Hygiene Hypothesis and The Gut.

The gut microbiomes of infants have an impact on autoimmunity

http://www.aalto.fi/en/current/news/2016-04-28-006/

Exposure to pathogens early in life is beneficial to the education and development of the human immune system.

Over the past few decades, the healthcare community has observed an intriguing phenomenon: diseases related to the immune system – type 1 diabetes, and other autoimmune diseases, allergies, and the like – have taken hold in countries that have thriving, modern economies, while barely making a mark in the developing world. One of the best-supported theories to explain this peculiar public health pattern has been dubbed the hygiene hypothesis. The theory is based on the premise that exposure to pathogens early in life is actually beneficial to the education and development of the human immune system.

– Exposure to bacteria may play a pivotal role in the immune system, and that we might be able to understand what that role is by studying the human microbiome, says Aleksandar Kostic, a postdoctoral fellow in the lab of Ramnik Xavier at the Broad Institute of MIT and Harvard.

The work is the product of an extensive collaboration involving researchers at Aalto University, Broad Institute, University of Helsinki, the Novartis Institute of Biomedical Research, and other organizations across the globe working together as part of the DIABIMMUNE Study Group. By looking at the gut microbiomes of infants from three different countries, the team uncovered evidence that not only supports the hygiene hypothesis, but also points to interactions among bacterial species that may account, at least in part, for the spike in immune disorders seen in western societies.

Silent microbiomes

The DIABIMMUNE Study Group recruited and began collecting monthly stool samples from infants in each of the three countries: Finland, Estonia and Russian Karelia. Along with the samples, from which they would identify and quantify the bacteria that made up the infants’ gut microbiomes, they also collected lab tests and questionnaires about such topics as breastfeeding, diet, allergies, infections, and family history. They evaluated all of this data, which was collected from birth to age three from over 200 infants, to see whether connections might exist between disease incidence and what they found in the microbiome.

By characterizing the microbial content of the stool samples, the team found a sharp distinction between the microbiomes of Finnish and Estonian infants and their Russian Karelian counterparts: the gut microbiomes of the Finnish and Estonian infants were dominated by Bacteroides species, while Russian Karelian infants had an overrepresentation of Bifidobacterium early in life and an overall greater variability in their microbiomes over the course of the three years that samples were collected.

– We can only speculate why this difference in bacterial populations exists; what we could show was what implications that difference in populations might have, says Tommi Vatanen, a Doctoral candidate at the Aalto University and Broad who was a co-first author of the Cell study.

LPS has been well-known for its ability to trigger the immune system that LPS from the bacteria E. coli is commonly used to stimulate immune cells in laboratory experiments. But, it turns out, not all LPS are created equal.

When the researchers looked at LPS signaling in the Russian Karelian microbiome, they saw a familiar pattern: E. coli LPS led the charge, likely performing its usual role triggering the immune response. However, when the researchers looked at LPS signaling in the Finnish and Estonian microbiomes, they found that the LPS from the Bacteroides species ruled the roost. What’s more, they discovered that the particular form of LPS found in Bacteroides fails to activate the immune system and even stifles the immune-activating LPS from the E. coli and other bacteria living in those communities.

– We believe that E. coli, which lives in the infant gut in all three countries, might be one of the immune educating bacteria responsible for training the immune system early in life. But, we found that if you mix Bacteroides with E. coli it can actually inhibit the immune-activating properties of E. Coli, and we suspect this might have consequences on the development of the immune system, Vatanen explains.

– In the Finnish and Estonian infants, where Bacteroides dominates, the gut microbiome is immunologically very silent, Kostic adds, and continues – We believe that, later on, this makes them more prone to strong inflammatory stimuli.

The researchers suspect that the LPS immune activation by E. coli seen in the Russian Karelian infants is reflective of the relationship humans developed with microbiota over the course of human evolution. The prevalence and dominance of Bacteroides, in contrast, is a more recent phenomenon related in some way to improved sanitation and standard of living.

The researchers say that they would next like to investigate how and why Bacteroides has come to dominate in the infant gut in these westernized countries. They also plan to expand their studies to include other geographic regions and hope to uncover additional mechanisms that help explain the connection between the microbiome and immune-related disease.

