Administration of thimerosal-containing vaccines to infant rhesus macaques does not result in autism-like behavior or neuropathology

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Some anecdotal reports suggest that ASD is related to exposure to ethyl mercury, in the form of the vaccine preservative, thimerosal, and/or receiving the measles, mumps, rubella (MMR) vaccine. Using infant rhesus macaques receiving thimerosal-containing vaccines (TCVs) following the recommended pediatric vaccine schedules from the 1990s and 2008, we examined behavior, and neuropathology in three brain regions found to exhibit neuropathology in postmortem ASD brains. No neuronal cellular or protein changes in the cerebellum, hippocampus, or amygdala were observed in animals following the 1990s or 2008 vaccine schedules. Analysis of social behavior in juvenile animals indicated that there were no significant differences in negative behaviors between animals in the control and experimental groups. These data indicate that administration of TCVs and/or the MMR vaccine to rhesus macaques does not result in neuropathological abnormalities, or aberrant behaviors, like those observed in ASD.

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Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

Molecular Brain ◽

10.1186/s13041-021-00769-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Kohei Kitagawa ◽

Kensuke Matsumura ◽

Masayuki Baba ◽

Momoka Kondo ◽

Tomoya Takemoto ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Behavior ◽

Mouse Model ◽

Mouse Models ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

De Novo Mutation ◽

Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

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Role of Oligodendrocytes and Myelin in the Pathophysiology of Autism Spectrum Disorder

Brain Sciences ◽

10.3390/brainsci10120951 ◽

2020 ◽

Vol 10 (12) ◽

pp. 951

Author(s):

Alma Y. Galvez-Contreras ◽

David Zarate-Lopez ◽

Ana L. Torres-Chavez ◽

Oscar Gonzalez-Perez

Keyword(s):

Autism Spectrum Disorder ◽

Interpersonal Communication ◽

Neurodevelopmental Disorder ◽

Brain Regions ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Abnormal Development ◽

Matter Production

Autism Spectrum Disorder (ASD) is an early neurodevelopmental disorder that involves deficits in interpersonal communication, social interaction, and repetitive behaviors. Although ASD pathophysiology is still uncertain, alterations in the abnormal development of the frontal lobe, limbic areas, and putamen generate an imbalance between inhibition and excitation of neuronal activity. Interestingly, recent findings suggest that a disruption in neuronal connectivity is associated with neural alterations in white matter production and myelination in diverse brain regions of patients with ASD. This review is aimed to summarize the most recent evidence that supports the notion that abnormalities in the oligodendrocyte generation and axonal myelination in specific brain regions are involved in the pathophysiology of ASD. Fundamental molecular mediators of these pathological processes are also examined. Determining the role of alterations in oligodendrogenesis and myelination is a fundamental step to understand the pathophysiology of ASD and identify possible therapeutic targets.

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The Parvalbumin Hypothesis of Autism Spectrum Disorder

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2020.577525 ◽

2020 ◽

Vol 14 ◽

Author(s):

Federica Filice ◽

Lucia Janickova ◽

Thomas Henzi ◽

Alessandro Bilella ◽

Beat Schwaller

Keyword(s):

Autism Spectrum Disorder ◽

Messenger Rna ◽

Energy Requirement ◽

Neurodevelopmental Disorder ◽

High Energy ◽

Brain Regions ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Supporting Evidence

The prevalence of autism spectrum disorder (ASD)—a type of neurodevelopmental disorder—is increasing and is around 2% in North America, Asia, and Europe. Besides the known genetic link, environmental, epigenetic, and metabolic factors have been implicated in ASD etiology. Although highly heterogeneous at the behavioral level, ASD comprises a set of core symptoms including impaired communication and social interaction skills as well as stereotyped and repetitive behaviors. This has led to the suggestion that a large part of the ASD phenotype is caused by changes in a few and common set of signaling pathways, the identification of which is a fundamental aim of autism research. Using advanced bioinformatics tools and the abundantly available genetic data, it is possible to classify the large number of ASD-associated genes according to cellular function and pathways. Cellular processes known to be impaired in ASD include gene regulation, synaptic transmission affecting the excitation/inhibition balance, neuronal Ca2+ signaling, development of short-/long-range connectivity (circuits and networks), and mitochondrial function. Such alterations often occur during early postnatal neurodevelopment. Among the neurons most affected in ASD as well as in schizophrenia are those expressing the Ca2+-binding protein parvalbumin (PV). These mainly inhibitory interneurons present in many different brain regions in humans and rodents are characterized by rapid, non-adaptive firing and have a high energy requirement. PV expression is often reduced at both messenger RNA (mRNA) and protein levels in human ASD brain samples and mouse ASD (and schizophrenia) models. Although the human PVALB gene is not a high-ranking susceptibility/risk gene for either disorder and is currently only listed in the SFARI Gene Archive, we propose and present supporting evidence for the Parvalbumin Hypothesis, which posits that decreased PV level is causally related to the etiology of ASD (and possibly schizophrenia).

