1. Azuma H, Mohri I, Tachibana M, Ohno Y, Taniike M. {{[An analysis of the developmental trajectory of children with autism spectrum disorders]}}. {No to hattatsu Brain and development}. 2014 Nov;46(6):429-37.
OBJECTIVE: To investigate the factors that affect the developmental trajectory in autism spectrum disorders (ASD) by means of a questionnaire-based retrospective analysis. METHOD: This study included 292 consecutive Japanese children with ASD who visited the pediatric developmental clinic at the Osaka University Hospital. Questionnaires were completed by caregivers on their first visit and were used for obtaining demographic information as well as nurturing environment and history of supportive intervention. Caregivers also fulfilled out The Infant Behavior Checklist (revised, in Japanese), and The Children’s Behavior Questionnaire (revised, in Japanese). The scores for autistic traits during infancy and at present were compared in order to evaluate the developmental trajectory. RESULTS: Early intervention may attenuate ASD symptoms, whereas unfavorable domestic conditions, any psychiatric or neurological disorder in a family member, and epilepsy as a co-morbidity may aggravate these symptoms. In addition, impaired social interaction among all other ASD symptoms was specifically improved by early intervention, even if such intervention was not tailored to ASD. CONCLUSION: Early intervention and family support are important for children with ASD to promote their social development.
2. Baronio D, Castro K, Gonchoroski T, de Melo GM, Nunes GD, Bambini-Junior V, Gottfried C, Riesgo R. {{Effects of an H3R Antagonist on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid}}. {PloS one}. 2015;10(1):e0116363.
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders primarily characterized by impaired social interaction and communication, and by restricted repetitive behaviors and interests. Ligands of histamine receptor 3 (H3R) are considered potential therapeutic agents for the treatment of different brain disorders and cognitive impairments. Considering this, the aim of the present study is to evaluate the actions of ciproxifan (CPX), an H3R antagonist, on the animal model of autism induced by prenatal exposure to valproic acid (VPA). Swiss mice were prenatally exposed to VPA on embryonic day 11 and assessed for social behavior, nociceptive threshold and repetitive behavior at 50 days of life. The treatment with CPX (3 mg/kg) or saline was administered 30 minutes before each behavioral test. The VPA group presented lower sociability index compared to VPA animals that were treated with CPX. Compared to the Control group, VPA animals presented a significantly higher nociceptive threshold, and treatment with CPX was not able to modify this parameter. In the marble burying test, the number of marbles buried by VPA animals was consistent with markedly repetitive behavior. VPA animals that received CPX buried a reduced amount of marbles. In summary, we report that an acute dose of CPX is able to attenuate sociability deficits and stereotypies present in the VPA model of autism. Our findings have the potential to help the investigations of both the molecular underpinnings of ASD and of possible treatments to ameliorate the ASD symptomatology, although more research is still necessary to corroborate and expand this initial data.
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3. Cef E, van den Berg WE, Ram B, Jaafar IA, Nieuwenhuizen-Bakker IM, Gasparini F, Kushner SA, Willemsen R. {{Fragile X mice have robust mGluR5-dependent alterations of social behaviour in the Automated Tube Test}}. {Neurobiology of disease}. 2015 Jan 3.
Fragile X syndrome is the most common monogenetic form of intellectual disability and autism. Although the Fmr1 knockout mouse model recapitulates many aspects of the human FXS condition, the establishment of robust social behavioural phenotypes suitable for drug screening has been difficult. Here, we describe a novel social behavioural paradigm, the Automated Tube Test (ATT), for which Fmr1 knockout mice demonstrate a highly reliable and robust phenotype. Fmr1 KO mice show highly dominant behaviour over wild-type littermates in the ATT. Consistent with previous findings, we observed a highly significant, albeit partial, rescue of the altered social behaviour of Fmr1 knockout mice in the ATT, using genetic (mGluR5 deletion) or pharmacological inhibition (mGluR5 antagonist) of mGluR5 signalling independently. Together, our results validate the Automated Tube Test as a robust outcome measure for social behaviour in preclinical research for FXS, and confirm the pathophysiological relevance of mGluR5 signalling. Moreover, our findings highlight the strategy of initiating pharmacological intervention in adulthood as holding significant clinical potential.
