Autism Spectrum Disorder Onset Research Articles

Head circumference growth in children with Autism Spectrum Disorder: trend and clinical correlates in the first five years of life.

Macrocephaly is described in almost 15% of children with Autism Spectrum Disorder (ASD). Relationships between head growth trajectories and clinical findings in ASD children show a high degree of variability, highlighting the complex heterogeneity of the disorder. The aim of this study was to measure differences of the early growth trajectory of head circumference (HC) in children with ASD and macrocephaly compared to ASD normocephalic children, examining clinical correlates in the two groups of patients. HC data were collected from birth to 5 years of age in a sample of children with a confirmed diagnosis of ASD. Participants were classified into two groups: ASD macrocephaly (ASD-M, Z-scores ≥1.88 in at least two consecutive HC measurements), and ASD non-macrocephaly (ASD-N). Based on the distribution of HC measurements (Z-scores), five age groups were identified for the longitudinal study. Developmental and behavioral characteristics of the ASD-M children compared to the ASD-N group were compared by using standardized scores. 20,8% of the children sample met criteria for macrocephaly. HC values became indicative of macrocephaly in the ASD-M group at the age range from 1 to 6 months, and persisted thereafter throughout the first five years of age. ASD-M children showed significantly higher developmental quotients of Griffiths III B and D subscales compared to ASD-N group. No significant differences in the severity of ASD symptoms assessed by ADOS-2 were observed between ASD-M and ASD-N groups. In this study HC size from birth to 5 years links to accelerated HC growth rate as early as the first 6 months of age in children with ASD and macrocephaly, preceding the onset and diagnosis of ASD. We found that in early childhood, children with ASD-M may exhibit some advantages in language and social communication and emotional skills without differences in autism severity, when compared with age-matched normocephalic ASD children. Longitudinal analyses are required to catch-up prospectively possible relationships between head size as proxy measure of brain development and neuro-developmental and behavioral features in children with ASD.

Contributions of Artificial Intelligence to Analysis of Gut Microbiota in Autism Spectrum Disorder: A Systematic Review.

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder whose etiology is not known today, but everything indicates that it is multifactorial. For example, genetic and epigenetic factors seem to be involved in the etiology of ASD. In recent years, there has been an increase in studies on the implications of gut microbiota (GM) on the behavior of children with ASD given that dysbiosis in GM may trigger the onset, development and progression of ASD through the microbiota-gut-brain axis. At the same time, significant progress has occurred in the development of artificial intelligence (AI). The aim of the present study was to perform a systematic review of articles using AI to analyze GM in individuals with ASD. In line with the PRISMA model, 12 articles using AI to analyze GM in ASD were selected. Outcomes reveal that the majority of relevant studies on this topic have been conducted in China (33.3%) and Italy (25%), followed by the Netherlands (16.6%), Mexico (16.6%) and South Korea (8.3%). The bacteria Bifidobacterium is the most relevant biomarker with regard to ASD. Although AI provides a very promising approach to data analysis, caution is needed to avoid the over-interpretation of preliminary findings. A first step must be taken to analyze GM in a representative general population and ASD samples in order to obtain a GM standard according to age, sex and country. Thus, more work is required to bridge the gap between AI in mental health research and clinical care in ASD.

Research progress on hippocampal neurogenesis in autism spectrum disorder.

Autism spectrum disorder (ASD) is a group of severe neurodevelopmental disorders with unclear etiology and significant heterogeneity that is emerging as a global public health concern. Increasing research suggests the involvement of hippocampal neurogenesis defects in the onset and development of ASD, drawing increasing amounts of attention to hippocampal neurogenesis issues in ASD. In this paper, we analyze relevant international studies on hippocampal neurogenesis in ASD, discuss the role of neurobiology in the pathogenesis of ASD, and explore the potential of improving hippocampal neurogenesis as a therapeutic approach for ASD. This review aims to provide new treatment perspectives and theoretical foundations for clinical practice.

