1. Ali Moussa HY, Shin KC, de la Fuente A, Bensmail I, Abdesselem HB, Ponraj J, Mansour S, Al-Shaban FA, Stanton LW, Abdulla SA, Park Y. Proteomics analysis of extracellular vesicles for biomarkers of autism spectrum disorder. Front Mol Biosci. 2024; 11: 1467398.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by symptoms that include social interaction deficits, language difficulties and restricted, repetitive behavior. Early intervention through medication and behavioral therapy can eliminate some ASD-related symptoms and significantly improve the life-quality of the affected individuals. Currently, the diagnosis of ASD is highly limited. METHODS: To investigate the feasibility of early diagnosis of ASD, we tested extracellular vesicles (EVs) proteins obtained from ASD cases. First, plasma EVs were isolated from healthy controls (HCs) and ASD individuals and were analyzed using proximity extension assay (PEA) technology to quantify 1,196 protein expression level. Second, machine learning analysis and bioinformatic approaches were applied to explore how a combination of EV proteins could serve as biomarkers for ASD diagnosis. RESULTS: No significant differences in the EV morphology and EV size distribution between HCs and ASD were observed, but the EV number was slightly lower in ASD plasma. We identified the top five downregulated proteins in plasma EVs isolated from ASD individuals: WW domain-containing protein 2 (WWP2), Heat shock protein 27 (HSP27), C-type lectin domain family 1 member B (CLEC1B), Cluster of differentiation 40 (CD40), and folate receptor alpha (FRalpha). Machine learning analysis and correlation analysis support the idea that these five EV proteins can be potential biomarkers for ASD. CONCLUSION: We identified the top five downregulated proteins in ASD EVs and examined that a combination of EV proteins could serve as biomarkers for ASD diagnosis.

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2. Backman A, Roll-Pettersson L, Mellblom A, Norman-Claesson E, Sundqvist E, Zander E, Vigerland S, Hirvikoski T. Internet-Delivered Psychoeducation (SCOPE) for Transition-Aged Autistic Youth: Pragmatic Randomized Controlled Trial. J Med Internet Res. 2024; 26: e49305.

BACKGROUND: Psychoeducation is a recommended first-line intervention for transition-aged autistic youth, but it has not been previously evaluated in an internet-delivered format. SCOPE (Spectrum Computerized Psychoeducation) is an 8-week individual, internet-delivered, therapist-supported psychoeducative intervention. OBJECTIVE: This study aimed to investigate the effectiveness of SCOPE through a 3-armed randomized controlled trial. The intervention aims to increase participants’ understanding of autism and, in doing so, increase their quality of life (QoL). METHODS: SCOPE was codeveloped with clinicians and autistic young adults. It contains 8 autism-related modules, each with (1) text describing the module topic, (2) four video vignettes with recurring characters who describe their lives and perspectives on the module topic, (3) a list of neurotypical characteristics related to the module’s topic, and (4) self-reflection using 3 or 4 questions about the module topic, answered by multiple-choice bullets and voluntary open-ended written comments. Participants were randomized (2:1:1) to SCOPE, an active control (web-based self-study), or treatment as usual (TAU). The primary outcome was participants’ autism knowledge, assessed using the Autism Spectrum Disorder Quiz, and secondary outcomes included acceptance of diagnosis, QoL, and symptoms of mental health problems. All outcomes were assessed at the baseline, postintervention, and 3-month follow-up time points, using mixed-effects models to assess change in outcome measures across time points. RESULTS: Between 2014 and 2020, a total of 141 participants were randomized to 1 of the 3 treatment arms. The SCOPE participants had significantly greater autism knowledge gains at the posttreatment time point compared to TAU participants with a moderate effect size (d=0.47; P=.05); gains were maintained at the 3-month follow-up (d=0.46; P=.05). The self-study participants also had increased knowledge gains compared to TAU participants at the posttreatment time point with a moderate effect size (d=0.60; P=.03) but did not maintain these gains at the 3-month follow-up, and their autism knowledge scores returned to baseline (mean change score: -0.13, 95% CI -1.20 to 0.94; P=.81). In addition, SCOPE participants reported improved QoL at the postintervention (d=0.37, P=.02) and 3-month follow-up time points (d=0.60; P=.001), compared to the combined controls. The gained autism knowledge was not mirrored by changes in symptoms of anxiety or depression. CONCLUSIONS: Effective internet-delivered interventions may facilitate first-line service access to individuals who are unable or unwilling to use traditional health care interventions or who live in geographically remote locations. Additionally, an intervention such as SCOPE could impart and sustain the knowledge gained through psychoeducation in transition-aged autistic youth. For future research, qualitative studies could further our understanding of the lived experiences of intervention participation and outcomes after internet-delivered psychoeducation. TRIAL REGISTRATION: ClinicalTrials.gov NCT03665363; https://clinicaltrials.gov/study/NCT03665363.