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4. Choi CH, Schoenfeld BP, Weisz ED, Bell AJ, Chambers DB, Hinchey J, Choi RJ, Hinchey P, Kollaros M, Gertner MJ, Ferrick NJ, Terlizzi AM, Yohn N, Koenigsberg E, Liebelt DA, Zukin RS, Woo NH, Tranfaglia MR, Louneva N, Arnold SE, Siegel SJ, Bolduc FV, McDonald TV, Jongens TA, McBride SM. {{PDE-4 Inhibition Rescues Aberrant Synaptic Plasticity in Drosophila and Mouse Models of Fragile X Syndrome}}. {The Journal of neuroscience : the official journal of the Society for Neuroscience}. 2015 Jan 7;35(1):396-408.
Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.
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5. Church BA, Rice CL, Dovgopoly A, Lopata CJ, Thomeer ML, Nelson A, Mercado E, 3rd. {{Learning, plasticity, and atypical generalization in children with autism}}. {Psychonomic bulletin & review}. 2015 Jan 6.
Individuals with autism spectrum disorder (ASD) show accelerated learning in some tasks, degraded learning in others, and distinct deficits when generalizing to novel situations. Recent simulations with connectionist models suggest that deficits in cortical plasticity mechanisms can account for atypical patterns of generalization shown by some children with ASD. We tested the surprising theoretical prediction, from past simulations, that the children with ASD who show atypical generalization in perceptual categorization tasks will benefit more from training with a single prototypical member of the category than from training with multiple examples, but children with ASD who generalize normally will be comparatively harmed. The experimental results confirmed this prediction, suggesting that plasticity deficits may well underlie the difficulties that some children with ASD have generalizing skills, and these deficits are not specific to the acquisition of social skills, but rather reflect a more general perceptual learning deficit that may impact many abilities.
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6. Heyman M, Hauser-Cram P. {{Negative life events predict performance on an executive function task in young adults with developmental disabilities}}. {Journal of intellectual disability research : JIDR}. 2015 Jan 6.
BACKGROUND: Recent research with typically developing children indicates that chronic stress can be detrimental to the development of executive function. This study extends this work to individuals with developmental disabilities and examines the longitudinal relationship between an indicator of chronic stress, negative life events, and performance on a task of executive function within a group of 30 individuals with early identified developmental disabilities. METHODS: Multilevel modelling was used to analyse the relationship between cumulative negative life events and response time on a Flanker task. RESULTS: As hypothesized, individuals who had experienced more cumulative negative life events in their families demonstrated longer response time, an indicator of less efficient executive function. CONCLUSIONS: The association between cumulative negative life events and executive function for children with developmental disabilities suggests the prominent role of the environment for development in this domain. These findings also suggest the importance of providing services, resources, and interventions that will help families adaptively cope with stressful circumstances.
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7. Hibberd N. {{Starting out – I adopted person-centred care by supporting a patient with autism}}. {Nursing standard (Royal College of Nursing (Great Britain) : 1987)}. 2015 Jan 7;29(19):29.
On clinical placement in a day surgery unit in my second year of training, I helped to care for a patient with autism, whom I will call Helen.
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8. Karp EA, Kuo AA. {{Maternal mental health after a child’s diagnosis of autism spectrum disorder}}. {Jama}. 2015 Jan 6;313(1):81-2.
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9. Richter J, Poustka L, Vomstein K, Haffner J, Parzer P, Stieltjes B, Henze R. {{Volumetric alterations in the heteromodal association cortex in children with autism spectrum disorder}}. {European psychiatry : the journal of the Association of European Psychiatrists}. 2015 Jan 2.
