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Summary of Advances Cover 2010

Summary of Advances

In Autism Spectrum Disorder Research


Question 2: Biology - How Can I Understand What Is Happening?

Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report.
Buie T, Campbell DB, Fuchs, GJ 3rd, Furuta GT, Levy J, VandeWater J, Whitaker AH, Atkins D, Bauman ML, Beaudet AL, Carr EG, Gershon MD, Hyman SL, Jirapinyo P, Jyonouchi H, Kooros K, Kushak R, Levitt P, Levy SE, Lewis JD, Murray KF, Natowicz MR, Sabra A, Wershil BK, Weston SC, Zeltzer L, Winter H. Pediatrics. 2010 Jan;125(Suppl 1):S1 -S18.

Recommendations for evaluation and treatment of common gastrointestinal problems in children with ASDs.
Buie T, Fuchs GJ 3rd, Furuta GT, Kooros K, Levy J, Lewis JD, Wershil BK, Winter H. Pediatrics. 2010 Jan;125(Suppl 1):S19-29.

A panel of experts reviewed the medical literature on ASD and gastrointestinal (GI) disorders and developed a consensus report (Buie, Cambell, Fuchs et al., 2010) and recommendations for evaluation, diagnosis, and treatment (Buie, Fuchs, Furuta et al., 2010). While GI issues are commonly reported among people with ASD, the actual rate of these co-occurring issues and the proper methods for diagnosis and treatment are not well understood. The panel reached a consensus that people with ASD who have GI symptoms should receive the same thorough evaluation as any other patient. In addition, the experts concluded that GI issues reported in people with ASD are also common to the general population and that there is not sufficient evidence of a GI disorder unique to people on the spectrum. Further, they stated that medical problems such as GI issues may manifest as behavioral problems in people with ASD and that the underlying cause may be difficult to diagnose, particularly if the person is non-verbal. It may be beneficial to coordinate behavioral and medical treatment simultaneously in these instances. The panel concluded that the bulk of the literature does not support the idea that diets restricting gluten and/or casein can lessen the symptoms of ASD. However, existing evidence has not ruled out the possibility that a particular subset may respond to a restricted diet. The panel advised those who choose to follow these diets to do so in consultation with a nutritionist. Currently, data do not support that intestinal inflammation, increased intestinal permeability (or "leaky gut"), food allergies, or immunological issues play a role in causing ASD. More research is needed to understand what, if any, part these issues play. Additionally, any future studies of ASD and GI should include genetic analysis to better define potential subgroups of individuals. Ultimately, researchers are working to gather enough information to develop evidence-based guidelines standardizing care for children with ASD who experience GI problems.

Describing the brain in autism in five dimensions – magnetic resonance imaging-assisted diagnosis of autism spectrum disorder using a multiparameter classification approach.
Ecker C, Marquand A, Mourao-Miranda J, Johnston P, Daly EM, Brammer MJ, Maltezos S, Murphy CM, Robertson D, Williams SC, Murphy DG. J Neurosci. 2010 Aug11;30(32):10612-23.

Using magnetic resonance imaging (MRI), researchers were able to identify people with ASD by measuring subtle differences in brain structure. The investigators used a complex mathematical process to predict whether or not the person had ASD based on five dimensions of the brain selected for study by the researchers. These dimensions included both size (volume) and shape of various brain regions. The researchers found that no one structural feature could definitively identify whether a person had ASD, but when all five dimensions were taken together, they could distinguish people with ASD from typically developing individuals with up to 90 percent accuracy. The technique showed a false-positive rate (misdiagnosing ASD in a typically developing person) of about 20 percent, and ASD identification was more accurate when measures were taken from the left hemisphere of the brain. The authors discuss the theory that brain structure changes are more prominent in the left hemispheres of people with ASD, resulting in enhanced asymmetry between and the left and right halves of the brain. The researchers also tested how accurately their technique could distinguish people with ADHD from those with ASD and found that the algorithm misdiagnosed ASD in someone with ADHD 21 percent of the time. Future research will be needed to refine the technique, but the study demonstrates its potential as a valuable tool for diagnosing and understanding the biological underpinnings of ASD.

Mitochondrial dysfunction in autism.
Giulivi C, Zhang YF, Omanska-Klusek A, Ross-Inta C, Wong S, Hertz-Picciotto I, Tassone F, Pessah IN. JAMA. 2010 Dec 1;304(21):2389-96.

A preliminary study found that children with classic autism were more likely to have impaired mitochondrial function and abnormalities in mitochondrial DNA when compared to their typically developing peers. Mitochondria supply energy to cells and have their own set of genetic instructions. Questions surrounding mitochondrial dysfunction and autism have long existed, and some have hypothesized that the inability to adequately fuel neurons could account for some of the cognitive issues associated with autism. Mitochondrial dysfunction has been linked to several other neurological disorders including Parkinson's disease, Alzheimer's disease, schizophrenia, and bipolar disorder. In the investigation, researchers randomly selected ten children with ASD participating in the Childhood Autism Risks from Genetics and Environment (CHARGE) study being conducted at the M.I.N.D. Institute in California and compared them with ten typically developing children also participating in the study. The investigators took blood samples from the children, who ranged from 2 to 5 years of age, and analyzed the mitochondria present in immune cells called lymphocytes. They found that the mitochondria in children with autism were consuming significantly less oxygen than controls, indicating lowered mitochondrial activity and decreased ability to supply energy to cells. Children with autism also had higher levels of pyruvate, the basic material mitochondria transform into energy, suggesting that they were unable to process pyruvate quickly enough to meet energy demands. Hydrogen peroxide levels in the mitochondria were also elevated, which could indicate higher levels of oxidative stress – an imbalance that results in cellular damage. Oxidative stress can cause mitochondria to produce extra copies of DNA, which was seen in half of children with autism. In addition, two of the ten children showed deletions in their mitochondrial DNA. The study provides evidence that mitochondrial dysfunction may be more common in children with autism and warrants further research.

