1. Bakheet SA, Alzahrani MZ, Nadeem A, Ansari MA, Zoheir KM, Attia SM, Al-Ayadhi LY, Ahmad SF. {{Resveratrol treatment attenuates chemokine receptor expression in the BTBR T+tf/J mouse model of autism}}. {Mol Cell Neurosci};2016 (Sep 29);77:1-10.
Autism is a neurodevelopmental disorder categorized by qualitative impairments in social interaction, communication, and repetitive stereotypic behavior. Emerging evidence increasingly suggests that chemokine receptors have a pivotal role in the central nervous system and are involved in the pathogenesis of numerous neuroinflammatory diseases. Resveratrol is widely used to treat neurodegenerative diseases, but its effect on autism has not been investigated. We investigated the effect of resveratrol (20 and 40mg/kg) in the spleen and brain tissues of BTBR T+tf/J (BTBR) and C57BL/6J (B6) mice as well as on the C-C chemokine receptor (CCR) and C-X-C motif chemokine receptor (CXCR) (CCR3+, CCR5+, CCR7+ and CCR9+, CXCR3+ and CXCR5+) in cluster of differentiation 4-positive (CD4+) T cells in the spleen. We also assessed the mRNA expression of CCR and CXCR receptors in the spleen and brain tissues. Our study revealed that the BTBR and B6 control mice showed different immune profiles. The BTBR mice showed characteristic higher levels of both CCR and CXCR production and expression in CD4+ T cells than the B6 control mice did. Treatment of B6 and BTBR mice with resveratrol (20 and 40mg/kg) induced a substantial decrease in the CCR and CXCR production and expression in CD4+ T cells compared with the respective untreated control groups. Moreover, resveratrol treatment decreased the mRNA expression levels of CCR and CXCR in the spleen and brain tissues. Resveratrol downregulated the chemokine receptor levels, which might provide unique targets for future therapies for autism.
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2. Cheung CH, Bedford R, Johnson MH, Charman T, Gliga T. {{Visual search performance in infants associates with later ASD diagnosis}}. {Dev Cogn Neurosci};2016 (Sep 30)
An enhanced ability to detect visual targets amongst distractors, known as visual search (VS), has often been documented in Autism Spectrum Disorders (ASD). Yet, it is unclear when this behaviour emerges in development and if it is specific to ASD. We followed up infants at high and low familial risk for ASD to investigate how early VS abilities links to later ASD diagnosis, the potential underlying mechanisms of this association and the specificity of superior VS to ASD. Clinical diagnosis of ASD as well as dimensional measures of ASD, attention-deficit/hyperactivity disorder (ADHD) and anxiety symptoms were ascertained at 3 years. At 9 and 15 months, but not at age 2 years, high-risk children who later met clinical criteria for ASD (HR-ASD) had better VS performance than those without later diagnosis and low-risk controls. Although HR-ASD children were also more attentive to the task at 9 months, this did not explain search performance. Superior VS specifically predicted 3 year-old ASD but not ADHD or anxiety symptoms. Our results demonstrate that atypical perception and core ASD symptoms of social interaction and communication are closely and selectively associated during early development, and suggest causal links between perceptual and social features of ASD.
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3. David N, Schneider TR, Peiker I, Al-Jawahiri R, Engel AK, Milne E. {{Variability of cortical oscillation patterns: A possible endophenotype in autism spectrum disorders?}}. {Neurosci Biobehav Rev};2016 (Oct 13);71:590-600.
Autism spectrum disorders (ASD) have been associated with altered neural oscillations, especially fast oscillatory activity in the gamma frequency range, suggesting fundamentally disturbed temporal coordination of activity during information processing. A detailed review of available cortical oscillation studies in ASD does not convey a clear-cut picture with respect to dysfunctional oscillation patterns in the gamma or other frequency ranges. Recent evidence suggests that instead of a general failure to activate or synchronize the cortex, there is greater intra-participant variability across behavioral, fMRI and EEG responses in ASD. Intra-individual fluctuations from one trial to another have been largely ignored in task-related neural oscillation studies of ASD, which instead have focused on mean changes in power. We highlight new avenues for the analysis of cortical oscillation patterns in ASD which are sensitive to trial-to-trial variability within the participant, in order to validate the significance of increased response variability as possible endophenotype of the disorder.
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4. Drenthen GS, Barendse EM, Aldenkamp AP, van Veenendaal TM, Puts NA, Edden RA, Zinger S, Thoonen G, Hendriks MP, Kessels RP, Jansen JF. {{Altered neurotransmitter metabolism in adolescents with high-functioning autism}}. {Psychiatry Res};2016 (Oct 30);256:44-49.
