Febrile Seizures and Autism – A Marker

Febrile Seizures and Epilepsy: Association With Autism and Other Neurodevelopmental Disorders in the Child and Adolescent Twin Study in Sweden.

https://www.ncbi.nlm.nih.gov/pubmed/28754226

BACKGROUND:

There is a recently well-documented association between childhood epilepsy and earlysymptomaticsyndromeselicitingneurodevelopmentalclinicalexaminations (ESSENCE) including autism spectrum disorder, but the relationship between febrile seizures and ESSENCE is less clear.

METHODS:

The Child and Adolescent Twin Study in Sweden (CATSS) is an ongoing population-based study targeting twins born in Sweden since July 1, 1992. Parents of 27,092 twins were interviewed using a validated DSM-IV-based interview for ESSENCE, in connection with the twins’ ninth or twelfth birthday. Diagnoses of febrile seizures (n = 492) and epilepsy (n = 282) were based on data from the Swedish National Patient Register. Prevalence of ESSENCE in individuals with febrile seizures and epilepsy was compared with prevalence in the twin population without seizures. The association between febrile seizures and ESSENCE was considered before and after adjustment for epilepsy. Age of diagnosis of febrile seizures and epilepsy was considered as a possible correlate of ESSENCE in febrile seizures and epilepsy.

RESULTS:

The rate of ESSENCE in febrile seizures and epilepsy was significantly higher than in the total population without seizures (all P < 0.001). After adjusting for epilepsy, a significant association between febrile seizures and autism spectrum disorder, developmental coordination disorder, and intellectual disability remained. Earlier age of onset was associated with all ESSENCE except attention-deficit/hyperactivity disorder in epilepsy but not with ESSENCE in febrile seizures.

CONCLUSIONS:

In a nationally representative sample of twins, there was an increased rate of ESSENCE in childhood epilepsy and in febrile seizures. Febrile seizures alone could occur as a marker for a broader ESSENCE phenotype.

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Early Life Immune Activation and ASD

Perinatal Immune Activation Produces Persistent Sleep Alterations and Epileptiform Activity in Male Mice.

https://www.ncbi.nlm.nih.gov/pubmed/28984294#

Abstract

Increasing evidence suggests a role for inflammation in neuropsychiatric conditions including autism spectrum disorder (ASD).

Previous work in rodents has established that immune activation during critical developmental periods can cause phenotypes that reproduce core features of ASD, including decreased social interaction, aberrant communication, and increased repetitive behavior.

In humans, ASD is frequently associated with co-morbid medical conditions including sleep disorders, motor hyperactivity, and seizures.

Here we use a ‘two-hit’ immune-activation paradigm to determine if perinatal immune activation can also produce these co-morbid features in mice. In this paradigm, we treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C), which simulates a viral infection, on gestational day 12.5 according to an established maternal immune activation regimen. A subset of the offspring also received a second ‘hit’ of lipopolysaccharide (LPS), which simulates a bacterial infection, on postnatal day 9.

At 6 weeks of age, mice were implanted with wireless telemetry transmitters that enabled continuous measurements of electroencephalography (EEG), electromyography (EMG), locomotor activity, and subcutaneous temperature.

Effects at 7 and 12 weeks of age were compared. Both prenatal Poly I:C and postnatal LPS produced changes in locomotor activity and temperature patterns, increases in slow-wave sleep, and shifts in EEG spectral power, several of which persisted at 12 weeks of age. Postnatal LPS also produced persistent increases in spontaneous bursts of epileptiform activity (spike-wave discharges) that occurred predominantly during sleep.

Our findings demonstrate that early-life immune activation can lead to long-lasting physiologic perturbations that resemble medical co-morbidities often seen in ASD and other neuropsychiatric conditions.

Neuropsychopharmacology accepted article preview online, 06 October 2017. doi:10.1038/npp.2017.243.

Posted in Autism, Bacteria, co-morbid, epilepsy, Immune System, Inflammation, Neurology, Physiology, Virus | Tagged , , , , , , , , , , , | Leave a comment

Maternal Immune System linked to Autism outcome

Mum’s immune response could trigger social deficits for kids with autism

Unlocking autism with applied research

Children with autism are more likely to show severe social symptoms if their mother had chronic asthma or allergies while pregnant, the University of Sydney’s Brain and Mind Centre reveals today in Molecular Psychiatry.

