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.
Autism is a very heterogeneous disorder. As the grand lady of neurology, Dr. Isabelle Rapin liked to emphasize when training new students “If you have seen one child with autism, you have seen one child with autism.” This heterogeneity has made understanding causes and designing effective treatments more challenging than it would be otherwise.
However, a new study published this week in Nature and supported by Autism Speaks’ Autism Tissue Program and Autism Genome Project reveals that the heterogeneity may not be as problematic as it initially seems. Differences in common molecular pathways appear to underlie the pathology in the brains of individuals with ASD.
Daniel Geschwind, M.D., Ph.D. (UCLA) launched an ambitious study to examine not just the variants of genes that may confer risk for autism, but the interaction with those genes and proteins working to support brain function. Looking for patterns of interaction in the brain, Dr. Geschwind and his colleagues sought to characterize the transcriptome – the set of fragments of instructions, called RNA, read from the gene DNA on the path to making functional proteins. Importantly, unlike the gene DNA that is relatively fixed for an individual’s life, the RNA transcriptome is modified through experience and interaction with the environment.
The authors analyzed patterns of expression of RNA for three areas of the post-mortem brain tissue from individuals with ASD or typically-developing individuals. Two areas of the late-developing cerebral cortex (prefrontal cortex and the superior temporal gyrus) and a region of the cerbellum known as the vermis were compared between the autism and typically developed brain tissue. The first big surprise was that although the cortex transcriptome revealed over 400 different genes with different expression between the autism and typical brain tissue samples, the similar comparison in the cerebellar transcriptome revealed exactly two differently expressed genes. Whatever differences exist in the brains of individuals with autism, these differences are greatest in the instructions that guide the structure and function of the cerebral cortex.
This, however, was just the beginning of what the research team found. Imagine the cerebral cortex of brain is like a bustling metropolis – one part of the city develops into a residential area and the other becomes a business district. Both neighborhoods have very distinctive features that make them unique due in part to the time and manner in which they developed and the people who inhabit them. So too for different regions of the typically-developing cerebral cortex. Different regions of the cortex develop at different times and with different inputs from the environment. The prefrontal cortex is one of the late-developing regions in the infant brain. Different regions also serve different functions, like integrating information from sight, sound and touch in the case of the superior temporal gyrus, and higher cognitive functions in the prefrontal cortex.
Importantly for Dr. Geschwind and his colleagues, these two cortical regions also have their own unique pattern of expression in brains from typically developed individuals. However, when looking for these unique signatures, the research team instead found surprisingly similar patterns of gene expression across the two regions in the brains of people with autism. Referring back to the metropolis analogy, in the autism brain samples, the residential and business districts are more alike than they ought to be.
There were also differences in expression of two gene networks between the autism and control brain samples. The first network of genes encodes synaptic function. This is reassuring because most of the autism risk genes identified through previous studies focused on synaptic function. The second network of differential gene expression was related to immune function and inflammation. This too harkens back to previous studies showing inflammation and immune system activation in the brains of individuals with autism. This gene network does not correlate with the results of large gene association studies like the synaptic network, indicating that secondary or environmental effects are involved in stimulating the observed inflammatory markers.
“This is the first study to show differences in the patterns of gene expression between brain regions, said Rob Ring, Ph.D., Autism Speaks vice president for translational research. “It’s those patterns of gene expression that enable the brain to function normally and to communicate properly with other regions of the brain.”
Taken together, these results have quite an impact on how we understand autism. The similarity of gene expression across different regions of cerebral cortex in the brains of individuals with autism tells us that we should look closely at very early brain development as these patterns in cerebral cortex emerge. The same goes for the network of synaptic genes that are differentially regulated in individuals with autism. However, the differences observed in immune and inflammation gene networks are more likely to be related to secondary or environmental effects. We must follow all the leads this research has provided if we are to make the next steps in developing supportive treatments and therapies for those living with autism spectrum disorders today.
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 email@example.com.
Read the press release on the Journal of Child Neurology publication here.
A new Autism Speaks-funded study reveals differences in brain connections in areas that redirect attention, mediate social interactions and modulate emotional responses.
