Pubmed du 05/05/20

mardi 5 mai 2020

1. Corrigendum to Doing things differently : Exploring attachment patterns and parental intentions in families where a child has a diagnosis of autism. Clinical child psychology and psychiatry. 2020 : 1359104520923481.

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2. Ahn Y, Sabouny R, Villa BR, Yee NC, Mychasiuk R, Uddin GM, Rho JM, Shutt TE. Aberrant Mitochondrial Morphology and Function in the BTBR Mouse Model of Autism Is Improved by Two Weeks of Ketogenic Diet. International journal of molecular sciences. 2020 ; 21(9).

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder that exhibits a common set of behavioral and cognitive impairments. Although the etiology of ASD remains unclear, mitochondrial dysfunction has recently emerged as a possible causative factor underlying ASD. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that augments mitochondrial function, and has been shown to reduce autistic behaviors in both humans and in rodent models of ASD. The aim of the current study was to examine mitochondrial bioenergetics in the BTBR mouse model of ASD and to determine whether the KD improves mitochondrial function. We also investigated changes in mitochondrial morphology, which can directly influence mitochondrial function. We found that BTBR mice had altered mitochondrial function and exhibited smaller more fragmented mitochondria compared to C57BL/6J controls, and that supplementation with the KD improved both mitochondrial function and morphology. We also identified activating phosphorylation of two fission proteins, pDRP1(S616) and pMFF(S146), in BTBR mice, consistent with the increased mitochondrial fragmentation that we observed. Intriguingly, we found that the KD decreased pDRP1(S616) levels in BTBR mice, likely contributing to the restoration of mitochondrial morphology. Overall, these data suggest that impaired mitochondrial bioenergetics and mitochondrial fragmentation may contribute to the etiology of ASD and that these alterations can be reversed with KD treatment.

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3. Al-Harbi NO, Nadeem A, Ahmad SF, Al-Ayadhi LY, Al-Harbi MM, As Sobeai HM, Ibrahim KE, Bakheet SA. Elevated expression of toll-like receptor 4 is associated with NADPH oxidase-induced oxidative stress in B cells of children with autism. International immunopharmacology. 2020 ; 84 : 106555.

Autism spectrum disorder (ASD) is a childhood disorder with neurodevelopmental dysfunction which manifests as impairment in social behavior and communication skills. B cells play an important role in immune dysfunction where toll-like receptor 4 (TLR4) may contribute through oxidative inflammatory process. TLR4 related signaling and oxidative stress have been reported in the periphery of ASD subjects, however it has not been evaluated in peripheral B cells of ASD subjects and compared with typically developing control (TDC) children. This study evaluated TLR4 expression and related signaling [Bruton’s tyrosine kinase (BTK), spleen tyrosine kinase (SYK), NF-kB, NADPH oxidase (NOX2), nitrotyrosine, superoxide dismutase (SOD)] in ASD and TDC subjects. Current investigation in B cells shows that ASD subjects have increased TLR4 expression and oxidative stress as exhibited by upregulated NOX2 and nitrotyrosine expression as compared to TDC subjects. B cell relevant pathways, BTK/SYK/NF-kB were also upregulated in B cells of ASD group. Treatment with TLR4 agonist, LPS led to upregulation of NOX2 and nitrotyrosine in B cells of ASD whereas it had no significant effect on TDC subjects. Treatment with NF-kB inhibitor caused inhibition of LPS-induced upregulation of NOX2 and nitrotyrosine in B cells of ASD. Therefore, current investigation proposes the notion that TLR4 expression is elevated in B cells which is associated with increased NF-kB signaling and oxidant stress in ASD subjects. In short, peripheral B cells could contribute to systemic oxidative inflammation and contribute to the immune dysfunction in ASD.

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4. Cauvet E, Van’t Westeinde A, Toro R, Kuja-Halkola R, Neufeld J, Mevel K, Bolte S. The Social Brain in Female Autism : A Structural Imaging Study of Twins. Soc Cogn Affect Neurosci. 2020.