The retrospective cohort study of 220 Australian children, conducted between 2011-2014, indicates that a “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.

The findings suggest an ‘immune-mediated subtype’ of autism driven by the body’s inflammatory and immunological systems.

Professor Adam Guastella, Brain and Mind Centre, University of Sydney

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.”

Children of mothers who reported a history of immune activation had more caregiver-reported social deficits.

Study leader and University of Sydney PhD candidate, Shrujna Patel

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.

____________________________________________________________

Further Readings of Interest

Allergy and Atopic

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

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

Posted in Allergy, Asthma, Autism, Bacteria, bowel disease, co-morbid, Depression, Environment, Gut, IBD, Immune System, Inflammation, influenza, Physiology, Treatment, Virus | Tagged , , , , , , , , , , , , | Leave a comment

Autism – Shared Epigenetic Changes at or near 12 Months for 68% of ASD

Shared epigenetic changes underlie different types of autism

 www.cell.com

Individuals with both rare and common types of autism spectrum disorder share a similar set of epigenetic modifications in the brain, according to a study published November 17 in Cell. More than 68% of individuals with different types of autism spectrum disorder show evidence of the same pattern of histone acetylation—a chemical modification of the protein scaffold around which DNA wraps. The findings suggest that a single global epigenetic pattern affecting shared molecular pathways in the brain could underlie diverse manifestations of this psychiatric disease.

“We find that are present in most patients with , or ASD,” says co-senior study author Shyam Prabhakar of the Genome Institute of Singapore. “This suggests that, despite tremendous heterogeneity in the primary causes of autism, such as DNA mutations and environmental perturbations during development, ASD has molecular features that are commonly shared. It is encouraging that ASD has common molecular changes, because this opens up the possibility of designing drugs to correct these changes.”

Various genetic and environmental factors are known to contribute to ASD. Many studies have focused on structural changes to the genome or DNA sequence variants in protein-coding genes, but these mutations are rare and account for only a small fraction of cases. As a result, scientists have proposed that epigenetic modifications—changes in gene activity that do not affect the DNA sequence—play an important role in ASD. However, many epigenetic studies have focused on a chemical modification of DNA known as methylation, ignoring other important changes that could affect the activity of genes implicated in .

In the new study, Prabhakar and co-senior study author Daniel Geschwind of the David Geffen School of Medicine at the University of California, Los Angeles, explored the potential role of histone acetylation in ASD. The researchers focused their analysis on an acetylation mark called H3K27ac because it is implicated in gene activation. They performed an epigenome-wide search for H3K27ac in post-mortem brain tissue samples from the prefrontal cortex, temporal cortex, and cerebellar cortex of individuals with ASD, along with control subjects, aged 10 years and above.

The findings showed that more than 68% of ASD cases shared a common histone acetylation pattern at 5,000 gene loci, despite the wide range of genetic and environmental causes of ASD. By analyzing BrainSpan, an atlas of the developing human brain, they found that gene activation at or near 12 months after birth, which corresponds to the stage of synapse formation and neuronal maturation, was particularly strongly associated with increased acetylation in the ASD brain.

 “This is the first large-scale study of how histone acetylation in the brain differs between disease and control samples, and part of a wave of new studies examining how the epigenome is perturbed in various diseases,” Geschwind says. “Epigenome profiling has allowed us to see shared, unifying themes in what is often considered to be an amalgam of many different diseases rather than one single disease.”

To achieve this milestone, the researchers had to overcome several hurdles. For one, it has only been in recent years that sequencing technology has become affordable enough for this kind of analysis. They also surmounted major challenges to build a robust experimental and computational pipeline and assemble a team with the right combination of expertise. This study is part of the larger collection of International Human Epigenetics Consortium papers, which demonstrate the value of epigenome profiling and reveal insights into disease origins and mechanisms and also potential treatments.