Previous studies have suggested that alterations in excitatory/inhibitory neurotransmitters might play a crucial role in autism spectrum disorder (ASD). Proton magnetic resonance spectroscopy (1H-MRS) can provide valuable information about abnormal brain metabolism and neurotransmitter concentrations. However, few 1H-MRS studies have been published on the imbalance of the two most abundant neurotransmitters in ASD: glutamate (Glu) and gamma-aminobutyric acid (GABA). Moreover, to our knowledge none of these published studies is performed with a study population consisting purely of high-functioning autism (HFA) adolescents. Selecting only individuals with HFA eliminates factors possibly related to intellectual impairment instead of ASD. This study aims to assess Glu and GABA neurotransmitter concentrations in HFA. Occipital concentrations of Glu and GABA plus macromolecules (GABA+) were obtained using 1H-MRS relative to creatine (Cr) in adolescents with HFA (n=15 and n=13 respectively) and a healthy control group (n=17). Multiple linear regression revealed significantly higher Glu/Cr and lower GABA+/Glu concentrations in the HFA group compared to the controls. These results imply that imbalanced neurotransmitter levels of excitation and inhibition are associated with HFA in adolescents.
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5. Fregeac J, Colleaux L, Nguyen LS. {{The emerging roles of MicroRNAs in Autism Spectrum Disorders}}. {Neurosci Biobehav Rev};2016 (Oct 25)
Autism spectrum disorders (ASD) are heritable neurodevelopmental conditions characterized by impairment in social interaction and communication and restricted, repetitive, stereotyped patterns of behavior. ASD likely involve deregulation of multiple genes related to brain function and development. MicroRNAs (miRNAs) are post-transcriptional regulators that play key roles in brain development, synapse formation and fine-tuning of genes underlying synaptic plasticity and memory formation. Here, we review recent studies providing genetic and molecular links between miRNA deregulation and ASD pathophysiology. These findings highlight the potential of miRNAs as both biomarkers and therapeutic tools in ASD.
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6. Haebig E, Sterling A, Hoover J. {{Examining the Language Phenotype in Children With Typical Development, Specific Language Impairment, and Fragile X Syndrome}}. {J Speech Lang Hear Res};2016 (Oct 1);59(5):1046-1058.
Purpose: One aspect of morphosyntax, finiteness marking, was compared in children with fragile X syndrome (FXS), specific language impairment (SLI), and typical development matched on mean length of utterance (MLU). Method: Nineteen children with typical development (mean age = 3.3 years), 20 children with SLI (mean age = 4.9 years), and 17 boys with FXS (mean age = 11.9 years) completed the Test of Early Grammatical Impairment (TEGI; Rice & Wexler, 2001), and other cognitive and language assessments. Quantitative comparisons on finiteness marking and qualitative comparisons of unscorable (i.e., nontarget) TEGI responses were conducted. Results: Children with typical development and FXS performed better on finiteness marking than children with SLI. Although unscorable responses were infrequent, boys with FXS produced more unscorable responses than children with typical development and SLI. Conclusions: Although boys with FXS have language deficits, they performed similarly to MLU-matched typically developing children on finiteness marking. This language profile differs from children with SLI, who present with a delay-within-a-delay profile with finiteness marking delays that exceed delays in MLU. Unscorable responses produced by the boys with FXS may reflect pragmatic deficits, which are prominent in this population. Assessment procedures should be carefully considered when examining language in boys with FXS.
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7. Hahn LJ, Brady NC, Fleming KK, Warren SF. {{Joint Engagement and Early Language in Young Children With Fragile X Syndrome}}. {J Speech Lang Hear Res};2016 (Oct 1);59(5):1087-1098.
Purpose: In this study, we examine joint engagement (JE) in young children with fragile X syndrome (FXS) and its relationship to language abilities and autism spectrum disorder symptomatology at 24 to 36 months (toddler period) and 59 to 68 months (child period). Method: Participants were 28 children with FXS (24 boys, four girls) and their mothers. Videotaped home observations were conducted during the toddler period and coded for JE. Language abilities were measured at both ages from a developmental assessment, a functional measure, and from a language sample. The Childhood Autism Rating Scale (Schopler, Reichler, & Renner, 1988) was completed at both ages. Results: Children with FXS spent more time in supported JE than in coordinated JE. Using a weighted JE variable, we found that children with FXS who had higher weighted JE scores also had more advanced expressive language skills at both the toddler and child periods. Weighted JE was negatively related to autism symptomatology in the toddler period. Conclusion: This study provides evidence that children with FXS who use more JE also have more advanced expressive language skills in early development. Therefore, existing early interventions that target JE behaviors may be effective for promoting language, social communication, and social interaction in this population.
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8. Hartman CA, Geurts HM, Franke B, Buitelaar JK, Rommelse NN. {{Changing ASD-ADHD symptom co-occurrence across the lifespan with adolescence as crucial time window: Illustrating the need to go beyond childhood}}. {Neurosci Biobehav Rev};2016 (Sep 11);71:529-541.
