists studying developmental neurological conditions such as autism must study brain tissue. Already, research has revealed altered cell organization in brains affected by autism. This research can continue and progress only by increasing donations of this precious resource. Autism Speaks is working with its partnering brain bank in the UK to expand collections into other European countries.
From Sweden, we traveled to London and shifted our focus from scientific research to autism awareness. In recent years, Autism Speaks has led global awareness efforts through initiatives such as our Ad Council campaigns, World Autism Awareness Day, GAPH and Light it up Blue. The measurable success of these efforts has led to expanded partnerships with European organizations. During our London visit, this crystallized in a meeting with European parent organizations and other autism advocates.
Present at the meeting were representatives of Autism Europe (which includes over 80 member associations), Autistica, Autism France, the Celtic Nations Autism Partnership, London’s Centre for Research in Autism and Education, the Hungarian Autism Society and Irish Autism Action. We spent the day learning about each other’s campaigns and brainstorming ways to increase global autism awareness. Everyone was familiar with our Light it Up Blue initiative and were actively planning their increased participation in the year ahead. The overall feeling was that, together, we can accomplish so much more. We will continue exploring this fruitful partnership in the months ahead.
Next it was a short hop to Utrecht, in the Netherlands, at the invitation of Nederlandse Vereniging voor Autisme (NVA), the country’s national autism organization. Its staff and members were eager to learn more about GAPH and our international awareness initiatives. Our team also took this opportunity to explore the development of a brain tissue bank in the Netherlands, to match our efforts in the UK and Sweden.
A highlight from this visit was the Netherlands National Autism meeting, the first national meeting of Dutch autism families and their research community. As special guests, we heard about Dutch research examining the relationship between genes and behavior, autism prevalence, nutrition, the elderly and autism, enabling technology and an intervention for young people with autism to help them understand sexuality. Over the next few weeks we will be inviting some of these researchers to describe their studies on our science blog.
There is much we can learn by working together with our European partners, and our visit was an important step in forging closer collaborations involving science and awareness. Goodbye for now; hejdå and dag to our Swedish and Dutch friends!
A major roadblock to our understanding of autism is our lack of known biological markers for this condition. Biological markers for a condition such as autism can include gene alterations and other measurable biochemical changes in the cells and tissue of those affected. The discovery of such markers is a tremendous boon as they can guide research into the causes and treatments of autism. Indeed, these markers can themselves become targets for interventions.
In the search for autism biological markers, there is an exciting lead in a small duplication of a DNA segment associated with a rare neurodevelopmental condition with similarities to autism. Chromosome 15q duplication syndrome (“dup15q,” for short) demonstrates symptoms similar to that of autism, including developmental delays in speech, language and thinking, as well as challenges in behavior and sensory processing. At present, around 3% to 5% of individuals with autism spectrum disorder (ASD) have dup15q. In other words, they display a “linkage” between these two distinct conditions. By studying the biomarker for dup15q syndrome—that is, the duplicated segment of chromosome 15—researchers can gain key insights into both conditions.
Last month, the Chromosome 15q Duplication Syndrome Advocacy group (IDEAS) (http://www.dup15q.org/) held its annual meeting in Philadelphia. Of particular focus was the frequency with which dup15q patients also experience seizures. This co-diagnosis of epilepsy is of keen interest to autism researchers because the prevalence of epilepsy is likewise elevated among people with autism.
Among the presenters at the conference, Dr. Jerzy Weigel, of the New York State Institute for Basic Research in Developmental Disabilities, discussed neurological structural changes found in dup15q brains. This unique and important research was accomplished through the donation of post-mortem brains of dup15q individuals by the Autism Tissue Program (ATP). By studying brain tissue directly, Dr. Weigel has shown that there are many specific microscopic changes within the brain of these individuals. The next exciting step is for researchers to discover how these tissue changes affect an individual with dup15q and how they may contribute to epilepsy. Such findings can further our understating of not only dup15q syndrome but also autism and epilepsy.
Autism Speaks and the Autism Tissue Program recognize the strong scientific links between autism and autism-associated disorders such as dup15q and epilepsy. As such, your donations (of time, funding, and participation) are supporting efforts to foster promising collaboration between disciplines that, in turn, can increase our understanding of autism and speed the discovery of new avenues for its prevention and treatment. A sincere thanks for your support. We’d love to hear your thoughts.
