1. Study uses stem cells to explore the causes of autism

    November 17, 2017 by Ashley

    From the Elsevier press release:

    Using human induced pluripotent stem cells (iPSCs) to model autism spectrum disorder (ASD), researchers at the University of São Paulo, Brazil and University of California, San Diego have revealed for the first time that abnormalities in the supporting cells of the brain, called astrocytes, may contribute to the cause of the disorder. The findings, published in Biological Psychiatry, help explain what happens at a biological level to produce ASD behavior, and may help researchers identify new treatments for patients with the disorder.

    Astrocytes play an important role in the development and function of the nervous system. But until now, iPSC models of autism have neglected their contribution. The new study, led by Dr. Patricia Beltrão-Braga and Dr. Alysson Muotri, used iPSCs to generate neurons and astrocytes to model the interaction between these brain cells and better understand how the brain forms in the disorder.

    “This new use of pluripotent stem cells suggests that neurobiological approaches to autism based solely on abnormal neuronal development may fail to account for complex interplay of neurons and astrocytes that may be an underappreciated component of the biology of this disorder,” said Dr. John Krystal, Editor of Biological Psychiatry.

    Induced pluripotent stem cell technology allows researchers to reprogram human cells into any cell in the body. In the study, first authors Dr. Fabiele Russo and Beatriz Freitas and colleagues used cells from three patients diagnosed with ASD and three healthy individuals to generate neurons and astrocytes. Neurons derived from ASD patients had less complex structure than healthy neurons, but adding healthy astrocytes to the ASD neurons improved their poorly developed structure. In reverse, pairing ASD astrocytes with healthy neurons interfered with their development, making them look more like the neurons from ASD patients.

    “The article highlights for the first time the influence of astrocytes in ASD, revealing that astrocytes play a fundamental role in neuronal structure and function,” said Beltrão-Braga.

    The researchers further investigated how the astrocytes exert their influence, and pegged a substance that astrocytes produce called IL-6, already suggested as a player in ASD, as the culprit for the defects. Astrocytes from the patients with ASD appeared to be producing too much of the substance, and the findings suggest that reducing IL-6 could be a beneficial treatment for neurons in ASD.

    Importantly, ASD has been a challenging disease to model using iPSCs because of its complexity. Several genes have been linked to ASD, but their contributions remain unknown, and genetic differences between patients have made it difficult to understand the cause and develop treatments for the disorder. But in this study, the ASD subjects were selected because they shared similar behaviors, rather than similar genes. According to Beltrão-Braga, this means the findings could provide a new alternative strategy for treating ASD symptoms, independent of the patient’s genotype.


  2. Study suggests brain activity is inherited, may inform treatment for ADHD, autism

    November 13, 2017 by Ashley

    From the Oregon Health & Science University press release:

    Every person has a distinct pattern of functional brain connectivity known as a connectotype, or brain fingerprint. A new study conducted at OHSU in Portland, Oregon, concludes that while individually unique, each connectotype demonstrates both familial and heritable relationships. The results published today in Network Neuroscience.

    “Similar to DNA, specific brain systems and connectivity patterns are passed down from adults to their children,” said the study’s principal investigator Damien Fair, Ph.D., P.A.-C., associate professor of behavioral neuroscience and psychiatry, OHSU School of Medicine. “This is significant because it may help us to better characterize aspects of altered brain activity, development or disease.”

    Using two data sets of functional MRI brain scans from more than 350 adult and child siblings during resting state, Fair and colleagues applied an innovative technique to characterize functional connectivity and machine learning to successfully identify siblings based on their connectotype.

    Through a similar process, the team also distinguished individual sibling and twin pairs from unrelated pairs in both children and adults.

    “This confirms that while unique to each individual, some aspects of the family connectome are inherited and maintained throughout development and may be useful as early biomarkers of mental or neurological conditions,” said lead author Oscar Miranda-Dominguez, Ph.D., research assistant professor of behavioral neuroscience, OHSU School of Medicine.

    Overall, the connectotype demonstrated heritability within five brain systems, the most prominent being the frontoparietal cortex, or the part of the brain that filters incoming information. The dorsal attention and default systems, important for attention or focus and internal mental thoughts or rumination, respectively, also showed significant occurrences.

    “These findings add to the way we think about normal and altered brain function,” said Fair. “Further, it creates more opportunity for personalized and targeted treatment approaches for conditions such as ADHD or autism.”


