1. Arpi MNT, Simpson TI. SFARI genes and where to find them; modelling Autism Spectrum Disorder specific gene expression dysregulation with RNA-seq data. Sci Rep;2022 (Jun 16);12(1):10158.

Autism Spectrum Disorders (ASD) have a strong, yet heterogeneous, genetic component. Among the various methods that are being developed to help reveal the underlying molecular aetiology of the disease one approach that is gaining popularity is the combination of gene expression and clinical genetic data, often using the SFARI-gene database, which comprises lists of curated genes considered to have causative roles in ASD when mutated in patients. We build a gene co-expression network to study the relationship between ASD-specific transcriptomic data and SFARI genes and then analyse it at different levels of granularity. No significant evidence is found of association between SFARI genes and differential gene expression patterns when comparing ASD samples to a control group, nor statistical enrichment of SFARI genes in gene co-expression network modules that have a strong correlation with ASD diagnosis. However, classification models that incorporate topological information from the whole ASD-specific gene co-expression network can predict novel SFARI candidate genes that share features of existing SFARI genes and have support for roles in ASD in the literature. A statistically significant association is also found between the absolute level of gene expression and SFARI’s genes and Scores, which can confound the analysis if uncorrected. We propose a novel approach to correct for this that is general enough to be applied to other problems affected by continuous sources of bias. It was found that only co-expression network analyses that integrate information from the whole network are able to reveal signatures linked to ASD diagnosis and novel candidate genes for the study of ASD, which individual gene or module analyses fail to do. It was also found that the influence of SFARI genes permeates not only other ASD scoring systems, but also lists of genes believed to be involved in other neurodevelopmental disorders.

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2. Brynge M, Gardner RM, Sjöqvist H, Lee BK, Dalman C, Karlsson H. Maternal Levels of Cytokines in Early Pregnancy and Risk of Autism Spectrum Disorders in Offspring. Front Public Health;2022;10:917563.

Previous studies indicate a role of immune disturbances during early development in the etiology of autism spectrum disorders (ASD). Any potential disturbances during fetal development are best addressed by prospective evaluation of maternal markers of inflammation. Previous studies have investigated maternal cytokines, a group of powerful effectors of the immune system, with inconsistent results. In this study, we aimed to clarify the relationship between maternal cytokines and ASD by evaluating levels of 17 cytokines in first trimester maternal serum samples, from 318 mothers to ASD-cases and 429 mothers to ASD-unaffected controls, nested within the register-based Stockholm Youth Cohort. Overall, we observed no consistent associations between levels of maternal cytokines and ASD. While we observed a number of individual associations, the patterns varied across the diagnostic sub-groups. Levels above the 90th percentile of IL-1β (OR = 2.31, 95% CI 1.16-4.60), IL-7 (OR = 2.28, 95% CI 1.20-4.33), IL-13 (OR = 2.42, 95% CI 1.29-4.55), and MCP-1 (OR = 2.09, 95% CI 1.03-4.24) were associated with increased odds of ASD with co-occurring intellectual disability (ID), whereas GMCSF (OR = 2.06, 95% CI 1.03-4.11) and TNF-α (OR = 2.31, 95% CI 1.18-4.50) were associated with increased odds of ASD with ADHD but none survived correction for multiple comparisons. Also, none of the measured maternal cytokines were associated with ASD without co-occurring ID or ADHD. Implementing a data-driven approach using machine learning (Random Forest’s Variable Importance measurement), we found no evidence to suggest that adding these cytokines and other markers of maternal immunity, to register-based maternal factors (e.g., psychiatric history) improves prediction of ASD. In summary, we found no robust evidence of an association between maternal immune markers during early pregnancy and ASD.