A Multi-Target mechanism of Withania somnifera bioactive compounds in autism spectrum disorder (ASD) Treatment: Network pharmacology, molecular docking, and molecular dynamics simulations studies

Autism spectrum disorder (ASD) is a developmental disorder resulting from variations in brain structure and function. Individuals with ASD often experience challenges in communication and social interaction, along with engaging in repetitive or restricted patterns of behavior and interests. The lack of documented data and the wide range of pathophysiological processes associated with ASDmake it challenging to work which causes a major financial burden on health care management. Withania somnifera, often referred to as ashwagandha is the tropical winter cherry in the Solanaceae family that can be used to treat several ailments such as asthma, stress, hypertension,diabetes, cancer, arthritic, and neural disorders including ASD. In this investigation, we examined the active compound-target-pathway network and discovered that Withanolide J, Withanone, and Withaferin A have a great role in the onset of ASD by influencing the IL6 gene. Later, the molecular docking method was applied for confirmation of the active compound's effective action against the prospective target. The molecular dynamics simulation exhibited that the complexes of Withanolide J and Withanone had stable intermolecular binding conformation and unveiled very stable dynamics during the simulation time. A combined network pharmacology and molecular docking approach demonstrated that W. somnifera exhibits a promising preventive impact on ASD by targeting relevant signaling pathways associated with the disorder. This establishes a foundation for comprehending the underlying mechanism of the anti-ASD activity of W. somnifera.

Serum interleukin-17 A and homocysteine levels in children with autism

BackgroundAutism Spectrum Disorder (ASD) is a neurodevelopmental condition that typically emerges early in childhood. This study aimed to explore the potential link between serum levels of vitamin B12 and homocysteine (Hcy) and the severity of ASD symptoms in children.MethodsIn this study, 50 children diagnosed with ASD comprised the observation group, while 50 healthy children constituted the control group. Serum levels of IL-17 A, Hcy, folate, and vitamin B12 were compared between the study group and control group, as well as among children with different degrees of ASD severity. The correlation between the Childhood Autism Rating Scale (CARS) score and serum levels of IL-17 A, Hcy, folate, and vitamin B12 was examined. Additionally, the relationship between serum IL-17 A and Hcy levels and their association with the severity ASD were explored.ResultsCompared to the control group, the observation group demonstrated elevated serum Hcy and IL-17 A levels alongside decreased folate and vitamin B12 levels. Individuals with severe ASD exhibited higher Hcy and IL-17 A levels but lower folate and vitamin B12 levels compared to those with mild to moderate ASD. The CARS score showed negative correlations with serum folate and vitamin B12 levels and positive correlations with serum IL-17 A and Hcy levels in ASD patients. Additionally, serum Hcy and IL-17 A levels were correlated with ASD severity.ConclusionChildren diagnosed with ASD presented with reduced serum vitamin B12 levels and increased levels of Hcy, potentially contributing to the onset and severity of ASD.

Role of Glia Cells in Autism Spectrum Disorders

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an increasing frequency, manifested by functional disorders in social communication and social interaction, limited interests, and repetitive behaviors. The etiology of autism spectrum disorder has not yet been fully elucidated and there are many areas that need further study. Increasing studies have shown that disruptions in synaptic functions are critical in the onset of ASD. Glial cells have a role in the regulation of synaptic functions. In ASD, changes are seen in the number of neurons and glia cells in the affected cerebral cortex, and these changes cause dysregulation in synaptic functions and affect behaviors. Studies provide information about the role of glia cells in the pathophysiology of ASD, but more data is needed on the relationship between ASD and glia cells. In this review, the importance of glial cells in the etiopathogenesis of ASD and studies will be discussed.

Gut microbiota functional profiling in autism spectrum disorders: bacterial VOCs and related metabolic pathways acting as disease biomarkers and predictors.