Science is one step closer to understanding how the brains of individuals with autism process information. Over the past decade it became clear that neural communication is disrupted in autism, although the details, and the causes, remained elusive. Two hypotheses emerged to explain the information processing differences found in individuals with autism spectrum disorder (ASD). First, scientists identified over-activity at the level of the synapse—the point where two neurons connect. Second, imaging studies showed that the balance of local versus long-range connections was skewed in autism in favor of strong local connections but weak long-range connections between distant brain regions. Complex behavior, such as language and social interaction, depend upon such long range connections. Although the findings supporting the two hypotheses were likely related, the mechanism relating over-activity at the synapse and biased local versus long-range connectivity was unclear.
Now, taking advantage of recent technical developments that facilitate the measurement of small structures within the brain, Autism Speaks’-funded researchers at Boston University have bridged these two hypotheses. Basilis Zikopoulos, Ph.D., and Helen Barbas, Ph.D., reconstructed the intricate fabric of neural “wires”—called axons—that connect prefrontal cortex with neighboring and distant brain regions. The prefrontal cortex is a collection of brain areas that are involved in higher cognitive functions such as attention, planning, social interactions, and abstract thinking. Using postmortem brain tissue generously donated by families of individuals with and without autism, the team measured features of the different axons traveling beneath the cortical surface.
Talking to itself
In comparison to the control samples, autism brain tissue had fewer large axons connecting regions of the prefrontal cortex to the other areas of cortex. Added to this connection imbalance is a thinner coat of axon insulation, called myelin. Myelin is a fatty substance that insulates axons to ensure faithful delivery of neural signals over long distances. Prefrontal axons from autism brain tissue traveling to distant brain areas have less myelin. Zikopoulos and Barbas also found more thin axons that connect neighboring regions in the prefrontal cortex in the autism brain tissue versus the control samples. This biased pattern of connectivity creates a situation in which prefrontal cortex is not efficiently exchanging information with other brain areas, but rather is operating in a solo fashion.
Pursuing the reason for the abundance of thin axons, the researchers first checked to see whether this was due to more neurons in the cortex just above. Detailed examination of neuron density showed no more neurons, just more axons. This finding led the team to speculate that atypical axon branching had occurred in the autism samples. By painstakingly tracing individual axon branches through a volume of tissue, Zikopoulos and Barbas confirmed that the abundance of thin axons emerged from overzealous branching. The thin axons found in autism samples formed tree-like braches that connected with many more cells in neighboring areas than is typical. This pattern of branching furthered the bias for local versus long-range communication.
Differences in axons and their insulation may offer some links between the two hypotheses that aim to explain disrupted communication in autism. Fewer large axons travel to distant brain regions. Thin axons form too many branches that make extra connections locally. These factors can handily explain the local over-connectivity and long-range under-connectivity observation made through imaging studies. The fact that small axons seem to branch more frequently would also lead to an over-abundance of synaptic connections in a neighboring region. This result can help to explain the synaptic connection hypothesis. Taken together, the results lead us to a deeper understanding of how information may be processed quite differently in the brains of individuals with autism.
Anatomy offers a closer look
Imaging studies aiming to understand brain connectivity use techniques such as magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). These techniques focus on the large swaths of axons, often called “white matter” because of myelin’s fatty white hue. While many of these studies have suggested an imbalance favoring local connectivity in the brains of individuals with autism and served as a stimulus for this study, the level of detail that comes from quantitative anatomy is much richer. “The study of brain tissue at high resolution is needed to pinpoint defects in the brain’s communication system, which is prerequisite to developing rational therapies. Studying pathways using DTI is comparable to looking down from a plane at 35,000 feet – you can see some of the major highways below but not the exits, and certainly not the driveway to your house to see if the car is there,” states Dr. Barbas.
Martha Herbert, M.D., Ph.D., of Massachusetts General Hospital and LADDERS, an imaging expert who was not involved with this study, was enthusiastic about the new results. “Zikopoulos and Barbas have given us a paper about the cellular level of white matter changes in autism that has needed to be written for quite some time. Their analysis is meticulous and comprehensive, and goes far in providing microscopic details to answer provocative questions raised by the larger scale observations in so many brain scan studies in autism. Their findings suggest that the insult occurs later in brain development, after the neurons migrate to where they will live in the brain. The time when these neurons hook up with each other through white matter is crucial and during this period environment and immune factors as well as genes may play a role in the observed changes. These specific details about white matter in autism matter greatly for how we understand autism and how we go about providing the help people with autism need.”