BACKGROUND: We investigated if alterations in higher-order association areas related to schizophrenia, namely the heteromodal association cortex (HASC), are also observable in subjects with autism spectrum disorder (ASD). METHODS: A group of 18 children with ASD and 18 healthy controls (HC) underwent magnetic resonance imaging (MRI). The examination comprised an analysis of group differences in gray matter (GM) volume, surface area (SA) and hemispheric lateralization. RESULTS: Differences in GM volumes in children with ASD and HC were detected in frontal and parietal areas related to the HASC. No HASC structure that showed changes in GM volume exhibited differences in SA. Alterations in hemispheric lateralization between ASD and HC are seen in a frontal area of the HASC. CONCLUSIONS: Our results indicate that changes in HASC areas are not restricted to schizophrenia, but extend to other psychiatric disorders, namely ASD. The lacking group differences in SA indicate that changes in GM volume are possibly evoked by other variables than SA in children with ASD.
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10. Ross JL, Tartaglia N, Merry DE, Dalva M, Zinn AR. {{Behavioral Phenotypes In Males With XYY and Possible Role of Increased NLGN4Y Expression in Autism Features}}. {Genes, brain, and behavior}. 2015 Jan 6.
INTRODUCTION: The male sex chromosome disorder 47,XYY syndrome (XYY) is associated with increased risk for social-emotional difficulties, attention deficit (ADHD), and autism spectrum disorders (ASD). We hypothesize that increased Y chromosome gene copy number in XYY leads to overexpression of Y-linked genes related to brain development and function, thereby increasing risk for these phenotypes. METHODS: We measured expression in blood of two Y genes NLGN4Y and RPS4Y in 26 boys with XYY and 11 male controls and evaluated whether NLGN4Y expression correlates with anxiety, ADHD, depression, and autistic behaviors (from questionnaires) in boys with XYY. RESULTS: The XYY cohort had increased risk of ASD behaviors on the Social Responsiveness Scale (SRS) and increased attention deficits on the Conners’ DSM-IV Inattention and Hyperactive scales. In contrast, there was no increase in reported symptoms of anxiety or depression by the XYY group. Peripheral expression of two Y genes in boys with XYY versus TD controls was increased two-fold in the XYY group. Results from the SRS Total and Autistic Mannerisms scales but not the attention, anxiety or depression measures correlated with peripheral expression of NLGN4Y in boys with XYY. CONCLUSIONS: Males with XYY have social phenotypes that include increased risk for autism related behaviors and ADHD. Expression of NLGN4Y, a gene that may be involved in synaptic function, is increased in boys with XYY, and the level of expression correlates with overall social responsiveness and autism symptoms. Thus, further investigation of NLGN4Y as a plausible ASD risk gene in XYY is warranted.
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11. Uno Y, Uchiyama T, Kurosawa M, Aleksic B, Ozaki N. {{Early exposure to the combined measles-mumps-rubella vaccine and thimerosal-containing vaccines and risk of autism spectrum disorder}}. {Vaccine}. 2015 Jan 3.
OBJECTIVE: This case-control study investigated the relationship between the risk of Autism Spectrum Disorder (ASD) onset, and early exposure to the combined Measles-Mumps-Rubella (MMR) vaccine and thimerosal consumption measured from vaccinations in the highly genetically homogenous Japanese population. METHODS: Vaccination histories at 1, 3, 6, 12, 18, 24, and 36 months from birth were investigated in ASD cases (189 samples), and controls (224 samples) matching age and sex in each case. Crude odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to determine relationship between MMR vaccination and ASD. The differences in mean values of the thimerosal dosage between cases and controls were analyzed using an unpaired t-test. MMR vaccination and thimerosal dosage were also investigated using a conditional multiple-regression model. RESULTS: There were no significant differences in MMR vaccination and thimerosal dosage between cases and controls at any age. Furthermore, the ORs (95% CIs) of MMR vaccination and thimerosal dosage associated with ASD in the conditional multiple regression model were, respectively, 0.875 (0.345-2.222) and 1.205 (0.862-1.683) at age 18 months, 0.724 (0.421-1.243) and 1.343 (0.997-1.808) at 24 months, and 1.040 (0.648-1.668) and 0.844 (0.632-1.128) at 36 months. Thus, there were no significant differences. CONCLUSIONS: No convincing evidence was found in this study that MMR vaccination and increasing thimerosal dose were associated with an increased risk of ASD onset.
