Dépouillements

Reversed gender ratio of autism spectrum disorder in Smith-Magenis syndrome / H. E. NAG in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 1p. Titre : Reversed gender ratio of autism spectrum disorder in Smith-Magenis syndrome Type de document : Texte imprimé et/ou numérique Auteurs : H. E. NAG, Auteur ; A. NORDGREN, Auteur ; Britt-Marie ANDERLID, Auteur ; T. NAERLAND, Auteur Article en page(s) : 1p. Langues : Anglais (eng) Mots-clés : Autism symptomatology  Gender  Smith-Magenis syndrome Index. décimale : PER Périodiques Résumé : Background: A substantial amount of research shows a higher rate of autistic type of problems in males compared to females. The 4:1 male to female ratio is one of the most consistent findings in autism spectrum disorder (ASD).Lately, the interest in studying ASD in genetic disorders has increased, and research has shown a higher prevalence of ASD in some genetic disorders than in the general population.Smith-Magenis syndrome (SMS) is a rare and complex genetic syndrome caused by an interstitial deletion of chromosome 17p11.2 or a mutation on the retinoic acid induced 1 gene. The disorder is characterised by intellectual disability, multiple congenital anomalies, obesity, neurobehavioural abnormalities and a disrupted circadian sleep-wake pattern. Methods: Parents of 28 persons with SMS between 5 and 50 years old participated in this study. A total of 12 of the persons with SMS were above the age of 18 at the time of the study. A total of 11 came from Sweden and 17 were from Norway.We collected information regarding the number of autism spectrum symptoms using the Social Communication Questionnaire (SCQ) and the Social Responsiveness Scale (SRS). Adaptive behaviour was also measured using the Vineland Adaptive Behavior Scale II. The level of intellectual disability was derived from a review of the medical chart. Results: We found significant gender differences in ASD symptomatology using the SCQ and SRS questionnaires. We found approximately three females per male above the SCQ cutoff. The same differences were not found in the intellectual level and adaptive behaviour or for behavioural and emotional problems.Gender had an independent contribution in a regression model predicting the total SCQ score, and neither the Vineland Adaptive Behavior Scale II nor the Developmental Behaviour Checklist had an independent contribution to the SCQ scores. Conclusion: We found a clear reversed gender difference in ASD symptomatology in persons with SMS. This may be relevant in the search for female protective factors assumed to explain the male bias in ASD. En ligne : http://dx.doi.org/10.1186/s13229-017-0184-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Reversed gender ratio of autism spectrum disorder in Smith-Magenis syndrome [Texte imprimé et/ou numérique] / H. E. NAG, Auteur ; A. NORDGREN, Auteur ; Britt-Marie ANDERLID, Auteur ; T. NAERLAND, Auteur . - 1p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 1p. Mots-clés : Autism symptomatology  Gender  Smith-Magenis syndrome Index. décimale : PER Périodiques Résumé : Background: A substantial amount of research shows a higher rate of autistic type of problems in males compared to females. The 4:1 male to female ratio is one of the most consistent findings in autism spectrum disorder (ASD).Lately, the interest in studying ASD in genetic disorders has increased, and research has shown a higher prevalence of ASD in some genetic disorders than in the general population.Smith-Magenis syndrome (SMS) is a rare and complex genetic syndrome caused by an interstitial deletion of chromosome 17p11.2 or a mutation on the retinoic acid induced 1 gene. The disorder is characterised by intellectual disability, multiple congenital anomalies, obesity, neurobehavioural abnormalities and a disrupted circadian sleep-wake pattern. Methods: Parents of 28 persons with SMS between 5 and 50 years old participated in this study. A total of 12 of the persons with SMS were above the age of 18 at the time of the study. A total of 11 came from Sweden and 17 were from Norway.We collected information regarding the number of autism spectrum symptoms using the Social Communication Questionnaire (SCQ) and the Social Responsiveness Scale (SRS). Adaptive behaviour was also measured using the Vineland Adaptive Behavior Scale II. The level of intellectual disability was derived from a review of the medical chart. Results: We found significant gender differences in ASD symptomatology using the SCQ and SRS questionnaires. We found approximately three females per male above the SCQ cutoff. The same differences were not found in the intellectual level and adaptive behaviour or for behavioural and emotional problems.Gender had an independent contribution in a regression model predicting the total SCQ score, and neither the Vineland Adaptive Behavior Scale II nor the Developmental Behaviour Checklist had an independent contribution to the SCQ scores. Conclusion: We found a clear reversed gender difference in ASD symptomatology in persons with SMS. This may be relevant in the search for female protective factors assumed to explain the male bias in ASD. En ligne : http://dx.doi.org/10.1186/s13229-017-0184-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Effect of epilepsy on autism symptoms in Angelman syndrome / K. A. BAKKE in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 2p. Titre : Effect of epilepsy on autism symptoms in Angelman syndrome Type de document : Texte imprimé et/ou numérique Auteurs : K. A. BAKKE, Auteur ; P. HOWLIN, Auteur ; L. RETTERSTOL, Auteur ; O. J. KANAVIN, Auteur ; A. HEIBERG, Auteur ; T. NAERLAND, Auteur Article en page(s) : 2p. Langues : Anglais (eng) Mots-clés : Angelman syndrome  Autism spectrum disorder  Epilepsy  Epileptic encephalopathy  Seizure onset Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder and epilepsy often co-occur; however, the extent to which the association between autism symptoms and epilepsy is due to shared aetiology or to the direct effects of seizures is a topic of ongoing debate. Angelman syndrome (AS) is presented as a suitable disease model to explore this association. Methods: Data from medical records and questionnaires were used to examine the association between age of epilepsy onset, autism symptoms, genetic aberration and communication level. Forty-eight participants had genetically verified AS (median age 14.5 years; range 1-57 years). A measure of autism symptoms (the Social Communication Questionnaire; SCQ) was completed for 38 individuals aged >/= 4 years. Genetic cause was subgrouped into deletion and other genetic aberrations of the 15q11-q13 area. The number of signs used to communicate (< 20 sign and >/= 20 signs) was used as a measure of nonverbal communication. Results: Mean age of epilepsy onset was 3.0 years (range 3 months-7.8 years). Mean SCQ score for individuals without epilepsy was 13.6 (SD = 6.7) and with epilepsy 17.0 (SD = 5.6; p = 0.17); 58% used fewer than 20 signs to communicate. There were no age differences between groups according to presence of epilepsy, level of nonverbal communication or type of genetic aberration. SCQ scores were higher in individuals with the deletion than in those with other genetic aberrations (18.7 vs 10.8 p = 0.008) and higher in the group who used < 20 signs to communicate (19.4 vs 14.1 p = 0.007). Age of epilepsy onset was correlated with SCQ (r = - 0.61, p < 0.001). Multiple regression showed that age of seizure onset was significantly related to SCQ score (beta = - 0.90; p = 0.006), even when the type of genetic abnormality was controlled (R(2) = 0.53; F = 10.7; p = 0.001). Conclusions: The study provides support for the notion that seizures themselves contribute more to autism symptoms than expected from the underlying genetic pathology alone. The study demonstrates how a rare genetic syndrome such as Angelman syndrome may be used to study the relation between epilepsy and autism symptomatology. En ligne : http://dx.doi.org/10.1186/s13229-017-0185-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Effect of epilepsy on autism symptoms in Angelman syndrome [Texte imprimé et/ou numérique] / K. A. BAKKE, Auteur ; P. HOWLIN, Auteur ; L. RETTERSTOL, Auteur ; O. J. KANAVIN, Auteur ; A. HEIBERG, Auteur ; T. NAERLAND, Auteur . - 2p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 2p. Mots-clés : Angelman syndrome  Autism spectrum disorder  Epilepsy  Epileptic encephalopathy  Seizure onset Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder and epilepsy often co-occur; however, the extent to which the association between autism symptoms and epilepsy is due to shared aetiology or to the direct effects of seizures is a topic of ongoing debate. Angelman syndrome (AS) is presented as a suitable disease model to explore this association. Methods: Data from medical records and questionnaires were used to examine the association between age of epilepsy onset, autism symptoms, genetic aberration and communication level. Forty-eight participants had genetically verified AS (median age 14.5 years; range 1-57 years). A measure of autism symptoms (the Social Communication Questionnaire; SCQ) was completed for 38 individuals aged >/= 4 years. Genetic cause was subgrouped into deletion and other genetic aberrations of the 15q11-q13 area. The number of signs used to communicate (< 20 sign and >/= 20 signs) was used as a measure of nonverbal communication. Results: Mean age of epilepsy onset was 3.0 years (range 3 months-7.8 years). Mean SCQ score for individuals without epilepsy was 13.6 (SD = 6.7) and with epilepsy 17.0 (SD = 5.6; p = 0.17); 58% used fewer than 20 signs to communicate. There were no age differences between groups according to presence of epilepsy, level of nonverbal communication or type of genetic aberration. SCQ scores were higher in individuals with the deletion than in those with other genetic aberrations (18.7 vs 10.8 p = 0.008) and higher in the group who used < 20 signs to communicate (19.4 vs 14.1 p = 0.007). Age of epilepsy onset was correlated with SCQ (r = - 0.61, p < 0.001). Multiple regression showed that age of seizure onset was significantly related to SCQ score (beta = - 0.90; p = 0.006), even when the type of genetic abnormality was controlled (R(2) = 0.53; F = 10.7; p = 0.001). Conclusions: The study provides support for the notion that seizures themselves contribute more to autism symptoms than expected from the underlying genetic pathology alone. The study demonstrates how a rare genetic syndrome such as Angelman syndrome may be used to study the relation between epilepsy and autism symptomatology. En ligne : http://dx.doi.org/10.1186/s13229-017-0185-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Advanced glycation endproducts, dityrosine and arginine transporter dysfunction in autism - a source of biomarkers for clinical diagnosis / A. ANWAR in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 3p. Titre : Advanced glycation endproducts, dityrosine and arginine transporter dysfunction in autism - a source of biomarkers for clinical diagnosis Type de document : Texte imprimé et/ou numérique Auteurs : A. ANWAR, Auteur ; P. M. ABRUZZO, Auteur ; S. PASHA, Auteur ; K. RAJPOOT, Auteur ; A. BOLOTTA, Auteur ; A. GHEZZO, Auteur ; M. MARINI, Auteur ; A. POSAR, Auteur ; Paola VISCONTI, Auteur ; P. J. THORNALLEY, Auteur ; N. RABBANI, Auteur Article en page(s) : 3p. Langues : Anglais (eng) Mots-clés : Advanced glycation endproducts (AGEs)  Amino acid metabolome  Autism spectrum disorder (ASD)  Machine learning  Oxidative stress  Ferrara (CE BIF) Index. décimale : PER Périodiques Résumé : Background: Clinical chemistry tests for autism spectrum disorder (ASD) are currently unavailable. The aim of this study was to explore the diagnostic utility of proteotoxic biomarkers in plasma and urine, plasma protein glycation, oxidation, and nitration adducts, and related glycated, oxidized, and nitrated amino acids (free adducts), for the clinical diagnosis of ASD. Methods: Thirty-eight children with ASD (29 male, 9 female; age 7.6 +/- 2.0 years) and 31 age-matched healthy controls (23 males, 8 females; 8.6 +/- 2.0 years) were recruited for this study. Plasma protein glycation, oxidation, and nitration adducts and amino acid metabolome in plasma and urine were determined by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Machine learning methods were then employed to explore and optimize combinations of analyte data for ASD diagnosis. Results: We found that children with ASD had increased advanced glycation endproducts (AGEs), Nepsilon-carboxymethyl-lysine (CML) and Nomega-carboxymethylarginine (CMA), and increased oxidation damage marker, dityrosine (DT), in plasma protein, with respect to healthy controls. We also found that children with ASD had increased CMA free adduct in plasma ultrafiltrate and increased urinary excretion of oxidation free adducts, alpha-aminoadipic semialdehyde and glutamic semialdehyde. From study of renal handling of amino acids, we found that children with ASD had decreased renal clearance of arginine and CMA with respect to healthy controls. Algorithms to discriminate between ASD and healthy controls gave strong diagnostic performance with features: plasma protein AGEs-CML, CMA-and 3-deoxyglucosone-derived hydroimidazolone, and oxidative damage marker, DT. The sensitivity, specificity, and receiver operating characteristic area-under-the-curve were 92%, 84%, and 0.94, respectively. Conclusions: Changes in plasma AGEs were likely indicative of dysfunctional metabolism of dicarbonyl metabolite precursors of AGEs, glyoxal and 3-deoxyglucosone. DT is formed enzymatically by dual oxidase (DUOX); selective increase of DT as an oxidative damage marker implicates increased DUOX activity in ASD possibly linked to impaired gut mucosal immunity. Decreased renal clearance of arginine and CMA in ASD is indicative of increased arginine transporter activity which may be a surrogate marker of disturbance of neuronal availability of amino acids. Data driven combination of these biomarkers perturbed by proteotoxic stress, plasma protein AGEs and DT, gave diagnostic algorithms of high sensitivity and specificity for ASD. En ligne : http://dx.doi.org/10.1186/s13229-017-0183-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Advanced glycation endproducts, dityrosine and arginine transporter dysfunction in autism - a source of biomarkers for clinical diagnosis [Texte imprimé et/ou numérique] / A. ANWAR, Auteur ; P. M. ABRUZZO, Auteur ; S. PASHA, Auteur ; K. RAJPOOT, Auteur ; A. BOLOTTA, Auteur ; A. GHEZZO, Auteur ; M. MARINI, Auteur ; A. POSAR, Auteur ; Paola VISCONTI, Auteur ; P. J. THORNALLEY, Auteur ; N. RABBANI, Auteur . - 3p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 3p. Mots-clés : Advanced glycation endproducts (AGEs)  Amino acid metabolome  Autism spectrum disorder (ASD)  Machine learning  Oxidative stress  Ferrara (CE BIF) Index. décimale : PER Périodiques Résumé : Background: Clinical chemistry tests for autism spectrum disorder (ASD) are currently unavailable. The aim of this study was to explore the diagnostic utility of proteotoxic biomarkers in plasma and urine, plasma protein glycation, oxidation, and nitration adducts, and related glycated, oxidized, and nitrated amino acids (free adducts), for the clinical diagnosis of ASD. Methods: Thirty-eight children with ASD (29 male, 9 female; age 7.6 +/- 2.0 years) and 31 age-matched healthy controls (23 males, 8 females; 8.6 +/- 2.0 years) were recruited for this study. Plasma protein glycation, oxidation, and nitration adducts and amino acid metabolome in plasma and urine were determined by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Machine learning methods were then employed to explore and optimize combinations of analyte data for ASD diagnosis. Results: We found that children with ASD had increased advanced glycation endproducts (AGEs), Nepsilon-carboxymethyl-lysine (CML) and Nomega-carboxymethylarginine (CMA), and increased oxidation damage marker, dityrosine (DT), in plasma protein, with respect to healthy controls. We also found that children with ASD had increased CMA free adduct in plasma ultrafiltrate and increased urinary excretion of oxidation free adducts, alpha-aminoadipic semialdehyde and glutamic semialdehyde. From study of renal handling of amino acids, we found that children with ASD had decreased renal clearance of arginine and CMA with respect to healthy controls. Algorithms to discriminate between ASD and healthy controls gave strong diagnostic performance