1. Carpenter KLH, Davis NO, Spanos M, Sabatos-DeVito M, Aiello R, Compton SN, Franz L, Schechter JC, Summers J, Dawson G. Cognitive Disengagement Syndrome in Young Autistic Children, Children with ADHD, and Autistic Children with ADHD. J Clin Child Adolesc Psychol;2024 (Jun 20):1-12.

OBJECTIVE: Cognitive Disengagement Syndrome (CDS; previously called Sluggish Cognitive Tempo) refers to a constellation of cognitive and motor behaviors characterized by a predisposition toward mind wandering (cognitive subdomain) and slowed motor behavior (hypoactive). While there are a number of studies linking CDS traits to greater global impairment in children with attention-deficit/hyperactivity disorder (ADHD) and autistic children, there are few studies examining the prevalence and impact of CDS traits in autistic children with co-occurring ADHD (Autistic+ADHD). The current study explored CDS traits in autistic children with and without co-occurring ADHD, children with ADHD, and neurotypical children. METHODS: Participants were 196 children between 3- and 7-years-of-age comprising four groups: Neurotypical (N = 44), ADHD (N = 51), Autistic (N = 55), and Autistic+ADHD (N = 46). CDS traits, social and communication skills, repetitive behaviors, and sensory processing were all assessed via parent report. RESULTS: Children diagnosed with ADHD, autistic children, and Autistic+ADHD children exhibited similar levels of overall CDS traits. However, when explored separately, Autistic+ADHD children had higher cognitive CDS trait scores compared to children with ADHD alone. Both overall CDS traits and the cognitive subdomain were associated with greater social difficulties, particularly social withdrawal, higher levels of repetitive behaviors, and more sensory sensitivities, regardless of diagnosis. CONCLUSIONS: Findings suggest that CDS traits may be an additional factor directly impact functional outcomes in both autistic and ADHD children. As such, clinicians should be assessing CDS traits in addition to other clinical domains associated with ADHD and autism when developing intervention plans for young neurodiverse children.

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2. Dalton GD, Siecinski SK, Nikolova VD, Cofer GP, Hornburg KJ, Qi Y, Johnson GA, Jiang YH, Moy SS, Gregory SG. Transcriptome analysis identifies an ASD-Like phenotype in oligodendrocytes and microglia from C58/J amygdala that is dependent on sex and sociability. Behav Brain Funct;2024 (Jun 19);20(1):14.

BACKGROUND: Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication, restricted interests that can be accompanied by repetitive behavior, and disturbances in social behavior. This study investigated brain mechanisms that contribute to sociability deficits and sex differences in an ASD animal model. METHODS: Sociability was measured in C58/J and C57BL/6J mice using the 3-chamber social choice test. Bulk RNA-Seq and snRNA-Seq identified transcriptional changes in C58/J and C57BL/6J amygdala within which DMRseq was used to measure differentially methylated regions in amygdala. RESULTS: C58/J mice displayed divergent social strata in the 3-chamber test. Transcriptional and pathway signatures revealed immune-related biological processes differ between C58/J and C57BL/6J amygdala. Hypermethylated and hypomethylated genes were identified in C58/J versus C57BL/6J amygdala. snRNA-Seq data in C58/J amygdala identified differential transcriptional signatures within oligodendrocytes and microglia characterized by increased ASD risk gene expression and predicted impaired myelination that was dependent on sex and sociability. RNA velocity, gene regulatory network, and cell communication analysis showed diminished oligodendrocyte/microglia differentiation. Findings were verified using Bulk RNA-Seq and demonstrated oxytocin’s beneficial effects on myelin gene expression. LIMITATIONS: Our findings are significant. However, limitations can be noted. The cellular mechanisms linking reduced oligodendrocyte differentiation and reduced myelination to an ASD phenotype in C58/J mice need further investigation. Additional snRNA-Seq and spatial studies would determine if effects in oligodendrocytes/microglia are unique to amygdala or if this occurs in other brain regions. Oxytocin’s effects need further examination to understand its’ potential as an ASD therapeutic. CONCLUSIONS: Our work demonstrates the C58/J mouse model’s utility in evaluating the influence of sex and sociability on the transcriptome in concomitant brain regions involved in ASD. Our single-nucleus transcriptome analysis elucidates potential pathological roles of oligodendrocytes and microglia in ASD. This investigation provides details regarding regulatory features disrupted in these cell types, including transcriptional gene dysregulation, aberrant cell differentiation, altered gene regulatory networks, and changes to key pathways that promote microglia/oligodendrocyte differentiation. Our studies provide insight into interactions between genetic risk and epigenetic processes associated with divergent affiliative behavior and lack of positive sociability.