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3. Boorom O, Liu T. A scoping review of interaction dynamics in minimally verbal autistic individuals. Front Psychol. 2024; 15: 1497800.

Interaction dynamics provide information about how social interactions unfold over time and have implications for communication development. Characterizing social interaction in autistic people who are minimally verbal (MV) has the potential to illuminate mechanisms of change in communication development and intervention. The purpose of this scoping review was to investigate the current evidence characterizing interaction dynamics in MV autistic individuals, methods used to measure interaction dynamics in this population, and opportunities for future research. Articles were included if participants were diagnosed with autism, considered MV, if interaction occurred with a human communication partner during live in-person interaction, and if variables were derived by measuring the relationship between behaviors in both partners. The seven articles included in this review demonstrate that limited research describes interaction dynamics in this population, and that behavioral coding measures can be leveraged to assess constructs such as turn-taking, social contingency, and balance in social interactions. While there is some evidence describing how MV autistic individuals and their communication partners construct reciprocal interaction, there is variability in how interaction dynamics are measured and limited evidence describing individual differences. Recommendations for future research are discussed.

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4. Carbonell-Roig J, Aaltonen A, Wilson K, Molinari M, Cartocci V, McGuirt A, Mosharov E, Kehr J, Lieberman OJ, Sulzer D, Borgkvist A, Santini E. Dysregulated acetylcholine-mediated dopamine neurotransmission in the eIF4E Tg mouse model of autism spectrum disorders. Cell Rep. 2024; 43(12): 114997.

Autism spectrum disorder (ASD) consists of diverse neurodevelopmental conditions where core behavioral symptoms are critical for diagnosis. Altered dopamine (DA) neurotransmission in the striatum has been suggested to contribute to the behavioral features of ASD. Here, we examine DA neurotransmission in a mouse model of ASD characterized by elevated expression of eukaryotic initiation factor 4E (eIF4E), a key regulator of cap-dependent translation, using a comprehensive approach that encompasses genetics, behavior, synaptic physiology, and imaging. The results indicate that increased eIF4E expression leads to behavioral inflexibility and impaired striatal DA release. The loss of normal DA neurotransmission is due to a defect in nicotinic receptor signaling that regulates calcium dynamics in dopaminergic axons. These findings provide a mechanistic understanding of ASD symptoms and offer a foundation for targeted therapeutic interventions by revealing the intricate interplay between eIF4E, DA neurotransmission, and behavioral flexibility.

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5. Costa MAD, Fernandes GZ, Maiochi E, Ebs MFP, Darós FDS, Bolan SJ, Costa RRN, de Rezende VL, da Silva GC, Bitencourt RM, Gonçalves CL. Effects of Cannabidiol Isolated or in Association With Risperidone in an Animal Model of Autism. Dev Neurobiol. 2025; 85(1): e22955.

Autism spectrum disorder (ASD) is characterized by deficits in communication, social interaction, and repetitive and stereotyped behaviors, with no specific drug therapy available. Studies have found that cannabidiol (CBD) can improve hyperactive and cognitive symptoms in children with ASD. However, little is known about the effect of CBD in combination with other medications, such as risperidone (RISP). This study aimed to evaluate the behavioral and biochemical effects of CBD in animals using a valproic acid (VPA)-induced ASD animal model. VPA was administered in pregnant Wistar rats on Day 12.5 of gestation to induce the ASD model. From the 10th to the 16th postnatal day (PND), the neurodevelopment of the animals was assessed through eye-opening, olfactory discrimination, and negative geotaxis behavioral tests. From PNDs 9 to 54, the animals were weighed. They were treated for 21 days with CBD alone (100 mg/kg, by gavage, twice a day) or in combination with RISP (0.1 mg/kg, by gavage, once a day). At PND 55, the animals were evaluated in social interaction and locomotor activity experiments. Finally, after behavioral assessment, the animals were euthanized, the brain was isolated, and oxidative stress parameters were evaluated in the hippocampus and cortex posterior. Animals exposed to VPA showed neurodevelopmental delays in opening their eyes, difficulties in turning around their axis, and took longer time to find the original nest when compared to control animals. They also exhibited impaired sociability and reduced exploratory activity, which indicates model impairments. Interestingly, animals exposed to VPA treated with CBD + RISP significantly improved sociability parameters, whereas isolated CBD did not affect this parameter. In the biochemical analysis, a significant decrease in the hippocampal sulfhydryl content was noted in the CT + CBD group and an increase in the VPA + CBD group. In conclusion, these results suggest that CBD, in combination with RISP, may be an interesting pharmacological approach to reducing ASD-related symptoms. Summary: Besides the increased prevalence of ASD cases in recent years, there are no medications to improve the central symptoms of autism. Numerous studies discuss CBD as an important medication for improving ASD symptoms; however, it is not known how CBD interacts with commonly used drugs in ASD individuals, such as RISP. This study demonstrated that CBD therapy, only when combined with RISP, improved sociability in a VPA-induced ASD animal model.

