1. Cengiz K, Rekik I. Cortical morphological networks for profiling autism spectrum disorder using tensor component analysis. Front Neurol;2024;15:1391950.

Atypical neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) can alter the cortex morphology at different levels: (i) a low-order level where cortical regions are examined individually, (ii) a high-order level where the relationship between two cortical regions is considered, and (iii) a multi-view high-order level where the relationship between regions is examined across multiple brain views. In this study, we propose to use the emerging multi-view cortical morphological network (CMN), which is derived from T1-w magnetic resonance imaging (MRI), to profile autistic and typical brains and pursue new ways of fingerprinting ‘cortical morphology’ at the intersection of ‘network neuroscience’. Each CMN view models the pairwise morphological dissimilarity at the connection level using a specific cortical attribute (e.g., thickness). Specifically, we set out to identify the inherently most representative morphological connectivities shared across different views of the cortex in both autistic and normal control (NC) populations using tensor component analysis. We thus discover the connectional profiles of both populations shared across different CMNs of the left and right hemispheres, respectively. One of the most representative morphological cortical attributes for assessing the abnormal brain structures in patients with ASD is cortical thickness. The most representative morphological connectivities in multi-view CMN population of normal control and ASD subjects, respectively, and in both left and right hemispheres within the temporal, frontal, and insular lobes of individuals with ASD. These representative connectivities are corresponded to specific clinical features observed in individuals with ASD.

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2. Centeno-Pla M, Alcaide-Consuegra E, Gibson S, Prat-Planas A, Gutiérrez-Ávila JD, Grinberg D, Urreizti R, Rabionet R, Balcells S. Subcellular localisation of truncated MAGEL2 proteins: insight into the molecular pathology of Schaaf-Yang syndrome. J Med Genet;2024 (Jul 19);61(8):780-782.

Schaaf-Yang syndrome (SYS) is an ultra-rare neurodevelopmental disorder caused by truncating mutations in MAGEL2 Heterologous expression of wild-type (WT) or a truncated (p.Gln638*) C-terminal HA-tagged MAGEL2 revealed a shift from a primarily cytoplasmic to a more nuclear localisation for the truncated protein variant. We now extend this analysis to six additional SYS mutations on a N-terminal FLAG-tagged MAGEL2. Our results replicate and extend our previous findings, showing that all the truncated MAGEL2 proteins consistently display a predominant nuclear localisation, irrespective of the C-terminal or N-terminal position and the chemistry of the tag. The variants associated with arthrogryposis multiplex congenita display a more pronounced nuclear retention phenotype, suggesting a correlation between clinical severity and the degree of nuclear mislocalisation. These results point to a neomorphic effect of truncated MAGEL2, which might contribute to the pathogenesis of SYS.

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3. Chen S, Zhang Y, Zhou F, Chan A, Li B, Li B, Tang T, Chun E, Chen Z. Focus-marking in a tonal language: Prosodic differences between Cantonese-speaking children with and without autism spectrum disorder. PLoS One;2024;19(7):e0306272.

Abnormal speech prosody has been widely reported in individuals with autism. Many studies on children and adults with autism spectrum disorder speaking a non-tonal language showed deficits in using prosodic cues to mark focus. However, focus marking by autistic children speaking a tonal language is rarely examined. Cantonese-speaking children may face additional difficulties because tonal languages require them to use prosodic cues to achieve multiple functions simultaneously such as lexical contrasting and focus marking. This study bridges this research gap by acoustically evaluating the use of Cantonese speech prosody to mark information structure by Cantonese-speaking children with and without autism spectrum disorder. We designed speech production tasks to elicit natural broad and narrow focus production among these children in sentences with different tone combinations. Acoustic correlates of prosodic focus marking like f0, duration and intensity of each syllable were analyzed to examine the effect of participant group, focus condition and lexical tones. Our results showed differences in focus marking patterns between Cantonese-speaking children with and without autism spectrum disorder. The autistic children not only showed insufficient on-focus expansion in terms of f0 range and duration when marking focus, but also produced less distinctive tone shapes in general. There was no evidence that the prosodic complexity (i.e. sentences with single tones or combinations of tones) significantly affected focus marking in these autistic children and their typically-developing (TD) peers.

