Autism Spectrum Disorder Patients Research Articles

A network meta-analysis of the effect of physical exercise on core symptoms in patients with autism spectrum disorders

ObjectiveTo compare the effects of various sports exercise programs on the core symptoms of patients with autism spectrum disorder (ASD).MethodsWe searched the China National Knowledge Infrastructure, VIP databases, Wanfang databases, Cochrane Library, PubMed, EMBASE, and Web of Science databases from their inception to February 2023 for randomized controlled trial that investigated the effect of sports exercise on the core symptoms of ASD. The overall risk of bias in the included literature was summarized using the revised Cochrane Randomized Trial Risk of Bias Tool (ROB2), and network meta-analysis was used to compare the intervention effects.ResultsA total of 30 studies involving 1,375 participants were included. The results showed that sports exercise programs, including 8–12 weeks of ball sports (SMD = −5.35, 95%CI: −7.57, −3.23), horse riding (SMD = −3.71, 95%CI: −6.18, −1.13), 8–12 weeks of comprehensive sports exercise (SMD = −2.17, 95%CI: −3.99, −0.44), and more than 12 weeks of comprehensive sports exercise (SMD = −3.75, 95%CI: −6.33, −1.24), significantly improved social interaction disorders. Furthermore, 8–12 weeks of ball sports (SMD = −4.36, 95%CI: 2.04, 6.73) and more than 12 weeks of comprehensive sports exercise (SMD = 3.65, 95%CI: 1.40, 6.08) significantly improved repetitive behaviors and restricted interests.ConclusionSports exercise can improve the core symptoms of ASD patients, and different symptoms show a selective response to different exercise elements.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42023455806.

DeepGCN based on variable multi‐graph and multimodal data for ASD diagnosis

AbstractDiagnosing individuals with autism spectrum disorder (ASD) accurately faces great challenges in clinical practice, primarily due to the data's high heterogeneity and limited sample size. To tackle this issue, the authors constructed a deep graph convolutional network (GCN) based on variable multi‐graph and multimodal data (VMM‐DGCN) for ASD diagnosis. Firstly, the functional connectivity matrix was constructed to extract primary features. Then, the authors constructed a variable multi‐graph construction strategy to capture the multi‐scale feature representations of each subject by utilising convolutional filters with varying kernel sizes. Furthermore, the authors brought the non‐imaging information into the feature representation at each scale and constructed multiple population graphs based on multimodal data by fully considering the correlation between subjects. After extracting the deeper features of population graphs using the deep GCN(DeepGCN), the authors fused the node features of multiple subgraphs to perform node classification tasks for typical control and ASD patients. The proposed algorithm was evaluated on the Autism Brain Imaging Data Exchange I (ABIDE I) dataset, achieving an accuracy of 91.62% and an area under the curve value of 95.74%. These results demonstrated its outstanding performance compared to other ASD diagnostic algorithms.

Use of an adaptive sensory environment in patients with autism spectrum disorder (ASD) in the perioperative environment: a parallel, randomized controlled trial

Patients with autism spectrum disorders (ASD) experience higher rates of perioperative anxiety and are likely to receive premedication. Little is known about nonpharmaceutical interventions which may decrease anxiety. This study aims to evaluate the use of an adaptive sensory environment (ASE) to reduce ASD patient anxiety during the perioperative process. Our feasibility study (ClinicalTrials.govNCT04994613) enrolled 60 patients in two parallel groups randomized to a control (no ASE) or intervention group (ASE). We included all surgical patients aged three to twelve years, with a formal diagnosis of ASD, Asperger's Syndrome, or pervasive developmental disorder not otherwise specified. Preoperative behaviors were recorded by an unblinded nurse utilizing the validated Modified Yale Preoperative Anxiety Scale (mYPAS). The difference in score on the mYPAS was the primary outcome, and an intention-to-treat analysis was employed. A generalized estimating equations model was used to compare mYPAS scores controlling for significant independent variables. 58 patients were analyzed after 1:1 randomization of 30 patients to each group. Groups were balanced except the median number of intraoperative pain medications was significantly lower in the ASE group (1 vs. 3, p=0.012). Mean (SD) age for all patients was 7.2 (2.9) years, range 2.6-12.7. 72.4% (42/58) were White and all were Non-Hispanic or Latino. 74% were Male (21/30 ASE and 22/28 Control) and 26% were Female (9/30 ASE and 6/28 Control). No differences were found in mYPAS scores between groups at three time periods (43.5 vs. 42, p=0.88, 47.8 vs. 48.4, p=0.76, and 36.4 vs. 43.8, p=0.15, ASE vs. control group, respectively). The ASE group had a significant within-group decrease in mYPAS scores from nursing intake to transition (p=0.030). An ASE did not significantly reduce perioperative anxiety. However, the promising results deserve further investigation. Dayton Children's Hospital Foundation Robert C. Cohn Memorial Research Grant.