Michael Knip of the University of Helsinki also served as a co-senior author of the study. Other researchers who contributed to the work include: Heli Siljander, Eric Franzosa, Moran Yassour, Raivo Kolde, Hera Vlamakis, Timothy Arthur, Anu-Maaria Hämäläinen, Aleksandr Peet, Vallo Tillmann, Raivo Uibo, Sergei Mokurov, Natalya Dorshakova, Jorma Ilonen, Suvi Virtanen, Susanne Szabo, Jeff Porter, Harri Lähdesmäki, Curtis Huttenhower, and Dirk Gevers.

Article:

Vatanen et al., Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans, Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.04.007

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Posted in Allergy, Asthma, Autism, Bacteria, bowel disease, co-morbid, diabetes, Environment, Epigenetics, Genetics, Gut, IBD, Immune System, Inflammation, Treatment | Leave a comment

Chronic Lack of Sleep – Linked to Neurological Damage – Implications for Autism ?

 Insomnia Linked to Damage in Brain Communication Networks

https://www2.rsna.org

At A Glance

  • Twenty-three insomnia patients and 30 healthy controls were examined with diffusion tensor imaging and given questionnaires to evaluate mental status and sleep patterns.
  • Compared to the healthy controls, insomnia patients had altered white matter tract integrity in brain regions that regulate sleep, consciousness, and alertness.
  • White matter integrity abnormalities in insomnia patients may be caused by loss of myelin.

OAK BROOK, Ill. — Using a sophisticated MRI technique, researchers have found abnormalities in the brain’s white matter tracts in patients with insomnia. Results of the study were published online in the journal Radiology.

Primary insomnia, in which individuals have difficulty falling or staying asleep for a month or longer, is associated with daytime fatigue, mood disruption and cognitive impairment. Insomnia can also lead to depression and anxiety disorders

“Insomnia is a remarkably prevalent disorder,” said researcher Shumei Li, M.S., from the Department of Medical Imaging, Guangdong No. 2 Provincial People’s Hospital, Guangzhou, China. “However, its causes and consequences remain elusive.”

For the study, Li, along with colleagues lead by investigator Guihua Jiang, M.D., set out to analyze the white matter tracts in insomnia patients and the relationship between abnormal white matter integrity and the duration and features of insomnia.

“White matter tracts are bundles of axons—or long fibers of nerve cells—that connect one part of the brain to another,” Li said. “If white matter tracts are impaired, communication between brain regions is disrupted.”

The study included 23 patients with primary insomnia and 30 healthy control volunteers. To evaluate mental status and sleep patterns, all participants completed questionnaires including the Pittsburgh Sleep Quality Index, the Insomnia Severity Index, the Self-Rating Anxiety Scale and the Self-Rating Depression Scale.

Each participant also underwent brain MRI with a specialized technique called diffusion tensor imaging (DTI). DTI allows researchers to analyze the pattern of water movement along white matter tracts to identify a loss of tract integrity.

“We used a new method called Tract-Based Spatial Statistics that is highly sensitive to the microstructure of the white matter tract and provides multiple diffusion measures,” Li said.

Results of the analysis showed that compared to the healthy controls, the insomnia patients had significantly reduced white matter integrity in several right-brain regions, and the thalamus which regulates consciousness, sleep and alertness.

“These impaired white matter tracts are mainly involved in the regulation of sleep and wakefulness, cognitive function and sensorimotor function,” Li said.

In addition, abnormalities in the thalamus and body corpus callosum—the largest white matter structure in the brain—were associated with the duration of patients’ insomnia and score on self-rating depression scale.

“The involvement of the thalamus in the pathology of insomnia is particularly critical, since the thalamus houses important constituents of the body’s biological clock,” she added.

The study also found that underlying cause of white matter integrity abnormalities in insomnia patients may be loss of myelin, the protective coating around nerve fibers.

The researchers caution that further study needs to be done on a larger sample to clarify the relationship between altered white matter integrity and insomnia.

