Recent Research into Autism and Related Disorders
Synopsis: Article covers research into autism spectrum disorders including Elevated Leptin and Inflammation, Gene Expression Patterns, and other areas.(1)
Author: Disabled World Contact: Disabled World
Main DigestQuestions have arisen through social media in regards to autism and different areas of research. One of these areas of research involves leptin and inflammation, while other areas involve IgG antibody transfer and early neurodevelopment, children with autism and Gene Expression Patterns, and mice models of thimerosal toxicity. In an attempt to explain these areas, this article will approach the subjects.
Elevated Leptin and Inflammation in Autism
Most of the hormone, 'leptin,' is produced in fat cells, which has led to the association of the neuroendocrine mediator with regulation of energy intake and expenditure, including the regulation of appetite and metabolism, and therefore to overweight and obesity conditions. However, as a study by UC Davis immunologist Judy Van de Water, Ph.D., and her colleagues explains - there is evidence from earlier studies to demonstrate the production of leptin also by inflammatory cells. Researchers have shown in animal studies that leptin deficiencies may shift the immune response and result in defective cell-mediated and humoral immunity.
Working with the hypothesis that, 'an altered immune response might impact other biological systems, including the neuroendocrine and nervous systems,' researchers compared plasma leptin levels measured in nanogram/milliliter (ng/ml) in a population of children with autism and controls. Controls included children both with and without forms of developmental disabilities. Due to the association between Body Mass Index (BMI) and leptin, researchers controlled for BMI-for-age, a modified calculation that is a more relevant measure for a population of children.
Even though researchers discovered that leptin levels were notably higher in children with autism than in averagely developing controls, they also found a dramatic difference among the children with autism themselves. When the children with autism were further categorized by symptom clusters, children with early-onset autism presented with significantly higher median and interquartile range levels of leptin than children with clinical regression - 2.62 (1.12-4.38) versus 1.38 (0.61-2.69) ng/ml. The researchers also found that children with the regressive form of autism were not notably different when compared with controls, both averagely developing and developmentally delayed.
The study is not the first report of a possible biochemical marker in autism that might be able to differentiate between disease phenotypes. The researchers acknowledged that it remains undetermined whether leptin levels are a cause or a secondary phenomenon of the condition. They concluded the findings provide a framework for additional studies to investigate changes in leptin levels over the lifetime of the disorder.
IgG Antibody Transfer and Early Neurodevelopment
A search for a biochemical marker of autism in an investigation of maternal plasma IgG antibodies against human fetal and adult brain proteins was also led by Dr. Van de Water. Investigators say the antibodies, which may easily cross the placental barrier, might have the ability to react to fetal, 'self,' proteins to provide a fetus with a subset of the maternal adaptive humoral immune system proteins. The proteins might potentially produce an autoimmune reaction in an infant which may then impact fetal neurodevelopment.
Researchers studied 61 mothers of children with autistic disorder (AU) and 102 matched controls with averagely developing (TD) children, or children with non-ASD developmental delays (DD). Separating proteins by weight, the researchers looked for patterns of reactivity in the range of 20-220 kilo-daltons (kDa), which is a measure of molecular weight used in chemiluminescent visualization of marker bands.
Autoreactivity to a Protein at Approximately 37kDa Discovered in Mothers
Researchers discovered patterns of reactivity against fetal, yet not adult, brain clustered by 2 points - 37kDa and 73kDa, that differentiated between mothers of AD children and mothers of TD and DD children. Auto-reactivity to a protein at around 37kDa was discovered in 26% of mothers of AD children, compared with 2.5% of mothers of DD children and 8.1% of mothers with TD children, yielding a 5.69 fold odds ratio associated with this particular band.
When reactivity against proteins at both molecular weights was studied, 11% of mothers of AU children showed the results at 37kDa and 73kDa. No mothers of DD or TD children showed the pattern of reactivity. Notably, 86% of mothers of AU children with reactivity to the pair of bands had children with the regressive form.
The researchers found support for their hypothesis that there is a possible role for maternal IgG antibody trans-placental transfer during pregnancy and subsequent binding to fetal brain cells as a cause of autism in some children. They also discovered a potential biomarker that might be able to predict the development of a specific phenotype of the disorder. Dr. Van de Water stated, "We are ...optimistic that in the future a prenatal test and therapeutic intervention preventing IgG exposure during pregnancy could protect some children from ever getting autism."
Children with Autism and Gene Expression Patterns
A CHARGE investigation of gene expression patterns in children with autism might provide researchers with new insights into the biological foundations of the disease and may be an important step in identifying new targets for therapies. Frank Sharp, M.D., led the UC Davis investigation and was the first to use genomic profiling of whole blood successfully to pinpoint differential gene expression patterns that distinguished children with autism (AU) diagnosed by both the, 'Autism Diagnostic Observation Schedule,' and the, 'Autism Diagnostic Interview,' from children in the general population. The team was also the first to identify gene expression patterns that were different between children with:
- The major phenotypes of subsets of AU
- The early onset without regression
- The regressive forms
The study population included 61 children enrolled in the ongoing CHARGE study - 35 diagnosed with AU, 14 diagnosed with Autism Spectrum Disorder (ASD), a term used for children who do not meet the full behavioral criteria for AU, as well as 12 averagely developing children from the general population - age and gender matched, with no evidence of ASD. RNA was isolated from blood drawn in the afternoon and then analyzed for gene expression patterns.
