1. Abuaish S, Al-Otaibi NM, Aabed K, Abujamel TS, Alzahrani SA, Alotaibi SM, Bhat RS, Arzoo S, El-Ansary A. The role of sex-differentiated variations in stress hormones, antioxidants, and neuroimmune responses in relation to social interaction impairment in a rodent model of autism. Metabolic brain disease. 2021; 36(6): 1369-79.

Males are more likely to develop autism as a neurodevelopmental disorder than females, but the mechanisms underlying male susceptibility are not fully understood. In this paper, we used a well-characterized propionic acid (PPA) rodent model of autism to study sex differences in stress hormones, antioxidants’ status, and the neuroimmune response that may contribute to the preponderance of autism in males. Sprague Dawley rats of both sexes were divided into a saline-treated group as controls and PPA-treated groups, receiving 250 mg/kg of PPA per day for three days. Animals’ social behavior was examined using the three-chamber social test. Hormones (ACTH, corticosterone, melatonin, and oxytocin), oxidative stress biomarkers (glutathione, glutathione-S-transferase, and ascorbic acid), and cytokines (IL-6, IL-1α, IL-10, and IFNγ) were measured in the brain tissue of all the animals. The results showed a sex dimorphic social response to PPA treatment, where males were more susceptible to the PPA treatment and exhibited a significant reduction in social behavior with no effects observed in females. Also, sex differences were observed in the levels of hormones, antioxidants, and cytokines. Female rats showed significantly higher corticosterone and lower oxytocin, antioxidants, and cytokine levels than males. The PPA treatment later modulated these baseline differences. Our study indicates that the behavioral manifestation of autism in PPA-treated males and not females could be linked to neural biochemical differences between the sexes at baseline, which might play a protective role in females. Our results can contribute to early intervention strategies and treatments used to control autism, an increasingly prevalent disorder.

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2. Afroz KF, Reyes N, Young K, Parikh K, Misra V, Alviña K. Altered gut microbiome and autism like behavior are associated with parental high salt diet in male mice. Scientific reports. 2021; 11(1): 8364.

Neurodevelopmental disorders are conditions caused by the abnormal development of the central nervous system. Autism spectrum disorder (ASD) is currently the most common form of such disorders, affecting 1% of the population worldwide. Despite its prevalence, the mechanisms underlying ASD are not fully known. Recent studies have suggested that the maternal gut microbiome can have profound effects on neurodevelopment. Considering that the gut microbial composition is modulated by diet, we tested the hypothesis that ASD-like behavior could be linked to maternal diet and its associated gut dysbiosis. Therefore, we used a mouse model of parental high salt diet (HSD), and specifically evaluated social and exploratory behaviors in their control-fed offspring. Using 16S genome sequencing of fecal samples, we first show that (1) as expected, HSD changed the maternal gut microbiome, and (2) this altered gut microbiome was shared with the offspring. More importantly, behavioral analysis of the offspring showed hyperactivity, increased repetitive behaviors, and impaired sociability in adult male mice from HSD-fed parents. Taken together, our data suggests that parental HSD consumption is strongly associated with offspring ASD-like behavioral abnormalities via changes in gut microbiome.

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3. Bou Khalil R, Yazbek JC. Potential importance of supplementation with zinc for autism spectrum disorder. L’Encephale. 2021; 47(6): 514-7.

Zinc is an essential micronutrient for cellular proliferation and subsequent body and brain development. Zinc deficiency is becoming a major public health issue equally in under-developed and developed countries. The lack of sufficient zinc, whether related to environmental or internal factors, is an important environmental stressor that is eligible to become elucidated as a contributing factor for the pathogenesis of autism spectrum disorder (ASD). The aim of this manuscript is to briefly overview available data regarding the relationship of zinc deficiency with the development of ASD and to relate these data with currently known pathogenetic mechanisms of this disorder namely brain growth disturbances and neuropeptides secretion. Zinc deficiency impacts brain connectivity and growth and alters adequate neurotransmission. In addition, zinc deficiency may indirectly act on the brain by disturbing the immune system and by altering the normal gut-brain connection. Zinc seems to be important for the social effect of neuropeptides. Zinc supplementation in pregnant women and newborn children with the aim of preventing ASD needs further consideration.

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4. Choi S, Song B, Shin H, Won C, Kim T, Yoshida H, Lee D, Chung J, Cho KS, Lee IS. Drosophila NSD deletion induces developmental anomalies similar to those seen in Sotos syndrome 1 patients. Genes & genomics. 2021; 43(7): 737-48.

BACKGROUND: Haploinsufficiency of the human nuclear receptor binding suppressor of variegation 3-9, enhancer of zeste, and trithorax (SET) domain 1 (NSD1) gene causes a developmental disorder called Sotos syndrome 1 (SOTOS1), which is associated with overgrowth and macrocephaly. NSD family proteins encoding histone H3 lysine 36 (H3K36) methyltransferases are conserved in many species, and Drosophila has a single NSD homolog gene, NSD. OBJECTIVE: To gain insight into the biological functions of NSD1 deficiency in the developmental anomalies seen in SOTOS1 patients using an NSD-deleted Drosophila mutant. METHODS: We deleted Drosophila NSD using CRISPR/Cas9-mediated targeted gene knock-out, and analyzed pleiotropic phenotypes of the homozygous mutant of NSD (NSD(-/-)) at various developmental stages to understand the roles of NSD in Drosophila. RESULTS: The site-specific NSD deletion was confirmed in the mutant. The H3K36 di-methylation levels were dramatically decreased in the NSD(-/-) fly. Compared with the control, the NSD(-/-) fly displayed an increase in the body size of larvae, similar to the childhood overgrowth phenotype of SOTOS1 patients. Although the NSD mutant flies survived to adulthood, their fecundity was dramatically decreased. Furthermore, the NSD(-/-) fly showed neurological dysfunctions, such as lower memory performance and motor defects, and a diminished extracellular signal-regulated kinase (ERK) activity. CONCLUSIONS: The NSD-deleted Drosophila phenotype resembles many of the phenotypes of SOTOS1 patients, such as learning disability, deregulated ERK signaling, and overgrowth; thus, this mutant fly is a relevant model organism to study various SOTOS1 phenotypes.

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5. Colvert E, Simonoff E, Capp SJ, Ronald A, Bolton P, Happé F. Autism Spectrum Disorder and Mental Health Problems: Patterns of Difficulties and Longitudinal Trajectories in a Population-Based Twin Sample. Journal of autism and developmental disorders. 2022; 52(3): 1077-91.

There is increasing concern regarding additional psychiatric problems that co-occur with Autism Spectrum Disorder (ASD), as reflected in recent changes to diagnostic schemes. However, there remains little research with population-based samples across childhood. We report on additional problems, as measured by the Strengths and Difficulties Questionnaire, in a population-based sample of 135 twins with ASD, 55 non-ASD co-twins, and 144 comparison twins low in ASD traits. Frequencies, associated demographic factors, and changes in mental health difficulties from age 4 to 13 years are presented. Our data confirm the high rates of additional difficulties reported in previous studies, and suggest that the profile, associated risk factors and longitudinal course of additional difficulties in ASD may differ from those in typically-developing populations.

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6. Fombonne E, MacFarlane H, Salem AC. Epidemiological surveys of ASD: advances and remaining challenges. Journal of autism and developmental disorders. 2021; 51(12): 4271-90.

Recent worldwide epidemiological surveys of autism conducted in 37 countries are reviewed; the median prevalence of autism is .97% in 26 high-income countries. Methodological advances and remaining challenges in designing and executing surveys are discussed, including the effects on prevalence of variable case definitions and nosography, of reliance on parental reports only, case ascertainment through mainstream school surveys, innovative approaches to screen school samples more efficiently, and consideration of age in interpreting surveys. Directions for the future of autism epidemiology are discussed, including the need to systematically examine cross-cultural variation in phenotypic expression and developing surveillance programs.

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7. Ishler KJ, Biegel DE, Wang F, Olgac T, Lytle S, Miner S, Edguer M, Kaplan R. Service Use Among Transition-Age Youth with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2022; 52(3): 1051-65.

This study explored predictors of service use among 174 transition-age youth (age 16-30) with an Autism Spectrum Disorder using Andersen’s (J Health Soc Behav 36(1):1-10, 1995) healthcare utilization model. Family caregivers were interviewed about past 6-month use of 15 services. On average, youth used 6.1 and needed 3.2 additional services. Greater service use was associated with two predisposing (caregiver college educated, caregiver not married/partnered), two enabling (youth has Medicaid waiver, youth in high school), and one need factor (lower adaptive functioning). Use of specific services was most strongly related to enabling (Medicaid waiver, in high school) and need factors (lower adaptive functioning, comorbid mental health diagnosis). Findings provide a snapshot of the « service cliff » faced by families and highlight the need for additional research.

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8. Jalal R, Nair A, Lin A, Eckfeld A, Kushan L, Zinberg J, Karlsgodt KH, Cannon TD, Bearden CE. Social cognition in 22q11.2 deletion syndrome and idiopathic developmental neuropsychiatric disorders. Journal of neurodevelopmental disorders. 2021; 13(1): 15.

BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is a common recurrent neurogenetic condition associated with elevated risk for developmental neuropsychiatric disorders and intellectual disability. Children and adults with 22q11DS often exhibit marked social impairment as well as neurocognitive deficits, and have elevated rates of both autism spectrum disorder (ASD) and psychosis. However, the relationship between the basic processes of social cognition and cognitive ability has not been well studied in 22q11DS. Here, we examined differences in social cognition in 22q11DS, relative to multiple groups of idiopathic neuropsychiatric disorders, and typically developing healthy controls (HC). Additionally, we examined differences in intellectual functioning and its relationship to social cognitive abilities. Finally, we examined the relationship between social cognitive abilities and real-world social behavior. METHODS: We examined social cognition and intellectual functioning in 273 participants (mean age = 17.74 ± 5.18% female = 44.3%): 50 with 22q11DS, 49 youth with first episode psychosis (FEP), 48 at clinical high-risk (CHR) for psychosis, 24 participants with ASD, and 102 HC. Social cognition was assessed using The Awareness of Social Inference Test (TASIT), while reciprocal social behavior was assessed via parent/caregiver ratings on the Social Responsiveness Scale (SRS). Participants were also administered the Wechsler Abbreviated Scale of Intelligence, 2nd edition (WASI-II) to assess intellectual functioning. RESULTS: The 22q11DS group exhibited significantly lower social cognitive abilities compared to CHR, FEP, and HC groups after controlling for intellectual functioning, but not in comparison to the ASD group. Significant positive correlations were found between social cognition, as measured by the TASIT and IQ across groups. In contrast, no significant relationships were found between TASIT and real-world social behavior (SRS) for any group. CONCLUSIONS: Our findings indicate social cognitive deficits are more prominent in 22q11DS than idiopathic neuropsychiatric conditions across the age range, even after adjusting for global intellectual function. These results contribute to our understanding of the intellectual and social vulnerabilities of 22q11DS in comparison to idiopathic neuropsychiatric disorders. Our findings of robust associations between intellectual ability and social cognition emphasizes the importance of accounting for neurocognitive deficits in social skills interventions and tailoring these existing treatment models for 22q11DS and other populations with intellectual impairment.

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9. Luelmo P, Kasari C. Randomized pilot study of a special education advocacy program for Latinx/minority parents of children with autism spectrum disorder. Autism : the international journal of research and practice. 2021; 25(6): 1809-15.

Persistent racial and ethnic disparities in obtaining an autism spectrum disorder diagnosis and services have been documented for Latinx children and other racial/ethnic minorities. This study reports on an educational intervention examining the effectiveness and feasibility of a low-intensity (i.e. three sessions), low-cost, parent advocacy for Latinx and other minority parents of children with autism. Results indicated significantly increased parental knowledge and in the immediate intervention group, but this knowledge did not lead to greater empowerment. While parents from low-income, racial/ethnic minority backgrounds, particularly Latinx parents, can significantly increase their advocacy skills with a low-intensity, low-cost program, they may need more support in changing their self-perceptions of empowerment and advocacy.

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10. Maslahati T, Bachmann CJ, Höfer J, Küpper C, Stroth S, Wolff N, Poustka L, Roessner V, Kamp-Becker I, Hoffmann F, Roepke S. How Do Adults with Autism Spectrum Disorder Participate in the Labor Market? A German Multi-center Survey. Journal of autism and developmental disorders. 2022; 52(3): 1066-76.

International studies show disadvantages for adults with autism spectrum disorder (ASD) in the labor market. Data about their participation in the German labor market are scarce. The aim of this study was to examine the integration of adults with ASD in the German labor market in terms of education, employment and type of occupation by means of a cross-sectional-study, using a postal questionnaire. Findings show above average levels of education for adults with ASD compared to the general population of Germany and simultaneously, below average rates of employment and high rates of financial dependency. That indicates a poor integration of adults with ASD in the German labor market and emphasizes the need for vocational support policies for adults with ASD.

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11. Petrasek T, Vojtechova I, Klovrza O, Tuckova K, Vejmola C, Rak J, Sulakova A, Kaping D, Bernhardt N, de Vries PJ, Otahal J, Waltereit R. mTOR inhibitor improves autistic-like behaviors related to Tsc2 haploinsufficiency but not following developmental status epilepticus. Journal of neurodevelopmental disorders. 2021; 13(1): 14.

BACKGROUND: Tuberous sclerosis complex (TSC), a multi-system genetic disorder often associated with autism spectrum disorder (ASD), is caused by mutations of TSC1 or TSC2, which lead to constitutive overactivation of mammalian target of rapamycin (mTOR). In several Tsc1+/- and Tsc2+/- animal models, cognitive and social behavior deficits were reversed by mTOR inhibitors. However, phase II studies have not shown amelioration of ASD and cognitive deficits in individuals with TSC during mTOR inhibitor therapy. We asked here if developmental epilepsy, common in the majority of individuals with TSC but absent in most animal models, could explain the discrepancy. METHODS: At postnatal day P12, developmental status epilepticus (DSE) was induced in male Tsc2+/- (Eker) and wild-type rats, establishing four experimental groups including controls. In adult animals (n = 36), the behavior was assessed in the paradigms of social interaction test, elevated plus-maze, light-dark test, Y-maze, and novel object recognition. The testing was carried out before medication (T1), during a 2-week treatment with the mTOR inhibitor everolimus (T2) and after an 8-week washing-out (T3). Electroencephalographic (EEG) activity was recorded in a separate set of animals (n = 18). RESULTS: Both Tsc2+/- mutation and DSE caused social behavior deficits and epileptiform EEG abnormalities (T1). Everolimus led to a persistent improvement of the social deficit induced by Tsc2+/-, while deficits related to DSE did not respond to everolimus (T2, T3). CONCLUSIONS: These findings may contribute to an explanation why ASD symptoms in individuals with TSC, where comorbid early-onset epilepsy is common, were not reliably ameliorated by mTOR inhibitors in clinical studies.

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12. Wittevrongel K, Mitchell W, Hébert ML, Nicholas DB, Zwicker JD. Acceptability of employment readiness measures in youth and young adults on the autism spectrum: a mixed-methods study. Disability and rehabilitation. 2021: 1-13.

PURPOSE: Reliable, valid, and pragmatic measures are essential for monitoring and evaluating employment readiness and comparing the effectiveness of alternative implementation strategies. The Work Readiness Inventory (WRI) and Ansell-Casey Life Skills Assessment (ACLSA) are valid measures of employment readiness in neurotypical populations; however, their acceptability (i.e., user perception of measure as agreeable/satisfactory) for persons on the autism spectrum is not yet known. This investigation assesses the acceptability of the WRI and a modified ACLSA (ACLSA-M) in measuring employment readiness in youth/young adults on the spectrum. METHODS: A concurrent triangulation mixed-methods study design utilizing quantitative pre-post measurement of a community-based employment readiness program alongside qualitative survey assessment was employed to determine concurrent acceptability. For robustness, further explication through peer debriefing of experts evaluated the retrospective acceptability via interview and acceptability-rate assessment. RESULTS: Findings indicated that both measures are acceptable, although individual- and job-specific item modifications are advised, particularly due to disability-specific needs. Significant change in employment readiness in youth/young adults on the spectrum supports concurrent acceptability. Peer debriefing provided rich data on retrospective acceptability. Acceptability-rates of 0.84 and 0.91 confirm broad acceptability of these measures. CONCLUSIONS: Implications are presented for clinicians and researchers, highlighting the relevance for autism-specific measurement development and acceptability.Implications for rehabilitationGiven the lower labor force participation of persons on the autism spectrum, a combination of measures should be used in the assessment of an individual’s employment readiness.In youth and young adults on the spectrum, employment readiness can be measured using the Work Readiness Inventory (WRI) and a modified version of the Ansell-Casey Life Skills Assessment (ACLSA-M).In clinical practice and research, modifying the contents of these measures may be advised to minimize language complexity, and maximize ease in self report.When designing, developing, and testing new measures in rehabilitation practice or research, the intent should be broadened by involving diverse representation from the project outset, by engaging both those on the spectrum and neurotypical populations.

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13. Zamir I, Stoltz Sjöström E, Ahlsson F, Hansen-Pupp I, Serenius F, Domellöf M. Neonatal hyperglycaemia is associated with worse neurodevelopmental outcomes in extremely preterm infants. Archives of disease in childhood Fetal and neonatal edition. 2021; 106(5): 460-6.

OBJECTIVE: To assess the associations between neonatal hyperglycaemia and insulin treatment, versus long-term neurodevelopmental outcomes in children born extremely preterm. DESIGN AND SETTING: Observational national cohort study (Extremely Preterm Infants in Sweden Study) using prospectively and retrospectively collected data. Neurodevelopmental assessment was performed at 6.5 years of age. PATIENTS: 533 infants born <27 gestational weeks during 2004-2007; 436 survivors were assessed at 6.5 years. OUTCOME MEASURES: Neurodevelopmental disability (NDD), survival without moderate to severe NDD, Wechsler Intelligence Scale for Children IV Full scale intelligence quotient (WISC-IV FSIQ) and Movement Assessment Battery for Children 2 (MABC-2) total score. RESULTS: Duration of neonatal hyperglycaemia >8 mmol/L was associated with WISC-IV scores-for each day with hyperglycaemia there was a decrease of 0.33 points (95% CI 0.03 to 0.62) in FSIQ. Neonatal hyperglycaemia >8 mmol/L occurring on 3 consecutive days was associated with lower MABC-2 scores (adjusted mean difference: -4.90; 95% CI -8.90 to -0.89). For each day with hyperglycaemia >8 mmol/L, there was a decrease of 0.55 points (95% CI 0.17 to 0.93) in MABC-2 total score. Insulin treatment was not associated with any of the outcome measures. CONCLUSION: Neonatal hyperglycaemia >8 mmol/L was associated with lower intelligence scores and worse motor outcomes at 6.5 years of age. Insulin treatment was not associated with either worsened or improved neurodevelopmental outcomes. Randomised controlled trials are needed to clarify the role of insulin in treating hyperglycaemia in extremely preterm infants.

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