While this tour-de-force study provided an understanding of the molecular changes shared across autism, it stopped short of providing an understanding whether these modifications play a causal role in ASD or are associated with other disease processes and how exactly they contribute to various symptoms. The authors are planning follow-up experiments to test these questions.

Because these epigenomic abnormalities point to specific genes and pathways that are altered in the ASD brain, some of them could turn out to be novel drug targets. Moreover, the study suggests that epigenetic drugs, which are increasingly entering the market as a result of discoveries in the cancer field, could potentially be repurposed for the treatment of ASD. “Currently there are no approved drug treatments specifically for ASD, but we do hope that studies such as ours, as well as the downstream work that is surely needed, will eventually lead to new treatments,” Prabhakar says.


Histone Acetylome-wide Association Study of Autism Spectrum Disorder

http://www.cell.com/cell/fulltext/S0092-8674(16)31451-9

Select quotes of Interest

” Surprisingly, however, we found even greater enrichment of ASD-Up DA peaks near genes upregulated at 10–12 months after birth, which corresponds to the stage of synapse formation, and neuronal maturation. In contrast, ASD-Down DA peaks did not show stage-specificity. Thus, although chromatin aberrations in ASD affect genes with a broad variety of developmental specificities, genes upregulated at or near 12 months after birth are particularly strongly associated with increased acetylation in ASD cortex.

“To examine the genetic basis of the epigenomic aberrations detected in ASD, we tested all high-coverage SNPs within DA peaks for genetic differentiation between patients and controls (chi-square test). The distribution of genetic differentiation p values was close to uniform (data not shown), suggesting that genetic variation in cis SNPs is not a major contributor to case-control acetylation differences at DA peaks. It is thus likely that ASD-specific differential acetylation is driven mostly by other factors such as environmental influences, SNPs in trans (at a different locus), indels, and larger chromosomal variants (Krumm et al., 2015).”

“We found evidence for shared pathways and functional themes among DA loci in ASD cerebral cortex (Figure 2). Among loci with increased H3K27ac, there was strong enrichment for genes related to ion channels, synaptic function, and epilepsy/neuronal excitability, all of which have previously been shown to be dysregulated in this disorder (Voineagu et al., 2011, Bourgeron, 2015). Moreover, these adult DA loci were strongly enriched for genes developmentally upregulated at or around 12 months of life (Figure 4), which coincides with the peak of early experience-dependent synaptogenesis.”

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Startling Discovery – Immune System Affects and may Control Social Behavior

Shocking New Role Found for the Immune System: Controlling Social Interactions

https://news.virginia.edu

In a startling discovery that raises fundamental questions about human behavior, researchers at the University of Virginia School of Medicine have determined that the immune system directly affects – and even controls – creatures’ social behavior, such as their desire to interact with others.

So could immune system problems contribute to an inability to have normal social interactions? The answer appears to be yes, and that finding could have significant implications for neurological diseases such as autism-spectrum disorders and schizophrenia.

“The brain and the adaptive immune system were thought to be isolated from each other, and any immune activity in the brain was perceived as sign of a pathology. And now, not only are we showing that they are closely interacting, but some of our behavior traits might have evolved because of our immune response to pathogens,” explained Jonathan Kipnis, chair of UVA’s Department of Neuroscience. “It’s crazy, but maybe we are just multicellular battlefields for two ancient forces: pathogens and the immune system. Part of our personality may actually be dictated by the immune system.”

Evolutionary Forces at Work

It was only last year that Kipnis, the director of UVA’s Center for Brain Immunology and Glia, and his team discovered that meningeal vessels directly link the brain with the lymphatic system. That overturned decades of textbook teaching that the brain was “immune privileged,” lacking a direct connection to the immune system. The discovery opened the door for entirely new ways of thinking about how the brain and the immune system interact.

The follow-up finding is equally illuminating, shedding light on both the workings of the brain and on evolution itself. The relationship between people and pathogens, the researchers suggest, could have directly affected the development of our social behavior, allowing us to engage in the social interactions necessary for the survival of the species while developing ways for our immune systems to protect us from the diseases that accompany those interactions. Social behavior is, of course, in the interest of pathogens, as it allows them to spread.