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4. Craddock E. Being a Woman Is 100% Significant to My Experiences of Attention Deficit Hyperactivity Disorder and Autism: Exploring the Gendered Implications of an Adulthood Combined Autism and Attention Deficit Hyperactivity Disorder Diagnosis. Qual Health Res;2024 (Jul 18):10497323241253412.

This article provides original insight into women’s experiences of adulthood diagnoses of attention deficit hyperactivity disorder (ADHD) and autism. Research exploring experiences of adulthood diagnoses of these conditions is emerging. Yet, there is no research about the gendered experiences of an adulthood combined ADHD and autism (AuDHD) diagnosis. This article addresses this gap through interpretative phenomenological analysis of email interviews with six late-diagnosed AuDHD women revealing the complex interplay between late diagnosis, being a woman, and combined diagnoses of ADHD and autism. It underscores how gender norms and stereotypes contribute to the oversight and dismissal of women’s neurodivergence. Interpretative phenomenological analysis reveals the inextricability of femininity and neurotypicality, the gendered burden, discomfort, and adverse consequences of masking, along with the adverse outcomes of insufficient masking. Being an undiagnosed AuDHD woman is a confusing and traumatising experience with profound and enduring repercussions. The impact of female hormones exacerbated participants’ struggles with (peri)menopause often being a catalyst for seeking diagnosis after decades of trauma. The epistemic injustice of not knowing they were neurodivergent compounded this trauma. Diagnosis enabled participants to overcome epistemic injustice and moved them into a feminist standpoint from which they challenge gendered inequalities relating to neurodiversity. This article aims to increase understanding and representation of late-diagnosed AuDHD women’s lived experiences. The findings advocate for trauma-informed pre- and post-diagnosis support which addresses the gendered dimension of women’s experiences of being missed and dismissed as neurodivergent. There needs to be better clinical and public understanding of how AuDHD presents in women to prevent epistemic injustice.

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5. Crasta JE, Martis J, Kromalic M, Jarrott S, Wengerd L, Darragh A. Characterizing Occupational Therapy Intervention for Children on the Autism Spectrum. Am J Occup Ther;2024 (Sep 1);78(5)

IMPORTANCE: Occupational therapy is one of the most used interventions for children on the autism spectrum. There is a critical need to develop an operationalized list of key treatment components of usual-care occupational therapy practice for children on the autism spectrum. OBJECTIVE: To identify and develop consensus on definitions and examples of key treatment components of usual-care occupational therapy for children on the autism spectrum, ages 6 to 13 yr. DESIGN: We conducted a Delphi study to obtain feedback from a panel of experts. SETTING: Electronic survey. PARTICIPANTS: 17 occupational therapy panelists with expertise in autism intervention. OUTCOMES AND MEASURES: Panelists rated the definition and example of each treatment component and provided feedback through multiple rounds of survey. RESULTS: On the basis of the panelists’ feedback on Delphi Round 1, the criteria rating form was revised to include four questions for the definition and example of each treatment component. Through four Delphi rounds of consensus building, we developed an operationalized list of 20 treatment components with definitions and examples that incorporated elements of usual-care occupational therapy intervention for children on the autism spectrum. CONCLUSIONS AND RELEVANCE: This operationalized list of treatment components serves as a foundational framework to improve education, practice, and research of occupational therapy intervention for children on the autism spectrum. Plain-Language Summary: This study identified and developed consensus on definitions and examples of key treatment components used in usual-care outpatient occupational therapy for children on the autism spectrum. Through four rounds of consensus building with 17 occupational therapy experts in autism, we identified 20 key treatment components central to occupational therapy practice. Our results have the potential to serve as a framework to improve education, practice, and clinical research in autism.

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6. Diehl E, O’Neill M, Gray L, Schwaede A, Kuntz N, Rao VK. Prevalence of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Individuals With Dystrophinopathy at a Tertiary Care Center in Chicago. Pediatr Neurol;2024 (May 19);158:94-99.

OBJECTIVE: To study the prevalence of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in individuals with dystrophinopathy compared with the general population. METHODS: Retrospective chart review to examine the prevalence of ADHD and ASD, diagnosed both formally and informally, in individuals with dystrophinopathy receiving care in the multidisciplinary neuromuscular clinic at the Ann and Robert H. Lurie Children’s Hospital of Chicago. RESULTS: Our results demonstrate an ADHD prevalence of 18.40% and ASD prevalence of 12.73%, both significantly higher than those reported for the general population. Our results revealed a significant association between ADHD diagnosis and a positive family history but did not show a statistically significant association between prevalence of ADHD and the use of steroids. CONCLUSION: Based on our current study results, we plan to further evaluate the prevalence, in a prospective cross-sectional manner, using validated screens for both ADHD and ASD.