Modeling the development of axon differences
The new axon data may also offer suggestions of what occurred to lead to this state of altered connectivity. Combining the axon data with what is known about the development of the cerebral cortex, the researchers devised a model that links differences in axons below frontal areas to a cascade of events in development that affects the growth of axons and their insulation. The hypotheses proposed are testable, and point to specific pathways that could to be targeted for the development of therapeutic interventions in autism.
One pathway that Zikopoulos and Barbas analyzed in detail was GAP-43, one of a myriad of signals that are exquisitely timed to encourage the proper growth and integration of developing neurons. GAP-43 stimulates axon branching. GAP-43 also interacts with other signals to prevent premature myelination, and is turned down after myelination begins. In the anterior cingulate cortex, a region of the prefrontal cortex that was the most profoundly affected in the brains studied, the neurons are sensitive to GAP-43 signals for an especially long duration in development. This is an important point because environmental agents such as estrogen-like compounds can increase the GAP-43 signal altering the timing of different aspects of neural development.
One take-home message from this study is how important it is to have diverse lines of inquiry investigating autism. The axon results were consistent across individuals studied. For example, the same changes were found regardless of whether or not the individual experienced seizures. Zikopoulos and Barbas also note that many of the genes that have been associated with autism exert effects on neural connectivity. Dr. Barbas says, “Genome-wide association studies are valuable in pointing out potential vulnerability in affected individuals. Our study suggests further that environmental factors (in utero, after birth, or both) can lead to abnormal connectivity because external factors up-regulate signals such as GAP-43 that regulate axon growth. We need studies to take into account all of these aspects of autism, not just one.”
This work was published in the Journal of Neuroscience and featured on the cover of the November 3 issue.
This research was made possible through funding from Autism Speaks and brain tissue supplied by Autism Speaks’ Autism Tissue Program. These groundbreaking results came from the brain tissue of ten generous individuals who chose to make a lasting gift to science. Importantly, only a small portion of each donated brain was needed for this study, making other sections of this incredibly valuable research resource available to others to uncover new insights into autism spectrum disorders. Please consider making a lasting gift to science by participating in the ATP.
Autism is a clinically diagnosed disorder. Much of our knowledge about autism comes from direct interactions with people diagnosed with autism spectrum disorders (ASD), listening to parents of children on the spectrum, and conducting clinical studies. Magnetic Resonance imaging (MRI) studies have added to our understanding by giving us a peek at the autistic brain and structural differences that may be present. Additionally, strong efforts in genetic analysis have discovered genes of interest and regions within our DNA that may play a part in the development of ASD. Though all these efforts have taught us much about autism, we still know relatively little about the autistic brain and why its development is altered. So how do we learn more?
We must look at things directly.
Consider the following analogy. If you were told to study an office building, but could not go inside, you may find yourself walking around the structure and studying its shape. You could interact with the building by touching the stone and steel that form the building. This would be analogous to clinical and behavioral observations typically made of individuals with autism. Engineering plans, may tell you what the building is comprised of (analogous to genetics studies) and even how it is shaped on the inside—where the rooms are and how stairs, elevators and hallways connect them. This last approach would be analogous to structural MRI studies. Despite the value of each of these perspectives, none of these examinations could reveal the happenings within the building. You would know nothing about the people working within the building, what they were doing, how they interacted with each other and what their jobs may have been.
In a similar way this is how we most often study autism, by looking at the outside, taking an indirect perspective. But there are some scientists who look at things differently. They go inside the building. They study brains directly. And what some of these exceptional scientists have learned so far is quite astounding.
Studying brain tissue directly from deceased individuals, enables researchers to look microscopically at the cells within human brains, how these cells are connected with one another, how they are structured on a molecular level and what that most interesting of molecules – DNA – is doing within the cell. Studying the brain directly allows a far more thorough level of research to be conducted; enabling researches to ask and answer questions that otherwise could not have been addressed, to study the cell and molecular bases behind autism, and granting the ability to look at the fundamental underpinnings behind ASD. Scientists need to study brains from both affected and unaffected individuals in order to make informative comparisons. Without both affected and unaffected individuals to study, the brain tissue loses context and is far less instructive.