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3. Erwin J, Paisi M, Neill S, Burns L, Vassallo I, Nelder A, Facenfield J, Devalia U, Vassallo T, Witton R. Factors influencing oral health behaviours, access and delivery of dental care for autistic children and adolescents: A mixed-methods systematic review. Health Expect;2022 (Jun 18)

BACKGROUND: Autistic children and young people (CYP) experience oral health (OH) inequalities. They are at high risk of dental disease and show significant levels of unmet need in relation to OH and access to dental care. AIM: This study aimed to gather evidence on the factors that influence OH behaviours, access to and delivery of dental care for autistic CYP. DESIGN: This was a mixed-methods narrative systematic review. DATA SOURCES: Embase, Web of Science, Dentistry & Oral Sciences Source, MEDLINE, Psychinfo, Scopus, CINAHL, SocINDEX and grey literature were the data sources for this study. REVIEW METHODS: A systematic search was conducted for qualitative, quantitative and mixed-methods research studies from countries with a High Development Index that related to OH behaviours, access to and delivery of dental care for autistic CYP. Results were analysed using narrative synthesis. RESULTS: From 59 eligible studies, 9 themes were generated: (1) affordability and accessibility; (2) autism-related factors and cognitive or motor skill differences; (3) the dental environment; (4) managing CYP’s behaviour; (5) responding and adapting to the needs of the autistic CYP and their parent/carer; (6) attitude of dental health professionals (DHPs) towards autistic CYP and their parents/carers; (7) knowledge of how to care for and support CYP’s OH; (8) empowerment of parents/carers and collaboration with DHPs; and (9) communication and building rapport. CONCLUSION: The adoption of healthy OH behaviours and access to dental care by autistic CYP is impacted by a range of factors including those intrinsically related to a diagnosis of autism, for example, communication and those often associated with autism, for example, sensory sensitivities. Access to better OH and dental care can be facilitated by responding to the individual needs of autistic CYP through accommodation, education and adaptation. This necessitates greater awareness and knowledge of autism amongst DHPs and the provision of appropriate services. More methodologically robust intervention studies are needed to identify effective ways to support autistic CYP in achieving good OH and access to dental care. PATIENT AND PUBLIC CONTRIBUTION: The review protocol was developed with members of the project patient and public involvement group who provided the autistic voice, contributing to the interpretation of the review findings and writing of the manuscript.

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4. Gao Y, Aljazi MB, He J. Kdm6b Haploinsufficiency Causes ASD/ADHD-Like Behavioral Deficits in Mice. Front Behav Neurosci;2022;16:905783.

Autism spectrum disorder (ASD) is a neurodevelopmental disease that has intellectual disability (ID) and attention-deficit/hyperactivity disorder (ADHD) as its common comorbidities. Recent genetic and clinical studies report that KDM6B, a gene encoding a histone H3 lysine 27-specific demethylase, is one of the highest ASD risk genes. However, the relationship between KDM6B mutations and neurodevelopmental diseases remains unclear. Here we use an animal model to show that genetic deletion of one Kdm6b allele in mice leads to autistic-like impaired sociability and object recognition memory. In addition, the mutant mice display markedly increased locomotor activity and impulsivity, two ADHD-like behavioral traits that are ameliorated by methylphenidate treatment. Thus, our study not only uncovers a potential causal link between disruptive KDM6B mutations and ASD/ADHD-like behavioral deficits but also provides a new mouse model for studying the cellular and molecular mechanisms underlying the Kdm6b-mutation-related neurodevelopmental diseases.

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5. Hu Z, Xu P, Ashour EA, Repka MA. Prediction and Construction of Drug-Polymer Binary System Thermodynamic Phase Diagram in Amorphous Solid Dispersions (ASDs). AAPS PharmSciTech;2022 (Jun 17);23(6):169.

Amorphous solid dispersion (ASD) has been well known as a potential strategy to improve the bioavailability and dissolution performance of poorly water-soluble drugs. The primary concern of this approach is the long-term stability of the amorphous drug in the solid dispersion. Accurate prediction and detection of the solubility and miscibility of drug in polymeric binary system will be a milestone to the development of ASDs. In this investigation, a method based on Flory-Huggins (F-H) theory was proposed to predict and calculate the solubility and miscibility of the drug in polymeric matrix and construct the phase diagram to identify the relevance between drug loading and temperature for ASDs development. Indomethacin (Indo) was chosen as the model drug, and polyvinyl pyrrolidone vinyl acetate (Kollidon® VA 64) was used as a polymeric carrier for the ASD systems. Physical mixtures were prepared with different drug loadings (10 to 90%) and analyzed by differential scanning calorimetry (DSC). The interaction parameter χ was calculated for physical mixtures by the melting point depression and solubility parameter contribution methods. The phase diagram was constructed to investigate the impact of other parameters like drug loading, processing temperature, and Gibbs free energy of mixing (ΔG(mix)). For further validation, formulations were developed using HME to verify the accuracy of the phase diagram and to guide in the hot-melt extrusion (HME) process design space and optimization.

