A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products. The damage to biological tissues is caused by superoxide and other free radicals generated by many factors, including exposure to alcohol, medications, trauma, cold, toxins, and radiation or by antimicrobial cellular immunity, metabolic abnormality, or “normal” aging; not synonymous with hypoxia or hyperoxia. Oxidative stress promotes a range of degenerative disorders, including cancer, diabetes, premature aging, Alzheimer’s, and many others. – NCI Thesaurus, U.S. National Cancer Institute
Highlights
• Thimerosal (TM) significantly affects mitochondrial bioenergetics in the brain.
• Mitochondrial integrity (membrane potential) was maintained after acute TM treatment.
• Ethylmercury released after the breakdown of TM compromised the cholinergic system.
• The brain is more sensitive to oxidative stress induced by TM compared to the liver.
Excerpts:
“As a result of these pieces of evidence (epidemiological, clinical and preclinical data) pointing to a potential causal association between early ABA (aluminum-based adjuvants) exposure and increased ASD risk, new hypotheses regarding neurological and immunological consequences of ABA-containing vaccines and novel clinical strategies (i.e., postponing of ABA-containing vaccines and replacement of ABAs with calcium phosphate are now being considered.“
“Our review presents the lack of fundamental scientific data demonstrating that Al adjuvants are safe and do not induce any long-term side effects. It also supports further investigation related to the effects of early Al adjuvant exposures occurring in combination with genetic susceptibility factors, including autophagy, immune and inflammation process genes. As accumulating evidence shows that modulating the levels of autophagy may increase the risk of NDDs, such studies will elucidate a new etiology for these complex disorders and contribute to develop potential new diagnostic and therapeutic tools.”
Excerpt:
“ASD is caused by oxidative stress in several ways, including protein post-translational changes (e.g., carbonylation), abnormal metabolism (e.g., lipid peroxidation), and toxic buildup [e.g., reactive oxygen species (ROS)].”
Excerpt:
“In this review article, we examine the connections between early disruption of the developing microbiome and gastrointestinal tract function, with particular regard to susceptibility to autism. The biological mechanisms that accompany individuals with autism are reviewed in this manuscript including immune system dysregulation, inflammation, oxidative stress, metabolic and methylation abnormalities as well as gastrointestinal distress.”
Abstract
Autism spectrum disorder (ASD) is a developmental disorder which is currently only diagnosed through behavioral testing. Impaired folate‐dependent one carbon metabolism (FOCM) and transsulfuration (TS) pathways have been implicated in ASD, and recently a study involving multivariate analysis based upon Fisher Discriminant Analysis returned very promising results for predicting an ASD diagnosis. This article takes another step toward the goal of developing a biochemical diagnostic for ASD by comparing five classification algorithms on existing data of FOCM/TS metabolites, and also validating the classification results with new data from an ASD cohort. The comparison results indicate a high sensitivity and specificity for the original data set and up to a 88% correct classification of the ASD cohort at an expected 5% misclassification rate for typically‐developing controls. These results form the foundation for the development of a biochemical test for ASD which promises to aid diagnosis of ASD and provide biochemical understanding of the disease, applicable to at least a subset of the ASD population.
Excerpt:
“The literature strongly supports that autism is most accurately seen as an acquired cellular detoxification deficiency syndrome with heterogeneous genetic predisposition that manifests pathophysiologic consequences of accumulated, run-away cellular toxicity. At a more general level, it is a form of a toxicant-induced loss of tolerance of toxins, and of chronic and sustained ER overload (“ER hyperstress”), contributing to neuronal and glial apoptosis via the unfolded protein response (UPR). Inherited risk of impaired cellular detoxification and circulating metal re-toxification in neurons and glial cells accompanied by chronic UPR is key.”