Literature on the co-occurrence between Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) is strongly biased by a focus on childhood age. A review of the adolescent and adult literature was made on core and related symptoms of ADHD and ASD. In addition, an empirical approach was used including 17,173 ASD-ADHD symptom ratings from participants aged 0 to 84 years. Results indicate that ASD/ADHD constellations peak during adolescence and are lower in early childhood and old age. We hypothesize that on the border of the expected transition to independent adulthood, ASD and ADHD co-occur most because social adaptation and EF skills matter most. Lower correlations in childhood and older age may be due to more diffuse symptoms reflecting respectively still differentiating and de-differentiating EF functions. We plea for a strong research focus in adolescence which may -after early childhood- be a second crucial time window for catching-up pattern explaining more optimal outcomes. We discuss obstacles and oppportunities of a full lifespan approach into old age.
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9. Ide-Okochi A, Tadaka E. {{A hybrid concept analysis of children of concern: Japanese healthcare professionals’ views of children at a high risk of developmental disability}}. {BMC Pediatr};2016 (Oct 28);16(1):171.
BACKGROUND: The new Diagnostic and Statistical Manual of Mental Disorders (fifth edition, DSM-5) redefined the boundaries of autism as a spectrum. It has been reported that the number of schoolchildren with undiagnosed developmental disorders (DDs) has risen in Japan. Such children referred to as kininaru-kodomo (KK, « children of concern ») by healthcare professionals fall into a gray area. Therefore, KK are often overlooked at infant medical checkups. This leaves KK without necessary medical care and special needs education. It is urgent to explore the KK concept to enable professionals to properly assess and provide for the healthcare needs of these children at a high risk of DD, ideally with early intervention. METHODS: A hybrid model of concept analysis was conducted. Working definitions were obtained from a systematic literature review in the theoretical phase. Subsequent in-depth personal interviews initiated in the fieldwork phase corroborated and refined the concept. These qualitative data were integrated in the final analytical phase to yield the practice-based real definition of KK in clinical settings. RESULTS: Three themes emerged regarding KK children: children who require special care, children whose special healthcare needs are owing to both individual and environmental factors, and children waiting for the development of a new support system for them or their parents. CONCLUSIONS: This study implies that KK are children who require special support because of individual and environmental factors. The concept of KK is considered useful for keeping children with undiagnosed DDs and/or other healthcare needs connected with support networks. It is strongly recommended that a screening tool be developed that reflects the concept of children at a high risk of DD so that children in this gray area may receive necessary support even before diagnosis.
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10. Kang E, Klein EF, Lillard AS, Lerner MD. {{Predictors and Moderators of Spontaneous Pretend Play in Children with and without Autism Spectrum Disorder}}. {Front Psychol};2016;7:1577.
Although pretend play has long been linked to children’s normative cognitive development, inconsistent findings call for greater rigor in examining this relation (Lillard et al., 2013). Spontaneous pretend play is often impacted in atypical development, notably in autism spectrum disorder (ASD). Since ASD traits exist along a continuum in the general population, investigating how pretend play varies across the range of ASD symptoms by indexing variations in ASD traits in both typically developing and ASD populations may provide insight into how ASD symptoms may influence the relation between pretend play and associated processes in cognitive development. This study used rigorous observational methods to assess spontaneous pretend play. Specifically, 5-min free-play sessions with two discrete toy sets were double-coded by blinded coders (coder assignment counterbalanced). Key facets of pretense development [attribution of pretend properties (APP), object substitution (OS), imaginary objects] were examined. These facets of pretend play production were then analyzed in relation to ASD symptoms, as well as plausible, long-theorized correlates [theory of mind (ToM), verbal ability, familiarity, and interest in specific toys]. Forty children (Mage = 6;5, SDage = 1.45; 29 males), six of whom met the threshold for ASD diagnosis via parent-reported ASD symptoms, participated in play sessions and completed measures of verbal IQ and ToM. Besides the measure of child ASD symptoms, parents completed a survey of their child’s interest in and familiarity with the play session toys. Overall, greater ToM predicted more APP, and more interest in the toys presented predicted more OS. In terms of overall pretend play production, two results were counterintuitive. First, among children with more ASD symptoms, verbal ability marginally negatively predicted pretend play production. Second, among children with fewer ASD symptoms, ToM negatively predicted pretend play production. Further probing revealed that the negative effect of ASD symptoms on pretend play was simultaneously moderated by both variables: low ToM and high verbal ability both related to less pretend play production among children with more ASD symptoms. Implications for assessment and subsequent treatment for pretend ability among children with varying degrees of ASD symptoms, as well as for future research, are discussed.
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11. Kaplan YC, Keskin-Arslan E, Acar S, Sozmen K. {{Prenatal selective serotonin reuptake inhibitor use and the risk of autism spectrum disorder in children: A systematic review and meta-analysis}}. {Reprod Toxicol};2016 (Sep 22);66:31-43.