with features: plasma protein AGEs-CML, CMA-and 3-deoxyglucosone-derived hydroimidazolone, and oxidative damage marker, DT. The sensitivity, specificity, and receiver operating characteristic area-under-the-curve were 92%, 84%, and 0.94, respectively. Conclusions: Changes in plasma AGEs were likely indicative of dysfunctional metabolism of dicarbonyl metabolite precursors of AGEs, glyoxal and 3-deoxyglucosone. DT is formed enzymatically by dual oxidase (DUOX); selective increase of DT as an oxidative damage marker implicates increased DUOX activity in ASD possibly linked to impaired gut mucosal immunity. Decreased renal clearance of arginine and CMA in ASD is indicative of increased arginine transporter activity which may be a surrogate marker of disturbance of neuronal availability of amino acids. Data driven combination of these biomarkers perturbed by proteotoxic stress, plasma protein AGEs and DT, gave diagnostic algorithms of high sensitivity and specificity for ASD. En ligne : http://dx.doi.org/10.1186/s13229-017-0183-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Oscillatory rhythm of reward: anticipation and processing of rewards in children with and without autism / K. K. STAVROPOULOS in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 4p. Titre : Oscillatory rhythm of reward: anticipation and processing of rewards in children with and without autism Type de document : Texte imprimé et/ou numérique Auteurs : K. K. STAVROPOULOS, Auteur ; Leslie J. CARVER, Auteur Article en page(s) : 4p. Langues : Anglais (eng) Mots-clés : Alpha asymmetry  Autism spectrum disorder  Reward processing  Social stimuli  Theta Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, and multiple theories have emerged concerning core social deficits. While the social motivation hypothesis proposes that deficits in the social reward system cause individuals with ASD to engage less in social interaction, the overly intense world hypothesis (sensory over-responsivity) proposes that individuals with ASD find stimuli to be too intense and may have hypersensitivity to social interaction, leading them to avoid these interactions. Methods: EEG was recorded during reward anticipation and reward processing. Reward anticipation was measured using alpha asymmetry, and post-feedback theta was utilized to measure reward processing. Additionally, we calculated post-feedback alpha suppression to measure attention and salience. Participants were 6- to 8-year-olds with (N = 20) and without (N = 23) ASD. Results: Children with ASD showed more left-dominant alpha suppression when anticipating rewards accompanied by nonsocial stimuli compared to social stimuli. During reward processing, children with ASD had less theta activity than typically developing (TD) children. Alpha activity after feedback showed the opposite pattern: children with ASD had greater alpha suppression than TD children. Significant correlations were observed between behavioral measures of autism severity and EEG activity in both the reward anticipation and reward processing time periods. Conclusions: The findings provide evidence that children with ASD have greater approach motivation prior to nonsocial (compared to social) stimuli. Results after feedback suggest that children with ASD evidence less robust activity thought to reflect evaluation and processing of rewards (e.g., theta) compared to TD children. However, children with ASD evidence greater alpha suppression after feedback compared to TD children. We hypothesize that post-feedback alpha suppression reflects general cognitive engagement-which suggests that children with ASD may experience feedback as overly intense. Taken together, these results suggest that aspects of both the social motivation hypothesis and the overly intense world hypothesis may be occurring simultaneously. En ligne : http://dx.doi.org/10.1186/s13229-018-0189-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Oscillatory rhythm of reward: anticipation and processing of rewards in children with and without autism [Texte imprimé et/ou numérique] / K. K. STAVROPOULOS, Auteur ; Leslie J. CARVER, Auteur . - 4p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 4p. Mots-clés : Alpha asymmetry  Autism spectrum disorder  Reward processing  Social stimuli  Theta Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, and multiple theories have emerged concerning core social deficits. While the social motivation hypothesis proposes that deficits in the social reward system cause individuals with ASD to engage less in social interaction, the overly intense world hypothesis (sensory over-responsivity) proposes that individuals with ASD find stimuli to be too intense and may have hypersensitivity to social interaction, leading them to avoid these interactions. Methods: EEG was recorded during reward anticipation and reward processing. Reward anticipation was measured using alpha asymmetry, and post-feedback theta was utilized to measure reward processing. Additionally, we calculated post-feedback alpha suppression to measure attention and salience. Participants were 6- to 8-year-olds with (N = 20) and without (N = 23) ASD. Results: Children with ASD showed more left-dominant alpha suppression when anticipating rewards accompanied by nonsocial stimuli compared to social stimuli. During reward processing, children with ASD had less theta activity than typically developing (TD) children. Alpha activity after feedback showed the opposite pattern: children with ASD had greater alpha suppression than TD children. Significant correlations were observed between behavioral measures of autism severity and EEG activity in both the reward anticipation and reward processing time periods. Conclusions: The findings provide evidence that children with ASD have greater approach motivation prior to nonsocial (compared to social) stimuli. Results after feedback suggest that children with ASD evidence less robust activity thought to reflect evaluation and processing of rewards (e.g., theta) compared to TD children. However, children with ASD evidence greater alpha suppression after feedback compared to TD children. We hypothesize that post-feedback alpha suppression reflects general cognitive engagement-which suggests that children with ASD may experience feedback as overly intense. Taken together, these results suggest that aspects of both the social motivation hypothesis and the overly intense world hypothesis may be occurring simultaneously. En ligne : http://dx.doi.org/10.1186/s13229-018-0189-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

EHMT1 mosaicism in apparently unaffected parents is associated with autism spectrum disorder and neurocognitive dysfunction / A. DE BOER in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 5p. Titre : EHMT1 mosaicism in apparently unaffected parents is associated with autism spectrum disorder and neurocognitive dysfunction Type de document : Texte imprimé et/ou numérique Auteurs : A. DE BOER, Auteur ; K. VERMEULEN, Auteur ; J. I. M. EGGER, Auteur ; J. G. E. JANZING, Auteur ; N. DE LEEUW, Auteur ; H. E. VEENSTRA-KNOL, Auteur ; N. S. DEN HOLLANDER, Auteur ; H. VAN BOKHOVEN, Auteur ; W. STAAL, Auteur ; T. KLEEFSTRA, Auteur Article en page(s) : 5p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Cognition  Ehtm1  Kleefstra syndrome  Major depressive disorder  Mosaicism Index. décimale : PER Périodiques Résumé : Background: Genetic mosaicism is only detected occasionally when there are no obvious health or developmental issues. Most cases concern healthy parents in whom mosaicism is identified upon targeted testing of a genetic defect that was initially detected in their children. A germline genetic defect affecting the euchromatin histone methyltransferase 1 (EHMT1) gene causes Kleefstra syndrome, which is associated with the typical triad of distinct facial appearance, (childhood) hypotonia, and intellectual disability. A high degree of psychopathology is associated with this syndrome. A few parents with a mosaic EHMT1 mutation have been detected upon testing after a child was diagnosed with a germline EHMT1 defect. At first glance, carriers of a mosaic EHMT1 mutation appeared to function normally. However, recent studies have shown that de novo, postzygotic mutations in important developmental genes significantly contribute to autism spectrum disorder (ASD). Therefore, we hypothesized that EHMT1 mosaicism could cause neuropsychiatric defects. To investigate this, we performed a detailed investigation of cognitive neuropsychiatric parameters in parents identified with EHMT1 mosaicism. Methods: Three adults (two males, one female) with a genetically confirmed diagnosis of EHMT1 mosaicism were examined by means of a battery of tests and observational instruments covering both neurocognitive and psychiatric features. The battery included the following instruments: the Autism Diagnostic Observation Schedule (ADOS), the mini Psychiatric Assessment Schedules for Adults with Developmental Disabilities (mini PAS-ADD), the Vineland Adaptive Behavior Scales (VABS), and the Cambridge Neuropsychological Test Automated Battery (CANTAB). These measures were compared with our previously reported data from Kleefstra syndrome patients with confirmed (germline) EHMT1 defects. Results: All three subjects achieved maximum total scores on the VABS, indicative of adequate (adaptive) functioning. In all, scores above cutoff were found on the ADOS for ASD and on the mini PAS-ADD for major depressive disorder (lifetime). Finally, results on the CANTAB showed impaired cognitive flexibility in all subjects. Conclusion: Individuals with EHMT1 mosaicism seem to have increased vulnerability for developing severe psychopathology, especially ASD and mood disorders. Although at first glance they appear to be well-adapted in their daily functioning, they may experience significant psychiatric symptoms and show reduced cognitive flexibility in comparison to the general population. En ligne : http://dx.doi.org/10.1186/s13229-018-0193-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] EHMT1 mosaicism in apparently unaffected parents is associated with autism spectrum disorder and neurocognitive dysfunction [Texte imprimé et/ou numérique] / A. DE BOER, Auteur ; K. VERMEULEN, Auteur ; J. I. M. EGGER, Auteur ; J. G. E. JANZING, Auteur ; N. DE LEEUW, Auteur ; H. E. VEENSTRA-KNOL, Auteur ; N. S. DEN HOLLANDER, Auteur ; H. VAN BOKHOVEN, Auteur ; W. STAAL, Auteur ; T. KLEEFSTRA, Auteur . - 5p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 5p. Mots-clés : Autism spectrum disorder  Cognition  Ehtm1  Kleefstra syndrome  Major depressive disorder  Mosaicism Index. décimale : PER Périodiques Résumé : Background: Genetic mosaicism is only detected occasionally when there are no obvious health or developmental issues. Most cases concern healthy parents in whom mosaicism is identified upon targeted testing of a genetic defect that was initially detected in their children. A germline genetic defect affecting the euchromatin histone methyltransferase 1 (EHMT1) gene causes Kleefstra syndrome, which is associated with the typical triad of distinct facial appearance, (childhood) hypotonia, and intellectual disability. A high degree of psychopathology is associated with this syndrome. A few parents with a mosaic EHMT1 mutation have been detected upon testing after a child was diagnosed with a germline EHMT1 defect. At first glance, carriers of a mosaic EHMT1 mutation appeared to function normally. However, recent studies have shown that de novo, postzygotic mutations in important developmental genes significantly contribute to autism spectrum disorder (ASD). Therefore, we hypothesized that EHMT1 mosaicism could cause neuropsychiatric defects. To investigate this, we performed a detailed investigation of cognitive neuropsychiatric parameters in parents identified with EHMT1 mosaicism. Methods: Three adults (two males, one female) with a genetically confirmed diagnosis of EHMT1 mosaicism were examined by means of a battery of tests and observational instruments covering both neurocognitive and psychiatric features. The battery included the following instruments: the Autism Diagnostic Observation Schedule (ADOS), the mini Psychiatric Assessment Schedules for Adults with Developmental Disabilities (mini PAS-ADD), the Vineland Adaptive Behavior Scales (VABS), and the Cambridge Neuropsychological Test Automated Battery (CANTAB). These measures were compared with our previously reported data from Kleefstra syndrome patients with confirmed (germline) EHMT1 defects. Results: All three subjects achieved maximum total scores on the VABS, indicative of adequate (adaptive) functioning. In all, scores above cutoff were found on the ADOS for ASD and on the mini PAS-ADD for major depressive disorder (lifetime). Finally, results on the CANTAB showed impaired cognitive flexibility in all subjects. Conclusion: Individuals with EHMT1 mosaicism seem to have increased vulnerability for developing severe psychopathology, especially ASD and mood disorders. Although at first glance they appear to be well-adapted in their daily functioning, they may experience significant psychiatric symptoms and show reduced cognitive flexibility in comparison to the general population. En ligne : http://dx.doi.org/10.1186/s13229-018-0193-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons / N. URRACA in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 6p. Titre : Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons Type de document : Texte imprimé et/ou numérique Auteurs : N. URRACA, Auteur ; K. HOPE, Auteur ; A. K. VICTOR, Auteur ; T. G. BELGARD, Auteur ; R. MEMON, Auteur ; S. GOORHA, Auteur ; C. VALDEZ, Auteur ; Q. T. TRAN, Auteur ; S. SANCHEZ, Auteur ; J. RAMIREZ, Auteur ; M. DONALDSON, Auteur ; D. BRIDGES, Auteur ; L. T. REITER, Auteur Article en page(s) : 6p. Langues : Anglais (eng) Mots-clés : Autism  Genomic disorders  Neurogenetic syndrome  Stem cells  mRNAseq Index. décimale : PER Périodiques Résumé : Background: The inability to analyze gene expression in living neurons from Angelman (AS) and Duplication 15q (Dup15q) syndrome subjects has limited our understanding of these disorders at the molecular level. Method: Here, we use dental pulp stem cells (DPSC) from AS deletion, 15q Duplication, and neurotypical control subjects for whole transcriptome analysis. We identified 20 genes unique to AS neurons, 120 genes unique to 15q duplication, and 3 shared transcripts that were differentially expressed in DPSC neurons vs controls. Results: Copy number correlated with gene expression for most genes across the 15q11.2-q13.1 critical region. Two thirds of the genes differentially expressed in 15q duplication neurons were downregulated compared to controls including several transcription factors, while in AS differential expression was restricted primarily to the 15q region. Here, we show significant downregulation of the transcription factors FOXO1 and HAND2 in neurons from 15q duplication, but not AS deletion subjects suggesting that disruptions in transcriptional regulation may be a driving factor in the autism phenotype in Dup15q syndrome. Downstream analysis revealed downregulation of the ASD associated genes EHPB2 and RORA, both genes with FOXO1 binding sites. Genes upregulated in either Dup15q cortex or idiopathic ASD cortex both overlapped significantly with the most upregulated genes in Dup15q DPSC-derived neurons. Conclusions: Finding a significant increase in both HERC2 and UBE3A in Dup15q neurons and significant decrease in these two genes in AS deletion neurons may explain differences between AS deletion class and UBE3A specific classes of AS mutation where HERC2 is expressed at normal levels. Also, we identified an enrichment for FOXO1-regulated transcripts in Dup15q neurons including ASD-associated genes EHPB2 and RORA indicating a possible connection between this syndromic form of ASD and idiopathic cases. En ligne : http://dx.doi.org/10.1186/s13229-018-0191-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons [Texte imprimé et/ou numérique] / N. URRACA, Auteur ; K. HOPE, Auteur ; A. K. VICTOR, Auteur ; T. G. BELGARD, Auteur ; R. MEMON, Auteur ; S. GOORHA, Auteur ; C. VALDEZ, Auteur ; Q. T. TRAN, Auteur ; S. SANCHEZ, Auteur ; J. RAMIREZ, Auteur ; M. DONALDSON, Auteur ; D. BRIDGES, Auteur ; L. T. REITER, Auteur . - 6p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 6p. Mots-clés : Autism  Genomic disorders  Neurogenetic syndrome  Stem cells  mRNAseq Index. décimale : PER Périodiques Résumé : Background: The