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6. Endo N, Hiraishi A, Goto S, Nozu H, Mannari-Sasagawa T, Horii-Hayashi N, Kitsuki M, Okuda M, Makinodan M, Nishi M. Dysregulated HPA axis during postnatal developmental stages in the BTBR T(+) Itpr3(tf)/J mouse: A model of autism spectrum disorder. Neuropsychopharmacol Rep. 2024.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder. Some children with ASD show enhanced cortisol response to stress. BTBR T(+) Itpr3(tf)/J (BTBR) mice, an ASD model, display behavior consistent with the three diagnostic categories of ASD and exhibit an exaggerated response to stress in adulthood. However, it remains unclear how basal corticosterone levels change and how the hypothalamic-pituitary-adrenal axis responds to stress during the early life stages in BTBR mice. In this study, we found that basal corticosterone levels showed characteristic changes, peaking at weaning during postnatal development in both BTBR and control C57BL/6J (B6J) mice. Furthermore, we observed higher corticosterone and corticotropin-releasing hormone levels in BTBR mice than in B6J mice following acute stress exposure during weaning; however, adrenocorticotropic hormone levels were lower in BTBR mice. Glucocorticoid receptor mRNA expression levels in the hippocampus and lateral septum after stress were higher in BTBR mice than in B6J mice. This study documented changes in corticosterone levels at baseline during postnatal development in mice and showed that BTBR mice exhibited disrupted stress responses at weaning.

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7. Furukawa S, Kushima I, Kato H, Kimura H, Nawa Y, Aleksic B, Banno M, Yamamoto M, Uematsu M, Nagasaki Y, Ogi T, Ozaki N, Ikeda M. Whole-genome sequencing analysis of Japanese autism spectrum disorder trios. Psychiatry Clin Neurosci. 2024.

AIM: Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous neurodevelopmental disorder with a strong genetic basis. Conducting the first comprehensive whole-genome sequencing (WGS) analysis of Japanese ASD trios, this study aimed to elucidate the clinical significance of pathogenic variants and enhance the understanding of ASD pathogenesis. METHODS: WGS was performed on 57 Japanese patients with ASD and their parents, investigating variants ranging from single-nucleotide variants to structural variants (SVs), short tandem repeats (STRs), mitochondrial variants, and polygenic risk score (PRS). RESULTS: Potentially pathogenic variants that could explain observed phenotypes were identified in 18 patients (31.6%) overall and in 10 of 23 patients (43.5%) with comorbid intellectual developmental disorder (IDD). De novo variants in PTEN, CHD7, and HNRNPH2 were identified in patients referred for genetic counseling who exhibited previously reported phenotypes, including one patient with ASD who had profound IDD and macrocephaly with PTEN L320S. Analysis of the AlphaFold3 protein structure indicated potential inhibition of intramolecular interactions within PTEN. SV analysis identified deletions in ARHGAP11B and TMLHE. A pathogenic de novo mitochondrial variant was identified in a patient with ASD who had a history of encephalitis and cognitive decline. GO enrichment analysis of genes with nonsense variants and missense variants (Missense badness, PolyPhen-2, and Constraint >1) showed associations with regulation of growth and ATP-dependent chromatin remodeler activity. No reportable results were obtained in the analysis of STR and PRS. CONCLUSION: Characterizing the comprehensive genetic architecture and phenotypes of ASD is a fundamental step towards unraveling its complex biology.

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8. Herrero-Martín J, Fonseca D, Caro-Via S, Canaleta X. Development of personalized profiles of students with autism spectrum disorder for interactive interventions with robots to enhance language and social skills. Front Psychiatry. 2024; 15: 1455627.

The inclusion of students with autism spectrum disorder (ASD) in mainstream education (primary and secondary, in the range of 4-5 to 8-10 years old) is a complex task that has long challenged both educators and health professionals. However, the correct use of digital technologies such as personalization settings and interaction with robots has clearly shown how these new technologies can benefit ASD students. However, it is essential to characterize the profile, problems, and needs of each student, since it is not possible to generalize an accessible approach for all users. The work presented shows the creation and validation, through pilot tests, of an instrument that outlines the main needs of a student with ASD, based on behavioral variables. In a later phase, instructional sequences will be designed and adapted through digital tablets and interaction with a robot to improve specific aspects identified in the initial profile. The results demonstrate the method’s ability to assess and prioritize profiles satisfactorily which helps create a design adjusted to each student. The first pilot tests have been well received by ASD students, who have shown increased interest in the contents and methods used in this approach. Motivation levels and engagement have also increased, and social interactions with their peers have improved.

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9. Hilal ML, Rosina E, Pedini G, Restivo L, Bagni C. Dysregulation of the mTOR-FMRP pathway and synaptic plasticity in an environmental model of ASD. Mol Psychiatry. 2024.