Abstract
The conceptualisation of autistic spectrum disorder and Alzheimer’s disease has undergone something of a paradigm shift in recent years and rather than being viewed as single illnesses with a unitary pathogenesis and pathophysiology they are increasingly considered to be heterogeneous syndromes with a complex multifactorial aetiopathogenesis, involving a highly complex and diverse combination of genetic, epigenetic and environmental factors. One such environmental factor implicated as a potential cause in both syndromes is aluminium, as an element or as part of a salt, received, for example, in oral form or as an adjuvant. Such administration has the potential to induce pathology via several routes such as provoking dysfunction and/or activation of glial cells which play an indispensable role in the regulation of central nervous system homeostasis and neurodevelopment. Other routes include the generation of oxidative stress, depletion of reduced glutathione, direct and indirect reductions in mitochondrial performance and integrity, and increasing the production of proinflammatory cytokines in both the brain and peripherally. The mechanisms whereby environmental aluminium could contribute to the development of the highly specific pattern of neuropathology seen in Alzheimer’s disease are described. Also detailed are several mechanisms whereby significant quantities of aluminium introduced via immunisation could produce chronic neuropathology in genetically susceptible children. Accordingly, it is recommended that the use of aluminium salts in immunisations should be discontinued and that adults should take steps to minimise their exposure to environmental aluminium.
Excerpt:
“Environmental mercury is neurotoxic at doses well below the current reference levels considered to be safe, with evidence of neurotoxicity in children exposed to environmental sources including fish consumption and ethylmercury-containing vaccines. Possible neurotoxic mechanisms of mercury include direct effects on sulfhydryl groups, pericytes and cerebral endothelial cells, accumulation within astrocytes, microglial activation, induction of chronic oxidative stress, activation of immune-inflammatory pathways and impairment of mitochondrial functioning. (Epi-)genetic factors which may increase susceptibility to the toxic effects of mercury in ASD include the following: a greater propensity of males to the long-term neurotoxic effects of postnatal exposure and genetic polymorphisms in glutathione transferases and other glutathione-related genes and in selenoproteins. Furthermore, immune and inflammatory responses to immunisations with mercury-containing adjuvants are strongly influenced by polymorphisms in the human leukocyte antigen (HLA) region and by genes encoding effector proteins such as cytokines and pattern recognition receptors. Some epidemiological studies investigating a possible relationship between high environmental exposure to methylmercury and impaired neurodevelopment have reported a positive dose-dependent effect.”
Abstract
and psychometric tools. However, physiological measurements should support these behavioral diagnoses in the future in order to enable earlier and more accurate diagnoses. Stepping towards this goal of incorporating biochemical data into ASD diagnosis, this paper analyzes measurements of metabolite concentrations of the folate-dependent one-carbon metabolism and transulfuration pathways taken from blood samples of 83 participants with ASD and 76 age-matched neurotypical peers. Fisher Discriminant Analysis enables multivariate classification of the participants as on the spectrum or neurotypical which results in 96.1% of all neurotypical participants being correctly identified as such while still correctly identifying 97.6% of the ASD cohort. Furthermore, kernel partial least squares is used to predict adaptive behavior, as measured by the Vineland Adaptive Behavior Composite score, where measurement of five metabolites of the pathways was sufficient to predict the Vineland score with an R2 of 0.45 after cross-validation. This level of accuracy for classification as well as severity prediction far exceeds any other approach in this field and is a strong indicator that the metabolites under consideration are strongly correlated with an ASD diagnosis but also that the statistical analysis used here offers tremendous potential for extracting important information from complex biochemical data sets.
Abstract
The number of diagnosed cases of Autism Spectrum Disorders (ASD) has increased dramatically over the last four decades; however, there is still considerable debate regarding the underlying pathophysiology of ASD. This lack of biological knowledge restricts diagnoses to be made based on behavioral observations and psychometric tools. However, physiological measurements should support these behavioral diagnoses in the future in order to enable earlier and more accurate diagnoses. Stepping towards this goal of incorporating biochemical data into ASD diagnosis, this paper analyzes measurements of metabolite concentrations of the folate-dependent one-carbon metabolism and transulfuration pathways taken from blood samples of 83 participants with ASD and 76 age-matched neurotypical peers. Fisher Discriminant Analysis enables multivariate classification of the participants as on the spectrum or neurotypical which results in 96.1% of all neurotypical participants being correctly identified as such while still correctly identifying 97.6% of the ASD cohort. Furthermore, kernel partial least squares is used to predict adaptive behavior, as measured by the Vineland Adaptive Behavior Composite score, where measurement of five metabolites of the pathways was sufficient to predict the Vineland score with an R2 of 0.45 after cross-validation. This level of accuracy for classification as well as severity prediction far exceeds any other approach in this field and is a strong indicator that the metabolites under consideration are strongly correlated with an ASD diagnosis but also that the statistical analysis used here offers tremendous potential for extracting important information from complex biochemical data sets.
