ArticleLiterature Review

Is autism an autoimmune disease?

December 2004
Autoimmunity Reviews 3(7-8):557-62

DOI:10.1016/j.autrev.2004.07.036

Source
PubMed

Authors:

Paul Ashwood

University of California, Davis

Judy Van de Water

University of California, Davis

Autism spectrum disorder (ASD) is a spectrum of behavioral anomalies characterized by impaired social interaction and communication, often accompanied by repetitive and stereotyped behavior. The condition manifests within the first 3 years of life and persists into adulthood. There are numerous hypotheses regarding the etiology and pathology of ASD, including a suggested role for immune dysfunction. However, to date, the evidence for involvement of the immune system in autism has been inconclusive. While immune system abnormalities have been reported in children with autistic disorder, there is little consensus regarding the nature of these differences which include both enhanced autoimmunity and reduced immune function. In this review, we discuss current findings with respect to immune function and the spectrum of autoimmune phenomena described in children with ASD.

Increased IgG-4 levels in a patient with autism spectrum disorder complicated by autoimmune pancreatitis

Article

Apr 2022

A Unifying Theory for Autism: The Pathogenetic Triad as a Theoretical Framework

Article

Full-text available

Nov 2021

Darko Sarovic

This paper presents a unifying theory for autism by applying the framework of a pathogenetic triad to the scientific literature. It proposes a deconstruction of autism into three contributing features (an autistic personality dimension, cognitive compensation, and neuropathological risk factors), and delineates how they interact to cause a maladaptive behavioral phenotype that may require a clinical diagnosis. The autistic personality represents a common core condition, which induces a set of behavioral issues when pronounced. These issues are compensated for by cognitive mechanisms, allowing the individual to remain adaptive and functional. Risk factors, both exogenous and endogenous ones, show pathophysiological convergence through their negative effects on neurodevelopment. This secondarily affects cognitive compensation, which disinhibits a maladaptive behavioral phenotype. The triad is operationalized and methods for quantification are presented. With respect to the breadth of findings in the literature that it can incorporate, it is the most comprehensive model yet for autism. Its main implications are that (1) it presents the broader autism phenotype as a non-pathological core personality domain, which is shared across the population and uncoupled from associated features such as low cognitive ability and immune dysfunction, (2) it proposes that common genetic variants underly the personality domain, and that rare variants act as risk factors through negative effects on neurodevelopment, (3) it outlines a common pathophysiological mechanism, through inhibition of neurodevelopment and cognitive dysfunction, by which a wide range of endogenous and exogenous risk factors lead to autism, and (4) it suggests that contributing risk factors, and findings of immune and autonomic dysfunction are clinically ascertained rather than part of the core autism construct.

Do Autism Spectrum and Autoimmune Disorders Share Predisposition Gene Signature Due to mTOR Signaling Pathway Controlling Expression?

Article

Full-text available

May 2021
INT J MOL SCI

Autism spectrum disorder (ASD) is characterized by uncommon genetic heterogeneity and a high heritability concurrently. Most autoimmune disorders (AID), similarly to ASD, are characterized by impressive genetic heterogeneity and heritability. We conducted gene-set analyses and revealed that 584 out of 992 genes (59%) included in a new release of the SFARI Gene database and 439 out of 871 AID-associated genes (50%) could be attributed to one of four groups: 1. FMRP (fragile X mental retardation protein) target genes, 2. mTOR signaling network genes, 3. mTOR-modulated genes, and 4. vitamin D3-sensitive genes. With the exception of FMRP targets, which are obviously associated with the direct involvement of local translation disturbance in the pathological mechanisms of ASD, the remaining categories are represented among AID genes in a very similar percentage as among ASD predisposition genes. Thus, mTOR signaling pathway genes make up 4% of ASD and 3% of AID genes, mTOR-modulated genes—31% of both ASD and AID genes, and vitamin D-sensitive genes—20% of ASD and 23% of AID genes. The network analysis revealed 3124 interactions between 528 out of 729 AID genes for the 0.7 cutoff, so the great majority (up to 67%) of AID genes are related to the mTOR signaling pathway directly or indirectly. Our present research and available published data allow us to hypothesize that both a certain part of ASD and AID comprise a connected set of disorders sharing a common aberrant pathway (mTOR signaling) rather than a vast set of different disorders. Furthermore, an immune subtype of the autism spectrum might be a specific type of autoimmune disorder with an early manifestation of a unique set of predominantly behavioral symptoms.

Examining the non-spatial pretraining effect on a Water Maze spatial learning task in rats treated with multiple intracerebroventricular (ICV) infusions of propionic acid: Contributions to a rodent model of ASD

Article

Jan 2021
BEHAV BRAIN RES

Propionic acid (PPA) is produced by enteric gut bacteria and is a dietary short chain fatty acid. Intracerebroventricular (ICV) infusions of PPA in rodents have been shown to produce behavioral changes, including adverse effects on cognition, similar to those seen in autism spectrum disorders (ASD). Previous research has shown that repeated ICV infusions of PPA result in impaired spatial learning in a Morris water maze (MWM) as evidenced by increased search latencies, fewer direct and circle swims, and more time spent in the periphery of the maze than control rats. In the current study rats were first given non-spatial pretraining (NSP) in the water maze in order to familiarize the animals with the general requirements of the non-spatial aspects of the task before spatial training was begun. Then the effects of ICV infusions of PPA on acquisition of spatial learning were examined. PPA treated rats failed to show the positive effects of the non-spatial pretraining procedure, relative to controls, as evidenced by increased search latencies, longer distances travelled, fewer direct and circle swims, and more time spent in the periphery of the maze than PBS controls. Thus, PPA treatment blocked the effects of the pretraining procedure, likely by impairing sensorimotor components or memory of the pretraining.

Immunoexcitoxicity as the possible major pathophysiology behind multiple sclerosis and other autoimmune disorders

Article

Full-text available

Jan 2025

Russell L. Blaylock

Autoimmune disorders are destructive processes considered to be an attack on “self ” antigens by the immune system CD-+4 T-cells that are directed toward antigens, in the case of multiple sclerosis (MS), particularly myelin antigens. Yet, there is growing evidence that the major destructive events in MS, as well as other non-central nervous system (CNS) autoimmune disorders, are much more than an immune attack on the CNS initiated by a misdirected immune system that attacks a “self ” antigen or antigens by a process called molecular mimicry. Extensive evidence suggests that inflammation, in turn, initiates excitotoxicity, which is responsible for the majority of pathological findings in all stages of the disease, especially a loss of oligodendroglia (source of myelin) and axon injury in MS. Excitotoxicity also is a better explanation for progressive MS, in which the immune attack has either slowed or is halted; yet, the destructive pathology continues to progress. It also explains the destructive lesions seen in gray matter, which is essentially devoid of inflammation. It has recently been shown that most of the damage to the oligodendrocytes, as well as axonal injury, is secondary to excitotoxicity. While there is a growing appreciation that excitotoxicity plays a major role, there has been little effort to link the immune changes to the excitotoxic process, recently named immunoexcitotoxicity, even though the role of excitotoxicity has been shown to occur in the inflammatory stage in the beginning and throughout the process of the disease, particularly the chronic progressive stage. It is also known that peripheral glutamate receptors exist throughout the body, thus making the process of immunoexcitotoxicity a possible integral part of all or most autoimmune disorders in which the immune system is intimately linked to enhancing the excitotoxic process. This is of special concern now that peripheral glutamate receptors have been isolated in many peripheral tissues and are known to be fully functional.

Prenatal, perinatal, and environmental risk factors contribute to the high prevalence of autism spectrum disorder in northeastern Bangladesh

Article

Jan 2025

Objectives Autism spectrum disorder (ASD) is a neurodevelopmental condition with increasing prevalence worldwide, including in Bangladesh. This study investigated prenatal, perinatal, and environmental risk factors associated with ASD in northeastern Bangladesh, where data on the disorder is scarce. Methods A cross-sectional study was conducted with 168 children diagnosed with ASD (CWA), 167 typically developing children (TDC), and 185 unaffected siblings (Sib), recruited from five government-approved specialized schools in Sylhet, northeastern Bangladesh. Diagnoses were confirmed using a modified ADI-R/ADOS, and logistic regression was used to analyze associated risk factors. Results Advanced maternal age, firstborn status, and a history of consanguinity were significant prevalence of prenatal/perinatal complications, including birth asphyxia and blood Rh incompatibility, compared to TDC and Sib. A considerable gap in scientific awareness was noted, with many parents attributing their child’s condition to associated with ASD. Parental exposure to mercury-based dental amalgam was also strongly linked to ASD. CWA had a higher generational or religious belief. Conclusions We identified critical risk factors contributing to the high prevalence of ASD in northeastern Bangladesh, underscoring the need for enhanced diagnostic, educational, and healthcare strategies to ensure good health and well-being and to provide quality education for individuals with ASD.

Autism: A review

Article

Full-text available

Oct 2024

Reduced eye contact, facial expressions, and body movements during the first three years of life are among the social behaviors and nonverbal interactions that define autism spectrum disorder (ASD), a collection of neurodevelopmental diseases. It is generally accepted that this condition is a multifactorial disorder resulting from the combination of both hereditary and non-genetic risk factors. It is not a single disorder. Studies on the genetics of ASD have found mutations that disrupt normal neurodevelopment from infancy through childhood. Axon mobility and synaptogenesis have been linked to these gene complexes. Advances in neuroimaging research have yielded numerous significant insights into the pathological alterations that take place in the brains of individuals with ASD while they are living their lives. Numerous neuropathological and neuroimaging studies have demonstrated the significance of the amygdala, a key component of the limbic system and the affective loop of the cortico-striatothalamo-cortical circuit, in cognition and ASD. The nucleus accumbens is seen as another important structure associated with the social reward response in ASD, in addition to the amygdala. While behavioral and educational interventions have traditionally been the cornerstones of ASD care, pharmaceutical and interventional therapies have also demonstrated some promise in ASD patients. Additionally, a small number of individuals have reportedly improved following deep brain stimulation, one of the interventional treatments.

Meta-analysis of set-based multiple phenotype association test based on GWAS summary statistics from different cohorts

Article

Full-text available

Sep 2024

Genome-wide association studies (GWAS) have emerged as popular tools for identifying genetic variants that are associated with complex diseases. Standard analysis of a GWAS involves assessing the association between each variant and a disease. However, this approach suffers from limited reproducibility and difficulties in detecting multi-variant and pleiotropic effects. Although joint analysis of multiple phenotypes for GWAS can identify and interpret pleiotropic loci which are essential to understand pleiotropy in diseases and complex traits, most of the multiple phenotype association tests are designed for a single variant, resulting in much lower power, especially when their effect sizes are small and only their cumulative effect is associated with multiple phenotypes. To overcome these limitations, set-based multiple phenotype association tests have been developed to enhance statistical power and facilitate the identification and interpretation of pleiotropic regions. In this research, we propose a new method, named Meta-TOW-S, which conducts joint association tests between multiple phenotypes and a set of variants (such as variants in a gene) utilizing GWAS summary statistics from different cohorts. Our approach applies the set-based method that Tests for the effect of an Optimal Weighted combination of variants in a gene (TOW) and accounts for sample size differences across GWAS cohorts by employing the Cauchy combination method. Meta-TOW-S combines the advantages of set-based tests and multi-phenotype association tests, exhibiting computational efficiency and enabling analysis across multiple phenotypes while accommodating overlapping samples from different GWAS cohorts. To assess the performance of Meta-TOW-S, we develop a phenotype simulator package that encompasses a comprehensive simulation scheme capable of modeling multiple phenotypes and multiple variants, including noise structures and diverse correlation patterns among phenotypes. Simulation studies validate that Meta-TOW-S maintains a desirable Type I error rate. Further simulation under different scenarios shows that Meta-TOW-S can improve power compared with other existing meta-analysis methods. When applied to four psychiatric disorders summary data, Meta-TOW-S detects a greater number of significant genes.