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3. Davis J. Individuals with autism are at a higher associated risk of developing cardiometabolic diseases. Evid Based Nurs;2024 (Jun 20);27(3):91.

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4. Gao RR, Si SW, Lin XX, Wang YZ, Wang N, Wang JY, Luo F. Differential relationships between autistic traits and anthropomorphic tendencies in adults and early adolescents. Front Psychol;2024;15:1281207.

Anthropomorphism, the attribution of human-like qualities (e.g., mental states) to nonhuman entities, is a universal but variable psychological experience. Adults with professionally diagnosed autism or high levels of subclinical autistic traits consistently show greater tendencies to anthropomorphize, which has been hypothesized to reflect 1) a compensatory mechanism for lack of social connectedness and 2) a persistence of childhood anthropomorphism into adulthood. Here, we directly tested these hypotheses in a general population sample consisting of both adults (N=685, 17-58 years old) and early adolescents (N=145, 12-14 years old) using the refined 9-item Anthropomorphism Questionnaire (AnthQ9), which measures both present and childhood anthropomorphic tendencies. We found that adults with heightened autistic traits reported increased present anthropomorphism (e.g., tend more to perceive computers as having minds), which held even after controlling for social connectedness. In contrast, adolescents with heightened autistic traits did not show increased present anthropomorphism, but rather reported reduced childhood anthropomorphism (e.g., less likely to perceive toys as having feelings) after controlling for social connectedness. We also found evidence that the present and childhood subscales of the AnthQ9 may tap into fundamentally different aspects of anthropomorphism. The results suggest that increased anthropomorphic tendencies in adults with heightened autistic traits cannot be explained solely by increased sociality motivation, but may be due to delayed development of anthropomorphism, although alternative possibilities of measurement problems cannot be ruled out. Implications for the measurement of anthropomorphism and its relation with theory of mind were also discussed.

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5. Guilbaud L, Carreras E, Garel C, Maiz N, Dhombres F, Deprest J, Jouannic JM. Proposal for standardized prenatal assessment of fetal open dysraphisms by the European reference network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies (ITHACA) and eUROGEN. Prenat Diagn;2024 (Jun 19)

Open dysraphisms, that is, myelomeningocele and myeloschisis, are rare diseases associated with a risk of severe disability, including lower limb motor and sensory deficiency, sphincter deficiency, and potential intellectual deficiency. Open dysraphism is diagnosed in Europe in 93.5% of cases. In case of suspicion of fetal open dysraphism, a detailed fetal morphologic assessment is required to confirm the diagnosis and exclude associated structural anomalies, as well as genetic assessment. In case of isolated fetal open dysraphism, assessment of prognosis is based on fetal imaging including the level of the lesion, the presence or not of a sac, the presence and nature of intra cranial anomalies, and the anatomical and functional evaluation of the lower extremities. Based on these biomarkers, a personalized prognosis as well as comprehensive information about prenatal management alternatives will allow parents to decide on further management options. Standardization of prenatal assessment is essential to compare outcomes with benchmark data and make assessment of surgical innovation possible. Herein, we propose a protocol for the standardized ultrasound assessment of fetuses with isolated open dysraphism.