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Four Social Brain Regions, Their Dysfunctions, and Sequelae, Extensively Explain Autism Spectrum Disorder Symptomatology

Brain Sciences ◽

10.3390/brainsci9060130 ◽

2019 ◽

Vol 9 (6) ◽

pp. 130 ◽

Cited By ~ 1

Author(s):

Charles S. E. Weston

Keyword(s):

Autism Spectrum Disorder ◽

Brain Research ◽

Inferior Frontal Gyrus ◽

Research Question ◽

Neurodevelopmental Disorder ◽

Repetitive Behavior ◽

Brain Regions ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Social Brain

Autism spectrum disorder (ASD) is a challenging neurodevelopmental disorder with symptoms in social, language, sensory, motor, cognitive, emotional, repetitive behavior, and self-sufficient living domains. The important research question examined is the elucidation of the pathogenic neurocircuitry that underlies ASD symptomatology in all its richness and heterogeneity. The presented model builds on earlier social brain research, and hypothesizes that four social brain regions largely drive ASD symptomatology: amygdala, orbitofrontal cortex (OFC), temporoparietal cortex (TPC), and insula. The amygdala’s contributions to ASD largely derive from its major involvement in fine-grained intangible knowledge representations and high-level guidance of gaze. In addition, disrupted brain regions can drive disturbance of strongly interconnected brain regions to produce further symptoms. These and related effects are proposed to underlie abnormalities of the visual cortex, inferior frontal gyrus (IFG), caudate nucleus, and hippocampus as well as associated symptoms. The model is supported by neuroimaging, neuropsychological, neuroanatomical, cellular, physiological, and behavioral evidence. Collectively, the model proposes a novel, parsimonious, and empirically testable account of the pathogenic neurocircuitry of ASD, an extensive account of its symptomatology, a novel physiological biomarker with potential for earlier diagnosis, and novel experiments to further elucidate the mechanisms of brain abnormalities and symptomatology in ASD.

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Functional connectivity-based subtypes of individuals with and without autism spectrum disorder

10.1101/198093 ◽

2017 ◽

Cited By ~ 1

Author(s):

Amanda K. Easson ◽

Zainab Fatima ◽

Anthony R. McIntosh

Keyword(s):

Autism Spectrum Disorder ◽

Functional Connectivity ◽

Social Communication ◽

Neurodevelopmental Disorder ◽

Brain Regions ◽

Autism Spectrum ◽

Spectrum Disorder ◽

The Other ◽

Repetitive Behaviours ◽

Subtype A

AbstractAutism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder, characterized by impairments in social communication and restricted, repetitive behaviours. Neuroimaging studies have shown complex patterns of functional connectivity (FC) in ASD, with no clear consensus on brain-behaviour relationships or shared patterns of FC with typically developing controls. Here, we used k-means clustering and multivariate statistical analyses to characterize distinct FC patterns and FC-behaviour relationships in participants with and without ASD. Two FC subtypes were identified by the clustering analysis. One subtype was defined by increased FC within resting-state networks and decreased FC across networks compared to the other subtype. A separate FC pattern distinguished ASD from controls, particularly within default mode, cingulo-opercular, sensorimotor, and occipital networks. There was no significant interaction between subtypes and diagnostic groups. Finally, analysis of FC patterns with behavioural measures of IQ, social responsiveness and ASD severity showed unique brain-behaviour relations in each subtype, and a continuum of brain-behavior relations from ASD to controls within one subtype. These results demonstrate that distinct clusters of FC patterns exist in both ASD and controls, and that FC subtypes can reveal unique information about brain-behaviour relationships.Author SummaryAutism spectrum disorder (ASD) is a neurodevelopmental disorder, with high variation in the types of severity of impairments in social communication and restricted, repetitive behaviours. Neuroimaging studies have shown complex patterns of communication between brain regions, or functional connectivity (FC), in ASD. Here, we defined two distinct FC patterns and relationships between FC and behaviour in participants with and without ASD. One subtype was defined by increased FC within distinct networks of brain regions, and decreased FC between networks compared to the other subtype. A separate FC pattern distinguished ASD from controls. The interaction between subtypes and diagnostic groups was not significant. Analysis of FC patterns with behavioural measures revealed unique information about brain-behaviour relations in each subtype.