The UVA researchers have shown that a specific immune molecule, interferon gamma, seems to be critical for social behavior and that a variety of creatures, such as flies, zebrafish, mice and rats, activate interferon gamma responses when they are social. Normally, this molecule is produced by the immune system in response to bacteria, viruses or parasites. Blocking the molecule in mice using genetic modification made regions of the brain hyperactive, causing the mice to become less social. Restoring the molecule restored the brain connectivity and behavior to normal. In a paper outlining their findings, the researchers note the immune molecule plays a “profound role in maintaining proper social function.”

“It’s extremely critical for an organism to be social for the survival of the species. It’s important for foraging, sexual reproduction, gathering, hunting,” said Anthony J. Filiano, Hartwell postdoctoral fellow in the Kipnis lab and lead author of the study. “So the hypothesis is that when organisms come together, you have a higher propensity to spread infection. So you need to be social, but [in doing so] you have a higher chance of spreading pathogens. The idea is that interferon gamma, in evolution, has been used as a more efficient way to both boost social behavior while boosting an anti-pathogen response.”

Understanding the Implications

The researchers note that a malfunctioning immune system may be responsible for “social deficits in numerous neurological and psychiatric disorders.” But exactly what this might mean for autism and other specific conditions requires further investigation. It is unlikely that any one molecule will be responsible for disease or the key to a cure. The researchers believe that the causes are likely to be much more complex. But the discovery that the immune system – and possibly germs, by extension – can control our interactions raises many exciting avenues for scientists to explore, both in terms of battling neurological disorders and understanding human behavior.

“Immune molecules are actually defining how the brain is functioning. So, what is the overall impact of the immune system on our brain development and function?” Kipnis said. “I think the philosophical aspects of this work are very interesting, but it also has potentially very important clinical implications.”

Findings Published

Kipnis and his team worked closely with UVA’s Department of Pharmacology and with Vladimir Litvak’s research group at the University of Massachusetts Medical School. Litvak’s team developed a computational approach to investigate the complex dialogue between immune signaling and brain function in health and disease.

“Using this approach we predicted a role for interferon gamma, an important cytokine secreted by T lymphocytes, in promoting social brain functions,” Litvak said. “Our findings contribute to a deeper understanding of social dysfunction in neurological disorders, such as autism and schizophrenia, and may open new avenues for therapeutic approaches.”

The findings have been published online by the prestigious journal Nature. The article was written by Filiano, Yang Xu, Nicholas J. Tustison, Rachel L. Marsh, Wendy Baker, Igor Smirnov, Christopher C. Overall, Sachin P. Gadani, Stephen D. Turner, Zhiping Weng, Sayeda Najamussahar Peerzade, Hao Chen, Kevin S. Lee, Michael M. Scott, Mark P. Beenhakker, Litvak and Kipnis.

This work was supported by the National Institutes of Health (grants No. AG034113, NS081026 and T32-AI007496) and the Hartwell Foundation.

____________________________________
Further Readings of Interest
Immune system and Autism
Posted in Allergy, Asthma, Autism, Bacteria, bowel disease, co-morbid, Environment, Gut, IBD, Immune System, Inflammation, influenza, Neurology, Physiology, Treatment, Virus | Leave a comment

Allergy, Inflammation and Autism

Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders

Free Full Paper

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931610/

Abstract

Autism spectrum disorders (ASDs) affect as many as 1 in 45 children and are characterized by deficits in sociability and communication, as well as stereotypic movements.

Many children also show severe anxiety.

The lack of distinct pathogenesis and reliable biomarkers hampers the development of effective treatments. As a result, most children with ASD are prescribed psychopharmacologic agents that do not address the core symptoms of ASD.

Autoantibodies against brain epitopes in mothers of children with ASD and many such children strongly correlate with allergic symptoms and indicate an aberrant immune response, as well as disruption of the blood–brain barrier (BBB).