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder. Major interplays between the gastrointestinal (GI) tract and the central nervous system (CNS) seem to be driven by gut microbiota (GM). Herein, we provide a GM functional characterization, based on GM metabolomics, mapping of bacterial biochemical pathways, and anamnestic, clinical, and nutritional patient metadata. Fecal samples collected from children with ASD and neurotypical children were analyzed by gas-chromatography mass spectrometry coupled with solid phase microextraction (GC-MS/SPME) to determine volatile organic compounds (VOCs) associated with the metataxonomic approach by 16S rRNA gene sequencing. Multivariate and univariate statistical analyses assessed differential VOC profiles and relationships with ASD anamnestic and clinical features for biomarker discovery. Multiple web-based and machine learning (ML) models identified metabolic predictors of disease and network analyses correlated GM ecological and metabolic patterns. The GM core volatilome for all ASD patients was characterized by a high concentration of 1-pentanol, 1-butanol, phenyl ethyl alcohol; benzeneacetaldehyde, octadecanal, tetradecanal; methyl isobutyl ketone, 2-hexanone, acetone; acetic, propanoic, 3-methyl-butanoic and 2-methyl-propanoic acids; indole and skatole; and o-cymene. Patients were stratified based on age, GI symptoms, and ASD severity symptoms. Disease risk prediction allowed us to associate butanoic acid with subjects older than 5 years, indole with the absence of GI symptoms and low disease severity, propanoic acid with the ASD risk group, and p-cymene with ASD symptoms, all based on the predictive CBCL-EXT scale. The HistGradientBoostingClassifier model classified ASD patients vs. CTRLs by an accuracy of 89%, based on methyl isobutyl ketone, benzeneacetaldehyde, phenyl ethyl alcohol, ethanol, butanoic acid, octadecane, acetic acid, skatole, and tetradecanal features. LogisticRegression models corroborated methyl isobutyl ketone, benzeneacetaldehyde, phenyl ethyl alcohol, skatole, and acetic acid as ASD predictors. Our results will aid the development of advanced clinical decision support systems (CDSSs), assisted by ML models, for advanced ASD-personalized medicine, based on omics data integrated into electronic health/medical records. Furthermore, new ASD screening strategies based on GM-related predictors could be used to improve ASD risk assessment by uncovering novel ASD onset and risk predictors.

A Review of the Nutritional Approach and the Role of Dietary Components in Children with Autism Spectrum Disorders in Light of the Latest Scientific Research

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects several areas of mental development. The onset of ASD occurs in the first few years of life, usually before the age of 3 years. Proper nutrition is important to ensure that an individual’s nutrient and energy requirements are met, and it can also have a moderating effect on the progression of the disorder. A systematic database search was conducted as a narrative review to determine whether nutrition and specific diets can potentially alter gastrointestinal symptoms and neurobehavioral disorders. Databases such as Science Direct, PubMed, Scopus, Web of Science (WoS), and Google Scholar were searched to find studies published between 2000 and September 2023 on the relationship between ASD, dietary approaches, and the role of dietary components. The review may indicate that despite extensive research into dietary interventions, there is a general lack of conclusive scientific data about the effect of therapeutic diets on ASD; therefore, no definitive recommendation can be made for any specific nutritional therapy as a standard treatment for ASD. An individualized dietary approach and the dietician’s role in the therapeutic team are very important elements of every therapy. Parents and caregivers should work with nutrition specialists, such as registered dietitians or healthcare providers, to design meal plans for autistic individuals, especially those who would like to implement an elimination diet.

Sleep quality and temperament in association with autism spectrum disorder among infants in Japan

BackgroundSleep problems and irritable temperaments are common among infants with autism spectrum disorder (ASD). The prospective association between such sleep problems and irritable temperaments and ASDs needs to be determined for elucidating the mechanism and exploring the future intervention study. Thus, in this study, we investigated whether sleep quality and temperament in 1-month-old infants are associated with the onset of ASD in 3-year-old children. We also assessed its sex-stratified associations.MethodsWe conducted a longitudinal study using data from 69,751 mothers and infants from a large-cohort study, the Japan Environment and Children’s Study. We examined the prospective association between infant sleep quality and temperament at 1 month of age and ASD diagnosis by 3 years of age.ResultsHere we show infants with longer daytime sleep have a higher risk of later ASD than those with shorter daytime sleep (risk ratio [RR]: 1.33, 95% confidence interval [CI]: 1.01–1.75). Infants who experienced intense crying have a higher risk of ASD than those who did not (RR: 1.31, 95% CI: 1.00–1.72). There is a difference in sex in the association between a bad mood and later ASD. In particular, female infants experiencing bad moods have a higher risk of ASD than others (RR: 3.59, 95% CI: 1.91–6.75).ConclusionsThe study findings provide important information for future intervention to reduce the risk of future ASD.

