Pubmed du 22/09/19

dimanche 22 septembre 2019

1. Baribeau DA, Vigod S, Pullenayegum E, Kerns CM, Mirena P, Smith IM, Vaillancourt T, Volden J, Waddell C, Zwaigenbaum L, Bennett T, Duku E, Elsabbagh M, Georgiades S, Ungar WJ, Zaidman-Zait A, Szatmari P. Repetitive Behavior Severity as an Early Indicator of Risk for Elevated Anxiety Symptoms in Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry ;2019 (Sep 18)

OBJECTIVE : A significant proportion of children with autism spectrum disorder (ASD) will develop an anxiety disorder during childhood. Restricted and repetitive behavior severity in ASD positively correlates with anxiety severity in cross-sectional surveys. The longitudinal relationship between restricted/repetitive behavior and future anxiety symptoms is unclear. METHOD : In a longitudinal cohort of children with ASD (n = 421), restricted/repetitive behavior severity at enrolment (age 2-5 years) was categorized as ’mild,’ ’moderate,’ or ’severe’ using the Autism Diagnostic Interview-Revised. Elevated anxiety symptoms were defined by a Child Behavior Checklist (parent report) Anxiety subscale T-score > 65 at ages 8-11 years. Multivariable logistic regression with multiple imputation for missing data was used to examine the association between restricted/repetitive behavior severity and elevated anxiety symptoms while adjusting for age, sex, adaptive functioning, baseline anxiety, income, and parenting stress, generating adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS : Approximately 58% of children with severe restricted/repetitive behavior at enrollment had elevated anxiety symptoms by age 11, compared to 41% of those with moderate, and 20% of those with mild restricted/repetitive behavior, respectively. Moderate and severe restricted/repetitive behavior were both associated with increased odds of elevated anxiety [moderate aOR : 2.5 (1.2 to 5.3) ; severe aOR : 3.2 (1.4 to 7.5)]. CONCLUSION : Restricted/repetitive behavior severity at time of ASD diagnosis indicates risk for future anxiety symptoms. This finding increases our understanding of which children with ASD will develop anxiety disorders and may guide research concerning early interventions and etiological mechanisms.

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2. Crawford H, Moss J, Groves L, Dowlen R, Nelson L, Reid D, Oliver C. A Behavioural Assessment of Social Anxiety and Social Motivation in Fragile X, Cornelia de Lange and Rubinstein-Taybi Syndromes. J Autism Dev Disord ;2019 (Sep 21)

Unique socio-behavioural phenotypes are reported for individuals with different neurodevelopmental disorders. Here, the effects of adult familiarity and nature of interaction on social anxiety and social motivation were investigated in individuals with fragile X (FXS ; n = 20), Cornelia de Lange (CdLS ; n = 20) and Rubinstein-Taybi (RTS ; n = 20) syndromes, compared to individuals with Down syndrome (DS ; n = 20). The Social Anxiety and Motivation Rating Scale was employed whilst participants completed four social tasks, each administered separately by a familiar adult, and also by an unfamiliar adult. Compared to participants with DS, those with FXS and RTS exhibited high levels of social anxiety but similar levels of social motivation. Participants with CdLS showed heightened social anxiety and reduced social motivation only during interactions with an unfamiliar adult when active participation was voluntary.

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3. Kryza-Lacombe M, Iturri N, Monk CS, Lee Wiggins J. Face Emotion Processing in Pediatric Irritability : Neural Mechanisms in a Sample Enriched for Irritability With Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry ;2019 (Sep 18)

OBJECTIVE : Characterizing the pathophysiology of irritability symptoms from a dimensional perspective above and beyond diagnostic boundaries is key to developing mechanism-based interventions that can be applied broadly. Face emotion processing deficits are present in youths with elevated levels of irritability. The present study aimed to identify the neural mechanisms of face emotion processing, in a sample enriched for irritability by including youth with high functioning autism spectrum disorder (HF-ASD). METHOD : Youths (N=120, age=8.3-19.2 years) completed an implicit face emotion task during fMRI acquisition. We evaluated how irritability, measured dimensionally, above and beyond diagnostic group, relates to whole-brain neural activation and amygdala connectivity in response to face emotions. RESULTS : Both neural activation and amygdala connectivity differed as a function of irritability level and face emotion in the prefrontal cortex. Youths with higher irritability levels had decreased activation in response to both fearful and happy faces in the left middle frontal gyrus and to happy faces in the left inferior frontal gyrus. Furthermore, increased irritability levels were associated with altered right amygdala connectivity to the left superior frontal gyrus when viewing fearful and sad faces. CONCLUSION : The neural mechanisms of face emotion processing differ in youths with higher irritability compared to their less irritable peers. The findings suggest that these irritability mechanisms may be common to both typically developing and HF-ASD youths. Understanding the neural mechanisms of pediatric irritability symptoms that cut across diagnostic boundaries may be leveraged for future intervention development.

