Autism spectrum disorders may be due to cerebral toxoplasmosis associated with chronic neuroinflammation causing persistent hypercytokinemia that resulted in an increased lipid peroxidation, oxidative stress, and depressed metabolism of endogenous and exo / Joseph PRANDOTA in Research in Autism Spectrum Disorders, 4-2 (April-June 2010)  

Public ISBD [article]  inResearch in Autism Spectrum Disorders > 4-2 (April-June 2010) . - p.119-155 Titre : Autism spectrum disorders may be due to cerebral toxoplasmosis associated with chronic neuroinflammation causing persistent hypercytokinemia that resulted in an increased lipid peroxidation, oxidative stress, and depressed metabolism of endogenous and exo Type de document : Texte imprimé et/ou numérique Auteurs : Joseph PRANDOTA, Auteur Année de publication : 2010 Article en page(s) : p.119-155 Langues : Anglais (eng) Mots-clés : Autistic-spectrum-disorders Cerebral-toxoplasmosis Immune-irregularities Hypercytokinemia Nitric-oxide Oxidative-stress Hypermetabolic-state Depressed-enzyme-activities Index. décimale : PER Périodiques Résumé : Worldwide, approximately 2 billion people are chronically infected with Toxoplasma gondii with largely yet unknown consequences. Patients with autism spectrum disorders (ASD) similarly as mice with chronic toxoplasmosis have persistent neuroinflammation, hypercytokinemia with hypermetabolism associated with enhanced lipid peroxidation, and extreme changes in the weight resulting in obesity or wasting. Data presented in this review suggest that environmental triggering factors such as pregnancy, viral/bacterial infections, vaccinations, medications, and other substances caused reactivation of latent cerebral toxoplasmosis because of changes in intensity of latent central nervous system T. gondii infection/inflammation and finally resulted in development of ASD. Examples of such environmental factors together with their respective biomarker abnormalities are: pregnancy (increased NO, IL-1β, TNF-α, IL-6, IL-10, prolactin; decreased IFN-γ, IL-12), neuroborreliosis (increased IL-1β, sIL-1R2, TNF-α, IFN-γ, IL-6, IL-10, IL-12, IL-18, transforming growth factor-β1 (TGF-β1)), viral infections (increased IL-1β, IL-6, IL-8, TNF-α, IFN-γ/α/β, TGF-β1), thimerosal (increased IL-5, IL-13; decreased IFN-γ, TNF-α, IL-6, IL-12p70, NOS), and valproic acid (increased NO, reactive oxygen species; decreased TNF-α, IL-6, IFN-γ). The imbalances in pro- and antiinflammatory processes could markedly hinder host defense mechanisms important for immune control of the parasite, such as the production of NO, cytokines, and reactive oxygen/nitrogen species, tryptophan degradation by indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase, limitation of the availability of intracellular iron to T. gondii, and the mechanisms mediated by an IFN-γ responsive gene family. These fluctuations could result in a recurrent profuse multiplication of T. gondii in the brain associated with persistent neuroinflammation, chronic overproduction of pro- and antiinflammatory cytokines, and NO causing increased oxidative stress, and significantly depressed activity of several enzymes including cytochrome P450 monooxygenase family responsible for metabolism of physiological substrates and xenobiotics, such as steroids, fatty acids, prostaglandins, drugs, pollutants, and carcinogens, finally leading to development of ASD. This reasoning may be supported by such abnormal metabolic events as: (1) patients with ASD have significantly decreased melatonin levels caused by marked deficit in acetylserotonin methyltransferase activity, possibly resulting from maternal and/or fetal/postnatal overproduction of NO, characteristic for this clinical entity; (2) thimerosal inhibited both insulin-like growth factor-1- and dopamine-stimulated methylation reactions, and depressed methionine synthase activity, the metabolic events important for promoting normal neurodevelopment; (3) valproic acid, a strong histone deacetylase inhibitor, have potent anti-T. gondii activity. Thus, patients with ASD should be tested for T. gondii infection. En ligne : http://dx.doi.org/10.1016/j.rasd.2009.09.011 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=973 [article] Autism spectrum disorders may be due to cerebral toxoplasmosis associated with chronic neuroinflammation