  3. Study suggests malfunctions in communication between brain cells could be at root of autism

    November 11, 2017 by Ashley

    From the Washington University School of Medicine press release:

    A defective gene linked to autism influences how neurons connect and communicate with each other in the brain, according to a study from Washington University School of Medicine in St. Louis. Rodents that lack the gene form too many connections between brain neurons and have difficulty learning.

    The findings, published Nov. 2 in Nature Communications, suggest that some of the diverse symptoms of autism may stem from a malfunction in communication among cells in the brain.

    “This study raises the possibility that there may be too many synapses in the brains of patients with autism,” said senior author Azad Bonni, MD, PhD, the Edison Professor of Neuroscience and head of the Department of Neuroscience at Washington University School of Medicine in St. Louis. “You might think that having more synapses would make the brain work better, but that doesn’t seem to be the case. An increased number of synapses creates miscommunication among neurons in the developing brain that correlates with impairments in learning, although we don’t know how.”

    Autism is a neurodevelopmental disorder affecting about one out of every 68 children. It is characterized by social and communication challenges.

    Among the many genes linked to autism in people are six genes that attach a molecular tag, called ubiquitin, to proteins. These genes, called ubiquitin ligases, function like a work order, telling the rest of the cell how to deal with the tagged proteins: This one should be discarded, that one should be rerouted to another part of the cell, a third needs to have its activity dialed up or down.

    Patients with autism may carry a mutation that prevents one of their ubiquitin genes from working properly. But how problems with tagging proteins affect how the brain is hardwired and operates, and why such problems may lead to autism, has remained poorly understood.

    To understand the role of ubiquitin genes in brain development, Bonni, first author Pamela Valnegri, PhD, and colleagues removed the ubiquitin gene RNF8 in neurons in the cerebellum of young mice. The cerebellum is one of the key brain regions affected by autism.

    The researchers found that neurons that lacked the RNF8 protein formed about 50 percent more synapses — the connections that allow neurons to send signals from one to another — than those with the gene. And the extra synapses worked. By measuring the electrical signal in the receiving cells, the researchers found that the strength of the signal was doubled in the mice that lacked the protein.

    The cerebellum is indispensable for movement and learning motor skills such as how to ride a bicycle. Some of the recognizable symptoms of autism — such as motor incoordination and a tendency to walk tippy-toed — involve control of movement.

    The animals missing the RNF8 gene in the neurons of their cerebellum did not have any obvious problems with movement: They walked normally and appeared coordinated. When the researchers tested their ability to learn motor skills, however, the mice without RNF8 failed miserably.

    The researchers trained the mice to associate a quick puff of air to the eye with the blinking of a light. Most mice learn to shut their eyes when they see the light blink, to avoid the irritation of the coming air puff. After a week of training, mice with a functioning copy of the gene closed their eyes in anticipation more than three quarters of the time, while mice without the gene shut their eyes just a third of the time.

    While it is best known for its role in movement, the cerebellum is also important in higher cognitive functions such as language and attention, both of which are affected in autism. People with autism often have language delays and pay unusually intense attention to objects or topics that interest them. The cerebellum may be involved not only in motor learning but in other features of autism as well, the researchers said.

    Of course, there is a world of difference between a mouse that can’t learn to shut its eyes and a person with autism who struggles to communicate. But the researchers said the findings suggest that changing how many connections neurons make with each other can have important implications for behavior.

    Since this paper was written, Bonni and colleagues have tested the other autism-associated ubiquitin genes. Inhibition of all genes tested cause an increase in the number of synapses in the cerebellum.

    “It’s possible that excessive connections between neurons contribute to autism,” Bonni said. “More work needs to be done to verify this hypothesis in people, but if that turns out to be true, then you can start looking at ways of controlling the number of synapses. It could potentially benefit not just people who have these rare mutations in ubiquitin genes but other patients with autism.”


  4. Autism study examines relational factors in music therapy

    November 5, 2017 by Ashley

    From the Uni Research press release:

    Relational factors in music therapy can contribute to a positive outcome of therapy for children with autism.

    It might not surprise that good relationships create good outcomes, as meaningful relational experiences are crucial to all of us in our everyday life. However, the development of a relationship with a child with autism may be disrupted due to the level of symptoms interfering with the typical development of emotional and social abilities.