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6. Hourani S, Pouladi MA. Oligodendroglia and myelin pathology in fragile X syndrome. J Neurochem;2024 (Jun 19)

Studies of the pathophysiology of fragile X syndrome (FXS) have predominantly focused on synaptic and neuronal disruptions in the disease. However, emerging studies highlight the consistency of white matter abnormalities in the disorder. Recent investigations using animal models of FXS have suggested a role for the fragile X translational regulator 1 protein (FMRP) in the development and function of oligodendrocytes, the myelinating cells of the central nervous system. These studies are starting to uncover FMRP’s involvement in the regulation of myelin-related genes, such as myelin basic protein, and its influence on the maturation and functionality of oligodendrocyte precursor cells and oligodendrocytes. Here, we consider evidence of white matter abnormalities in FXS, review our current understanding of FMRP’s role in oligodendrocyte development and function, and highlight gaps in our knowledge of the pathogenic mechanisms that may contribute to white matter abnormalities in FXS. Addressing these gaps may help identify new therapeutic strategies aimed at enhancing outcomes for individuals affected by FXS.

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7. Lecciso F, Narzisi A. Editorial: Psychometrics in Psychiatry 2022: Autism. Front Psychiatry;2024;15:1416556.

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8. Ltaief SM, Elsayed AK, Al-Shammari AR. Generation of nine induced pluripotent stem cell lines from six young children with autism spectrum disorder and three matched control subjects from the Qatari population. Stem Cell Res;2024 (Jun 11);79:103470.

Autism spectrum disorder (ASD) is a complex developmental disorder characterized by challenges with social interactions and restricted/repetitive behaviors. Here, we recruited nine Qatari children of Arab ethnicity (males, aged 2-4 years), including six ASD subjects (n = 3 mild-to-moderate ASD and n = 3 severe ASD) and three control subjects. We generated induced pluripotent stem cell (iPSC) lines from PBMC samples of these subjects using non-integrating Sendai viral vectors. These iPSC lines were fully characterized and exhibited pluripotency characteristics, normal karyotypes, and trilineage differentiation potential. These iPSC lines provide valuable cell models for understanding ASD pathophysiology and developing new therapeutics for ASD.

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9. Lu X, Ni P, Suarez-Meade P, Ma Y, Forrest EN, Wang G, Wang Y, Quiñones-Hinojosa A, Gerstein M, Jiang YH. Transcriptional determinism and stochasticity contribute to the complexity of autism-associated SHANK family genes. Cell Rep;2024 (Jun 18);43(7):114376.

Precision of transcription is critical because transcriptional dysregulation is disease causing. Traditional methods of transcriptional profiling are inadequate to elucidate the full spectrum of the transcriptome, particularly for longer and less abundant mRNAs. SHANK3 is one of the most common autism causative genes. Twenty-four Shank3-mutant animal lines have been developed for autism modeling. However, their preclinical validity has been questioned due to incomplete Shank3 transcript structure. We apply an integrative approach combining cDNA-capture and long-read sequencing to profile the SHANK3 transcriptome in humans and mice. We unexpectedly discover an extremely complex SHANK3 transcriptome. Specific SHANK3 transcripts are altered in Shank3-mutant mice and postmortem brain tissues from individuals with autism spectrum disorder. The enhanced SHANK3 transcriptome significantly improves the detection rate for potential deleterious variants from genomics studies of neuropsychiatric disorders. Our findings suggest that both deterministic and stochastic transcription of the genome is associated with SHANK family genes.

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10. Parr J, Wigham S, Farr W, Male I, Isard L, Lees R, Reddy V, Saunders G, Grahame V. A national research survey of childhood autism assessment services in the UK: empirical evidence of diagnostic practice, challenges and improvement opportunities. BMJ Paediatr Open;2024 (Jun 18);8(1)