Combination of machine learning-based bulk and single-cell genomics reveals necroptosis-related molecular subtypes and immunological features in autism spectrum disorder.

Necroptosis is a novel form of controlled cell death that contributes to the progression of various illnesses. Nonetheless, the function and significance of necroptosis in autism spectrum disorders (ASD) remain unknown and require further investigation. We utilized single-nucleus RNA sequencing (snRNA-seq) data to assess the expression patterns of necroptosis in children with autism spectrum disorder (ASD) based on 159 necroptosis-related genes. We identified differentially expressed NRGs and used an unsupervised clustering approach to divide ASD children into distinct molecular subgroups. We also evaluated immunological infiltrations and immune checkpoints using the CIBERSORT algorithm. Characteristic NRGs, identified by the LASSO, RF, and SVM-RFE algorithms, were utilized to construct a risk model. Moreover, functional enrichment, immune infiltration, and CMap analysis were further explored. Additionally, external validation was performed using RT-PCR analysis. Both snRNA-seq and bulk transcriptome data demonstrated a greater necroptosis score in ASD children. Among these cell subtypes, excitatory neurons, inhibitory neurons, and endothelials displayed the highest activity of necroptosis. Children with ASD were categorized into two subtypes of necroptosis, and subtype2 exhibited higher immune activity. Four characteristic NRGs (TICAM1, CASP1, CAPN1, and CHMP4A) identified using three machine learning algorithms could predict the onset of ASD. Nomograms, calibration curves, and decision curve analysis (DCA) based on 3-NRG have been shown to have clinical benefit in children with ASD. Furthermore, necroptosis-based riskScore was found to be positively associated with immune activation. Finally, RT-PCR demonstrated differentially expressed of these four NRGs in human peripheral blood samples. A comprehensive identification of necroptosis may shed light on the underlying pathogenic process driving ASD onset. The classification of necroptosis subtypes and construction of a necroptosis-related risk model may yield significant insights for the individualized treatment of children with ASD.

CSMD3 Deficiency Leads to Motor Impairments and Autism-Like Behaviors via Dysfunction of Cerebellar Purkinje Cells in Mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with highly heritable heterogeneity. Mutations of CUB and sushi multiple domains 3 (CSMD3) gene have been reported in individuals with ASD. However, the underlying mechanisms of CSMD3 for the onset of ASD remain unexplored. Here, using male CSMD3 knock-out (CSMD3 -/-) mice, we found that genetic deletion of CSMD3 produced core autistic-like symptoms (social interaction deficits, restricted interests, and repetitive and stereotyped behaviors) and motor dysfunction in mice, indicating that the CSMD3 gene can be considered as a candidate for ASD. Moreover, we discovered that the ablation of CSMD3 in mice led to abnormal cerebellar Purkinje cell (PC) morphology in Crus I/II lobules, including aberrant developmental dendritogenesis and spinogenesis of PCs. Furthermore, combining in vivo fiber photometry calcium imaging and ex vivo electrophysiological recordings, we showed that the CSMD3 -/- mice exhibited an increased neuronal activity (calcium fluorescence signals) in PCs of Crus I/II lobules in response to movement activity, as well as an enhanced intrinsic excitability of PCs and an increase of excitatory rather than inhibitory synaptic input to the PCs, and an impaired long-term depression at the parallel fiber-PC synapse. These results suggest that CSMD3 plays an important role in the development of cerebellar PCs. Loss of CSMD3 causes abnormal PC morphology and dysfunction in the cerebellum, which may underlie the pathogenesis of motor deficits and core autistic-like symptoms in CSMD3 -/- mice. Our findings provide novel insight into the pathophysiological mechanisms by which CSMD3 mutations cause impairments in cerebellar function that may contribute to ASD.SIGNIFICANCE STATEMENT Autism spectrum disorder (ASD) is a neurodevelopmental disorder with highly heritable heterogeneity. Advances in genomic analysis have contributed to numerous candidate genes for the risk of ASD. Recently, a novel giant gene CSMD3 encoding a protein with CUB and sushi multiple domains (CSMDs) has been identified as a candidate gene for ASD. However, the underlying mechanisms of CSMD3 for the onset of ASD remain largely unknown. Here, we unravel that loss of CSMD3 results in abnormal morphology, increased intrinsic excitabilities, and impaired synaptic plasticity in cerebellar PCs, subsequently leading to motor deficits and ASD-like behaviors in mice. These results provide novel insight into the pathophysiological mechanisms by which CSMD3 mutations cause impairments in cerebellar function that may contribute to ASD.