Recent epidemiological studies have shown a strong statistical correlation between risk for ASD and either maternal or infantile atopic diseases, such as asthma, eczema, food allergies and food intolerance, all of which involve activation of mast cells (MCs). These unique tissue immune cells are located perivascularly in all tissues, including the thalamus and hypothalamus, which regulate emotions. MC-derived inflammatory and vasoactive mediators increase BBB permeability. Expression of the inflammatory molecules interleukin (IL-1β), IL-6, 1 L-17 and tumor necrosis factor (TNF) is increased in the brain, cerebrospinal fluid and serum of some patients with ASD, while NF-kB is activated in brain samples and stimulated peripheral blood immune cells of other patients; however, these molecules are not specific. Instead the peptide neurotensin is uniquely elevated in the serum of children with ASD, as is corticotropin-releasing hormone, secreted from the hypothalamus under stress. Both peptides trigger MC to release IL-6 and TNF, which in turn, stimulate microglia proliferation and activation, leading to disruption of neuronal connectivity. MC-derived IL-6 and TGFβ induce maturation of Th17 cells and MCs also secrete IL-17, which is increased in ASD. Serum IL-6 and TNF may define an ASD subgroup that benefits most from treatment with the natural flavonoid luteolin.

Atopic diseases may create a phenotype susceptible to ASD and formulations targeting focal inflammation of the brain could have great promise in the treatment of ASD.

_____________________________

Further Readings of Interest

Allergy and Atopic

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

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

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

The Gut, Microbes and Rheumatoid Arthritis

Study: Gut Bacteria can Cause, Predict and Prevent Rheumatoid Arthritis

http://newsnetwork.mayoclinic.org

ROCHESTER, Minn. — The bacteria in your gut do more than break down your food. They also can predict susceptibility to rheumatoid arthritis, suggests Veena Taneja, Ph.D., an immunologist at Mayo Clinic’s Center for Individualized Medicine. Dr. Taneja recently published two studies ─ one in Genome Medicine and one in Arthritis and Rheumatology ─ connecting the dots between gut microbiota and rheumatoid arthritis.

More than 1.5 million Americans have rheumatoid arthritis, a disorder that causes painful swelling in the joints. Scientists have a limited understanding of the processes that trigger the disease. Dr. Taneja and her team identified intestinal bacteria as a possible cause; their studies indicate that testing for specific microbiota in the gut can help physicians predict and prevent the onset of rheumatoid arthritis.

“These are exciting discoveries that we may be able to use to personalize treatment for patients,” Dr. Taneja says.

The paper published in Genome Medicine summarizes a study of rheumatoid arthritis patients, their relatives and a healthy control group. The study aimed to find a biomarker — or a substance that indicates a disease, condition or phenomena — that predicts susceptibility to rheumatoid arthritis. They noted that an abundance of certain rare bacterial lineages causes a microbial imbalance that is found in rheumatoid arthritis patients.

“Using genomic sequencing technology, we were able to pin down some gut microbes that were normally rare and of low abundance in healthy individuals, but expanded in patients with rheumatoid arthritis,” Dr. Taneja says.

Implications for predicting and preventing rheumatoid arthritis

After further research in mice and, eventually, humans, intestinal microbiota and metabolic signatures could help scientists build a predictive profile for who is likely to develop rheumatoid arthritis and the course the disease will take, Dr. Taneja says.

Based on mouse studies, researchers found an association between the gut microbe Collinsella and the arthritis phenotype. The presence of these bacteria may lead to new ways to diagnose patients and to reduce the imbalance that causes rheumatoid arthritis before or in its early stages, according to John Davis III, M.D., and Eric Matteson, M.D., Mayo Clinic rheumatologists and study co-authors. Continued research could lead to preventive treatments.

Possibility for more effective treatment with fewer side effects

The second paper, published in Arthritis and Rheumatology, explored another facet of gut bacteria. Dr. Taneja treated one group of arthritis-susceptible mice with a bacterium, Prevotella histicola, and compared that to a group that had no treatment. The study found that mice treated with the bacterium had decreased symptom frequency and severity, and fewer inflammatory conditions associated with rheumatoid arthritis. The treatment produced fewer side effects, such as weight gain and villous atrophy — a condition that prevents the gut from absorbing nutrients — that may be linked with other, more traditional  treatments.