causing persistent hypercytokinemia that resulted in an increased lipid peroxidation, oxidative stress, and depressed metabolism of endogenous and exo [Texte imprimé et/ou numérique] / Joseph PRANDOTA, Auteur . - 2010 . - p.119-155. Langues : Anglais (eng) in Research in Autism Spectrum Disorders > 4-2 (April-June 2010) . - p.119-155 Mots-clés : Autistic-spectrum-disorders Cerebral-toxoplasmosis Immune-irregularities Hypercytokinemia Nitric-oxide Oxidative-stress Hypermetabolic-state Depressed-enzyme-activities Index. décimale : PER Périodiques Résumé : Worldwide, approximately 2 billion people are chronically infected with Toxoplasma gondii with largely yet unknown consequences. Patients with autism spectrum disorders (ASD) similarly as mice with chronic toxoplasmosis have persistent neuroinflammation, hypercytokinemia with hypermetabolism associated with enhanced lipid peroxidation, and extreme changes in the weight resulting in obesity or wasting. Data presented in this review suggest that environmental triggering factors such as pregnancy, viral/bacterial infections, vaccinations, medications, and other substances caused reactivation of latent cerebral toxoplasmosis because of changes in intensity of latent central nervous system T. gondii infection/inflammation and finally resulted in development of ASD. Examples of such environmental factors together with their respective biomarker abnormalities are: pregnancy (increased NO, IL-1β, TNF-α, IL-6, IL-10, prolactin; decreased IFN-γ, IL-12), neuroborreliosis (increased IL-1β, sIL-1R2, TNF-α, IFN-γ, IL-6, IL-10, IL-12, IL-18, transforming growth factor-β1 (TGF-β1)), viral infections (increased IL-1β, IL-6, IL-8, TNF-α, IFN-γ/α/β, TGF-β1), thimerosal (increased IL-5, IL-13; decreased IFN-γ, TNF-α, IL-6, IL-12p70, NOS), and valproic acid (increased NO, reactive oxygen species; decreased TNF-α, IL-6, IFN-γ). The imbalances in pro- and antiinflammatory processes could markedly hinder host defense mechanisms important for immune control of the parasite, such as the production of NO, cytokines, and reactive oxygen/nitrogen species, tryptophan degradation by indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase, limitation of the availability of intracellular iron to T. gondii, and the mechanisms mediated by an IFN-γ responsive gene family. These fluctuations could result in a recurrent profuse multiplication of T. gondii in the brain associated with persistent neuroinflammation, chronic overproduction of pro- and antiinflammatory cytokines, and NO causing increased oxidative stress, and significantly depressed activity of several enzymes including cytochrome P450 monooxygenase family responsible for metabolism of physiological substrates and xenobiotics, such as steroids, fatty acids, prostaglandins, drugs, pollutants, and carcinogens, finally leading to development of ASD. This reasoning may be supported by such abnormal metabolic events as: (1) patients with ASD have significantly decreased melatonin levels caused by marked deficit in acetylserotonin methyltransferase activity, possibly resulting from maternal and/or fetal/postnatal overproduction of NO, characteristic for this clinical entity; (2) thimerosal inhibited both insulin-like growth factor-1- and dopamine-stimulated methylation reactions, and depressed methionine synthase activity, the metabolic events important for promoting normal neurodevelopment; (3) valproic acid, a strong histone deacetylase inhibitor, have potent anti-T. gondii activity. Thus, patients with ASD should be tested for T. gondii infection. En ligne : http://dx.doi.org/10.1016/j.rasd.2009.09.011 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=973

Metabolic, immune, epigenetic, endocrine and phenotypic abnormalities found in individuals with autism spectrum disorders, Down syndrome and Alzheimer disease may be caused by congenital and/or acquired chronic cerebral toxoplasmosis / Joseph PRANDOTA in Research in Autism Spectrum Disorders, 5-1 (January-March 2011)  