Molecular mechanisms of exercise intervention in alleviating the symptoms of autism spectrum disorder: Targeting the structural alterations of synapse.

Autism spectrum disorder (ASD) is a complex and heterogeneous neurodevelopmental disorder characterized by stereotyped behaviors, specific interests, and impaired social and communication skills. Synapses are fundamental structures for transmitting information between neurons. It has been reported that synaptic deficits, such as the increased or decreased density of synapses, may contribute to the onset of ASD, which affects the synaptic function and neuronal circuits. Therefore, targeting the recovery of the synaptic normal structure and function may be a promising therapeutic strategy to alleviate ASD symptoms. Exercise intervention has been shown to regulate the structural plasticity of synapses and improve ASD symptoms, but the underlying molecular mechanisms require further exploration. In this review, we highlight the characteristics of synaptic structural alterations in the context of ASD and the beneficial effects of an exercise intervention on improving ASD symptoms. Finally, we explore the possible molecular mechanisms of improving ASD symptoms through exercise intervention from the perspective of regulating synaptic structural plasticity, which contributes to further optimizing the related strategies of exercise intervention promoting ASD rehabilitation in future.

Neuroinflammation and Oxidative Stress in the Pathogenesis of Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) characterized by impairments in social communication, repetitive behaviors, restricted interests, and hyperesthesia/hypesthesia caused by genetic and/or environmental factors. In recent years, inflammation and oxidative stress have been implicated in the pathogenesis of ASD. In this review, we discuss the inflammation and oxidative stress in the pathophysiology of ASD, particularly focusing on maternal immune activation (MIA). MIA is a one of the common environmental risk factors for the onset of ASD during pregnancy. It induces an immune reaction in the pregnant mother's body, resulting in further inflammation and oxidative stress in the placenta and fetal brain. These negative factors cause neurodevelopmental impairments in the developing fetal brain and subsequently cause behavioral symptoms in the offspring. In addition, we also discuss the effects of anti-inflammatory drugs and antioxidants in basic studies on animals and clinical studies of ASD. Our review provides the latest findings and new insights into the involvements of inflammation and oxidative stress in the pathogenesis of ASD.

Prenatal low-dose methylmercury exposure causes premature neuronal differentiation and autism-like behaviors in a rodent model

Aberrant neurodevelopment is a core deficit of autism spectrum disorder (ASD). Here we ask whether a non-genetic factor, prenatal exposure to the environmental pollutant methylmercury (MeHg), is a contributing factor in ASD onset. We showed that adult mice prenatally exposed to non-apoptotic MeHg exhibited key ASD characteristics, including impaired communication, reduced sociability, and increased restrictive repetitive behaviors, whereas in the embryonic cortex, prenatal MeHg exposure caused premature neuronal differentiation. Further single-cell RNA sequencing (scRNA-seq) analysis disclosed that prenatal exposure to MeHg resultedin cortical radial glial precursors (RGPs) favoring asymmetric differentiation to directly generate cortical neurons, omitting the intermediate progenitor stage. In addition, MeHg exposure in cultured RGPs increased CREB phosphorylation and enhanced the interaction between CREB and CREB binding protein (CBP). Intriguingly, metformin, an FDA-approved drug, can reverse MeHg-induced premature neuronal differentiation via CREB/CBP repulsion. These findings provide insights into ASD etiology, its underlying mechanism, and a potential therapeutic strategy.