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6. Jure R. The « Primitive Brain Dysfunction » Theory of Autism: The Superior Colliculus Role. Front Integr Neurosci;2022;16:797391.

A better understanding of the pathogenesis of autism will help clarify our conception of the complexity of normal brain development. The crucial deficit may lie in the postnatal changes that vision produces in the brainstem nuclei during early life. The superior colliculus is the primary brainstem visual center. Although difficult to examine in humans with present techniques, it is known to support behaviors essential for every vertebrate to survive, such as the ability to pay attention to relevant stimuli and to produce automatic motor responses based on sensory input. From birth to death, it acts as a brain sentinel that influences basic aspects of our behavior. It is the main brainstem hub that lies between the environment and the rest of the higher neural system, making continuous, implicit decisions about where to direct our attention. The conserved cortex-like organization of the superior colliculus in all vertebrates allows the early appearance of primitive emotionally-related behaviors essential for survival. It contains first-line specialized neurons enabling the detection and tracking of faces and movements from birth. During development, it also sends the appropriate impulses to help shape brain areas necessary for social-communicative abilities. These abilities require the analysis of numerous variables, such as the simultaneous evaluation of incoming information sustained by separate brain networks (visual, auditory and sensory-motor, social, emotional, etc.), and predictive capabilities which compare present events to previous experiences and possible responses. These critical aspects of decision-making allow us to evaluate the impact that our response or behavior may provoke in others. The purpose of this review is to show that several enigmas about the complexity of autism might be explained by disruptions of collicular and brainstem functions. The results of two separate lines of investigation: 1. the cognitive, etiologic, and pathogenic aspects of autism on one hand, and two. the functional anatomy of the colliculus on the other, are considered in order to bridge the gap between basic brain science and clinical studies and to promote future research in this unexplored area.

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7. Kim A, Zisman CR, Holingue C. Influences of the Immune System and Microbiome on the Etiology of ASD and GI Symptomology of Autistic Individuals. Curr Top Behav Neurosci;2022 (Jun 17)

Autism Spectrum Disorder is a developmental condition associated with impairments in communication and social interactions, and repetitive and restricted behavior or interests. Autistic individuals are more likely to experience gastrointestinal (GI) symptoms than neurotypical individuals. This may be partially due to dysbiosis of the gut microbiome. In this article, we describe the interaction of the microbiome and immune system on autism etiology. We also summarize the links between the microbiome and gastrointestinal and related symptoms among autistic individuals. We report that microbial interventions, including diet, probiotics, antibiotics, and fecal transplants, and immune-modulating therapies such as cytokine blockade during the preconception, pregnancy, and postnatal period may impact the neurodevelopment, behavior, and gastrointestinal health of autistic individuals.

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8. Li J, Wang H, Qing W, Liu F, Zeng N, Wu F, Shi Y, Gao X, Cheng M, Li H, Shen W, Meng F, He Y, Chen M, Li Z, Zhou H, Wang Q. Congenitally underdeveloped intestine drives autism-related gut microbiota and behavior. Brain Behav Immun;2022 (Jun 14)

Autism spectrum disorder (ASD) is a neurological and developmental disorder accompanied by gut dysbiosis and gastrointestinal symptoms in most cases, while how autism-related gut microbiota occurs and its relationship with intestinal dysfunction in ASD remains unclear. Using a valproic acid (VPA)-induced ASD mouse model, we showed a congenitally immature intestine of VPA-exposed mice accompanied by prominent oxidative stress and inflammation. Of note, the gut microbiota composition of VPA-exposed mice resembled that of control mice within 24 h after birth; however, their gut microbiota compositions differed on postnatal days 7 and 21. Oral administration of superoxide dismutase (SOD) to attenuate intestinal oxidative stress either before weaning or during juvenile restored the autism-associated gut microbiota, leading to the amelioration of autism-related behaviors. These findings collectively suggest the congenitally underdeveloped intestine as an early driving force shaping the autism-associated gut microbiota and host neurodevelopment through enhancing oxidative stress.

