Pubmed du 12/09/19

jeudi 12 septembre 2019

1. Bahado-Singh RO, Vishweswaraiah S, Aydas B, Mishra NK, Yilmaz A, Guda C, Radhakrishna U. Artificial intelligence analysis of Newborn Leucocyte epigenomic markers for the Prediction of Autism. Brain Res ;2019 (Sep 12):146457.

A great diversity of factors contribute to the pathogenesis of Autism and Autism spectrum disorder (ASD). Early detection is known to correlate with improved long term outcomes. There is therefore intense scientific interest in the pathogenesis of and early prediction of autism. Recent reports suggest that epigenetic alterations may play a vital role in disease pathophysiology. We conducted an epigenome-wide analysis of newborn leucocyte (blood spot) DNA in autism as defined at the time of sample collection. Our goal was to investigate the epigenetic basis of autism and identification of early biomarkers for disease prediction. Infinium HumanMethylation450 BeadChip assay was performed to measure DNA methylation level in 14 autism cases and 10 controls. The accuracy of cytosine methylation for autism detection using six different Machine Learning/Artificial Intelligence (AI) approaches including Deep-Learning (DL) was determined. Ingenuity Pathway Analysis (IPA) was further used to interrogate autism pathogenesis by identifying over-represented biological pathways. We found highly significant dysregulation of CpG methylation in 230 loci (249 genes). DL yielded an AUC (95% CI)=1.00 (0.80-1.00) with 97.5% sensitivity and 100.0% specificity for autism detection. Epigenetic dysregulation was identified in several important candidate genes including some previously linked to autism development e.g. : EIF4E, FYN, SHANK1, VIM, LMX1B, GABRB1, SDHAP3 and PACS2. We observed significant enrichment of molecular pathways involved in neuroinflammation signaling, synaptic long term potentiation, serotonin degradation, mTOR signaling and signaling by Rho-Family GTPases. Our findings suggest significant epigenetic role in autism development and epigenetic markers appeared highly accurate for newborn prediction.

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2. Barnhart WR, Ellsworth DW, Robinson AC, Myers JV, Andridge RR, Havercamp SM. Caregiving in the shadows : National analysis of health outcomes and intensity and duration of care among those who care for people with mental illness and for people with developmental disabilities. Disabil Health J ;2019 (Sep 3):100837.

BACKGROUND : The health impacts of caring for people with mental illness (MI) and developmental disabilities (DD) are not well understood. OBJECTIVE : The present study explored whether health outcomes differed between MI and DD caregivers, and if intensity and duration of care moderated health outcomes. METHODS : Nationally representative 2016 Behavioral Risk Factor Surveillance System survey data were used to explore how caring for people with MI (n=1071) and DD (n=888) impacted general health status and physical and mental health days, and whether intensity and duration of care moderated health outcomes. Logistic regression models and cumulative logistic regression models were used to model health outcomes. RESULTS : Caregivers had worse health (p=0.0001) and more poor physical (p<0.0001) and mental health days (p<0.0001) than non-caregivers. Relative to DD caregivers, MI caregivers had worse health status (p=0.02) and more poor physical (p=0.02) and mental (p=0.003) health days. As intensity of care increased, MI caregivers had more poor physical health days (p=0.04) than DD caregivers and as duration of care increased, MI caregivers had worse health status (p=0.03) than DD caregivers. CONCLUSIONS : Although the care provided to adults with DD was more intense and for a longer duration, MI caregivers had poorer health outcomes and were more impacted by intensity and duration of care. Implications for supporting MI and DD caregivers are discussed.

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3. Bechi M, Agostoni G, Buonocore M, Bosinelli F, Spangaro M, Bianchi L, Cocchi F, Guglielmino C, Cavallaro R, Bosia M. The Influence of Premorbid Adjustment and Autistic Traits on Social Cognitive Dysfunction in Schizophrenia. J Int Neuropsychol Soc ;2019 (Sep 11):1-10.