OBJECTIVE: To determine whether an up-to-date systematic review and meta-analysis of observational studies would support the previously suggested associations regarding prenatal selective serotonin reuptake inhibitor (SSRI) use and the risk for autism spectrum disorders (ASD) in children. METHODS: PubMed/MEDLINE, Cochrane Central Register of Controlled Trials and Reprotox databases were searched; observational studies with an exposed and unexposed group were included. RESULTS: The meta-analysis of case-control studies demonstrated a significantly increased risk of ASD in the children whose mothers were prenatally exposed to SSRIs during different exposure time windows (except third trimester). The qualitative review of the cohort studies suggested inconsistent findings. CONCLUSIONS: The significant association between preconception-only SSRI exposure and ASD in the children and negative/inconsistent findings among cohort studies weaken the significant associations detected in this meta-analysis. We suggest that confounding by indication still cannot be ruled out regarding prenatal SSRI exposure and ASD in children.
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12. Keenan BM, Newman LK, Gray KM, Rinehart NJ. {{A qualitative study of attachment relationships in ASD during middle childhood}}. {Attach Hum Dev};2016 (Oct 28):1-21.
Although research has indicated that children with Autism Spectrum Disorder (ASD) display normative attachment behaviours, to date there has been limited qualitative research exploring these relationships. This study aimed to describe qualitative features of the child-caregiver attachment relationship in children with ASD. Primary caregivers to 26 children with ASD (aged 7-14 years) and 23 typically developing children (aged 7-13 years) were administered the Disturbances of Attachment Interview (Smyke & Zeanah, 1999) to elicit descriptions of children’s attachment behaviours. Thematic analysis of interview transcripts indicated that while children with ASD demonstrated a range of normative attachment behaviours, they displayed impairments in the use of the caregiver as a secure base and co-regulating agent. ASD-associated impairments in emotion processing, sharing/reciprocity, and emotion co-regulation, as well as the caregiver’s experience, were important in understanding attachment relationships in ASD. Findings highlight the need to consider the bidirectional nature of the attachment relationship in ASD.
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13. Kessler K, Seymour RA, Rippon G. {{Brain oscillations and connectivity in autism spectrum disorders (ASD): new approaches to methodology, measurement and modelling}}. {Neurosci Biobehav Rev};2016 (Oct 5);71:601-620.
Although atypical social behaviour remains a key characterisation of ASD, the presence of sensory and perceptual abnormalities has been given a more central role in recent classification changes. An understanding of the origins of such aberrations could thus prove a fruitful focus for ASD research. Early neurocognitive models of ASD suggested that the study of high frequency activity in the brain as a measure of cortical connectivity might provide the key to understanding the neural correlates of sensory and perceptual deviations in ASD. As our review shows, the findings from subsequent research have been inconsistent, with a lack of agreement about the nature of any high frequency disturbances in ASD brains. Based on the application of new techniques using more sophisticated measures of brain synchronisation, direction of information flow, and invoking the coupling between high and low frequency bands, we propose a framework which could reconcile apparently conflicting findings in this area and would be consistent both with emerging neurocognitive models of autism and with the heterogeneity of the condition.
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14. Kim JW, Seung H, Kim KC, Gonzales EL, Oh HA, Yang SM, Ko MJ, Han SH, Banerjee S, Shin CY. {{Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism}}. {Neuropharmacology};2016 (Sep 14);113(Pt A):71-81.
Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized primarily by two core behavioral symptoms of social communication deficits and restricted/repetitive behaviors. Investigating the etiological process and identifying an appropriate therapeutic target remain as formidable challenges to overcome ASD due to numerous risk factors and complex symptoms associated with the disorder. Among the various mechanisms that contribute to ASD, the maintenance of excitation and inhibition balance emerged as a key factor to regulate proper functioning of neuronal circuitry. Interestingly, our previous study involving the valproic acid animal model of autism (VPA animal model) has demonstrated excitatory-inhibitory imbalance (E/I imbalance) due to enhanced differentiation of glutamatergic neurons and reduced GABAergic neurons. Here, we investigated the potential of agmatine, an endogenous NMDA receptor antagonist, as a novel therapeutic candidate in ameliorating ASD symptoms by modulating E/I imbalance using the VPA animal model. We observed that a single treatment of agmatine rescued the impaired social behaviors as well as hyperactive and repetitive behaviors in the VPA animal model. We also observed that agmatine treatment rescued the overly activated ERK1/2 signaling in the prefrontal cortex and hippocampus of VPA animal models, possibly, by modulating over-excitability due to enhanced excitatory neural circuit. Taken together, our results have provided experimental evidence suggesting a possible therapeutic role of agmatine in ameliorating ASD-like symptoms in the VPA animal model of ASD.
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15. Kim SH, Joseph RM, Frazier JA, O’Shea TM, Chawarska K, Allred EN, Leviton A, Kuban KK. {{Predictive Validity of the Modified Checklist for Autism in Toddlers (M-CHAT) Born Very Preterm}}. {J Pediatr};2016 (Nov);178:101-107 e102.