Autism Spectrum Disorder (ASD) is caused by genetic, epigenetic, and environmental factors. Mutations in the human FMR1 gene, encoding the Fragile X Messenger Ribonucleoprotein 1 (FMRP), cause the most common monogenic form of ASD, the Fragile X Syndrome (FXS). This study explored the interaction between the FMR1 gene and a viral-like infection as an environmental insult, focusing on the impact on core autistic-like behaviors and the mGluR1/5-mTOR pathway. Pregnant heterozygous Fmr1 mouse females were exposed to maternal immune activation (MIA), by injecting the immunostimulant Poly (I:C) at the embryonic stage 12.5, simulating viral infections. Subsequently, ASD-like behaviors were analyzed in the adult offspring, at 8-10 weeks of age. MIA exposure in wild-type mice led to ASD-like behaviors in the adult offspring. These effects were specifically confined to the intrauterine infection, as immune activation at later stages, namely puberty (Pubertal Immune Activation, PIA) at post-natal day 35 or adulthood (Adult Immune Activation, AIA) at post-natal day 56, did not alter adult behavior. Importantly, combining the Fmr1 mutation with MIA exposure did not intensify core autistic-like behaviors, suggesting an occlusion effect. Mechanistically, MIA provided a strong activation of the mGluR1/5-mTOR pathway, leading to increased LTP and downregulation of FMRP specifically in the hippocampus. Finally, FMRP modulates mTOR activity via TSC2. These findings further strengthen the key role of the mGluR1/5-mTOR pathway in causing ASD-like core symptoms.

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10. Kadekaru R, Okanishi T, Maegaki Y, Inoue M. Effectiveness of Online Parent Training for Parents of Adolescents with Developmental Disabilities: A Retrospective Observational Study Comparing Clinical- and Community-Based Online Parent Training. Yonago Acta Med. 2024; 67(4): 341-54.

BACKGROUND: Parent training (PT) is an effective program for improving the parenting skills and mental health of parents of children with developmental disabilities (DD) and for improving children’s behavioral problems. However, studies must substantiate the effectiveness of PT for the parents of adolescents with DD in improving parental mental health and children’s problem behaviors with ample scientific evidence. This study is a retrospective observational study and has two objectives. The first is to examine the effectiveness of online adolescent PT (ON-APT), in which lectures on counseling skills are incorporated for the parents of adolescents with DD. The second aim is to examine the effects of different delivery conditions on community- and clinical-based ON-APT. METHODS: Data from seven parents and children who participated in community-based ON-APT and 14 parents and 12 children who participated in clinical-based ON-APT were included in the analysis. Prior to the intervention (pre-test) and after the intervention (post-test), paired t-tests were conducted using the CBCL, BDI-II, and PATS scores to demonstrate the effectiveness of the ON-APT program. Second, a two-way repeated measures analysis of variance with aligned rank transform was conducted to assess the impact of varying ON-APT delivery conditions (clinical- versus community-based ON-APT) and time (pre- and post-tests) on the outcome variables. RESULTS: ON-APT resulted in significant improvements in some children’s problem behaviors (withdrawal). Community-based ON-APT resulted in improvements in some children’s problem behaviors (total score, withdrawal, and social problems scales) compared with clinical-based ON-APT. CONCLUSION: This study shows the potential effectiveness of ON-APT, in which lectures on counseling skills are incorporated for parents of adolescents with DD. Further, a comparison between clinical-based and community-based ON-APT showed that integrating face-to-face consultations into ON-APT may improve children’s problem behaviors. However, this study provides preliminary evidence for its potential efficacy, and future studies should demonstrate this efficacy through a validation design.

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11. Links PS, Aslam H, O’Donnell M. Personality Disorders and Clinical Disorders: The Challenge of Comorbid Autism Spectrum Disorder (ASD), Eating Disorders (EDs), Posttraumatic Stress Disorder (PTSD), or Somatic Symptom Disorder (SSD). Curr Psychiatry Rep. 2024.

PURPOSE OF THE REVIEW: The purpose of this review is to report on prevalence of co-occurrence, possible etiologic mechanisms, and course and treatment implications of each of these challenging clinical disorders (Autism Spectrum Disorder, Eating Disorders, Posttraumatic Stress Disorder) comorbid with Personality Disorders. RECENT FINDINGS: These comorbidities often increase the symptom severity, worsen the course and outcome, and increase the risk of self-harm and suicidal behavior. For EDs and PTSD, existing therapies may prove somewhat helpful but novel approaches are needed and under investigation in the context of comorbid PDs and ASD, EDs and PTSD to address common underlying diatheses. Treatments for these comorbid disorders need to incorporate interventions addressing suicide risk, emotion dysregulation, be trauma-informed and attend to patient engagement. Future research should prioritize studying the course and outcome of ASD comorbid with PDs, novel therapies for EDs comorbid with PDs; refining the concept of Complex PTSD and commencing study of SSD comorbid with PDs.

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12. Mørdre M, Ørbeck B, Hoel RE, Øvergaard KR. Food selectivity in children and adolescents with autism spectrum disorders – a systematic literature review. Tidsskr Nor Laegeforen. 2024; 144(14).