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9. Lu C, Rong J, Fu C, Wang W, Xu J, Ju XD. Overall Rebalancing of Gut Microbiota Is Key to Autism Intervention. Front Psychol;2022;13:862719.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with unclear etiology, and due to the lack of effective treatment, ASD patients bring enormous economic and psychological burden to families and society. In recent years, many studies have found that children with ASD are associated with gastrointestinal diseases, and the composition of intestinal microbiota (GM) is different from that of typical developing children. Thus, many researchers believe that the gut-brain axis may play an important role in the occurrence and development of ASD. Indeed, some clinical trials and animal studies have reported changes in neurological function, behavior, and comorbid symptoms of autistic children after rebalancing the composition of the GM through the use of antibiotics, prebiotics, and probiotics or microbiota transfer therapy (MMT). In view of the emergence of new therapies based on the modulation of GM, characterizing the individual gut bacterial profile evaluating the effectiveness of intervention therapies could help provide a better quality of life for subjects with ASD. This article reviews current studies on interventions to rebalance the GM in children with ASD. The results showed that Lactobacillus plantarum may be an effective strain for the probiotic treatment of ASD. However, the greater effectiveness of MMT treatment suggests that it may be more important to pay attention to the overall balance of the patient’s GM. Based on these findings, a more thorough assessment of the GM is expected to contribute to personalized microbial intervention, which can be used as a supplementary treatment for ASD.

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10. McCormick CEB, Peskova V, Morgan A, Carlson E, Mason RA. « Setting Them Up for Success »: Including Youth on the Autism Spectrum in 4-H. Front Psychiatry;2022;13:913600.

Youth on the autism spectrum often face challenges accessing services in rural communities compared to those who live in higher resource areas. There is a particular need for services that support skills that will help youth transition to adulthood and future employment. 4-H is a national youth development program that is well-positioned to address the needs of youth on the autism spectrum; however, minimal empirical evidence exists about the implementation and effectiveness of inclusive practices in 4-H programs. The goal of this study was to better understand barriers to enrollment and to identify gaps in support for youth on the autism spectrum participating in 4-H. Twenty Extension Educators in Indiana participated in two focus groups. Thematic analysis of focus group transcripts identified barriers to enrollment including awareness of 4-H as an inclusive program and difficulties navigating 4-H culture. Our analysis identified themes related to new training content and delivery including a resource portfolio, communication, individualized accommodations, and working within the existing leadership training structure. Findings support the benefits of 4-H as a program that can promote life skills and personal development for youth on the autism spectrum but also highlight a significant need for additional training opportunities and resources to increase uptake and improve the implementation of inclusive practices.

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11. Mills WR, Huffman MM, Roosa J, Pitzen K, Boyd R, Schraer B, Poltavski D. Provision of Home-Based Primary Care to Individuals With Intellectual and/or Developmental Disability Is Associated With a Lower Hospitalization Rate Than a Traditional Primary Care Model. J Am Med Dir Assoc;2022 (Jun 14)

OBJECTIVES: The objective of this study was to determine if providing home-based primary care (HBPC) to individuals with intellectual and/or developmental disabilities (IDDs) was associated with a lower hospitalization rate than a control group receiving traditional primary care. DESIGN AND INTERVENTION: Individuals with IDDs living in supported residential settings in Ohio were offered HBPC. Individuals electing HBPC made up the intervention group. Those who did not opt for HBPC continued to receive traditional primary care services and made up the control group. Hospitalizations were tracked in both groups. SETTING AND PARTICIPANTS: The 757 study participants had IDD diagnoses and received residential support services throughout the study period. METHODS: Annualized hospitalization rate was determined in both groups and was compared using generalized estimating equations while controlling for patients’ age and hospitalization rate in the year prior to the study. RESULTS: The results showed that group membership had a significant effect on the hospitalization rate (Wald χ(2) = 20.71, P < .01). Being in the control group was associated with a 2.12-fold increase in annual hospitalization rate for a given patient. The overall population hospitalization rate was 329 hospitalizations per 1000 per year in the HBPC-receiving individuals and 619 hospitalizations per 1000 per year in the control group. CONCLUSIONS AND IMPLICATIONS: We found that individuals with IDDs receiving HBPC were hospitalized at a lower rate than a control group receiving traditional primary care. Expanding access to HBPC may be a worthwhile priority for organizations that support individuals with IDDs.