    In a new study, researchers from GAMUT, Uni Research Health and University of Bergen, could show that the quality of the therapeutic relationship predicts generalized changes in social skills in children diagnosed with an autism spectrum condition (ASC).

    This predictor study included 48 children between 4 and 7 years who received improvisational music therapy weekly over a period of 5 months. Outcomes related to the child’s social skills were measured before and after treatment. Based on session videos the researchers assessed the relationship between the child and the therapist.

    Findings of this study show a significant symptom reduction, if a relationship was developed in which the therapist was emotionally and musically attuned to the child’s expressions. Especially an improvement of communication and language skills was associated with the quality of the therapeutic relationship.

    Attunement as mechanism of change

    Attunement processes between humans are particularly described for early interactions between infants and their caregivers. It has been suggested that the caregiver’s capability to attune and synchronize to the infant’s movements, rhythms, and affects influences attachment and the development of social understanding. Within these attuned musical exchanges, the infant experiences being experienced and understood emotionally.

    – In music therapy with children with autism, therapists try to transfer principles from early interaction processes by making music that is specifically tailored to the child’s sounds, movements, postures, and affect. This should allow for moments of synchronization and attunement, Karin Mössler at Uni Research explains. Mössler is the principal investigator of the study.

    Children with childhood autism

    Focusing on musical and emotional attunement might be especially important for children with low functioning childhood autism as it might be specifically powerful when working with sensory processing, affect regulation, or deviations related to the child’s movements all of which can be crucially affected in these children. Even though the primary results of a related study investigating the effects of music therapy with children with autism, do not show that music therapy works better than other therapies, subgroup analysis identified that children with childhood autism or coexisting intellectual disability improve to a greater extend from music therapy than children with another autism diagnosis.

    Stereotypical behavior as resource

    In this sense, special focus should be given to intervention strategies fostering relationship through musical and emotional attunement. These strategies should help therapists but also parents of children with ASC to cope with the child’s symptom level by, for example, using its repetitive or stereotype movements and affective expressions as a resource and starting point for attunement.


  5. Study suggests signaling pathway may be key to why autism is more common in boys

    October 17, 2017 by Ashley

    From the University of Iowa Health Care press release:

    Researchers aiming to understand why autism spectrum disorders (ASD) are more common in boys have discovered differences in a brain signaling pathway involved in reward learning and motivation that make male mice more vulnerable to an autism-causing genetic glitch.

    “One intriguing aspect of autism is that it predominantly affects males; four boys are affected for every one girl,” says senior study author Ted Abel, PhD, director of the Iowa Neuroscience Institute at the University of Iowa Carver College of Medicine. “We don’t understand what it is about this disorder that predisposes boys as compared to girls to develop autism.”

    This male bias is also seen in other neurodevelopmental disorders, like attention deficit hyperactivity disorder (ADHD) and specific language impairments.

    Nearly one in every 200 cases of autism is caused by the deletion of a section of DNA on a particular chromosome. This type of disorder is also known as a copy number variation (CNV). The mouse model of autism used by the research team is missing the same stretch of DNA.

    The researchers tested the mice for abnormalities in reward-learning behavior — learning to associate actions with rewarding outcomes. This type of learning is mediated by a part of the brain called the striatum and is disrupted in people with autism and other neurodevelopmental disorders.

    The study, published online Oct. 17 in Molecular Psychiatry, shows that only male mice with the autism-associated genetic deletion have abnormal reward-learning behavior. Female mice with the same genetic deletion are not affected. Moreover, these sex-specific behavioral differences are accompanied by sex differences in molecular signaling pathways in the striatum brain region.

    Problems with reward learning could explain why individuals with autism don’t interact socially — because they don’t find it rewarding in the same way. It could explain why people with autism have restricted interests — because they find only very selective things rewarding — and it could explain the differences in language acquisition — because the neural circuitry involved in reward learning is the same circuitry that mediates both language learning and production,” says Abel, who also is the Roy J. Carver Chair in Neuroscience and UI professor of molecular physiology and biophysics.