BACKGROUND: Autism spectrum disorders involve problems with social communication and interaction as well as restricted, repetitive patterns of behaviour and interests. Food selectivity is common among individuals with autism spectrum disorders when their average intellectual ability is below the normal range. This literature review examines the degree to which the same applies for children and adolescents with an intellectual ability level in the normal range. KNOWLEDGE BASE: We undertook searches in the MEDLINE and PsycInfo (Ovid) databases until June 2024 for original papers on the prevalence, characteristics and somatic consequences of food selectivity in autism spectrum disorders. We restricted our searches to studies that included individuals with an intellectual ability in the normal range and/or an autism spectrum disorder for which this is a prerequisite, and with an average age of 6-18 years. The GRADE system was used to rate the quality of the studies. We gave emphasis to consistency between findings, the number of studies and their sizes. RESULTS: The inclusion criteria were met by 20 studies. There was a high prevalence (21-76 %) of food selectivity in those with autism spectrum disorders and an intellectual ability level in the normal range. Sensory sensitivity to food texture and taste were key characteristics (approximately 2-10 times more frequent in children with autism spectrum disorders than in control individuals). While the intellectual ability level was of little importance, autism symptoms were of some significance in respect of the prevalence of food selectivity patterns. The somatic consequences tended to be obstipation and overweight/obesity. Our level of confidence in the studies varied from high (prevalence) to low (somatic consequences). INTERPRETATION: Food selectivity patterns should be surveyed whenever individuals are examined for autism spectrum disorders, irrespective of their intellectual ability level.

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13. Mossa A, Dierdorff L, Lukin J, Park Y, Fiorenzani C, Akpinar Z, Garcia-Forn M, De Rubeis S. Sex-specific perturbations of neuronal development caused by mutations in the autism risk gene DDX3X. bioRxiv. 2024.

DDX3X is an X-linked RNA helicases that escapes X chromosome inactivation and is expressed at higher levels in female brains. Mutations in DDX3X are associated with intellectual disability (ID) and autism spectrum disorder (ASD) and are predominantly identified in females. Using cellular and mouse models, we show that Ddx3x mediates sexual dimorphisms in brain development at a molecular, cellular, and behavioral level. During cortical neuronal development, Ddx3x sustains a female-biased signature of enhanced ribosomal biogenesis and mRNA translation. Female neurons display higher levels of ribosomal proteins and larger nucleoli, and these sex dimorphisms are obliterated by Ddx3x loss. Ddx3x regulates dendritic outgrowth in a sex- and dose-dependent manner in both female and male neurons, and dendritic spine development only in female neurons. Further, ablating Ddx3x conditionally in forebrain neurons is sufficient to yield sex-specific changes in developmental outcomes and motor function. Together, these findings pose Ddx3x as a mediator of sexual differentiation during neurodevelopment and open new avenues to understand sex differences in health and disease.

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14. Namgung JY, Mun J, Park Y, Kim J, Park BY. Sex differences in autism spectrum disorder using class imbalance adjusted functional connectivity. Neuroimage. 2024: 120956.

Autism spectrum disorder (ASD) is an atypical neurodevelopmental condition with a diagnostic ratio largely differing between male and female participants. Due to the sex imbalance in participants with ASD, we lack an understanding of the differences in connectome organization of the brain between male and female participants with ASD. In this study, we matched the sex ratio using a Gaussian mixture model-based oversampling technique and investigated the differences in functional connectivity between male and female participants with ASD using low-dimensional principal gradients. Between-group comparisons of the gradient values revealed significant interaction effects of sex in the sensorimotor, attention, and default mode networks. The sex-related differences in the gradients were highly associated with higher-order cognitive control processes. Transcriptomic association analysis provided potential biological underpinnings, specifying gene enrichment in the cortex, thalamus, and striatum during development. Finally, the principal gradients were differentially associated with symptom severity of ASD between sexes, highlighting significant effects in female participants with ASD. Our work proposed an oversampling method to mitigate sex imbalance in ASD and observed significant sex-related differences in functional connectome organization. The findings may advance our knowledge about the sex heterogeneity in large-scale brain networks in ASD.

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15. Ng-Cordell E, Pickard H, Bedford R, Richard A, Zaidman-Zait A, Zwaigenbaum L, Duku E, Bennett T, Georgiades S, Smith IM, Vaillancourt T, Szatmari P, Elsabbagh M, Kerns CM. Longitudinal associations between autistic children’s anxiety and social communication differences: The moderating role of executive function behaviours. Autism. 2024: 13623613241296589.