OBJECTIVE: To examine the predictive validity of the Modified Checklist for Autism in Toddlers (M-CHAT) administered at age 24 months for autism spectrum disorder (ASD) diagnosed at 10 years of age in a US cohort of 827 extremely low gestational age newborns (ELGANs) followed from birth. STUDY DESIGN: We examined the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the M-CHAT in predicting an ASD diagnosis at age 10 years based on gold standard diagnostic instruments. We then assessed how these predictive parameters were affected by sensorimotor and cognitive impairments, socioeconomic status (SES), and emotional/behavioral dysregulation at age 2 years. RESULTS: Using standard criteria, the M-CHAT had a sensitivity of 52%, a specificity of 84%, a PPV of 20%, and an NPV of 96%. False-positive and false-negative rates were high among children with hearing and vision impairments. High false-positive rates also were associated with lower SES, motor and cognitive impairments, and emotional/behavioral dysregulation at age 2 years. CONCLUSIONS: Among extremely preterm children with ASD, almost one-half were not correctly screened by the M-CHAT at age 2 years. Sensorimotor and cognitive impairments, SES, and emotional/behavioral dysregulation contributed significantly to M-CHAT misclassifications. Clinicians are advised to consider these factors when screening very preterm toddlers for ASD.
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16. Kraneveld AD, Szklany K, de Theije CG, Garssen J. {{Gut-to-Brain Axis in Autism Spectrum Disorders: Central Role for the Microbiome}}. {Int Rev Neurobiol};2016;131:263-287.
Autism spectrum disorders (ASDs) are neurodevelopmental disorders, which occur in early childhood and persist into adulthood. Although the etiology of these disorders is largely unknown, genetic and environmental factors are thought to interplay in the development of ASD. Intestinal microbial dysbiosis, in prenatal and postnatal phases, is an important example of these environmental factors, and gastrointestinal problems including adverse reactions to foods are often reported in these children. In this review, we address the clinical and preclinical findings on the role of the intestinal microbiome in ASD and suggest possible underlying mechanisms. Furthermore, opportunities for (nutritional) interventions in ASD are provided.
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17. Larsen E, Menashe I, Ziats MN, Pereanu W, Packer A, Banerjee-Basu S. {{A systematic variant annotation approach for ranking genes associated with autism spectrum disorders}}. {Mol Autism};2016;7:44.
BACKGROUND: The search for genetic factors underlying autism spectrum disorders (ASD) has led to the identification of hundreds of genes containing thousands of variants that differ in mode of inheritance, effect size, frequency, and function. A major challenge involves assessing the collective evidence in an unbiased, systematic manner for their functional relevance. METHODS: Here, we describe a scoring algorithm for prioritization of candidate genes based on the cumulative strength of evidence for each ASD-associated variant cataloged in AutDB (also known as SFARI Gene). We retrieved data from 889 publications to generate a dataset of 2187 rare and 711 common variants distributed across 461 genes implicated in ASD. Each individual variant was manually annotated with multiple attributes extracted from the original report, followed by score assignment using a set of standardized parameters yielding a single score for each gene. RESULTS: There was a wide variation in scores; SHANK3, CHD8, and ADNP had distinctly higher scores than all other genes in the dataset. Our gene scores were significantly correlated with other recently published rankings of ASD genes (RSpearman = 0.40-0.63; p< 0.0001), providing support for our scoring algorithm. CONCLUSIONS: This new resource, which is freely available, for the first time aggregates on one-platform variants identified from various study types (simplex, multiplex, multigenerational, and consanguineous families), from both common and rare variants, and also incorporates their putative functional consequences to arrive at a genetically and biologically driven ranking scheme. This work represents a major step in moving from simply cataloging autism variants to using data-driven approaches to gain insight into their significance. Lien vers le texte intégral (Open Access ou abonnement)
18. Mesbah-Oskui L, Penna A, Orser BA, Horner RL. {{Reduced expression of alpha5GABAA receptors elicits autism-like alterations in EEG patterns and sleep-wake behavior}}. {Neurotoxicol Teratol};2016 (Oct 25)