    Female protective effect

    One of the genes contained in the missing section of DNA is an important signaling protein called ERK1. Activity of this protein affects the function of the striatum — the part of the brain that’s involved in reward learning and motivation. The researchers found that male mice carrying this genetic deletion have increased activation of ERK1 in the striatum coupled with decreased amounts of another protein that reduces ERK1 activity. In contrast, the female mice carrying the genetic deletion do not have overactivated ERK1. In addition, despite the genetic deletion, the female deletion mice have higher levels of ERK1 than the male deletion mice. All of these molecular differences mean that ERK1 signaling is particularly sensitive to disruption in male mice.

    “This is some of the first evidence in a mouse model of autism of a ‘female protective effect,’ from the behavioral to the molecular level,” says Nicola Grissom, first author of the study who is now an assistant professor of psychology at the University of Minnesota. “These findings shed valuable new light on the science of neurodevelopmental disorders, many of which are more common in boys. However, they also address the broader question of how sex and gender influence the neurobiology of how we learn and behave, which may be involved in the different levels of risk between women and men for developing many other neuropsychiatric conditions, as well.”

    The study also found that male mice carrying this genetic alteration linked to autism have increased expression of a receptor for dopamine; the D2 receptor. The level of D2 expression did not increase in the female autism mice. Abel notes that risperidone, one of very few drugs that is approved by the Food and Drug Administration to treat ASD symptoms, targets D2 dopamine receptors.

    “We think we are on the right track,” Abel says. “We have begun to identify what may be an underlying reason why neurodevelopmental disorders predominantly affect boys, and that involves the function of the striatum and reward learning. This has implications for how we think about the underlying behavioral differences in autism and implications for how we develop both behavioral or pharmacological therapies to improve the lives of those with autism.”

    The new findings are part of a bigger study where Abel and his colleagues are investigating many different mouse models of autism, in which different autism-linked genes have been disrupted. The researchers are seeking commonalities among the different models. One emerging theme, supported by the new study, is that a deficit in reward learning may be a common feature of ASD, and males are specifically deficient in this type of behavior.

    Abel notes that funding from the Simons Foundation was critical to the success of the project.

    “None of this would have happened without the support of the Simons Foundation Autism Research Initiative (SFARI). The impact they have had on autism research has been tremendous,” he says.


  6. Study suggests link between mothers’ immune response and social deficits for kids with autism

    October 14, 2017 by Ashley

    From the University of Sydney press release:

    The retrospective cohort study of 220 Australian children, conducted between 2011-2014, indicates that an “immune-mediated subtype” of autism driven by the body’s inflammatory and immunological systems may be pivotal, according to the University of Sydney’s Professor Adam Guastella.

    Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders, characterised by impaired reciprocal interaction and communication skills, and restricted and repetitive behaviours and interests. It occurs in one in every 68 people around the world.

    Maternal immune activation (MIA) has been highlighted as a factor that might increase the risk of ASD; however, this new study is believed to be the first to examine whether MIA is linked to poorer outcomes in children with ASD. MIA is defined as an active immune response during pregnancy that can be triggered by an external event such as infection or autoimmune disorders.

    The mechanisms by which MIA increases the risk of ASD are largely unknown but research suggests that an immune-mediated subtype in ASD may be driven by changes in cytokine, chemokine or antibody levels in the mother and/or child.

    The researchers say the identification of an immune system-mediated subtype in ASD driven by MIA and immune biomarkers would enable more streamlined diagnosis and management in clinical settings.

    Preclinical animal models have shown that immune activation during pregnancy causes ASD-like phenotypes in offspring, which supports the MIA hypothesis.

    Children recruited to the study were administered the Autism Diagnostic Observation Schedule-Generic (ADOS-G) that uses simple activities and questions designed to prompt and observe communication, social and stereotyped behaviours relevant to the diagnosis of ASD.

    A primary caregiver also completed the Social Responsiveness Scale (SRS), a 65-item rating scale measuring social interaction, language and repetitive/restricted behaviours and interests in the child. The SRS provides a total score and individual scores on five subscales: awareness, cognition, communication, motivation and mannerisms.

    A primary caregiver completed a family history questionnaire, which included a medical history including any diagnosed illnesses or chronic conditions.

    Results of the study support the identification of an immune-mediated subtype of autism that could have both diagnostic and treatment implications.

    Natalie Pollard said trying to understand why her eldest son, Ethan, 7, has autism was a “long journey,” but the findings were a positive step.

    The University of Sydney academic from Dural doesn’t suffer from asthma and allergies, and her two younger sons do not have autism.