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Further Readings of Interest

Sleep

https://asdresearchinitiative.wordpress.com/?s=sleep

Posted in Autism, co-morbid, Environment, Neurology, Physiology, Treatment | Leave a comment

Environment x Genes – Fungicides and Autism

Could a new class of fungicides play a role in autism, neurodegenerative diseases?

http://news.unchealthcare.org/news/2016/march/could-a-new-class-of-fungicides-play-a-role-in-autism-neurodegenerative-diseases

A new UNC School of Medicine study shows how chemicals designed to protect crops can cause gene expression changes in mouse brain cells that look strikingly similar to changes in the brains of people with autism and Alzheimer’s disease.

March 31, 2016

CHAPEL HILL, NC – Scientists at the UNC School of Medicine have found a class of commonly used fungicides that produce gene expression changes similar to those in people with autism and neurodegenerative conditions, including Alzheimer’s disease and Huntington’s disease.

The study, published today in the journal Nature Communications, describes a new way to home in on chemicals that have the potential to affect brain functions.

Mark Zylka, PhD, senior author of the study and associate professor of cell biology and physiology at UNC, and his team exposed mouse neurons to approximately 300 different chemicals. Then the researchers sequenced RNA from these neurons to find out which genes were misregulated when compared to untreated neurons. This work created hundreds of data sets of gene expression; genes give rise to products, including proteins or RNA.

Zylka’s team then used computer programs to deduce which chemicals caused gene expression changes that were similar to each other.

“Based on RNA sequencing, we describe six groups of chemicals,” Zylka said. “We found that chemicals within each group altered expression in a common manner. One of these groups of chemicals altered the levels of many of the same genes that are altered in the brains of people with autism or Alzheimer’s disease.”

Chemicals in this group included the pesticides rotenone, pyridaben, and fenpyroximate, and a new class of fungicides that includes pyraclostrobin, trifloxystrobin, fenamidone, and famoxadone. Azoxystrobin, fluoxastrobin, and kresoxim-methyl are also in this fungicide class.

“We cannot say that these chemicals cause these conditions in people,” Zylka cautioned. “Many additional studies will be needed to determine if any of these chemicals represent real risks to the human brain.”

Zylka, a member of the UNC Neuroscience Center, and his group found that these chemicals reduced the expression of genes involved in synaptic transmission – the connections important for communication between neurons. If these genes are not expressed properly, then our brains cannot function normally. Also, these chemicals caused an elevated expression of genes associated with inflammation in the nervous system.  This so-called neuroinflammation is commonly seen in autism and neurodegenerative conditions.

The researchers also found that these chemicals stimulated the production of free radicals – particles that can damage the basic building blocks of cells and that have been implicated in a number of brain diseases. The chemicals also disrupted neuron microtubules.

“Disrupting microtubules affects the function of synapses in mature neurons and can impair the movement of cells as the brain develops,” Zylka said. “We know that deficits in neuron migration can lead to neurodevelopmental abnormalities. We have not yet evaluated whether these chemicals impair brain development in animal models or people.”

Jeannie T. Lee, MD, PhD, professor of genetics at Harvard Medical School and Massachusetts General Hospital, who was not involved in this research, said, “This is a very important study that should serve as a wake-up call to regulatory agencies and the general medical community. The work is timely and has wide-ranging implications not only for diseases like autism, Parkinson’s, and cancer, but also for the health of future generations. I suspect that a number of these chemicals will turn out to have effects on transgenerational inheritance.”

Zylka’s group also analyzed information from the U.S. Geological Survey, which monitors countywide pesticide usage, as well as the Food and Drug Administration and the U.S. Department of Agriculture, which test foodstuffs yearly for pesticide residues.

Of the chemicals Zylka’s team studied, only the usage of pyridaben has decreased since 2000. Rotenone use has remained the same since 2000. However, the use of all the fungicides in this group has increased dramatically over the past decade.

Indeed, a study from the Environmental Protection Agency found that pyraclostrobin is found on foods at levels that could potentially affect human biology, and another study linked pyraclostrobin usage to honeybee colony collapse disorder.