Neural signatures of autism.
Kaiser MD, Hudac CM, Shultz S, Lee SM, Cheung C, Berken AM, Deen B, Pitskel NB, Sugrue DR, Voos AC, Saulnier CA, Ventola P, Wolf JM, Klin A, Vander Wyk BC, Pelphrey KA. Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):21223-8.

Researchers have identified patterns of brain activity that are unique to people with autism spectrum disorder. These distinct patterns, also called neural signatures, may be useful in diagnosis and identifying subgroups of people with ASD. Using functional magnetic resonance imaging (fMRI), investigators performed scans of 62 children, 4 to 17 years of age, while they watched animations of biological motion (movements such as walking or running simplified to dots representing the major joints). Children in the study were diagnosed with ASD, typically developing, or siblings of children with ASD who did not have the diagnosis themselves. The study found that children with ASD showed less activity in certain brain regions when viewing the biological motion than did typically developing children. Interestingly, their siblings showed similarly reduced brain activation patterns although they did not have ASD. These similar patterns of decreased activity shared by ASD children and their unaffected siblings are called "trait markers." The researchers also identified other distinct brain regions that showed decreased activity only in the children with ASD, which they termed "state markers." Because these state markers are unique to ASD children, they could potentially serve as biomarkers for the disorder. Finally, the scientists identified brain regions in unaffected siblings that showed heightened levels of activity that they termed "compensatory regions." The increased activity in these regions may provide clues about why – with similar genetic risk – only one of the siblings developed ASD. The study gives insight into the brain basis of ASD and may help to improve diagnosis based on the newly identified neural signatures.

A model for neural development and treatment for Rett syndrome using human induced pluripotent stem cells.
Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, Chen G, Gage FH, Muotri AR. Cell. 2010 Nov 12;143(4):527-39.

Researchers were able to create a neuronal model of Rett syndrome, a disorder on the autism spectrum with a known genetic cause, using induced pluripotent stem cells (iPSCs) from people with the disorder. Studying neurons produced from human Rett syndrome patients may help scientists gain a better understanding of the biological basis of Rett syndrome and be useful in testing potential drug interventions. This is the first time an iPSC model of ASD has been created. In the study, researchers collected skin cells from four female patients with Rett syndrome and five healthy controls. By introducing a retrovirus, the scientists were able to reprogram the cells to behave like embryonic stem cells – giving them the ability to become an assortment of different cell types. Using the iPSCs, the researchers created functional neurons that were identical in many ways to those found in mouse models of Rett syndrome and postmortem brain tissue from individuals with the disorder. The neurons created from the participants with Rett syndrome showed structural and functional defects when compared to the cells from healthy controls. They were found to have 50 percent fewer synapses, a reduced number of dendritic spines (which help to send cellular signals), and smaller cell bodies. The neurons also showed abnormalities in their signaling abilities. With additional tests, the researchers were able to show that the abnormalities seen in the neurons stemmed from the mutations in the gene MECP2 that causes Rett syndrome. With this knowledge, they were able to treat the neurons with several drugs, reversing the cell defects and restoring normal cell signaling. The effective drugs included insulin growth factor 1 (IGF-1), previously shown to restore function in mouse models of Rett, and the antibiotic gentamicin, which increased MECP2 levels by suppressing a type of mutation that commonly causes Rett syndrome. The study suggests that drug therapies could be effective for children with Rett syndrome when used early in development, before symptoms arise at 6 to 18 months of age. The ability to create patient-specific cellular models of a neurodevelopmental disorder offers a powerful new tool for researchers studying potential drug treatments.

Longitudinal MRI study of cortical development through early childhood in autism.
Schumann CM, Bloss CS, Barnes CC, Wideman GM, Carper RA, Akshoomoff N, Pierce K, Hagler D, Schork N, Lord C, Courchesne E. J Neurosci. 2010 Mar 24;30(12):4419-27.

An imaging study conducted over several years confirmed what many researchers have long hypothesized – children with ASD experience a period of early brain overgrowth beginning at a very young age. While this hypothesis has been supported by studies of head circumference and cross-sectional magnetic resonance imaging (MRI) of the brain, it had not been confirmed through a longitudinal study of brain growth during the critical period when symptoms of ASD first arise. Using functional MRI, researchers collected brain scans from toddlers who were later diagnosed with ASD and their typically developing peers at several points between 1½ years and 5 years of age. The study included 193 scans from 44 typically developing children and 41 children who went on to be diagnosed with ASD at around 4 years of age. The scans showed that by 2½ years of age, the brain's two major components – white and gray matter – were significantly enlarged in toddlers with ASD when compared to their peers. The greatest amount of enlargement occurred in regions of the brain known as the frontal, temporal, and cingulate cortices. As the children with ASD aged, overgrowth was seen in almost all parts of the brain. There were significant differences between genders, with girls showing more dramatic overgrowth in more regions. This suggests that the abnormal brain development in males and females with ASD may be fundamentally different. Based on the results of this research, the authors recommend including younger children in future studies to determine when brain overgrowth begins. They also suggest considering genetic information and other biomarkers to better understand the underlying biological processes that affect the brain and result in the symptoms of ASD. As a caveat, the authors note that autism is a very heterogeneous disorder and not all children with ASD show brain enlargement. Future studies may help to identify the different patterns of neurodevelopment of individual subgroups.

Question 2

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