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7. Hu C, Yang T, Chen J, Dai Y, Wei H, Wu Q, Chen H, Long D, Feng Y, Wei Q, Zhang Q, Chen L, Li T. Phenotypic characteristics and rehabilitation effect of children with regressive autism spectrum disorder: a prospective cohort study. BMC Psychiatry;2024 (Jul 19);24(1):514.

BACKGROUND: In this prospective cohort study, we determined the phenotypic characteristics of children with regressive autism spectrum disorder (ASD) and explored the effects of rehabilitation. METHODS: We recruited 370 children with ASD aged 1.5-7 years. Based on the Regression Supplement Form, the children were assigned to two groups: regressive and non-regressive. The core symptoms and neurodevelopmental levels of ASD were assessed before and after 1 year of behavioral intervention using the Autism Diagnostic Observation Schedule (ADOS), Social Response Scale (SRS), Children Autism Rating Scale (CARS), and Gesell Developmental Scale (GDS). RESULTS: Among the 370 children with ASD, 28.38% (105/370) experienced regression. Regression was primarily observed in social communication and language skills. Children with regressive ASD exhibited higher SRS and CARS scores and lower GDS scores than those with non-regressive ASD. After 1 year of behavioral intervention, the symptom scale scores significantly decreased for all children with ASD; however, a lesser degree of improvement was observed in children with regressive ASD than in those with non-regressive ASD. In addition, the symptom scores of children with regressive ASD below 4 years old significantly decreased, whereas the scores of those over 4 years old did not significantly improve. Children with regressive ASD showed higher core symptom scores and lower neurodevelopmental levels. Nevertheless, after behavioral intervention, some symptoms exhibited significant improvements in children with regressive ASD under 4 years of age. CONCLUSION: Early intervention should be considered for children with ASD, particularly for those with regressive ASD.

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8. Hull L, Stark I, Lundberg M, Ahlqvist VH, Nordström SI, Ohlis A, Hadlaczky G, Rai D, Magnusson C. Sex differences in self-harm and suicide in young autistic adults. Acta Psychiatr Scand;2024 (Jul 19)

INTRODUCTION: Both suicide and self-harm are disproportionately common in autistic people. Sex differences in risk of self-harm and suicide are observed in the general population, but findings are mixed for autistic people. Self-cutting may be a particularly risky self-harm behaviour for suicide in autistic people. We aimed to explore sex differences and differences in method of self-harm in the association between self-harm and suicide in autistic and non-autistic adolescents and young adults. METHODS: We used a total population register of 2.8 million Swedish residents. Participants were followed from age 12 until December 2021 for medical treatment because of self-harm, and death from suicide. We used Cox proportional hazard regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of death from suicide following self-harm, and Relative Excessive Risk due to Interaction (RERI) to explore the interaction between self-harm and autism in females and males. RESULTS: We identified 85,143 autistic individuals (31,288 female; 53,855 male) and 2,628,382 non-autistic individuals (1,286,481 female; 1,341,901 male) aged 12-37 years. Incidence of suicide following self-harm was higher in autistic males (incidence per 100,000 risk-years = 169.0 [95% CI 135.1, 211.3]) than females (125.4 [99.4, 158.3]). The relative risk was higher for autistic females (HR 26.1 [95% CI 20.2, 33.7]) than autistic males (12.5 [9.9, 15.8]). An additive effect of both autism and self-harm was observed in both females (RERI = 9.8) and males (2.0). Autistic individuals who self-harmed through cutting were at greatest risk of death from suicide (HR 25.1 [17.9, 35.2]), compared to other methods. CONCLUSION: Autistic males and females are at increased risk of death from suicide following severe self-harm, particularly self-cutting.