Вальпроат-индуцированная модель расстройств аутистического спектра

Article

May 2024

К. C. Ферешетян

Autism is аneurodevelopmental disorder characterized by impairments in social communication and interaction and by repetitive patterns of behavior. While autism has a strong genetic component, environmental factors including toxins, infection and drugs are known to confer autism susceptibility, likely by inducing epigenetic changes. In particular, exposure to valproic acid (VPA) during pregnancy has been demonstrated to increase the risk of autism in children. Prenatal administration of valproic acid has become an accepted animal model of ASD. This model might better represent the many cases of idiopathic autism which are of environmental/epigenetic origins than do transgenic models carrying mutations in single autism-associated genes. The VPA model provides a valuable tool to investigate the neurobiology underlying autistic behavior and to screen for novel therapeutics. Here we review the VPA-induced rodent model of autism, highlighting its importance and reliability as an environmentally induced animal model of autism. Աուտիզմի սպեկտրի խանգարումը նյարդային համակարգի զարգացման խանգարում է, որը բնութագրվում է սոցիալական հաղորդակցության և փոխազդեցության խանգարումներով, ինչպես նաև կրկնվող և կարծրատիպային վարքագծով: Ի լրումն ուժեղ գենետիկ բաղադրիչի, շրջակա միջավայրի գործոնները, ներառյալ տոքսինները, վարակները և դեղամիջոցները, հայտնի են որպես ռիսկի գործոններ՝ հավանաբար առաջացնելով էպիգենետիկ փոփոխություններ: Մասնավորապես ապացուցվել է, որ հղիության ընթացքում վալպրոյաթթվի օգտագործումը մեծացնում է երեխաների մոտ աուտիզմի վտանգը: Վալպրոյաթթվի կիրառումը հղի կենդանիների մոտ աուտիզմի սպեկտրի խանգարումների հաստատված կենդանական մոդել է: Այս մոդելը կարող է ավելի լավ ներկայացնել իդիոպաթիկ աուտիզմի բազմաթիվ դեպքեր, քան տրանսգենային մոդելները, որոնք կրում են աուտիզմի հետ կապված առանձին գեների մուտացիաներ: Կենդանական մոդելը կարևոր է աուտիս-տիկ վարքագծի հիմքում ընկած նյարդակենսաբանական խանգարումների ուսումնասիրության և նոր թերապևտիկ նյութերի գնահատման համար: Այս հոդվածը վերանայում է վալպրոյաթթվով մակածված աուտիզմի կենդանական մոդելը՝ ընդգծելով դրա կարևորությունն ու հուսալիությունը՝ որպես աուտիզմի ոչ տրանսգենային մոդել:

Intranasal Borneol Improves the Behavioral Problems and Enhances the Immunologic Function in Children with Autism

Article

Jan 2016

Excessive Gadget Exposure and Children Speech Delay: The Case of Autism Spectrum Risk Factor

Article

Full-text available

Apr 2022

Smartphones and gadgets are considered as one of the main factors in children's speech delays, especially those under three years. This delay is also accompanied by a child's social impairment like the symptoms of the autism spectrum. This article attempts to demonstrate the statistical correlation between smartphone usage and children's speech delay. Employing a mixed method design by combining statistical inference and qualitative descriptive methods with 70 respondents who were parents of children 1 - 5 years old in Indonesia, the researchers collected data using questionnaires and interviews and further thematically analyzed the responses. This article could show a negatively significant correlation between the duration of gadget use and speech habits, which means that the longer a child spends time playing with gadgets, the worse his/her early-stage language proficiency will be. Thus, it can be concluded that the excessive usage of gadgets has a detrimental impact on children's cognitive and verbal growth. In addition, the researcher found that children with autism spectrum attributes had a relationship with the duration of gadget usage. Further implications on parenting and language teaching are discussed to examine the novelty of the findings.

Dynamic Interrogation of Stochastic Transcriptome Trajectories Using Disease Associated Genes Reveals Distinct Origins of Neurological and Psychiatric Disorders

Article

Full-text available

Jun 2022

The advent of open access to genomic data offers new opportunities to revisit old clinical debates while approaching them from a different angle. We examine anew the question of whether psychiatric and neurological disorders are different from each other by assessing the pool of genes associated with disorders that are understood as psychiatric or as neurological. We do so in the context of transcriptome data tracked as human embryonic stem cells differentiate and become neurons. Building upon probabilistic layers of increasing complexity, we describe the dynamics and stochastic trajectories of the full transcriptome and the embedded genes associated with psychiatric and/or neurological disorders. From marginal distributions of a gene’s expression across hundreds of cells, to joint interactions taken globally to determine degree of pairwise dependency, to networks derived from probabilistic graphs along maximal spanning trees, we have discovered two fundamentally different classes of genes underlying these disorders and differentiating them. One class of genes boasts higher variability in expression and lower dependencies (High Expression Variability-HEV genes); the other has lower variability and higher dependencies (Low Expression Variability-LEV genes). They give rise to different network architectures and different transitional states. HEV genes have large hubs and a fragile topology, whereas LEV genes show more distributed code during the maturation toward neuronal state. LEV genes boost differentiation between psychiatric and neurological disorders also at the level of tissue across the brain, spinal cord, and glands. These genes, with their low variability and asynchronous ON/OFF states that have been treated as gross data and excluded from traditional analyses, are helping us settle this old argument at more than one level of inquiry.

Neuronal Cell Adhesion Molecules May Mediate Neuroinflammation in Autism Spectrum Disorder

Article

Full-text available

Apr 2022

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by restrictive and repetitive behaviors, alongside deficits in social interaction and communication. The etiology of ASD is largely unknown but is strongly linked to genetic variants in neuronal cell adhesion molecules (CAMs), cell-surface proteins that have important roles in neurodevelopment. A combination of environmental and genetic factors are believed to contribute to ASD pathogenesis. Inflammation in ASD has been identified as one of these factors, demonstrated through the presence of proinflammatory cytokines, maternal immune activation, and activation of glial cells in ASD brains. Glial cells are the main source of cytokines within the brain and, therefore, their activity is vital in mediating inflammation in the central nervous system. However, it is unclear whether the aforementioned neuronal CAMs are involved in modulating neuroimmune signaling or glial behavior. This review aims to address the largely unexplored role that neuronal CAMs may play in mediating inflammatory cascades that underpin neuroinflammation in ASD, primarily focusing on the Notch, nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) cascades. We will also evaluate the available evidence on how neuronal CAMs may influence glial activity associated with inflammation. This is important when considering the impact of environmental factors and inflammatory responses on ASD development. In particular, neural CAM1 (NCAM1) can regulate NF-κB transcription in neurons, directly altering proinflammatory signaling. Additionally, NCAM1 and contactin-1 appear to mediate astrocyte and oligodendrocyte precursor proliferation which can alter the neuroimmune response. Importantly, although this review highlights the limited information available, there is evidence of a neuronal CAM regulatory role in inflammatory signaling. This warrants further investigation into the role other neuronal CAM family members may have in mediating inflammatory cascades and would advance our understanding of how neuroinflammation can contribute to ASD pathology.

Développement de radiotraceurs de la neuroinflammation pour l'imagerie des pathologies neurodégénératives

Thesis

Oct 2007

Fabien Chauveau

Des processus inflammatoires tels que l’activation des cellules microgliales et de l’endothélium vasculaire sont impliqués dans de nombreuses pathologies neurodégénératives. L’imagerie de la neuroinflammation offre des perspectives d’étude, de diagnostic précoce, et d’évaluation thérapeutique pour un large spectre de neuropathologies. Premièrement, un aptamère a été sélectionné contre un fragment recombinant de la cible endothéliale VCAM-1, mais perd sa spécificité de reconnaissance de la protéine lorsqu’elle est exprimée en conformation native par la cellule. Deuxièmement, cinq radioligands du récepteur périphérique aux benzodiazépines, marqueur de l’activation microgliale, ont été évalués in vivo en imagerie TEP et comparés au [11C]PK11195 en utilisant des rats lésés. Quatre ont montré des performances supérieures au [11C]PK11195 via un contraste amélioré. Dans un domaine en pleine expansion, ces travaux définissent un crible efficace pour la sélection d’un radiotraceur d’intérêt.

Feeding and Swallowing Issues in Children With Neuro-Developmental Disorders

Chapter

Jan 2022

The chapter highlights the feeding and swallowing issues seen in children with neuro-developmental disorders, types, and extent of the problem across different disorders; its relation with the neuro-development of the child; effect on the quality of life of the parents/caregivers along with the child, specifically in the Indian context. It also focuses on the importance of assessment, team approach, and review of available tests for the assessment of feeding and swallowing problems in these children. The chapter is also going to give a few insights into the challenges faced by speech-language pathologists during the assessment of the feeding and swallowing issues in these children in the Indian scenario. The chapter will also include a section on applications of ICF model to feeding and swallowing issues in children with neurodevelopmental disorders.

Effect of mitochondrial dysfunction and oxidative stress on the pathogenesis of autism spectrum disorders

Article

Full-text available

Sep 2021

There are certain aspects of autism spectrum disorder that seem to be related to the pathogenesis of mitochondrial dysfunction or the chain of events and pathways associated with mitochondrial dysfunction. In this mini-review article, we aimed to summarize these two entities separately and review how they are linked to oxidative stress pathways, genetic abnormalities, transcriptional factor changes, metabolic disorders, changes in the enteric composition of the microbiota, gene expression, and regional alterations in regulatory proteins. Some ideas on how these new findings of the current link may affect therapeutic approaches were also discussed.

Retrospective observational study of daytime add-on administration of zopiclone to difficult-to-treat psychiatric inpatients with unpredictable aggressive behavior, with or without EEG dysrhythmia.

Article

Full-text available

Aug 2021

Retrospective Observational Study of Daytime Add-On Administration of Zopiclone to Difficult-to-Treat Psychiatric Inpatients With Unpredictable Aggressive Behavior, With or Without EEG Dysrhythmia

Article

Full-text available

Aug 2021

Managing violent behavior is a particularly challenging aspect of hospital psychiatric care. Available pharmacological interventions are often unsatisfactory. Aim: To assess the effectiveness and safety of daytime zopiclone add-on administration in violent and difficult-to-treat psychiatric inpatients. Methods: Chart review of inpatients treated with daytime zopiclone, between 2014 and 2018, with up to 12 weeks follow-up. Effectiveness was retrospectively assessed with the Clinical Global Impression rating scale (CGI) and the frequency and severity of aggressive incidents recorded with the Staff Observation Aggression Scale-Revised (SOAS-R). Results: Forty-five (30 male, 15 female) cases, 18–69 years age range, average (SD) baseline CGI-S score of 5.4 (1.0), and a variety of diagnoses. Sixty-nine percent showed CGI-S improvement of any degree. For patients with at least one aggressive incident within 7 days prior to initiation of zopiclone (N = 22), average (SD) SOAS-R-Severity LOCF to baseline change was −3.5 (2.7) P < 0.0001. Most patients reported no side effects; 24% reported one or more side effects, and 11% discontinued zopiclone due to sedation (4), insomnia (1) or slurred speech (1). No SAEs were recorded. Zopiclone maximum daily dose correlated with CGI-S baseline-to-LOCF change (rho = −0.5, P = 0.0003). The ROC AUC of zopiclone maximum daily dose and improvement on CGI-S was 0.84 (95% CI 0.70–0.93, P < 0.0001). The ROC AUC of zopiclone maximum daily dose and SOAS-R-N improvement was 0.80 (95% CI 0.58–0.92; P = 0.0008) and maximum Youden's index value was achieved at a dose of >30 mg. Conclusions: Zopiclone doses >30 mg daily achieved the best anti-aggressive effect.

A novel automated autism spectrum disorder detection system

Article

Full-text available

Jun 2021

Autism spectrum disorder (ASD) is a neurological and developmental disorder that begins early in childhood and lasts throughout a person’s life. Autism is influenced by both genetic and environmental factors. Lack of social interaction, communication problems, and a limited range of behaviors and interests are possible characteristics of autism in children, alongside other symptoms. Electroencephalograms provide useful information about changes in brain activity and hence are efficaciously used for diagnosis of neurological disease. Eighteen nonlinear features were extracted from EEG signals of 40 children with a diagnosis of autism spectrum disorder and 37 children with no diagnosis of neuro developmental disorder children. Feature selection was performed using Student’s t test, and Marginal Fisher Analysis was employed for data reduction. The features were ranked according to Student’s t test. The three most significant features were used to develop the autism index, while the ranked feature set was input to SVM polynomials 1, 2, and 3 for classification. The SVM polynomial 2 yielded the highest classification accuracy of 98.70% with 20 features. The developed classification system is likely to aid healthcare professionals as a diagnostic tool to detect autism. With more data, in our future work, we intend to employ deep learning models and to explore a cloud-based detection system for the detection of autism. Our study is novel, as we have analyzed all nonlinear features, and we are one of the first groups to have uniquely developed an autism (ASD) index using the extracted features.