Anxiety is a mental health concern affecting many autistic children, and has been linked to greater differences in social communication and interaction style. Executive functioning (i.e. the ability to direct and regulate attention and behaviour) plays an important role in autistic children’s and social-emotional development. We tested whether anxiety (reported by parents) predicts social communication and interaction differences (reported by teachers) over time or vice versa among autistic preadolescents. We also investigated whether the link between anxiety and social communication and interaction differed depending on children’s EF abilities (reported by teachers). We found less parent-reported anxiety predicted more teacher-reported social communication and interaction differences a year later – but only for children who had heightened behavioural dysregulation (an aspect of executive functioning that includes impulse and emotion control). Our work suggests autistic preadolescents with behavioural dysregulation and limited anxiety may be at greater risk for social difficulties, and may need more support in this area. Executive functioning may be a useful mechanism to target in treatment for this group of children.

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16. Sherawat K, Mehan S, Khan Z, Tiwari A, Gupta GD, Narula AS. Neuroprotective Potential of Tanshinone-IIA in Mitigating Propionic Acidinduced Experimental Autism-like Behavioral and Neurochemical Alterations: Insights into c-JNK and p38MAPK Pathways. Curr Mol Pharmacol. 2024.

INTRODUCTION: Autism is a neurodevelopmental disorder associated with mitochondrial dysfunction, apoptosis, and neuroinflammation. These factors can lead to the overactivation of c-JNK and p38MAPK. METHODS: In rats, stereotactic intracerebroventricular (ICV) injection of propionic acid (PPA) results in autistic-like characteristics such as poor social interaction, repetitive behaviours, and restricted communication. Research has demonstrated the beneficial effects of phytochemicals derived from plants in treating neurological disorders. Tanshinone-IIA (Tan-IIA) is a chemical found in the root of Salvia miltiorrhiza. It has neuroprotective potential by inhibiting c-JNK and p38MAPK against behavioral and neurochemical alterations in PPA-induced autistic rats. We observe behavioral changes, alterations in apoptotic markers, myelin basic protein (MBP), neurofilament-Light (NEFL), inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and neurotransmitter imbalances using different brain regions (cerebral cortex, hippocampus, striatum), as well as biological samples, cerebrospinal fluid (CSF), and blood plasma. RESULTS: Persistent administration of 30 mg/kg and 60 mg/kg Tan-IIA via intraperitoneal injection reduced these alterations dose-dependently. Anisomycin (3 mg/kg.,i.p.) as a SAPK (c-JNK and p38MAPK) agonist was administered to assess the neuroprotective effect of Tan-IIA in autistic rats. Tan- IIA’s molecular interactions with c-JNK and p38MAPK were confirmed using silico analysis. We also observed gross morphological, histopathological, and Luxol Fast Blue (LFB) myelin straining changes in whole and coronal brain sections. CONCLUSION: Thus, Tan-IIA has a neuroprotective potential by inhibiting the c-JNK and p38MAPK signalling pathways, which reduces the behavioral and neurochemical abnormalities induced by PPA in adult Wistar rats, indicating that current results should be studied further for the diagnosis and treatment of autism.

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17. Sollis LJ, Wall DP, Washington PY. Evaluating Multicultural Autism Screening for Toddlers Using Machine Learning on the QCHAT-10. medRxiv. 2024.

Early identification and intervention often leads to improved life outcomes for individuals with Autism Spectrum Disorder (ASD). However, traditional diagnostic methods are time-consuming, frequently delaying treatment. This study examines the application of machine learning (ML) techniques to 10-question Quantitative Checklist for Autism in Toddlers (QCHAT-10) datasets, aiming to evaluate the predictive value of questionnaire features and overall accuracy metrics across different cultures. We trained models using three distinct datasets from three different countries: Poland, New Zealand, and Saudi Arabia. The New Zealand and Saudi Arabian-trained models were both tested on the Polish dataset, which consisted of diagnostic class labels derived from clinical diagnostic processes. The Decision Tree, Random Forest, and XGBoost models were evaluated, with XGBoost consistently performing best. Feature importance rankings revealed little consistency across models; however, Recursive Feature Elimination (RFE) to select the models with the four most predictive features retained three common features. Both models performed similarly on the Polish test dataset with clinical diagnostic labels, with the New Zealand models with all 13 features achieving an AUROC of 0.94 ± 0.06, and the Saudi Model having an AUROC of 93% ± 6. This compared favorably to the cross-validation analysis of a Polish-trained model, which had an AUROC of 94% ± 5, suggesting that answers to the QCHAT-10 can be predictive of an official autism diagnosis, even across cultures. The New Zealand model with four features had an AUROC of 85% ± 13, and the Saudi model had a similar result of 87% ± 11. These results were somewhat lower than the Polish cross-validation AUROC of 91% ± 5. Adjusting probability thresholds improved sensitivity in some models, which is crucial for screening tools. However, this threshold adjustment often resulted in low levels of specificity during the final testing phase. Our findings suggest that these screening tools may generalize well across cultures; however, more research is needed regarding differences in feature importance for different populations.

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18. Song Y, Zhang X, Wang B, Luo X, Zhang K, Zhang X, Wu Q, Sun M. BPAP induces autism-like behavior by affecting the expression of neurodevelopmental genes in Drosophila melanogaster. Ecotoxicol Environ Saf. 2024; 288: 117405.