inability to analyze gene expression in living neurons from Angelman (AS) and Duplication 15q (Dup15q) syndrome subjects has limited our understanding of these disorders at the molecular level. Method: Here, we use dental pulp stem cells (DPSC) from AS deletion, 15q Duplication, and neurotypical control subjects for whole transcriptome analysis. We identified 20 genes unique to AS neurons, 120 genes unique to 15q duplication, and 3 shared transcripts that were differentially expressed in DPSC neurons vs controls. Results: Copy number correlated with gene expression for most genes across the 15q11.2-q13.1 critical region. Two thirds of the genes differentially expressed in 15q duplication neurons were downregulated compared to controls including several transcription factors, while in AS differential expression was restricted primarily to the 15q region. Here, we show significant downregulation of the transcription factors FOXO1 and HAND2 in neurons from 15q duplication, but not AS deletion subjects suggesting that disruptions in transcriptional regulation may be a driving factor in the autism phenotype in Dup15q syndrome. Downstream analysis revealed downregulation of the ASD associated genes EHPB2 and RORA, both genes with FOXO1 binding sites. Genes upregulated in either Dup15q cortex or idiopathic ASD cortex both overlapped significantly with the most upregulated genes in Dup15q DPSC-derived neurons. Conclusions: Finding a significant increase in both HERC2 and UBE3A in Dup15q neurons and significant decrease in these two genes in AS deletion neurons may explain differences between AS deletion class and UBE3A specific classes of AS mutation where HERC2 is expressed at normal levels. Also, we identified an enrichment for FOXO1-regulated transcripts in Dup15q neurons including ASD-associated genes EHPB2 and RORA indicating a possible connection between this syndromic form of ASD and idiopathic cases. En ligne : http://dx.doi.org/10.1186/s13229-018-0191-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Facial expression recognition as a candidate marker for autism spectrum disorder: how frequent and severe are deficits? / E. LOTH in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 7p. Titre : Facial expression recognition as a candidate marker for autism spectrum disorder: how frequent and severe are deficits? Type de document : Texte imprimé et/ou numérique Auteurs : E. LOTH, Auteur ; L. GARRIDO, Auteur ; Jumana AHMAD, Auteur ; E. WATSON, Auteur ; A. DUFF, Auteur ; B. DUCHAINE, Auteur Article en page(s) : 7p. Langues : Anglais (eng) Mots-clés : Autism Spectrum disorder  Biomarker  Facial expression recognition Index. décimale : PER Périodiques Résumé : Background: Impairments in social communication are a core feature of Autism Spectrum Disorder (ASD). Because the ability to infer other people's emotions from their facial expressions is critical for many aspects of social communication, deficits in expression recognition are a plausible candidate marker for ASD. However, previous studies on facial expression recognition produced mixed results, which may be due to differences in the sensitivity of the many tests used and/or the heterogeneity among individuals with ASD. To ascertain whether expression recognition may serve as a diagnostic marker (which distinguishes people with ASD from a comparison group) or a stratification marker (which helps to divide ASD into more homogeneous subgroups), a crucial first step is to move beyond identification of mean group differences and to better understand the frequency and severity of impairments. Methods: This study tested 46 individuals with ASD and 52 age- and IQ-matched typically developing (TD) participants on the Films Expression Task, which combines three key features of real-life expression recognition: naturalistic facial expressions, a broad range of simple and complex emotions, and short presentation time. Test-retest reliability was assessed in 28 individuals who did not participate in the main study and revealed acceptable reliability (ICC r = .74). Results: Case-control comparisons showed highly significant mean group differences for accuracy (p = 1.1 x 10(- 10)), with an effect size (Cohen's d = 1.6), more than twice as large as the mean effect size reported in a previous meta-analysis (Uljarevic and Hamilton, 2012, J Autism Dev Disord). The ASD group also had significantly increased mean reaction times overall (p = .00015, d = .83) and on correct trials (p = .0002, d = .78). However, whereas 63% of people with ASD showed severe deficits (they performed below two standard deviations of the TD mean, a small subgroup (15.3%) performed normally (within one standard deviation of the mean). Conclusion: These findings indicate that the majority of people with ASD have severe expression recognition deficits and that the Films Expression Test is a sensitive task for biomarker research in ASD. Future work is needed to establish whether ASD subgroups with and without expression recognition deficits differ from one another in terms of their symptom profile or neurobiological underpinnings. En ligne : http://dx.doi.org/10.1186/s13229-018-0187-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Facial expression recognition as a candidate marker for autism spectrum disorder: how frequent and severe are deficits? [Texte imprimé et/ou numérique] / E. LOTH, Auteur ; L. GARRIDO, Auteur ; Jumana AHMAD, Auteur ; E. WATSON, Auteur ; A. DUFF, Auteur ; B. DUCHAINE, Auteur . - 7p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 7p. Mots-clés : Autism Spectrum disorder  Biomarker  Facial expression recognition Index. décimale : PER Périodiques Résumé : Background: Impairments in social communication are a core feature of Autism Spectrum Disorder (ASD). Because the ability to infer other people's emotions from their facial expressions is critical for many aspects of social communication, deficits in expression recognition are a plausible candidate marker for ASD. However, previous studies on facial expression recognition produced mixed results, which may be due to differences in the sensitivity of the many tests used and/or the heterogeneity among individuals with ASD. To ascertain whether expression recognition may serve as a diagnostic marker (which distinguishes people with ASD from a comparison group) or a stratification marker (which helps to divide ASD into more homogeneous subgroups), a crucial first step is to move beyond identification of mean group differences and to better understand the frequency and severity of impairments. Methods: This study tested 46 individuals with ASD and 52 age- and IQ-matched typically developing (TD) participants on the Films Expression Task, which combines three key features of real-life expression recognition: naturalistic facial expressions, a broad range of simple and complex emotions, and short presentation time. Test-retest reliability was assessed in 28 individuals who did not participate in the main study and revealed acceptable reliability (ICC r = .74). Results: Case-control comparisons showed highly significant mean group differences for accuracy (p = 1.1 x 10(- 10)), with an effect size (Cohen's d = 1.6), more than twice as large as the mean effect size reported in a previous meta-analysis (Uljarevic and Hamilton, 2012, J Autism Dev Disord). The ASD group also had significantly increased mean reaction times overall (p = .00015, d = .83) and on correct trials (p = .0002, d = .78). However, whereas 63% of people with ASD showed severe deficits (they performed below two standard deviations of the TD mean, a small subgroup (15.3%) performed normally (within one standard deviation of the mean). Conclusion: These findings indicate that the majority of people with ASD have severe expression recognition deficits and that the Films Expression Test is a sensitive task for biomarker research in ASD. Future work is needed to establish whether ASD subgroups with and without expression recognition deficits differ from one another in terms of their symptom profile or neurobiological underpinnings. En ligne : http://dx.doi.org/10.1186/s13229-018-0187-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

The bidirectional association between sleep problems and autism spectrum disorder: a population-based cohort study / M. E. VERHOEFF in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 8p. Titre : The bidirectional association between sleep problems and autism spectrum disorder: a population-based cohort study Type de document : Texte imprimé et/ou numérique Auteurs : M. E. VERHOEFF, Auteur ; Laura M. E. BLANKEN, Auteur ; D. KOCEVSKA, Auteur ; V. R. MILEVA-SEITZ, Auteur ; Vincent W.V. JADDOE, Auteur ; T. WHITE, Auteur ; F. VERHULST, Auteur ; Mpcm LUIJK, Auteur ; H. TIEMEIER, Auteur Article en page(s) : 8p. Langues : Anglais (eng) Mots-clés : Autism  Bidirectional  Birth cohort  General population  Sleep problems Index. décimale : PER Périodiques Résumé : Background: Sleep difficulties are prevalent in children with autism spectrum disorder (ASD). The temporal nature of the association between sleep problems and ASD is unclear because longitudinal studies are lacking. Our aim is to clarify whether sleep problems precede and worsen autistic traits and ASD or occur as a consequence of the disorder. Methods: Repeated sleep measures were available at 1.5, 3, 6, and 9 years of age in 5151 children participating in the Generation R Study, a large prospective birth cohort in the Netherlands. Autistic traits were determined with the Pervasive Developmental Problems score (PDP) of the Child Behavior Checklist (CBCL) at 1.5 and 3 years and the Social Responsiveness Scale (SRS) at 6 years. This cohort included 81 children diagnosed with ASD. Results: Sleep problems in early childhood were prospectively associated with a higher SRS score, but not when correcting for baseline PDP score. By contrast, a higher SRS score and an ASD diagnosis were associated with more sleep problems at later ages, even when adjusting for baseline sleep problems. Likewise, a trajectory of increasing sleep problems was associated with ASD. Conclusions: Sleep problems and ASD are not bidirectionally associated. Sleep problems do not precede and worsen autistic behavior but rather co-occur with autistic traits in early childhood. Over time, children with ASD have an increase in sleep problems, whereas typically developing children have a decrease in sleep problems. Our findings suggest that sleep problems are part of the construct ASD. En ligne : http://dx.doi.org/10.1186/s13229-018-0194-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] The bidirectional association between sleep problems and autism spectrum disorder: a population-based cohort study [Texte imprimé et/ou numérique] / M. E. VERHOEFF, Auteur ; Laura M. E. BLANKEN, Auteur ; D. KOCEVSKA, Auteur ; V. R. MILEVA-SEITZ, Auteur ; Vincent W.V. JADDOE, Auteur ; T. WHITE, Auteur ; F. VERHULST, Auteur ; Mpcm LUIJK, Auteur ; H. TIEMEIER, Auteur . - 8p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 8p. Mots-clés : Autism  Bidirectional  Birth cohort  General population  Sleep problems Index. décimale : PER Périodiques Résumé : Background: Sleep difficulties are prevalent in children with autism spectrum disorder (ASD). The temporal nature of the association between sleep problems and ASD is unclear because longitudinal studies are lacking. Our aim is to clarify whether sleep problems precede and worsen autistic traits and ASD or occur as a consequence of the disorder. Methods: Repeated sleep measures were available at 1.5, 3, 6, and 9 years of age in 5151 children participating in the Generation R Study, a large prospective birth cohort in the Netherlands. Autistic traits were determined with the Pervasive Developmental Problems score (PDP) of the Child Behavior Checklist (CBCL) at 1.5 and 3 years and the Social Responsiveness Scale (SRS) at 6 years. This cohort included 81 children diagnosed with ASD. Results: Sleep problems in early childhood were prospectively associated with a higher SRS score, but not when correcting for baseline PDP score. By contrast, a higher SRS score and an ASD diagnosis were associated with more sleep problems at later ages, even when adjusting for baseline sleep problems. Likewise, a trajectory of increasing sleep problems was associated with ASD. Conclusions: Sleep problems and ASD are not bidirectionally associated. Sleep problems do not precede and worsen autistic behavior but rather co-occur with autistic traits in early childhood. Over time, children with ASD have an increase in sleep problems, whereas typically developing children have a decrease in sleep problems. Our findings suggest that sleep problems are part of the construct ASD. En ligne : http://dx.doi.org/10.1186/s13229-018-0194-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Altered reward system reactivity for personalized circumscribed interests in autism / G. KOHLS in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 9p. Titre : Altered reward system reactivity for personalized circumscribed interests in autism Type de document : Texte imprimé et/ou numérique Auteurs : G. KOHLS, Auteur ; Ligia ANTEZANA, Auteur ; M. G. MOSNER, Auteur ; Robert T. SCHULTZ, Auteur ; B. E. YERYS, Auteur Article en page(s) : 9p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorders  Caudate nucleus  Circumscribed interests  Functional magnetic resonance imaging  Motivation  Restricted and repetitive behaviors and interests  Reward  Reward system  Striatum Index. décimale : PER Périodiques Résumé : Background: Neurobiological research in autism spectrum disorders (ASD) has paid little attention on brain mechanisms that cause and maintain restricted and repetitive behaviors and interests (RRBIs). Evidence indicates an imbalance in the brain's reward system responsiveness to social and non-social stimuli may contribute to both social deficits and RRBIs. Thus, this study's central aim was to compare brain responsiveness to individual RRBI (i.e., circumscribed interests), with social rewards (i.e., social approval), in youth with ASD relative to typically developing controls (TDCs). Methods: We conducted a 3T functional magnetic resonance imaging (fMRI) study to investigate the blood-oxygenation-level-dependent effect of personalized circumscribed interest rewards versus social rewards in 39 youth with ASD relative to 22 TDC. To probe the reward system, we employed short video clips as reinforcement in an instrumental incentive delay task. This optimization increased the task's ecological validity compared to still pictures that are often used in this line of research. Results: Compared to TDCs, youth with ASD had stronger reward system responses for CIs mostly within the non-social realm (e.g., video games) than social rewards (e.g., approval). Additionally, this imbalance within the caudate nucleus' responsiveness was related to greater social impairment. Conclusions: The current data support the idea of reward system dysfunction that may contribute to enhanced motivation for RRBIs in ASD, accompanied by diminished motivation for social engagement. If a dysregulated reward system indeed supports the emergence and maintenance of social and non-social symptoms of ASD, then strategically targeting the reward system in future treatment endeavors may allow for more efficacious treatment practices that help improve outcomes for individuals with ASD and their families. En ligne : http://dx.doi.org/10.1186/s13229-018-0195-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Altered reward system reactivity for personalized circumscribed interests in autism [Texte imprimé et/ou numérique] / G. KOHLS, Auteur ; Ligia ANTEZANA, Auteur ; M. G. MOSNER, Auteur ; Robert T. SCHULTZ, Auteur ; B. E. YERYS, Auteur . - 9p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 9p. Mots-clés : Autism spectrum disorders  Caudate nucleus  Circumscribed interests  Functional magnetic resonance imaging  Motivation  Restricted and repetitive behaviors and interests  Reward  Reward system  Striatum Index. décimale : PER Périodiques Résumé : Background: Neurobiological research in autism spectrum disorders (ASD) has paid little attention on brain mechanisms that cause and maintain restricted and repetitive behaviors and interests (RRBIs). Evidence indicates an imbalance in the brain's reward system responsiveness to social and non-social stimuli may contribute to both social deficits and RRBIs. Thus, this study's central aim was to compare brain responsiveness to individual RRBI (i.e., circumscribed