Recent breakthroughs in brain tissue research
With brain tissue, scientists can look at the many components needed to make and organize proteins within a cell for proper brain function. Investigators have explored genes that synthesize a major inhibitory transmitter (GABA) in the neural cells and found decreased activity in a special type of protein called an enzyme. In addition, other molecules that detect and bind to GABA (called receptors) are decreased in prevalence in several brain regions. Enzymes and receptors are targets for therapeutics (drug intervention) and are therefore important to understand.
A report investigating 26 brains from the Brain Atlas Project describes some of the atypical findings in the brains of individuals with autism: namely defects in the production, development and organization of new neurons in the brain. Using digital images available to researchers from the Brain Atlas Project, investigators showed that cell populations in the brain, organized in distinct patterns termed minicolumns, are more numerous in the autism brains. Scientists postulate that this increase of minicolumns results in higher sensitivity to stimuli coming into the brain, but at a cost to processing and output in the form of behaviors that characterize autism.
Brain tissue evaluation of mitochrondria reveals differences in these critical cell powerhouses. Mitochondria are responsible for producing most of the energy inside a cell. Brain tissue research has revealed defects in mitochondrial proteins important for shuttling molecules across brain cell membranes. Much like a battery, controlling the flow of molecules within different compartments of a cell is one of the key components to the energy production process and one that appears to be functioning differently in individuals with autism.
Oxytocin is a hormone with a role in social recognition, pair bonding, anxiety, and maternal behaviors. Brain tissue research provides evidence of oxytocin receptor deficiencies resulting in a lower level of effectiveness. This means that even if the hormone is produced normally, it has a reduced effect. Treatments to increase oxytocin functionality in the brain are being explored and brain research will continue to contribute to the understanding of the role of this hormone in the brain.
Scientists also use brain tissue to explore findings from other medical assessments. Analysis of cerebral spinal fluid (CSF) from subjects with autism has shown immune markers of neuroinflammation. Immune activity found in cells from the brain support the concept that specialized brain cells that respond to infection or damage are active in autism brain samples.
How you can help
Unfortunately, brain tissue is exceptionally rare, thereby hindering this rigorous approach to understating autism
The Autism Tissue Program (ATP), a clinical 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 makes brain tissue available to as many qualified scientists as possible to advance autism research and unravel the mysteries of this and related neurological conditions. In fact, it is the only program solely dedicated to increasing and enhancing the availability of post-mortem brain tissue for basic research in autism. You can make a profound difference to all those who struggle with autism by registering as a brain tissue donor with the ATP.
A large part about why we, at the ATP, keep working is that when people with autism die, it is sometimes unexpectedly and with little to explain the cause of death. Detailed analysis of the donated tissue helps provide answers as to why death occurred and helps us learn more about these unique individuals in addition to helping researchers understand autism.
If you are the parent of a child or children with an autism spectrum disorder, are related to a person with an autism spectrum disorder, have autism yourself or are unaffected, your donation can greatly affect our progress in understanding autism. We encourage entire families to consider donations of brain tissue for research.
While in some states and countries, registration for organ donation makes the process automatic at the time of death (as on your driver’s license), this is not the case for brain tissue donation. Because brain tissue is used for research and not transplantation, it is not included on most organ donation registries. Therefore, by registering with the ATP, you declare your intent to donate brain tissue as well as making your wishes known to your family in a formalized way. However, registration does not make tissue donation automatic at the time death. This final choice of donation is made by your next-of-kin, which in legal terms, is defined in this order: spouse, adult children, either parent, adult siblings, or guardian at the time of death. Should you choose to become an ATP registrant, and wish to donate your brain upon death, to the ATP in support of autism research, we encourage you to inform others of your wishes, including your immediate and extended family. Helping your friends and family learn more about the ATP and its mission will help them understand your unique choice.
For more information about the ATP and becoming a registered donor, visit our site at www.autismtissue program.org.
This is a guest post by Autism Speaks staffer Jane Pickett, Ph.D.
The 10th annual international gathering of autism scientists, researchers and advocates, known as IMFAR, (International Meeting for Autism Research), was held last month. At the meeting, the prestigious Slifka/Ritvo award for research innovation went to a project using post mortem brain tissue to help researchers using MRI on living subjects to define boundaries between various brain regions. This research is important because every brain is a little bit different and we need new tools to accurately compare brain areas across individuals.