The Metabolic Insight into Autism Spectrum Disorder: Evaluating Adiponectin's Impact on Severity and Therapy

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with a complex interplay of genetic and environmental factors. Recent research has suggested a significant link between metabolic alterations and ASD pathology, particularly focusing on adiponectin, a hormone related to glucose regulation and fatty acid breakdown. Anomalies in adiponectin levels have been associated with cognitive impairment and the severity of ASD. Objective: This study aims to evaluate the potential of the ADIPOQ gene as a biomarker for dementia in individuals with ASD, exploring its correlation with cognitive decline and metabolic dysregulation. Methods: A total of 108 EDTA blood samples from ASD patients and 32 from healthy controls were collected after obtaining written informed consent. The inclusion criteria included individuals aged over 40 with Type II Diabetes Mellitus and confirmed cases of diabetes and dementia. Exclusion criteria comprised the absence of clinical history, refusal of consent, and secondary autism. Adiponectin levels were quantified using ELISA, and cognitive function was assessed via MMSE scores over a six-month follow-up period. Data analysis was conducted using GraphPad Prism 9.0 with ANOVA for statistical significance. Results: The study found a significant decrease in adiponectin levels among ASD patients (5.17±1.04 µg/mL) compared to healthy controls (11.37±4.14 µg/mL, p=0.014). MMSE scores were notably lower in the ASD group (10.26±2.56) than in controls (23.1±3.12, p=0.006). A marked underexpression of ADIPOQ gene (fold change of 4.9) was observed in patients with dementia. Conclusion: The ADIPOQ gene shows potential as a biomarker for the early detection of dementia in ASD, offering avenues for personalized medical interventions and preventative healthcare measures. Recognizing its role could lead to improved therapeutic strategies and a reduction in the healthcare burden due to neurodegenerative diseases associated with ASD.

Autism in patients with eosinophilic gastrointestinal disease: A systematic review with meta-analysis.

Neurodevelopmental disorders, such as autism spectrum disorder (ASD), have been increasingly associated with eosinophilic gastrointestinal disorders (EGID). However, the relationship between these diseases remains unclear. We performed a systematic review with meta-analysis to address this issue. The search was performed according to the PRISMA guidelines using descriptors for ASD and EGIDs from the MEDLINE, Embase, PsycInfo, LILACS, and Web of Science databases. Observational studies with the prevalence of ASD in any EGID were included. The study protocol was registered on the PROSPERO platform under the number CRD42023455177. The total dataset comprised 766,082 participants. The result of the single-arm meta-analysis showed an overall prevalence of ASD in the population with EGID of 21.59% (95% CI: 10.73-38.67). There was an association between EGID and ASD (OR: 3.44; 95% CI: 1.25-2.21), also significant when restricted only to EoE (OR: 3.70; 95% CI: 2.71-5.70). Recent studies have implicated the influence of an inadequate epithelial barrier integrity in the pathogenesis of several diseases. The role of this mechanism can be extended to situations beyond allergic reactions, including other conditions with underlying immunological mechanisms. Several diseases are potentially related to the systemic effect of bacterial translocation in tissues with defective epithelial barriers. Our meta-analysis provides evidence that supports the consideration of EGID in patients with ASD and ASD in patients with EGID. Despite its limitations, the results should also be validated by future studies, preferably using multicenter prospective designs in populations with low referral bias.

Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice.

Thalamocortical (TC) circuits are essential for sensory information processing. Clinical and preclinical studies of autism spectrum disorders (ASDs) have highlighted abnormal thalamic development and TC circuit dysfunction. However, mechanistic understanding of how TC dysfunction contributes to behavioral abnormalities in ASDs is limited. Here, our study on a Shank3 mouse model of ASD reveals TC neuron hyperexcitability with excessive burst firing and a temporal mismatch relationship with slow cortical rhythms during sleep. These TC electrophysiological alterations and the consequent sensory hypersensitivity and sleep fragmentation in Shank3 mutant mice are causally linked to HCN2 channelopathy. Restoring HCN2 function early in postnatal development via a viral approach or lamotrigine (LTG) ameliorates sensory and sleep problems. A retrospective case series also supports beneficial effects of LTG treatment on sensory behavior in ASD patients. Our study identifies a clinically relevant circuit mechanism and proposes a targeted molecular intervention for ASD-related behavioral impairments.