Aberrant Complement System Activation in Neurological Disorders

Article

Full-text available

Apr 2021
INT J MOL SCI

The complement system is an assembly of proteins that collectively participate in the functions of the healthy and diseased brain. The complement system plays an important role in the maintenance of uninjured (healthy) brain homeostasis, contributing to the clearance of invading pathogens and apoptotic cells, and limiting the inflammatory immune response. However, overactivation or underregulation of the entire complement cascade within the brain may lead to neuronal damage and disturbances in brain function. During the last decade, there has been a growing interest in the role that this cascading pathway plays in the neuropathology of a diverse array of brain disorders (e.g., acute neurotraumatic insult, chronic neurodegenerative diseases, and psychiatric disturbances) in which interruption of neuronal homeostasis triggers complement activation. Dysfunction of the complement promotes a disease-specific response that may have either beneficial or detrimental effects. Despite recent advances, the explicit link between complement component regulation and brain disorders remains unclear. Therefore, a comprehensible understanding of such relationships at different stages of diseases could provide new insight into potential therapeutic targets to ameliorate or slow progression of currently intractable disorders in the nervous system. Hence, the aim of this review is to provide a summary of the literature on the emerging role of the complement system in certain brain disorders.

Altered Sulfur Amino Acid Metabolism In Immune Cells of Children Diagnosed With Autism

Article

Full-text available

Jan 2008

Brain Opioid Activity and Oxidative Injury: Different Molecular Scenarios Connecting Celiac Disease and Autistic Spectrum Disorder

Article

Full-text available

Jul 2020
BSRCCS

Celiac Disease (CD) is an immune-mediated disease triggered by the ingestion of wheat gliadin and related prolamins from other cereals, such as barley and rye. Immunity against these cereal-derived proteins is mediated by pro-inflammatory cytokines produced by both innate and adaptive system response in individuals unable to adequately digest them. Peptides generated in this condition are absorbed across the gut barrier, which in these patients is characterized by the deregulation of its permeability. Here, we discuss a possible correlation between CD and Autistic Spectrum Disorder (ASD) pathogenesis. ASD can be induced by an excessive and inappropriate brain opioid activity during the neonatal period. Cereal-derived peptides produced in celiac patients cross the blood–brain barrier and bind to endogenous opioid receptors interfering with neurotransmission and generating deleterious effects on brain maturation, learning and social relations. Moreover, an increase in oxidative stress and a decrease in the antioxidant capacity, as well as an extended mitochondrial impairment in the brain, could represent a possible connection between ASD and CD. Therefore, we critically discuss the proposed relationship between ASD and CD and the possible usefulness of a gluten-free diet in ASD patients.

Stepping Out of Isolation: Autistic People and COVID-19

Article

Apr 2020

Jacquiline den Houting

Feeding and Swallowing Issues in Children With Neuro Developmental Disorders

Chapter

Full-text available

Jun 2019

Autism Associated With Anti-NMDAR Encephalitis: Glutamate-Related Therapy

Article

Full-text available

Jun 2019

The purpose of this review is to correlate autism with autoimmune dysfunction in the absence of an explanation for the etiology of autism spectrum disorder. The anti-N-methyl-D-aspartate receptor (anti-NMDAR) autoantibody is a typical synaptic protein that can bind to synaptic NMDA glutamate receptors, leading to dysfunctional glutamate neurotransmission in the brain that manifests as psychiatric symptoms (psychosis, hallucinations, and personality changes). Detection of autoantibodies, cytokines, decreased lymphocytes, serum immunoglobulin level imbalance, T-cell mediated immune profile, maternal infection history, and children’s infection history can all be vital biological markers of autoimmune autism. Diagnosing autoimmune encephalitis sooner can increase the effectiveness of curative treatments—such as immune therapy or immune modulatory therapy—that may prevent the long-term consequence of being misdiagnosed with autism spectrum disorder. Glutamate therapy primarily normalizes glutamate neurotransmission and can be a new add-on intervention alongside antipsychotics for treating autoimmune autism.

Impaired Spatial Cognition in Adult Rats Treated with Multiple Intracerebroventricular (ICV) Infusions of the Enteric Bacterial Metabolite, Propionic Acid, and Return to Baseline After 1 Week of No Treatment: Contribution to a Rodent Model of ASD

Article

Full-text available

May 2019
NEUROTOX RES

Propionic acid (PPA) is a dietary short chain fatty acid and an enteric bacterial metabolite. Intracerebroventricular (ICV) infusions of PPA in rodents have been shown to produce behavioral changes similar to those seen in autism spectrum disorders (ASD), including perseveration. The effects of ICV infusions of PPA on spatial cognition were examined by giving rats infusions of either PPA (0.26 M, pH 7.4, 4 μl/infusion) or phosphate buffered saline (PBS, 0.1 M) twice a day for 7 days. The rats were then tested in the Morris Water Maze (MWM) for acquisition of spatial learning. After a recovery period of one week of no treatment the rats were then tested for reversal of spatial learning in the MWM. PPA-treated rats showed impaired spatial learning in the maze, relative to controls, as demonstrated by increased search latencies, fewer direct and circle swims, and more time spent in the periphery of the maze than PBS controls. After a recovery period of one week of no treatment, these animals exhibited normal spatial reversal learning indicating that the behavioral cognitive deficits caused by PPA seem to be reversible.

Plant and human aquaporins: pathogenesis from gut to brain

Article

Full-text available

Feb 2019

Corn, soybean, spinach leaf, and tomato aquaporins have been shown to share homology with human aquaporin-4, which is abundantly expressed by brain astrocytic endfeet. Thus, antibodies formed against the dietary aquaporins may potentially cross-react with brain aquaporin, leading to blood-brain barrier permeability and setting the stage for neuroautoimmunity and neurodegeneration. Here, we review the role of aquaporins in plants and humans in maintaining a healthy organism and mechanisms by which dietary aquaporins may contribute to neurological disorders. We include clinical data on the correlation between four real-world, dietary aquaporin and five neurological tissue antibodies. Our findings showed the percent of neurological tissue antibody production increased with the number of positive food aquaporins. Of the four food aquaporins, spinach was the most common reactive. Of the neurological tissues assessed, tubulin was the most common positive. Patients with antibody reactivity to dietary aquaporins may consider abstaining from the aquaporin-containing food in order to prevent neurological tissue damage.

Cerebrospinal fluid and the early brain development of autism

Article

Full-text available

Dec 2018
J NEURODEV DISORD

Mark D Shen

Background: There is currently a renaissance of interest in the many functions of cerebrospinal fluid (CSF). Altered flow of CSF, for example, has been shown to impair the clearance of pathogenic inflammatory proteins involved in neurodegenerative diseases, such as amyloid-β. In addition, the role of CSF in the newly discovered lymphatic system of the brain has become a prominently researched area in clinical neuroscience, as CSF serves as a conduit between the central nervous system and immune system. Main body: This article will review the importance of CSF in regulating normal brain development and function, from the prenatal period throughout the lifespan, and highlight recent research that CSF abnormalities in autism spectrum disorder (ASD) are present in infancy, are detectable by conventional structural MRI, and could serve as an early indicator of altered neurodevelopment. Conclusion: The identification of early CSF abnormalities in children with ASD, along with emerging knowledge of the underlying pathogenic mechanisms, has the potential to serve as early stratification biomarkers that separate children with ASD into biological subtypes that share a common pathophysiology. Such subtypes could help parse the phenotypic heterogeneity of ASD and map on to targeted, biologically based treatments.

A Prospective Study of Environmental Exposures and Early Biomarkers in Autism Spectrum Disorder: Design, Protocols, and Preliminary Data from the MARBLES Study

Article

Full-text available

Nov 2018

Background: Until recently, environmental factors in autism spectrum disorder (ASD) were largely ignored. Over the last decade, altered risks from lifestyle, medical, chemical, and other factors have emerged through various study designs: whole population cohorts linked to diagnostic and/or exposure-related databases, large case-control studies, and smaller cohorts of children at elevated risk for ASD. Objectives: This study aimed to introduce the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) prospective study and its goals, motivate the enhanced-risk cohort design, describe protocols and main exposures of interest, and present initial descriptive results for the study population. Methods: Families having one or more previous child with ASD were contacted before or during a pregnancy, and once the woman became pregnant, were invited to enroll. Data and biological samples were collected throughout pregnancy, at birth, and until the child's third birthday. Neurodevelopment was assessed longitudinally. The study began enrolling in 2006 and is ongoing. Results: As of 30 June 2018, 463 pregnant mothers have enrolled. Most mothers ([Formula: see text]) were thirty years of age or over, including 7.9% who are fourty years of age or over. The sample includes 22% Hispanic and another 25% nonHispanic Black, Asian, or multiracial participants; 24% were born outside the United States. Retention is high: 84% of participants whose pregnancies did not end in miscarriage completed the study or are still currently active. Among children evaluated at 36 months of age, 24% met criteria for ASD, and another 25% were assessed as nonASD nontypical development. Conclusion: Few environmental studies of ASD prospectively obtain early-life exposure measurements. The MARBLES study fills this gap with extensive data and specimen collection beginning in pregnancy and has achieved excellent retention in an ethnically diverse study population. The 24% familial recurrence risk is consistent with recent reported risks observed in large samples of siblings of children diagnosed with ASD. https://doi.org/10.1289/EHP535.

Increasing indoxyl sulfate induces iNOS expression via aryl hydrocarbon receptor leading to microglia hyperactivation in the prefrontal cortex of autism-like offspring rats

Article

Jun 2025
NEUROSCI LETT

The biological and sociological implications of diversity, equity, and inclusion (DEI): life within microbiomes and on earth

Article

Apr 2025
J TOXICOL ENV HEAL B

From a biological point of view, Diversity, Equity, and Inclusion (DEI) are important at multiple levels, which include our genetics, microbiomes, diets, and all organ system interactions. Considering only DEI's sociological aspects is equivalent to the error of "throwing out the baby with the bath water." Variances in microbial diversity within our microbiomes might affect our health through systemic interactions affecting metabolites, maintaining immune homeostasis, and wound healing of cellular damage from an infection, physical stress, or psychological trauma. An imbalance of our immune cell subsets, both innate and adaptive, and the microbes in any of our microbiomes might lead to more cellular damage from excessive inflammation and oxidative stress and less immune regulation. The immune dysregulation may occur due to the loss of endometrial barriers enabling the spread of microbes, environmental pollutants, and allergens. Heat waves, sleep deprivation, and increased prevalence of pollutants such as polychlorinated biphenyls, which weaken endothelial barriers, may be responsible for the enhanced prevalence of physical and psychological stresses. Leakage of our useful gut microbiota into the periphery might initiate inflammatory responses, and an altered gut microbiome might affect the gut-brain axis that influences physical and mental health.