The Relationship Between Dietary Patterns and ASD

The dietary intake pattern of the mother when preparing for pregnancy, during pregnancy, and the nutritional exposure of the infant after birth have a bearing on the likelihood of the infant developing autism spectrum disorder (ASD). Many types of research have revealed a relationship between diet and the onset of ASD. However, it has not been established whether diet can be used to control the manifestation of ASD or in the prevention of ASD in unborn children. Therefore, there is an interest in ascertaining the main reasons for the relationship between dietary patterns and ASD. This paper analyzes studies about nutrition and its influence on ASD. In addition, the research explores the whole spectrum of environmental factors, namely external and internal ones, and their potential impact on an infant. Furthermore, the paper discusses the nutrition of the offspring and an approach to preventing the risk of ASD. The combination of different factors such as the mother's nutrition at various stages, the nutrition available to the infant, and the environment have been indicated in the results of the analysis to determine the level of risk for ASD in children. In this regard, further investigation of ASD prevention among infants is highly important and should be encouraged.

9 Congenital Heart Disease and Autism Spectrum Disorders: Is There a Link?

Abstract Background Congenital heart disease (CHD) has been linked to an increased incidence of intellectual disability and neurodevelopmental impairments in young patients. The relationship between CHD and autism spectrum disorders (ASD) is not well investigated. Objectives We performed a systematic review and meta-analysis of the medical literature to assess the evidence linking CHD to incidence of ASD. Design/Methods A systematic review of studies on CHD and ASD in PubMed, Cochrane and ISI from 1965 to May 2021 was conducted. Only retrospective or prospective cohort, case-control and cross-sectional human studies in the English language were included. Quantitative estimates of association between CHD and ASD were extracted from eligible studies for the meta-analysis. Pooled estimates were obtained using a random effect models fit by a generalised linear mixed model. Quantitative results not included in the meta-analysis were summarized using descriptive statistics. Results We screened 2,709 articles and 24 articles were included in this review. Among the 24 studies, there was a total of 348,771 subjects (12,114 CHD, 9,829 ASD and 326,828 controls). Patient age (range of 0 to 26 years) was reported in all studies. The proportion of males in CHD, ASD and controls were 50%, 80%, and 55%. CHD diagnosis ranged from non-specific (9/16), single ventricle lesion (2/16), dextro-transposition of the great arteries (2/16), and tetralogy of Fallot (1/16). Overall, seven articles reported a 4.66 times increase in the percentage of ASD cases in patients with CHD compared to the percentage of ASD cases in the general population: (5.87% vs 1.14% of ASD cases in CHD vs the general population). Seven of 24 studies were eligible for the meta-analysis, which included information on a total of 250,611 subjects (3,984 CHD, 9,829 ASD, and 236,798 controls). The summary estimate indicated that CHD patients are associated with almost double the odds of being diagnosed with autism compared with non-CHD patients: (OR 1.99, 95% CI 1.77-2.24, p<0.01). Early developmental delay, perinatal factors, genetics and neurological development were potential risk factors and etiologies for the onset of ASD in CHD patients. Suggestions for improvement of future clinical care include early identification and treatment of ASD among the CHD population. Limitations of this study include few articles explicitly exploring the link between CHD and ASD and lack of standardized ASD endpoints. Conclusion This review outlines that CHD patients are at an increased risk of presenting with a diagnosis or symptoms suggestive of ASD.

Chemical Modulators for Targeting Autism Spectrum Disorders: From Bench to Clinic.

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by diverse behavioral symptoms such as repetitive behaviors, social deficits, anxiety, hyperactivity, and irritability. Despite their increasing incidence, the specific pathological mechanisms of ASD are still unknown, and the degree and types of symptoms that vary from patient to patient make it difficult to develop drugs that target the core symptoms of ASD. Although various atypical antipsychotics and antidepressants have been applied to regulate ASD symptoms, these drugs can only alleviate the symptoms and do not target the major causes. Therefore, development of novel drugs targeting factors directly related to the onset of ASD is required. Among the various factors related to the onset of ASD, several chemical modulators to treat ASD, focused on serotonin (5-hydroxytryptamine, 5-HT) and glutamate receptors, microbial metabolites, and inflammatory cytokines, are explored in this study. In particular, we focus on the chemical drugs that have improved various aspects of ASD symptoms in animal models and in clinical trials for various ages of patients with ASD.

Association between maternal prenatal psychological distress and autism spectrum disorder among 3-year-old children: The Japan Environment and Children's Study.