Public ISBD [article]  inResearch in Autism Spectrum Disorders > 5-1 (January-March 2011) . - p.14-59 Titre : Metabolic, immune, epigenetic, endocrine and phenotypic abnormalities found in individuals with autism spectrum disorders, Down syndrome and Alzheimer disease may be caused by congenital and/or acquired chronic cerebral toxoplasmosis Type de document : Texte imprimé et/ou numérique Auteurs : Joseph PRANDOTA, Auteur Année de publication : 2011 Article en page(s) : p.14-59 Langues : Anglais (eng) Mots-clés : Autism-spectrum-disorders Alzheimer-disease Down-syndrome Metabolism-disturbances Immune-changes Epigenetic-irregularities Carbohydrate-metabolism Phenotypic-abnormalities Testosterone-levels Amyloid-β-plaques Index. décimale : PER Périodiques Résumé : Toxoplasma gondii is a protozoan parasite that infects about a third of human population. It is generally believed that in immunocompetent hosts, the parasite infection takes usually asymptomatic course and induces self-limiting disease, but in immunocompromised individuals may cause significant morbidity and mortality. T. gondii uses sulfated proteoglycans for host cell invasion and sulfated sugars on the surface of host cells may functions as key parasite receptors. Patients with autism spectrum disorders (ASD) have many inborn or acquired abnormalities of metabolism, including impaired sulfation and sulfoxidation. The impaired sulfation of dehydroepiandrosterone (DHEA) to DHEA-S affected normal development of various brain functions because DHEA-S inhibited vascular neuroinflammation in ASD individuals probably caused by cerebral toxoplasmosis (CT). Treatment of endothelial cells with DHEA-S dramatically inhibited the TNF-α-induced activation of NF-κB, an inflammatory transcription factor, and increased protein levels of the NF-κB inhibitor, IκB-α. A significant decrease in sulfation capacity found during pregnancy compared with post partum probably reflect a defense reaction of the host due to increased production of proinflammatory cytokines associated with frequent and widespread infection with this parasite. This suggestion may be supported by the finding that TNF and IL-1 mediated inhibitory effect of lipopolysaccharide on DHEA sulfotransferase mRNA level in Hep3B human hepatoma cells. It seems however that the impaired sulfation and sulfonation may be also beneficial for the host because lack or a markedly diminished anionic charge of the host cells associated with this event did not promote binding to the negatively charged outer leaflet of T. gondii plasma membranes. Phosphorylation of the parasite and/or host proteins is also of great importance in the process of T. gondii–host cell interaction. Furthermore, the increased male to female ratio characteristic for autistic participants most likely resulted from significantly increased testosterone levels associated with congenital T. gondii infection. It was demonstrated that the parasite, aging and dietary restriction have been able to induce DNA breakage, therefore one may suggest that such an epigenetic mechanism play an important role in development of Down syndrome (DS). Several data may support this notion: (a) autism occurs 10 times more often in children with trisomy 21 than in the general population, (b) the parasite can be transmitted by semen and ovum, (c) autistic children exhibit impaired DNA methylation capacity, and (d) T. gondii affect chromatin structure and may cause dysregulation of the host cell cycle. Alzheimer disease (AD) also may be caused by CT because this abnormality is more prevalent in women, characterizes with a skewed capacity for xenobiotic metabolism especially of compounds containing sulfur that manifest as a decreased plasma levels of DHEA-S, and has marked immune irregularies in part due to aging. Moreover, chronic neuroinflammation characteristic for AD and DS individuals is associated with vascular lesions, patients with AD have increased levels of DNA breaks in the cerebral cortex, markedly enhanced production of proinflammatory cytokines, reactive oxygen species, and lipid peroxidation, disturbances in glucose metabolism, and irregularities in hypothalamic–pituitary axis. It must be noted that similar metabolic and endocrine disturbances have been reported also in humans and mice with chronic toxoplasmosis. Overproduction of IFN-γ and other proinflammatory cytokines associated with persistent neuroinflammation resulted in neurodegeneration and induced amyloid-β production also in DS, as well as accounted for cognitive impairment. Because bradyzoites and sporozoites throughout their life cycle accumulate large amounts of crystalline