Comparison of The Effectiveness of Fones and Modified Bass Teeth Brushing Methods on Reducing Plaque Index in Autism Spectrum Disorders Children Aged 6-12 Years

Children with special needs, such as Autism Spectrum Disorders (ASD), are at a higher risk of developing caries. Brushing teeth is the most effective preventive measure to avoid the risk of developing dental and oral diseases. The Fones teeth brushing method has been proven to reduce dental plaque in ASD patients due to its simplicity. The modified Bass method is also reported to be effective in removing interdental plaque. This study is to investigate whether there is a difference in the effectiveness of teeth brushing techniques, specifically the Fones method and the modified Bass method, in reducing the plaque index in children with ASD.   A quasi-experimental study with a pre-test and post-test design was conducted, with 24 ASD participants aged between 6-12 years. The Loe and Silness Plaque Index was used to measure the plaque index. Data analysis was conducted by comparing the two methods using a Paired t-test and a one-way ANOVA test. Indicate that there is a significant difference between the two treatments with a significance value of 0.039 (P<0.05). The average plaque index from the Fones method was found to be 0.444 greater than the modified Bass method. In conclusion: There is a difference in effectiveness between the Fones teeth brushing method and the modified Bass teeth brushing method in reducing the plaque index in children with ASD aged 6-12 years.

Relationship between serum cortisol levels, stereotypies, and the presence of autism spectrum disorder in patients with severe intellectual disability

Stereotypies are one of the diagnostic criteria for autism spectrum disorder (ASD) and are common to both ASD and intellectual disability (ID). Previous studies have been inconclusive, with some showing a positive correlation between stereotypies and cortisol, while others have shown a negative correlation. We hypothesised and investigated the presence of ASD as one of the variables involved in this discrepancy. We tested the following hypotheses on serum cortisol in a total of 84 hospitalised patients with severe ID and ASD with severe ID. Hypothesis (1) Higher levels of stereotypies are associated with higher levels of serum cortisol. Hypothesis (2) The presence of ASD will moderate the association between stereotypies and high serum cortisol levels. The results of the analysis supported hypotheses (1) and (2). We also found that in the population with ID, serum cortisol levels were significantly lower in the ASD group compared to the non-ASD group. The present findings that the association between stereotypies and serum cortisol levels in people with severe ID is moderated by the presence of ASD suggest that the stress response system may function differently in people with ID and ASD than in the general population.

Assessing the Revised Safer Dx Instrument® in the understanding of ambulatory system design changes for type 1 diabetes and autism spectrum disorder in pediatrics.

We sought within an ambulatory safety study to understand if the Revised Safer Dx instrument may be helpful in identification of diagnostic missed opportunities in care of children with type 1 diabetes (T1D) and autism spectrum disorder (ASD). We reviewed two months of emergency department (ED) encounters for all patients at our tertiary care site with T1D and a sample of such encounters for patients with ASD over a 15-month period, and their pre-visit communication methods to better understand opportunities to improve diagnosis. We applied the Revised Safer Dx instrument to each diagnostic journey. We chose potentially preventable ED visits for hyperglycemia, diabetic ketoacidosis, and behavioral crises, and reviewed electronic health record data over the prior three months related to the illness that resulted in the ED visit. We identified 63 T1D and 27 ASD ED visits. Using theRevised Safer Dx instrument, we did not identify any potentially missed opportunities to improve diagnosis in T1D. We found two potential missed opportunities (Safer Dx overall score of 5) in ASD, related to potential for ambulatory medical management to be improved. Over this period, 40 % of T1D and 52 % of ASD patients used communication prior to the ED visit. Using the Revised Safer Dx instrument, we uncommonly identified missed opportunities to improve diagnosis in patients who presented to the ED with potentially preventable complications of their chronic diseases. Future researchers should consider prospectively collected data as well as development or adaptation of tools like the Safer Dx.

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.