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9. Le Belle JE, Condro M, Cepeda C, Oikonomou KD, Tessema K, Dudley L, Schoenfield J, Kawaguchi R, Geschwind D, Silva AJ, Zhang Z, Shokat K, Harris NG, Kornblum HI. Acute rapamycin treatment reveals novel mechanisms of behavioral, physiological, and functional dysfunction in a maternal inflammation mouse model of autism and sensory over-responsivity. bioRxiv;2024 (Jul 11)

Maternal inflammatory response (MIR) during early gestation in mice induces a cascade of physiological and behavioral changes that have been associated with autism spectrum disorder (ASD). In a prior study and the current one, we find that mild MIR results in chronic systemic and neuro-inflammation, mTOR pathway activation, mild brain overgrowth followed by regionally specific volumetric changes, sensory processing dysregulation, and social and repetitive behavior abnormalities. Prior studies of rapamycin treatment in autism models have focused on chronic treatments that might be expected to alter or prevent physical brain changes. Here, we have focused on the acute effects of rapamycin to uncover novel mechanisms of dysfunction and related to mTOR pathway signaling. We find that within 2 hours, rapamycin treatment could rapidly rescue neuronal hyper-excitability, seizure susceptibility, functional network connectivity and brain community structure, and repetitive behaviors and sensory over-responsivity in adult offspring with persistent brain overgrowth. These CNS-mediated effects are also associated with alteration of the expression of several ASD-,ion channel-, and epilepsy-associated genes, in the same time frame. Our findings suggest that mTOR dysregulation in MIR offspring is a key contributor to various levels of brain dysfunction, including neuronal excitability, altered gene expression in multiple cell types, sensory functional network connectivity, and modulation of information flow. However, we demonstrate that the adult MIR brain is also amenable to rapid normalization of these functional changes which results in the rescue of both core and comorbid ASD behaviors in adult animals without requiring long-term physical alterations to the brain. Thus, restoring excitatory/inhibitory imbalance and sensory functional network modularity may be important targets for therapeutically addressing both primary sensory and social behavior phenotypes, and compensatory repetitive behavior phenotypes.

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10. Li X, Zhou Q. Relationship of weight-adjusted waist index and developmental disabilities in children 6 to 17 years of age: a cross-sectional study. Front Endocrinol (Lausanne);2024;15:1406996.

PURPOSE: The development of multiple system diseases is increased by obesity. However, the connection between obesity and developmental disabilities (DDs) in children is unclear. As an obesity index, the weight-adjusted waist index (WWI) assessed fat distribution and muscle mass. In this study, we examined the correlation between WWI and DDs among children 6 to 17 years of age. METHODS: This study used data from the National Health and Nutrition Examination Survey database (NHANES) covering 2003 to 2018, which included the data of 17,899 participants between 6 and 17 years of age. Data regarding their waist circumference, weight, and DDs were collected via physical examinations and questionnaire, respectively. A person’s WWI is calculated by dividing their waist circumference by their weight squared. The correlation between WWI and DDs was studied using weighted multiple logistic regression models. Additionally, a sensitivity analysis was conducted utilizing a generalized additive model and smooth curve fitting. RESULTS: After adjusting for all covariates, WWI was positively related to DDs in children ages 6-17. Based on the sensitivity analysis, the correlation between the WWI and prevalence of DDs remained consistent across subgroups. Additionally, there was a J-shaped correlation between the WWI and the prevalence of DDs in children ages 6 through 11. CONCLUSION: Children 6-17 years of age with a high WWI were at greater risk for DDs; however, the causal relationships and potential mechanisms require further exploration.

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11. Lu XY, Li MQ, Li YT, Yao JY, Zhang LX, Zeng ZH, Yu L, Chen ZR, Li CQ, Zhou XF, Li F. Oral edaravone ameliorates behavioral deficits and pathologies in a valproic acid-induced rat model of autism spectrum disorder. Neuropharmacology;2024 (Jul 19):110089.

Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies.