Maternal prenatal psychological distress, which includes depression and anxiety, affects the onset of autism spectrum disorder (ASD). However, there is no consistent knowledge regarding at which term during pregnancy psychological distress affects the risk of ASD among children. We used a dataset obtained from the Japan Environment and Children's Study, which is a nationwide prospective birth cohort study, to evaluate the association between the six-item Kessler Psychological Distress Scale (K6) and ASD among 3-year-old children. A total of 78,745 children were analyzed, and 355 of them were diagnosed with ASD (0.45%). The maternal K6 was administered twice during pregnancy: at a median of 15.1 weeks (M-T1) and at that of 27.4 weeks (M-T2) of gestation. Multivariate logistic regression analyses demonstrated that the group with a maternal K6 score of ≥5 at both M-T1 and M-T2 was significantly associated with ASD among the children (adjusted odds ratio, 1.440; 95% confidence interval, 1.104-1.877) compared to the group with a score of ≤4 at both M-T1 and M-T2. There was no significant difference between the group with a score of ≥5 only at M-T1 or M-T2 and that with a score of ≤4 at both M-T1 and M-T2. In conclusion, from the first to the second half of pregnancy, continuous maternal psychological distress was associated with ASD among 3-year-old children. Contrarily, in the group without persistent maternal psychological distress during pregnancy, there was no significant association.

Study Protocol: Gut microbiota profiles implicated in the onset of autism spectrum disorders in preterm infants: A two-year follow-up study

IntroductionPreterm infants are at high-risk of developing autism spectrum disorders (ASD). The underlying mechanisms that explain the link between prematurity and ASD are unclear. Perinatal environmental factors may disrupt the gut-brain communication, when the gut microbiome composition is established and brain programming occurs. Therefore, the disruption of the gut-brain axis communication in response to perinatal environmental events may shed light on the association between prematurity and ASD.ObjectivesTo describe a new research project protocol which aim is to develop a dynamic model of gut microbiota variation in response to environmental factors that modulate the ASD risk in preterm infants.MethodsA two-year prospective observational study will be carried out, in which preterm infants will be assessed at birth, 40th postmenstrual week, at 6, 12, and 24 months of corrected age. Two-hundred preterm infants will be recruited. A comprehensive assessment will be conducted by collecting data on sociodemographic characteristics, medical history, family functioning, neurodevelopment, ASD screening, and diagnosis. Microbiome composition and microbial activity will be determined from feces.ResultsThe expected results are: i) to characterize ASD since its early manifestations in an at-risk population, allowing an early diagnosis and intervention to improve clinical outcomes; ii) to identify early microbiota biomarkers in order to find potential pathophysiological pathways; iii) to understand the protective and risk factors associated to ASD since perinatal period.ConclusionsA two-year predictive model will be generated based on environmental and gut microbiota variables. This predictive model of ASD would allow prevention, early diagnosis, improvement of prognosis, and personalized treatments in preterm infants.DisclosureNo significant relationships.

Investigation of OLIG2 as a candidate gene for schizophrenia and autism spectrum disorder.

ABSTRACTA number of genomic mutations that are thought to be strongly involved in the development of schizophrenia (SCZ) and autism spectrum disorder (ASD) have been identified. Abnormalities involving oligodendrocytes have been reported in SCZ, and as a related gene, oligodendrocyte lineage transcription factor 2 (OLIG2) has been reported to be strongly associated with SCZ. In this study, based on the common disease–rare variant hypothesis, target sequencing of candidate genes was performed to identify rare mutations with a high effect size and the possibility that the identified mutations may increase the risks of SCZ and ASD in the Japanese population. In this study, the exon region of OLIG2 was targeted; 370 patients with SCZ and 192 with ASD were subjected to next-generation sequencing. As a result, one rare missense mutation (A33T) was detected. We used the Sanger method to validate this missense mutation with a low frequency (<1%), and then carried out a genetic association analysis involving 3299 unrelated individuals (1447 with SCZ, 380 with ASD, and 1472 healthy controls) to clarify whether A33T was associated with SCZ or ASD. A33T was not found in either case group, and in only one control. We did not find evidence that p.A33T is involved in the onset of ASD or SCZ; however, associations with this variant need to be evaluated in larger samples to confirm our results.