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4. Matsumura K, Baba M, Nagayasu K, Yamamoto K, Kondo M, Kitagawa K, Takemoto T, Seiriki K, Kasai A, Ago Y, Hayata-Takano A, Shintani N, Kuriu T, Iguchi T, Sato M, Takuma K, Hashimoto R, Hashimoto H, Nakazawa T. Autism-associated protein kinase D2 regulates embryonic cortical neuron development. Biochem Biophys Res Commun ;2019 (Sep 17)

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder, characterized by impaired social interaction, repetitive behavior and restricted interests. Although the molecular etiology of ASD remains largely unknown, recent studies have suggested that de novo mutations are significantly involved in the risk of ASD. We and others recently identified spontaneous de novo mutations in PKD2, a protein kinase D family member, in sporadic ASD cases. However, the biological significance of the de novo PKD2 mutations and the role of PKD2 in brain development remain unclear. Here, we performed functional analysis of PKD2 in cortical neuron development using in utero electroporation. PKD2 is highly expressed in cortical neural stem cells in the developing cortex and regulates cortical neuron development, including the neuronal differentiation of neural stem cells and migration of newborn neurons. Importantly, we determined that the ASD-associated de novo mutations impair the kinase activity of PKD2, suggesting that the de novo PKD2 mutations can be a risk factor for the disease by loss of function of PKD2. Our current findings provide novel insight into the molecular and cellular pathogenesis of ASD.

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5. Rajabioun M, Motie Nasrabadi A, Shamsollahi MB, Coben R. Effective brain connectivity estimation between active brain regions in autism using the dual Kalman-based method. Biomed Tech (Berl) ;2019 (Sep 21)

Brain connectivity estimation is a useful method to study brain functions and diagnose neuroscience disorders. Effective connectivity is a subdivision of brain connectivity which discusses the causal relationship between different parts of the brain. In this study, a dual Kalman-based method is used for effective connectivity estimation. Because of connectivity changes in autism, the method is applied to autistic signals for effective connectivity estimation. For method validation, the dual Kalman based method is compared with other connectivity estimation methods by estimation error and the dual Kalman-based method gives acceptable results with less estimation errors. Then, connectivities between active brain regions of autistic and normal children in the resting state are estimated and compared. In this simulation, the brain is divided into eight regions and the connectivity between regions and within them is calculated. It can be concluded from the results that in the resting state condition the effective connectivity of active regions is decreased between regions and is increased within each region in autistic children. In another result, by averaging the connectivity between the extracted active sources of each region, the connectivity between the left and right of the central part is more than that in other regions and the connectivity in the occipital part is less than that in others.

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6. Ross PJ, Zhang WB, Mok RSF, Zaslavsky K, Deneault E, D’Abate L, Rodrigues DC, Yuen RKC, Faheem M, Mufteev M, Piekna A, Wei W, Pasceri P, Landa RJ, Nagy A, Varga B, Salter MW, Scherer SW, Ellis J. Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS. Biol Psychiatry ;2019 (Jul 29)

BACKGROUND : The Xp22.11 locus that encompasses PTCHD1, DDX53, and the long noncoding RNA PTCHD1-AS is frequently disrupted in male subjects with autism spectrum disorder (ASD), but the functional consequences of these genetic risk factors for ASD are unknown. METHODS : To evaluate the functional consequences of PTCHD1 locus deletions, we generated induced pluripotent stem cells (iPSCs) from unaffected control subjects and 3 subjects with ASD with microdeletions affecting PTCHD1-AS/PTCHD1, PTCHD1-AS/DDX53, or PTCHD1-AS alone. Function of iPSC-derived cortical neurons was assessed using molecular approaches and electrophysiology. We also compiled novel and known genetic variants of the PTCHD1 locus to explore the roles of PTCHD1 and PTCHD1-AS in genetic risk for ASD and other neurodevelopmental disorders. Finally, genome editing was used to explore the functional consequences of deleting a single conserved exon of PTCHD1-AS. RESULTS : iPSC-derived neurons from subjects with ASD exhibited reduced miniature excitatory postsynaptic current frequency and N-methyl-D-aspartate receptor hypofunction. We found that 35 ASD-associated deletions mapping to the PTCHD1 locus disrupted exons of PTCHD1-AS. We also found a novel ASD-associated deletion of PTCHD1-AS exon 3 and showed that exon 3 loss altered PTCHD1-AS splicing without affecting expression of the neighboring PTCHD1 coding gene. Finally, targeted disruption of PTCHD1-AS exon 3 recapitulated diminished miniature excitatory postsynaptic current frequency, supporting a role for the long noncoding RNA in the etiology of ASD. CONCLUSIONS : Our genetic findings provide strong evidence that PTCHD1-AS deletions are risk factors for ASD, and human iPSC-derived neurons implicate these deletions in the neurophysiology of excitatory synapses and in ASD-associated synaptic impairment.