Drs. Thomas Avino and Jeffrey Hutsler at the University of Reno tackled the problem of defining the border between brain cells making up the ‘gray matter’ and the ‘white matter’ located in the center of the brain) by examining brain tissue of donors to the Autism Tissue Program. Their project, ‘Quantification of the gray/white matter boundary in Autism Spectrum Disorders’, assessed 3 brain regions in 8 males with autism and 8 age- and sex-matched control donors.
The images at the left mark the location of neurons in the lower cellular layer of the cortex, Layer VI, and also the white matter below it. The image (left) of an unaffected donor shows a typical transition zone; the autism brain specimens have a poorly defined zone, with the cell bodies of neurons spilling into areas where they are not expected to be. Looking directly at brain cells, it is easy to understand the MRI reports of ‘poor distinctiveness’ between cortical gray and white matter and now imaging researchers have a mathematical model to consider in their assessments of gray/white matter as they study brain development in children with autism.
Independent examination of other autism brain samples by post doctoral student Adrian Oblak from Boston University School of Medicine also showed many neurons atypically located in white matter. More specifically, these neurons were found in the cortex involved in emotion and memory process and face processing. Microscopic images of marked cells in this area, the posterior cingulate gyrus, show cells on the right, in the autism brain, massing into the white matter.
Why is this important in today’s autism world? Years of study of the developing human brain show that at embryonic brain cells begin to ‘climb’ up to the cortical surface and by 5 months gestation virtually all are located above the new myelin-dense ‘white matter’. A delay in this migration during the second trimester of pregnancy is thought to be caused by a lack of proper cell signaling due to a genetic and/or environmental impact on the developing brain. What is important is that this change in brain structure is seen into adulthood in brains of donors with autism; therefore, further research of brain cell architecture, combined with brain tissue genotyping, will reveal more about changes occurring during the development of the central nervous system. The correct configuration of the cortical cell layers is crucial for further maturation and functionality of the brain. A number of coordinated events need to occur for this early development such as proper signals for cell birth, migration, maturation and final proper distribution of new brain cells. Genes that guide these events are becoming better understood (read about a new genetics study).
What does this have to do with you? None of this research is possible without brain donation. If you are interested in learning more about the Autism Tissue Program, or registering you and your family with the program, please visit our website at www.autismtisssueprogram.org, email us at firstname.lastname@example.org or call 1-877-333-0999.
One of the challenges in pursuing the causes of autism spectrum disorders is the heterogeneity of symptoms and life history of the individuals affected. On Wednesday, one day before the start of the International Meeting for Autism Research (IMFAR), meetings of two family foundations centered on specific genetic syndromes for autism moved past these challenges to offer hope for recovery.
The Phelan-McDermid Syndrome Foundation (PMSF) was one of the family foundations that hosted a meeting of international scientists, clinicians and parents to better understand PMSF. Katy Phelan, Ph.D. (Molecular Pathology Laboratory Network, TN) presented a characterization of the individuals affected, as many scientists working with animal models of this disorder have met very few, if any, persons with PMS. Dr. Phelan reviewed the cluster of symptoms present typically early in life, including a “floppy” infant, general developmental delays and poor or absent speech. She also reviewed evidence that led to the recognition that individuals with PMS had some form of mutation in the SHANK 3 gene on chromosome 22.
The meeting soon shifted to animal models and presentations from several researchers who presented greater detail about the role of the protein SHANK 3 at synapses, or junctions of neurons, which are crucial for learning and memory functions. It was shown that SHANK 3 is responsible for tying together two receptors for the common excitatory transmitter glutamate at the synapse. Through a series of careful experiments examining the structure and function of synapses when more or less SHANK 3 protein was present, Joseph Buxbaum, Ph.D. (Mount Sinai School of Medicine, NY) and colleagues learned that SHANK 3 controlled the physical connections that underlie plasticity of the synapses (the mechanism that underlies learning and memory). After achieving this detailed understanding of how the system develops and stabilizes in the animal, the next step was to attempt to rescue normal function in these animals that lack SHANK 3. A related set of receptors present on the cells (AMPA receptors) was targeted with the drug called IGF1. Injections of IGF1 into the mouse travelled across the protective barrier that encases the brain and had the desired effects on the cells, rescuing the structure and function of the synapses that had the atypical SHANK 3 proteins.