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12. Visser EM, Berger HJ, Van Schrojenstein Lantman-De Valk HM, Prins JB, Teunisse JP. {{Cognitive shifting and externalising problem behaviour in intellectual disability and autism spectrum disorder}}. {Journal of intellectual disability research : JIDR}. 2015 Jan 5.
BACKGROUND: Behavioural problems are frequently reported in residential care for people with an intellectual disability (ID) in particular when they are additionally diagnosed with autism spectrum disorder (ASD). There are indications that impairment in cognitive shifting may be associated with problem behaviour. The objectives of this study were (1) to examine the relationship of cognitive shifting and severity of ASD symptoms with externalising problem behaviour in individuals with ID, with and without ASD, and (2) to examine whether a diagnosis based on shifting impairment is more predictive of externalising problem behaviour than an ASD diagnosis. METHOD: Participants consisted of adolescents and young adults with mild ID, with and without ASD (n = 41). Pearson intercorrelations were computed to explore the relationship between shifting impairment and severity of ASD symptoms on the one hand and ratings of externalising problem behaviour on the other hand. t-Tests were performed to analyse differences in externalising problem behaviour. RESULTS: Unlike ASD symptom severity, shifting scores were found to be associated with externalising problem behaviour, but only if shifting was measured using rating scales and not when using neuropsychological tasks. Externalising problem behaviour scores significantly differed when groups were classified according to shifting impairment (impaired vs. non-impaired) but not when they were classified according to ID and ASD diagnoses. CONCLUSIONS: It is proposed to use a cognition-based approach when analysing problem behaviour, thus concentrating not so much on ID and ASD diagnosis and their corresponding symptoms, but rather placing the focus on cognitive symptoms.
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13. Yang H, Huh SO, Hong JS. {{Enhancement of Short-Term Memory by Methyl-6-(Phenylethynyl)-Pyridine in the BTBR T+tf/J Mouse Model of Autism Spectrum Disorder}}. {Endocrinology and metabolism (Seoul, Korea)}. 2015 Jan 5.
BACKGROUND: Autism spectrum disorder (ASD) encompasses a range of disorders that are characterized by social and communication deficits and repetitive behaviors. This study evaluated the effect of methyl-6-(phenylethynyl)-pyridine (MPEP), an antagonist of the mGluR5 metabotropic glutamate receptor, on memory enhancement in the BTBR T+tf/J (BTBR) mouse strain, which has been recognized as a model of ASD. METHODS: The pharmacological effects of MPEP on memory and motor coordination were assessed using the Morris water maze and rotarod tests in BTBR and C57BL/6J (B6) mice. Furthermore, we performed morphological analyses of cerebellar foliation in BTBR and B6 mice using hematoxylin and eosin staining. RESULTS: MPEP-treated BTBR mice exhibited improved learning and memory in the Morris water maze test. MPEP administration also improved motor coordination in the rotarod test. However, no significant difference was observed regarding the numbers of Purkinje cells in the cerebella of BTBR versus normal B6 mice. CONCLUSION: This study suggests that the mGluR5 antagonist MPEP has the potential to ameliorate learning and memory dysfunction and impaired motor coordination in BTBR mice. These results further suggest that the BTBR mouse model may be useful in pharmacological studies investigating drugs that could potentially alleviate cognitive dysfunction in ASD.