interests), with social rewards (i.e., social approval), in youth with ASD relative to typically developing controls (TDCs). Methods: We conducted a 3T functional magnetic resonance imaging (fMRI) study to investigate the blood-oxygenation-level-dependent effect of personalized circumscribed interest rewards versus social rewards in 39 youth with ASD relative to 22 TDC. To probe the reward system, we employed short video clips as reinforcement in an instrumental incentive delay task. This optimization increased the task's ecological validity compared to still pictures that are often used in this line of research. Results: Compared to TDCs, youth with ASD had stronger reward system responses for CIs mostly within the non-social realm (e.g., video games) than social rewards (e.g., approval). Additionally, this imbalance within the caudate nucleus' responsiveness was related to greater social impairment. Conclusions: The current data support the idea of reward system dysfunction that may contribute to enhanced motivation for RRBIs in ASD, accompanied by diminished motivation for social engagement. If a dysregulated reward system indeed supports the emergence and maintenance of social and non-social symptoms of ASD, then strategically targeting the reward system in future treatment endeavors may allow for more efficacious treatment practices that help improve outcomes for individuals with ASD and their families. En ligne : http://dx.doi.org/10.1186/s13229-018-0195-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Alterations in the inferior longitudinal fasciculus in autism and associations with visual processing: a diffusion-weighted MRI study / Bart BOETS in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 10p. Titre : Alterations in the inferior longitudinal fasciculus in autism and associations with visual processing: a diffusion-weighted MRI study Type de document : Texte imprimé et/ou numérique Auteurs : Bart BOETS, Auteur ; L. VAN EYLEN, Auteur ; K. SITEK, Auteur ; P. MOORS, Auteur ; I. NOENS, Auteur ; J. STEYAERT, Auteur ; S. SUNAERT, Auteur ; J. WAGEMANS, Auteur Article en page(s) : 10p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Diffusion-weighted imaging  Inferior longitudinal fasciculus  Structural connectivity  Visual processing Index. décimale : PER Périodiques Résumé : Background: One of the most reported neural features of autism spectrum disorder (ASD) is the alteration of multiple long-range white matter fiber tracts, as assessed by diffusion-weighted imaging and indexed by reduced fractional anisotropy (FA). Recent methodological advances, however, have shown that this same pattern of reduced FA may be an artifact resulting from excessive head motion and poorer data quality and that aberrant structural connectivity in children with ASD is confined to the right inferior longitudinal fasciculus (ILF). This study aimed at replicating the observation of reduced FA along the right ILF in ASD, while controlling for group differences in head motion and data quality. In addition, we explored associations between reduced FA in the right ILF and quantitative ASD characteristics, and the involvement of the right ILF in visual processing, which is known to be altered in ASD. Method: Global probabilistic tractography was performed on diffusion-weighted imaging data of 17 adolescent boys with ASD and 17 typically developing boys, matched for age, performance IQ, handedness, and data quality. Four tasks were administered to measure various aspects of visual information processing, together with questionnaires assessing ASD characteristics. Group differences were examined and the neural data were integrated with previously published findings using Bayesian statistics to quantify evidence for replication and to pool data and thus increase statistical power. (Partial) correlations were calculated to investigate associations between measures. Results: The ASD group showed consistently reduced FA only in the right ILF and slower performance on the visual search task. Bayesian statistics pooling data across studies confirmed that group differences in FA were confined to the right ILF only, with the evidence for altered FA in the left ILF being indecisive. Lower FA in the right ILF tended to covary with slower visual search and a more fragmented part-oriented processing style. Individual differences in FA of the right ILF were not reliably associated with the severity of ASD traits after controlling for clinical status. Conclusion: Our findings support the growing evidence for reduced FA along a specific fiber tract in ASD, the right ILF. En ligne : http://dx.doi.org/10.1186/s13229-018-0188-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Alterations in the inferior longitudinal fasciculus in autism and associations with visual processing: a diffusion-weighted MRI study [Texte imprimé et/ou numérique] / Bart BOETS, Auteur ; L. VAN EYLEN, Auteur ; K. SITEK, Auteur ; P. MOORS, Auteur ; I. NOENS, Auteur ; J. STEYAERT, Auteur ; S. SUNAERT, Auteur ; J. WAGEMANS, Auteur . - 10p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 10p. Mots-clés : Autism spectrum disorder  Diffusion-weighted imaging  Inferior longitudinal fasciculus  Structural connectivity  Visual processing Index. décimale : PER Périodiques Résumé : Background: One of the most reported neural features of autism spectrum disorder (ASD) is the alteration of multiple long-range white matter fiber tracts, as assessed by diffusion-weighted imaging and indexed by reduced fractional anisotropy (FA). Recent methodological advances, however, have shown that this same pattern of reduced FA may be an artifact resulting from excessive head motion and poorer data quality and that aberrant structural connectivity in children with ASD is confined to the right inferior longitudinal fasciculus (ILF). This study aimed at replicating the observation of reduced FA along the right ILF in ASD, while controlling for group differences in head motion and data quality. In addition, we explored associations between reduced FA in the right ILF and quantitative ASD characteristics, and the involvement of the right ILF in visual processing, which is known to be altered in ASD. Method: Global probabilistic tractography was performed on diffusion-weighted imaging data of 17 adolescent boys with ASD and 17 typically developing boys, matched for age, performance IQ, handedness, and data quality. Four tasks were administered to measure various aspects of visual information processing, together with questionnaires assessing ASD characteristics. Group differences were examined and the neural data were integrated with previously published findings using Bayesian statistics to quantify evidence for replication and to pool data and thus increase statistical power. (Partial) correlations were calculated to investigate associations between measures. Results: The ASD group showed consistently reduced FA only in the right ILF and slower performance on the visual search task. Bayesian statistics pooling data across studies confirmed that group differences in FA were confined to the right ILF only, with the evidence for altered FA in the left ILF being indecisive. Lower FA in the right ILF tended to covary with slower visual search and a more fragmented part-oriented processing style. Individual differences in FA of the right ILF were not reliably associated with the severity of ASD traits after controlling for clinical status. Conclusion: Our findings support the growing evidence for reduced FA along a specific fiber tract in ASD, the right ILF. En ligne : http://dx.doi.org/10.1186/s13229-018-0188-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Impairment of social behaviors in Arhgef10 knockout mice / D. H. LU in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 11p. Titre : Impairment of social behaviors in Arhgef10 knockout mice Type de document : Texte imprimé et/ou numérique Auteurs : D. H. LU, Auteur ; H. M. LIAO, Auteur ; C. H. CHEN, Auteur ; H. J. TU, Auteur ; H. C. LIOU, Auteur ; S. S. GAU, Auteur ; W. M. FU, Auteur Article en page(s) : 11p. Langues : Anglais (eng) Mots-clés : Arhgef10  Autism spectrum disorder  Norepinephrine  Serotonin  Social deficits Index. décimale : PER Périodiques Résumé : Background: Impaired social interaction is one of the essential features of autism spectrum disorder (ASD). Our previous copy number variation (CNV) study discovered a novel deleted region associated with ASD. One of the genes included in the deleted region is ARHGEF10. A missense mutation of ARHGEF10 has been reported to be one of the contributing factors in several diseases of the central nervous system. However, the relationship between the loss of ARHGEF10 and the clinical symptoms of ASD is unclear. Methods: We generated Arhgef10 knockout mice as a model of ASD and characterized the social behavior and the biochemical changes in the brains of the knockout mice. Results: Compared with their wild-type littermates, the Arhgef10-depleted mice showed social interaction impairment, hyperactivity, and decreased depression-like and anxiety-like behavior. Behavioral measures of learning in the Morris water maze were not affected by Arhgef10 deficiency. Moreover, neurotransmitters including serotonin, norepinephrine, and dopamine were significantly increased in different brain regions of the Arhgef10 knockout mice. In addition, monoamine oxidase A (MAO-A) decreased in several brain regions. Conclusions: These results suggest that ARHGEF10 is a candidate risk gene for ASD and that the Arhgef10 knockout model could be a tool for studying the mechanisms of neurotransmission in ASD. Trial registration: Animal studies were approved by the Institutional Animal Care and Use Committee of National Taiwan University (IACUC 20150023). Registered 1 August 2015. En ligne : http://dx.doi.org/10.1186/s13229-018-0197-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Impairment of social behaviors in Arhgef10 knockout mice [Texte imprimé et/ou numérique] / D. H. LU, Auteur ; H. M. LIAO, Auteur ; C. H. CHEN, Auteur ; H. J. TU, Auteur ; H. C. LIOU, Auteur ; S. S. GAU, Auteur ; W. M. FU, Auteur . - 11p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 11p. Mots-clés : Arhgef10  Autism spectrum disorder  Norepinephrine  Serotonin  Social deficits Index. décimale : PER Périodiques Résumé : Background: Impaired social interaction is one of the essential features of autism spectrum disorder (ASD). Our previous copy number variation (CNV) study discovered a novel deleted region associated with ASD. One of the genes included in the deleted region is ARHGEF10. A missense mutation of ARHGEF10 has been reported to be one of the contributing factors in several diseases of the central nervous system. However, the relationship between the loss of ARHGEF10 and the clinical symptoms of ASD is unclear. Methods: We generated Arhgef10 knockout mice as a model of ASD and characterized the social behavior and the biochemical changes in the brains of the knockout mice. Results: Compared with their wild-type littermates, the Arhgef10-depleted mice showed social interaction impairment, hyperactivity, and decreased depression-like and anxiety-like behavior. Behavioral measures of learning in the Morris water maze were not affected by Arhgef10 deficiency. Moreover, neurotransmitters including serotonin, norepinephrine, and dopamine were significantly increased in different brain regions of the Arhgef10 knockout mice. In addition, monoamine oxidase A (MAO-A) decreased in several brain regions. Conclusions: These results suggest that ARHGEF10 is a candidate risk gene for ASD and that the Arhgef10 knockout model could be a tool for studying the mechanisms of neurotransmission in ASD. Trial registration: Animal studies were approved by the Institutional Animal Care and Use Committee of National Taiwan University (IACUC 20150023). Registered 1 August 2015. En ligne : http://dx.doi.org/10.1186/s13229-018-0197-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA) / S. STIVAROS in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 12p. Titre : Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA) Type de document : Texte imprimé et/ou numérique Auteurs : S. STIVAROS, Auteur ; S. GARG, Auteur ; M. TZIRAKI, Auteur ; Y. CAI, Auteur ; O. THOMAS, Auteur ; J. MELLOR, Auteur ; A. A. MORRIS, Auteur ; C. JIM, Auteur ; K. SZUMANSKA-RYT, Auteur ; L. M. PARKES, Auteur ; H. A. HAROON, Auteur ; D. MONTALDI, Auteur ; N. WEBB, Auteur ; J. KEANE, Auteur ; Francisco Xavier CASTELLANOS, Auteur ; A. J. SILVA, Auteur ; S. HUSON, Auteur ; S. WILLIAMS, Auteur ; D. GARETH EVANS, Auteur ; R. EMSLEY, Auteur ; J. GREEN, Auteur Article en page(s) : 12p. Langues : Anglais (eng) Mots-clés : Autism  Neurofibromatosis type 1  Neuroimaging  Randomised controlled trial  Simvastatin  Statin Index. décimale : PER Périodiques Résumé : Background: Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes. Methods: A single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression). Results: Thirty subjects had a mean age of 8.1 years (SD 1.8). Simvastatin was well tolerated. The amount of imaging data varied by test. Simvastatin treatment was associated with (i) increased frontal white matter MRS GABA (t(12) = - 2.12, p = .055), GABA/Glx ratio (t(12) = - 2.78, p = .016), and reduced grey nuclei Glx (ANCOVA p < 0.05, Mann-Whitney p < 0.01); (ii) increased ASL perfusion in ventral diencephalon (Mann-Whitney p < 0.01); and (iii) decreased ADC in cingulate gyrus (Mann-Whitney p < 0.01). Machine-learning classification of imaging outcomes achieved 79% (p < .05) accuracy differentiating groups at endpoint against chance level (64%, p = 0.25) at baseline. Three of 12 (25%) simvastatin cases compared to none in placebo met 'clinical responder' criteria for behavioural outcome. Conclusions: We show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network. Trial registration: EU Clinical Trial Register (EudraCT) 2012-005742-38 (www.clinicaltrialsregister.eu). En ligne : http://dx.doi.org/10.1186/s13229-018-0190-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA) [Texte imprimé et/ou numérique] / S. STIVAROS, Auteur ; S. GARG, Auteur ; M. TZIRAKI, Auteur ; Y. CAI, Auteur ; O. THOMAS, Auteur ; J. MELLOR, Auteur ; A. A. MORRIS, Auteur ; C. JIM, Auteur ; K. SZUMANSKA-RYT, Auteur ; L. M. PARKES, Auteur ; H. A. HAROON, Auteur ; D. MONTALDI, Auteur ; N. WEBB, Auteur ; J. KEANE, Auteur ; Francisco Xavier CASTELLANOS, Auteur ; A. J. SILVA, Auteur ; S. HUSON, Auteur ; S. WILLIAMS, Auteur ; D. GARETH EVANS, Auteur ; R. EMSLEY, Auteur ; J. GREEN, Auteur . - 12p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 12p. Mots-clés : Autism  Neurofibromatosis type 1  Neuroimaging  Randomised controlled trial  Simvastatin  Statin Index. décimale : PER Périodiques Résumé : Background: Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes. Methods: A single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression). Results: Thirty subjects had a mean age of 8.1 years (SD 1.8). Simvastatin was well tolerated. The amount of imaging data varied by test. Simvastatin treatment was associated with (i) increased frontal white matter MRS GABA (t(12) = - 2.12, p = .055), GABA/Glx ratio (t(12) = - 2.78, p = .016), and reduced grey nuclei Glx (ANCOVA p < 0.05, Mann-Whitney p < 0.01); (ii) increased ASL perfusion in ventral diencephalon (Mann-Whitney p < 0.01); and (iii) decreased ADC in cingulate gyrus (Mann-Whitney p < 0.01). Machine-learning classification of imaging outcomes achieved 79% (p < .05) accuracy differentiating groups at endpoint against chance level (64%, p = 0.25) at baseline. Three of 12 (25%) simvastatin cases compared to none in placebo met 'clinical responder' criteria for behavioural outcome. Conclusions: We show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network. Trial registration: EU Clinical Trial Register (EudraCT) 2012-005742-38 (www.clinicaltrialsregister.eu). En ligne : http://dx.doi.org/10.1186/s13229-018-0190-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Insulin receptor sensitization restores neocortical excitation/inhibition balance in a mouse model of autism / F. S. LO in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 13p. Titre : Insulin receptor sensitization restores neocortical excitation/inhibition balance in a mouse model of autism Type de document : Texte imprimé et/ou numérique Auteurs : F. S. LO, Auteur ; R. S. ERZURUMLU, Auteur Article en page(s) : 13p. Langues : Anglais (eng) Mots-clés : Barrel cortex  GABAA receptors  Homeostatic plasticity  Met receptor