The pesticide rotenone was previously implicated in Parkinson’s disease through replicated animal experiments and through human epidemiological studies. A separate 2015 UNC study found that Parkinson’s disease is much more common in older adults with autism than in older adults without autism.

Previous work has also shown that a single dose of the fungicide trifloxystrobin reduced motor activity for several hours in female rats and for days in male rats. Disrupted motor function is a common symptom of Parkinson’s disease and other neurological disorders.  The related fungicide picoxystrobin impaired motor activity in rats at the lowest dose tested.

Zylka added, “The real tough question is: if you eat fruits, vegetables or cereals that contain these chemicals, do they get into your blood stream and at what concentration?  That information doesn’t exist.” Also, given their presence on a variety of foodstuffs, might long term exposure to these chemicals – even at low doses – have a cumulative effect on the brain?

Zylka noted that conventionally grown leafy green vegetables such as lettuce, spinach, and kale have the highest levels of these fungicides.  But due to each chemical’s effectiveness at reducing fungal blights and rust, crop yields have increased and farmers are expanding their use of these chemicals to include many additional types of food crops.

Zylka’s team hopes their research will encourage other scientists and regulatory agencies to take a closer look at these fungicides and follow up with epidemiological studies.

“Virtually nothing is known about how these chemicals impact the developing or adult brain,” Zylka said. “Yet these chemicals are being used at increasing levels on many of the foods we eat.”

This research was funded by three of the National Institutes of Health: the National Institute of Environmental Health Sciences, the National Institute on Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Mark Zylka, PhD, is a member of the Carolina Institute for Developmental Disabilities and the UNC Lineberger Comprehensive Cancer Center. He was named director of the UNC Neuroscience Center in January and will take over for current director William Snider, MD, in July. Brandon Pearson, PhD, and Jeremy Simon, PhD, were co-first authors on the study. Additional authors from UNC include Eric McCoy, PhD, Giulia Fragola, PhD, and Gabriela Salazar.

 

Zylka’s previous work on drugs that affect autism-linked genes, published in Nature, can be found here.

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Further Readings of Interest

Pesticides

https://asdresearchinitiative.wordpress.com/?s=pesticides

 

 

Posted in Autism, co-morbid, Environment, Immune System, Inflammation, Neurology | Leave a comment

2016 CDC Autism Prevalence – 1 in 68

U.S. Autism Rate Unchanged in New CDC Report

http://www.jhsph.edu

Researchers say it’s too early to tell if rate has stabilized

Researchers at the Johns Hopkins Bloomberg School of Public Health contributed to a new U.S. Centers for Disease Control and Prevention (CDC) report that finds the prevalence of autism spectrum disorder (ASD) largely unchanged from two years ago, at one in 68 children (or 1.46 percent). Boys were 4.5 times more likely to be identified with ASD than girls, an established trend. The rate is one in 42 among boys and one in 189 among girls.

ASD is a developmental disorder characterized by social and communication impairments, limited interest and repetitive behaviors. Early diagnosis and intervention are important to improving learning and skills. Rates have been rising since the 1960s, but researchers do not know how much of this rise is due to more children being diagnosed with ASD or if actual cases are increasing or a combination of both. The CDC’s first prevalance report, which was released in 2007 and was based on 2000 and 2002 data, found that one in 150 children had ASD.  

For this new report, the CDC collected data at 11 regional monitoring sites that are part of the Autism and Developmental Disabilities Monitoring (ADDM) Network in the following states: Arkansas, Arizona, Colorado, Georgia, Maryland, Missouri, New Jersey, North Carolina, South Carolina, Utah, and Wisconsin. The Maryland monitoring site is based at the Johns Hopkins Bloomberg School of Public Health.

“Although we did not observe a significant increase in the overall prevalence rates in the monitoring sites, we continue to see the disparity among racial and ethnic groups,” says Dr. Li-Ching Lee, PhD, ScM, a psychiatric epidemiologist with the Bloomberg School’s departments of Epidemiology and Mental Health, and the principal investigator for the Maryland-ADDM.  “For example, in Maryland, we found that Hispanic children were less likely to be evaluated for developmental concerns and therefore less likely to be identified.”

