Conclusions : The etiology and pathogeneis of ASD are not well understood. Autism Spectrum Disorders comprise a complex of clinical syndromes found predominantly in infants and younger people consisting of disturbances in cognition and comprehension, communication disorders, epilepsy, and behavior that have an underlying common pathology of neurodegeneration of the cerebellar Purkinje cells and other areas of the brain. Other studies in humans have shown chronic inflammatory changes in the brain, particularly in the cerebellum, and involvement of the microglia in this pathology.
Our review presents evidence suggesting a hypothesis unifying the syndromes in ASD. The clinical as well as pathological findings of the ASD have a set of pathological events with the common denominator being immunoexcitotoxicity leading to neurodegeneration and abnormalities in the connectome, particularly in developing brains in the neonate and young with evidence that explains the clinical presentation of ASD.
Our hypothesis is supported by experimental evidence from animal models and by some clinical testing and pathology studies that give credibility to the concept of immunoexcitotoxicity as the underlying cause of ASD. A great number of conditions can trigger both the inflammatory and the excitotoxic cascade, including sequential vaccination, infections, hypomagnesemia, ROS, RNS and LPP, fluoride and Al3+ as well as a number of other neurotoxic metals and industrial chemicals. Chronic activation of the brain’s immune system increases extracellular glutamate levels sufficiently to trigger the excitotoxic cascade, which in conjunction with inflammatory cytokines and prostaglandins, magnifies the damaging effects of both. This mechanism explains most of the features of the ASD, including the behavioral difficulties, language problems, repetitive behaviors, intellectual delay, and episodic dyscontrol of anger. In addition, these mechanisms explain the pathological findings as well, including the changes in the cerebellum, abnormalities in connectivity and the widespread activation of microglia and astrocytes. It also explains why ASD has not disappeared despite the removal of mercury from most childhood vaccines, since excessive immune activation is the initiating and sustaining event in ASD. Evidence is presented that the abundance of fluoride added to the water worldwide and the widespread availability of aluminum particularly to infants and young children through aluminum containing vaccinations, singly or together as aluminofluoride can be potent factors in producing the condition of immunoexcitotoxicity that leads to the pathological changes seen in ASD. The vaccination program should be evaluated to reduce the excessive stimulation of immature immune system and to replace Al3+-adjuvants.
We have also reviewed studies that indicate that fluoride and Al3+, as ubiquitous environmental and food-derived toxins, can exacerbate the pathological and clinical problems of ASD. In synergistic action as AlF4− these elements induce numerous chronic pathophysiological consequences at several times lower concentrations than either Al3+ or fluoride acting alone. AlF4− may evoke several signaling disorders and act as an endocrine disruptor. Moreover, most of the excitotoxic events may enhance the subclinical pathological alterations and/or the genetic susceptibility seen in ASD. The full genetic potential of the child for brain and mental development may be also compromised due to deficiency of micronutrients.
Our immunoexcitotoxic hypothesis opens the door to a number of new modes of prevention and amelioration of ASD. Elimination of various sources of fluoride and Al3+ in early development and consumption of a diet containing essential nutrients and antioxidants have been shown to be beneficial to brain function. As a multifaceted disorder, ASD requires a multifaceted approach, one that should include the protection against excitotoxicity, as well as the protection against microglial activation.
There are several experimental studies that can be constructed to test the immunoexcitotoxic hypothesis, especially as regards vaccines. Such a study would require the use of non-human primates at various stages of development, from intrauterine life to early post-natal development corresponding to human neurodevelopment during vulnerable neurodevelopmental milestones. The study would follow the vaccine schedules used with human newborns and pre-schoolers. One would need to use the exact vaccines used in the human vaccine schedules but of comparable doses based on weight.
To measure microglial activation in response to the vaccines, it would be necessary to use microglial activation PET scanning techniques at various time schedules before and following the vaccines. Newer microglial activation PET scanning techniques are being developed that hold the possibility of differentiating between M1 and M2 microglial activation phenotypes. Long-term follow-up scanning would be necessary to delineate prolonged microglial activation as has been observed in cases of autism. Measure of glutamate levels in the affected areas of the brain should also be conducted, perhaps in a separate set of monkeys to prevent inadvertent activation of local microglia. More extensive studies could be envisioned, such as measures of EAATs, glutaminase, and NADPH oxidase within affected brain areas in response to vaccination.
In addition, studies should be conducted measuring the aluminum, fluoride and aluminofluoride complex concentration in the affected areas of the brain in autopsied cases of autism. This should include the various cell types as well as cellular compartments. This could also be done experimentally in the non-human primate studies using human vaccines described above. Controls could establish the levels of these toxicants to establish the baseline levels in non-vaccinated animals.