tyrosine kinase  Pioglitazone  Thalamocortical circuitry Index. décimale : PER Périodiques Résumé : Background: Met receptor tyrosine kinase regulates neurogenesis, differentiation, migration, connectivity, and synaptic plasticity. The human Met gene has been identified as a prominent risk factor for autism spectrum disorder (ASD). Met gene-altered mice serve as useful models for mechanistic studies of ASD. Inactivation of Met in excitatory cortical neurons in mice (Emx1(cre)/Met(flox) mice) yields a phenotype in which significantly decreased GABAA receptor-mediated inhibition shifts the excitation/inhibition (E/I) balance toward excitation in the somatosensory cortex. Further, unlike that seen in wild-type mice, insulin does not increase inhibition in the mutant cortex, suggesting that one of the consequences of kinase inactive Met gene could be desensitization of insulin receptors. To test this hypothesis, we investigated the effects of insulin receptor sensitizer, pioglitazone, on inhibition in the somatosensory thalamocortical circuitry. Methods: We used whole-cell patch clamp electrophysiology and analyzed excitatory and inhibitory responses of cortical layer IV excitatory cells following stimulation of their thalamic input in thalamocortical pathway intact brain slices. We applied insulin alone and insulin + a thiazolidinedione, pioglitazone (PIO), to test the effects of sensitizing insulin receptors on inhibitory responses mediated by GABAA receptors in the somatosensory cortex of Emx1(cre)/Met(flox) mice. Results: In WT brain slices, application of insulin together with PIO did not enhance the effect of insulin alone. In contrast, PIO application induced a much larger inhibition than that of insulin alone in Met-defective cortex. Thus, insulin resistance of GABAA receptor-mediated response in Met mutant mice may result from desensitized insulin receptors. Conclusions: Sporadic clinical studies reported improved behavioral symptoms in children with autism following PIO treatment. We show that PIO can aid in normalization of the E/I balance in the primary somatosensory cortex, a potential physiological mechanism underlying the positive effects of PIO treatment. En ligne : http://dx.doi.org/10.1186/s13229-018-0196-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Insulin receptor sensitization restores neocortical excitation/inhibition balance in a mouse model of autism [Texte imprimé et/ou numérique] / F. S. LO, Auteur ; R. S. ERZURUMLU, Auteur . - 13p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 13p. Mots-clés : Barrel cortex  GABAA receptors  Homeostatic plasticity  Met receptor tyrosine kinase  Pioglitazone  Thalamocortical circuitry Index. décimale : PER Périodiques Résumé : Background: Met receptor tyrosine kinase regulates neurogenesis, differentiation, migration, connectivity, and synaptic plasticity. The human Met gene has been identified as a prominent risk factor for autism spectrum disorder (ASD). Met gene-altered mice serve as useful models for mechanistic studies of ASD. Inactivation of Met in excitatory cortical neurons in mice (Emx1(cre)/Met(flox) mice) yields a phenotype in which significantly decreased GABAA receptor-mediated inhibition shifts the excitation/inhibition (E/I) balance toward excitation in the somatosensory cortex. Further, unlike that seen in wild-type mice, insulin does not increase inhibition in the mutant cortex, suggesting that one of the consequences of kinase inactive Met gene could be desensitization of insulin receptors. To test this hypothesis, we investigated the effects of insulin receptor sensitizer, pioglitazone, on inhibition in the somatosensory thalamocortical circuitry. Methods: We used whole-cell patch clamp electrophysiology and analyzed excitatory and inhibitory responses of cortical layer IV excitatory cells following stimulation of their thalamic input in thalamocortical pathway intact brain slices. We applied insulin alone and insulin + a thiazolidinedione, pioglitazone (PIO), to test the effects of sensitizing insulin receptors on inhibitory responses mediated by GABAA receptors in the somatosensory cortex of Emx1(cre)/Met(flox) mice. Results: In WT brain slices, application of insulin together with PIO did not enhance the effect of insulin alone. In contrast, PIO application induced a much larger inhibition than that of insulin alone in Met-defective cortex. Thus, insulin resistance of GABAA receptor-mediated response in Met mutant mice may result from desensitized insulin receptors. Conclusions: Sporadic clinical studies reported improved behavioral symptoms in children with autism following PIO treatment. We show that PIO can aid in normalization of the E/I balance in the primary somatosensory cortex, a potential physiological mechanism underlying the positive effects of PIO treatment. En ligne : http://dx.doi.org/10.1186/s13229-018-0196-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Objective measurement of head movement differences in children with and without autism spectrum disorder / K. B. MARTIN in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 14p. Titre : Objective measurement of head movement differences in children with and without autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : K. B. MARTIN, Auteur ; Z. HAMMAL, Auteur ; G. REN, Auteur ; Jeffrey F. COHN, Auteur ; J. CASSELL, Auteur ; M. OGIHARA, Auteur ; Jennifer C. BRITTON, Auteur ; A. GUTIERREZ, Auteur ; D. S. MESSINGER, Auteur Article en page(s) : 14p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Head movement  Motor movement  Social processing Index. décimale : PER Périodiques Résumé : Background: Deficits in motor movement in children with autism spectrum disorder (ASD) have typically been characterized qualitatively by human observers. Although clinicians have noted the importance of atypical head positioning (e.g. social peering and repetitive head banging) when diagnosing children with ASD, a quantitative understanding of head movement in ASD is lacking. Here, we conduct a quantitative comparison of head movement dynamics in children with and without ASD using automated, person-independent computer-vision based head tracking (Zface). Because children with ASD often exhibit preferential attention to nonsocial versus social stimuli, we investigated whether children with and without ASD differed in their head movement dynamics depending on stimulus sociality. Methods: The current study examined differences in head movement dynamics in children with (n = 21) and without ASD (n = 21). Children were video-recorded while watching a 16-min video of social and nonsocial stimuli. Three dimensions of rigid head movement-pitch (head nods), yaw (head turns), and roll (lateral head inclinations)-were tracked using Zface. The root mean square of pitch, yaw, and roll was calculated to index the magnitude of head angular displacement (quantity of head movement) and angular velocity (speed). Results: Compared with children without ASD, children with ASD exhibited greater yaw displacement, indicating greater head turning, and greater velocity of yaw and roll, indicating faster head turning and inclination. Follow-up analyses indicated that differences in head movement dynamics were specific to the social rather than the nonsocial stimulus condition. Conclusions: Head movement dynamics (displacement and velocity) were greater in children with ASD than in children without ASD, providing a quantitative foundation for previous clinical reports. Head movement differences were evident in lateral (yaw and roll) but not vertical (pitch) movement and were specific to a social rather than nonsocial condition. When presented with social stimuli, children with ASD had higher levels of head movement and moved their heads more quickly than children without ASD. Children with ASD may use head movement to modulate their perception of social scenes. En ligne : http://dx.doi.org/10.1186/s13229-018-0198-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Objective measurement of head movement differences in children with and without autism spectrum disorder [Texte imprimé et/ou numérique] / K. B. MARTIN, Auteur ; Z. HAMMAL, Auteur ; G. REN, Auteur ; Jeffrey F. COHN, Auteur ; J. CASSELL, Auteur ; M. OGIHARA, Auteur ; Jennifer C. BRITTON, Auteur ; A. GUTIERREZ, Auteur ; D. S. MESSINGER, Auteur . - 14p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 14p. Mots-clés : Autism spectrum disorder  Head movement  Motor movement  Social processing Index. décimale : PER Périodiques Résumé : Background: Deficits in motor movement in children with autism spectrum disorder (ASD) have typically been characterized qualitatively by human observers. Although clinicians have noted the importance of atypical head positioning (e.g. social peering and repetitive head banging) when diagnosing children with ASD, a quantitative understanding of head movement in ASD is lacking. Here, we conduct a quantitative comparison of head movement dynamics in children with and without ASD using automated, person-independent computer-vision based head tracking (Zface). Because children with ASD often exhibit preferential attention to nonsocial versus social stimuli, we investigated whether children with and without ASD differed in their head movement dynamics depending on stimulus sociality. Methods: The current study examined differences in head movement dynamics in children with (n = 21) and without ASD (n = 21). Children were video-recorded while watching a 16-min video of social and nonsocial stimuli. Three dimensions of rigid head movement-pitch (head nods), yaw (head turns), and roll (lateral head inclinations)-were tracked using Zface. The root mean square of pitch, yaw, and roll was calculated to index the magnitude of head angular displacement (quantity of head movement) and angular velocity (speed). Results: Compared with children without ASD, children with ASD exhibited greater yaw displacement, indicating greater head turning, and greater velocity of yaw and roll, indicating faster head turning and inclination. Follow-up analyses indicated that differences in head movement dynamics were specific to the social rather than the nonsocial stimulus condition. Conclusions: Head movement dynamics (displacement and velocity) were greater in children with ASD than in children without ASD, providing a quantitative foundation for previous clinical reports. Head movement differences were evident in lateral (yaw and roll) but not vertical (pitch) movement and were specific to a social rather than nonsocial condition. When presented with social stimuli, children with ASD had higher levels of head movement and moved their heads more quickly than children without ASD. Children with ASD may use head movement to modulate their perception of social scenes. En ligne : http://dx.doi.org/10.1186/s13229-018-0198-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

17-beta estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms / F. FILICE in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 15p. Titre : 17-beta estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms Type de document : Texte imprimé et/ou numérique Auteurs : F. FILICE, Auteur ; E. LAUBER, Auteur ; K. J. VORCKEL, Auteur ; M. WOHR, Auteur ; B. SCHWALLER, Auteur Article en page(s) : 15p. Langues : Anglais (eng) Mots-clés : 17-beta estradiol  Asd  Estradiol treatment  Excitation/inhibition balance  Parvalbumin  Social behavior  Ultrasonic vocalizations Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by two core symptoms: impaired social interaction and communication, and restricted, repetitive behaviors and interests. The pathophysiology of ASD is not yet fully understood, due to a plethora of genetic and environmental risk factors that might be associated with or causal for ASD. Recent findings suggest that one putative convergent pathway for some forms of ASD might be the downregulation of the calcium-binding protein parvalbumin (PV). PV-deficient mice (PV-/-, PV+/-), as well as Shank1-/-, Shank3-/-, and VPA mice, which show behavioral deficits relevant to all human ASD core symptoms, are all characterized by lower PV expression levels. Methods: Based on the hypothesis that PV expression might be increased by 17-beta estradiol (E2), PV+/- mice were treated with E2 from postnatal days 5-15 and ASD-related behavior was tested between postnatal days 25 and 31. Results: PV expression levels were significantly increased after E2 treatment and, concomitantly, sociability deficits in PV+/- mice in the direct reciprocal social interaction and the 3-chamber social approach assay, as well as repetitive behaviors, were attenuated. E2 treatment of PV+/+ mice did not increase PV levels and had detrimental effects on sociability and repetitive behavior. In PV-/- mice, E2 obviously did not affect PV levels; tested behaviors were not different from the ones in vehicle-treated PV-/- mice. Conclusion: Our results suggest that the E2-linked amelioration of ASD-like behaviors is specifically occurring in PV+/- mice, indicating that PV upregulation is required for the E2-mediated rescue of ASD-relevant behavioral impairments. En ligne : http://dx.doi.org/10.1186/s13229-018-0199-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] 17-beta estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms [Texte imprimé et/ou numérique] / F. FILICE, Auteur ; E. LAUBER, Auteur ; K. J. VORCKEL, Auteur ; M. WOHR, Auteur ; B. SCHWALLER, Auteur . - 15p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 15p. Mots-clés : 17-beta estradiol  Asd  Estradiol treatment  Excitation/inhibition balance  Parvalbumin  Social behavior  Ultrasonic vocalizations Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by two core symptoms: impaired social interaction and communication, and restricted, repetitive behaviors and interests. The pathophysiology of ASD is not yet fully understood, due to a plethora of genetic and environmental risk factors that might be associated with or causal for ASD. Recent findings suggest that one putative convergent pathway for some forms of ASD might be the downregulation of the calcium-binding protein parvalbumin (PV). PV-deficient mice (PV-/-, PV+/-), as well as Shank1-/-, Shank3-/-, and VPA mice, which show behavioral deficits relevant to all human ASD core symptoms, are all characterized by lower PV expression levels. Methods: Based on the hypothesis that PV expression might be increased by 17-beta estradiol (E2), PV+/- mice were treated with E2 from postnatal days 5-15 and ASD-related behavior was tested between postnatal days 25 and 31. Results: PV expression levels were significantly increased after E2 treatment and, concomitantly, sociability deficits in PV+/- mice in the direct reciprocal social interaction and the 3-chamber social approach assay, as well as repetitive behaviors, were attenuated. E2 treatment of PV+/+ mice did not increase PV levels and had detrimental effects on sociability and repetitive behavior. In PV-/- mice, E2 obviously did not affect PV levels; tested behaviors were not different from the ones in vehicle-treated PV-/- mice. Conclusion: Our results suggest that the E2-linked amelioration of ASD-like behaviors is specifically occurring in PV+/- mice, indicating that PV upregulation is required for the E2-mediated rescue of ASD-relevant behavioral impairments. En ligne : http://dx.doi.org/10.1186/s13229-018-0199-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Practice patterns and determinants of wait time for autism spectrum disorder diagnosis in Canada / M. PENNER in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 16p. Titre : Practice patterns and determinants of wait time for autism spectrum disorder diagnosis in Canada Type de document : Texte imprimé et/ou numérique Auteurs : M. PENNER, Auteur ; Evdokia ANAGNOSTOU, Auteur ; W. J. UNGAR, Auteur Article en page(s) : 16p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Diagnosis  Early detection  Health services research  Pediatrics Index. décimale : PER Périodiques Résumé : Background: Inefficient diagnostic practices for autism spectrum disorder (ASD) may contribute to longer wait times, delaying access to intervention. The objectives were to describe the diagnostic practices of Canadian pediatricians and to identify determinants of longer wait time for ASD diagnosis. Methods: An online survey was conducted through the Canadian Paediatric Society's developmental pediatrics, community pediatrics, and mental health sections. Participants were asked for demographic information, whether they diagnosed ASD, and