In Maryland, Lee notes, the vast majority of children (95 percent) identified with ASD had a developmental concern in their records by age three, but only 55 percent of them received a comprehensive evaluation by age three. “This lag may delay the timing for children with ASD to get diagnosed and receive needed services,” Lee says.

The prevalence in Maryland was one in 55 children (1.82 percent) with one in 34 among boys and one in 161 among girls. The data were derived from health and special education records of children who were eight years old and living in Baltimore County in 2012.

This is the sixth report by the CDC’s Autism and Developmental Disabilities Monitoring Network (ADDM), which has used the same surveillance methods for more than a decade.  Estimated prevalence rates of ASD in the U.S. reported by previous data were:

  • one in 68 children in the 2014 report that looked at 2010 data
  • one in 88 children in the 2012 report that looked at 2008 data
  • one in 110 children in the 2009 report that looked at 2006 data
  • one in 150 children in the 2007 report that looked at 2000 and 2002 data

The researchers say it is too early to tell if the overall prevalence rate has stabilized because the numbers vary widely across ADDM communities. In communities where both health and education records were reviewed, the rates are from a low of 1.24% in parts of South Carolina to a high of 2.46% in parts of New Jersey. 

Some trends in the latest CDC report data remain consistent, such as the greater likelihood of boys being diagnosed with ASD. Disparities by race/ethnicity in estimated ASD prevalence, the age of earliest comprehensive evaluation and presence of a previous ASD diagnosis or classification persist. Specifically, non-white children with ASD are being identified and evaluated at a later age than non-Hispanic white children.  The majority of children identified with ASD by the ADDM Network (82 percent) had a previous ASD diagnosis or a special educational classification.

The causes of autism are not completely understood; studies show that both environment and genetics may play a role. There is no known cure, and no treatment or intervention has been proven to reduce the prevalence of ASD. The CDC recommends that parents track their child’s development,  act quickly and get their child screened if they have a concern. Free checklists and information for parents, physicians and child care providers are available at http://www.cdc.gov/ActEarly.

A full copy of the report, “Prevalence of Autism Spectrum Disorder – Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012,” is available on the CDC website here.

A copy of the Community Report with individual state statistics is available here.

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Further Readings of Interest

Prevalence

https://asdresearchinitiative.wordpress.com/?s=prevalence

Posted in Autism, Environment, Genetics | Leave a comment

Environmental Enrichment as a Treatment for Early Life Inflammation

Environmental enrichment rescues the effects of early life inflammation on markers of synaptic transmission and plasticity.

http://www.ncbi.nlm.nih.gov/pubmed/27002704

 Abstract

Environmental enrichment (EE) has been successful at rescuing the brain from a variety of early-life psychogenic stressors.

However, its ability to reverse the behavioral and neural alterations induced by a prenatal maternal infection model of schizophrenia is less clear. Moreover, the specific interactions between the components (i.e. social enhancement, novelty, physical activity) of EE that lead to its success as a supportive intervention have not been adequately identified.

In the current study, standard housed female Sprague-Dawley rats were administered either the inflammatory endotoxin lipopolysaccharide (LPS; 100μg/kg) or pyrogen-free saline (equivolume) on gestational day 15.

On postnatal day 50, offspring were randomized into one of three conditions: EE (group housed in a large multi-level cage with novel toys, tubes and ramps), Colony Nesting (CN; socially-housed in a larger style cage), or Standard Care (SC; pair-housed in standard cages).

Six weeks later we scored social engagement and performance in the object-in-place task. Afterwards hippocampus and prefrontal cortex (n=7-9) were collected and evaluated for excitatory amino acid transporter (EAAT) 1-3, brain-derived neurotrophic factor (BDNF), and neurotrophic tyrosine kinase, receptor type 2 (TrkB) gene expression (normalized to GAPDH) using qPCR methods.

Overall, we show that gestational inflammation downregulates genes critical to synaptic transmission and plasticity, which may underlie the pathogenesis of neurodevelopmental disorders such as schizophrenia and autism. Additionally, we observed disruptions in both social engagement and spatial discrimination. Importantly, behavioral and neurophysiological effects were rescued in an experience dependent manner. Given the evidence that schizophrenia and autism may be associated with infection during pregnancy, these data have compelling implications for the prevention and reversibility of the consequences that follow immune activation in early in life.