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12. Mouat JS, Krigbaum NY, Hakam S, Thrall E, Mellis J, Yasui DH, Cirillo PM, Ludena Y, Schmidt RJ, La Merrill MA, Hertz-Picciotto I, Cohn BA, LaSalle JM. Females with autism spectrum disorders show stronger DNA methylation signatures than males in perinatal tissues. bioRxiv;2024 (Jul 13)

Autism spectrum disorder (ASD) comprises a group of neurodevelopmental conditions currently diagnosed by behavioral assessment in childhood, with reported underdiagnosis in females. Though diagnosis in early life is linked to improved outcomes, we currently lack objective screening tools for newborns. To address this gap, we sought to identify a sex-specific DNA methylation signature for ASD using perinatal tissues that reflect dysregulation in the brain. DNA methylation was assayed from ASD and typically developing (TD) newborn blood, umbilical cord blood, placenta, and post-mortem cortex samples using whole genome bisulfite sequencing (WGBS) in a total of 511 samples. We found that methylation levels of differentially methylated regions (DMRs) differentiated samples by ASD diagnosis in females more than males across the perinatal tissues. We tested three theories for ASD sex differences in newborn blood, finding epigenetic support for an X chromosome-related female protective effect, as well as a high replication rate of DMRs (48.1%) in females across two independent cohorts. In our pan-tissue analysis, three genes (X-linked BCOR , GALNT9 , OPCML ) mapped to ASD DMRs replicated in all four female tissues. ASD DMRs from all tissues were enriched for neuro-related processes (females) and SFARI ASD-risk genes (females and males). Overall, we found a highly replicated methylation signature of ASD in females across perinatal tissues that reflected dysregulation in the brain and involvement of X chromosome epigenetics. This comparative study of perinatal tissues shows the promise of newborn blood DNA methylation biomarkers for early detection of females at risk for ASD and emphasizes the importance of sex-stratification in ASD studies.

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13. Ottosson F, Russo F, Abrahamsson A, MacSween N, Courraud J, Skogstrand K, Melander O, Ericson U, Orho-Melander M, Cohen AS, Grove J, Mortensen PB, Hougaard DM, Ernst M. Unraveling the metabolomic architecture of autism in a large Danish population-based cohort. BMC Med;2024 (Jul 19);22(1):302.

BACKGROUND: The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children, and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental, and prenatal factors, the molecular etiology of autism is largely unknown. Here, we use untargeted metabolomics to characterize the neonatal metabolome from dried blood spots collected shortly after birth. METHODS: We analyze the metabolomic profiles of a subset of a large Danish population-based cohort (iPSYCH2015) consisting of over 1400 newborns, who later are diagnosed with autism and matching controls and in two Swedish population-based cohorts comprising over 7000 adult participants. Mass spectrometry analysis was performed by a timsTOF Pro operated in QTOF mode, using data-dependent acquisition. By applying an untargeted metabolomics approach, we could reproducibly measure over 800 metabolite features. RESULTS: We detected underlying molecular perturbations across several metabolite classes that precede autism. In particular, the cyclic dipeptide cyclo-leucine-proline (FDR-adjusted p = 0.003) and the carnitine-related 5-aminovaleric acid betaine (5-AVAB) (FDR-adjusted p = 0.03), were associated with an increased probability for autism, independently of known prenatal and genetic risk factors. Analysis of genetic and dietary data in adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy (FDR-adjusted p < 0.05) and with variants near SLC22A4 and SLC22A5 (p < 5.0e - 8), coding for a transmembrane carnitine transporter protein involved in controlling intracellular carnitine levels. CONCLUSIONS: Cyclo-leucine-proline and 5-AVAB are associated with future diagnosis of autism in Danish neonates, both representing novel early biomarkers for autism. 5-AVAB is potentially modifiable and may influence carnitine homeostasis.

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14. Percy AK, Neul JL, Benke TA, Berry-Kravis EM, Glaze DG, Marsh ED, Barrett AM, An D, Bishop KM, Youakim JM. Trofinetide for the treatment of Rett syndrome: Long-term safety and efficacy results of the 32-month, open-label LILAC-2 study. Med;2024 (Jul 16)