OBJECTIVES : Premorbid dysfunction during childhood and adolescence is well documented in patients with schizophrenia. Literature pointed out multiple premorbid trajectories leading to different patients’ cognitive status, symptomatology, and global functioning after disease onset. This study aimed at identifying groups of premorbid trajectories and disentangling between group differences in clinical and cognitive measures, focusing on theory of mind (ToM) and autistic traits (ATs). METHODS : Ninety-seven patients with schizophrenia were recruited and assessed for cognitive and ToM abilities, psychopathology, and ATs. A two-step cluster analysis identified three different groups of patients based on premorbid adjustment during childhood, adolescence, and late adolescence (i.e., stable-good, stable-poor, and "deteriorating"). RESULTS : Compared to 66 healthy controls, results showed a widespread impairment in cognitive and ToM abilities among all groups of patients, except for affective ToM and executive functions in the stable-good group. Moreover, the stable-poor group exhibited more pronounced ATs and a more severe ToM impairment, compared to the other two groups of patients. CONCLUSIONS : Our findings highlight the existence of a group of patients with poor premorbid adjustment since childhood, more pronounced ATs and a severe ToM impairment affecting those basic mentalizing skills that are usually preserved in schizophrenia. Results might have intriguing implications in identifying underpinning endophenotypes and implementing cutting-edge rehabilitation programs.

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4. Datta G, Durbin K, Odell A, Ramirez-Inscoe J, Twomey T. An analysis of the five year outcomes of a cohort of 46 deaf children with severe (SLD) or profound and multiple learning difficulties (PMLD) and associated complex needs, including autism (ASD), tracked using the Nottingham Early Cognitive and Listening Links (Early CaLL) : This framework monitors the relationship between sound processor use and listening, spoken language, cognition and communicative development, following cochlear implantation. Cochlear Implants Int ;2019 (Sep 12):1-11.

Objectives : In 2018, routine data of the five year outcomes from a cohort of 46 children, (18 PMLD and 28 SLD, including nine SLD children with an additional diagnosis of ASD), was analysed to investigate the type and amount of benefit provided by cochlear implantation and to examine any differences in outcome patterns across the populations. Methods : The level of functional sound processor use achieved over time was reviewed in relation to listening and spoken language outcomes, alongside social engagement, communicative and cognitive development. The extent to which children were able to close the gap between their overall development and their listening abilities was quantified. The outcomes of the children with an additional diagnosis of ASD, was compared to those of the SLD population as a whole. Results : Although equipment management presented long term challenges, after five years, 80% of children were able to attach some meaning to sound. Children with SLD acquired more auditory skills and spoken language than those with PMLD. Most of the children used a mix of augmentative and alternative communication approaches (AAC), with 7%, all SLD children, acquiring some simple spoken language. An additional diagnosis of ASD had a negative effect on outcomes. Discussion : For 80% of the patients, the provision of cochlear implants provided benefits, although changes were slow to develop and required high levels of adult persistence. Conclusion : Outcomes measures which are population specific and acknowledge challenges, alongside providing ways to recognise individual achievements, by matching them against individual capacity, are of great value to families and practitioners.

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5. Gentles SJ, Nicholas DB, Jack SM, McKibbon KA, Szatmari P. Coming to understand the child has autism : A process illustrating parents’ evolving readiness for engaging in care. Autism ;2019 (Sep 11):1362361319874647.

We report results from a large qualitative study regarding the process of parents coming to understand the child has autism starting from the time of initial developmental concerns. Specifically, we present findings relevant to understanding how parents become motivated and prepared for engaging in care at this early stage. The study included primary data from 45 intensive interviews with 32 mothers and 9 expert professionals from urban and rural regions of Ontario, Canada. Grounded theory methods were used to guide data collection and analysis. Parents’ readiness (motivation and capacity) for engagement develops progressively at different rates as they follow individual paths of meaning making. Four optional steps account for their varied trajectories : forming an image of difference, starting to question the signs, knowing something is wrong, and being convinced it’s autism. Both the nature of the information and professional help parents seek, and the urgency with which they seek them, evolve in predictable ways depending on how far they have progressed in understanding their child has autism. Results indicate the need for sensitivity to parents’ varying awareness and readiness for involvement when engaging with them in early care, tailoring parent support interventions, and otherwise planning family-centered care pathways.