Copyright © 2016 Elsevier Inc. All rights reserved.

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Further Readings of Interest

Inflammation

https://asdresearchinitiative.wordpress.com/?s=inflammation

Environmental Enrichment

https://asdresearchinitiative.wordpress.com/?s=environmental+enrichment

 

Posted in Autism, Environment, Gut, IBD, Immune System, Inflammation, Neurology, Physiology, Schizophrenia, Treatment, Virus | Leave a comment

Microglia, Inflammation, the Immune System, Cerebral Palsy and Autism

Microglial migration and interactions with dendrimer nanoparticles are altered in the presence of neuroinflammation.

http://www.ncbi.nlm.nih.gov/pubmed/27004516

 Abstract

BACKGROUND:

Microglial cells have been implicated in neuroinflammation-mediated injury in the brain, including neurodevelopmental disorders such as cerebral palsy (CP) and autism. Pro-inflammatory activation of microglial cells results in the impairment of their neuroprotective functions, leading to an exaggerated, ongoing immune dysregulation that can persist long after the initial insult. We have previously shown that dendrimer-mediated delivery of an anti-inflammatory agent can attenuate inflammation in a rabbit model of maternal inflammation-induced CP and significantly improve the motor phenotype, due to the ability of the dendrimer to selectively localize in activated microglia.

METHODS:

To elucidate the interactions between dendrimers and microglia, we created an organotypic whole-hemisphere brain slice culture model from newborn rabbits with and without exposure to inflammation in utero. We then used this model to analyze the dynamics of microglial migration and their interactions with dendrimers in the presence of neuroinflammation.

RESULTS:

Microglial cells in animals with CP had an amoeboid morphology and impaired cell migration, demonstrated by decreased migration distance and velocity when compared to cells in healthy, age-matched controls. However, this decreased migration was associated with a greater, more rapid dendrimer uptake compared to microglial cells from healthy controls.

CONCLUSIONS:

This study demonstrates that maternal intrauterine inflammation is associated with impaired microglial function and movement in the newborn brain. This microglial impairment may play a role in the development of ongoing brain injury and CP in the offspring. Increased uptake of dendrimers by the “impaired” microglia can be exploited to deliver drugs specifically to these cells and modulate their functions. Host tissue and target cell characteristics are important aspects to be considered in the design and evaluation of targeted dendrimer-based nanotherapeutics for improved and sustained efficacy. This ex vivo model also provides a rapid screening tool for evaluation of the effects of various therapies on microglial function.

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Further Readings of Interest

Microglia

https://asdresearchinitiative.wordpress.com/?s=microglia

Inflammation

https://asdresearchinitiative.wordpress.com/?s=inflammation

 

Posted in Autism, co-morbid, Environment, Immune System, Inflammation, Neurology, Physiology, Treatment, Virus | Leave a comment

New Shift in Understanding – We are all Autism

Autism genes are in all of us, new research reveals

http://www.bristol.ac.uk/news/2016/march/autism-genetics-population.html

New light has been shed on the genetic relationship between autistic spectrum disorders (ASD) and ASD-related traits in the wider population, by a team of international researchers including academics from the University of Bristol, the Broad Institute of Harvard and MIT, and Massachusetts General Hospital (MGH).

The researchers studied whether there is a genetic relationship between ASD and the expression of ASD-related traits in populations not considered to have ASD. Their findings, published this week in Nature Genetics, suggest that genetic risk underlying ASD, including both inherited variants and de novo influences (not seen in an individual’s parents), affects a range of behavioural and developmental traits across the population, with those diagnosed with ASD representing a severe presentation of those traits.

Autism spectrum disorders (ASD) are a class of neurodevelopmental conditions affecting about 1 in 100 children. They are characterised by social interaction difficulties, communication and language impairments, as well as stereotyped and repetitive behaviour. These core symptoms are central to the definition of an ASD diagnosis but also occur, to varying degrees, in unaffected individuals and form an underlying behavioural continuum.