BACKGROUND: The UK National Health Service (NHS) Long Term Plan aims to reduce waiting times for childhood autism diagnostic assessment and improve parent and child satisfaction. This empirical research investigated current childhood diagnostic practice provision, and changes made by teams to address challenges faced. METHODS: Data were collected using an online semi-structured research questionnaire. UK childhood autism diagnostic assessment services (for children aged 1-18 years) were invited to participate through multidisciplinary clinical networks, special interest groups and professionals mailing lists. The study was on the National Institute for Health Research Clinical Research Network portfolio. RESULTS: 128 clinicians from diverse NHS services responded including: 10 (8%) integrated services, 46 (36%) Child and Adolescent Mental Health Services (CAMHS) and 72 (56%) paediatric services. A minority of services (23, 17.9%) reported always meeting the National Institute for Health and Care Excellence guidance for assessment. Referrals rose 115% between 2015 and 2019. Clinicians described increased child and family complexity compared with previously; children had more co-occurring physical, mental health and neurodevelopmental conditions and there were more frequent family health problems and safeguarding concerns. Most services (97, 75.8%) reported recent funding stayed constant/decreased. Incomplete multidisciplinary teams (MDTs) were frequently reported; a minority of services reported increased availability of professionals, and some experienced reductions in key professionals. Many teams were unable to undertake assessments or make recommendations for associated neurodevelopmental and co-existing conditions. Teams described improvement strategies implemented (eg, adapting professionals’ roles, supporting parents). CONCLUSIONS: Most UK autism paediatric and CAMHS diagnostic teams experience significant challenges affecting the assessment of children with possible autism, and recommendations regarding treatment/intervention. Where CAMHS or paediatric services work in isolation, there are often competency gaps in MDTs and ability to deliver full neurodevelopmental and mental health assessments. Teams identified service improvement strategies; however, investment in MDT expertise is required to enable services to implement changes to meet the needs of children and families.

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11. Russell-Giller S, Allen EG, Hunter JE, Shubeck L, Hinton VJ. Intrasubject variability of sustained attention is associated with elevated self-reported attention deficits in women with a fragile X premutation allele. Neuropsychology;2024 (Jun 20)

OBJECTIVE: Women with a fragile X premutation (PM) self-report higher rates of attention difficulties than women without a PM; however, results of studies using objective measures of attention are inconsistent. The present study assessed whether intrasubject variability during a sustained attention task better predicted functional outcomes in women with a PM than the previously published standard reaction time and accuracy variables. METHOD: We analyzed continuous performance test, a computerized measure of sustained attention, and the Conners’ Adult Attention-Deficit/Hyperactivity Disorder Rating Scale Report (CAARS) data from 273 women with a PM and 175 women without a PM aged 18-50 years. Separate analyses using Pearson correlations and independent t tests were performed on the full range of coefficient of variation (CV) of reaction time scores and the subset of scores that showed higher variability. RESULTS: Performance variability of sustained attention measured by the continuous performance test was associated with functional outcomes measured by the CAARS in women with a PM but not women without a PM. Specifically, the CV in those with higher variability was correlated with two CAARS subscale scores (p = .006). Independent t tests showed significant differences in CV between CAARS scores dichotomized for the presence of subclinical symptoms for two subscales (p ≤ .001-.007). Correlation between the full range of CV scores and the CAARS Inattention/Memory Problems subscale approached significance (p = .012). CONCLUSIONS: Findings highlight the importance of including intrasubject variability in analyzing attention in clinical populations as a more sensitive objective measure associated with reported symptoms and to assist in predicting functional outcomes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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12. Schiano N, Sivori T, Dumont R, Weaver M, Shehadeh A, Ridgway E, Schaaf R. Ayres Sensory Integration® Intervention for Autistic Children: A Telehealth Adaptation. Am J Occup Ther;2024 (Jul 1);78(4)

IMPORTANCE: Ayres Sensory Integration® is an evidence-based, manualized occupational therapy intervention for autism that is delivered in person. A telehealth adaptation could bridge service gaps for families who may have challenges accessing services. OBJECTIVE: To create a telehealth adaptation of the evidence-based manualized protocol of Ayres Sensory Integration using best practice for telehealth guidelines and to obtain input on the adaptation from experts. SETTING: Online survey of U.S. telehealth experts and occupational therapy clinicians in fall and winter 2022. PARTICIPANTS: Two telehealth experts and six occupational therapy clinicians. OUTCOMES AND MEASURES: Two Qualtrics surveys focused on perceived feasibility and acceptability, resources included, and clarity of instructions. RESULTS: Telehealth experts and occupational therapy clinicians rated the Ayres Sensory Integration telehealth adapted manual as easy to follow, aligned with telehealth best practices, and feasible for remote delivery. Suggestions for additional adaptations included adding resources for technology troubleshooting, intervention planning, rapport building, and continuing education. CONCLUSIONS AND RELEVANCE: Suggested adaptations were made; the manual is ready for feasibility testing. Plain-Language Summary: This report is the first to describe a telehealth adaptation of Ayres Sensory Integration®. The manual provides comprehensive training and resources to support clinicians in delivering sensory integration, telehealth-based interventions to autistic children. Two telehealth experts and six occupational therapy clinicians rated the Ayres Sensory Integration telehealth adapted manual as easy to follow, aligned with telehealth best practices, and feasible for remote delivery. The manual will be available to clinicians after feasibility and pilot testing.