storage polysaccharide granules analogous to amylopectin within the cytoplasm and are able to build more complex macromolecules, they may be at least in part responsible for the production of amyloid-β senile plaques. Moreover, it seems that the accumulation of iron in senile plaques reflect a defense of the host against T. gondii because this transition metallic ion is necessary for proliferation of tachyzoites. Finally, the beneficial effects of ibuprofen in the patients with AD that restored cellular immunity, decreased production of proinflammatory cytokines, NO, amyloid-β, reduced lipid peroxidation and free radical generation, were consistent with the suggestion that congenital and/or acquired chronic latent CT play an important role in development of these types of neurodegeneration. En ligne : http://dx.doi.org/10.1016/j.rasd.2010.03.009 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=111 [article] Metabolic, immune, epigenetic, endocrine and phenotypic abnormalities found in individuals with autism spectrum disorders, Down syndrome and Alzheimer disease may be caused by congenital and/or acquired chronic cerebral toxoplasmosis [Texte imprimé et/ou numérique] / Joseph PRANDOTA, Auteur . - 2011 . - p.14-59. Langues : Anglais (eng) in Research in Autism Spectrum Disorders > 5-1 (January-March 2011) . - p.14-59 Mots-clés : Autism-spectrum-disorders Alzheimer-disease Down-syndrome Metabolism-disturbances Immune-changes Epigenetic-irregularities Carbohydrate-metabolism Phenotypic-abnormalities Testosterone-levels Amyloid-β-plaques Index. décimale : PER Périodiques Résumé : Toxoplasma gondii is a protozoan parasite that infects about a third of human population. It is generally believed that in immunocompetent hosts, the parasite infection takes usually asymptomatic course and induces self-limiting disease, but in immunocompromised individuals may cause significant morbidity and mortality. T. gondii uses sulfated proteoglycans for host cell invasion and sulfated sugars on the surface of host cells may functions as key parasite receptors. Patients with autism spectrum disorders (ASD) have many inborn or acquired abnormalities of metabolism, including impaired sulfation and sulfoxidation. The impaired sulfation of dehydroepiandrosterone (DHEA) to DHEA-S affected normal development of various brain functions because DHEA-S inhibited vascular neuroinflammation in ASD individuals probably caused by cerebral toxoplasmosis (CT). Treatment of endothelial cells with DHEA-S dramatically inhibited the TNF-α-induced activation of NF-κB, an inflammatory transcription factor, and increased protein levels of the NF-κB inhibitor, IκB-α. A significant decrease in sulfation capacity found during pregnancy compared with post partum probably reflect a defense reaction of the host due to increased production of proinflammatory cytokines associated with frequent and widespread infection with this parasite. This suggestion may be supported by the finding that TNF and IL-1 mediated inhibitory effect of lipopolysaccharide on DHEA sulfotransferase mRNA level in Hep3B human hepatoma cells. It seems however that the impaired sulfation and sulfonation may be also beneficial for the host because lack or a markedly diminished anionic charge of the host cells associated with this event did not promote binding to the negatively charged outer leaflet of T. gondii plasma membranes. Phosphorylation of the parasite and/or host proteins is also of great importance in the process of T. gondii–host cell interaction. Furthermore, the increased male to female ratio characteristic for autistic participants most likely resulted from significantly increased testosterone levels associated with congenital T. gondii infection. It was demonstrated that the parasite, aging and dietary restriction have been able to induce DNA breakage, therefore one may suggest that such an epigenetic mechanism play an important role in development of Down syndrome (DS). Several data may support this notion: (a) autism occurs 10 times more often in children with trisomy 21 than in the general population, (b) the parasite can be transmitted by semen and ovum, (c) autistic children exhibit impaired DNA methylation capacity, and (d) T. gondii affect chromatin structure and may cause dysregulation of the host cell cycle. Alzheimer