A reduction in the activity of GABAA receptors, particularly alpha5 subunit-containing GABAA receptors (alpha5GABAARs), has been implicated in the etiology of Autism Spectrum Disorders (ASD). Genetically modified mice that lack alpha5GABAARs (Gabra5-/-) exhibit autism-like behaviors and both enhanced and impaired learning and memory, depending on the behavioral task. The aim of this study was to examine the electroencephalogram (EEG) activity and sleep-wake behaviors in Gabra5-/- mice and wild-type mice. In addition, since some individuals with ASD can exhibit elevated innate immune response, mice were treated with lipopolysaccharide (LPS; 125mg/kg intraperitoneal injection) or vehicle and EEG and sleep-wake patterns were assessed. The results showed that Gabra5-/- mice (n=3) exhibited elevated 0-2Hz EEG activity during all sleep-wake states (all p<0.04), decreased 8-12Hz EEG activity during REM sleep (p=0.04), and decreased sleep spindles under baseline conditions compared to wild-type controls (n=4) (all pLien vers le texte intégral (Open Access ou abonnement)
19. Pickles A, Le Couteur A, Leadbitter K, Salomone E, Cole-Fletcher R, Tobin H, Gammer I, Lowry J, Vamvakas G, Byford S, Aldred C, Slonims V, McConachie H, Howlin P, Parr JR, Charman T, Green J. {{Parent-mediated social communication therapy for young children with autism (PACT): long-term follow-up of a randomised controlled trial}}. {Lancet};2016 (Oct 24)
BACKGROUND: It is not known whether early intervention can improve long-term autism symptom outcomes. We aimed to follow-up the Preschool Autism Communication Trial (PACT), to investigate whether the PACT intervention had a long-term effect on autism symptoms and continued effects on parent and child social interaction. METHODS: PACT was a randomised controlled trial of a parent-mediated social communication intervention for children aged 2-4 years with core autism. Follow-up ascertainment was done at three specialised clinical services centres in the UK (London, Manchester, and Newcastle) at a median of 5.75 years (IQR 5.42-5.92) from the original trial endpoint. The main blinded outcomes were the comparative severity score (CSS) from the Autism Diagnostic Observation Schedule (ADOS), the Dyadic Communication Assessment Measure (DCMA) of the proportion of child initiatiations when interacting with the parent, and an expressive-receptive language composite. All analyses followed the intention-to-treat principle. PACT is registered with the ISRCTN registry, number ISRCTN58133827. FINDINGS: 121 (80%) of the 152 trial participants (59 [77%] of 77 assigned to PACT intervention vs 62 [83%] of 75 assigned to treatment as usual) were traced and consented to be assessed between July, 2013, and September, 2014. Mean age at follow-up was 10.5 years (SD 0.8). Group difference in favour of the PACT intervention based on ADOS CSS of log-odds effect size (ES) was 0.64 (95% CI 0.07 to 1.20) at treatment endpoint and ES 0.70 (95% CI -0.05 to 1.47) at follow-up, giving an overall reduction in symptom severity over the course of the whole trial and follow-up period (ES 0.55, 95% CI 0.14 to 0.91, p=0.004). Group difference in DCMA child initiations at follow-up showed a Cohen’s d ES of 0.29 (95% CI -0.02 to 0.57) and was significant over the course of the study (ES 0.33, 95% CI 0.11 to 0.57, p=0.004). There were no group differences in the language composite at follow-up (ES 0.15, 95% CI -0.23 to 0.53). INTERPRETATION: The results are the first to show long-term symptom reduction after a randomised controlled trial of early intervention in autism spectrum disorder. They support the clinical value of the PACT intervention and have implications for developmental theory. FUNDING: Medical Research Council.
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20. Schelinski S, Borowiak K, von Kriegstein K. {{Temporal voice areas exist in autism spectrum disorder but are dysfunctional for voice identity recognition}}. {Soc Cogn Affect Neurosci};2016 (Nov);11(11):1812-1822.
The ability to recognise the identity of others is a key requirement for successful communication. Brain regions that respond selectively to voices exist in humans from early infancy on. Currently, it is unclear whether dysfunction of these voice-sensitive regions can explain voice identity recognition impairments. Here, we used two independent functional magnetic resonance imaging studies to investigate voice processing in a population that has been reported to have no voice-sensitive regions: autism spectrum disorder (ASD). Our results refute the earlier report that individuals with ASD have no responses in voice-sensitive regions: Passive listening to vocal, compared to non-vocal, sounds elicited typical responses in voice-sensitive regions in the high-functioning ASD group and controls. In contrast, the ASD group had a dysfunction in voice-sensitive regions during voice identity but not speech recognition in the right posterior superior temporal sulcus/gyrus (STS/STG)-a region implicated in processing complex spectrotemporal voice features and unfamiliar voices. The right anterior STS/STG correlated with voice identity recognition performance in controls but not in the ASD group. The findings suggest that right STS/STG dysfunction is critical for explaining voice recognition impairments in high-functioning ASD and show that ASD is not characterised by a general lack of voice-sensitive responses.
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21. Shedlock K, Susi A, Gorman GH, Hisle-Gorman E, Erdie-Lalena CR, Nylund CM. {{Autism Spectrum Disorders and Metabolic Complications of Obesity}}. {J Pediatr};2016 (Nov);178:183-187 e181.