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7. Kimura R, Nakata M, Funabiki Y, Suzuki S, Awaya T, Murai T, Hagiwara M. An epigenetic biomarker for adult high-functioning autism spectrum disorder. Sci Rep ;2019 (Sep 20) ;9(1):13662.

Increasing evidence suggests that epigenetic mechanisms play a role in the etiology of autism spectrum disorder (ASD). To date, several studies have attempted to identify epigenetic biomarkers for ASD. However, reliable markers remain to be established and most of these studies have focused on pediatric patients with ASD. In this study, we sought to find an epigenetic DNA methylation biomarker from peripheral blood for adult patients with high-functioning ASD. DNA methylation profiles were analyzed using the Illumina 450 K methylation array. To identify robust candidate markers, we employed two types of machine-learning algorithms for marker selection. We identified a potential marker (cg20793532) for which is the AUC value was 0.79. Notably, cg20793532 was annotated to the PPP2R2C gene, which was hypermethylated and down-regulated in blood from ASD patients compared to that in the controls. Although requiring careful interpretation, this pilot study seems to provide a potential blood biomarker for identifying individuals with high-functioning ASD.

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8. Bruyneel E, Demurie E, Warreyn P, Roeyers H. The mediating role of joint attention in the relationship between motor skills and receptive and expressive language in siblings at risk for autism spectrum disorder. Infant Behav Dev ;2019 (Sep 18) ;57:101377.

Language problems are highly prevalent in younger siblings of children with autism spectrum disorder (HR-sibs), yet little is known about early predictors. There is growing evidence that motor and language development are linked and this connection might be mediated by joint attention. Developmental changes in motor abilities change how children interact with objects and people (e.g., by showing), which may influence language development. This association has however not yet been studied in HR-sibs. The interrelationship between motor, joint attention and language skills was explored in younger siblings of typically developing children (LR-sibs, N = 31) and HR-sibs (N = 32). In both groups, motor skills (composite of fine and gross motor skills) at 10 months influenced receptive and expressive language at 36 months directly and indirectly through joint attention at 14 months. Group status moderated this direct and indirect effect with mainly significant effects in HR-sibs. This indicates that lower motor skills can have cascading effects on joint attention and language in HR-sibs. Consequently, assessment of early motor skills in HR-sibs might hold promise for early identification of motor difficulties but can also be indicative of language difficulties later in life, especially when difficulties with joint attention are also present.

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9. Kazlauskas N, Seiffe A, Campolongo M, Zappala C, Depino AM. Sex-specific effects of prenatal valproic acid exposure on sociability and neuroinflammation : Relevance for susceptibility and resilience in autism. Psychoneuroendocrinology ;2019 (Sep 11) ;110:104441.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with an incidence four times higher in boys than in girls. By analyzing the effect of sex in a mouse model of ASD, we were able to identify immune alterations that could underlie this sex bias. Pregnant mice were injected subcutaneously with 600mg/kg of valproic acid (VPA) or saline at gestational day 12.5. Their male and female offspring were evaluated in a social interaction test at adulthood, and only male VPA mice showed reduced sociability levels and a lack of preference for the social stimulus over a novel object. We then analyzed the corticosterone (CORT) response to an inflammatory stimulus, as a measure of the hypothalamus-pituitary-adrenal (HPA) function, and the neuroinflammatory state in adult and young animals. Adult VPA males exhibited increased basal CORT levels, while VPA females showed levels comparable to controls. As male mice showed a blunted CORT response at PD21 when compared to female mice, we propose that this early dimorphism could explain the different effects of VPA on HPA function. In addition, prenatal VPA exposure resulted in altered astroglial and microglial cell density levels in the cerebellum and dentate gyrus of adult mice. These neuroinflammatory effects were more pronounced in females than males, and appeared at early developmental stages. Hence, these postnatal glial density differences could underlie the behavioral alterations observed in adulthood, when only males show a social deficit. Our work contributes to the understanding of biological mechanisms affected by VPA on male and female rodents and shed light on the study of possible resilience mechanisms in the female population and/or susceptibility to ASD in boys.

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