Pubmed du 16/03/20

lundi 16 mars 2020

1. Chao OY, de Velasco EMF, Pathak SS, Maitra S, Zhang H, Duvick L, Wickman K, Orr HT, Hirai H, Yang YM. Targeting inhibitory cerebellar circuitry to alleviate behavioral deficits in a mouse model for studying idiopathic autism. Neuropsychopharmacology. 2020.

Autism spectrum disorder (ASD) encompasses wide-ranging neuropsychiatric symptoms with unclear etiology. Although the cerebellum is a key region implicated in ASD, it remains elusive how the cerebellar circuitry is altered and whether the cerebellum can serve as a therapeutic target to rectify the phenotype of idiopathic ASD with polygenic abnormalities. Using a syndromic ASD model, e.g., Black and Tan BRachyury T(+)Itpr3(tf)/J (BTBR) mice, we revealed that increased excitability of presynaptic interneurons (INs) and decreased intrinsic excitability of postsynaptic Purkinje neurons (PNs) resulted in low PN firing rates in the cerebellum. Knowing that downregulation of Kv1.2 potassium channel in the IN nerve terminals likely augmented their excitability and GABA release, we applied a positive Kv1.2 modulator to mitigate the presynaptic over-inhibition and social impairment of BTBR mice. Selective restoration of the PN activity by a new chemogenetic approach alleviated core ASD-like behaviors of the BTBR strain. These findings highlight complex mechanisms converging onto the cerebellar dysfunction in the phenotypic model and provide effective strategies for potential therapies of ASD.

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2. Guo BQ, Ding SB, Li HB. Blood Biomarker Levels of Methylation Capacity in Autism Spectrum Disorder : A Systematic Review and Meta-analysis. Acta Psychiatr Scand. 2020.

OBJECTIVE : To compare the peripheral blood levels of methionine (Met), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and the SAM/SAH ratio (the most core and predictive indices of cellular methylation ability) between patients with autism spectrum disorder (ASD) and control subjects. METHODS : PubMed, EMBASE, PsycINFO, Web of Science, and Cochrane Library were searched from inception to August 2, 2019, without language restriction. The random-effects model was used to summarize effect sizes. RESULTS : We retrieved 1,493 records, of which 22 studies met inclusion criteria. Our overall analyses findings revealed that individuals with ASD had significantly decreased levels of Met (22 studies ; Hedges’ g = -0.62 ; 95% confidence interval [CI] : -0.89, -0.35), SAM (8 studies ; Hedges’ g = -0.60 ; 95% CI : -0.86, -0.34), and the SAM/SAH ratio (8 studies ; Hedges’ g = -0.98 ; 95% CI : -1.30, -0.66) and significantly increased levels of SAH (8 studies ; Hedges’ g = 0.69 ; 95% CI : 0.43, 0.94). The findings of the overall analyses were quite stable after being verified by sensitivity analyses and in agreement with the corresponding outcomes of subgroup analyses. Additionally, our results from meta-analytic techniques confirmed that the effect estimates of this meta-analysis did not originate from publication bias. CONCLUSION : Individuals with ASD have substantially aberrant peripheral blood levels of Met, SAM, SAH, and the SAM/SAH ratio, which supports the association between impaired methylation capacity and ASD. Therefore, further investigations into these indices as potential biomarkers for diagnosis and therapeutic targets of ASD are warranted.

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3. Freitag CM, Poustka L, Kamp-Becker I, Vogeley K, Tebartz van Elst L. [Transition in autism spectrum disorders]. Zeitschrift fur Kinder- und Jugendpsychiatrie und Psychotherapie. 2020 : 1-3.

Transition in autism spectrum disorders Abstract. Children and adolescents with autism spectrum disorder (ASD) are regularly seen by child and adolescent psychiatrists. Many diagnostic and therapeutic interventions are available for this age group. However, ASD is a rather unknown disorder in adult services, including psychiatry - despite the chronic course and the individual need for diagnosis, intervention, and support also in adulthood. Transition from childhood into adulthood is a rather complex topic that includes the challenge of mastering education and employment. This article presents these transition-related aspects and recommendations to improve healthcare in Germany.

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4. Freitag CM, Jensen K, Teufel K, Luh M, Todorova A, Lalk C, Vllasaliu L. [Empirically based developmental and behavioral intervention programs targeting the core symptoms and language development in toddlers and preschool children with autism spectrum disorder]. Zeitschrift fur Kinder- und Jugendpsychiatrie und Psychotherapie. 2020 : 1-18.