Fifty years ago, researchers discovered elevated levels of serotonin in the blood of children with autism. What would it mean to our understanding of autism if serotonin—a highly active neurochemical—was also increased in the brain?
In 1961, Schain and Freedman reported that about 40% of autistic children are born with high circulating blood levels of serotonin. This finding has been repeated many times by other researchers. What are the implications? Despite around 600 published research papers looking at autism and serotonin, we’re not really sure. But we’re getting closer to providing answers thanks to crucial help from Autism Speaks.
In the young, developing brain, serotonin stimulates the growth of neurons, or nerve cells. So it follows logically that if serotonin levels are increased in the brains of autistic children, then their brains should be larger. In fact, macrocephaly (big heads) in young children with autism is common. Not only are the brains larger, but certain sensory responses appear earlier in children with autism.
But these findings raise new questions: What do serotonin-producing neurons look like in the brains of children with autism? Would the size and number of serotonin-producing neurons suggest that these cells function earlier in children with autism than in children whose brains develop typically?
The best way to answer such questions is to examine brains of individuals with autism after death. Autism Speaks supports the Autism Tissue Program (ATP), which provides researchers such as myself with access to a the precious resource of brains from autism donors (whose identities are always kept confidential). For instance, ATP records have already confirmed that the brain weights of donors between the ages of 3 and 18 years who had autism are significantly heavier the brains of donors without autism.
To examine the details of serotonin-producing neurons, I and my colleagues prepare and stain slices of brain tissue to reveal the presence of proteins that distinguish serotonin neurons. This procedure allow us to follow how the branches, or axons, of these cells reach out and connect with neighboring cells. Such studies have shown a stark increase in the number of serotonin axons in the brains of children with autism, with these changes appearing in the youngest brains studied (age 3 years) and peaking at around 18 year so of age. Analyses of axon size and branching pattern confirm this increase in an area of the brain associated with auditory sensation and language—the superior temporal cortex. It is hypothesized that the earlier maturation of cortical neurons in this primary auditory area may hinder their incorporation into complex circuits underlying speech.
Of particular interest, my lab has found increased serotonin neuron connections that, on first impression, seem inconsistent with observations widely reported in the scientific literature. Let’s examine them:
First, imaging studies show a decreased rate of serotonin creation and use in the brains of children with autism following administration of tryptophan, a chemical that the body needs to make serotonin. Second, many of the behaviors associated with autism suggest a decrease in serotonin activity. In fact, doctors typically treat hyperactivity, repetitive behavior, and insomnia in adults with drugs that increase serotonin. Paradoxically, recent clinical studies show that drugs that increase serotonin (e.g., selective serotonin re-uptake inhibitors) actually worsen symptoms in children with autism.
The observation that serotonin axons are increased in the brains of people with autism may provide answers to these inconsistencies. Much work needs to done, and the availability of valuable postmortem tissue should be used to its greatest advantage to study not only serotonin neurons, but also other types of brain cells that can affect neurological development. Using the precious resource of donated brain tissue, scientists are able to perform the detailed analyses necessary to see which cells have problems, when and where those problems begin, and what mechanisms may be involved.
Autism Speaks’ Autism Tissue Program supports specialized neuropathology research by providing approved scientists access to the most rare and necessary of resources, post mortem human brain tissue. We wish to recognize the commitment and generosity by our ATP donor families. More information can be found at http://www.autismtissueprogram.org or call 877-333-0999 for information or to initiate a brain donation.
2. Azmitia EC, Singh JS, Whitaker-Azmitia PM. (2011) Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors. Neuropharmacology. 2011 Jun;60(7-8):1347-54.
Standing before the audience at the New York State Autism Consortium Meeting for Proposed Tissue Collaboration in March, Judith Omidvaran relayed the events that changed her life nearly four years ago. Judith and her husband were the parents of Sina, a 29 year old young man with high functioning autism and epilepsy. Sina had endured previous seizures, but this one took him from his loving parents forever. Reflecting back on that day, now seared into her memory, Judith recalled making a very important and lasting choice. Sina was gone from their everyday lives but she and her husband could donate his brain tissue. In that moment the grieving parents chose to make a lasting contribution to autism research and provide hope for a greater understanding of the lives and all too often untimely deaths of individuals with ASD.