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12. Mishaal RA, Weikum WM, Brooks B, Derry K, Lanphear NE. Appraising the need for audiological assessment before autism spectrum disorder referral. Paediatr Child Health;2022 (Jun);27(3):176-182.

OBJECTIVES: Mandatory audiological testing before autism spectrum disorder (ASD) assessment is common practice. Hearing impairment (HI) in the general paediatric population is estimated at 3%; however, hearing impairment prevalence among children with ASD is poorly established. Our objective was to determine which children referred for ASD assessment require preliminary audiological assessment. METHODS: Retrospective chart review of children (n=4,173; 0 to 19 years) referred to British Columbia’s Autism Assessment Network (2010 to 2014). We analyzed HI rate, risk factors, and timing of HI diagnosis relative to ASD referral. RESULTS: ASD was diagnosed in 53.4%. HI rates among ASD referrals was 3.3% and not significantly higher in children with ASD (ASD+; 3.5%) versus No-ASD (3.0%). No significant differences in HI severity or type were found, but more ASD+ females (5.5%) than ASD+ males (3.1%) had HI (P<0.05). Six HI risk factors were significant (problems with intellect, language, vision/eye, ear, genetic abnormalities, and prematurity) and HI was associated with more risk factors (P<0.01). Only 12 children (8.9%) were diagnosed with HI after ASD referral; all males 6 years or younger and only one had no risk factors. ASD+ children with HI were older at ASD referral than No-ASD (P<0.05). CONCLUSIONS: Children with ASD have similar hearing impairment rates to those without ASD. HI may delay referral for ASD assessment. As most children were diagnosed with HI before ASD referral or had at least one risk factor, we suggest that routine testing for HI among ASD referrals should only be required for children with risk factors.

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13. Mohammad F, Sani N, Oshvandi K, Masoumi SZ, Khazaei S, Bashirian S, Jenabi E, Barati M, Rezaei M, Borzou SR. Care burden, coping styles and involvement in care in mothers of autistic children in pandemic of COVID-19. Nurs Open;2022 (Jun 17)

AIM: The aim of the present study was to investigate the burden of care, coping styles and involvement in the care of mothers of autistic children in the pandemic of COVID-19 in Iranian society. DESIGN: A cross-sectional study. METHODS: A total of 134 mothers completed questionnaires online. Data were analysed by descriptive statistics (frequency, percentage, mean and standard deviation) and independent t-test, ANOVA and multiple linear regressions. The significance level was considered p < .05. RESULT: Findings of the study found that burden of care has a strong and direct correlation with involvement in care (p < .001, r = .78) and strongly and indirectly correlated with coping styles (p < .001, r = -.82). Variables of coping styles, involvement in care, mothers' occupation and number of children, age and functional level of autism can predict 81.27% of the variance in care burden in these mothers.

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14. Schaffler MD, Elias LJ, Abdus-Saboor I. Correction to: Mechanisms of Tactile Sensory Phenotypes in Autism: Current Understanding and Future Directions for Research. Curr Psychiatry Rep;2022 (Jun 18)

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15. Shovlin S, Delepine C, Swanson L, Bach S, Sahin M, Sur M, Kaufmann WE, Tropea D. Molecular Signatures of Response to Mecasermin in Children With Rett Syndrome. Front Neurosci;2022;16:868008.