Metal Dyshomeostasis as a Driver of Gut Pathology in Autism Spectrum Disorders

Article

Full-text available

Mar 2025
J NEUROCHEM

Despite being classified as neurodevelopmental disorders, in recent years, there has been a growing interest in the association between autism spectrum disorders (ASDs) and gut pathology. This comprehensive and systematic review explores a potential mechanism underlying gut pathology in ASDs, including alterations in gut microbiota, intestinal permeability, immune dysregulation, and gastrointestinal (GI) symptoms. Specifically, it delves into the role of toxic and essential metals and their interplay, affecting the development and function of the GI tract. The review also discusses the potential implications of this gut pathology in the development and management of ASDs. Studies have shown that heavy metal exposure, whether through environmental sources or dietary intake, can disrupt the delicate balance of trace elements in the gut. This disruption can adversely affect zinc homeostasis, potentially exacerbating gut pathology in individuals with ASDs. The impaired zinc absorption resulting from heavy metal exposure may contribute to the immune dysregulation, oxidative stress, and inflammation observed in the gut of individuals with ASDs. By shedding light on the multifaceted nature of gut pathology, including the impact of metal dyshomeostasis as a non‐genetic factor in ASD, this review underscores the significance of the gut‐brain axis in the etiology and management of ASDs. image

Suspected Autism Spectrum Disorder in a Young Bull Terrier Cross: Clinical Management and Treatment Outcome

Article

Feb 2025

This case report explores the diagnosis and management of a young Bull Terrier cross presenting with behaviors resembling autism spectrum disorder (ASD), complicated by the presence of Addison’s disease. The dog exhibited intense compulsive behaviors, such as prolonged fixation, erratic social interactions, and excessive barking, which are traits often associated with ASD in humans. A comprehensive evaluation, including MRI, revealed atypical cortical sulcal morphology and ventricular enlargement, suggestive of neurodevelopmental abnormalities. Medical history further revealed gastrointestinal symptoms, and Addison’s disease was subsequently diagnosed, introducing additional complexity to the clinical picture. To manage the dog’s behavior, a treatment regimen was implemented, including fluoxetine, gabapentin, clonidine, and cyproterone acetate, alongside structured behavioral interventions. The case emphasizes the value of combining pharmacological and behavioral therapies in veterinary practice, particularly in complex cases involving neurodevelopmental conditions. This report contributes to the growing field of veterinary psychiatry, providing insights into ASD-like disorders in dogs and suggesting future directions for research in veterinary behavioral science. Information © The Authors 2025

Etiological and Co-etiological Factors of Autism

Chapter

Full-text available

Oct 2024

Michele Di Salvo

1. Epigenetic factors 2. The prenatal environment: Obstructive sleep apnoea in pregnancy; Infectious processes; Environmental agents; Autoimmune and inflammatory diseases; Other maternity-related conditions. 3. Perinatal environment 4. Postnatal environment: Amygdala neurons; Autoimmune diseases 5. Intermezzo: the brain's immune system and its relationship with the gut 6. Postnatal environment: Gastrointestinal connections; Endogenous opiate precursor theory; Nutrition-related factors; Toxic exposure; Locus coeruleus-noradrenergic system; Oxidative stress. The role of genes is increasingly interpreted as a factor that interacts with others, generically called environmental factors, in determining the onset of the syndrome. For example, the possible involvement of particular conditions that may occur during foetal and neonatal development (pregnancy progression, infections contracted by the mother, factors linked to childbirth conditions) is being actively studied. An important area of research concerns the role of exposure to toxic agents during development. In this chapter, I will attempt to summarise 'the state of the art' on these important and seemingly increasingly relevant research fronts. In this context, it must necessarily be noted that, while it is true that the claim that cases of autism have increased disproportionately (as we shall see in more detail in the next chapter) is highly critical, it is also true that—if the relationship with broadly understood environmental factors were to be confirmed—at least part of this increase would be attributable to ecological changes over the last century, broadly understood. At present, many causes of autism have been proposed, but the understanding of the theory of autism causality is incomplete. As we have seen, an attempt has been made to incorporate known genetic and environmental causes into a causal framework. In its most recent definition, autism is a neurodevelopmental disorder characterised by impairments in communication skills and social interaction and limited/repetitive behaviours, interests or activities that are not appropriate to the individual's developmental stage, and the severity of symptoms and functional impairment vary from individual to individual. In recent years, the number of people diagnosed with the disorder has increased dramatically, at least taking into account official statistics. There are several potential reasons for this phenomenon, in particular changes in diagnostic criteria. In fact, it is evident that the broader the spectrum, the more open the criteria and the greater the number of cases that may fall within a descriptive case.

Decreased levels of L‐selectin and platelet‐endothelial cell adhesion molecule‐1 in children with autism spectrum disorder

Article

Sep 2024

Objective This study aimed to ascertain the serum levels of selectins (E, L, P) and platelet‐endothelial adhesion molecule‐1 (PECAM‐1) in preschool children with autism spectrum disorder (ASD) and to establish a comparison with the levels observed in healthy controls. Methods The study included 34 children aged 2–7 years diagnosed with ASD (ASD group) and 34 randomly selected healthy children matched for age and sex to the ASD group. The children were free of any genetic or physical disease, clinically active infection, or medication use. The sociodemographic data form was completed by all parents. The Childhood Autism Rating Scale (CARS) and the Autism Behavior Checklist (ABC) were administered to the patient group, and the Aberrant Behavior Checklist (AbBC) was completed by the families of all children. Serum selectin (E, L, P) and PECAM‐1 levels were measured using enzyme‐linked immunosorbent assay (ELISA) kits. Results The results showed that the levels of both L‐selectin ( p = 0.007) and PECAM‐1 ( p = 0.019) were significantly lower in the ASD group than in the control group. No significant difference was observed between the groups concerning E‐selectin and P‐selectin levels ( p > 0.05). It was observed that P‐selectin variables were statistically significant in predicting the presence of ASD ( p = 0.019). A remarkable inverse correlation was found between the AbBC irritability subscale score and L‐selectin (r = −0.296, p = 0.014) and PECAM‐1 (r = −0.276, p = 0. 023); the AbBC Lethargy‐Social Withdrawal subscale score and E‐Selectin (r = −0.239, p = 0.049), L‐Selectin (r = −0.297, p = 0.014) and PECAM‐1 (r = −0.264, p = 0.029); L‐Selectin levels and the AbBC stereotypic behavior subscale (r = −0.248, p = 0.042). No statistically significant relationship was observed between selectins (E, L, P) and PECAM‐1 levels and CARS scale, ABC subscale or total scores and age variables ( p > 0.05). Conclusions These study results suggest that L‐selectin, P‐selectin and PECAM‐1 may play a role in the pathophysiology of ASD.

Autoimmune Connective Tissue and Dermatologic Diseases in Children with Autism Spectrum Disorder

Article

Jun 2024
J INVEST DERMATOL

ASD Detection System

Article

Dec 2023

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition that presents a wide range of challenges for affected individuals and their families. Early detection and intervention are crucial in improving outcomes for individuals with ASD. This abstract introduces the development of an innovative ASD detection system, which combines advanced technology and machine learning techniques to assist in early diagnosis. The ASD detection system leverages various data sources, including behavioral observations, medical records, and genetic information, to create a comprehensive profile of individuals at risk for ASD. It utilizes sophisticated machine learning algorithms to analyze and interpret this data, aiming to identify subtle patterns and markers associated with ASD. The system's user-friendly interface allows healthcare professionals to input and access data easily, streamlining the diagnostic process.

Immunogenetics of autism spectrum disorder: A systematic literature review

Article

Sep 2023
BRAIN BEHAV IMMUN

Maternal immune dysregulation and autism spectrum disorder

Chapter

Jan 2023

TH1/Treg ratio may be a marker of autism in children with immune dysfunction

Article

Mar 2023
RES AUTISM SPECT DIS

Evidence suggests a link between autism spectrum disorder (ASD), behavioral symptoms in the context of ASD, and presence of an altered immune function. Several studies have highlighted differences in T-lymphocyte subpopulations, their activation status, and their response to stimulation in children and adults with ASD. These T cell abnormalities have often been associated with more impaired behaviors. However, few studies have attempted to address whether T cell subsets have the potential to serve as biomarkers in ASD. Moreover, although many studies have been performed in Western populations, few (if any) have been performed in Asian populations in mainland China. In this study we used intracellular cytokine flow cytometry to assess the frequencies of CD4⁺ T-cell subpopulations (T-helper (TH) 1, TH2, TH17, Foxp3⁺ regulatory T cells (Treg) as well as CD8⁺, subpopulations of T cytotoxic (TC) 1, TC2, and TC17 in 82 children with ASD and 50 healthy typical developing children from the Second Affiliated Hospital of Kunming Medical University of Yunnan province. To further elucidate immune status cytokine levels were also measured in the plasma and serum using a bead-based cytokine assay. Our results showed that the frequency of circulating Treg cells and the levels of active TGF-β1 in plasma were lower in children with ASD than in healthy controls. In contrast, the frequencies of TH1, TH2, TH17 and TC1 cells were increased. Proinflammatory cytokine levels of TNF-α, IL-4, IL-5 and IL-17A were higher in the plasma of children with ASD compared to typical controls. We also found an association between the severity of behavior impairments in ASD children and altered immune responses as measured using the effector T cell responses and regulatory responses (using Teff/Treg ratios). Higher the Teff/Treg ratios, were associated with more severe problematic behavioral symptoms. Further, the potential biomarker relevance of Teff/Treg ratio was evaluated by the receiver operating characteristics curve. Data suggests that high TH1/Treg cell ratios could also be used as a potential marker for the diagnosis of children with ASD. Overall, our data suggest an imbalance in inflammatory and regulatory immune responses in ASD. Ratios of inflammatory/regulatory cells or cell frequencies such as Teff/Treg cells may be useful biomarkers for children with ASD with immune dysfunction.

Diseases with Long-Term Consequences in Search of a Microbial Agent

Chapter

Apr 2014

The moderating effect of financial stress and autism severity on development of depression among parents and caregivers of Autistic children in Taif, Saudi Arabia

Article

Full-text available

Mar 2021

Background: Autistic spectrum disorder (ASD) is a common problem in the Kingdom of Saudi Arabia. However, little research explored the extent of anxiety and depressive disorders in parents of children with ASD. Method: Descriptive questionnaire-based cross-sectional survey of a sample of parents of children with ASD who attended Prince Mohammed Bin Salman Autistic Centre, Ministry of defense, Taif city. Results: The study included (n = 50) parents. The prevalence of mild depression was 30%, whereas the prevalence of moderately severe depression was 68%. Increased ASD severity level was associated with a significant impact on the PHQ-9 total score (level II was 1.293 times level I to have an increased PHQ-9 score, and level III was 1.530 times level I to have an increased PHQ-9 score). Economic status did not significantly alter depressive symptoms. Discussion and conclusion: ASD diagnosis in Saudi children is associated with high parental depressive prevalence. However, this result could be bidirectional. Stigma, future-related worry, and stress could mediate parental depressive symptoms. Our findings in Saudi parents of children with ASD corroborate the established association between parental depressive symptoms and ASD severity. Our results corroborated previous findings that neither parental gender nor child gender exert any substantial effect on predictability of depressive symptoms among parents of children with ASD. Comprehensive therapeutic packages for children with ASD should include treatment of emotional problems arising out of carer burden among their parents. Screening for parental emotional problems should be routine in autism treatment facilities.

A profile and review of findings from the Early Markers for Autism study: unique contributions from a population-based case–control study in California

Article

Full-text available

Mar 2021

Background The Early Markers for Autism (EMA) study is a population-based case–control study designed to learn more about early biologic processes involved in ASD. Methods Participants were drawn from Southern California births from 2000 to 2003 with archived prenatal and neonatal screening specimens. Across two phases, children with ASD ( n = 629) and intellectual disability without ASD (ID, n = 230) were ascertained from the California Department of Developmental Services (DDS), with diagnoses confirmed according to DSM-IV-TR criteria based on expert clinical review of abstracted records. General population controls (GP, n = 599) were randomly sampled from birth certificate files and matched to ASD cases by sex, birth month and year after excluding individuals with DDS records. EMA has published over 20 papers examining immune markers, endogenous hormones, environmental chemicals, and genetic factors in association with ASD and ID. This review summarizes the results across these studies, as well as the EMA study design and future directions. Results EMA enabled several key contributions to the literature, including the examination of biomarker levels in biospecimens prospectively collected during critical windows of neurodevelopment. Key findings from EMA include demonstration of elevated cytokine and chemokine levels in maternal mid-pregnancy serum samples in association with ASD, as well as aberrations in other immune marker levels; suggestions of increased odds of ASD with prenatal exposure to certain endocrine disrupting chemicals, though not in mixture analyses; and demonstration of maternal and fetal genetic influence on prenatal chemical, and maternal and neonatal immune marker and vitamin D levels. We also observed an overall lack of association with ASD and measured maternal and neonatal vitamin D, mercury, and brain-derived neurotrophic factor (BDNF) levels. Limitations Covariate and outcome data were limited to information in Vital Statistics and DDS records. As a study based in Southern California, generalizability for certain environmental exposures may be reduced. Conclusions Results across EMA studies support the importance of the prenatal and neonatal periods in ASD etiology, and provide evidence for the role of the maternal immune response during pregnancy. Future directions for EMA, and the field of ASD in general, include interrogation of mechanistic pathways and examination of combined effects of exposures.