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6. Hense M, Badde S, Kohne S, Dziobek I, Roder B. Visual and Proprioceptive Influences on Tactile Spatial Processing in Adults with Autism Spectrum Disorders. Autism Res ;2019 (Sep 11)

Children with autism spectrum disorders (ASDs) often exhibit altered representations of the external world. Consistently, when localizing touch, children with ASDs were less influenced than their peers by changes of the stimulated limb’s location in external space [Wada et al., Scientific Reports 2015, 4(1), 5985]. However, given the protracted development of an external-spatial dominance in tactile processing in typically developing children, this difference might reflect a developmental delay rather than a set suppression of external space in ASDs. Here, adults with ASDs and matched control-participants completed (a) the tactile temporal order judgment (TOJ) task previously used to test external-spatial representation of touch in children with ASDs and (b) a tactile-visual cross-modal congruency (CC) task which assesses benefits of task-irrelevant visual stimuli on tactile localization in external space. In both experiments, participants localized tactile stimuli to the fingers of each hand, while holding their hands either crossed or uncrossed. Performance differences between hand postures reflect the influence of external-spatial codes. In both groups, tactile TOJ-performance markedly decreased when participants crossed their hands and CC-effects were especially large if the visual stimulus was presented at the same side of external space as the task-relevant touch. The absence of group differences was statistically confirmed using Bayesian statistical modeling : adults with ASDs weighted external-spatial codes comparable to typically developed adults during tactile and visual-tactile spatio-temporal tasks. Thus, atypicalities in the spatial coding of touch for children with ASDs appear to reflect a developmental delay rather than a stable characteristic of ASD. Autism Res 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : A touched limb’s location can be described twofold, with respect to the body (right hand) or the external world (right side). Children and adolescents with autism spectrum disorder (ASD) reportedly rely less than their peers on the external world. Here, adults with and without ASDs completed two tactile localization tasks. Both groups relied to the same degree on external world locations. This opens the possibility that the tendency to relate touch to the external world is typical in individuals with ASDs but emerges with a delay.

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7. Ho WY, Chang JC, Tyan SH, Yen YC, Lim K, Tan BSY, Ong J, Tucker-Kellogg G, Wong P, Koo E, Ling SC. FUS-mediated dysregulation of Sema5a, an autism-related gene, in FUS mice with hippocampus-dependent cognitive deficits. Hum Mol Genet ;2019 (Sep 11)

Pathological FUS inclusions are found in 10% of patients with frontotemporal dementia (FTD) and those with amyotrophic lateral sclerosis (ALS) carrying FUS mutations. Current work indicates that FUS mutations may incur gain-of-toxic functions to drive ALS pathogenesis. However, how FUS dysfunction may affect cognition remains elusive. Using a mouse model expressing wild-type human FUS mimicking the endogenous expression pattern and level within the central nervous system, we found that they developed hippocampus-mediated cognitive deficits accompanied by an age-dependent reduction in spine density and long-term potentiation (LTP) in their hippocampus. However, there were no apparent FUS aggregates, nuclear envelope defects and cytosolic FUS accumulation. These suggest that these proposed pathogenic mechanisms may not be the underlying causes for the observed cognitive deficits. Unbiased transcriptomic analysis identified expression changes in a small set of genes with preferential expression in the neurons and oligodendrocyte lineage cells. Of these, we focused on Sema5a, a gene involved in axon guidance, spine dynamics, Parkinson’s disease and autism spectrum disorders. Critically, FUS binds directly to Sema5a mRNA and regulates Sema5a expression in a FUS-dose-dependent manner. Taken together, our data suggest that FUS-driven Sema5a deregulation may underlie the cognitive deficits in FUS transgenic mice.