Bisphenol AP (BPAP), an environmental endocrine disruptor, may cause neurodevelopmental disorders affecting human health. Studies have shown that BPAP impacts hormone synthesis and metabolism, causes social behavior abnormalities, and induces anxiety-like behavioral impairments in mice. However, evidence for the neurobehavioral effects of BPAP is still lacking. Here, we examined the toxic effects of BPAP on neurodevelopment using a Drosophila model. We assessed the role of BPAP exposure in autism-like behavior and explored the underlying mechanisms. Our findings indicated that BPAP exposure reduced pupation and eclosion rates and delayed growth in Drosophila. Furthermore, BPAP exposure caused autism-like behaviors, characterized by increased grooming times and aberrant social interactions, along with abnormalities in locomotor activity, as well as learning and memory ability. Mechanistically, we found that BPAP decreases the number of neuroblasts (NBs) and mature intermediate neural progenitors (INPs) in the 3rd larval brain, impairing axon guidance in the mushroom body of the adult Drosophila brain. Additionally, our transcriptome analysis revealed that BPAP exposure alters the expression of neurodevelopment-related genes (Nplp3, sand, lush, and orco) and affects the estrogen signaling pathway (Hsp70Ab, Hsp70Bc, Hsp70Ba, and Hsp70Bb). These changes potentially explain the BPAP-induced autism-like behavior in Drosophila.

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19. Teter OM, McQuade A, Hagan V, Liang W, Dräger NM, Sattler SM, Holmes BB, Castillo VC, Papakis V, Leng K, Boggess S, Nowakowski TJ, Wells J, Kampmann M. CRISPRi-based screen of Autism Spectrum Disorder risk genes in microglia uncovers roles of ADNP in microglia endocytosis and synaptic pruning. bioRxiv. 2024.

Autism Spectrum Disorders (ASD) are a set of neurodevelopmental disorders with complex biology. The identification of ASD risk genes from exome-wide association studies and de novo variation analyses has enabled mechanistic investigations into how ASD-risk genes alter development. Most functional genomics studies have focused on the role of these genes in neurons and neural progenitor cells. However, roles for ASD risk genes in other cell types are largely uncharacterized. There is evidence from postmortem tissue that microglia, the resident immune cells of the brain, appear activated in ASD. Here, we used CRISPRi-based functional genomics to systematically assess the impact of ASD risk gene knockdown on microglia activation and phagocytosis. We developed an iPSC-derived microglia-neuron coculture system and high-throughput flow cytometry readout for synaptic pruning to enable parallel CRISPRi-based screening of phagocytosis of beads, synaptosomes, and synaptic pruning. Our screen identified ADNP , a high-confidence ASD risk genes, as a modifier of microglial synaptic pruning. We found that microglia with ADNP loss have altered endocytic trafficking, remodeled proteomes, and increased motility in coculture.

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20. Thomas BR, Ludwig NN, Pelletier D, Bauer M, Hommer R, Smith-Hicks C, O’Connor JT. Cortical Vision Impairment (CVI)-informed assessment and treatment of challenging behavior in a child with SCN2A-related disorder. J Neurodev Disord. 2024; 16(1): 66.

This report presents results of parent-implemented behavioral treatments for a child with cortical visual impairment (CVI), intellectual disability (ID), epilepsy, and autism spectrum disorder (ASD) associated with a pathogenic variant in the SCN2A gene (i.e., SCN2A-Related Disorder). Treatment evaluations were informed by combined results of functional behavior assessment (FBA) and functional vision assessment (FVA) which yielded CVI-related accommodations. The treatment of escape-maintained challenging behavior involved the evaluation of behavioral prompting strategies in accordance with CVI-related accommodations, extinction (EXT), and differential reinforcement modifications. The treatment for behavior problems maintained by access to food (tangible-edible) included functional communication training (FCT), EXT, and schedule thinning with schedule-correlated visual signals. Overall, integrating child-specific CVI-related accommodations was essential for developing effective behavioral interventions for this child. FVAs are accessible and practical for uptake by behavior analysts in vision-informed assessment and treatment of challenging behavior.

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21. Wai-Yan Tang J, Cheuk-Fung Hau C, Tong WM, Watt RM, Yiu CKY, Kar-Man Shum K. Alterations of Oral Microbiota in Young Children with Autism: Unraveling Potential Biomarkers for Early Detection. J Dent. 2024: 105486.