Autism Spectrum Disorder and Gut Microbiome: A Brief Review

Article

Full-text available

Feb 2021

The human microbiota consists of the 10-100 trillion symbiotic microbial cells harbored by each person, primarily bacteria in the gut. The association of the gut microbiota with human health and disease has been widely studied. A number of human disorders and diseases have been directly and indirectly associated with the microbiome. Children with Autism Spectrum Disorder (ASD) have distinctive gut microbiota compared to neurotypical children. Autism spectrum disorder (ASD) is associated with several oropharyngeal abnormalities, including dysbiosis in the oral microbiota. As there is a correlation between abnormal microbiota and development of autism like behaviour, so, modifying the gut microbiome by probiotics, prebiotics, antibiotics and fecal microbiota transplant (FMT) could be a potential route to improve GI and behavioural symptoms in children with ASD.

The aetiology of social deficits within mental health disorders: The role of the immune system and endogenous opioids

Article

Full-text available

Jan 2020

The American National Institute for Mental Health (NIMH) has put out a set of research goals that include a long-term plan to identify more reliable endogenous explanations for a wide variety of mental health disorders (Insel, 2013). In response to this, we have identified a major symptom that underlies multiple mental health disorders – social bonding dysfunction. We suggest that endogenous opioid abnormalities can lead to altered social bonding, which is a symptom of various mental health disorders, including depression, schizophrenia and ASD. This article first outlines how endogenous opioids play a role in social bonding. Then we show their association with the body’s inflammation immune function, and review recent literature linking inflammation to mental health ‘immunophenotypes’. We finish by explaining how these immunophenotypes may be caused by alterations in the endogenous opioid system. This is the first overview of the role of inflammation across multiple disorders where we provide a biochemical explanation for why immunophenotypes might exist across diagnoses. We propose a novel mechanism of how the immune system may be causing ‘sickness-type’ behaviours (fatigue, appetite change, social withdrawal and inhibited motivation) in those who have these immunophenotypes. We hope that this novel aetiology can be used as a basis for future research in mental health.

Role of Vitamin D in Autism Spectrum Disorder

Article

Nov 2019

Loai Alzghoul

Autism spectrum disorder (ASD) is a pervasive developmental disorder with heterogeneous etiology. Vitamin D and can function as fat soluble vitamin as well as a hormone, and can exert its effect via both genomic and non-genomic mechanisms. In the last decades, several studies have examined the relationship between vitamin D levels and ASD. These studies demonstrated that low vitamin D status in early development has been hypothesized as an environmental risk factor for ASD. Both in vivo and in vitro studies have demonstrated that vitamin D deficiency in early life can alter brain development, dysregulate neurotransmitter balance in the brain, decreases body and brain antioxidant ability, and alter immune system in ways that resemble common pathological features commonly seen ASD. In this review we focused on the association between vitamin D and ASD. In addition, the above mentioned mechanisms of action that link vitamin D deficiency with ASD were also discussed. Finally, clinical trials of vitamin D supplementation treatment of ASD have been also discussed.

Autism and arousal

Chapter

Jan 2019

Helminth therapy for autism under gut-brain axis- hypothesis

Article

Full-text available

Feb 2019
MED HYPOTHESES

Celia Arroyo-López

Abstract Autism is a neurodevelopmental disease included within Autism Syndrome Disorder (ASD) spectrum. ASD has been linked to a series of genes that play a role in immune response function and patients with autism, commonly suffer from immune-related comorbidities. Despite the complex pathophysiology of autism, Gut-brain axis is gaining strength in the understanding of several neurological disorders. In addition, recent publications have shown the correlation between immune dysfunctions, gut microbiota and brain with the behavioral alterations and comorbid symptoms found in autism. Gut-brain axis acts as the “second brain”, in a communication network established between neural, endocrine and the immunological systems. On the other hand, Hygiene Hypothesis suggests that the increase in the incidence of autoimmune diseases in the modern world can be attributed to the decrease of exposure to infectious agents, as parasitic nematodes. Helminths induce modulatory and protective effects against several inflammatory disorders, maintaining gastrointestinal homeostasis and modulating brain functions. Helminthic therapy has been previously performed in diseases such as ulcerative colitis, Crohn’s disease, diabetes, multiple sclerosis, asthma, rheumatoid arthritis, and food allergies. Considering gut-brain axis, Hygiene Hypothesis, and the modulatory effects of helminths I hypothesized that a treatment with Trichuris suis soluble products represents a feasible holistic treatment for autism, and the key for the development of novel treatments. Preclinical studies are required to test this hypothesis.

Updated View on the Relation of the Pineal Gland to Autism Spectrum Disorders

Article

Full-text available

Feb 2019

Identification of the biological features of autism is essential for designing an efficient treatment and for prevention of the disorder. Though the subject of extensive research, the neurophysiological features of autism remain unclear. One of the proposed biological causes of autism is malfunction of the pineal gland and deficiency of its principal hormone, melatonin. The main function of melatonin is to link and synchronize the body's homeostasis processes to the circadian and seasonal rhythms, and to regulate the sleep-wake cycle. Therefore, pineal dysfunction has been implicated based on the common observation of low melatonin levels and sleep disorders associated with autism. In this perspective, we highlight several recent findings that support the hypothesis of pineal gland/melatonin involvement in autism. Another common symptom of autism is abnormal neuroplasticity, such as cortical overgrowth and dendritic spine dysgenesis. Here, we synthesize recent information and speculate on the possibility that this abnormal neuroplasticity is caused by hyperactivity of endogenous N,N-dimethyltryptamine (DMT). The pineal gland was proposed as the source of DMT in the brain and therefore, our assumption is that besides melatonin deficiency, pineal dysfunction might also play a part in the development of autism through abnormal metabolism of DMT. We hope that this manuscript will encourage future research of the DMT hypothesis and reexamination of several observations that were previously attributed to other factors, to see if they could be related to pineal gland/melatonin malfunction. Such research could contribute to the development of autism treatment by exogenous melatonin and monitored light exposure.

Autism: The centrality of active pathophysiology and the shift from static to chronic dynamic encephalopathy

Chapter

Jan 2009

Martha Reed Herbert

The purpose of this chapter is to reflect upon the implications of the identification of active pathophysiological processes in autism spectrum disorders (ASD), and to reflect back upon prior findings and formulations in the light of these recent discoveries. This chapter articulates challenges posed by these discoveries to deeply held assumptions about the ASD. These assumptions are embodied in a classical model framing the ASD as a problem of genes, brain, and behavior, i.e., as a genetically determined developmental disorder of the brain whose main manifestation is behavioral alterations based on an indelible static encephalopathy; this model would not have predicted the growing documentation of pathophysiological disturbances. This chapter also describes an emerging pathophysiology-centered model of autism that can subsume genes, brain, and behavior but also includes much more. Prior findings and models are reevaluated to support the framing of the ASD as (1) not only a developmental but also a chronic condition based on active pathophysiology, (2) not only having behavioral but also having somatic and systemic features that are not secondary but rather intrinsic consequences of underlying mechanisms, (3) not only genetic but also environmental, (4) not a static encephalopathy but a dynamic, recalcitrant encephalopathy, and (5) not a set of discrete behavioral features neatly mapping to specific genetic mechanisms but a set of emergent properties dynamically arising from pathophysiological systems whose parameters have been dramatically and interactively perturbed. It is argued that a research program based on this approach will incorporate the strengths of the classical model, will encourage many more routes to investigations with practical and treatment applications, and may be a much more rapid path to provide much-needed help to affected individuals and their families.

Co-localisation of IgG and complement C1q on the small intestinal epithelium in an autistic child

Article

Full-text available

Apr 2002
MOL PSYCHIATR

Double labelling with fluorescent antibodies against IgG (FITC—green) and complement C1q (TRITC—red) of a small intestinal biopsy from an 8-year-old child with a history of regressive autism. Where IgG and C1q co-localise, the resultant colour is yellow. The subepithelial basement membrane is seen as an intensely stained yellow line beneath the enterocytes. The honeycomb appearance outside the basement membrane is due to co-localised IgG and C1q on the basolateral epithelial surface. These findings are suggestive of an autoimmune process. For further information on this topic see the article by Torrente et al (pages 375–382).

Autoimmunity and Heavy Metals

Article

Full-text available

Jan 1995
LUPUS

Pierluigi E. Bigazzi

This brief review is focused on those heavy metals (cadmium, gold and mercury) that have strong associations with autoimmunity. Cadmium treatment of rats and mice results in autoimmune responses that vary with species and inbred strain of animals. However, there is no solid evidence demonstrating that the renal pathology observed in humans exposed to cadmium has an autoimmune pathogenesis. More clear-cut are the autoimmune effects of preparations containing gold salts, that have been widely used in the treatment of rheumatoid arthritis. Gold may cause autoimmune thrombocytopenia, immune complex-mediated glomerulonephritis and other autoimmune disorders. Similarly, there is solid evidence that mercury can induce autoimmune disease both in humans and experimental animals. The lessons to be derived from metal-induced autoimmunity relate to structure-activity relationship, pathogenesis, etiology and genetics. They probably apply to xenobiotic-induced autoimmune disease in general.

Correlation between disease phenotype and genetic heterogeneity in rheumatoid arthritis

Article

Full-text available

Jun 1995

RA is a heterogeneous group of disorders characterized by variations in clinical manifestations, disease course, and probably response to therapeutic interventions. We have addressed the question whether genetically and potentially etiologically more homogeneous subgroups of RA patients can be defined based upon the expression of the RA-linked sequence motif in the third hypervariable region of the HLA-DRB1 gene. Genetic comparison of patients classified upon clinical manifestation and disease course demonstrated that patients with mild disease were genetically distinct from those progressing to severe and destructive disease. Specifically, rheumatoid factor (RF) negative patients preferentially expressed RA-linked HLA-DRB1 alleles with an arginine substitution in position 71, whereas the alleles with a lysine substitution in position 71 accumulated in RF+ patients. RF- patients were further subdivided based on clinical markers (time of onset of erosive disease and requirement for aggressive therapy). Clinical heterogeneity correlated with genetic heterogeneity. Patients with early erosive disease and patients requiring aggressive therapy frequently typed HLA-DRB1*04+. Patients with late erosive/nonerosive disease or a benign disease course manageable with nonaggressive treatment preferentially expressed HLA-DRB1*01 or lacked an RA-linked haplotype. These data indicate that the heterogeneity of RA reflects genetic differences. Sequence variations within the disease-linked sequence motif, as well as polymorphisms surrounding the candidate genetic element, affect pattern, course, and treatment response of RA. Amino acid position 71 in the HLA-DRB1 gene has a unique role, the understanding of which may provide important clues to disease etiology.

Etiology of infantile autism: A review of recent advances in genetic and neurobiological research

Article

Full-text available

Apr 1999

The etiology of autism is complex, and in most cases the underlying pathologic mechanisms are unknown. Autism is a hetereogeneous disorder, diagnosed subjectively on the basis of a large number of criteria. Recent research has investigated genetics, in utero insults and brain function as well as neurochemical and immunological factors. On the basis of family and twin studies, there appears to be a genetic basis for a wide "autistic syndrome." About a quarter of cases of autism are associated with genetic disorders such as fragile X syndrome or with infectious diseases such as congenital rubella. Genetic studies have shown an association between autism markers of brain development such as 3 markers of the c-Harvey-ros oncogene and the homeobox gene EN2. In some cases, autism is associated with insults early in gestation, including thalidomide embryopathy. Autism may arise from abnormal central nervous system functioning, since most autistic patients have indications of brain dysfunction, and about half of them have abnormal electroencephalograms. Similarly, the pattern of evoked response potentials and conduction time is altered in autistic children. There is substantial evidence from neuroimaging studies that dysfunctions in the cerebellum and possibly the temporal lobe and association cortex occur in autistic symptoms. Neurochemical studies have investigated the role of serotonin, epinephrine and norepinephrine, since levels of these neurotransmitters are altered in autism, although other hypotheses implicate overactive brain opioid systems and changes in oxytocin neurotransmission. Autoimmunity may also play a role; antibodies against myelin basic protein are often found in children with autism, who also have increased eosinophil and basophil response to IgE-mediated reactions. In summary, the prevailing view is that autism is caused by a pathophysiologic process arising from the interaction of an early environmental insult and a genetic predisposition.