Subcortical-cortical white matter connectivity in adults with autism spectrum disorder and schizophrenia patients

Autism spectrum disorder (ASD) and schizophrenia (SZ) are neuropsychiatric disorders that overlap in symptoms associated with social-cognitive impairment. Alterations of the cingulate cortex, subcortical, medial-temporal, and orbitofrontal structures are frequently reported in both disorders. In this study, we examined white-matter connectivity between these structures in adults with ASD and SZ patients compared with their respective neurotypical controls and indirectly with each other, using probabilistic and local DTI tractography. This exploratory study utilized publicly available neuroimaging databases, of adults with ASD (ABIDE II; n = 28) and SZ (COBRE; n = 38), age-gender matched neurotypicals (NT) and associated phenotypic data. Tractography was performed using Freesurfer and MRtrix software, and diffusion metrics of white-matter tracts between cingulate-, orbitofrontal- cortices, subcortical structures, parahippocampal, entorhinal cortex were assessed. In ASD, atypical diffusivity parameters were found in the isthmus cingulate and parahippocampal connectivity to subcortical and rostral-anterior cingulate, which were also associated with IQ and social skills (SRS). In contrast, atypical diffusivity parameters were observed between the medial-orbitofrontal cortex and subcortical structures in SZ, and were associated with executive function (i.e., IQ, processing speed) and emotional regulation. Overall, the results suggest that defects in the isthmus cingulate, medial-orbitofrontal, and striato-limbic white matter connectivity may help unravel the neural underpinnings of executive and social-emotional dysfunction at the core of neuropsychiatric disorders.

De novo copy number variations in candidate genomic regions in patients of severe autism spectrum disorder in Vietnam.

Autism spectrum disorder (ASD) is a developmental disorder with a prevalence of around 1% children worldwide and characterized by patient behaviour (communication, social interaction, and personal development). Data on the efficacy of diagnostic tests using copy number variations (CNVs) in candidate genes in ASD is currently around 10% but it is overrepresented by patients of Caucasian background. We report here that the diagnostic success of de novo candidate CNVs in Vietnamese ASD patients is around 6%. We recruited one hundred trios (both parents and a child) where the child was clinically diagnosed with ASD while the parents were not affected. We performed genetic screening to exclude RETT syndrome and Fragile X syndrome and performed genome-wide DNA microarray (aCGH) on all probands and their parents to analyse for de novo CNVs. We detected 1708 non-redundant CNVs in 100 patients and 118 (7%) of them were de novo. Using the filter for known CNVs from the Simons Foundation Autism Research Initiative (SFARI) database, we identified six CNVs (one gain and five loss CNVs) in six patients (3 males and 3 females). Notably, 3 of our patients had a deletion involving the SHANK3 gene-which is the highest compared to previous reports. This is the first report of candidate CNVs in ASD patients from Vietnam and provides the framework for building a CNV based test as the first tier screening for clinical management.

The Hidden Impact of ADHD Symptoms in Preschool Children with Autism: Is There a Link to Somatic and Sleep Disorders?

Neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), do often present in comorbidity among them and with other medical conditions, including sleep and gastrointestinal (GI) disorders and somatic complaints. An anonymous online survey based on standardized questionnaires (SDSC, KL-ASD, APSI, ROME V CRITERIA, CPRS, CBCL) was completed by the parents of 46 preschoolers diagnosed with ASD. A high prevalence (47%) of ADHD symptoms in this population was found, surpassing previous estimates. Sleep disturbances, especially difficulties in initiating and maintaining sleep and sleep-wake transition, are more pronounced in ASD patients with comorbid ADHD. Additionally, in patients over 4 years old, there is a high prevalence of functional GI symptoms (Rome V criteria: 38%). Parental stress is significantly associated with ADHD symptoms, sleep disorders, and GI symptoms. Comprehensive assessments considering both core symptoms of neurodevelopmental disorders and associated comorbidities are crucial for more effective treatment strategies and improved wellbeing in affected individuals and their families.

The complex etiology of autism spectrum disorder due to missense mutations of CHD8.

CHD8 is an ATP-dependent chromatin-remodeling factor encoded by the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Although many studies have examined the consequences of CHD8 haploinsufficiency in cells and mice, few have focused on missense mutations, the most common type of CHD8 alteration in ASD patients. We here characterized CHD8 missense mutations in ASD patients according to six prediction scores and experimentally examined the effects of such mutations on the biochemical activities of CHD8, neural differentiation of embryonic stem cells, and mouse behavior. Only mutations with high prediction scores gave rise to ASD-like phenotypes in mice, suggesting that not all CHD8 missense mutations detected in ASD patients are directly responsible for the development of ASD. Furthermore, we found that mutations with high scores cause ASD by mechanisms either dependent on or independent of loss of chromatin-remodeling function. Our results thus provide insight into the molecular underpinnings of ASD pathogenesis caused by missense mutations of CHD8.