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13. Yang C, Xiao H, Zhu H, Du Y, Wang L. Revealing the gut microbiome mystery: A meta-analysis revealing differences between individuals with autism spectrum disorder and neurotypical children. Biosci Trends;2024 (Jun 18)

The brain-gut axis intricately links gut microbiota (GM) dysbiosis to the development or worsening of autism spectrum disorder (ASD). However, the precise GM composition in ASD and the effectiveness of probiotics are unclear. To address this, we performed a thorough meta-analysis of 28 studies spanning PubMed, PsycINFO, Web of Science, Scopus, and MEDLINE, involving 1,256 children with ASD and 1042 neurotypical children, up to February 2024. Using Revman 5.3, we analyzed the relative abundance of 8 phyla and 64 genera. While individuals with ASD did not exhibit significant differences in included phyla, they exhibited elevated levels of Parabacteroides, Anaerostipes, Faecalibacterium, Clostridium, Dorea, Phascolarctobacterium, Lachnoclostridium, Catenibacterium, and Collinsella along with reduced percentages of Barnesiella, Odoribacter, Paraprevotella, Blautia, Turicibacter, Lachnospira, Pseudomonas, Parasutterella, Haemophilus, and Bifidobacterium. Notably, discrepancies in Faecalibacterium, Clostridium, Dorea, Phascolarctobacterium, Catenibacterium, Odoribacter, and Bifidobacterium persisted even upon systematic exclusion of individual studies. Consequently, the GM of individuals with ASD demonstrates an imbalance, with potential increases or decreases in both beneficial and harmful bacteria. Therefore, personalized probiotic interventions tailored to ASD specifics are imperative, rather than a one-size-fits-all approach.

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14. Zhang S, Yang J, Ji D, Meng X, Zhu C, Zheng G, Glessner J, Qu HQ, Cui Y, Liu Y, Wang W, Li X, Zhang H, Xiu Z, Sun Y, Sun L, Li J, Hakonarson H, Li J, Xia Q. NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways. J Med Genet;2024 (Jun 20);61(7):677-688.

BACKGROUND: Epigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic genes involved in ASD aetiology. METHODS: Trio-based whole exome sequencing was conducted on ASD families. Genome editing technique was used to knock out the candidate causal gene in a relevant cell line. ATAC-seq, ChIP-seq and RNA-seq were performed to investigate the functional impact of knockout (KO) or mutation in the candidate gene. RESULTS: We identified a novel candidate gene NASP (nuclear autoantigenic sperm protein) for epigenetic dysregulation in ASD in a Chinese nuclear family including one proband with autism and comorbid atopic disease. The de novo likely gene disruptive variant tNASP(Q289X) subjects the expression of tNASP to nonsense-mediated decay. tNASP KO increases chromatin accessibility, promotes the active promoter state of genes enriched in synaptic signalling and leads to upregulated expression of genes in the neural signalling and immune signalling pathways. Compared with wild-type tNASP, tNASP(Q289X) enhances chromatin accessibility of the genes with enriched expression in the brain. RNA-seq revealed that genes involved in neural and immune signalling are affected by the tNASP mutation, consistent with the phenotypic impact and molecular effects of nasp-1 mutations in Caenorhabditis elegans. Two additional patients with ASD were found carrying deletion or deleterious mutation in the NASP gene. CONCLUSION: We identified novel epigenetic mechanisms mediated by tNASP which may contribute to the pathogenesis of ASD and its immune comorbidity.

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