A female advantage in social cognition (SoC) might contribute to women’s underrepresentation in autism (ASD). The latter could be underpinned by sex differences in social brain structure. This study investigated the relationship between structural social brain networks and social cognition in females and males in relation to ASD and autistic traits in twins. We used a co-twin design, in 77 twin pairs (39 female) aged 12.5 to 31.0 years. Twin pairs were discordant or concordant for ASD or autistic traits, discordant or concordant for other neurodevelopmental disorders, or concordant for neurotypical development. They underwent structural magnetic resonance imaging and were assessed for SoC using the naturalistic Movie for the Assessment of Social Cognition (MASC). Autistic traits predicted reduced SoC capacities predominantly in male twins, despite a comparable extent of autistic traits in each sex, although the association between SoC and autistic traits did not differ significantly between the sexes. Consistently, within-pair associations between SoC and social brain structure revealed that lower SoC ability was associated with increased cortical thickness of several brain regions, particularly in males. Our findings confirm the notion that sex differences in social cognition in association with ASD are underpinned by sex differences in brain structure.

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5. Hosozawa M, Sacker A, Mandy W, Midouhas E, Flouri E, Cable N. Determinants of an autism spectrum disorder diagnosis in childhood and adolescence : Evidence from the UK Millennium Cohort Study. Autism. 2020 : 1362361320913671.

This study aimed to identify determinants of a late autism spectrum disorder diagnosis, including diagnoses made ’very late’ (i.e., in adolescence), using the Millennium Cohort Study, a nationally representative population-based cohort in the United Kingdom. Children diagnosed with autism spectrum disorder by age 14 (N = 581) were included and grouped by the parent-reported timing of diagnosis : before school (up to age 5), during primary school (age 5-11) and during secondary school (age 11-14). Predictors of diagnostic timing, at the child, family and school levels, were investigated using multinomial logistic regression. Most (79%) children with autism spectrum disorder were diagnosed after school entry, and 28% were not diagnosed until secondary school. Among those not diagnosed until secondary school, 75% had been identified at age 5 years by a parent and/or teacher as having socio-behavioural difficulties. Being diagnosed after starting school was predicted by living in poverty (adjusted relative risk ratio : primary = 1.90, 95% confidence interval : 1.03-3.53 ; secondary = 2.15, 1.05-4.42) and/or having no initial parental concerns (primary = 0.32, 0.15-0.70 ; secondary = 0.19, 0.09-0.43). Having typical-range intelligence also predicted diagnosis during secondary school. The result indicates that those without cognitive delays and poorer children were at risk of ’very late’ (i.e. adolescent) diagnosis. Strategies to promote earlier identification, targeting age at primary school entry, could help those more likely to be diagnosed late. Lay abstract Despite policy emphasis on early identification, many children with autism spectrum disorder are diagnosed late, with some being diagnosed as late as in adolescence. However, evidence on what determines the timing of autism spectrum disorder diagnosis including children diagnosed in adolescence is lacking. Understanding these determinants, particularly in those diagnosed later than is ideal, can inform the development of effective strategies to improve earlier identification of autism spectrum disorder. This study used a nationally representative population-based cohort in the United Kingdom to explore child, family and school level predictors of timing of autism spectrum disorder diagnosis. In the United Kingdom, 79% of the children with autism spectrum disorder were diagnosed after entering primary school and 28% during secondary school. Among those not diagnosed until secondary school, 75% had shown social difficulties noticed by parents and/or teachers at age 5 years. The results suggest that healthcare providers should be aware that, even for universal systems of care, those living in poverty and having higher intelligence are most likely to miss out on a timely diagnosis. Strategies to promote earlier identification among school-aged children, including targeting primary school entry age (i.e. around age 5) and that encouraging referrals for a formal assessment at the first report of concerns over the child’s social development may benefit those children who would otherwise be diagnosed later.

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6. Kozhemiako N, Nunes AS, Vakorin V, Iarocci G, Ribary U, Doesburg SM. Alterations in Local Connectivity and Their Developmental Trajectories in Autism Spectrum Disorder : Does Being Female Matter ?. Cereb Cortex. 2020.