Vasoactive Intestinal Peptide Synergizes with TNF-α in Inducing Human Dendritic Cell Maturation

Article

Full-text available

Oct 1999

We investigated the effects of different neuropeptides on human dendritic cells (DC) maturation. Immature DC, derived from monocytes cultured for 6 days with IL-4 plus GM-CSF, have been exposed to somatostatin, substance P, or vasoactive intestinal peptide (VIP). Among these neuropeptides, only VIP induces the production of bioactive IL-12 and the neoexpression of CD83 on a fraction of the DC population, with an effect significant at 100 and 10 nM, respectively. These effects of VIP are dose-dependent, unaffected by polymixin B, and partly prevented by a VIP receptor antagonist. Although the effects of VIP alone remain modest, it synergizes with TNF-alpha to induce DC maturation. In the presence of a suboptimal concentration of TNF-alpha, which has no detectable effect on DC by itself, VIP induces the production of high levels of bioactive IL-12, the neoexpression of CD83 on almost all the DC population (with an effect significant at 10 and 0.1 nM, respectively), and the up-regulation of various adhesion and costimulatory molecule expression. Moreover, DC exposed to VIP plus a suboptimal concentration of TNF-alpha are as potent as mature DC obtained by treatment with an optimal concentration of TNF-alpha in stimulating allogenic T cell proliferation. Our data suggest that, in inflammatory sites, VIP may cooperate with proinflammatory mediators, such as TNF-alpha, to induce DC maturation.

The Oxytocin Receptor System: Structure, Function, and Regulation

Article

Full-text available

May 2001

The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-beta. The high-affinity receptor state requires both Mg(2+) and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has been characterized by mutagenesis and molecular modeling and is different from the antagonist binding site. The function and physiological regulation of the OT system is strongly steroid dependent. However, this is, unexpectedly, only partially reflected by the promoter sequences in the OT receptor gene. The classical actions of OT are stimulation of uterine smooth muscle contraction during labor and milk ejection during lactation. While the essential role of OT for the milk let-down reflex has been confirmed in OT-deficient mice, OT's role in parturition is obviously more complex. Before the onset of labor, uterine sensitivity to OT markedly increases concomitant with a strong upregulation of OT receptors in the myometrium and, to a lesser extent, in the decidua where OT stimulates the release of PGF(2 alpha). Experiments with transgenic mice suggest that OT acts as a luteotrophic hormone opposing the luteolytic action of PGF(2 alpha). Thus, to initiate labor, it might be essential to generate sufficient PGF(2 alpha) to overcome the luteotrophic action of OT in late gestation. OT also plays an important role in many other reproduction-related functions, such as control of the estrous cycle length, follicle luteinization in the ovary, and ovarian steroidogenesis. In the male, OT is a potent stimulator of spontaneous erections in rats and is involved in ejaculation. OT receptors have also been identified in other tissues, including the kidney, heart, thymus, pancreas, and adipocytes. For example, in the rat, OT is a cardiovascular hormone acting in concert with atrial natriuretic peptide to induce natriuresis and kaliuresis. The central actions of OT range from the modulation of the neuroendocrine reflexes to the establishment of complex social and bonding behaviors related to the reproduction and care of the offspring. OT exerts potent antistress effects that may facilitate pair bonds. Overall, the regulation by gonadal and adrenal steroids is one of the most remarkable features of the OT system and is, unfortunately, the least understood. One has to conclude that the physiological regulation of the OT system will remain puzzling as long as the molecular mechanisms of genomic and nongenomic actions of steroids have not been clarified.

Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder

Article

Full-text available

Feb 2002
MOL PSYCHIATR

Previous studies have provided conflicting evidence regarding the association of the serotonin transporter (5-HTT) gene with autism. Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron 2 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short and long variants. Positive associations of the 5-HTTLPR polymorphism with autism have been reported by two family-based studies, but one found preferential transmission of the short allele and the other of the long allele. Two subsequent studies failed to find evidence of transmission disequilibrium at the 5-HTTLPR locus. These conflicting results could be due to heterogeneity of clinical samples with regard to serotonin (5-HT) blood levels, which have been found to be elevated in some autistic subjects. Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the 5-HTT gene with autism, and we investigated the relationship between 5-HTT variants and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism.

Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism

Article

Full-text available

Feb 2002
MOL PSYCHIATR

We have reported lymphocytic colitis in children with regressive autism, with epithelial damage prominent. We now compare duodenal biopsies in 25 children with regressive autism to 11 with coeliac disease, five with cerebral palsy and mental retardation and 18 histologically normal controls. Immunohistochemistry was performed for lymphocyte and epithelial lineage and functional markers. We determined the density of intraepithelial and lamina propria lymphocyte populations, and studied mucosal immunoglobulin and complement C1q localisation. Standard histopathology showed increased enterocyte and Paneth cell numbers in the autistic children. Immunohistochemistry demonstrated increased lymphocyte infiltration in both epithelium and lamina propria with upregulated crypt cell proliferation, compared to normal and cerebral palsy controls. Intraepithelial lymphocytes and lamina propria plasma cells were lower than in coeliac disease, but lamina propria T cell populations were higher and crypt proliferation similar. Most strikingly, IgG deposition was seen on the basolateral epithelial surface in 23/25 autistic children, co-localising with complement C1q. This was not seen in the other conditions. These findings demonstrate a novel form of enteropathy in autistic children, in which increases in mucosal lymphocyte density and crypt cell proliferation occur with epithelial IgG deposition. The features are suggestive of an autoimmune lesion.

Increased Prevalence of Familial Autoimmunity in Probands With Pervasive Developmental Disorders

Article

Full-text available

Dec 2003
Pediatrics

Increased prevalence of familial autoimmune disease is a common finding among probands with various autoimmune disorders. Autistic disorder (autism) is a highly genetic disorder with known immune and immunogenetic abnormalities. Previous research has found an increased frequency of autoimmune disorders in families with autistic probands. We further investigated this association by determining the frequency of autoimmune disorders in families that have probands with pervasive developmental disorders (PDDs), including autism, compared with 2 control groups. Three well-defined study groups, including 1) families that have a child with a PDD, 2) families that have a child with an autoimmune disorder, and 3) families with a healthy control child, constituted the sample. A questionnaire inquiring about which first- and second-degree family members had received a diagnosis of having specific autoimmune disorders was completed by 101 families in each group. The frequency of autoimmune disorders was significantly higher in families of the PDD probands compared with families of both the autoimmune and healthy control probands. Autoimmunity was highest among the parents of PDD probands compared with parents of the healthy control subjects. Hypothyroidism/Hashimoto's thyroiditis and rheumatic fever were significantly more common in families with PDD probands than in the healthy control families. Autoimmunity was increased significantly in families with PDD compared with those of healthy and autoimmune control subjects. These preliminary findings warrant additional investigation into immune and autoimmune mechanisms in autism.

Neurotoxic effects of postnatal thimerosal are mouse strain dependent

Article

Full-text available

Oct 2004
MOL PSYCHIATR

The developing brain is uniquely susceptible to the neurotoxic hazard posed by mercurials. Host differences in maturation, metabolism, nutrition, sex, and autoimmunity influence outcomes. How population-based variability affects the safety of the ethylmercury-containing vaccine preservative, thimerosal, is unknown. Reported increases in the prevalence of autism, a highly heritable neuropsychiatric condition, are intensifying public focus on environmental exposures such as thimerosal. Immune profiles and family history in autism are frequently consistent with autoimmunity. We hypothesized that autoimmune propensity influences outcomes in mice following thimerosal challenges that mimic routine childhood immunizations. Autoimmune disease-sensitive SJL/J mice showed growth delay; reduced locomotion; exaggerated response to novelty; and densely packed, hyperchromic hippocampal neurons with altered glutamate receptors and transporters. Strains resistant to autoimmunity, C57BL/6J and BALB/cJ, were not susceptible. These findings implicate genetic influences and provide a model for investigating thimerosal-related neurotoxicity.

Strong association of the third hypervariable region of HLA-DRB1 with autism

Article

Jul 1996
J NEUROIMMUNOL

We reported that the major histocompatibility complex (MHC) including the null allele of the C4B gene and the extended haplotype B44-C30-DR4 is associated with autism. We report now that the third hypervariable region (HVR-3) of certain DR β l alleles have very strong association with autism. The HVR-3 of DRβ1∗ 0401 or the shared HVR-3 alleles DR01∗ 0404 and DRβ1∗ 0101, was expressed on extended haplotypes in 23 of 50 (46%) autistic subjects as compared to only 6 of 79 (7.5%) normal subjects. Another HVR-3 sequence, the DRβ1∗ 0701 allele, was carried on extended haplotypes in 16 (32.0%) of the autistic subjects as compared to 8 (10.1 %) of the normal subjects.

Familial autoimmunity in pedigrees of idiopathic inflammatory myopathy patients suggests common genetic risk factors for many autoimmune diseases

Article

Mar 1998
ARTHRIT RHEUM-ARTHR

Objective To test the hypothesis that many autoimmune diseases share common genetic risk factors and to define the frequency and distribution of autoimmune diseases in relatives of patients with very rare disorders, the idiopathic inflammatory myopathies (IIM).Methods We evaluated, in a prospective case-control study, consecutive patients with IIM who were referred to our center and ascertained without regard to family history or known risk factors for autoimmunity, and all available family members. We used a standardized assessment to determine the presence and type of autoimmune disease in each subject. A matched comparison group of control subjects without autoimmune disease who were referred to our center and their families were similarly assessed.ResultsAutoimmune diseases were significantly increased in prevalence (21.9%) in the 151 first-degree relatives of the 21 IIM probands compared with the prevalence (4.9%) in the 143 relatives of the 21 control probands (odds ratio [OR] by regression analysis 7.9, 95% confidence interval [95% CI] 2.9-21.9, P < 0.001). Women had more autoimmune disease than men (OR by regression analysis 4.6, 95% CI 2.3-9.0) and the odds ratio for autoimmune disease increased 0.02 per year of age. These disorders tended to follow the frequency distribution of autoimmune diseases in the general population. Genetic modeling studies showed that a non-Mendelian polygenic inheritance pattern for autoimmune disease was most consistent with these data.Conclusion Autoimmune diseases are significantly increased in frequency in first-degree relatives of IIM patients, affect more women than men, increase with age, and are distributed in a pattern similar to that in the general population. Many autoimmune disorders share genes that together act as polygenic risk factors for autoimmunity.

Maternal neuronal antibodies associated with autism and a language disorder

Article

Apr 2003
ANN NEUROL

Neurodevelopmental disorders could be caused by maternal antibodies or other serum factors. We detected serum antibodies binding to rodent Purkinje cells and other neurons in a mother of three children: the first normal, the second with autism, and the third with a severe specific language disorder. We injected the serum (0.5–1.0ml/day) into pregnant mice during gestation and found altered exploration and motor coordination and changes in cerebellar magnetic resonance spectroscopy in the mouse offspring, comparing with offspring of mice injected with sera from mothers of healthy children. This evidence supports a role for maternal antibodies in some forms of neurodevelopmental disorder. Ann Neurol 2003;53:533–537

Autism and autoimmune disease: A family study

Article

Jun 1971

A family is presented to demonstrate the rare phenomenon of early infantile autism in the presence of autoimmune disease. The youngest son in the family has a multiple diagnosis of autism, Addison's disease, and moniliasis. The next older brother has hypoparathyroidism, Addison's disease, moniliasis, and diabetes mellitus. The next older brother has hypoparathyroidism, Addison's disease, moniliasis, and alopecia totalis. The oldest son and first born child in this family of four is, along with the parents, symptom free. Whereas autism in the youngest son might be attributed to the traumatic family situation, in which there exists the constant threat of near-death, it might conceivably be attributed also to a primary effect of autoimmune impairment from the formation of autoantibodies affecting the central nervous system.

Take home messages

Article

Jan 2008

In this final chapter we present some ‘take home message’. We set out what we believe are some of the most important learnings to have emerged to date from Finding a Voice, and some of their implications.

A sensitive ELISA for glial fibrillary acidic protein: Application in CSF of children

Article

Sep 1992
J NEUROSCI METH

In the present study we describe a sensitive ELISA for determination of glial fibrillary acidic protein (GFAP). To validate the method combined determinations of GFAP and S-100 protein were performed in cerebrospinal fluid (CSF) of normal children and children with autism. The GFAP ELISA is of sandwich type and uses the biotin-avidin system. Sensitivity was 16 pg/ml. Between-day precision was 0.079 (coeff. of variance). S-100 protein concentrations were measured using a commercially available ELISA kit. Normal CSF from children and young adults were analysed. The CSF levels of GFAP in normal children were low (16-163 pg/ml). Both GFAP and S-100 protein concentrations correlated with age (P < 0.01 and P < 0.05, respectively), but the GFAP increment was more pronounced, probably reflecting the age-dependent expansion of the fibrillary astrocytes in the central nervous system (CNS). GFAP levels in children with infantile autism were higher than those in normal children of the same age range. S-100 protein concentrations were similar in both groups. High levels of GFAP in combination with normal S-100 protein concentrations in CSF indicates reactive astrogliosis in the CNS. In conclusion, the sensitive ELISA described makes it possible to measure low levels of GFAP present in the CSF of children. Combined assays of GFAP and S-100 protein can be used to discriminate between acute and chronic brain disorders in children.

