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Abstract

Recent studies of genomic variation associated with autism have suggested the existence of extreme heterogeneity. Large-scale transcriptomics should complement these results to identify core molecular pathways underlying autism. Here we report results from a large-scale RNA sequencing effort, utilizing region-matched autism and control brains to identify neuronal and microglial genes robustly dysregulated in autism cortical brain. 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.

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  • December 10, 2014

Abstract

A role for immunological involvement in autism spectrum disorder (ASD) has long been hypothesized. This review includes four sections describing (1) evidence for a relationship between familial autoimmune disorders and ASD; (2) results from post-mortem and neuroimaging studies that investigated aspects of neuroinflammation in ASD; (3) findings from animal model work in ASD involving inflammatory processes; and (4) outcomes from trials of anti-inflammatory/immune-modulating drugs in ASD that have appeared in the literature. Following each section, ideas are provided for future research, suggesting paths forward in the continuing effort to define the role of immune factors and inflammation in the pathophysiology of a subtype of ASD

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  • November 13, 2014

Abstract

The autism spectrum disorders (ASD) are a group of related neurodevelopmental disorders that have been increasing in incidence since the 1980s. Despite a considerable amount of data being collected from cases, a central mechanism has not been offered. A careful review of ASD cases discloses a number of events that adhere to an immunoexcitotoxic mechanism. This mechanism explains the link between excessive vaccination, use of aluminum and ethylmercury as vaccine adjuvants, food allergies, gut dysbiosis, and abnormal formation of the developing brain. It has now been shown that chronic microglial activation is present in autistic brains from age 5 years to age 44 years. A considerable amount of evidence, both experimental and clinical, indicates that repeated microglial activation can initiate priming of the microglia and that subsequent stimulation can produce an exaggerated microglial response that can be prolonged. It is also known that one phenotypic form of microglia activation can result in an outpouring of neurotoxic levels of the excitotoxins, glutamate and quinolinic acid. Studies have shown that careful control of brain glutamate levels is essential to brain pathway development and that excesses can result in arrest of neural migration, as well as dendritic and synaptic loss. It has also been shown that certain cytokines, such as TNF-alpha, can, via its receptor, interact with glutamate receptors to enhance the neurotoxic reaction. To describe this interaction I have coined the term immunoexcitotoxicity, which is described in this article.

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  • November 1, 2014

Excerpts:
“Febrile seizures represent a serious adverse event following measles, mumps and rubella (MMR) vaccination.”

“In conclusion, using detailed health register information on vaccinations and febrile seizure episodes, we identified common variants at two loci associated with febrile seizures as an adverse event following MMR vaccination. From a public health perspective, it is essential to study the underlying causes of any serious adverse event of the MMR vaccine, a preventive pharmaceutical product given to millions of children each year, and our findings provide important leads for further research in the fields of immunogenetics and vaccinology. Concomitantly, we identified four loci associated with febrile seizures in general, which together with supporting evidence from electrophysiological experiments underline the importance of altered ion channel function in this common childhood disorder. Further functional studies will illuminate the biological mechanisms behind the associations reported here and might also provide more general insights into mechanisms of epileptogenesis and neuronal hyperexcitability.”

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  • October 26, 2014

Excerpts:
“Animal models of neurological disease plainly suggest that the ubiquitous presence of Al in human beings implicates Al toxicants as causally involved in Lou Gehrig’s disease (ALS), Alzheimer’s disease and autism spectrum disorders.”

“All these findings plausibly implicate Al adjuvants in pediatric vaccines as causal factors contributing to increased rates of autism spectrum disorders in countries where multiple doses are almost universally administered.“

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  • October 2, 2014

Results
The CDDS and IDEA data sets are qualitatively consistent in suggesting a strong increase in autism prevalence over recent decades. The quantitative comparison of IDEA snapshot and constant-age tracking trend slopes suggests that ~75-80% of the tracked increase in autism since 1988 is due to an actual increase in the disorder rather than to changing diagnostic criteria. Most of the suspected environmental toxins examined have flat or decreasing temporal trends that correlate poorly to the rise in autism. Some, including lead, organochlorine pesticides and vehicular emissions, have strongly decreasing trends. Among the suspected toxins surveyed, polybrominated diphenyl ethers, aluminum adjuvants, and the herbicide glyphosate have increasing trends that correlate positively to the rise in autism.

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  • September 5, 2014