disease (AD) also may be caused by CT because this abnormality is more prevalent in women, characterizes with a skewed capacity for xenobiotic metabolism especially of compounds containing sulfur that manifest as a decreased plasma levels of DHEA-S, and has marked immune irregularies in part due to aging. Moreover, chronic neuroinflammation characteristic for AD and DS individuals is associated with vascular lesions, patients with AD have increased levels of DNA breaks in the cerebral cortex, markedly enhanced production of proinflammatory cytokines, reactive oxygen species, and lipid peroxidation, disturbances in glucose metabolism, and irregularities in hypothalamic–pituitary axis. It must be noted that similar metabolic and endocrine disturbances have been reported also in humans and mice with chronic toxoplasmosis. Overproduction of IFN-γ and other proinflammatory cytokines associated with persistent neuroinflammation resulted in neurodegeneration and induced amyloid-β production also in DS, as well as accounted for cognitive impairment. Because bradyzoites and sporozoites throughout their life cycle accumulate large amounts of crystalline storage polysaccharide granules analogous to amylopectin within the cytoplasm and are able to build more complex macromolecules, they may be at least in part responsible for the production of amyloid-β senile plaques. Moreover, it seems that the accumulation of iron in senile plaques reflect a defense of the host against T. gondii because this transition metallic ion is necessary for proliferation of tachyzoites. Finally, the beneficial effects of ibuprofen in the patients with AD that restored cellular immunity, decreased production of proinflammatory cytokines, NO, amyloid-β, reduced lipid peroxidation and free radical generation, were consistent with the suggestion that congenital and/or acquired chronic latent CT play an important role in development of these types of neurodegeneration. En ligne : http://dx.doi.org/10.1016/j.rasd.2010.03.009 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=111

Neuropathological changes and clinical features of autism spectrum disorder participants are similar to that reported in congenital and chronic cerebral toxoplasmosis in humans and mice / Joseph PRANDOTA in Research in Autism Spectrum Disorders, 4-2 (April-June 2010)  

Public ISBD [article]  inResearch in Autism Spectrum Disorders > 4-2 (April-June 2010) . - p.103-118 Titre : Neuropathological changes and clinical features of autism spectrum disorder participants are similar to that reported in congenital and chronic cerebral toxoplasmosis in humans and mice Type de document : Texte imprimé et/ou numérique Auteurs : Joseph PRANDOTA, Auteur Année de publication : 2010 Article en page(s) : p.103-118 Langues : Anglais (eng) Mots-clés : Autism Cerebral-toxoplasmosis Chronic-neuroinflammation Neuropathological-changes Behavior-personality-profile-abnormalities Congenital-acquired-toxoplasmosis Index. décimale : PER Périodiques Résumé : Anatomic, histopathologic, and MRI/SPET studies of autistic spectrum disorders (ASD) patients’ brains confirm existence of very early developmental deficits. In congenital and chronic murine toxoplasmosis several cerebral anomalies also have been reported, and worldwide, approximately two billion people are chronically infected with T. gondii with largely yet unknown consequences. The aim of the study was therefore to compare brain abnormalities in ASD patients with those found in mice with cerebral toxoplasmosis (CT) because this may help in understanding pathophysiology of ASD. Data from available published studies were analyzed to compare postmortem pathologic changes found in the brains of ASD patients with those of mice developed after intraperitoneal T. gondii infection. Patients with ASD had the following brain abnormalities: active neuroinflammatory process notably in cerebellum, microglial nodules, accumulation of perivascular macrophages, decreased number and size of Purkinje cells in cerebellar nuclei and inferior olive, hypoperfusion of brain. Mice with congenital toxoplasmosis also had persistent neuroinflammation and ventricular enlargement, periventricular edema, meningeal and perivascular inflammation, and focal loss of Purkinje and granule cells. In murine acquired CT, the brain anomalies