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8. Jan RK, Rihs TA, Kojovic N, Sperdin HF, Franchini M, Custo A, Tomescu MI, Michel CM, Schaer M. Neural Processing of Dynamic Animated Social Interactions in Young Children With Autism Spectrum Disorder : A High-Density Electroencephalography Study. Front Psychiatry ;2019 ;10:582.

Background : Atypical neural processing of social visual information contributes to impaired social cognition in autism spectrum disorder. However, evidence for early developmental alterations in neural processing of social contingencies is scarce. Most studies in the literature have been conducted in older children and adults. Here, we aimed to investigate alterations in neural processing of social visual information in children with autism spectrum disorder compared to age-matched typically developing peers. Methods : We used a combination of 129-channel electroencephalography and high-resolution eye-tracking to study differences in the neural processing of dynamic cartoons containing human-like social interactions between 14 male children with autism spectrum disorder and 14 typically developing male children, aged 2-5 years. Using a microstate approach, we identified four prototypical maps in both groups and compared the temporal characteristics and inverse solutions (activation of neural sources) of these maps between groups. Results : Inverse solutions of the group maps that were most dominant during free viewing of the dynamic cartoons indicated decreased prefrontal and cingulate activation, impaired activation of the premotor cortex, and increased activation of parietal, temporal, occipital, and cerebellar regions in children with autism spectrum disorder compared to their typically developing peers. Conclusions : Our findings suggest that impairments in brain regions involved in processing social contingencies embedded in dynamic cartoons are present from an early age in autism spectrum disorder. To the best of our knowledge, this is the first study to investigate neural processing of social interactions of children with autism spectrum disorder using dynamic semi-naturalistic stimuli.

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9. Monteiro SA, Dempsey J, Berry LN, Voigt RG, Goin-Kochel RP. Screening and Referral Practices for Autism Spectrum Disorder in Primary Pediatric Care. Pediatrics ;2019 (Sep 12)

OBJECTIVES : To examine screening practices for autism spectrum disorder (ASD), subsequent referrals, and diagnostic outcomes within a large network of primary pediatric care practices. METHODS : Rates of ASD screening with the Modified Checklist for Autism in Toddlers (M-CHAT) at 18- and 24-month well-child visits were examined among 290 primary care providers within 54 pediatric practices between June 2014 and June 2016. Demographic, referral, and diagnostic data were abstracted from the medical records for all children who failed the M-CHAT (ie, score of >/=3) at either or both visits. RESULTS : Rates of M-CHAT screening were 93% at 18 months and 82% at 24 months. Among 23 514 screens, scores of 648 (3%) were >/=3 (386 at 18 months, 262 at 24 months) among 530 unique children who failed 1 or both screenings. Among screen-failed cases, 18% received a diagnosis of ASD and 59% received >/=1 non-ASD neurodevelopmental disorder diagnosis within the follow-up period. Only 31% of children were referred to a specialist for additional evaluation. CONCLUSIONS : High rates of ASD-specific screening do not necessarily translate to increases in subsequent referrals for ASD evaluation or ASD diagnoses. Low rates of referrals and/or lack of follow-through on referrals appear to contribute to delays in children’s receipt of ASD diagnoses. Additional education of primary care providers regarding the referral process after a failed ASD screening is warranted.

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10. Murakami Y, Imamura Y, Saito K, Sakai D, Motyama J. Altered kynurenine pathway metabolites in a mouse model of human attention-deficit hyperactivity/autism spectrum disorders : A potential new biological diagnostic marker. Sci Rep ;2019 (Sep 12) ;9(1):13182.