With recent advances in genome sequencing and analysis, a picture of ASD’s genetic landscape has started to take shape. Research has shown that most ASD risk is polygenic (stemming from the combined small effects of thousands of genetic differences, distributed across the genome). Some cases are also associated with rare genetic variants of large effect, which are usually de novo.

“There has been a lot of strong but indirect evidence that has suggested these findings,” said Dr Mark Daly, co-director of the Broad Institute’s Medical and Population Genetics (MPG) Program and senior author of the study.

“Once we had measurable genetic signals in hand – both polygenic risk and specific de novo mutations known to contribute to ASD – we were able to make an incontrovertible case that the genetic risk contributing to autism is genetic risk that exists in all of us, and influences our behaviour and social communication.”

Study co-first author Dr Elise Robinson, from MGH, said: “We can use behavioural and cognitive data in the general population to untangle the mechanisms through which different types of genetic risk are operating. We now have a better path forward in terms of expecting what types of disorders and traits are going to be associated with certain types of genetic risk.”

“Our study shows that collecting and using phenotypic and genetic data in typically developing children can be useful in terms of the design and interpretation of studies targeting complex neurodevelopmental and psychiatric disorders,” said study co-first author Dr Beate St Pourcain, from the Medical Research Council Integrative Epidemiology Unit at the University of Bristol and the Max Planck Institute for Psycholinguistics.

“Based on the genetic link between population-based social-communication difficulties and clinical ASD, we may now gain further phenotypic insight into a defined set of genetically-influenced ASD symptoms. This may help us to identify and investigate biological processes in typically-developing children, which are disturbed in children with ASD.”

The data on unaffected individuals came from a general population cohort (the Bristol-based Avon Longitudinal Study of Parents and Children) and a nuclear family cohort (the Simons Simplex Collection) of ASD cases and unaffected siblings; ASD collections included several large, international autism genetic studies: the Psychiatric Genomics Consortium Autism group, the iPSYCH autism project in Denmark, the SSC, and the Autism Sequencing Consortium.

Professor George Davey Smith, co-author and scientific director of ALSPAC, said: “Many traits that related to disease risk – like blood pressure or cholesterol levels – demonstrate a similar continuum of risk, with contributions from common and rare genetic variants, plus environmental and chance events. The present study demonstrates how this continuum applies to a condition generally thought of as either existing or not.”

The researchers expect the approach to be used to explore the associations between genetic risk and behavioural traits in other neuropsychiatric disorders such as schizophrenia in the future.

Paper

‘Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population’ by Robinson, EB, St. Pourcain, B et al in Nature Genetics. Online March 21, 2016

Posted in Autism, co-morbid, Environment, Genetics, Treatment | Leave a comment

Immune Response and Complement system play a Major role in Epilepsy

Identification of novel gene and pathway targets for human epilepsy treatment.

http://www.ncbi.nlm.nih.gov/pubmed/26742644

 Abstract

BACKGROUND:

The aim of this study was to explore epilepsy-related mechanism so as to figure out the possible targets for epilepsy treatment.

METHODS:

The gene expression profile dataset GES32534 was downloaded from Gene Expression Omnibus database. We identified the differentially expressed genes (DEGs) by Affy package. Then the DEGs were used to perform gene ontology (GO) and pathway enrichment analyses. Furthermore, a protein-protein interaction (PPI) network was constructed with the DEGs followed by co-expression modules construction and analysis.

RESULTS:

Total 420 DEGs were screened out, including 214 up-regulated and 206 down-regulated genes. Functional enrichment analysis revealed that down-regulated genes were mainly involved in the process of immunity regulation and biological repairing process while up-regulated genes were closely related to transporter activity. PPI network analysis showed the top ten genes with high degrees were all down-regulated, among which FN1 had the highest degree. The up-regulated and down-regulated DEGs in the PPI network generated two obvious sub-co-expression modules, respectively. In up-co-expression module, SCN3B (sodium channel, voltage gated, type III beta subunit) was enriched in GO:0006814 ~ sodium ion transport. In down-co-expression module, C1QB (complement C1s), C1S (complement component 1, S subcomponent) and CFI (complement factor I) were enriched in GO:0006955 ~ immune response.