included: ventricular dilatation probably reflecting loss of brain parenchyma; perivascular inflammation particularly in hippocampus, and periaqueductal/periventricular areas, Purkinje cell layer markedly disfigured with focal loss of cells; perivascular cuffing by mononuclear cells and localized microglial/inflammatory nodules. Infection of mice with different strains of T. gondii resulted in distinctive neuropathological changes and various stadium of maturity of cysts and the parasite itself, which is in line with the diversity of the autistic phenotypes. Also, the abnormalities in behavior and clinical features associated with autism resembled that reported in chronic latent toxoplasmosis in humans and rodents. All these similarities suggest that T. gondii should be regarded as an important infectious factor that may trigger development of ASD and some other neurodegenerative diseases, such as obsessive–compulsive and attention-deficit/hyperactivity disorders, and cryptogenic epilepsy. Thus, all these patients should be tested for T. gondii infection. En ligne : http://dx.doi.org/10.1016/j.rasd.2009.09.007 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=973 [article] Neuropathological changes and clinical features of autism spectrum disorder participants are similar to that reported in congenital and chronic cerebral toxoplasmosis in humans and mice [Texte imprimé et/ou numérique] / Joseph PRANDOTA, Auteur . - 2010 . - p.103-118. Langues : Anglais (eng) in Research in Autism Spectrum Disorders > 4-2 (April-June 2010) . - p.103-118 Mots-clés : Autism Cerebral-toxoplasmosis Chronic-neuroinflammation Neuropathological-changes Behavior-personality-profile-abnormalities Congenital-acquired-toxoplasmosis Index. décimale : PER Périodiques Résumé : Anatomic, histopathologic, and MRI/SPET studies of autistic spectrum disorders (ASD) patients’ brains confirm existence of very early developmental deficits. In congenital and chronic murine toxoplasmosis several cerebral anomalies also have been reported, and worldwide, approximately two billion people are chronically infected with T. gondii with largely yet unknown consequences. The aim of the study was therefore to compare brain abnormalities in ASD patients with those found in mice with cerebral toxoplasmosis (CT) because this may help in understanding pathophysiology of ASD. Data from available published studies were analyzed to compare postmortem pathologic changes found in the brains of ASD patients with those of mice developed after intraperitoneal T. gondii infection. Patients with ASD had the following brain abnormalities: active neuroinflammatory process notably in cerebellum, microglial nodules, accumulation of perivascular macrophages, decreased number and size of Purkinje cells in cerebellar nuclei and inferior olive, hypoperfusion of brain. Mice with congenital toxoplasmosis also had persistent neuroinflammation and ventricular enlargement, periventricular edema, meningeal and perivascular inflammation, and focal loss of Purkinje and granule cells. In murine acquired CT, the brain anomalies included: ventricular dilatation probably reflecting loss of brain parenchyma; perivascular inflammation particularly in hippocampus, and periaqueductal/periventricular areas, Purkinje cell layer markedly disfigured with focal loss of cells; perivascular cuffing by mononuclear cells and localized microglial/inflammatory nodules. Infection of mice with different strains of T. gondii resulted in distinctive neuropathological changes and various stadium of maturity of cysts and the parasite itself, which is in line with the diversity of the autistic phenotypes. Also, the abnormalities in behavior and clinical features associated with autism resembled that reported in chronic latent toxoplasmosis in humans and rodents. All these similarities suggest that T. gondii should be regarded as an important infectious factor that may trigger development of ASD and some other neurodegenerative diseases, such as obsessive–compulsive and attention-deficit/hyperactivity disorders, and cryptogenic epilepsy. Thus, all these patients should be tested for T. gondii infection. En ligne : http://dx.doi.org/10.1016/j.rasd.2009.09.007 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=973

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