    “I knew something wasn’t quite right early on, and his development was slower and he would scream for hours,” she said.

    “As a mum, I think the findings are great, because we need more information out there and it could potentially help solve the puzzle of autism, which is multi-factorial.”

    Results

    • A history of allergies or asthma in the mother was associated with increased severity of social symptoms
    • A history of autoimmune conditions in the mother was not associated with increased symptom severity

    “Our results build on existing research by showing an associated between maternal immune activation caused by asthma and allergies and ASD symptom severity in children with ASD, said Shrujna Patel, a University of Sydney PhD candidate who led the study with colleagues at the Brain and Mind Centre, Children’s Hospital Westmead, Macquarie University and the Telethon Kids Institute.

    “Children of mothers who reported a history of immune activation had significantly higher Social Responsiveness Scale total scores, suggesting they had more severe caregiver-reported deficits,” she said.

    “Specifically, they had higher scores on cognition and mannerisms subscales, suggesting they had more difficulty understanding social situations and displayed more restricted behaviours or unusual interests.”

    The researchers said the identification of an immune system-mediated subtype in ASD driven by MIA and immune biomarkers would enable more streamlined diagnosis and management in clinical settings.

    The findings also support the investigation of biomarkers in this sub-group and present potential new targets for immune-modulating drug therapies.


  7. Study reveals gender-specific risk of autism occurrence among siblings

    October 5, 2017 by Ashley

    From the Harvard Medical School press release:

    Having one child with autism is a well-known risk factor for having another one with the same disorder, but whether and how a sibling’s gender influences this risk has remained largely unknown.

    Now new research led by scientists at Harvard Medical School has for the first time successfully quantified the likelihood that a family who has one child with autism would have another one with the same disorder based on the siblings’ gender.

    Overall, the results, published Sept. 25 in JAMA Pediatrics, reveal that having an older female child diagnosed with autism spelled elevated risk for younger siblings and that the risk was highest among younger male siblings. They also affirm past research findings that having one child with autism or an autism spectrum disorder (ASD) portends higher risk for subsequent children, that the disorder is somewhat rare — slightly more than 1.2 percent of children in the study were affected — and that boys have a notably higher overall risk than girls.

    The findings can arm physicians and genetic counselors with information useful in counseling families and clarifying the risk for younger siblings in families who already have one child with autism.

    “Our results give us a fair degree of confidence to gauge the risk of autism recurrence in families affected by it based on a child’s gender,” said study first author Nathan Palmer, instructor in biomedical informatics at Harvard Medical School. “It is important to be able to provide worried parents who have one child with the condition some sense of what they can expect with their next child. That information is critical given how much better we’ve become at screening for the disease earlier and earlier in life.”

    Such knowledge, the researchers added, could be particularly important in light of physicians’ growing ability to detect autism’s manifestations early in a child’s life and intervene promptly.

    “This study is a powerful example of how big data can illuminate patterns and give us insights that allow us to empower parents and pediatricians to implement anticipatory and far more precise medicine,” said study senior author Isaac Kohane, head of the Department of Biomedical Informatics at Harvard Medical School.

    The newly published results stem from the largest study of its kind. Researchers analyzed de-identified health insurance records of more than 1.5 million U.S. families with two children between the ages of 4 and 18, tracking patterns of recurrence among siblings over a year or longer. Of the more than 3.1 million children in the study, some 39,000, or about 1.2 percent — 2 percent of boys and 0.5 percent of girls — received a diagnosis of autism or an ASD.

    The results confirm previous research showing that, overall, boys have a higher risk of autism and related disorders than girls.

    The results, however, also reveal a curious pattern of recurrence based on gender: Siblings born after a female child with autism or a related disorder had a higher risk than siblings born after a male child with autism. Male children were, overall, more susceptible to autism than females. In other words, boys with older female siblings with autism had the highest risk for autism themselves, while female siblings with older brothers with autism had the lowest risk.

    For every 100 boys with an older female sibling with autism, 17 received a diagnosis of autism or a related disorder. Male children with older male siblings with ASD had a 13 percent risk of an ASD diagnosis, followed by younger female siblings with older male siblings with ASD (7.6 percent). The lowest risk — 4 percent — was observed among younger female siblings who had an older brother with autism or an ASD.