Sudden, unexplained death related to epilepsy (SUDEP) is a most uncomfortable topic, but also a very important one. A new study led by members of Autism Speaks’ staff and published in the Journal of Child Neurology revealed that individuals with ASD who also have a seizure disorder have a risk of death that is eight times greater those with ASD and no seizure disorder. Seizures are not always evident at the time of diagnosis of ASD, and often begin to manifest in adolescence. The difficulties of living with a chronic developmental disorder would seem to be enough, without the weight of worry that these statistics convey. However, one cannot be forearmed if not forewarned.
The release of these data may have been disturbing to some members of the autism community.
Roger Dunlap III was diagnosed with autism at three, and his parents went through the all preparations of caring for the lifelong needs of a child with special needs. Young Roger’s parents, Roger and Heather, began an organization to support the long term care of Roger and others who shared his challenges when these children would need support after their parents had passed. In a twist of cruel irony, young Roger died unexpectedly in his sleep at 9 years old. He was never diagnosed with epilepsy and the exact cause of death remains unknown. The Dunlaps also made an important choice at a difficult time. Their involvement in the autism community connected them with the Autism Tissue Program and they got a call about donation soon after young Roger’s passing. They have continued their remarkable support for the autism community both through their own organization and Autism Speaks.
At this point, however, our understanding of sudden death in autism and epilepsy is poor. An analysis of data on deaths from the California Department of Developmental Services reveal that the cause of death is unknown in 40% of cases. This particular area is one that the Autism Tissue Program is working to improve through detailed analyses of all donated tissue and also though a survey of ASD families who experienced a sudden death of their loved one with ASD .
Autism Speaks, in partnership with the International League Against Epilepsy (ILAE) and Citizens United for Research in Epilepsy (CURE), hosted a meeting in December 2010. The meeting brought together experts in epilepsy research and autism to discuss areas of greatest need and priority in research. The seven key points they developed include:
1) Identifying infants with seizures at risk for autism and those with autism at risk for epilepsy.
2) Identifying risk factors common to autism and epilepsy.
3) Developing new tools to effectively evaluate data specific to epilepsy and autism.
4) Identify and develop animal models, biomarkers and assessment tools that inform outcome in infants with epilepsy that go on to develop autism and infants with autism that go on to develop epilepsy.
5) Explore the underlying mechanisms of convergence between autism and epilepsy.
6) Coordinate tissue and brain banking efforts in epilepsy and autism.
7) Develop behavioral and pharmacological treatment models and methods in infants with epilepsy and autism (or with one and at risk for the other).
These aims are indeed important for taking the next research steps, however, the fortitude of parents in a time of crisis may be the greatest contribution toward advancing our understanding of sudden death in epilepsy and autism. If you wish to learn more about the Autism Tissue Program, or want to share a story and participate in a survey about sudden unexpected death of a family member with ASD, please go to their website for more information or email firstname.lastname@example.org.
Read the press release on the Journal of Child Neurology publication here.
We still know very little about the human brain. With an estimated 100 billion neurons (nerve cells) in the human brain, scientists grapple to understand what these neurons do, how they interact with one another and how they make us who we are. It is therefore not surprising that we are still some way from fully understanding the human brain, and more significantly the autistic brain and why its development is altered. There are many scientific approaches that can be used to visually inspect the human brain, such as magnetic resonance imaging (MRI), but only one way of directly studying the human brain – and that is by looking at post-mortem brain tissue. For this very reason, brain tissue is a critical element in the process of neurological scientific discovery. Unfortunately, tissue donation remains rare, hindering the very research that will help us to understand autism.
The Autism Tissue Program (ATP), a Scientific Program of Autism Speaks, is dedicated to supporting scientists worldwide in their efforts to understand autism, autism related disorders and the human brain. The ATP is a tissue based repository (bio-bank), among only a few worldwide, that makes brain tissue available to qualified scientists in order to advance autism research.
In an effort to improve the worldwide availability of tissue-based resources in autism research, Autism Speaks has been seeking to expand its efforts by establishing sister programs in other countries. In 2009, Autism Speaks partnered with UK charity Autistica in creating a 2nd bio-repository based at the University of Oxford in the United Kingdom (UK). There are already 15 brains that have been donated to this tissue bank and, in addition, awareness of the importance of brain donation for autism research within the British autism stakeholder community and general public has increased enormously.