Deleterious mutations in patchd1 domain containing 1 (PTCHD1) gene have been identified in patients with intellectual disability and/or autism spectrum disorder (ASD). To clarify the causal relationship between Ptchd1 deficiency and behavioral defects relevant to neurodevelopmental disorders, we generated global Ptchd1 knockout (KO) mice. Ptchd1 KO mice displayed hyperlocomotion, increased impulsivity, and lower recognition memory, which resemble attention-deficit hyperactivity disorder (ADHD)-like behaviors. Acute or chronic treatment with atomoxetine ameliorated almost all behavioral deficits in Pthcd1 KO mice. We next determined possible involvement of the kynurenine pathway (KP) metabolites in neurodevelopmental disorders in Ptchd1 KO mice and assessed the potential of KP metabolites as biomarkers for ADHD and/or ASD. Ptchd1 KO mice showed drastic changes in KP metabolite concentrations in the serum and the brain, indicating that the activated KP is associated with ADHD-like behaviors. Our findings indicate that Ptchd1 KO mice can be used as an animal model of human ADHD and/or ASD, and KP metabolites are potential diagnostic biomarkers for neurodevelopmental disorders.

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11. Ribeiro R, Nicoli JR, Santos G, Lima-Santos J. Impact of vitamin deficiency on microbiota composition and immunomodulation : relevance to autistic spectrum disorders. Nutr Neurosci ;2019 (Sep 11):1-13.

OBJECTIVES : Inappropriate vitamin supply is a public health problem and is related to abnormalities in brain development, immune response and, more recently, in changes of gut microbial composition. It is known that low levels of vitamin in early life are linked to increased susceptibility to neurodevelopmental disorders, such as Autism Spectrum Disorders (ASD). Unfortunately, the possible peripheral influences of vitamin deficiency that leads to alterations in the gut microbiota-immune-brain axis, one important modulator of the ASD pathology, remain unclear. This narrative review discusses how the impact of vitamin deficiency results in changes in the immune regulation and in the gut microbiota composition, trying to understand how these changes may contribute for the development and severity of ASD. METHODS : The papers were selected using Pubmed and other databases. This review discusses the following topics : (1) vitamin deficiency in alterations of central nervous system in autism, (2) the impact of low levels of vitamins in immunomodulation and how it can favor imbalance in gut microbiota composition and gastrointestinal (GI) disturbances, (3) gut microbiota imbalance/inflammation associated with the ASD pathophysiology, and (4) possible evidences of the role of vitamin deficiency in dysfunctional gut microbiota-immune-brain axis in ASD. RESULTS : Studies indicate that hypovitaminosis A, B12, D, and K have been co-related with the ASD neuropathology. Furthermore, it was shown that low levels of these vitamins favor the Th1/Th17 environment in the gut, as well as the growth of enteropathogens linked to GI disorders. DISCUSSION : GI disorders and alterations in the gut microbiota-immune-brain axis seems to be linked with ASD severity. Although unclear, hypovitaminosis appears to regulate peripherally the ASD pathophysiology by modulating the gut microbiota-immune-brain axis, however, more research is still necessary to confirm this hypothesis.

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12. Vaidya CJ, You X, Mostofsky S, Pereira F, Berl MM, Kenworthy L. Data-driven identification of subtypes of executive function across typical development, attention deficit hyperactivity disorder, and autism spectrum disorders. J Child Psychol Psychiatry ;2019 (Sep 11)