OBJECTIVES: To assess for an increased risk of obesity, type 2 diabetes mellitus, hypertension, hyperlipidemia, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis in children with autism spectrum disorders (ASD). Additionally, to determine the rates of prescribed treatment for obesity-related metabolic disorders and to determine whether treatment with psychotropic medications is associated with the development of obesity for children with ASD. STUDY DESIGN: A retrospective 1:5 case-control study was performed by use of the Military Health System database from October 2000 to September 2013. For children with ASD and matched controls, International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes for obesity, type 2 diabetes mellitus, hypertension, hyperlipidemia, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, and prescriptions were obtained. Conditional logistic regression determined ORs and 95% CIs. RESULTS: A total of 48 762 individuals with ASD and 243 810 matched controls were identified. Children with ASD had significantly greater odds of having obesity (OR 1.85; 95% CI 1.78-1.92), having obesity-related disorders, and being prescribed a medication when they had these diseases. In children with ASD, mood stabilizers, antipsychotics, antiepileptic drugs, and selective serotonin reuptake inhibitors were associated with obesity. CONCLUSIONS: Children with ASD have an increased risk of obesity and obesity-related metabolic disorders. They are more likely to be prescribed medications to treat these complications, suggesting they may have more severe disease. There is a significant association between the use of some psychotropic categories and a diagnosis of obesity, suggesting that obesity in children with ASD may be partially iatrogenic.
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22. Shen Y, Ou J, Liu M, Shi L, Li Y, Xiao L, Dong H, Zhang F, Xia K, Zhao J. {{Altered plasma levels of chemokines in autism and their association with social behaviors}}. {Psychiatry Res};2016 (Oct 30);244:300-305.
Autism Spectrum Disorder (ASD) is a group of neurodevelopment disorders with an unclear etiology. Chemokines have been implicated in the etiology and pathogenesis of ASD. The current study investigated the plasma levels of seven chemokines (RANTES, Eotaxin, MIP-1 alpha, MIP-1 beta, MCP-1, IP-10, and MIG) in 42 young autistic patients and 35 age-matched typically developing (TD) children. The study also tested the association between these chemokine levels and social behaviors, as measured by the Social Responsiveness Scale (SRS). Compared to the TD children, RANTES, MIP-1alpha, and MIP-1beta were higher, while IP-10 and MIG were lower in the autistic patients, after correcting for multiple comparisons. Among these seven chemokines, MIP-1alpha, MIP-1beta and IP-10 levels were found to be associated with social behaviors in all the participants. Moreover, MIP-1alpha and IP-10 were found to be independent predictors of social behaviors. The results of our study support the hypothesis that altered chemokine levels are involved in the pathophysiology of ASD and they indicate that chemokines plasma levels could be potential biomarkers for ASD.
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23. Sigafoos J, Waddington H. {{6 year follow-up supports early autism intervention}}. {Lancet};2016 (Oct 24)
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24. Tabet R, Vitale N, Moine H. {{Fragile X syndrome: Are signaling lipids the missing culprits?}}. {Biochimie};2016 (Nov);130:188-194.
Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and autism. FXS results from the absence of FMRP, an RNA binding protein associated to ribosomes that influences the translation of specific mRNAs in post-synaptic compartments of neurons. The main molecular consequence of the absence of FMRP is an excessive translation of neuronal protein in several areas of the brain. This local protein synthesis deregulation is proposed to underlie the defect in synaptic plasticity responsible for FXS. Recent findings in neurons of the fragile X mouse model (Fmr1-KO) uncovered another consequence of the lack of FMRP: a deregulation of the diacylglycerol (DAG)/phosphatidic acid (PA) homeostasis. DAG and PA are two interconvertible lipids that influence membrane architecture and that act as essential signaling molecules that activate various downstream effectors, including master regulators of local protein synthesis and actin polymerization. As a consequence, DAG and PA govern a variety of cellular processes, including cell proliferation, vesicle/membrane trafficking and cytoskeletal organization. At the synapse, the level of these lipids is proposed to influence the synaptic activation status. FMRP appears as a master regulator of this neuronal process by controlling the translation of a diacylglycerol kinase enzyme that converts DAG into PA. The deregulated levels of DAG and PA caused by the absence of FMRP could represent a novel therapeutic target for the treatment of FXS.
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25. Thiemann-Bourque K, Brady N, McGuff S, Stump K, Naylor A. {{Picture Exchange Communication System and Pals: A Peer-Mediated Augmentative and Alternative Communication Intervention for Minimally Verbal Preschoolers With Autism}}. {J Speech Lang Hear Res};2016 (Oct 1);59(5):1133-1145.
Purpose: This study was conducted to investigate the effectiveness of a social intervention that integrates peer-mediated approaches and the Picture Exchange Communication System (PECS). Method: Effects were evaluated using a series of A-B designs replicated across 4 children with severe autism and limited verbal skills. Seven peers without disabilities were trained to use PECS and facilitative social skills. Measures of changes included rates of communication behaviors, modes, functions, and engagement. Results: Outcomes revealed an intervention effect for 1 child with autism, and this effect was replicated across 3 other children. All children improved in peer-directed communication, with greater increases for 2 children during snack time. For each child with autism, the primary communication behavior was to initiate with picture symbols to request; the peer’s primary communication was to respond. Two children increased communicative functions to comment and to share, and all 4 children showed improved social engagement. All peers increased their communication with the children with autism. Conclusions: These findings add to the limited research on the benefits of teaching typically developing peers to be responsive listeners to preschoolers with autism by learning to use PECS. These results invite further investigation of teaching peers other augmentative and alternative communication approaches and how to increase children’s communication with peers for different purposes.