The mast cells - Cytokines axis in Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a neurodevelopmental disturbance, diagnosed in early childhood. It is associated with varying degrees of dysfunctional communication and social skills, repetitive and stereotypic behaviors. Regardless of the constant increase in the number of diagnosed patients, there are still no established treatment schemes in global practice. Many children with ASD have allergic symptoms, often in the absence of mast cell (MC) positive tests. Activation of MCs may release molecules related to inflammation and neurotoxicity, which contribute to the pathogenesis of ASD. The aim of the present paper is to enrich the current knowledge regarding the relationship between MCs and ASD by providing PPI network analysis-based data that reveal key molecules and immune pathways associated with MCs in the pathogenesis of autism. Network and enrichment analyzes were performed using receptor information and secreted molecules from activated MCs identified in ASD patients. Our analyses revealed cytokines and key marker molecules for MCs degranulation, molecular pathways of key mediators released during cell degranulation, as well as various receptors. Understanding the relationship between ASD and the activation of MCs, as well as the involved molecules and interactions, is important for elucidating the pathogenesis of ASD and developing effective future treatments for autistic patients by discovering new therapeutic target molecules.

Developmental Dopaminergic Signaling Modulates Neural Circuit Formation and Contributes to Autism Spectrum Disorder–Related Phenotypes

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with a complex etiology. Recent evidence suggests that dopamine plays a crucial role in neural development. However, it remains unclear whether and how disrupted dopaminergic signaling during development contributes to ASD. In this study, human brain RNA-seq transcriptome analysis revealed a significant correlation between changes in dopaminergic signaling pathways and neural developmental signaling in ASD patients. In the zebrafish model, disrupted developmental dopaminergic signaling led to neural circuit abnormalities and behavior reminiscent of autism. Dopaminergic signaling may impact neuronal specification by potentially modulating integrins. These findings shed light on the mechanisms underlying the link between disrupted developmental dopamine signaling and ASD, and they point to the possibility of targeting dopaminergic signaling in early development for ASD treatment.

A comprehensive diversity analysis on the gut microbiomes of ASD patients: from alpha, beta to gamma diversities.

Autism spectrum disorder (ASD) is estimated to influence as many as 1% children worldwide, but its etiology is still unclear. It has been suggested that gut microbiomes play an important role in regulating abnormal behaviors associated with ASD. A de facto standard analysis on the microbiome-associated diseases has been diversity analysis, and nevertheless, existing studies on ASD-microbiome relationship have not produced a consensus. Here, we perform a comprehensive analysis of the diversity changes associated with ASD involving alpha-, beta-, and gamma-diversity metrics, based on 8 published data sets consisting of 898 ASD samples and 467 healthy controls (HC) from 16S-rRNA sequencing. Our findings include: (i) In terms of alpha-diversity, in approximately 1/3 of the studies cases, ASD patients exhibited significantly higher alpha-diversity than the HC, which seems to be consistent with the "1/3 conjecture" of diversity-disease relationship (DDR). (ii) In terms of beta-diversity, the AKP (Anna Karenina principle) that predict all healthy microbiomes should be similar, and every diseased microbiome should be dissimilar in its own way seems to be true in approximately 1/2 to 3/4 studies cases. (iii) In terms of gamma-diversity, the DAR (diversity-area relationship) modeling suggests that ASD patients seem to have large diversity-area scaling parameter than the HC, which is consistent with the AKP results. However, the MAD (maximum accrual diversity) and RIP (ratio of individual to population diversity) parameters did not suggest significant differences between ASD patients and HC. Throughout the study, we adopted Hill numbers to measure diversity, which stratified the diversity measures in terms of the rarity-commonness-dominance spectrum. It appears that the differences between ASD patients and HC are more propounding on rare-species side than on dominant-species side. Finally, we discuss the apparent inconsistent diversity-ASD relationships among different case studies and postulate that the relationships are not monotonic.