CONCLUSION:

The immune response and complement system play a major role in the pathogenesis of epilepsy. Additionally, C1QB, C1S, CFI, SCN3B and FN1 may be potential therapeutic targets for epilepsy.

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Further Readings of Interest

https://asdresearchinitiative.wordpress.com/?s=inflammation

https://asdresearchinitiative.wordpress.com/?s=epilepsy+immune

 

Posted in Autism, co-morbid, epilepsy, Immune System, Inflammation, Neurology, Treatment, Uncategorized | Leave a comment

Inflammatory Pathways in Epilepsy

Inflammatory mediators in human epilepsy: A systematic review and meta-analysis.

http://www.ncbi.nlm.nih.gov/pubmed/26877106

Abstract

BACKGROUND:

Accumulating evidence suggests a role for inflammation in the pathophysiology of epilepsy.

METHODS:

We performed a systematic review and meta-analysis of studies that investigated inflammatory mediators in human epilepsy. Studies reporting on inflammatory mediators in serum, cerebrospinal fluid or brain tissue of epilepsy patients were included. Studies comparing patients to controls were included in a meta-analysis.

RESULTS:

66 articles reporting on 1934 patients were included. IL-1ra, IL-1β, IL-6, IL-10, IFN-γ and TNF-α were the most extensively investigated proteins. Elevated levels for IL-1ra, IL-1β, IL-6 and CXCL8/IL-8 were reported in several different epilepsy etiologies and media, while other proteins were specifically increased for one etiology. IL-1α, IL-7 and IL-13, as well as the chemokines CCL2-5, -19 and -22, were increased exclusively in brain tissue. In an aggregate meta-analysis, we found significantly different protein levels for serum IL-6, IL-17 and CSF IL-1β and IL-10.

CONCLUSION:

Inflammatory pathways are involved in epilepsy. Future studies may further clarify their role, and prove potential of targeted anti-inflammatory treatment.

Copyright © 2016 Elsevier Ltd. All rights reserved.

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Further Readings of Interest

https://asdresearchinitiative.wordpress.com/?s=epilepsy

https://asdresearchinitiative.wordpress.com/?s=inflammation

 

Posted in Autism, co-morbid, epilepsy, Immune System, Inflammation, Neurology, Treatment | Leave a comment

Autism co-morbidity in Epilepsy – New Spanish Research

Prognosis of symptomatic epilepsies in relation to their age of onset, monitored at a neuropediatric section of regional reference over a period of three years].

http://www.ncbi.nlm.nih.gov/pubmed/26961422

AIM:

To analyze the factors involved in the prognosis of symptomatic epilepsies in relation to their age at onset, monitored at a neuropediatric section of regional reference over a period of three years.

PATIENTS AND METHODS:

Children diagnosed with symptomatic epilepsy, supervised from January 1, 2008 to December 31, 2010, collecting epidemiological, clinical and developmental data.

RESULTS:

Of the 4595 children attended during the period, the diagnosis of epilepsy was established at 605 (13.17%): 277 (45.79%) symptomatic epilepsies. Symptomatic etiology predomininates in epileptic patients that started below one year of age, 67.72%, and between 1-3 years, 61.39%. 37.54% of symptomatic epilepsy is refractory, 72.92% have cognitive impairment, 55.23% have motor impairment and 17.32% have autism spectrum disorder. The younger the patient, the higher the percentage of refractoriness and display of any neurological or associated development impact. Some etiologies have higher rates of refractoriness.

CONCLUSIONS:

A useful classification would be etiological, with two groups: a large group with established etiology or very likely genetic syndromes and another with no established cause. The age of onset of epilepsy in each etiological group adds prognostic orientation. Prognosis of epilepsy is overshadowed by refractoriness and associated neurodevelopmental disorders, which are generally worse at an earlier onset and in certain etiologies.

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Further Readings of Interest

https://asdresearchinitiative.wordpress.com/?s=epilepsy

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