    The investigators caution that families should keep the risk in perspective because autism and related disorders remain relatively rare, affecting roughly 1 percent of the general population.

    Even for the group at highest risk — males with an older female sibling with autism — the odds are still about five to one that the child will be unaffected,” Palmer said. “What we have provided here is context for families who already have children with autism or another similar disorder and need a clearer perspective on recurrence risk.”

    The results, the researchers said, underscore the notion that autism and related disorders likely arise from the complex interplay between genes and environment and, for reasons yet to be understood, these conditions disproportionately affect more males than females even within families. The stark gender variance, however, hints at a possible role of inherent biological sex differences that may precipitate the development of such disorders under the right environmental conditions, the research team said.

    Autism-spectrum disorders are neurodevelopmental conditions that typically emerge in the first few years. They are marked by a range of brain problems, impaired social interactions and compromised communication skills. The Centers for Disease Control and Prevention estimate that autism spectrum disorders affect 1 in 68 children in the United States, with males having four times greater risk than females — an observation also borne out in the new study.

    Yet exactly what portion of these diagnoses are strictly rooted in genetic mutation and how many are influenced by environmental factors has long mystified scientists. While some forms of autism arise from a single genetic mutation, most cases appear to be the result of a complex interplay between genes and environment.


  8. Study identifies biomarker for atypical development in infants at risk for developing autism

    September 24, 2017 by Ashley

    From the Columbia University Medical Center press release:

    New research from the Sackler Institute for Developmental Psychobiology at Columbia University Medical Center (CUMC) identifies a potential biomarker that predicts atypical development in 1- to 2-month-old infants at high versus low familial risk for developing autism spectrum disorders (ASD). The search for neurobiological markers that precede atypical trajectories is important in infants with a high risk for developing autism-related disorders because early recognition allows for early intervention and mitigation of difficulties later in life.

    Using data from National Database for Autism Research (NDAR), lead author Kristina Denisova, PhD, Assistant Professor of Psychiatry at CUMC and Fellow at the Sackler Institute, studied 71 high and low risk infants who underwent two functional Magnetic Resonance imaging brain scans either at 1-2 months or at 9-10 months: one during a resting period of sleep and a second while native language was presented to the infants. After extracting measures of head movements during the scans, the statistical characteristics of these movements were quantified.

    The study found that infants at high risk for developing ASD have elevated levels of “noise” and increased randomness in their spontaneous head movements during sleep, a pattern possibly suggestive of problems with sleep. In addition, 1- to 2-month-old high risk infants showed more similar signatures while listening to native language and while sleeping while low risk infants showed distinct signatures during the two conditions.

    Further, specific features of head movements during sleep at 1-2 months predicted future flatter (delayed) early learning developmental trajectories in the high-risk babies. The existence of generally atypical learning trajectories in the high risk group was verified in separate data sets from four representative high risk infant-sibling studies comprising a total of 1,445 infants with known ASD outcomes as children. These analyses showed that high risk infants — even those without ASD diagnoses — have significantly lower functioning in childhood relative to low risk infants. The current study reveals a possible way to predict which 1-2 months-old infants will show atypical developmental trajectories as toddlers.

    Dr. Denisova said, “The finding that head movement signatures are responsive to high context stimuli (native language speech) in low but not high risk infants is informative because it suggests that infants whose siblings were diagnosed with ASD are less attuned to evolutionarily important stimuli early in life.” She added that this response pattern may underlie atypical information processing in individuals with neurodevelopmental disorders.

    Dr. Jeremy Veenstra-VanderWeele, MD, an autism researcher who was not involved in this study, noted, “This study is a good example of how existing data can be mined for new insights. Additional work is needed to replicate the current findings and understand the underlying mechanisms, but this work suggests new ways to look at movement or motor function in infants at high risk of ASD.”


  9. Using DNA to predict schizophrenia, autism

    September 15, 2017 by Ashley

    From the Osaka University press release:

    Osaka University researchers show in a multi-institute collaboration that a single amino acid substitution in the protein CX3CR1 may act as predictor for schizophrenia and autism.

    Huntington’s disease, cystic fibrosis, and muscular dystrophy are all diseases that can be traced to a single mutation. Diagnosis in asymptomatic patient for these diseases is relatively easy — You have the mutation? Then you are at risk. Complex diseases, on the other hand, do not have a clear mutational footprint. A new multi-institutional study by Japanese researchers shows a potential rare gene mutation that could act as a predictor for two neurodevelopmental disorders, schizophrenia and autism.