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26. Vanwong N, Prommas S, Puangpetch A, Hongkaew Y, Nuntamool N, Nakorn CN, Ngamsamut N, Limsila P, Sukasem C. {{Development and Validation of Liquid Chromatography/Tandem Mass Spectrometry Analysis for Therapeutic Drug Monitoring of Risperidone and 9-Hydroxyrisperidone in Pediatric Patients with Autism Spectrum Disorders}}. {J Clin Lab Anal};2016 (Nov);30(6):1236-1246.
BACKGROUND: Risperidone (RIS) is a widely used atypical antipsychotic drug. We developed and validated a sensitive and accurate LC-MS/MS method, which requires a small-volume of plasma and small-volume injection for measurement of RIS levels in ASD pediatric patients. We also investigated the relationship between RIS levels and RIS dosages, including prolactin levels. METHOD: Blood samples were processed by protein precipitation extraction. Only 1 mul of sample was injected. Plasma samples were separated on a C18 column (4.6 cm x 50 mm; 1.8 mum particle size). Detection was by MS-MS with an analytical run time of 6 min. RESULTS: The inter-day accuracy of RIS was 101.33-107.68% and 95.24-103.67% for 9-OH-RIS. The inter-day precision of RIS was Lien vers le texte intégral (Open Access ou abonnement)
27. Varga E, Nemes C, Tancos Z, Bock I, Berzsenyi S, Levay G, Roman V, Kobolak J, Dinnyes A. {{Establishment of EHMT1 mutant induced pluripotent stem cell (iPSC) line from a 11-year-old Kleefstra syndrome (KS) patient with autism and normal intellectual performance}}. {Stem Cell Res};2016 (Oct 2);17(3):531-533.
Peripheral blood was collected from a clinically characterized female Kleefstra syndrome patient with a heterozygous, de novo, premature termination codon (PTC) mutation (NM_024757.4(EHMT1):c.3413G>A; p.Trp1138Ter). Peripheral blood mononuclear cells (PBMCs) were reprogrammed with the human OSKM transcription factors using the Sendai-virus (SeV) delivery system. The pluripotency of transgene-free iPSC line was verified by the expression of pluripotency-associated markers and by in vitro spontaneous differentiation towards the 3 germ layers. Furthermore, the iPSC line showed normal karyotype. Our model might offer a good platform to study the pathomechanism of Kleefstra syndrome, also for drug testing, early biomarker discovery and gene therapy studies.
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28. Wang Y, Picard M, Gu Z. {{Genetic Evidence for Elevated Pathogenicity of Mitochondrial DNA Heteroplasmy in Autism Spectrum Disorder}}. {PLoS Genet};2016 (Oct);12(10):e1006391.
Increasing clinical and biochemical evidence implicate mitochondrial dysfunction in the pathophysiology of Autism Spectrum Disorder (ASD), but little is known about the biological basis for this connection. A possible cause of ASD is the genetic variation in the mitochondrial DNA (mtDNA) sequence, which has yet to be thoroughly investigated in large genomic studies of ASD. Here we evaluated mtDNA variation, including the mixture of different mtDNA molecules in the same individual (i.e., heteroplasmy), using whole-exome sequencing data from mother-proband-sibling trios from simplex families (n = 903) where only one child is affected by ASD. We found that heteroplasmic mutations in autistic probands were enriched at non-polymorphic mtDNA sites (P = 0.0015), which were more likely to confer deleterious effects than heteroplasmies at polymorphic mtDNA sites. Accordingly, we observed a ~1.5-fold enrichment of nonsynonymous mutations (P = 0.0028) as well as a ~2.2-fold enrichment of predicted pathogenic mutations (P = 0.0016) in autistic probands compared to their non-autistic siblings. Both nonsynonymous and predicted pathogenic mutations private to probands conferred increased risk of ASD (Odds Ratio, OR[95% CI] = 1.87[1.14-3.11] and 2.55[1.26-5.51], respectively), and their influence on ASD was most pronounced in families with probands showing diminished IQ and/or impaired social behavior compared to their non-autistic siblings. We also showed that the genetic transmission pattern of mtDNA heteroplasmies with high pathogenic potential differed between mother-autistic proband pairs and mother-sibling pairs, implicating developmental and possibly in utero contributions. Taken together, our genetic findings substantiate pathogenic mtDNA mutations as a potential cause for ASD and synergize with recent work calling attention to their unique metabolic phenotypes for diagnosis and treatment of children with ASD.