The Medical Research Council (MRC) – the UK’s equivalent of the NIH – has recently formed a network of UK brain banks, including the Oxford autism bank as a key member. This new infrastructure will be a vehicle for facilitating the awareness of the need for autism tissue collection as well as the donation of tissue from controls (individuals who have no underlying neurological or psychiatric disorder) and related neurodevelopmental disorders (e.g. Fragile X syndrome). By encouraging international collaboration and the establishment of a bio-bank network, we can increase the numbers of donations of this precious resource and build the capacity needed for research in this field.
Autism Speaks’ staff recently visited the brain bank in the Netherlands to explore new collaborative opportunities. Due to their geographical size and national organization, the Netherlands have a unique resource in that all brain donations are sent to a single bank based in Amsterdam. This streamlined system enables a higher rate of tissue donations and the administration is relatively straight forward. With the support of the Dutch autism research community and our partners at the Netherlands Autism Society we are hoping that the Netherlands Brain Bank could soon begin collecting autism tissue. Similar opportunities are also being explored in Sweden and Canada.
We are making great strides in scientific discovery and the last few years have seen significant advances in the genetics of autism. More than ever this highlights the importance of using autism tissue collections to explore how genetic differences in people with autism affect the cellular and molecular development of the brain. In turn, these research investments will guide the development of new pharmacological treatments for people with autism to alleviate some of the core and secondary symptoms. With more than 100 research publications resulting from the efforts of Autism Speaks, The Autism Tissue Program, Autistica, and most significantly the brains generously donated by families, we are off to a promising start.
To learn more about brain donation please visit the ATP at www.autismspeaks.org (1-877-333-0999) and UK Brain Bank for Autism & Related Developmental Research at www.brainbankforautism.org.uk (44 0800 089 0707).
A journal article published this week studying sex-linked hormones in brain is the 100th paper describing results from brain tissue provided by the Autism Tissue Program. Taken together, the 100 papers, all published in peer-reviewed scientific journals, represent a huge advance in our understanding of the brains of individuals with autism.
The first publications were released in 2001 and built on existing evidence of developmental changes in the brain of those with autism. The increase to 100 papers in 10 years mirrors the growth of the brain tissue resource from about 20 brains at the start to currently over 100 brains from individuals with a clear diagnosis of autism, ranging in age from 3 to 60. The papers also show the use of a wide range of specialized resources developed by the Autism Tissue Program including MRI, brain tissue biopsies, genetic material from brain tissue and a large permanent brain library of slides all derived from post mortem brains.
The 100th publication is by Valerie Hu, Ph.D. and colleagues at the George Washington University Medical Center titled: ‘Sex hormones in autism: Androgens and estrogens differentially and reciprocally regulate RORA, a novel candidate gene for autism’. The aim of the research, funded in part by Autism Speaks, was to examine a particular sex-linked candidate gene found throughout the human body, including brain tissue. This line of research could provide some rationale for the fact that four times more males are affected with autism than females. Dr. Hu’s research shows that both male and female hormones have varying and significant effects on the activity of the RORA gene product. The RORA gene product regulates an enzyme (aromatase) that converts testosterone into estrogen.
This study offers a molecular mechanism for understanding the sex bias towards males by increasing levels of testosterone. This paper is the first report a sex hormone-responsive candidate gene for ASD. RORA is important for the development of a part of the brain called the cerebellum. The cerebellum is involved in controlling some types of movement, but also plays a role in cognitive tasks such as redirecting attention. RORA also serves to protect neurons against inflammation and oxidative stress.
Dr. Hu and colleagues showed that the female hormone estrogen increases the expression of RORA, while the male hormone androgen (dihydrotestosterone) decreases it. Interestingly, the interaction is somewhat circular as RORA regulates the expression of aromatase, an enzyme that converts testosterone to estrogen. According to Dr. Hu, “We observed in the brains of individuals with autism a link between decreased in activity of RORA and a reduction of aromatase activity. This reduced activity would lead to build up of testosterone and a decrease in estrogen.”
This study provides a molecular explanation for the higher levels of testosterone observed in some individuals with autism. These findings also suggest a mechanism for the male bias in ASD because female brain tissue may benefit from the protective effects of naturally higher levels of estrogen In addition, the estrogen receptor shares some of the same target genes as RORA, thus compensating for RORA deficiency, which the research team has also observed in some individuals with ASD.