Lastly before a dinner gathering where parents scientists and clinicians can share ideas with each other more informally, Sarah Curran, Ph.D. (Kings College, London) presented on new technology that may allow the creation of stem cell lines for deeper analysis of the effect of a single individual’s mutations (the SHANK 3 gene can have mutations at several places, potentially leading to different effects on the functioning of the SHANK 3 protein) by analyzing a single complete hair from an affected person.
The Isodicentric 15 Exchange, Advocacy and Support group (IDEAS) is another family foundation that hosted a meeting of clinicians, scientists and parents. Of the several genetic disorders that have a ‘causal’ relationship to autism, the duplication of a portion of chromosome 15q (IDIC15q) figures prominently in post-mortem brain research. In fact, one out of every ten brain donors to the Autism Tissue Program comes from this specific population that is represented by the IDEAS organization. A major concern of the group and a factor in the high brain donation rate in this group of only 650 known affected individuals is sudden unexplained deaths, a fact reviewed by Edwin Cook, MD (University of Illinois at Chicago) at the meeting. Seizure activity is many of the individuals is thought to underlie their apparent vulnerability and the IDEAS group has been proactive in publicizing recommendations from their physician-advisors, including Carolyn Schanen, M.D., Ph.D. (University of Delaware) who gave the opening presentation at this meeting. The physician-advisors also promote brain donation to understand the causes of death and look for developmental changes consistent with autism and/or epilepsy.
The meeting brought together researchers and parent advocates in a significant effort to understand the research to date and fine tune future efforts. Jerzy Wegiel, V.M.D., Ph.D. (New York Institute for Basic Research) described neuropathology in 5 brain studies completed to date that shows unexpected ongoing production of new brain cells (neurogenesis), a atypical early migration of brain cells, and distortion of the cell structure reflecting an altered course of maturation of brain cells. Each of these brain anomalies can contribute to seizure activity and the study of brains and clinical evaluations of the donors will continue.
In conjunction with the neuropathologic examinations of brain donors, IDEAS asked its families to participate in a seizure survey. Preliminary results from about 85 participants shows various types of seizures and onsets; results will be posted on the IDEAS site and communicated via the Autism Speaks blog. Since sudden deaths often occurred during sleep, Sanjeev Kothare, M.D. (Children’s Hospital, Boston, MA) was present to provide information on his studies of breathing abnormalities in patients with IDIC15q. He reviewed the clinical spectrum of duplications on chromosome 15q: epilepsy, low muscle tone, atypical facial features, moderate-severe developmental delay, and autistic behaviors. He speculated that the increased risk of sudden death is due to abnormalities of sleep, cardio-vascular function, mitochondrial function and epilepsy. The results of his sleep study on 5 children with IDIC15q revealed central sleep apnea that occurs when the brain does not send proper signals to the muscles that control breathing often in conjunction with seizure activity. This very important work will continue and many of the IDEAS families have worked with their own doctors to obtain a sleep study to determine both seizure and breathing activity.
An additional highlight of the meeting was a talk by James Sutcliffe, Ph.D. (Vanderbilt University) on one of the genes of interest in the duplicated piece of chromosome 15 – the GABA B3 receptor. GABA is the main inhibitory neurotransmitter and any dysfunction in its receptor is thought to increase brain activity and might contribute to seizures. He is studying rare point mutation in this gene that was also found in a condition known as Childhood Absence Epilepsy. A presentation by Larry Reiter, Ph.D. (University of Tennessee Health Science Center) focused on a subset of 15q duplications called ‘interstitial duplications’. These are also duplications of genes in the 15q portion of the chromosome but instead of arising de novo in the child, are inherited from the mother or father. Overall, the future goals are aimed at learning more about the conditions that affect mortality such as low muscle tone, apnea and seizures. Further genetic studies on molecular mechanisms to find drug targets will include mouse models and analysis of DNA and brain tissue.
Taken together these meetings offered a positive view for the future. Families are working closely with clinicians and researchers to find effective new therapies for genetic syndromes that present as autism. The larger hope is that as these syndromes reveal their secrets, they will provide us with new tool with which to treat other forms of autism.
Thank you to Andy Mitz, Ph.D. of NIH for providing input on the PMSF meeting.
To read complete IMFAR coverage, please visit http://www.autismspeaks.org/science/science_news/imfar_2010.php.