BACKGROUND: Trofinetide was approved for the treatment of Rett syndrome (RTT) in patients aged ≥2 years based on the results of the 12-week, randomized, phase 3 LAVENDER study. In LILAC, a 40-week, open-label extension study of LAVENDER, trofinetide continued to improve the symptoms of RTT, with a similar safety profile as LAVENDER. Here, we report long-term safety and efficacy results of LILAC-2, a 32-month, open-label extension study. METHODS: Females aged 5-22 years who completed LILAC were eligible to enter LILAC-2. Safety and tolerability were assessed with the incidence of adverse events (AEs). Efficacy was assessed with Rett Syndrome Behaviour Questionnaire (RSBQ) and Clinical Global Impression-Improvement (CGI-I) scores. Caregiver interviews explored the patient’s experience with RTT and the efficacy of trofinetide during study participation. FINDINGS: In total, 77 participants were enrolled in LILAC-2. The most common AEs were diarrhea (53.2%), COVID-19 (27.3%), and vomiting (19.5%). The mean (standard error [SE]) change in RSBQ score from LAVENDER baseline to week 104 of LILAC-2 was -11.8 (2.45). The mean (SE) CGI-I score from LILAC baseline to week 12 of LILAC-2 was 3.1 (0.10). Most caregivers (96%; n = 24/25) were satisfied or very satisfied with the benefits of trofinetide. CONCLUSIONS: Long-term treatment with trofinetide continued to improve RTT symptoms, without new safety concerns. Caregivers reported satisfaction with trofinetide related to improvements that were meaningful for their child and themselves. FUNDING: The study was supported by Acadia Pharmaceuticals (San Diego, CA, USA). This study was registered at ClinicalTrials.gov: NCT04776746.

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15. Pravikova PD, Arssan MA, Zalivina EA, Kondaurova EM, Kulikova EA, Belokopytova, II, Naumenko VS. Dopamine receptors and key elements of the neurotrophins (BDNF, CDNF) expression patterns during critical periods of ontogenesis in the brain structures of mice with autism-like behavior (BTBR) or its absence (С57BL/6 J). Vavilovskii Zhurnal Genet Selektsii;2024 (Jul);28(4):407-415.

Analysis of the mechanisms underlying autism spectrum disorder (ASD) is an urgent task due to the ever-increasing prevalence of this condition. The study of critical periods of neuroontogenesis is of interest, since the manifestation of ASD is often associated with prenatal disorders of the brain development. One of the currently promising hypotheses postulates a connection between the pathogenesis of ASD and the dysfunction of neurotransmitters and neurotrophins. In this study, we investigated the expression of key dopamine receptors (Drd1, Drd2), brain-derived neurotrophic factor (Bdnf), its receptors (Ntrkb2, Ngfr) and the transcription factor Creb1 that mediates BDNF action, as well as cerebral dopamine neurotrophic factor (Cdnf) during the critical periods of embryogenesis (e14 and e18) and postnatal development (p14, p28, p60) in the hippocampus and frontal cortex of BTBR mice with autism-like behavior compared to the neurotypical C57BL/6 J strain. In BTBR embryos, on the 14th day of prenatal development, an increase in the expression of the Ngfr gene encoding the p75NTR receptor, which may lead to the activation of apoptosis, was found in the hippocampus and frontal cortex. A decrease in the expression of Cdnf, Bdnf and its receptor Ntrkb2, as well as dopamine receptors (Drd1, Drd2) was detected in BTBR mice in the postnatal period of ontogenesis mainly in the frontal cortex, while in the hippocampus of mature mice (p60), only a decrease in the Drd2 mRNA level was revealed. The obtained results suggest that the decrease in the expression levels of CDNF, BDNF-TrkB and dopamine receptors in the frontal cortex in the postnatal period can lead to significant changes in both the morphology of neurons and dopamine neurotransmission in cortical brain structures. At the same time, the increase in p75NTR receptor gene expression observed on the 14th day of embryogenesis, crucial for hippocampus and frontal cortex development, may have direct relevance to the manifestation of early autism.

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16. Speer L. Similar Rates of Autism With Lamotrigine, Topiramate, and No Treatment; Rate With Valproate Is Higher. Am Fam Physician;2024 (Jul);110(1):90-91.

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17. Sterrett K, Clarke E, Nofer J, Piven J, Lord C. Toward a functional classification for autism in adulthood. Autism Res;2024 (Jul 19)

Autism spectrum disorder (ASD) is a heterogeneous condition that affects development and functioning from infancy through adulthood. Efforts to parse the heterogeneity of the autism spectrum through subgroups such as Asperger’s and Profound Autism have been controversial, and have consistently struggled with issues of reliability, validity, and interpretability. Nonetheless, methods for successfully identifying clinically meaningful subgroups within autism are needed to ensure that research, interventions, and services address the range of needs experienced by autistic individuals. The purpose of this study was to generate and test whether a simple set of questions, organized in a flowchart, could be used in clinical practice and research to differentiate meaningful subgroups based on individuals’ level of functioning. Once generated, subgroups could also be compared to the recently proposed administrative category of Profound Autism and to groupings based on standardized adaptive measures. Ninety-seven adults with autism or related neurodevelopmental disorders participating in a longstanding longitudinal study, or their caregivers if they could not answer for themselves, completed phone interviews when the participants were ~30 years old. Information from these phone interviews was used to generate vignettes summarizing characteristics and aspects of the daily lives of each participant (e.g., language level, vocational activities, and social relationships). Three expert clinicians then used these vignettes to classify each participant based on their level of support needs. Meaningfully distinct subgroups within the sample were identified which could be reliably distinguished from one another. Implications of such categorizations and future directions are discussed.