Empirically based developmental and behavioral intervention programs targeting the core symptoms and language development in toddlers and preschool children with autism spectrum disorder Abstract. This systematic review summarizes findings of articles included in the German AWMF-S3 clinical guideline on early intervention in autism spectrum disorders (ASD). We present the current state-of the art of evidence-based interventions for toddlers and preschool-aged children with ASD, specifically targeting the core symptoms and language development. We included studies on manualized developmental and behavioral interventions for children with ASD aged <7 years according to DSM-III(R), DSM-IV(TR), DSM-5, and ICD-10. The publication dates ranged from 1 January 2011 to 31 August 2018 or as included in the NICE-children guidelines. Studies were included by an iterative hierarchy : systematic review > randomized-controlled trial > clinically controlled trial. Outcome measures were core ASD symptoms and precursor abilities, or language abilities. The interventions were collated by (1) frequency and (2) approach. The studies focused on low-intensive interventions targeting parental synchrony, the child’s initiations, reciprocity, joint attention, play and imitation skills as well as comprehensive interventions. Improvement of core ASD symptoms regarding social communication was observed for low-intensive training of parental synchrony and child’s reciprocity as well as for low-intensive comprehensive developmental interventions implementing natural-learning paradigms. High-frequency discrete trial interventions did not improve social communication. Language abilities improved by comprehensive interventions. In conclusion, intervention recommendations are summarized.

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5. Ding Q, Sethna F, Wu XT, Miao Z, Chen P, Zhang Y, Xiao H, Feng W, Feng Y, Li X, Wang H. Transcriptome signature analysis repurposes trifluoperazine for the treatment of fragile X syndrome in mouse model. Communications biology. 2020 ; 3(1) : 127.

Fragile X syndrome (FXS) is a prevailing genetic disorder of intellectual disability and autism. There is no efficacious medication for FXS. Through in silico screening with a public database, computational analysis of transcriptome profile in FXS mouse neurons predicts therapeutic value of an FDA-approved drug trifluoperazine. Systemic administration of low-dose trifluoperazine at 0.05 mg/kg attenuates multiple FXS- and autism-related behavioral symptoms. Moreover, computational analysis of transcriptome alteration caused by trifluoperazine suggests a new mechanism of action against PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) activity. Consistently, trifluoperazine suppresses PI3K activity and its down-stream targets Akt (protein kinase B) and S6K1 (S6 kinase 1) in neurons. Further, trifluoperazine normalizes the aberrantly elevated activity of Akt and S6K1 and enhanced protein synthesis in FXS mouse. Together, our data demonstrate a promising value of transcriptome-based computation in identification of therapeutic strategy and repurposing drugs for neurological disorders, and suggest trifluoperazine as a potential treatment for FXS.

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6. Forgeot d’Arc B, Devaine M, Daunizeau J. Social behavioural adaptation in Autism. PLoS computational biology. 2020 ; 16(3) : e1007700.

Autism is still diagnosed on the basis of subjective assessments of elusive notions such as interpersonal contact and social reciprocity. We propose to decompose reciprocal social interactions in their basic computational constituents. Specifically, we test the assumption that autistic individuals disregard information regarding the stakes of social interactions when adapting to others. We compared 24 adult autistic participants to 24 neurotypical (NT) participants engaging in a repeated dyadic competitive game against artificial agents with calibrated reciprocal adaptation capabilities. Critically, participants were framed to believe either that they were competing against somebody else or that they were playing a gambling game. Only the NT participants did alter their adaptation strategy when they held information regarding others’ competitive incentives, in which case they outperformed the AS group. Computational analyses of trial-by-trial choice sequences show that the behavioural repertoire of autistic people exhibits subnormal flexibility and mentalizing sophistication, especially when information regarding opponents’ incentives was available. These two computational phenotypes yield 79% diagnosis classification accuracy and explain 62% of the severity of social symptoms in autistic participants. Such computational decomposition of the autistic social phenotype may prove relevant for drawing novel diagnostic boundaries and guiding individualized clinical interventions in autism.

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7. Monteiro MA, Santos A, Gomes LMM, Rito R. AUTISM SPECTRUM DISORDER : A SYSTEMATIC REVIEW ABOUT NUTRITIONAL INTERVENTIONS. Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo. 2020 ; 38 : e2018262.

OBJECTIVE : To identify and analyze the scientific evidence of nutritional interventions performed in children and adolescents with Autism Spectrum Disorder. DATA SOURCES : A systematic review was conducted in the MEDLINE, Cochrane Library, Embase, LILACS, Google Scholar, PubMed, PsycINFO and Periodicos CAPES databases, using a search strategy to identify studies published between January 2003 and March 2018, in Portuguese, English and Spanish. Were included studies that described nutritional interventions in children and adolescents with autism spectrum disorders and assessed autistic behavior and/or gastrointestinal symptoms. We excluded other review articles and studies that did not include a control group in the research design. The studies were reviewed for descriptive information, and the quality of evidence was assessed through the GRADE system. DATA SYNTHESIS : 18 studies were included in the review, being 16 randomized clinical trials, 1 case-control study and 1 open-label trial. As a result, the implementation of a gluten-free and casein-free diet was the most used intervention among the studies. Of the total, 10 studies showed a positive association of intervention with the evaluated results, while 8 did not find of a significant association. CONCLUSIONS : Although some authors report progress in the symptoms associated with autism in individuals with Autistic Spectrum Disorder undergoing nutritional interventions, there is little scientific evidence to support the use of nutritional supplements or dietary therapies in children and adolescents with autism.

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