The results indicated that the groups with autism shared 11 differentially expressed genes in natural killer (NK) cells, a number of which belong to the NK cytotoxicity pathway identified in the Kyoto Encyclopedia of Genes and Genomes. The writers observed that, "the importance of these findings is that NK cells are a primary, innate defense against viral, bacterial, and parasitic infections or malignant transformation."
Another finding, yet also important in the diagnosis of forms of AU, involves differentially expressed gene patterns that are different between children with autism and children in the general population - a set of 140 genes, and between children with autism and those without, a set of 20 genes. Gene expression data supporting different forms of AU might be able to assist with defining the genetics, etiology, and clinical phenotype as well as the outcome in autism, according to the writers.
Mice Models of Thimerosal Toxicity
Thimerosal Toxicity Mouse Study Group Injected With certain ailments.
Concerned parents and some researchers, in the long and at times frustrating search for what environmental factors may trigger autism (AU) and autism spectrum disorders (ASD), have speculated that vaccine-level exposure to, 'ethylmercury,' in thimerosal-preserved childhood vaccines might play a role. Advocates of the thimerosal connection hypothesized that deficits in immune function among some children might make their developing nervous systems vulnerable to pervasive developmental toxicity, thus leading to ASD and AU.
A study from the year 2004 of the autoimmune susceptible SJL/J mice strain conducted by Mady Hornig, M.D., and associates at Columbia University's Mailman School of Public Health reported findings consistent with the idea that immune dysfunction may exacerbate the effects of thimerosal. The study found gross morphological changes in the hippocampus as a result of early post-natal injections of thimerosal.
A research team that included NIEHS Neuro-toxicology Group Head G. Jean Harry, Ph.D., tried to replicate Hornig's findings. The team consisted of researchers experienced in the design and conduct of developmental neuro-toxicology studies and with expertise in statistical and morphological analysis. The animal studies were conducted in laboratories at the University of California Davis and used a similar injection schedule to the one reported by Hornig. SJL/J pups from 51 different litters were injected with 5 different solutions in accordance with a regimen that modeled childhood vaccination schedules.
A, 'within-litter,' dosing design was used to control for the large impact that maternal factors - both genetic and behavioral, have on the neuro-behavioral functioning of the offspring. Tissue mercury levels were used to confirm that there was no cross contamination with the litters from the pups injected with thimerosal. The first group received a dose of thimerosal comparable to the maximum dose a child may have been exposed to with thimerosal-preserved vaccines against:
- Hepatitis B
- Hemophilus influenza B (HiB)
- Diphtheria tetanus pertussis (DPT)
A control group received a phosphate-buffered saline vehicle (VEH). The other groups received vaccine alone (VAC), 1X + VAC, and 10X +VAC to evaluate the effects of different levels of thimerosal and the components of vaccines.
After the mice had completed the injection schedule, the research team evaluated some different things. These included:
- Hippocampal morphology
- Body weight growth indices of early development
The research team put the mice through a number of behavioral tests related to core neurological deficits, to include sensory gating, social interaction and anxiety.
In one cohort of mice, total mercury levels were measured in blood, brain and kidney at 2 time points selected based on prior work by the UC Davis laboratory and Harry lab at NIEHS. Morphological examination of the hippocampus was conducted using an advanced computerized methodology of unbiased stereology performed by an expert. In every case, data collection and analysis was conducted on coded animals and samples to maintain a completely unbiased assessment, with researchers blind to individual animal treatment groups. The code was maintained during the statistical analysis as well.
In contrast to the study by Hornig, the mice in this particular study maintained overall positive health and showed no adverse behaviors. The researchers found no evidence of structural abnormalities in the hippocampus, or of neuro-behavioral changes in activity levels or social behavior in the offspring due to injections of thimerosal - either by itself, or in combination with VAC. As expected, pups injected with the higher 10X and 10X + VAC presented with higher blood levels of mercury; however, the other results were similar to groups with lower exposure.
- 1: Tactile Defensiveness and the Autism Spectrum : Thomas C Weiss (2014/01/30)
- 2: Autism: Complementary and Alternative Medicine : Thomas C. Weiss (2014/02/04)
- 3: Life and Health: Developmental Disorders - Autism : Disabled World (2008/01/08)
- 4: Autism Communication and Conflict Resolution : Disabled World (2014/02/11)
- 5: Sulforaphane in Vegetables May Improve Autism : Massachusetts General Hospital (2014/10/14)
- 6: Playing with Building Blocks of Creativity Help Children with Autism : University of Rochester Medical Center (2010/11/29)
- 7: Autism Spectrum Disorders: Genetic and Environmental Influences : The Mount Sinai Hospital / Mount Sinai School of Medicine (2014/05/05)
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