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Development and Validation of a Questionnaire to Assess Parent Reported Quality of Life Pre and Post Vision Therapy in a Population with Autism Spectrum Disorder

Vision Development & Rehabilitation ◽

10.31707/vdr2019.5.3.p195 ◽

2019 ◽

pp. 195-207

Keyword(s):

Quality Of Life ◽

Autism Spectrum Disorder ◽

Social Behavior ◽

Psychometric Properties ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Visual Behavior ◽

The Mean ◽

Vision Therapy

Background: Autism spectrum disorder is characterized in part by atypical behavior in the communication, social, and visual domains. Success in vision therapy is judged not only by changes in optometric findings, but through improvement in quality of life involving communication, social behavior and visual behavior. It would therefore be beneficial to have a validated questionnaire to assess parent reported quality of life pre and post vision therapy specific to patients with autism spectrum disorder. To our knowledge, a questionnaire of this nature has not been previously published in the literature. Methods: Questionnaire items were generated through surveying medical literature based on symptoms in three different categories: visual behavior, social behavior and communication. A pool of 34 questions was developed initially and then with thorough discussion with other experts, a 20-point questionnaire was developed with each item reflected in the construct concept. A draft of 20 questions was then sent to 10 subject experts with clinical experience in the field for more than 20 years, to review the pooled items. Validity and reliability was established prior to assessing the psychometric properties of the ASD/QOL-VT. Prospective observational study was conducted for a duration of 18 months. The study included individuals undergoing vision therapy in the age range of 3 to 15 years who had been diagnosed with ASD. The questionnaire was administered to parents of these children prior to the start of vision therapy. All subjects completed a minimum of 60 vision therapy sessions. The questionnaire was readministered after completing 60 sessions of vision therapy. Results: Cronbach’s alpha value for this questionnaire was 0.93, which reflected very good internal consistency. Factorial analysis yielded four factors with an Eigen value exceeding 1.0 which accounted for 68% variation in the model. The Cronbach alpha value for subscales identified by factorial analysis is 0.97 indicating excellent internal reliability. The mean pre vision therapy social behavior, communication and visual behavior score was 12.0±3.21, 17.07±4.57 and 26.97±6.41 respectively. The mean post vision therapy scores for social behavior, communication and visual behavior was 8.27±4.16, 11.33±5.27 and 17.93±6.52 respectively. On paired t test, the mean difference in score was statistically significant with P<0.001 in all three subcategories. Conclusions: Our study presents the development of a valid and reliable parent questionnaire, the ASD/QOL-VT, that judges communication, social behavior, and visual behavior in autism. Results of the study conducted indicate that vision therapy can result in significant improvements in the quality of life of patients with ASD as judged by their parents. This is evidenced by statistically significant changes in psychometric properties of the ASD/QOL-VT in social behavior, communication and visual behavior.

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Specialized Diet Therapies: Exploration for Improving Behavior in Autism Spectrum Disorder (ASD)

Current Medicinal Chemistry ◽

10.2174/0929867327666200217101908 ◽

2020 ◽

Vol 27 (40) ◽

pp. 6771-6786

Author(s):

Geir Bjørklund ◽

Nagwa Abdel Meguid ◽

Maryam Dadar ◽

Lyudmila Pivina ◽

Joanna Kałużna-Czaplińska ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Neurodevelopmental Disorder ◽

Caloric Intake ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Nutritional Deficiencies ◽

Childhood And Adolescence ◽

Restricted Interests ◽

Balanced Diet ◽

The Individual

As a major neurodevelopmental disorder, Autism Spectrum Disorder (ASD) encompasses deficits in communication and repetitive and restricted interests or behaviors in childhood and adolescence. Its etiology may come from either a genetic, epigenetic, neurological, hormonal, or an environmental cause, generating pathways that often altogether play a synergistic role in the development of ASD pathogenesis. Furthermore, the metabolic origin of ASD should be important as well. A balanced diet consisting of the essential and special nutrients, alongside the recommended caloric intake, is highly recommended to promote growth and development that withstand the physiologic and behavioral challenges experienced by ASD children. In this review paper, we evaluated many studies that show a relationship between ASD and diet to develop a better understanding of the specific effects of the overall diet and the individual nutrients required for this population. This review will add a comprehensive update of knowledge in the field and shed light on the possible nutritional deficiencies, metabolic impairments (particularly in the gut microbiome), and malnutrition in individuals with ASD, which should be recognized in order to maintain the improved socio-behavioral habit and physical health.