    “Aberrant synapse formation is important in the pathogenesis of schizophrenia and autism,” says Osaka University Professor Toshihide Yamashita, one of the authors of the study. “Microglia contribute to the structure and function of synapse connectivities.”

    Microglia are the only cells in the brain that express the receptor CX3CR1. Mutations in this receptor are known to affect synapse connectivity and cause abnormal social behavior in mice. They have also been associated with neuroinflammatory diseases such as multiple sclerosis, but no study has shown a role in neurodevelopment disorders.

    Working with this hypothesis, the researchers conducted a statistical analysis of the CX3CR1 gene in over 7000 schizophrenia and autism patients and healthy subjects, finding one mutant candidate, a single amino acid switch from alanine to threonine, as a candidate marker for prediction.

    “Rare variants alter gene function but occur at low frequency in a population. They are of high interest for the study of complex diseases that have no clear mutational cause,” said Yamashita, who added the alanine threonine substitution was a rare variant.

    The structure of CX3CR1 includes a domain known as Helix 8, which is important for initiating a signaling cascade. Computer models showed that one amino acid change is enough to compromise the signaling.

    “The variant changes the region from hydrophobic to hydrophilic and destabilize Helix 8. We overexpressed the mutation in cells and found Akt signaling was disrupted,” explains Yamashita.

    According to Yamashita, the findings are the first to connect a genetic variation in microglia with neurodevelopment disorders. Moreover, he hopes that the discovery could become a basis for predictive diagnostics.

    “There is no reliable way to diagnose schizophrenia or autism in asymptomatic patients. Deeper understanding of the genetic risk factors will help us develop preventative measures.”


  10. Origins of autism: Abnormalities in sensory processing at six months

    September 13, 2017 by Ashley

    From the McGill University press release:

    The origins of autism remain mysterious. What areas of the brain are involved, and when do the first signs appear? New findings published in Biological Psychiatry brings us closer to understanding the pathology of autism, and the point at which it begins to take shape in the human brain. Such knowledge will allow earlier interventions in the future and better outcomes for autistic children.

    Scientists used a type of magnetic resonance imaging (MRI), known as diffusion weighted imaging, to measure the brain connectivity in 260 infants at the ages of 6 and 12 months, who had either high or low risks of autism. The lengths and strengths of the connections between brain regions was used to estimate the network efficiency, a measure of how well each region is connected to other regions. A previous study with 24-month-old children found that network efficiency in autistic children was lower in regions of the brain involved in language and other behaviours related to autism. The goal of this new study was to establish how early these abnormalities occur.

    Lead author John Lewis, a researcher at the Montreal Neurological Institute and Hospital of McGill University and the Ludmer Centre for Bioinformatics and Mental Health, found network inefficiencies had already been established in six-month-old infants who went on to be diagnosed with autism. Inefficiencies in the six-month-olds appeared in the auditory cortex. He also found the extent of the inefficiency at six months of age was positively related to the severity of autistic symptoms at 24 months. As the children aged, areas involved in processing of vision and touch, as well as a larger set of areas involved in sound and language, also showed such a relation between inefficiency and symptom severity.

    Identifying the earliest signs of autism is important because it may allow for diagnosis before behavioural changes appear, leading to earlier intervention and better prospects for a positive outcome. By pinpointing the brain regions involved in processing sensory inputs as the earliest known locations of neural dysfunction related to autism, researchers narrow down the genetic factors and mechanisms that could be responsible for its development. The fact that neurological signs are already present at six months also eliminates some environmental factors as potential causes of the disorder.

    “Our goal was to discover when and where in the brain the network inefficiencies first appeared,” says Lewis. “The results indicate that there are differences in the brains of infants who go on to develop autism spectrum disorder even at six months of age, and that those early differences are found in areas involved in processing sensory inputs, not areas involved in higher cognitive functions. We hope that these findings will prove useful in understanding the causal mechanisms in autism spectrum disorder, and in developing effective interventions.”

    The research comes from the Infant Brain Imaging Study (IBIS), a collaborative effort by investigators at the Montreal Neurological Institute, and four clinical sites in the United States, coordinated to conduct a longitudinal brain imaging and behavioural study of infants at high risk for autism.