The new study suggests that autism-linked mutations tend to strike genes involved in neurons’ functions. By contrast, the activation of microglia-related genes appears to be unrelated to mutations.
However, it is too early to say how neuronal dysfunction and microglia activation are related, if at all. “Are microglia responding to alterations in neuronal or synaptic function? Or could they be playing a more early and direct role in driving some of that dysfunction?” says Beth Stevens, assistant professor of neurology at Boston Children’s Hospital, who was not involved in the study. “I think that question is still out there.”
The findings fit with those from an imaging study published last year, which found that microglia are more activated in people with autism than in controls. It is still unclear whether microglia activation is helpful or harmful in the brains of people with autism. “This study raises a lot of important questions for us in the field to try to understand,” Stevens says.
Symptoms of immune dysfunction in ASD include neuroinflammation, presence of autoantibodies, increased T cell responses, and enhanced innate NK cell and monocyte immune responses. Moreover these responses are frequently associated with more impairment in core ASD features including impaired social interactions, repetitive behaviors and communication. In mouse models replacing immune components in animals that exhibit autistic relevant features leads to improvement in behavior in these animals. Taken together this research suggests that the immune dysfunction often seen in ASD directly affects aspects of neurodevelopment and neurological processes leading to changes in behavior.
“There are many different ways of getting autism, but we found that they all have the same downstream effect,” says Dan Arking, Ph.D., an associate professor in the McKusick-Nathans Institute for Genetic Medicine at the Johns Hopkins University School of Medicine. “What we don’t know is whether this immune response is making things better in the short term and worse in the long term.”
Dr. Philip Landrigan of Mount Sinai School of Medicine in New York and Dr. Philippe Grandjean of the Harvard School of Public Health in Boston have spent 30 years studying industrial chemicals and have published lists of the worst neurotoxins. These “impact brain development and can cause a number of neurodevelopmental disabilities including attention-deficit hyperactivity disorder, autism, dyslexia and other cognitive damage” (CNN).
Increasing evidence indicates that brain inflammation is involved in the pathogenesis of neuropsychiatric diseases. Mast cells (MCs) are located perivascularly close to neurons and microglia, primarily in the leptomeninges, thalamus, hypothalamus and especially the median eminence. Corticotropin-releasing factor (CRF) is secreted from the hypothalamus under stress and, together with neurotensin (NT), can stimulate brain MCs to release inflammatory and neurotoxic mediators that disrupt the blood–brain barrier (BBB), stimulate microglia and cause focal inflammation.
Remarkably, we note that a gene expression module corresponding to M2-activation states in microglia is negatively correlated with a differentially expressed neuronal module, implicating dysregulated microglial responses in concert with altered neuronal activity-dependent genes in autism brains. These observations provide pathways and candidate genes that highlight the interplay between innate immunity and neuronal activity in the aetiology of autism.
Higher oxidative stress in cells of children with autism was evidenced by higher rates of mitochondrial reactive oxygen species production (1.6-fold), higher mitochondrial DNA copy number per cell (1.5-fold), and increased deletions. Mitochondrial dysfunction in children with autism was accompanied by a lower (26% of TD children) oxidative burst by PMA-stimulated reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and by a lower gene expression (45% of TD children's mean values) of the nuclear factor erythroid 2–related factor 2 transcription factor involved in the antioxidant response. Given that the majority of granulocytes of children with autism exhibited defects in oxidative phosphorylation, immune response, and antioxidant defense, our results support the concept that immunity and response to oxidative stress may be regulated by basic mitochondrial functions as part of an integrated metabolic network.
However, evidence is accumulating that ASD is characterized by certain physiological abnormalities, including oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation. While these abnormalities have been reported in studies that have examined peripheral biomarkers such as blood and urine, more recent studies have also reported these abnormalities in brain tissue derived from individuals diagnosed with ASD as compared to brain tissue derived from control individuals. A majority of these brain tissue studies have been published since 2010. The brain regions found to contain these physiological abnormalities in individuals with ASD are involved in speech and auditory processing, social behavior, memory, and sensory and motor coordination. This manuscript examines the evidence linking oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation in the brain of ASD individuals, suggesting that ASD has a clear biological basis with features of known medical disorders. This understanding may lead to new testing and treatment strategies in individuals with ASD.
Hospitalizations for autism increased nearly threefold over 10 years, especially at the oldest ages, while hospitalizations for the other groups did not change. Leading discharge diagnoses for each age group in children with autism included mental health and nervous system disorders.