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18. Uglik-Marucha N, Mason D, Belcher H, Happé F, Vitoratou S. Protocol for a systematic review evaluating psychometric properties and gender-related measurement (non)invariance of self-report assessment tools for autism in adults. Syst Rev;2024 (Jul 19);13(1):188.

BACKGROUND: Given the recent evidence on gender differences in the presentation of autism, there is an increasing concern that current tools for autism do not adequately capture traits more often found in women. If tools for autism measure autistic traits differently based on gender alone, their validity may be compromised as they may not be measuring the same construct across genders. Measurement invariance investigations of autism measures can help assess the validity of autism constructs for different genders. The aim of this systematic review is to identify and critically appraise the psychometric properties of all self-report tools for autism in adults that meet two criteria: (a) they have been published since or included in the NICE (2014) recommendations, and (b) they have undergone gender-related measurement invariance investigations as part of their validation process. METHODS: A search of electronic databases will be conducted from 2014 until the present using MEDLINE, Embase, and PsycINFO using predefined search terms to identify eligible studies. The search for grey literature will include sources such as OpenGrey, APA PsycEXTRA, and Scopus. Two reviewers will independently screen titles, abstracts, and full texts for eligibility. The references of included studies will be searched for additional records. The methodological quality of the studies will be evaluated using the COSMIN Risk of Bias checklist, while psychometric quality of findings will be assessed based on criteria for good measurement properties and ConPsy checklist. The quality of the total body of evidence will be appraised using the approach outlined in the modified GRADE guidelines. DISCUSSION: This systematic review will be among the first to assess the psychometric properties and gender-related measurement invariance of self-reported measures for autism in adults that were published since (or included in) NICE (2014) guidelines. The review will provide recommendations for the most suitable tool to assess for autism without gender bias. If no such measure is found, it will identify existing tools with promising psychometric properties that require further testing, or suggest developing a new measure. SYSTEMATIC REVIEW REGISTRATION: The protocol has been registered at the International Prospective Register of Systematic Reviews (PROSPERO). The registration number is CRD42023429350.

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19. Vasileva S, Yap CX, Whitehouse AJO, Gratten J, Eyles D. Absence of association between maternal adverse events and long-term gut microbiome outcomes in the Australian autism biobank. Brain Behav Immun Health;2024 (Aug);39:100814.

INTRODUCTION: Maternal immune activation (MIA) and prenatal maternal stress (MatS) are well-studied risk factors for psychiatric conditions such as autism and schizophrenia. Animal studies have proposed the gut microbiome as a mechanism underlying this association and have found that risk factor-related gut microbiome alterations persist in the adult offspring. In this cross-sectional study, we assessed whether maternal immune activation and prenatal maternal stress were associated with long-term gut microbiome alterations in children using shotgun metagenomics. METHODS: This cross-sectional study included children diagnosed with autism (N = 92), siblings without a diagnosis (N = 42), and unrelated children (N = 40) without a diagnosis who were recruited into the Australian Autism Biobank and provided a faecal sample. MIA exposure was inferred from self-reported data and included asthma/allergies, complications during pregnancy triggering an immune response, auto-immune conditions, and acute inflammation. Maternal stress included any of up to 9 stressful life events during pregnancy, such as divorce, job loss, and money problems. Data were analysed for a total of 174 children, of whom 63 (36%) were born to mothers with MIA and 84 (48%) were born to mothers who experienced maternal stress during pregnancy (where 33 [19%] experienced both). Gut microbiome data was assessed using shotgun metagenomic sequencing of the children’s faecal samples. RESULTS: In our cohort, MIA, but not MatS, was associated with ASD. Variance component analysis revealed no associations between any of the gut microbiome datasets and neither MIA nor MatS. After adjusting for age, sex, diet and autism diagnosis, there was no significant difference between groups for bacterial richness, α-diversity or β-diversity. We found no significant differences in species abundance in the main analyses. However, when stratifying the cohort by age, we found that Faecalibacterium prausnitzii E was significantly decreased in MIA children aged 11-17. DISCUSSION: Consistent with previous findings, we found that children who were born to mothers with MIA were more likely to be diagnosed with autism. Unlike within animal studies, we found negligible microbiome differences associated with MIA and maternal stress. Given the current interest in the microbiome-gut-brain axis, researchers should exercise caution in translating microbiome findings from animal models to human contexts and the clinical setting.

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20. Wilson KP, Valazza E, Price C. Video Modeling to Support Social Communication Goals of Autistic Adults: A Tutorial. Am J Speech Lang Pathol;2024 (Jul 19):1-17.

PURPOSE: Decades of research have shown video modeling to be an effective tool for teaching and supporting a variety of skills in autistic children. More recently, video modeling has emerged as an effective support for autistic adults, with much of the literature focused on vocational success through support of language skills. The purpose of this tutorial is to provide speech-language pathologists, autistic adults, and other team members with evidence-based guidelines for use of video modeling to support success with social communication across settings. METHOD: This evidence-based tutorial draws from the literature on video modeling for autistic adults in the area of social communication, presenting empirically supported guidelines for speech-language pathologists considering video modeling as a tool to support social communication within this population and their interaction partners. This tutorial presents an evidence-based, step-by-step guide to the planning, creation, and use of video models with and by autistic adults, along with important additional considerations based on relevant literature. CONCLUSIONS: Video modeling is a social communication support that is backed by the scientific literature as an efficacious tool for use by autistic adults. This tutorial will guide speech-language pathologists’ use of this evidence-based tool as they work alongside autistic adults and others to help meet social communication goals across settings.

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21. Yin H, Zhang J, Chen Y, Guo J, Li Q, Dinnyes A, Sun Q, Liu X, He G, Zhu B, Liu Y, Xu P, Xu W, Xie J. Placenta-specific CYP11A1 overexpression lead to autism-like symptom in offspring with altered steroid hormone biosynthesis in the placenta-brain axis and rescued by vitamin D intervention. Brain Behav Immun;2024 (Jul 16);121:13-25.

Alterations in steroid hormone regulation have been implicated in the etiology and progression of autism spectrum disorders (ASD), with the enzyme cytochrome P450 family 11 subfamily A member 1 (CYP11A1)-a key catalyst in cholesterol side-chain cleavage, prominently expressed in the adrenal glands, ovaries, testes, and placenta-standing at the forefront of these investigations. The potential link between aberrations in placental Cyp11a1 expression and the resultant neurodevelopmental disorders, along with the mechanisms underpinning such associations, remains inadequately delineated. In this study, we employed a placental trophoblast-specific Cyp11a1 Hipp11 (H11) knock-in murine model to dissect the phenotypic manifestations within the placenta and progeny, thereby elucidating the underlying mechanistic pathways. Behavioral analyses revealed a diminution in social interaction capabilities alongside an augmented anxiety phenotype, as evidenced by open field and elevated plus maze assessments; both phenotypes were ameliorated after vitamin D3 supplementation. Electrophysiological assays underscored the augmented inhibition of paired-pulse facilitation, indicating impaired neuroplasticity in Cyp11a1 H11-modified mice. An elevation in progesterone concentrations was noted, alongside a significant upregulation of Th1-related cytokines (IL-6 and TNFα) across the plasma, placental, and frontal cortex-a pathological state mitigable through vitamin D3 intervention. Western blotting revealed a vitamin D-mediated rectification of vitamin D receptor and PGC-1α expression dysregulations. Immunofluorescence assays revealed microglial activation in the knock-in model, which was reversible upon vitamin D3 treatment. In conclusion, Cyp11a1 overexpression in the placenta recapitulated an autism-like phenotype in murine models, and vitamin D3 administration effectively ameliorated the resultant neurobehavioral and neuroinflammatory derangements. This study substantiates the application of Cyp11a1 as a biomarker in prenatal diagnostics and posits that prenatal vitamin D3 supplementation is a viable prophylactic measure against perturbations in steroid hormone metabolism associated with ASD pathogenesis.

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