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Preliminary Results Regarding Sleep in a Zebrafish Model of Autism Spectrum Disorder

Brain Sciences ◽

10.3390/brainsci11050556 ◽

2021 ◽

Vol 11 (5) ◽

pp. 556

Author(s):

Madalina Andreea Robea ◽

Alin Ciobica ◽

Alexandrina-Stefania Curpan ◽

Gabriel Plavan ◽

Stefan Strungaru ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Valproic Acid ◽

Social Behavior ◽

Antiepileptic Drug ◽

Alternative Model ◽

Neurological Diseases ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Zebrafish Model ◽

Developmental Defects

Autism spectrum disorder (ASD) is one of the most salient developmental neurological diseases and remarkable similarities have been found between humans and model animals of ASD. A common method of inducing ASD in zebrafish is by administrating valproic acid (VPA), which is an antiepileptic drug that is strongly linked with developmental defects in children. In the present study we replicated and extended the findings of VPA on social behavior in zebrafish by adding several sleep observations. Juvenile zebrafish manifested hyperactivity and an increase in ASD-like social behaviors but, interestingly, only exhibited minimal alterations in sleep. Our study confirmed that VPA can generate specific ASD symptoms, indicating that the zebrafish is an alternative model in this field of research.

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Genetic architecture of reciprocal social behavior in toddlers: Implications for heterogeneity in the early origins of autism spectrum disorder

Development and Psychopathology ◽

10.1017/s0954579420000723 ◽

2020 ◽

Vol 32 (4) ◽

pp. 1190-1205

Author(s):

Natasha Marrus ◽

Julia D. Grant ◽

Brooke Harris-Olenak ◽

Jordan Albright ◽

Drew Bolster ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Behavior ◽

Genetic Architecture ◽

Ethnically Diverse ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Genetic Influences ◽

Heritable Trait ◽

Birth Registries

AbstractImpairment in reciprocal social behavior (RSB), an essential component of early social competence, clinically defines autism spectrum disorder (ASD). However, the behavioral and genetic architecture of RSB in toddlerhood, when ASD first emerges, has not been fully characterized. We analyzed data from a quantitative video-referenced rating of RSB (vrRSB) in two toddler samples: a community-based volunteer research registry (n = 1,563) and an ethnically diverse, longitudinal twin sample ascertained from two state birth registries (n = 714). Variation in RSB was continuously distributed, temporally stable, significantly associated with ASD risk at age 18 months, and only modestly explained by sociodemographic and medical factors (r2 = 9.4%). Five latent RSB factors were identified and corresponded to aspects of social communication or restricted repetitive behaviors, the two core ASD symptom domains. Quantitative genetic analyses indicated substantial heritability for all factors at age 24 months (h2 ≥ .61). Genetic influences strongly overlapped across all factors, with a social motivation factor showing evidence of newly-emerging genetic influences between the ages of 18 and 24 months. RSB constitutes a heritable, trait-like competency whose factorial and genetic structure is generalized across diverse populations, demonstrating its role as an early, enduring dimension of inherited variation in human social behavior. Substantially overlapping RSB domains, measurable when core ASD features arise and consolidate, may serve as markers of specific pathways to autism and anchors to inform determinants of autism's heterogeneity.

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In Silico Exploration of the Potential Role of Acetaminophen and Pesticides in the Etiology of Autism Spectrum Disorder

Toxics ◽

10.3390/toxics9050097 ◽

2021 ◽

Vol 9 (5) ◽

pp. 97

Author(s):

Tristan Furnary ◽

Rolando Garcia-Milian ◽

Zeyan Liew ◽

Shannon Whirledge ◽

Vasilis Vasiliou

Keyword(s):

Autism Spectrum Disorder ◽

Prenatal Exposure ◽

Pesticide Exposure ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Biomedical Literature ◽

Spectrum Disorder ◽

Biological Processes ◽

Genetic Associations ◽

Increased Risk

Recent epidemiological studies suggest that prenatal exposure to acetaminophen (APAP) is associated with increased risk of Autism Spectrum Disorder (ASD), a neurodevelopmental disorder affecting 1 in 59 children in the US. Maternal and prenatal exposure to pesticides from food and environmental sources have also been implicated to affect fetal neurodevelopment. However, the underlying mechanisms for ASD are so far unknown, likely with complex and multifactorial etiology. The aim of this study was to explore the potential effects of APAP and pesticide exposure on development with regards to the etiology of ASD by highlighting common genes and biological pathways. Genes associated with APAP, pesticides, and ASD through human research were retrieved from molecular and biomedical literature databases. The interaction network of overlapping genetic associations was subjected to network topology analysis and functional annotation of the resulting clusters. These genes were over-represented in pathways and biological processes (FDR p < 0.05) related to apoptosis, metabolism of reactive oxygen species (ROS), and carbohydrate metabolism. Since these three biological processes are frequently implicated in ASD, our findings support the hypothesis that cell death processes and specific metabolic pathways, both of which appear to be targeted by APAP and pesticide exposure, may be involved in the etiology of ASD. This novel exposures-gene-disease database mining might inspire future work on understanding the biological underpinnings of various ASD risk factors.

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