Serotonin and vitamin D have been proposed to play a role in autism; however, no causal mechanism has been established. Here, we present evidence that vitamin D hormone (calcitriol) activates the transcription of the serotonin-synthesizing gene tryptophan hydroxylase 2 (TPH2) in the brain at a vitamin D response element (VDRE) and represses the transcription of TPH1 in tissues outside the blood-brain barrier at a distinct VDRE. The proposed mechanism explains 4 major characteristics associated with autism: the low concentrations of serotonin in the brain and its elevated concentrations in tissues outside the blood-brain barrier; the low concentrations of the vitamin D hormone precursor 25-hydroxyvitamin D [25(OH)D3]; the high male prevalence of autism; and the presence of maternal antibodies against fetal brain tissue.
In a report on the research published online last week in the journal Brain, Behavior and Immunity, the investigators say that the part of the brain responsible for memory and spatial navigation (the hippocampus) was smaller over the long term in the male offspring exposed to the overactive immune system in the womb. The males also had fewer nerve cells in their brains and their brains contained a type of immune cell that shouldn’t be present there.
“Our research suggests that in mice, males may be more vulnerable to the effects of maternal inflammation than females, and the impact may be life long,” says study leader Irina Burd, M.D., Ph.D., an assistant professor of gynecology/obstetrics and neurology at the Johns Hopkins University School of Medicine and director of the Integrated Research Center for Fetal Medicine. “Now we wonder if this could explain why more males have diseases such as autism and schizophrenia, which appear to have neurobiological causes.”
Our results suggest that weak connectivity of voice-selective cortex and brain structures involved in reward and emotion may impair the ability of children with ASD to experience speech as a pleasurable stimulus, thereby impacting language and social skill development in this population. Our study provides support for the social motivation theory of ASD.
We conclude that the information gain in the brain's resting state provides quantitative evidence for perhaps the most typical characteristic in autism: withdrawal into one's inner world.
Three studies published over the past two months have found significant evidence that children and adolescents with autism have brains that are overly connected compared with the brains of controls
It is a multifactorial disorder resulting from interactions between genetic, environmental and immunological factors. Excitotoxicity and oxidative stress are potential mechanisms, which are likely to serve as a converging point to these risk factors. Substantial evidence suggests that excitotoxicity, oxidative stress and impaired mitochondrial function are the leading cause of neuronal dysfunction in autistic patients. Glutamate is the primary excitatory neurotransmitter produced in the CNS, and overactivity of glutamate and its receptors leads to excitotoxicity. The over excitatory action of glutamate, and the glutamatergic receptors NMDA and AMPA, leads to activation of enzymes that damage cellular structure, membrane permeability and electrochemical gradients. The role of excitotoxicity and the mechanism behind its action in autistic subjects is delineated in this review.
These biomarkers represent three unifying concepts of the cause of autism: oxidative stress, immune glutamatergic dysfunction, and pineal gland malfunction
Increasing evidence indicates that brain inflammation is involved in the pathogenesis of neuropsychiatric diseases... Many children with ASD regress at about age 3 years, often after a specific event such as reaction to vaccination, infection, stress or trauma implying some epigenetic triggers, and may constitute a distinct phenotype... ASD children respond disproportionally to stress and are also affected by food and skin allergies. Corticotropin-releasing hormone (CRH) is secreted under stress and together with neurotensin (NT stimulates mast cells and microglia resulting in focal brain inflammation and neurotoxicity. NT is significantly increased in serum of ASD chidren along with mitochondrial DNA (mtDNA). NT stimulates mast cell secretion of mtDNA that is misconstrued as an innate pathogen triggering an auto-inflammatory response. The phosphatase and tensin homolog (PTEN) gene mutation, associated with the higher risk of ASD, which leads to hyper-active mammalian target of rapamycin (mTOR) signalling that is crucial for cellular homeostasis. CRH, NT and environmental triggers could hyperstimulate the already activated mTOR, as well as stimulate mast cell and microglia activation and proliferation. The natural flavonoid luteolin inhibits mTOR, mast cells and microglia and could have a significant benefit to ASD
Commentary: This study not only identifies key genetic mutations (PTEN) that correlate with cellular homeostasis, but also measures significant alterations in neurotensin (NT) and mitochondrial DNA (mtDNA) in children with ASD. NT with mtDNA triggers an auto-inflammatory response stimulating mast cell and microglia activation. We already know because of the Khan et al study that aluminum adjuvant nanoparticals are accumulating in the microglia, which in ASD children who have mutations in PTEN and high levels of NT with mtDNA are primmed for an auto-inflammaoty response. Now with an added neurotoxic stimulator being aluminum adjuvants that risk is increased. We also know through the Rose et al study when comparing ASD brains with neuro-typical peers there is a finding of oxidative damage and inflammation further confirming this process
The etiology of this developmental disorder is poorly understood, and no biomarkers have been identified. Identification of novel biochemical markers related to autism would be advantageous for earlier clinical diagnosis and intervention. Studies suggest that oxidative stress-induced mechanisms and reduced antioxidant defense, mitochondrial dysfunction, and impaired energy metabolism (NAD(+), NADH, ATP, pyruvate, and lactate), are major causes of ASD. This review provides renewed insight regarding current autism research related to oxidative stress, mitochondrial dysfunction, and altered tryptophan metabolism in ASD.