Autism: Review of neurochemical investigation

Article

Jan 1990

Edwin H Cook

The neurochemistry of autism, the most well-validated childhood neuropsychiatric disorder, has been studied extensively over the past three decades. Autism is of interest neurochemically because it represents a relatively homogeneous disorder with a triad of social, communicative, and intellectual developmental disturbance. Because a sufficient animal model has been lacking and relatively few diagnosed people with autism have died, most investigation has been of peripheral fluids and tissues. The most consistent finding has been that over 25% of autistic children and adolescents are hyperserotonemic. However, after 29 years of investigation, the mechanism of hyperserotonemia has not been determined. Hyperserotonemia has been found to be familial. Elevated plasma norepinephrine has also been a replicated finding. Cerebrospinal fluid (CSF) opiate activity has been found to be elevated in two studies. Plasma cyclic adenosine monophosphate (cAMP) has been found to be elevated in autistic children. A high rate of nonsuppression after dexamethasone and blunted or delayed growth hormone response to L-dopa have been found. Abnormal cell-mediated immunity has been replicated consistently in autism. Although several pharmacological trials have been conducted and shown promise in initial open trials, only "typical" antipsychotic drugs have shown replicable chronic ameliorating effects in double-blind trials. However, chronic neurotoxicity (tardive dyskinesia) has also been revealed. Findings of morphological changes in the cerebellum have been replicated. Findings in need of replication include diminished platelet function, increased baseline CSF homovanillic acid, decreased nerve cell adhesion molecule serum fragment, blunted prolactin response to fenfluramine, amelioration of symptoms by naltrexone and bromocriptine, reduced electroretinographic (ERG) b-wave amplitude, and morphological changes in the hippocampus, amygdala, and septal nuclei. In addition to refining and replicating past findings, future directions that may be fruitful include investigation of neurochemical aspects of platelet function, of interactions between monoaminergic systems, of phosphatidylinositides, and of pharmacological response to "atypical" antipsychotic agents and relatively selective serotonin receptor subtype agonists or antagonists.

Methyl mercury exposure via placenta and milk impairs natural killer (NK) cell function in newborn rats

Article

Nov 1991
TOXICOL LETT

The effect of methyl mercury (MeHg) exposure (3.9 micrograms/g diet) on the development of immune function was studied in the newborn Sprague-Dawley rat after MeHg exposure via placenta and/or milk. No consistent alterations were observed between control and treated offspring (at the age of 15 days) on the following parameters: body weights, lymphoid organ weights or cell number, and the lymphoproliferative response to B-cell mitogen. The lymphoproliferative response to T-cell mitogen was increased in thymocytes (by 30-48%), but decreased in splenocytes (by 30-32%). This decreased activity was only observed in the groups exposed during lactation. White blood cell counts (WBC) were increased in all groups. Natural killer (NK) cell activity was reduced (by 42%, P less than 0.01) in the group that was exposed both via placenta and milk. These results indicate that placental and lactational transfer of MeHg does adversely affect the developing immune system of the rat.

Demonstration of Inter- and Intraspecies Differences in Serotonin Binding Sites by Antibodies from an Autistic Child

Article

Feb 1985

Serotonin (5-HT) binding sites from bovine and rat cerebral cortex membranes share pharmacological properties that allow both to be subclassified by the same criteria. We show here that [3H]5-HT binding sites from human cortex also possess pharmacological properties that follow the same subclassification scheme as for bovine and rat cortex. In addition, we show that solubilized 5-HT1 and 5-HT3 sites from all three species have an s20,w value of 3.4. Despite these similar pharmacological and physical characteristics, we can demonstrate antigenic differences between receptor types and species. Human 5-HT1A sites can be distinguished from human 5-HT1B, 5-HT2, and 5-HT3 sites and from equivalent sites in rat and bovine cortex. The anti-human 5-HT1A antibodies were discovered in the blood of an autistic child and may have clinical or etiologic significance for this disorder.

Anti-CNS Antibodies in Childhood Neurologic Diseases

Article

Jun 1989

To study the incidence of circulating anti-CNS antibodies in childhood neurologic diseases, a population study was undertaken. Serum samples were obtained from a total of 348 children and stored at - 80°C until being studied. The samples were collected when routine blood tests were being performed. In all cases informed consent was obtained. This study was approved by hospital ethics review committees. One hundred and ninety-nine of the samples were from children with no known neurologic illnesses and served as the control group. One hundred and twenty-one of the samples were from children with epilepsy and the remaining 28 from a number of different neurologic conditions. The serum samples were screened against normal, adult, autopsy-derived cerebellar and frontal cortex tissue sections and Western blots. Serum immunoreactivity was revealed using HRP-conjugated anti-human IgG. Significant findings included: (1) patients with epilepsy had an increased incidence of anti-CNS reactivity as revealed on frontal cortex immunoblots (p < 0.05) but not on cerebellar immunoblots; (2) there was an increase in the incidence of immunoblot reactivity with age in the controls and the neurology cases; (3) there was an increased incidence of immunoblot reactivity in those cases with a presumed inflammatory central or peripheral neurologic disease; (4) in six additional cases with opsoclonus-myoclonus there was cerebellar-specific immunoreactivity with identified antigenic molecular weights of 27 and 35, and 62 kDaltons; (5) in 31 additional cases of systemic lupus erythematosus there was significant immunoblot reactivity (p < 0.001) when compared to a subset of age-matched controls. There was no difference in immunoreactivity between males and females. There was no significant increase in immunoreactivity in those children with cognitive disturbances including developmental delay and mental retardation.

Antibrain antibodies in infantile autism

Article

Apr 1988
BIOL PSYCHIAT

Autism and autoimmune disease: a family study

Article

Apr 1971
J Autism Child Schizophr

Antibodies to Myelin Basic Protein in Children with Autistic Behavior

Article

Mar 1993

Based on a possible pathological relationship of autoimmunity to autism, antibodies reactive with myelin basic protein (anti-MBP) were investigated in the sera of autistic children. Using a screening serum dilution of 1:400 in the protein-immunoblotting technique, approximately 58% (19 of 33) sera of autistic children (< or = 10 years of age) were found to be positive for anti-MBP. This result in autistics was significantly (p < or = .0001) different from the controls (8 of 88 or only 9% positive), which included age-matched children with normal health, idiopathic mental retardation (MR) and Down syndrome (DS), and normal adults of 20 to 40 years of age. Since autism is a syndrome of unknown etiology, it is possible that anti-MBP antibodies are associated with the development of autistic behavior.

Receptor inhibition by immunoglobulins: Specific inhibition by autistic children, their relatives, and control subjects

Article

Mar 1993

Forty-two parents of children with autistic disorder, 15 children with autistic disorder, 17 siblings of children with autistic disorder, and 12 unrelated normal adult controls were studied to determine if immunoglobulins isolated from their plasma would inhibit binding of the 5HT1A agonist, [3 H]-8-hydroxy-N,N-dipropyl-2-aminotetralin (DPAT) to 5HT1A receptors in human hippocampal membranes. There were no significant differences among the means of percentage inhibition of DPAT binding of parents, children with autistic disorder, siblings, or unrelated controls. In addition, there were no differences in the proportion of subjects with >15% DPAT inhibition among autistic children, their parents, their siblings, or unrelated controls. Immunoglobulin inhibition was not specific for the 5HT1A receptor binding site, since immunoglobulins inhibited binding to 5HT2 , D1 , D2 , and α2-adrenergic binding sites. The immunoglobulins isolated from normal controls inhibited [3 H]-rauwolscine binding at α2-adrenergic sites less than immunoglobulins of children with autistic disorder and their parents and siblings. This study did not support the hypothesis that autoantibodies to 5HT1A or 5HT2 receptors are characteristic of autistic disorder.

Thiol compounds inhibit mercury-induced immunological and immunopathological alterations in susceptible mice

Article

Feb 1997

In vitro mercury induces a high proliferative response in splenic lymphocytes and in vivo it induces a systemic autoimmune disease in susceptible mouse strains. This disease is characterized by increased serum levels of IgE and IgG1 antibodies, by the production of anti-nucleolar antibodies and by the formation of renal immune complex deposits. We have previously found that the presence of 2-mercaptoethanol (2-ME) inhibited mercury-induced cell proliferation in vitro. In this study, we tested the effects of four other thiol compounds, namely dithiothreitol (DTT), L-cysteine, meso-2,3-dimercaptosuccinic acid (meso-DMSA) and 2,3-dimercapto-1-propanesulfonic acid, Na salt (DMPS) on mercury-induced immunological changes both in vitro and in vivo. We found that in vitro, the addition of all thiol compounds abrogated mercury-induced cell aggregation and proliferation. In vivo, injection of meso-DMSA and/or DMPS (s.c. or i.p.) immediately following exposure to mercury markedly decreased IgG1 synthesis in spleen cells and serum IgE levels in mercury-susceptible SJL mice. Treatment with DMPS also prevented mercury-induced IgG1 anti-nucleolar antibody synthesis and the development of mesangial IgG1 immune complex deposits in SJL mice.

The serotonin system in autism

Article

Sep 1996

The serotonin system has been implicated as a factor in some cases of autism since the finding in 1961 of elevated serotonin (5-hydroxytryptamine) levels in the blood of patients with autism. This has been clarified as elevation in the platelet content of serotonin. Subjects with elevated whole blood serotonin levels have been shown to have elevated platelet serotonin transport into platelets and decreased serotonin 5-HT2 receptor binding. Most individuals with autism who are treated with potent serotonin transporter inhibitors have a reduction in ritualistic behavior and aggression. Reduction of central nervous system serotonin, induced by acute tryptophan depletion, causes a worsening of stereotyped behavior. Recent developments in the molecular biology of serotonin receptors are reviewed.

Hyperserotoninemia and Serotonin Receptor Antibodies in Children with Autism but Not Mental Retardation

Article

Apr 1997
BIOL PSYCHIAT

Autism and the Immune System

Article

Apr 1997

As our knowledge of the interactions of the immune, nervous and endocrine systems progresses, complex links with the origin and course of psychopathology in childhood are revealed. In this article the neuroimmunological literature on autism is reviewed. Relevant aspects of immune functioning and the neuroendocrine-immune network are described. We present the immunological findings in autistic patients within two related conceptual frameworks: a viral and an autoimmune hypothesis. Interpretation of data is hampered by conceptual and methodological differences between studies. Both the clinical significance of the immune changes and the causal connection between immune changes and psychopathological phenomena in autism remain to be elucidated. Recommendations for further research are given.

Circulating Autoantibodies to Neuronal and Glial Filament Proteins in Autism

Article

Aug 1997
PEDIATR NEUROL

Autoimmunity may be a pathogenic factor in autism, a behavioral disorder of early childhood onset. Circulating autoantibodies are produced in organ-specific autoimmunity; therefore, we investigated them in the plasma of autistic subjects, mentally retarded (MR) subjects, and healthy controls. Autoantibodies (IgG isotype) to neuron-axon filament protein (anti-NAFP) and glial fibrillary acidic protein (anti-GFAP) were analyzed by the Western immunoblotting technique. We found a significant increase in incidence of anti-NAFP (P = .004) and anti-GFAP (P = .002) in autistic subjects, but not in MR subjects. Clinically, these autoantibodies may be related to autoimmune pathology in autism.

Cytokines in Brain Development and Function

Article

Feb 1998
ADV PROTEIN CHEM

This chapter explains how cytokines control brain development. The role of cytokines in lineage commitment and cell survival is somewhat analogous to the role of hematopoietins in blood cell development. The chapter outlines the significant developmental signposts that are involved in the progressive sculpting of the central and peripheral nervous systems, following neurulation and dorsoventral patterning of the neural tube and will discuss the cytokines associated with each of these stages of development. It then describes the specific roles of individual cytokines in mediating discrete cellular events during neurogenesis and the developmental profiles of expression of the relevant ligands and receptor subunits. The interrelationships between progressive developmental events and their modulation by subclasses of epigenetic signals will then be placed within a specific biological context to allow predictions to be made concerning the likely future course of cytokine research in developmental neurobiology.

Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders

Article

May 1999
J Pediatr

Etiologically unexplained disorders of language and social development have often been reported to improve in patients treated with immune-modulating regimens. Here we determined the frequency of autoantibodies to brain among such children. We collected sera from a cohort of children with (1) pure Landau-Kleffner syndrome (n = 2), (2) Landau-Kleffner syndrome variant (LKSV, n = 11), and (3) autistic spectrum disorder (ASD, n = 11). None had received immune-modulating treatment before the serum sample was obtained. Control sera (n = 71) were from 29 healthy children, 22 with non-neurologic illnesses (NNIs), and 20 children with other neurologic disorders (ONDs). We identified brain autoantibodies by immunostaining of human temporal cortex and antinuclear autoantibodies using commercially available kits. IgG anti-brain autoantibodies were present in 45% of sera from children with LKSV, 27% with ASD, and 10% with ONDs compared with 2% from healthy children and control children with NNIs. IgM autoantibodies were present in 36% of sera from children with ASD, 9% with LKSV, and 15% with ONDs compared with 0% of control sera. Labeling studies identified one antigenic target to be endothelial cells. Antinuclear antibodies with titers >/=1:80 were more common in children with ASD and control children with ONDs. Children with LKSV and ASD have a greater frequency of serum antibodies to brain endothelial cells and to nuclei than children with NNIs or healthy children. The presence of these antibodies raises the possibility that autoimmunity plays a role in the pathogenesis of language and social developmental abnormalities in a subset of children with these disorders.

Familial Clustering of Autoimmune Disorders and Evaluation of Medical Risk Factors in Autism

Article

Jul 1999

Autism is an age-dependent neurologic disorder that is often associated with autoimmune disorders in the patients' relatives. To evaluate the frequency of autoimmune disorders, as well as various prenatal and postnatal events in autism, we surveyed the families of 61 autistic patients and 46 healthy controls using questionnaires. The mean number of autoimmune disorders was greater in families with autism; 46% had two or more members with autoimmune disorders. As the number of family members with autoimmune disorders increased from one to three, the risk of autism was greater, with an odds ratio that increased from 1.9 to 5.5, respectively. In mothers and first-degree relatives of autistic children, there were more autoimmune disorders (16% and 21%) as compared to controls (2% and 4%), with odds ratios of 8.8 and 6.0, respectively. The most common autoimmune disorders in both groups were type 1 diabetes, adult rheumatoid arthritis, hypothyroidism, and systemic lupus erythematosus. Forty-six percent of the autism group reported having relatives with rheumatoid diseases, as compared to 26% of the controls. Prenatal maternal urinary tract, upper respiratory, and vaginal infections; asphyxia; prematurity, and seizures were more common in the autistic group, although the differences were not significant. Thirty-nine percent of the controls, but only 11% of the autistic, group, reported allergies. An increased number of autoimmune disorders suggests that in some families with autism, immune dysfunction could interact with various environmental factors to play a role in autism pathogenesis.

[Nerve growth factor auto-antibodies in children with various forms of mental dysontogenesis and in schizophrenia high risk group]

Article

Jan 2000
ZH NEVROL PSIKHIATR

The level of autoantibodies (AAb) to nerve growth factor was evaluated in blood serum of 163 children with different forms of mental dysontogenesis of endogenic, residual-organic, psychogenic and deprivative origin. Significant elevation of the level of AAb was found in all forms of psychic dysontogenesis. The most significant elevation of the level of AAb (p < 0.01), as compared with the controls (45 children), was characteristic for endogenic forms of dysontogenesis (schizophrenia, early children's autism, schizotypic diathesis). The level of AAb was also found as an indicator of the acuteness of the pathologic state. Besides, its elevation was observed 1-2 weeks prior to the onset of the clinical exacerbation. Elevation of AAb level was also found in psychic dysontogenesis of residual-organic nature (children with perinatal encephalopathy), but it was not so significant as compared with the controls (p < 0.05%). The analysis in the age dynamics of children from this group revealed, that AAb level may serve as some prognostic index of the severity of psychic dysontogenesis. The level of AAb differs some states in schizotypic diathesis and deprivative dysontogenesis, which are clinically quite similar. The method for the estimation of serum AAb level may be proposed as screening in prophylactic medical examination of children from the first year of life under conditions of pediatric outpatient service for identification of risk-groups by psychic dysontogenesis to perform early special psychoprophylaxis.

Functional neuroimaging of autistic disorders

Article

Jan 2000

Functional neuroimaging methods hold promise for elucidating the neurobiology of autistic disorders, yet they present difficult practical and scientific challenges when applied to these complex and heterogeneous syndromes. Single-state studies of brain metabolism and blood flow thus far have failed to yield consistent findings, but suggest considerable variability in regional patterns of cerebral synaptic activity. Patients with idiopathic autism are less likely to show abnormalities than are patients with comorbid illness or epilepsy. Activation studies have begun to suggest alterations in brain organization for language and cognition. Neurotransmitter studies using positron emission tomography (PET) suggest abnormalities of serotonergic and dopaminergic function. Studies using magnetic resonance spectroscopy (MRS) have begun to document metabolic deficits in the frontal cortex and cerebellum. A single study using magnetoencephalography suggests a high incidence of epileptiform activity in children with autistic regression. Research needs include well-controlled developmental studies, particularly of young subjects and relatively homogeneous subgroups, which balance scientific rigor with ethical constraints. Investigations of the serotonergic and dopaminergic systems, limbic-based memory and emotional systems, and the role of epileptiform activity in autism represent priorities for future research.

Prevalence of Pervasive Developmental Disorders in the British Nationwide Survey of Child Mental Health

Article

Jul 2001

Objective: The prevalence of pervasive developmental disorders (PDD) is not well established and needs monitoring. The prevalence of PDD in the 1999 nationwide British survey of child and adolescent mental health was investigated. Method: A randomized, stratified sample of children (N= 12,529) aged 5 to 15 years was generated from the Child Benefit Register. Trained interviewers interviewed parents and youths aged 11 or older with a standardized diagnostic interview (Development and Well-Being Assessment), and questionnaire data (Strengths and Difficulties Questionnaire) were obtained from teachers and parents, who also completed self-report measures of psychological distress. Final diagnostic determination was achieved by a team of experienced clinicians using all data sources. Results: A total of 10,438 (83%) interviews were conducted. There were 2 girls with Rett syndrome (weighted prevalence: 3.8/10,000 girls) and 27 children with other PDD (weighted prevalence: 26.1/10,000). Compared with children with a psychiatric disorder other than PDD, social but not behavioral problems were more frequent in the PDD group. Parents of children with PDD had higher rates of psychological distress than those from the two comparison groups. Conclusions: Consistent with other recent surveys, PDD rates are higher than those reported 30 years ago. The burden associated with PDD is very high.

Diagnosis of autism

Article

Sep 2003
Br Med J

Parents want autism to be diagnosed as early as possible, and early intervention may improve long term outcomes. The authors of this review discuss the identification and assessment process for children with autism and autistic spectrum disorder.

Prevalence of serum antibodies to caudate nucleus in autistic children

Article

Feb 2004
NEUROSCI LETT

Autism may involve autoimmunity to brain. We studied regional distribution of antibodies to rat caudate nucleus, cerebral cortex, cerebellum, brain stem and hippocampus. The study included 30 normal and 68 autistic children. Antibodies were assayed by immunoblotting. Autistic children, but not normal children, had antibodies to caudate nucleus (49% positive sera), cerebral cortex (18% positive sera) and cerebellum (9% positive sera). Brain stem and hippocampus were negative. Antibodies to caudate nucleus were directed towards three proteins having 160, 115 and 49 kD molecular weights. Since a significant number of autistic children had antibodies to caudate nucleus, we propose that an autoimmune reaction to this brain region may cause neurological impairments in autistic children. Thus, the caudate nucleus might be involved in the neurobiology of autism.

Autoantibody repertoires to brain tissue in autism nuclear families

Article

Aug 2004
J NEUROIMMUNOL

The hypothesis of an immune dysfunction in autism spectrum disorders has previously been put forward without, however, compelling evidence of a direct relation to its etiology or pathogenesis. To further understand if autoimmunity could play a significant role in autism, we analyzed autoantibody repertoires to brain tissue extract in the plasma of 171 autism children, their parents, and 54 controls, by quantitative immunoblotting. Multiparametric analysis revealed significant differences between patients and controls, and showed that one single reactivity in Section 32 of the blot had the most power to discriminate between these samples. Family correlation coefficients and heritability estimates did not provide any evidence that this reactivity was genetically determined. While the molecular weight of the target protein suggested that it might be an isoform of Myelin Basic Protein (MBP), inhibition assays with human MBP argued against this hypothesis. The study evidences the widespread occurrence of autoreactivities to brain tissue in autism patients, which may represent the immune system's neuroprotective response to a previous brain injury occurred during neurodevelopment. The molecular identification of the target protein in Section 32 will contribute to the understanding of the role of immune responses against brain antigens in autistic patients.

Maternal Autoimmune Diseases, Asthma and Allergies, and Childhood Autism Spectrum Disorders

Article

Mar 2005
Arch Pediatr Adolesc Med

To investigate the association between physician-documented diagnoses of maternal autoimmune diseases, allergies, and asthma around the time of pregnancy and subsequent diagnoses of autism in children. A case-control study nested within a cohort of infants born between January 1995 and June 1999. Northern California Kaiser Permanente Medical Care Program. Cases (n = 420) were children with at least 1 diagnosis of an autism spectrum disorder (ASD) recorded in Kaiser Permanente outpatient clinical databases. Controls (n = 2100) were children without an ASD diagnosis who were frequency matched to cases on sex, birth year, and hospital of birth. Frequencies of maternal immunologic disorders were compared between cases and controls with a chi2 statistic, and relative risks were estimated by crude and adjusted odds ratios and 95% confidence intervals using logistic regression. The final study population included 407 cases and 2095 controls. A similar proportion of case and control mothers had a diagnosis of any autoimmune disease in the 4-year period surrounding pregnancy (10.3% vs 8.2%, P = .15). After adjustment for maternal factors, only 1 autoimmune condition, psoriasis, was significantly associated with ASDs (adjusted odds ratio, 2.7; 95% confidence interval, 1.3-5.8). A greater than 2-fold elevated risk of ASD was observed for maternal asthma and allergy diagnoses recorded during the second trimester of pregnancy. These findings suggest that maternal autoimmune disorders present in women around the time of pregnancy are unlikely to contribute significantly to autism risk. Further etiologic investigations are needed to confirm these results and should include objective documentation of diagnoses and consider a larger set of maternal immune-related conditions, including asthma and allergies.

A Sensitive ELISA for glial fibrillary acidic protein: application in CSF of children Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism

Oct 1992
113-9375

Le Rosengren
G Ahlsen
M Belfrage
C Gillberg
Kg Haglid
A Hamberger
F Torrente
P Ashwood
R Day
N Machado
Ri Furlano
A Anthony

Rosengren LE, Ahlsen G, Belfrage M, Gillberg C, Haglid KG, Hamberger A. A Sensitive ELISA for glial fibrillary acidic protein: application in CSF of children. J Neurosci Methods 1992 (Sep.);44(2–3):113 – 9. [27] Torrente F, Ashwood P, Day R, Machado N, Furlano RI, Anthony A, et al. Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism. Mol Psychiatry 2002;7(4):375 – 82 334.

Maternal autoimmune diseases, asthma and allergies and childhood autism

Jan 2004

La Croen
Jk Grether
Ck Yoshida
R Oduli
Van
J Water

Croen LA, Grether JK, Yoshida CK, Oduli R, Van de Water J. Maternal autoimmune diseases, asthma and allergies and childhood autism. Arch Pediatr Adolesc Med 2004 [accepted for publication].

A Sensitive ELISA for glial fibrillary acidic

Rosengren Le G Ahlsen
M Belfrage
C Gillberg
Haglid Kg
Hamberger

Rosengren LE, Ahlsen G, Belfrage M, Gillberg C, Haglid KG, Hamberger A. A Sensitive ELISA for glial fibrillary acidic

Prevalence of pervasive developmental disorders in the British nationwide survey of child mental health

Jan 2001
820

Fombonne

Is autism an autoimmune disease?

Abstract

No full-text available

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