Zeroing in on specific gene effects in the brain is one of several research avenues undertaken by scientists that can only be done through the direct examination of human brain tissue. The value of the study of human brain tissue is the interpretation of the data in the context of the current knowledge about autism. Combined with post mortem imaging and genetic analysis scientists can gain a broader and more thorough understanding of ASD.
Scientists studying brain tissue today need to consider disorders that can co-exist with autism. The Autism Tissue Program takes great care to fully document medical conditions of brain donors. The informatics portal catalogs over sixty disorders or conditions occurring in those with a diagnosis of autism including epilepsy, Fragile X, Tuberous Sclerosis Complex, Duschenne Muscular Dystrophy, Angleman, Rett and Asperger Syndromes and partial duplications or deletions of several chromosomes.
The Autism Tissue Program has emerged as an important resource of not only brain tissue but also as in informational hub of research results from an international group of scientists. None of this work would be possible without the dedication of the families who chose to donate brain tissue of loved ones to the Autism Tissue Program. To register you or your family in the brain donor program, please visit www.autismtissueprogram.org for information and online registration, or call 877-333-0999 for information or to initiate a brain donation.
Click here to view the full list of 100 papers the Autism Tissue Program has made possible.
This Science post is by staff blogger Jane Pickett, Ph.D.
Researchers have several ways to peer into the human brain. A commonly-used tool is magnetic resonance imaging (MRI) and unlike the two-dimensional pixels in photography, voxels are used to describe the volume of brain measured by MRI. Currently, the standard voxel is a of ~1mm, about the size of coarse sea salt. Combining millions of voxels produces the 3D image of the brain you see in the figure. The view of the brain at this high resolution has led to some common ideas about the ‘autism’ brain.
Cynthia Schumann, Ph.D. and Christine Nordahl, Ph.D. of the MIND Institute at UC Davis, show how imaging, when paired with the microscopic inspection of the post mortem human brain, can help answer questions about typical and disordered brain development. MRI studies of autism have revealed an atypical trajectory of brain growth during early childhood, characterized by brain overgrowth, that is present especially in the frontal cortex (involved in higher mental functions) and also in specific structures such as the amygdala (involved in memory functions, particularly of emotional experiences).
Why are these areas growing larger than normal in young children? One way to answer this question is to look at the cells in these enlarged areas. That solution requires samples of donated postmortem brain tissue.
To give an idea of what’s in a voxel in a typical 3 year old child’s brain: there are an estimated 40,000 neurons in the space of a voxel in the cortex and 7000 in each voxel in the amygdala. The pictures in row C show just a portion of cells in a single voxel in the brain areas indicated. Some evidence indicates that neurons and another cell type called glia are more abundant in the brains of individuals with autism. Connections between cells need space and the more numerous brain cell branching that has been found can also lead to a size increase of a given area.
In addition to counting cells and their connections, fine-scale anatomy allows us to examine the layered organization of cells in the cerebral cortex and other local relationships in different brain areas. When researchers observe cells that are “out of place”, this suggests differences in the functioning of that local network of cells.
Researchers can also use antibodies to localize various molecules in post-mortem brain tissue. With these techniques scientists can identify cells that carry a particular type of neurotransmitter, or other cellular signals. One can also extract and analyze the building blocks for proteins in RNA and DNA and look for regions where a certain gene may have been “turned on” or off more than expected.
Given the coarse resolution of MRI, the field must look towards post-mortem human brain research to help us understand the neurobiological underpinnings of the difference in brain growth patterns that have been found in MRI studies. MRI studies are very helpful in targeting which brain regions should be explored further in post-mortem studies.
Autism Speaks’ Autism Tissue Program supports specialized neuropathology research by providing approved scientists access to the most rare and necessary of resources, post mortem human brain tissue. We wish to recognize the commitment and generosity by our ATP donor families. More information can be found at www.autismtissueprogram.org or call 877-333-0999 for information or to initiate a brain donation.
Brain Research will be publishing a special issue of articles that feature presentations at the 2010 Brain Research meeting. Dr. Schumann’s paper is currently available online with appropriate institutional access or for purchase.
Schumann, CM and CW Nordahl. Bridging the gap between MRI and postmortem research in autism. Brain Res. (2010), doi:10.1016/j.brainres.2010.09.061.