Digital interventions for autism spectrum disorders: A systematic review and meta‐analysis

ABSTRACTImportanceDigital technology is now widely available for the interventions of autism, but its validity and feasibility remain to be proved.ObjectiveThis study aimed to investigate the effectiveness of digital health interventions (DHIs) in improving core symptoms or intelligence quotient in patients with autism spectrum disorder (ASD).MethodsThree databases including PubMed, Cochrane, and Scopus, were searched on November 15, 2022. Randomized clinical trials that enrolled patients with ASD who received DHIs and a control group without DHI treatment were included. Cochrane risk of bias tool (RoB 2) was applied to assess the risk of bias.ResultsA total of 33 studies, involving 1285 participants (658 [51.2%] in DHI groups and 627 [48.8%] in control groups), were analyzed to investigate the differences between DHI groups and control groups. Significantly greater improvements in the overall performance of ASD were observed in the DHI groups compared to the control groups (including active, waitlist, treatment‐as‐usual, and no treatment) with an effect size of 1.89 (Cohen's d 95% confidence interval [CI]: 1.26–2.52). Studies with treatment‐as‐usual, waitlist, and no treatment control demonstrated large effect sizes of Cohen's d 3.41 (95% CI: 0.84–5.97), Cohen's d 4.27 (95% CI: 1.95–6.59), and Cohen's d 4.52 (95% CI: 2.98–6.06) respectively. In contrast, studies with active control revealed insignificant effect sizes (Cohen's d 0.73, 95% CI: 0.12–1.33).InterpretationThis meta‐analysis found significantly greater improvements in core symptoms or intelligence quotient in ASD patients receiving DHIs compared to those in control conditions. ASD patients may benefit from the DHIs and reduce the economic burden.

The NMDA receptor modulator zelquistinel durably relieves behavioral deficits in three mouse models of autism spectrum disorder

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders characterized by deficient social communication and interaction together with restricted, stereotyped behaviors. Currently approved treatments relieve comorbidities rather than core symptoms. Since excitation/inhibition balance and synaptic plasticity are disrupted in ASD, molecules targeting excitatory synaptic transmission appear as highly promising candidates to treat this pathology. Among glutamatergic receptors, the NMDA receptor has received particular attention through the last decade to develop novel allosteric modulators. Here, we show that positive NMDA receptor modulation by zelquistinel, a spirocyclic β-lactam platform chemical, relieves core symptoms in two genetic and one environmental mouse models of ASD. A single oral dose of zelquistinel rescued, in a dose-response manner, social deficits and stereotypic behavior in Shank3Δex13-16−/− mice while chronic intraperitoneal administration promoted a long-lasting relief of such autistic-like features in these mice. Subchronic oral mid-dose zelquistinel treatment demonstrated durable effects in Shank3Δex13-16−/−, Fmr1−/− and in utero valproate-exposed mice. Carry-over effects were best maintained in the Fmr1 null mouse model, with social parameters being still fully recovered two weeks after treatment withdrawal. Among recently developed NMDA receptor subunit modulators, zelquistinel displays a promising therapeutic potential to relieve core symptoms in ASD patients, with oral bioavailability and long-lasting effects boding well for clinical applications. Efficacy in three mouse models with different etiologies supports high translational value. Further, this compound represents an innovative pharmacological tool to investigate plasticity mechanisms underlying behavioral deficits in animal models of ASD.

Alteration of the gut microbiota profile in children with autism spectrum disorder in China.

Autism spectrum disorder (ASD) is associated with alterations in the gut microbiome. However, there are few studies on gut microbiota of children with ASD in China, and there is a lack of consensus on the changes of bacterial species. Autism spectrum disorder (ASD) is associated with alterations in the gut microbiome. However, there are few studies on gut microbiota of children with ASD in China, and there is a lack of consensus on the changes of bacterial species. We used 16S rRNA sequencing to analyze ASD children (2 to 12 years), HC (2 to 12 years). Our findings showed that the α-diversity, composition, and relative abundance of gut microbiota in the ASD group were significantly different from those in the HC groups. Compared with the HC group, the α-diversity in the ASD group was significantly decreased. At the genus level, the relative abundance of g_Faecalibacterium, g_Blautia, g_Eubacterium_eligens_group, g_Parasutterella, g_Lachnospiraceae_NK4A136_group and g_Veillonella in ASD group was significantly increased than that in HC groups, while the relative abundance of g_Prevotella 9 and g_Agathobacter was significantly decreased than that in HC groups. In addition, KEGG pathway analysis showed that the microbial functional abnormalities in ASD patients were mainly concentrated in metabolic pathways related to fatty acid, amino acid metabolism and aromatic compound metabolism, and were partially involved in neurotransmitter metabolism. This study revealed the characteristics of gut microbiota of Chinese children with ASD and provided further evidence of gut microbial dysbiosis in ASD.