elements of their diagnostic assessment. A multiple linear regression of total wait time (time from referral to communication of the diagnosis to the family) as a function of practice characteristics was conducted. Results: A total of 90 participants completed the survey, of whom 57 diagnosed ASD in their practices (63.3%). Respondents reported varied use of multi-disciplinary teams, with 53% reporting participation in a team. No two identically composed teams were reported. Respondents also had varied use of diagnostic tools, with 21% reporting no use of tools. The median reported total wait for ASD diagnosis time was 7 months (interquartile range 4-12 months). Longer time spent on assessment was the only variable that remained significantly associated with longer wait time in multiple regression (p = 0.002). Use of diagnostic tools did not significantly affect wait time. Conclusion: Canadian ASD diagnostic practices vary widely and wait times for these assessments are substantial-7 months from referral to receipt of diagnosis. Time spent on the assessment is a significant determinant of wait time, highlighting the need for efficient assessment practices. En ligne : http://dx.doi.org/10.1186/s13229-018-0201-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Practice patterns and determinants of wait time for autism spectrum disorder diagnosis in Canada [Texte imprimé et/ou numérique] / M. PENNER, Auteur ; Evdokia ANAGNOSTOU, Auteur ; W. J. UNGAR, Auteur . - 16p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 16p. Mots-clés : Autism spectrum disorder  Diagnosis  Early detection  Health services research  Pediatrics Index. décimale : PER Périodiques Résumé : Background: Inefficient diagnostic practices for autism spectrum disorder (ASD) may contribute to longer wait times, delaying access to intervention. The objectives were to describe the diagnostic practices of Canadian pediatricians and to identify determinants of longer wait time for ASD diagnosis. Methods: An online survey was conducted through the Canadian Paediatric Society's developmental pediatrics, community pediatrics, and mental health sections. Participants were asked for demographic information, whether they diagnosed ASD, and elements of their diagnostic assessment. A multiple linear regression of total wait time (time from referral to communication of the diagnosis to the family) as a function of practice characteristics was conducted. Results: A total of 90 participants completed the survey, of whom 57 diagnosed ASD in their practices (63.3%). Respondents reported varied use of multi-disciplinary teams, with 53% reporting participation in a team. No two identically composed teams were reported. Respondents also had varied use of diagnostic tools, with 21% reporting no use of tools. The median reported total wait for ASD diagnosis time was 7 months (interquartile range 4-12 months). Longer time spent on assessment was the only variable that remained significantly associated with longer wait time in multiple regression (p = 0.002). Use of diagnostic tools did not significantly affect wait time. Conclusion: Canadian ASD diagnostic practices vary widely and wait times for these assessments are substantial-7 months from referral to receipt of diagnosis. Time spent on the assessment is a significant determinant of wait time, highlighting the need for efficient assessment practices. En ligne : http://dx.doi.org/10.1186/s13229-018-0201-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Network-specific sex differentiation of intrinsic brain function in males with autism / D. L. FLORIS in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 17p. Titre : Network-specific sex differentiation of intrinsic brain function in males with autism Type de document : Texte imprimé et/ou numérique Auteurs : D. L. FLORIS, Auteur ; Meng-Chuan LAI, Auteur ; T. NATH, Auteur ; M. P. MILHAM, Auteur ; A. DI MARTINO, Auteur Article en page(s) : 17p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Extreme Male Brain  Gender Incoherence  Resting-state fMRI  Sex differentiation  Sex mosaicism Index. décimale : PER Périodiques Résumé : Background: The male predominance in the prevalence of autism spectrum disorder (ASD) has motivated research on sex differentiation in ASD. Multiple sources of evidence have suggested a neurophenotypic convergence of ASD-related characteristics and typical sex differences. Two existing, albeit competing, models provide predictions on such neurophenotypic convergence. These two models are testable with neuroimaging. Specifically, the Extreme Male Brain (EMB) model predicts that ASD is associated with enhanced brain maleness in both males and females with ASD (i.e., a shift-towards-maleness). In contrast, the Gender Incoherence (GI) model predicts a shift-towards-maleness in females, yet a shift-towards-femaleness in males with ASD. Methods: To clarify whether either model applies to the intrinsic functional properties of the brain in males with ASD, we measured the statistical overlap between typical sex differences and ASD-related atypicalities in resting-state fMRI (R-fMRI) datasets largely available in males. Main analyses focused on two large-scale R-fMRI samples: 357 neurotypical (NT) males and 471 NT females from the 1000 Functional Connectome Project and 360 males with ASD and 403 NT males from the Autism Brain Imaging Data Exchange. Results: Across all R-fMRI metrics, results revealed coexisting, but network-specific, shift-towards-maleness and shift-towards-femaleness in males with ASD. A shift-towards-maleness mostly involved the default network, while a shift-towards-femaleness mostly occurred in the somatomotor network. Explorations of the associated cognitive processes using available cognitive ontology maps indicated that higher-order social cognitive functions corresponded to the shift-towards-maleness, while lower-order sensory motor processes corresponded to the shift-towards-femaleness. Conclusions: The present findings suggest that atypical intrinsic brain properties in males with ASD partly reflect mechanisms involved in sexual differentiation. A model based on network-dependent atypical sex mosaicism can synthesize prior competing theories on factors involved in sex differentiation in ASD. En ligne : http://dx.doi.org/10.1186/s13229-018-0192-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Network-specific sex differentiation of intrinsic brain function in males with autism [Texte imprimé et/ou numérique] / D. L. FLORIS, Auteur ; Meng-Chuan LAI, Auteur ; T. NATH, Auteur ; M. P. MILHAM, Auteur ; A. DI MARTINO, Auteur . - 17p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 17p. Mots-clés : Autism spectrum disorder  Extreme Male Brain  Gender Incoherence  Resting-state fMRI  Sex differentiation  Sex mosaicism Index. décimale : PER Périodiques Résumé : Background: The male predominance in the prevalence of autism spectrum disorder (ASD) has motivated research on sex differentiation in ASD. Multiple sources of evidence have suggested a neurophenotypic convergence of ASD-related characteristics and typical sex differences. Two existing, albeit competing, models provide predictions on such neurophenotypic convergence. These two models are testable with neuroimaging. Specifically, the Extreme Male Brain (EMB) model predicts that ASD is associated with enhanced brain maleness in both males and females with ASD (i.e., a shift-towards-maleness). In contrast, the Gender Incoherence (GI) model predicts a shift-towards-maleness in females, yet a shift-towards-femaleness in males with ASD. Methods: To clarify whether either model applies to the intrinsic functional properties of the brain in males with ASD, we measured the statistical overlap between typical sex differences and ASD-related atypicalities in resting-state fMRI (R-fMRI) datasets largely available in males. Main analyses focused on two large-scale R-fMRI samples: 357 neurotypical (NT) males and 471 NT females from the 1000 Functional Connectome Project and 360 males with ASD and 403 NT males from the Autism Brain Imaging Data Exchange. Results: Across all R-fMRI metrics, results revealed coexisting, but network-specific, shift-towards-maleness and shift-towards-femaleness in males with ASD. A shift-towards-maleness mostly involved the default network, while a shift-towards-femaleness mostly occurred in the somatomotor network. Explorations of the associated cognitive processes using available cognitive ontology maps indicated that higher-order social cognitive functions corresponded to the shift-towards-maleness, while lower-order sensory motor processes corresponded to the shift-towards-femaleness. Conclusions: The present findings suggest that atypical intrinsic brain properties in males with ASD partly reflect mechanisms involved in sexual differentiation. A model based on network-dependent atypical sex mosaicism can synthesize prior competing theories on factors involved in sex differentiation in ASD. En ligne : http://dx.doi.org/10.1186/s13229-018-0192-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Plasma anandamide concentrations are lower in children with autism spectrum disorder / Debra S. KARHSON in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 18p. Titre : Plasma anandamide concentrations are lower in children with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Debra S. KARHSON, Auteur ; K. M. KRASINSKA, Auteur ; J. A. DALLAIRE, Auteur ; R. A. LIBOVE, Auteur ; J. M. PHILLIPS, Auteur ; A. S. CHIEN, Auteur ; J. P. GARNER, Auteur ; A. Y. HARDAN, Auteur ; Karen J. PARKER, Auteur Article en page(s) : 18p. Langues : Anglais (eng) Mots-clés : Anandamide  Autism spectrum disorder  Blood biomarker  Cannabinoid Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted, stereotyped behaviors and impairments in social communication. Although the underlying biological mechanisms of ASD remain poorly understood, recent preclinical research has implicated the endogenous cannabinoid (or endocannabinoid), anandamide, as a significant neuromodulator in rodent models of ASD. Despite this promising preclinical evidence, no clinical studies to date have tested whether endocannabinoids are dysregulated in individuals with ASD. Here, we addressed this critical gap in knowledge by optimizing liquid chromatography-tandem mass spectrometry methodology to quantitatively analyze anandamide concentrations in banked blood samples collected from a cohort of children with and without ASD (N = 112). Findings: Anandamide concentrations significantly differentiated ASD cases (N = 59) from controls (N = 53), such that children with lower anandamide concentrations were more likely to have ASD (p = 0.041). In keeping with this notion, anandamide concentrations were also significantly lower in ASD compared to control children (p = 0.034). Conclusions: These findings are the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD. Although preliminary, these data suggest that impaired anandamide signaling may be involved in the pathophysiology of ASD. En ligne : http://dx.doi.org/10.1186/s13229-018-0203-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Plasma anandamide concentrations are lower in children with autism spectrum disorder [Texte imprimé et/ou numérique] / Debra S. KARHSON, Auteur ; K. M. KRASINSKA, Auteur ; J. A. DALLAIRE, Auteur ; R. A. LIBOVE, Auteur ; J. M. PHILLIPS, Auteur ; A. S. CHIEN, Auteur ; J. P. GARNER, Auteur ; A. Y. HARDAN, Auteur ; Karen J. PARKER, Auteur . - 18p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 18p. Mots-clés : Anandamide  Autism spectrum disorder  Blood biomarker  Cannabinoid Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted, stereotyped behaviors and impairments in social communication. Although the underlying biological mechanisms of ASD remain poorly understood, recent preclinical research has implicated the endogenous cannabinoid (or endocannabinoid), anandamide, as a significant neuromodulator in rodent models of ASD. Despite this promising preclinical evidence, no clinical studies to date have tested whether endocannabinoids are dysregulated in individuals with ASD. Here, we addressed this critical gap in knowledge by optimizing liquid chromatography-tandem mass spectrometry methodology to quantitatively analyze anandamide concentrations in banked blood samples collected from a cohort of children with and without ASD (N = 112). Findings: Anandamide concentrations significantly differentiated ASD cases (N = 59) from controls (N = 53), such that children with lower anandamide concentrations were more likely to have ASD (p = 0.041). In keeping with this notion, anandamide concentrations were also significantly lower in ASD compared to control children (p = 0.034). Conclusions: These findings are the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD. Although preliminary, these data suggest that impaired anandamide signaling may be involved in the pathophysiology of ASD. En ligne : http://dx.doi.org/10.1186/s13229-018-0203-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

The geometric preference subtype in ASD: identifying a consistent, early-emerging phenomenon through eye tracking / A. MOORE in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 19p. Titre : The geometric preference subtype in ASD: identifying a consistent, early-emerging phenomenon through eye tracking Type de document : Texte imprimé et/ou numérique Auteurs : A. MOORE, Auteur ; M. WOZNIAK, Auteur ; A. YOUSEF, Auteur ; C. C. BARNES, Auteur ; D. CHA, Auteur ; E. COURCHESNE, Auteur ; K. PIERCE, Auteur Article en page(s) : 19p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Early identification  Eye tracking  Geometric preference  Social attention Index. décimale : PER Périodiques Résumé : Background: The wide range of ability and disability in ASD creates a need for tools that parse the phenotypic heterogeneity into meaningful subtypes. Using eye tracking, our past studies revealed that when presented with social and geometric images, a subset of ASD toddlers preferred viewing geometric images, and these toddlers also had greater symptom severity than ASD toddlers with greater social attention. This study tests whether this "GeoPref test" effect would generalize across different social stimuli. Methods: Two hundred and twenty-seven toddlers (76 ASD) watched a 90-s video, the Complex Social GeoPref test, of dynamic geometric images paired with social images of children interacting and moving. Proportion of visual fixation time and number of saccades per second to both images were calculated. To allow for cross-paradigm comparisons, a subset of 126 toddlers also participated in the original GeoPref test. Measures of cognitive and social functioning (MSEL, ADOS, VABS) were collected and related to eye tracking data. To examine utility as a diagnostic indicator to detect ASD toddlers, validation statistics (e.g., sensitivity, specificity, ROC, AUC) were calculated for the Complex Social GeoPref test alone and when combined with the original GeoPref test. Results: ASD toddlers spent a significantly greater amount of time viewing geometric images than any other diagnostic group. Fixation patterns from ASD toddlers who participated in both tests revealed a significant correlation, supporting the idea that these tests identify a phenotypically meaningful ASD subgroup. Combined use of both original and Complex Social GeoPref tests identified a subgroup of about 1 in 3 ASD toddlers from the "GeoPref" subtype (sensitivity 35%, specificity 94%, AUC 0.75.) Replicating our previous studies, more time looking at geometric images was associated with significantly greater ADOS symptom severity. Conclusions: Regardless of the complexity of the social images used (low in the original GeoPref test vs high in the new Complex Social GeoPref test), eye tracking of toddlers can accurately identify a specific ASD "GeoPref" subtype with elevated symptom severity. The GeoPref tests are predictive of ASD at the individual subject level and thus potentially useful for various clinical applications (e.g., early identification, prognosis, or development of subtype-specific treatments). En ligne : http://dx.doi.org/10.1186/s13229-018-0202-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] The geometric preference subtype in ASD: identifying a consistent, early-emerging phenomenon through eye tracking [Texte imprimé et/ou numérique] / A. MOORE, Auteur ; M. WOZNIAK, Auteur ; A. YOUSEF, Auteur ; C. C. BARNES, Auteur ; D. CHA, Auteur ; E. COURCHESNE, Auteur ; K. PIERCE, Auteur . - 