Autism spectrum disorder (ASD) is diagnosed more often in males with a ratio of 1:4 females/males. This bias is even stronger in neuroimaging studies. There is a growing evidence suggesting that local connectivity and its developmental trajectory is altered in ASD. Here, we aim to investigate how local connectivity and its age-related trajectories vary with ASD in both males and females. We used resting-state fMRI data from the ABIDE I and II repository : males (n = 102) and females (n = 92) with ASD, and typically developing males (n = 104) and females (n = 92) aged between 6 and 26. Local connectivity was quantified as regional homogeneity. We found increases in local connectivity in participants with ASD in the somatomotor and limbic networks and decreased local connectivity within the default mode network. These alterations were more pronounced in females with ASD. In addition, the association between local connectivity and ASD symptoms was more robust in females. Females with ASD had the most distinct developmental trajectories of local connectivity compared with other groups. Overall, our findings of more pronounced local connectivity alterations in females with ASD could indicate a greater etiological load for an ASD diagnosis in this group congruent with the female protective effect hypothesis.

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7. Shen L, Zhou Y. Epistemic Egocentrism and Processing of Vaccine Misinformation (Vis-a-vis Scientific Evidence) : The Case of Vaccine-Autism Link. Health Commun. 2020 : 1-12.

A web-based 2 (preexisting position : vaccine-inclined vs. -hesitant) by 2 (message type : scientific evidence vs. misinformation) experimental study was conducted to investigate individuals’ processing of misinformation (vis-a-vis scientific evidence) on the vaccine-autism link within the framework of epistemic egocentrism. Data (N = 996) collected with Qualtrics panel demonstrated that preexisting position shaped individuals’ responses to vaccine-related messages differently such that vaccine-hesitant individuals processed the message more superficially while vaccine-inclined individuals more systematically. There was evidence that involvement moderated information processing. Vaccine-hesitant and -inclined individuals’ intentions to seek further information and to engage others with opposite views in public deliberation were shaped by message perception and source perceptions (trustworthiness and expertise), but in different patterns. Implications of the findings for vaccine-related health communication are discussed.

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8. Wenderski W, Wang L, Krokhotin A, Walsh JJ, Li H, Shoji H, Ghosh S, George RD, Miller EL, Elias L, Gillespie MA, Son EY, Staahl BT, Baek ST, Stanley V, Moncada C, Shipony Z, Linker SB, Marchetto MCN, Gage FH, Chen D, Sultan T, Zaki MS, Ranish JA, Miyakawa T, Luo L, Malenka RC, Crabtree GR, Gleeson JG. Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism. Proceedings of the National Academy of Sciences of the United States of America. 2020 ; 117(18) : 10055-66.

Synaptic activity in neurons leads to the rapid activation of genes involved in mammalian behavior. ATP-dependent chromatin remodelers such as the BAF complex contribute to these responses and are generally thought to activate transcription. However, the mechanisms keeping such "early activation" genes silent have been a mystery. In the course of investigating Mendelian recessive autism, we identified six families with segregating loss-of-function mutations in the neuronal BAF (nBAF) subunit ACTL6B (originally named BAF53b). Accordingly, ACTL6B was the most significantly mutated gene in the Simons Recessive Autism Cohort. At least 14 subunits of the nBAF complex are mutated in autism, collectively making it a major contributor to autism spectrum disorder (ASD). Patient mutations destabilized ACTL6B protein in neurons and rerouted dendrites to the wrong glomerulus in the fly olfactory system. Humans and mice lacking ACTL6B showed corpus callosum hypoplasia, indicating a conserved role for ACTL6B in facilitating neural connectivity. Actl6b knockout mice on two genetic backgrounds exhibited ASD-related behaviors, including social and memory impairments, repetitive behaviors, and hyperactivity. Surprisingly, mutation of Actl6b relieved repression of early response genes including AP1 transcription factors (Fos, Fosl2, Fosb, and Junb), increased chromatin accessibility at AP1 binding sites, and transcriptional changes in late response genes associated with early response transcription factor activity. ACTL6B loss is thus an important cause of recessive ASD, with impaired neuron-specific chromatin repression indicated as a potential mechanism.

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