While human trials have not yet taken place, the mice’s immune systems and arthritis mimic humans, and shows promise for similar, positive effects. Since this bacterium is a part of healthy human gut, treatment is less likely to have side effects, says study co-author Joseph Murray, M.D., a Mayo Clinic gastroenterologist.

Rheumatoid arthritis is an autoimmune disorder; it occurs when the body mistakenly attacks itself. The body breaks down tissues around joints, causing swelling that can erode bone and deform the joints. The disease can damage other parts of the body, including the skin, eyes, heart, lung and blood vessels.

The study was funded by the Mayo Clinic Center for Individualized Medicine, which supports research that aims to find treatments compatible with a patient’s unique genetic structure. It also supports the transformation of research discoveries into practical applications for patient care.

MEDIA CONTACT: Colette Rector, Mayo Clinic Public Affairs, 507-284-5005, newsbureau@mayo.edu

###

About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit http://www.mayoclinic.org/about-mayo-clinic or http://newsnetwork.mayoclinic.org/.


Further Readings of Interest

Gut

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

 

Arthritis

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

Posted in Autism, Bacteria, bowel disease, co-morbid, Environment, Gut, IBD, Immune System, Inflammation, Mice, Treatment | Leave a comment

The Gut, Microbes and MS

Changes Uncovered in the Gut Bacteria of Patients with Multiple Sclerosis
http://www.brighamandwomens.org

A connection between the bacteria living in the gut and immunological disorders such as multiple sclerosis have long been suspected, but for the first time, researchers have detected clear evidence of changes that tie the two together. Investigators from Brigham and Women’s Hospital (BWH) have found that people with multiple sclerosis have different patterns of gut microorganisms than those of their healthy counterparts. In addition, patients receiving treatment for MS have different patterns than untreated patients. The new research, published in Nature Communications, supports recent studies linking immunological disorders to the gut microbiome and may have implications for pursuing new therapies for MS.

“Our findings raise the possibility that by affecting the gut microbiome, one could come up with treatments for MS – treatments that affect the microbiome, and, in turn, the immune response,” said Howard L. Weiner, MD, director of the Partners MS Center and co-director of the Ann Romney Center for Neurologic Disease at Brigham Women’s Hospital, . “There are a number of ways that the microbiome could play a role in MS and this opens up a whole new world of looking at the disease in a way that it’s never been looked at before.”

Weiner and colleagues conducted their investigations using data and samples from subjects who are part of the CLIMB (Comprehensive Longitudinal Investigation of Multiple Sclerosis) study at Brigham and Women’s Hospital. The team analyzed stool samples from 60 people with MS and 43 control subjects, performing gene sequencing to detect differences in the microbial communities of the subjects.

Samples from MS patients contained higher levels of certain bacterial species – including Methanobrevibacter and Akkermansia – and lower levels of others – such as Butyricimonas – when compared to healthy samples. Other studies have found that several of these microorganisms may drive inflammation or are associated with autoimmunity. Importantly, the team also found that microbial changes in the gut correlated with changes in the activity of genes that play a role in the immune system. The team also collected breath samples from subjects, finding that, as a result of increased levels of Methanobrevibacter, patients with MS had higher levels of methane in their breath samples.

The researchers also investigated the gut microbe communities of untreated MS patients, finding that MS disease-modifying therapy appeared to normalize the gut microbiomes of MS patients. The researchers note that further study will be required to determine the exact role that these microbes may be playing in the progression of disease and whether or not modifying the microbiome may be helpful in treating MS. They plan to continue to explore the connection between the gut and the immune system in a larger group of patients and follow changes over time to better understand disease progression and interventions.

“This work provides a window into how the gut can affect the immune system which can then affect the brain,” said Weiner, who is also a professor of Neurology at Harvard Medical School. “Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are at risk.”

Funding support for this work included grants from the NIH/NINDS, The National Multiple Sclerosis Society and from The Harvard Digestive Disease Center.

Paper cited: Jangi S et al. “Alterations of the human gut microbiome in multiple sclerosis.” Nature Communications. DOI: 10.1038/NCOMMS12015

 

 

Posted in co-morbid, Environment, Gut, IBD, Immune System, Inflammation, Uncategorized | Leave a comment

Neuropathology of Seizures in Autism

Neuropathological Mechanisms of Seizures in Autism Spectrum Disorder.

http://www.ncbi.nlm.nih.gov/pubmed/27242398

Abstract

This manuscript reviews biological abnormalities shared by autism spectrum disorder (ASD) and epilepsy.