BACKGROUND : Impairment of executive function (EF), the goal-directed regulation of thoughts, actions, and emotions, drives negative outcomes and is common across neurodevelopmental disorders including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). A primary challenge to its amelioration is heterogeneity in symptom expression within and across disorders. Parsing this heterogeneity is necessary to attain diagnostic precision, a goal of the NIMH Research Domain Criteria Initiative. We aimed to identify transdiagnostic subtypes of EF that span the normal to impaired spectrum and establish their predictive and neurobiological validity. METHODS : Community detection was applied to clinical parent-report measures in 8-14-year-old children with and without ADHD and ASD from two independent cohorts (discovery N = 320 ; replication N = 692) to identify subgroups with distinct behavioral profiles. Support vector machine (SVM) classification was used to predict subgroup membership of unseen cases. Preliminary neurobiological validation was obtained with existing functional magnetic resonance imaging (fMRI) data on a subsample (N = 84) by testing hypotheses about sensitivity of EF subgroups versus DSM categories. RESULTS : We observed three transdiagnostic EF subtypes characterized by behavioral profiles that were defined by relative weakness in : (a) flexibility and emotion regulation ; (b) inhibition ; and (c) working memory, organization, and planning. The same tripartite structure was also present in the typically developing children. SVM trained on the discovery sample and tested on the replication sample classified subgroup membership with 77.0% accuracy. Split-half SVM classification on the combined sample (N = 1,012) yielded 88.9% accuracy (this SVM is available for public use). As hypothesized, frontal-parietal engagement was better distinguished by EF subtype than DSM diagnosis and the subgroup characterized with inflexibility failed to modulate right IPL activation in response to increased executive demands. CONCLUSIONS : The observed transdiagnostic subtypes refine current diagnostic nosology and augment clinical decision-making for personalizing treatment of executive dysfunction in children.

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13. Warrier V, Toro R, Won H, Leblond CS, Cliquet F, Delorme R, De Witte W, Bralten J, Chakrabarti B, Borglum AD, Grove J, Poelmans G, Hinds DA, Bourgeron T, Baron-Cohen S. Social and non-social autism symptoms and trait domains are genetically dissociable. Commun Biol ;2019 ;2:328.

The core diagnostic criteria for autism comprise two symptom domains - social and communication difficulties, and unusually repetitive and restricted behaviour, interests and activities. There is some evidence to suggest that these two domains are dissociable, though this hypothesis has not yet been tested using molecular genetics. We test this using a genome-wide association study (N = 51,564) of a non-social trait related to autism, systemising, defined as the drive to analyse and build systems. We demonstrate that systemising is heritable and genetically correlated with autism. In contrast, we do not identify significant genetic correlations between social autistic traits and systemising. Supporting this, polygenic scores for systemising are significantly and positively associated with restricted and repetitive behaviour but not with social difficulties in autistic individuals. These findings strongly suggest that the two core domains of autism are genetically dissociable, and point at how to fractionate the genetics of autism.

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14. Yamasue H. [Development of Novel Therapeutics for Core Symptoms of Autism Spectrum Disorder : An Integrative Approach of Clinical Trials, Neuroimaging, and Genomics]. Brain Nerve ;2019 (Sep) ;71(9):971-980.

Discrepancies in the efficacy between single-dose and repeated administrations of oxytocin on autism spectrum disorder (ASD) indicate a time-course change in efficacy. However, the hypothesis cannot be tested without a repeatable, objective, and quantitative measurement of the core symptoms of ASD. The author’s research group comprehensively examined recently examined reported single-site exploratory (n=18, crossover) and multi-site confirmatory (n=106, parallel-group), double-blind, placebo-controlled trials of six-week intranasal oxytocin (48 IU/day) in adult males with ASD. The outcomes were statistically representative values of the objectively quantified facial expression intensity during a semi-structured social interaction in the Autism Diagnostic Observation Schedule. The quantitative facial expression analyses on data from these two independent clinical trials successfully detected and verified the therapeutic effect of repeated administrations of intranasal oxytocin on autistic features in facial expressions during social interaction. Furthermore, for the first time, the recent study demonstrated a time-course change in the efficacy : deterioration during the repetitive administration phase and preservation during the post-treatment phase. Together with our recent study regarding neurochemical mechanisms of deteriorating efficacy of oxytocin, the findings are expected to promote further development of optimized objective, quantitative, and repeatable outcome measures for autistic social deficits and to establish an optimized regimen of oxytocin treatment in ASD.

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