19p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 19p. Mots-clés : Autism spectrum disorder  Early identification  Eye tracking  Geometric preference  Social attention Index. décimale : PER Périodiques Résumé : Background: The wide range of ability and disability in ASD creates a need for tools that parse the phenotypic heterogeneity into meaningful subtypes. Using eye tracking, our past studies revealed that when presented with social and geometric images, a subset of ASD toddlers preferred viewing geometric images, and these toddlers also had greater symptom severity than ASD toddlers with greater social attention. This study tests whether this "GeoPref test" effect would generalize across different social stimuli. Methods: Two hundred and twenty-seven toddlers (76 ASD) watched a 90-s video, the Complex Social GeoPref test, of dynamic geometric images paired with social images of children interacting and moving. Proportion of visual fixation time and number of saccades per second to both images were calculated. To allow for cross-paradigm comparisons, a subset of 126 toddlers also participated in the original GeoPref test. Measures of cognitive and social functioning (MSEL, ADOS, VABS) were collected and related to eye tracking data. To examine utility as a diagnostic indicator to detect ASD toddlers, validation statistics (e.g., sensitivity, specificity, ROC, AUC) were calculated for the Complex Social GeoPref test alone and when combined with the original GeoPref test. Results: ASD toddlers spent a significantly greater amount of time viewing geometric images than any other diagnostic group. Fixation patterns from ASD toddlers who participated in both tests revealed a significant correlation, supporting the idea that these tests identify a phenotypically meaningful ASD subgroup. Combined use of both original and Complex Social GeoPref tests identified a subgroup of about 1 in 3 ASD toddlers from the "GeoPref" subtype (sensitivity 35%, specificity 94%, AUC 0.75.) Replicating our previous studies, more time looking at geometric images was associated with significantly greater ADOS symptom severity. Conclusions: Regardless of the complexity of the social images used (low in the original GeoPref test vs high in the new Complex Social GeoPref test), eye tracking of toddlers can accurately identify a specific ASD "GeoPref" subtype with elevated symptom severity. The GeoPref tests are predictive of ASD at the individual subject level and thus potentially useful for various clinical applications (e.g., early identification, prognosis, or development of subtype-specific treatments). En ligne : http://dx.doi.org/10.1186/s13229-018-0202-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Analysis of the expression pattern of the schizophrenia-risk and intellectual disability gene TCF4 in the developing and adult brain suggests a role in development and plasticity of cortical and hippocampal neurons / M. JUNG in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 20p. Titre : Analysis of the expression pattern of the schizophrenia-risk and intellectual disability gene TCF4 in the developing and adult brain suggests a role in development and plasticity of cortical and hippocampal neurons Type de document : Texte imprimé et/ou numérique Auteurs : M. JUNG, Auteur ; B. M. HABERLE, Auteur ; T. TSCHAIKOWSKY, Auteur ; M. T. WITTMANN, Auteur ; E. A. BALTA, Auteur ; V. C. STADLER, Auteur ; C. ZWEIER, Auteur ; A. DORFLER, Auteur ; C. J. GLOECKNER, Auteur ; D. C. LIE, Auteur Article en page(s) : 20p. Langues : Anglais (eng) Mots-clés : Neurodevelopment  Pitt-Hopkins syndrome  Schizophrenia  TCF4 Index. décimale : PER Périodiques Résumé : Background: Haploinsufficiency of the class I bHLH transcription factor TCF4 causes Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder, while common variants in the TCF4 gene have been identified as susceptibility factors for schizophrenia. It remains largely unknown, which brain regions are dependent on TCF4 for their development and function. Methods: We systematically analyzed the expression pattern of TCF4 in the developing and adult mouse brain. We used immunofluorescent staining to identify candidate regions whose development and function depend on TCF4. In addition, we determined TCF4 expression in the developing rhesus monkey brain and in the developing and adult human brain through analysis of transcriptomic datasets and compared the expression pattern between species. Finally, we morphometrically and histologically analyzed selected brain structures in Tcf4-haploinsufficient mice and compared our morphometric findings to neuroanatomical findings in PTHS patients. Results: TCF4 is broadly expressed in cortical and subcortical structures in the developing and adult mouse brain. The TCF4 expression pattern was highly similar between humans, rhesus monkeys, and mice. Moreover, Tcf4 haploinsufficiency in mice replicated structural brain anomalies observed in PTHS patients. Conclusion: Our data suggests that TCF4 is involved in the development and function of multiple brain regions and indicates that its regulation is evolutionary conserved. Moreover, our data validate Tcf4-haploinsufficient mice as a model to study the neurodevelopmental basis of PTHS. En ligne : http://dx.doi.org/10.1186/s13229-018-0200-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Analysis of the expression pattern of the schizophrenia-risk and intellectual disability gene TCF4 in the developing and adult brain suggests a role in development and plasticity of cortical and hippocampal neurons [Texte imprimé et/ou numérique] / M. JUNG, Auteur ; B. M. HABERLE, Auteur ; T. TSCHAIKOWSKY, Auteur ; M. T. WITTMANN, Auteur ; E. A. BALTA, Auteur ; V. C. STADLER, Auteur ; C. ZWEIER, Auteur ; A. DORFLER, Auteur ; C. J. GLOECKNER, Auteur ; D. C. LIE, Auteur . - 20p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 20p. Mots-clés : Neurodevelopment  Pitt-Hopkins syndrome  Schizophrenia  TCF4 Index. décimale : PER Périodiques Résumé : Background: Haploinsufficiency of the class I bHLH transcription factor TCF4 causes Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder, while common variants in the TCF4 gene have been identified as susceptibility factors for schizophrenia. It remains largely unknown, which brain regions are dependent on TCF4 for their development and function. Methods: We systematically analyzed the expression pattern of TCF4 in the developing and adult mouse brain. We used immunofluorescent staining to identify candidate regions whose development and function depend on TCF4. In addition, we determined TCF4 expression in the developing rhesus monkey brain and in the developing and adult human brain through analysis of transcriptomic datasets and compared the expression pattern between species. Finally, we morphometrically and histologically analyzed selected brain structures in Tcf4-haploinsufficient mice and compared our morphometric findings to neuroanatomical findings in PTHS patients. Results: TCF4 is broadly expressed in cortical and subcortical structures in the developing and adult mouse brain. The TCF4 expression pattern was highly similar between humans, rhesus monkeys, and mice. Moreover, Tcf4 haploinsufficiency in mice replicated structural brain anomalies observed in PTHS patients. Conclusion: Our data suggests that TCF4 is involved in the development and function of multiple brain regions and indicates that its regulation is evolutionary conserved. Moreover, our data validate Tcf4-haploinsufficient mice as a model to study the neurodevelopmental basis of PTHS. En ligne : http://dx.doi.org/10.1186/s13229-018-0200-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Association between maternal antidepressant use during pregnancy and autism spectrum disorder: an updated meta-analysis / X. H. ZHOU in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 21p. Titre : Association between maternal antidepressant use during pregnancy and autism spectrum disorder: an updated meta-analysis Type de document : Texte imprimé et/ou numérique Auteurs : X. H. ZHOU, Auteur ; Y. J. LI, Auteur ; J. J. OU, Auteur ; Y. M. LI, Auteur Article en page(s) : 21p. Langues : Anglais (eng) Mots-clés : Antidepressant exposure  Autism spectrum disorder  Meta-analysis  Offspring Index. décimale : PER Périodiques Résumé : Studies have investigated the risk of autism spectrum disorder (ASD) in children exposed in utero to antidepressant, with inconsistent results. Given the substantial public health implications on this topic, here, we presented an updated meta-analysis of the association between maternal antidepressant use during pregnancy and ASD. Cochrane Library, EMBASE, PsycINFO, and PubMed databases were systematically searched. A random effects model was used to pool the adjusted relative risk (RR) for cohort studies and the adjusted odds ratio (OR) for case-control studies as well as their corresponding 95% confidence intervals (CIs). Meta-analysis restricted to sibling studies was also conducted. Publication bias was systematically assessed. Fourteen studies were identified (eight cohort studies and six case-control studies). Pooled adjusted RR for cohort studies (n = 2,839,980) was 1.13 (0.93-1.39) showed a non-significant association; while two studies were potentially missing from the test of publication bias, filled estimates also showed a non-significant association (filled RR 0.97, 95% CI 0.79-1.19). Pooled OR was 1.51 (1.15-1.99) for case-control studies (n = 117,737) showed a significant association; two studies were potentially missing; however, the filled estimates suggested a non-significant association (filled OR 1.26, 95% CI 0.98-1.62). Analyses restricted to sibling studies also showed a non-significant association (RR 0.99, 95% CI 0.81-1.22). In summary, we did not evidence a significant association between maternal antidepressant use during pregnancy and ASD. En ligne : http://dx.doi.org/10.1186/s13229-018-0207-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Association between maternal antidepressant use during pregnancy and autism spectrum disorder: an updated meta-analysis [Texte imprimé et/ou numérique] / X. H. ZHOU, Auteur ; Y. J. LI, Auteur ; J. J. OU, Auteur ; Y. M. LI, Auteur . - 21p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 21p. Mots-clés : Antidepressant exposure  Autism spectrum disorder  Meta-analysis  Offspring Index. décimale : PER Périodiques Résumé : Studies have investigated the risk of autism spectrum disorder (ASD) in children exposed in utero to antidepressant, with inconsistent results. Given the substantial public health implications on this topic, here, we presented an updated meta-analysis of the association between maternal antidepressant use during pregnancy and ASD. Cochrane Library, EMBASE, PsycINFO, and PubMed databases were systematically searched. A random effects model was used to pool the adjusted relative risk (RR) for cohort studies and the adjusted odds ratio (OR) for case-control studies as well as their corresponding 95% confidence intervals (CIs). Meta-analysis restricted to sibling studies was also conducted. Publication bias was systematically assessed. Fourteen studies were identified (eight cohort studies and six case-control studies). Pooled adjusted RR for cohort studies (n = 2,839,980) was 1.13 (0.93-1.39) showed a non-significant association; while two studies were potentially missing from the test of publication bias, filled estimates also showed a non-significant association (filled RR 0.97, 95% CI 0.79-1.19). Pooled OR was 1.51 (1.15-1.99) for case-control studies (n = 117,737) showed a significant association; two studies were potentially missing; however, the filled estimates suggested a non-significant association (filled OR 1.26, 95% CI 0.98-1.62). Analyses restricted to sibling studies also showed a non-significant association (RR 0.99, 95% CI 0.81-1.22). In summary, we did not evidence a significant association between maternal antidepressant use during pregnancy and ASD. En ligne : http://dx.doi.org/10.1186/s13229-018-0207-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Sleep disturbances are associated with specific sensory sensitivities in children with autism / O. TZISCHINSKY in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 22p. Titre : Sleep disturbances are associated with specific sensory sensitivities in children with autism Type de document : Texte imprimé et/ou numérique Auteurs : O. TZISCHINSKY, Auteur ; G. MEIRI, Auteur ; L. MANELIS, Auteur ; A. BAR-SINAI, Auteur ; H. FLUSSER, Auteur ; A. MICHAELOVSKI, Auteur ; O. ZIVAN, Auteur ; M. ILAN, Auteur ; M. FAROY, Auteur ; I. MENASHE, Auteur ; I. DINSTEIN, Auteur Article en page(s) : 22p. Langues : Anglais (eng) Mots-clés : Autism  Children  Hypersensitivity towards touch  Sensory abnormalities  Sleep disturbances Index. décimale : PER Périodiques Résumé : Background: Sensory abnormalities and sleep disturbances are highly prevalent in children with autism, but the potential relationship between these two domains has rarely been explored. Understanding such relationships is important for identifying children with autism who exhibit more homogeneous symptoms. Methods: Here, we examined this relationship using the Caregiver Sensory Profile and the Children's Sleep Habits Questionnaire, which were completed by parents of 69 children with autism and 62 age-matched controls. Results: In line with previous studies, children with autism exhibited more severe sensory abnormalities and sleep disturbances than age-matched controls. The sleep disturbance scores were moderately associated with touch and oral sensitivities in the autism group and with touch and vestibular sensitivities in the control group. Hypersensitivity towards touch, in particular, exhibited the strongest relationship with sleep disturbances in the autism group and single-handedly explained 24% of the variance in total sleep disturbance scores. In contrast, sensitivity in other sensory domains such as vision and audition was not associated with sleep quality in either group. Conclusions: While it is often assumed that sensitivities in all sensory domains are similarly associated with sleep problems, our results suggest that hypersensitivity towards touch exhibits the strongest relationship with sleep disturbances when examining children autism. We speculate that hypersensitivity towards touch interferes with sleep onset and maintenance in a considerable number of children with autism who exhibit severe sleep disturbances. This may indicate the existence of a specific sleep disturbance mechanism that is associated with sensitivity to touch, which may be important to consider in future scientific and clinical studies. En ligne : http://dx.doi.org/10.1186/s13229-018-0206-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Sleep disturbances are associated with specific sensory sensitivities in children with autism [Texte imprimé et/ou numérique] / O. TZISCHINSKY, Auteur ; G. MEIRI, Auteur ; L. MANELIS, Auteur ; A. BAR-SINAI, Auteur ; H. FLUSSER, Auteur ; A. MICHAELOVSKI, Auteur ; O. ZIVAN, Auteur ; M. ILAN, Auteur ; M. FAROY, Auteur ; I. MENASHE, Auteur ; I. DINSTEIN, Auteur . - 22p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 22p. Mots-clés : Autism  Children  Hypersensitivity towards touch  Sensory abnormalities  Sleep disturbances Index. décimale : PER Périodiques Résumé : Background: Sensory abnormalities and sleep disturbances are highly prevalent in children with autism, but the potential relationship between these two domains has rarely been explored. Understanding such relationships is important for identifying children with autism who exhibit more homogeneous symptoms. Methods: Here, we examined this relationship using the Caregiver Sensory Profile and the Children's Sleep Habits Questionnaire, which were completed by parents of 69 children with autism and 62 age-matched controls. Results: In line with previous studies, children with autism exhibited more severe sensory abnormalities and sleep disturbances than age-matched controls. The sleep disturbance scores were moderately associated with touch and oral sensitivities in the autism group and with touch and vestibular sensitivities in the control group. Hypersensitivity towards touch, in particular, exhibited the strongest relationship with sleep disturbances in the autism group and single-handedly explained 24% of the variance in total sleep disturbance scores. In contrast, sensitivity in other sensory domains such as vision and audition was not associated with sleep quality in either group. Conclusions: While it is often assumed that sensitivities in all sensory domains are similarly associated with sleep problems, our results suggest that hypersensitivity towards touch exhibits the strongest relationship with sleep disturbances when examining children autism. We speculate that hypersensitivity towards touch interferes with sleep onset and maintenance in a considerable number of children with autism who exhibit severe sleep disturbances. This may indicate the existence of a specific sleep disturbance mechanism that is associated with sensitivity to touch, which may be important to consider in future scientific and clinical studies. En ligne : http://dx.doi.org/10.1186/s13229-018-0206-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