Two neuropathological findings are shared by ASD and epilepsy:

abnormalities in minicolumn architecture and

γ-aminobutyric acid (GABA) neurotransmission.

The peripheral neuropil, which is the region that contains the inhibition circuits of the minicolumns, has been found to be decreased in the post-mortem ASD brain. ASD and epilepsy are associated with inhibitory GABA neurotransmission abnormalities including reduced GABAA and GABAB subunit expression. These abnormalities can elevate the excitation-to-inhibition balance, resulting in hyperexcitablity of the cortex and, in turn, increase the risk of seizures.

Medical abnormalities associated with both epilepsy and ASD are discussed. These include specific genetic syndromes, specific metabolic disorders including disorders of energy metabolism and GABA and glutamate neurotransmission, mineral and vitamin deficiencies, heavy metal exposures and immune dysfunction.

Many of these medical abnormalities can result in an elevation of the excitatory-to-inhibitory balance. Fragile X is linked to dysfunction of the mGluR5 receptor and Fragile X, Angelman and Rett syndromes are linked to a reduction in GABAA receptor expression. Defects in energy metabolism can reduce GABA interneuron function. Both pyridoxine dependent seizures and succinic semialdehyde dehydrogenase deficiency cause GABA deficiencies while urea cycle defects and phenylketonuria cause abnormalities in glutamate neurotransmission. Mineral deficiencies can cause glutamate and GABA neurotransmission abnormalities and heavy metals can cause mitochondrial dysfunction which disrupts GABA metabolism.

Thus, both ASD and epilepsy are associated with similar abnormalities that may alter the excitatory-to-inhibitory balance of the cortex. These parallels may explain the high prevalence of epilepsy in ASD and the elevated prevalence of ASD features in individuals with epilepsy.


Other Readings of Interest

 

Epilepsy and Autism

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

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

Immune System, Epilepsy and the Eye

Immune response in the eye following epileptic seizures

http://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-016-0618-3

 

Abstract

Background

Epileptic seizures are associated with an immune response in the brain. However, it is not known whether it can extend to remote areas of the brain, such as the eyes. Hence, we investigated whether epileptic seizures induce inflammation in the retina.

Methods

Adult rats underwent electrically induced temporal status epilepticus, and the eyes were studied 6 h, 1, and 7 weeks later with biochemical and immunohistochemical analyses. An additional group of animals received CX3CR1 antibody intracerebroventricularly for 6 weeks after status epilepticus.

Results

Biochemical analyses and immunohistochemistry revealed no increased cell death and unaltered expression of several immune-related cytokines and chemokines as well as no microglial activation, 6 h post-status epilepticus compared to non-stimulated controls. At 1 week, again, retinal cytoarchitecture appeared normal and there was no cell death or micro- or macroglial reaction, apart from a small decrease in interleukin-10. However, at 7 weeks, even if the cytoarchitecture remained normal and no ongoing cell death was detected, the numbers of microglia were increased ipsi- and contralateral to the epileptic focus. The microglia remained within the synaptic layers but often in clusters and with more processes extending into the outer nuclear layer. Morphological analyses revealed a decrease in surveying and an increase in activated microglia. In addition, increased levels of the chemokine KC/GRO and cytokine interleukin-1β were found. Furthermore, macroglial activation was noted in the inner retina. No alterations in numbers of phagocytic cells, infiltrating macrophages, or vascular pericytes were observed. Post-synaptic density-95 cluster intensity was reduced in the outer nuclear layer, reflecting seizure-induced synaptic changes without disrupted cytoarchitecture in areas with increased microglial activation. The retinal gliosis was decreased by a CX3CR1 immune modulation known to reduce gliosis within epileptic foci, suggesting a common immunological reaction.

Conclusions

Our results are the first evidence that epileptic seizures induce an immune response in the retina. It has a potential to become a novel non-invasive tool for detecting brain inflammation through the eyes.

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