The GM chemical changes between 3 and 10 years of age differentiated the children with ASD from those with DD. Most notably, a dynamic reversal of GM NAA reductions was observed in the children with ASD. By contrast, persistent GM NAA reductions in the children with DD suggest a different, more static, underlying developmental process.
Commentary: The authors of the article also point out that genetic and environmental factors play a role in the etiology of autism. They also compare these chemical changes to other disorders like multiple sclerosis, epilepsy, and traumatic brain injury. They suggest that the N-acetylaspartate levels are reduced at the time of onset or insult and rebound with treatment or recovery.
The researchers found a strong correlation between the micro-structural abnormalities in the white matter of the posterior cerebral tracts focused on sensory processing and the auditory, multisensory and inattention scores reported by parents in the Sensory Profile. the strongest correlation was for auditory processing, with other correlations observed fro multi-sensory integration, vision, tactile and inattention
Salience network hyperconnectivity may be a distinguishing feature in children with ASD. Quantification of brain network connectivity is a step toward developing biomarkers for objectively identifying children with ASD
This new research links social difficulties to a deficit in sonatic markers in the brain, explaining these characteristics in adults with epilepsy.
The findings appear in the journal Molecular Psychiatry and add to mounting evidence that an overactive immune response can alter the development of the central nervous system in the fetus
To their surprise, the scientists found that microglia were engulfing healthy precursor cells in developing brain tissue... Past studies have linked infections and immune activation during pregnancy with neurodevelopmental disorders such as schizophrenia and autism
The present study suggests that plasma glutamate and glutamine levels can serve as a diagnostic tool for the early detection of autism, especially normal IQ autism. These findings indicate that glutamatergic abnormalities in the brain may be associated with the pathobiology of autism.
Repeated trauma to the brain may prevent the normal microglial switching from a proinflammatory mode to a reparative mode, resulting in chronic microglial immunoexcitotoxic activity and subsequent neurodegeneration. And, as demonstrated, several studies have shown that high levels of glutamate and quniolinic acid can significantly increase the deposition of hyperphosphorylated tau protein resulting in the observed NFT accumulation.
Evaluation of trends between the four major areas and the four comparison areas demonstrated that the largest relative growth was in immune dysregulation/inflammation, oxidative stress, toxicant exposures, genetics and neuroimaging. Research on mitochondrial dysfunction started growing in the last 5 years. Theory of mind and neuropathology research has declined in recent years. Although most publications implicated an association between the four major areas and ASD, publication bias may have led to an overestimation of this association. Further research into these physiological areas may provide insight into general or subset-specific processes that could contribute to the development of ASD and other psychiatric disorders.
A multiplex assay for cytokines and chemokines was applied to plasma samples from male subjects with high-functioning ASD (n = 28) and matched controls (n = 28). Among a total of 48 analytes examined, the plasma concentrations of IL-1β, IL-1RA, IL-5, IL-8, IL-12(p70), IL-13, IL-17 and GRO-α were significantly higher in subjects with ASD compared with the corresponding values of matched controls after correction for multiple comparisons
Documented causes of autism include genetic mutations and/or deletions, viral infections, and encephalitis following vaccination
Two other clear-cut patterns emerged when the scientists compared the autistic and healthy brains. First, the autistic brain showed a drop in the levels of genes responsible for neuron function and communication. Second, the autistic brain displayed a jump in the levels of genes involved in immune function and inflammatory response.
This convergence of findings and models suggests that a systems- and chronic disease-based reformulation of function and pathophysiology in autism needs to be considered, and it opens the possibility for new treatment targets
Decreased quinolinic acid and neopterin in cerebrospinal fluid are paradoxical and suggest dysmaturation of metabolic pathways and absence of concurrent infection, respectively, in autism. Alternatively, they may be produced by microglia but remain localized and not expressed in cerebrospinal fluid.
An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism