1. Gogliotti R, Fisher N, Stansley B, Jones C, Lindsley C, Conn J, Niswender C. {{Total RNA-sequencing of Rett Syndrome Autopsy Samples Identifies the M4 Muscarinic Receptor as a Novel Therapeutic Target}}. {The Journal of pharmacology and experimental therapeutics}. 2018.
Mutations in the Methyl CpG Binding Protein 2 (MECP2) gene are responsible for the neurodevelopmental disorder Rett syndrome (RTT). MeCP2 is a DNA-binding protein whose abundance and ability to complex with HDAC3 is linked to the regulation of chromatin structure. Consequently, loss-of-function mutations in MeCP2 are predicted to have broad effects on gene expression. However, to date, studies in mouse models of RTT have identified a limited number of gene or pathway-level disruptions, and even fewer genes have been identified that could be considered amenable to classical drug discovery approaches. Here, we performed RNA-sequencing (seq) on 9 motor cortex and 6 cerebellar autopsy samples from RTT patients and controls. This approach identified 1,883 significantly affected genes in the motor cortex and 2,110 genes in the cerebellum, with a global trend towards increased expression. Pathway-level analysis identified enrichment in genes associated with MAPK-signaling, long-term potentiation, and axon guidance. A survey of our RNA-seq results also identified a significant decrease in expression of the muscarinic acetylcholine receptor 4 (CHRM4) gene, which encodes a receptor (M4) that is the subject of multiple large drug discovery efforts for schizophrenia and Alzheimer’s disease. We confirmed that CHRM4 expression was decreased in RTT patients, and, excitingly, we demonstrated that M4 potentiation normalizes social and cognitive phenotypes in Mecp2+/- mice. This work provides an experimental paradigm in which translationally relevant targets can be identified using transcriptomics in RTT autopsy samples, back-modeled in Mecp2+/- mice, and assessed for preclinical efficacy using existing pharmacological tool compounds.
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2. Hogeveen J, Krug MK, Elliott MV, Solomon M. {{Insula-Retrosplenial Cortex Overconnectivity Increases Internalizing via Reduced Insight in Autism}}. {Biol Psychiatry}. 2018.
BACKGROUND: Internalizing symptoms like anxiety and depression are common and impairing in autism spectrum disorder (ASD). Here, we test the hypothesis that aberrant functional connectivity among three brain networks (salience network [SN], default mode network [DMN], and frontoparietal network [FPN]) plays a role in the pathophysiology of internalizing in ASD. METHODS: We examined the association between resting-state functional connectivity and internalizing in 102 adolescents and young adults with ASD (n = 49) or typical development (n = 53). Seed-to-target functional connectivity was contrasted between adolescents and young adults with ASD and typically developing subjects using a recent parcellation of the human cerebral cortex, and connections that were aberrant in ASD were analyzed dimensionally as a function of parent-reported internalizing symptoms. RESULTS: Three connections demonstrated robust overconnectivity in ASD: 1) the anterior insula to the retrosplenial cortex (i.e., SN-DMN), 2) the anterior insula to the frontal pole (i.e., SN-FPN), and 3) the dorsolateral prefrontal cortex to the retrosplenial cortex (i.e., FPN-DMN). These differences remained significant after controlling for age, and no age-related effects survived correction. The SN-DMN connection was associated with greater internalizing in ASD, mediated by a bigger difference between self- and parent-reported internalizing. Control analyses found that the other two connections were not associated with internalizing, and SN-DMN connectivity was not associated with a well-matched control measure (externalizing symptoms). CONCLUSIONS: The present findings provide novel evidence for a specific link between SN-DMN overconnectivity and internalizing in ASD. Further, the mediation results suggest that intact anterior insula-retrosplenial connectivity may play a role in an individual’s generating insight into his or her own psychopathology.
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3. Kent C, Cordier R, Joosten A, Wilkes-Gillan S, Bundy A. {{Peer-mediated intervention to improve play skills in children with autism spectrum disorder: A feasibility study}}. {Australian occupational therapy journal}. 2018.
BACKGROUND/AIM: Children with autism spectrum disorder (ASD) frequently demonstrate impaired play skills and poor quality social interactions compared to typically developing peers. Complex interventions to improve play skills should be investigated with randomised control trials (RCT) where possible to support evidence-based practice for occupational therapists. Prior to a RCT, multiple feasibility studies are recommended to identify barriers to the trial. The aim of this study is to adapt a complex intervention to improve play skills in children with ASD and investigate the feasibility of conducting a RCT. METHODS: Participants were 10 children with ASD paired with typically developing playmates chosen by their families. Pairs attended 10 intervention sessions involving video modelling, therapist- and peer-mediation and free play. Participant numbers needed for future investigation of effectiveness were calculated and time and cost considerations were reviewed. The Test of Playfulness (ToP) was the primary outcome measure; both parent- and child-report outcome measures were evaluated for appropriateness. RESULTS: To determine effectiveness of the intervention 34 pairs in both control and intervention groups will be needed to conduct a RCT over an 18-month timeframe. ToP scores showed a positive, but not statistically significant trend from pre- to post-intervention. These improvements were maintained at follow-up in both clinic and home environments. The Piers-Harris 2 and the Parent Relationship Questionnaire were identified as appropriate secondary outcome measures; additional parent- and teacher-report outcome measures are recommended for the RCT. CONCLUSION: A RCT to investigate effectiveness of this intervention for improving play skills of children with ASD and their playmates are feasible.
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4. Li C, Wang L, Block ME, Sum RKW, Wu Y. {{Psychometric Properties of the Physical Educators’ Self-Efficacy Toward Including Students With Disabilities-Autism Among Chinese Preservice Physical Education Teachers}}. {Adapted physical activity quarterly : APAQ}. 2018: 1-16.
Teachers’ self-efficacy is a critical predictor for successful inclusive physical education. However, little is known about preservice physical educators’ self-efficacy toward teaching students with autism spectrum disorders in China. A sound instrument is necessary to measure their self-efficacy level. This validation study examined the psychometric properties of the Chinese version of the Physical Educators’ Self-Efficacy Toward Including Students with Disabilities-Autism. A multisection survey form was administered to preservice physical educators in Mainland China (n = 205) and Hong Kong (n = 227). The results of confirmatory factor analysis confirmed the one-factor model of the scale in the total sample and each of the two samples. Invariance tests across the two samples supported configural and metric invariance but not scalar invariance. The scale scores showed good internal reliability and were correlated with theoretically relevant constructs (i.e., burnout and life satisfaction) in the total sample and subsamples. These findings generally support the utility of the scale for use among Chinese preservice physical educators.
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5. Lin CY, Chang KW, Lin CY, Wu JY, Coon H, Huang PH, Ho HN, Akbarian S, Gau SS, Huang HS. {{Allele-specific expression in a family quartet with autism reveals mono-to-biallelic switch and novel transcriptional processes of autism susceptibility genes}}. {Sci Rep}. 2018; 8(1): 4277.
Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, and the exact causal mechanism is unknown. Dysregulated allele-specific expression (ASE) has been identified in persons with ASD; however, a comprehensive analysis of ASE has not been conducted in a family quartet with ASD. To fill this gap, we analyzed ASE using genomic DNA from parent and offspring and RNA from offspring’s postmortem prefrontal cortex (PFC); one of the two offspring had been diagnosed with ASD. DNA- and RNA-sequencing revealed distinct ASE patterns from the PFC of both offspring. However, only the PFC of the offspring with ASD exhibited a mono-to-biallelic switch for LRP2BP and ZNF407. We also identified a novel site of RNA-editing in KMT2C in addition to new monoallelically-expressed genes and miRNAs. Our results demonstrate the prevalence of ASE in human PFC and ASE abnormalities in the PFC of a person with ASD. Taken together, these findings may provide mechanistic insights into the pathogenesis of ASD.
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6. Ozonoff S, Gangi D, Hanzel EP, Hill A, Hill MM, Miller M, Schwichtenberg AJ, Steinfeld MB, Parikh C, Iosif AM. {{Onset patterns in autism: Variation across informants, methods, and timing}}. {Autism Res}. 2018.
While previous studies suggested that regressive forms of onset were not common in autism spectrum disorder (ASD), more recent investigations suggest that the rates are quite high and may be under-reported using certain methods. The current study undertook a systematic investigation of how rates of regression differed by measurement method. Infants with (n = 147) and without a family history of ASD (n = 83) were seen prospectively for up to 7 visits in the first three years of life. Reports of symptom onset were collected using four measures that systematically varied the informant (examiner vs. parent), the decision type (categorical [regression absent or present] vs. dimensional [frequency of social behaviors]), and the timing of the assessment (retrospective vs. prospective). Latent class growth models were used to classify individual trajectories to see whether regressive onset patterns were infrequent or widespread within the ASD group. A majority of the sample was classified as having a regressive onset using either examiner (88%) or parent (69%) prospective dimensional ratings. Rates of regression were much lower using retrospective or categorical measures (from 29 to 47%). Agreement among different measurement methods was low. Declining trajectories of development, consistent with a regressive onset pattern, are common in children with ASD and may be more the rule than the exception. The accuracy of widely used methods of measuring onset is questionable and the present findings argue against their widespread use. Autism Res 2018. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study examines different ways of measuring the onset of symptoms in autism spectrum disorder (ASD). The present findings suggest that declining developmental skills, consistent with a regressive onset pattern, are common in children with ASD and may be more the rule than the exception. The results question the accuracy of widely used methods of measuring symptom onset and argue against their widespread use.
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7. Soke GN, Maenner MJ, Christensen D, Kurzius-Spencer M, Schieve LA. {{Prevalence of Co-occurring Medical and Behavioral Conditions/Symptoms Among 4- and 8-Year-Old Children with Autism Spectrum Disorder in Selected Areas of the United States in 2010}}. {J Autism Dev Disord}. 2018.
We compared the prevalence of various medical and behavioral co-occurring conditions/symptoms between 4- and 8-year-olds with autism spectrum disorder (ASD) from five sites in the Autism and Developmental Disabilities Monitoring Network during the 2010 survey year, accounting for sociodemographic differences. Over 95% of children had at least one co-occurring condition/symptom. Overall, the prevalence was higher in 8- than 4-year-olds for 67% of co-occurring conditions/symptoms examined. Further, our data suggested that co-occurring conditions/symptoms increased or decreased the age at which children were first evaluated for ASD. Similarly, among the 8-year-olds, the prevalence of most co-occurring conditions/symptoms was higher in children with a previous ASD diagnosis documented in their records. These findings are informative for understanding and screening co-occurring conditions/symptoms in ASD.
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8. Yu M, Cao T, Yu D, Huang F. {{Association Study Between Metallothionein-3 Protein Polymorphisms and Autism}}. {Neurotoxicity research}. 2018.
Genetic susceptibility to high mercury body burden has been suggested as an autism risk factor in children. Metallothionein III (MT3) is the brain-specific form of the metallothionein family, which plays a key role in metal metabolism. We therefore looked for genetic variations in the MT3 gene that might increase the predisposition to autism. DNA was extracted from 132 autistic children and 132 age and gender-matched unrelated controls. All the samples were analyzed for nine single nucleotide polymorphisms (SNPs) with minor allele frequency > 10% in the MT3 gene. The mRNA levels of MT3 in white blood cells were evaluated by real-time PCR. We did not detect any association between these MT3 polymorphisms and the mRNA levels of MT3. We did not detect any association between MT3 polymorphisms and autism risk. However, we detected four novel MT3 SNPs that are not in the human SNP database. The clinical importance of these SNPs needs further investigation. Our data suggest that MT3 gene polymorphisms are not associated with autism.
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9. Zwart FS, Vissers C, Maes JHR. {{The Association Between Sequence Learning on the Serial Reaction Time Task and Social Impairments in Autism}}. {J Autism Dev Disord}. 2018.
It is assumed that learning on the Serial Reaction Time (SRT) task is related to learning involved in social skill development affected in autism, but this assumption has hardly been investigated. We have therefore examined associations between SRT task learning and social impairment measured by the Social Responsiveness Scale in 72 autistic and non-autistic adults. Results revealed a positive correlation between deterministic sequence learning, putatively involving explicit learning, and social impairment in autistic adults but not in non-autistic adults. No correlations with probabilistic learning were found. These results suggest that the type of learning that helps autistic adults during a deterministic SRT task hinders them during social development, and call for further investigating the ecological validity of the SRT task.