OBJECTIVES: This study investigated the oral microbiota in young children with autism spectrum disorder (ASD) to determine possible alterations in microbial composition and identify potential biomarkers for early detection. METHODS: Dental plaque samples from 25 children with ASD (aged 3-6 years; M = 4.79, SD = 0.83) and 30 age- and sex-matched typically developing (TD) children were analyzed using 16S rRNA sequencing. RESULTS: The results showed lower bacterial diversity in children with ASD compared to controls, with distinct microbial compositions in the ASD and TD groups. Six discriminatory species (Microbacterium flavescens, Leptotrichia sp. HMT-212, Prevotella jejuni, Capnocytophaga leadbetteri, Leptotrichia sp. HMT-392, and Porphyromonas sp. HMT-278) were identified in the oral microbiota of ASD children, while five discriminatory species (Fusobacterium nucleatum subsp. polymorphum, Schaalia sp. HMT-180, Leptotrichia sp. HMT-498, Actinomyces gerencseriae, and Campylobacter concisus) were identified in TD controls. A model generated by random forest and leave-one-out cross-validation achieved an accuracy of 0.813. Receiver operating characteristic analysis yielded a sensitivity of 0.778, a specificity of 0.857, and an AUC (area under curve) of 0.937 (95% CI: 0.82 – 1.00) for differentiating children with and without ASD. CONCLUSION: The present study has unveiled significant disparities in the oral microbial composition between ASD and TD children. SIGNIFICANCE: These findings contribute to understanding the microbiome-brain connection in ASD and its implications for early detection and management. Further research is needed to validate these oral bacterial biomarkers and explore their mechanistic association with ASD pathophysiology.

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22. Wertheimer O, Hart Y. Autism spectrum disorder variation as a computational trade-off via dynamic range of neuronal population responses. Nat Neurosci. 2024.

Individuals diagnosed with autism spectrum disorder (ASD) show neural and behavioral characteristics differing from the neurotypical population. This may stem from a computational principle that relates inference and computational dynamics to the dynamic range of neuronal population responses, reflecting the signal levels for which the system is responsive. In the present study, we showed that an increased dynamic range (IDR), indicating a gradual response of a neuronal population to changes in input, accounts for neural and behavioral variations in individuals diagnosed with ASD across diverse tasks. We validated the model with data from finger-tapping synchronization, orientation reproduction and global motion coherence tasks. We suggested that increased heterogeneity in the half-activation point of individual neurons may be the biological mechanism underlying the IDR in ASD. Taken together, this model provides a proof of concept for a new computational principle that may account for ASD and generates new testable and distinct predictions regarding its behavioral, neural and biological foundations.

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23. Wieseler C, Chávez EM, Yellowitz JA. Ageism and Ableism in Individuals Aging with Intellectual and Developmental Disabilities. Dent Clin North Am. 2025; 69(1): 103-14.

Biomedical and structural factors impact oral health for people with intellectual and developmental disabilities (IDD). The onset of age prevalent chronic diseases and conditions can result in new cognitive or physical disabilities leaving individuals with IDD to contend with ageism as well as ableism and further exclusion from the oral health care systems. Environments and attitudes that inform how health care systems are built and maintained significantly impact quality of life and outcomes, more than the fact of being disabled or old. Understanding and easing the transitions that lay ahead of individuals aging with IDD will come from an inter-professional inclusive approach.

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24. Zhang Y, Yahia A, Sandin S, Åden U, Tammimies K. Prematurity and Genetic Liability for Autism Spectrum Disorder. medRxiv. 2024.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by diverse presentations and a strong genetic component. Environmental factors, such as prematurity, have also been linked to increased liability for ASD, though the interaction between genetic predisposition and prematurity remains unclear. This study aims to investigate the impact of genetic liability and preterm birth on ASD conditions. METHODS: We analyzed phenotype and genetic data from two large ASD cohorts, the Simons Foundation Powering Autism Research for Knowledge (SPARK) and Simons Simplex Collection (SSC), encompassing 78,559 individuals for phenotype analysis, 12,519 individuals with genome sequencing data, and 8,104 individuals with exome sequencing data. Statistical significance of differences in clinical measures were evaluated between individuals with different ASD and preterm status. We assessed the rare variants burden using generalized estimating equations (GEE) models and polygenic load using ASD-associated polygenic risk score (PRS). Furthermore, we developed a machine learning model to predict ASD in preterm children using phenotype and genetic features available at birth. RESULTS: Individuals with both preterm birth and ASD exhibit more severe phenotypic outcomes despite similar levels of genetic liability for ASD across the term and preterm groups. Notable, preterm ASD individuals showed an elevated rate of de novo variants identified in exome sequencing (GEE model with Poisson family, p-value = 0.005) in comparison to the non-ASD preterm group. Additionally, a GEE model showed that a higher ASD PRS, preterm birth, and male sex were positively associated with a higher predicted probability for ASD, reaching a probability close to 90%. Lastly, we developed a machine learning model using phenotype and genetic features available at birth with limited predictive power (AUROC = 0.65). CONCLUSIONS: Preterm birth may exacerbate the multimorbidity present in ASD, which was not due to the ASD genetic factors. However, increased genetic factors may elevate the likelihood of a preterm child being diagnosed with ASD. Additionally, a polygenic load of ASD-associated variants had an additive role with preterm birth in the predicted probability for ASD, especially for boys. We propose that incorporating genetic assessment into neonatal care could benefit early ASD identification and intervention for preterm infants.

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