Rett syndrome (RTT) is a devastating neurodevelopmental disorder without effective treatments. Attempts at developing targetted therapies have been relatively unsuccessful, at least in part, because the genotypical and phenotypical variability of the disorder. Therefore, identification of biomarkers of response and patients’ stratification are high priorities. Administration of Insulin-like Growth Factor 1 (IGF-1) and related compounds leads to significant reversal of RTT-like symptoms in preclinical mouse models. However, improvements in corresponding clinical trials have not been consistent. A 20-weeks phase I open label trial of mecasermin (recombinant human IGF-1) in children with RTT demonstrated significant improvements in breathing phenotypes. However, a subsequent randomised controlled phase II trial did not show significant improvements in primary outcomes although two secondary clinical endpoints showed positive changes. To identify molecular biomarkers of response and surrogate endpoints, we used RNA sequencing to measure differential gene expression in whole blood samples of participants in the abovementioned phase I mecasermin trial. When all participants (n = 9) were analysed, gene expression was unchanged during the study (baseline vs. end of treatment, T0-T3). However, when participants were subclassified in terms of breathing phenotype improvement, specifically by their plethysmography-based apnoea index, individuals with moderate-severe apnoea and breathing improvement (Responder group) displayed significantly different transcript profiles compared to the other participants in the study (Mecasermin Study Reference group, MSR). Many of the differentially expressed genes are involved in the regulation of cell cycle processes and immune responses, as well as in IGF-1 signalling and breathing regulation. While the Responder group showed limited gene expression changes in response to mecasermin, the MSR group displayed marked differences in the expression of genes associated with inflammatory processes (e.g., neutrophil activation, complement activation) throughout the trial. Our analyses revealed gene expression profiles associated with severe breathing phenotype and its improvement after mecasermin administration in RTT, and suggest that inflammatory/immune pathways and IGF-1 signalling contribute to treatment response. Overall, these data support the notion that transcript profiles have potential as biomarkers of response to IGF-1 and related compounds.

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16. Sterman J, Gustafson E, Eisenmenger L, Hamm L, Edwards J. Autistic Adult Perspectives on Occupational Therapy for Autistic Children and Youth. OTJR (Thorofare N J);2022 (Jun 17):15394492221103850.

The Autistic community values neurodiversity-positive approaches rather than behavioral interventions for Autistic children; however, little is known about what that would look like in occupational therapy. Frequently, researchers seek parent perspectives for understanding Autistic children’s preferences, while to date insufficient attention has been paid to Autistic adults as valuable informants on the Autistic experience of Autistic children. The objective of the study was to understand Autistic adult perspectives on pediatric occupational therapy for Autistic children. We sought and thematically analyzed data from a large Facebook group and an occupational therapy podcast on Autistic values, needs, and experiences in pediatric occupational therapy. Participants described wanting therapy that supported Autistic identities rather than trying to « fix » children, changing environments or tasks to promote participation, and setting goals that address self-advocacy and autonomy. Occupational therapy practitioners should critically reflect on their practice’s alignment with Autistic values and start to shift their practice as needed.

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17. Toczylowska B, Zieminska E, Polowy R, Olszynski KH, Lazarewicz JW. NMR-Based Metabolomics of Rat Hippocampus, Serum, and Urine in Two Models of Autism. Mol Neurobiol;2022 (Jun 17)

Autism spectrum disorders (ASDs) are increasingly diagnosed as developmental disabilities of unclear etiology related to genetic, epigenetic, or environmental factors. The diagnosis of ASD in children is based on the recognition of typical behavioral symptoms, while no reliable biomarkers are available. Rats in whom ASD-like symptoms are due to maternal administration of the teratogenic drugs valproate or thalidomide on critical day 11 of pregnancy are widely used models in autism research. The present studies, aimed at detecting changes in the levels of hydrophilic and hydrophobic metabolites, were carried out on 1-month-old rats belonging to the abovementioned two ASD models and on a control group. Analysis of both hydrophilic and hydrophobic metabolite levels gives a broader view of possible mechanisms involved in the pathogenesis of autism. Hippocampal proton magnetic resonance (MRS) spectroscopy and ex vivo nuclear magnetic resonance (NMR) analysis of serum and urine samples were used. The results were analyzed using advanced statistical tests. Both the results of our present MRS studies of the hippocampus and of the NMR studies of body fluids in both ASD models, particularly from the THAL model, appeared to be consistent with previously published NMR results of hippocampal homogenates and data from the literature on autistic children. We detected symptoms of disturbances in neurotransmitter metabolism, energy deficit, and oxidative stress, as well as intestinal malfunction, which shed light on the pathogenesis of ASD and could be used for diagnostic purposes. These results confirm the usefulness of the noninvasive techniques used in ASD studies.

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18. Trembath D, Stainer M, Caithness T, Dissanayake C, Eapen V, Fordyce K, Frewer V, Frost G, Hudry K, Iacono T, Mahler N, Masi A, Paynter J, Pye K, Quan S, Shellshear L, Sutherland R, Sievers S, Thirumanickam A, Westerveld MF, Tucker M. Correction to: Spoken Language Change in Children on the Autism Spectrum Receiving Community-Based Interventions. J Autism Dev Disord;2022 (Jun 18)

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