CRISPR/Cas9-induced shank3b mutant zebrafish display autism-like behaviors / C. X. LIU in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 23p. Titre : CRISPR/Cas9-induced shank3b mutant zebrafish display autism-like behaviors Type de document : Texte imprimé et/ou numérique Auteurs : C. X. LIU, Auteur ; C. Y. LI, Auteur ; C. C. HU, Auteur ; Y. WANG, Auteur ; J. LIN, Auteur ; Y. H. JIANG, Auteur ; Q. LI, Auteur ; X. XU, Auteur Article en page(s) : 23p. Langues : Anglais (eng) Mots-clés : Asd  Animal model  CRISPR/Cas9  Social behavior  Zebrafish  shank3 Index. décimale : PER Périodiques Résumé : Background: Human genetic and genomic studies have supported a strong causal role of SHANK3 deficiency in autism spectrum disorder (ASD). However, the molecular mechanism underlying SHANK3 deficiency resulting in ASD is not fully understood. Recently, the zebrafish has become an attractive organism to model ASD because of its high efficiency of genetic manipulation and robust behavioral phenotypes. The orthologous gene to human SHANK3 is duplicated in the zebrafish genome and has two homologs, shank3a and shank3b. Previous studies have reported shank3 morphants in zebrafish using the morpholino method. Here, we report the generation and characterization of shank3b mutant zebrafish in larval and adult stages using the CRISPR/Cas9 genome editing technique. Methods: CRISPR/Cas9 was applied to generate a shank3b loss-of-function mutation (shank3b(-/-) ) in zebrafish. A series of morphological measurements, behavioral tests, and molecular analyses were performed to systematically characterize the behavioral and molecular changes in shank3b mutant zebrafish. Results: shank3b(-/-) zebrafish exhibited abnormal morphology in early development. They showed reduced locomotor activity both as larvae and adults, reduced social interaction and time spent near conspecifics, and significant repetitive swimming behaviors. Additionally, the levels of both postsynaptic homer1 and presynaptic synaptophysin were significantly reduced in the adult brain of shank3b-deficient zebrafish. Conclusions: We generated the first inheritable shank3b mutant zebrafish model using CRISPR/Cas9 gene editing approach. shank3b(-/-) zebrafish displayed robust autism-like behaviors and altered levels of the synaptic proteins homer1 and synaptophysin. The versatility of zebrafish as a model for studying neurodevelopment and conducting drug screening will likely have a significant contribution to future studies of human SHANK3 function and ASD. En ligne : http://dx.doi.org/10.1186/s13229-018-0204-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] CRISPR/Cas9-induced shank3b mutant zebrafish display autism-like behaviors [Texte imprimé et/ou numérique] / C. X. LIU, Auteur ; C. Y. LI, Auteur ; C. C. HU, Auteur ; Y. WANG, Auteur ; J. LIN, Auteur ; Y. H. JIANG, Auteur ; Q. LI, Auteur ; X. XU, Auteur . - 23p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 23p. Mots-clés : Asd  Animal model  CRISPR/Cas9  Social behavior  Zebrafish  shank3 Index. décimale : PER Périodiques Résumé : Background: Human genetic and genomic studies have supported a strong causal role of SHANK3 deficiency in autism spectrum disorder (ASD). However, the molecular mechanism underlying SHANK3 deficiency resulting in ASD is not fully understood. Recently, the zebrafish has become an attractive organism to model ASD because of its high efficiency of genetic manipulation and robust behavioral phenotypes. The orthologous gene to human SHANK3 is duplicated in the zebrafish genome and has two homologs, shank3a and shank3b. Previous studies have reported shank3 morphants in zebrafish using the morpholino method. Here, we report the generation and characterization of shank3b mutant zebrafish in larval and adult stages using the CRISPR/Cas9 genome editing technique. Methods: CRISPR/Cas9 was applied to generate a shank3b loss-of-function mutation (shank3b(-/-) ) in zebrafish. A series of morphological measurements, behavioral tests, and molecular analyses were performed to systematically characterize the behavioral and molecular changes in shank3b mutant zebrafish. Results: shank3b(-/-) zebrafish exhibited abnormal morphology in early development. They showed reduced locomotor activity both as larvae and adults, reduced social interaction and time spent near conspecifics, and significant repetitive swimming behaviors. Additionally, the levels of both postsynaptic homer1 and presynaptic synaptophysin were significantly reduced in the adult brain of shank3b-deficient zebrafish. Conclusions: We generated the first inheritable shank3b mutant zebrafish model using CRISPR/Cas9 gene editing approach. shank3b(-/-) zebrafish displayed robust autism-like behaviors and altered levels of the synaptic proteins homer1 and synaptophysin. The versatility of zebrafish as a model for studying neurodevelopment and conducting drug screening will likely have a significant contribution to future studies of human SHANK3 function and ASD. En ligne : http://dx.doi.org/10.1186/s13229-018-0204-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Intranasal administration of exosomes derived from mesenchymal stem cells ameliorates autistic-like behaviors of BTBR mice / N. PERETS in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 57p. Titre : Intranasal administration of exosomes derived from mesenchymal stem cells ameliorates autistic-like behaviors of BTBR mice Type de document : Texte imprimé et/ou numérique Auteurs : N. PERETS, Auteur ; S. HERTZ, Auteur ; M. LONDON, Auteur ; Daniel OFFEN, Auteur Article en page(s) : 57p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by three core symptoms that include social interaction deficits, cognitive inflexibility, and communication disorders. They have been steadily increasing in children over the past several years, with no effective treatment. BTBR T+tf/J (BTBR) mice are an accepted model of evaluating autistic-like behaviors as they present all core symptoms of ASD. We have previously shown that transplantation of human bone marrow mesenchymal stem cells (MSC) to the lateral ventricles of BTBR mice results in long lasting improvement in their autistic behavioral phenotypes. Recent studies point exosomes as the main mediators of the therapeutic effect of MSC. Here, we tested whether treatment with the exosomes secreted from MSC (MSC-exo) will show similar beneficial effects. We found that intranasal administration of MSC-exo increased male to male social interaction and reduced repetitive behaviors. Moreover, the treatment led to increases of male to female ultrasonic vocalizations and significant improvement in maternal behaviors of pup retrieval. No negative symptoms were detected following MSC-exo intranasal treatments in BTBR or healthy C57BL mice. The marked beneficial effects of the exosomes in BTBR mice may translate to a novel, non-invasive, and therapeutic strategy to reduce the symptoms of ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0240-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Intranasal administration of exosomes derived from mesenchymal stem cells ameliorates autistic-like behaviors of BTBR mice [Texte imprimé et/ou numérique] / N. PERETS, Auteur ; S. HERTZ, Auteur ; M. LONDON, Auteur ; Daniel OFFEN, Auteur . - 57p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 57p. Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by three core symptoms that include social interaction deficits, cognitive inflexibility, and communication disorders. They have been steadily increasing in children over the past several years, with no effective treatment. BTBR T+tf/J (BTBR) mice are an accepted model of evaluating autistic-like behaviors as they present all core symptoms of ASD. We have previously shown that transplantation of human bone marrow mesenchymal stem cells (MSC) to the lateral ventricles of BTBR mice results in long lasting improvement in their autistic behavioral phenotypes. Recent studies point exosomes as the main mediators of the therapeutic effect of MSC. Here, we tested whether treatment with the exosomes secreted from MSC (MSC-exo) will show similar beneficial effects. We found that intranasal administration of MSC-exo increased male to male social interaction and reduced repetitive behaviors. Moreover, the treatment led to increases of male to female ultrasonic vocalizations and significant improvement in maternal behaviors of pup retrieval. No negative symptoms were detected following MSC-exo intranasal treatments in BTBR or healthy C57BL mice. The marked beneficial effects of the exosomes in BTBR mice may translate to a novel, non-invasive, and therapeutic strategy to reduce the symptoms of ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0240-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Brain hyperserotonemia causes autism-relevant social deficits in mice / M. TANAKA in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 60p. Titre : Brain hyperserotonemia causes autism-relevant social deficits in mice Type de document : Texte imprimé et/ou numérique Auteurs : M. TANAKA, Auteur ; A. SATO, Auteur ; S. KASAI, Auteur ; Y. HAGINO, Auteur ; H. KOTAJIMA-MURAKAMI, Auteur ; H. KASHII, Auteur ; Y. TAKAMATSU, Auteur ; Y. NISHITO, Auteur ; M. INAGAKI, Auteur ; M. MIZUGUCHI, Auteur ; F. S. HALL, Auteur ; G. R. UHL, Auteur ; D. MURPHY, Auteur ; I. SORA, Auteur ; K. IKEDA, Auteur Article en page(s) : 60p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Heterozygous mice  Serotonin transporter  Tryptophan depletion Index. décimale : PER Périodiques Résumé : Background: Hyperserotonemia in the brain is suspected to be an endophenotype of autism spectrum disorder (ASD). Reducing serotonin levels in the brain through modulation of serotonin transporter function may improve ASD symptoms. Methods: We analyzed behavior and gene expression to unveil the causal mechanism of ASD-relevant social deficits using serotonin transporter (Sert) knockout mice. Results: Social deficits were observed in both heterozygous knockout mice (HZ) and homozygous knockout mice (KO), but increases in general anxiety were only observed in KO mice. Two weeks of dietary restriction of the serotonin precursor tryptophan ameliorated both brain hyperserotonemia and ASD-relevant social deficits in Sert HZ and KO mice. The expression of rather distinct sets of genes was altered in Sert HZ and KO mice, and a substantial portion of these genes was also affected by tryptophan depletion. Tryptophan depletion in Sert HZ and KO mice was associated with alterations in the expression of genes involved in signal transduction pathways initiated by changes in extracellular serotonin or melatonin, a derivative of serotonin. Only expression of the AU015836 gene was altered in both Sert HZ and KO mice. AU015836 expression and ASD-relevant social deficits normalized after dietary tryptophan restriction. Conclusions: These findings reveal a Sert gene dose-dependent effect on brain hyperserotonemia and related behavioral sequelae in ASD and a possible therapeutic target to normalize brain hyperserotonemia and ASD-relevant social deficits. En ligne : https://dx.doi.org/10.1186/s13229-018-0243-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Brain hyperserotonemia causes autism-relevant social deficits in mice [Texte imprimé et/ou numérique] / M. TANAKA, Auteur ; A. SATO, Auteur ; S. KASAI, Auteur ; Y. HAGINO, Auteur ; H. KOTAJIMA-MURAKAMI, Auteur ; H. KASHII, Auteur ; Y. TAKAMATSU, Auteur ; Y. NISHITO, Auteur ; M. INAGAKI, Auteur ; M. MIZUGUCHI, Auteur ; F. S. HALL, Auteur ; G. R. UHL, Auteur ; D. MURPHY, Auteur ; I. SORA, Auteur ; K. IKEDA, Auteur . - 60p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 60p. Mots-clés : Autism spectrum disorder  Heterozygous mice  Serotonin transporter  Tryptophan depletion Index. décimale : PER Périodiques Résumé : Background: Hyperserotonemia in the brain is suspected to be an endophenotype of autism spectrum disorder (ASD). Reducing serotonin levels in the brain through modulation of serotonin transporter function may improve ASD symptoms. Methods: We analyzed behavior and gene expression to unveil the causal mechanism of ASD-relevant social deficits using serotonin transporter (Sert) knockout mice. Results: Social deficits were observed in both heterozygous knockout mice (HZ) and homozygous knockout mice (KO), but increases in general anxiety were only observed in KO mice. Two weeks of dietary restriction of the serotonin precursor tryptophan ameliorated both brain hyperserotonemia and ASD-relevant social deficits in Sert HZ and KO mice. The expression of rather distinct sets of genes was altered in Sert HZ and KO mice, and a substantial portion of these genes was also affected by tryptophan depletion. Tryptophan depletion in Sert HZ and KO mice was associated with alterations in the expression of genes involved in signal transduction pathways initiated by changes in extracellular serotonin or melatonin, a derivative of serotonin. Only expression of the AU015836 gene was altered in both Sert HZ and KO mice. AU015836 expression and ASD-relevant social deficits normalized after dietary tryptophan restriction. Conclusions: These findings reveal a Sert gene dose-dependent effect on brain hyperserotonemia and related behavioral sequelae in ASD and a possible therapeutic target to normalize brain hyperserotonemia and ASD-relevant social deficits. En ligne : https://dx.doi.org/10.1186/s13229-018-0243-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

A pilot dose finding study of pioglitazone in autistic children / L. CAPANO in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 59p. Titre : A pilot dose finding study of pioglitazone in autistic children Type de document : Texte imprimé et/ou numérique Auteurs : L. CAPANO, Auteur ; A. DUPUIS, Auteur ; Jessica BRIAN, Auteur ; D. MANKAD, Auteur ; L. GENORE, Auteur ; R. HASTIE ADAMS, Auteur ; S. SMILE, Auteur ; T. LUI, Auteur ; D. ODROBINA, Auteur ; J. A. FOSTER, Auteur ; Evdokia ANAGNOSTOU, Auteur Article en page(s) : 59p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Clinical trial  Cytokines  Drug therapy  Efficacy  Inflammation  Maximum tolerated dose (MTD)  Physiological effects of drugs  Pioglitazone  Safety profile  Treatment Index. décimale : PER Périodiques Résumé : Background: Pioglitazone is a promising compound for treatment of core autism spectrum disorder (ASD) symptoms as it targets multiple relevant pathways, including immune system alterations. Objective: This pilot study aimed to elucidate the maximum tolerated dose, safety, preliminary evidence of efficacy, and appropriate outcome measures in autistic children ages 5-12 years old. Methods: We conducted a 16-week prospective cohort, single blind, single arm, 2-week placebo run-in, dose-finding study of pioglitazone. Twenty-five participants completed treatment. A modified dose finding method was used to determine safety and dose response among three dose levels: 0.25 mg/kg, 0.5 mg/kg, and 0.75 mg/kg once daily. Results: Maximum tolerated dose: there were no serious adverse events (SAEs) and as such the maximum tolerated dose within the range tested was 0.75 mg/Kg once daily.Safety: overall, pioglitazone was well tolerated. Two participants discontinued intervention due to perceived non-efficacy and one due to the inability to tolerate interim blood work. Three participants experienced mild neutropenia.Early evidence of efficacy: statistically significant improvement was observed in social withdrawal, repetitive behaviors, and externalizing behaviors as measured by the Aberrant Behavior Checklist (ABC), Child Yale-Brown Obsessive Compulsive Scale (CY-BOCS), and Repetitive Behavior Scale-Revised (RBS-R). Forty-six percent of those enrolled were deemed to be global responders. Conclusions and relevance: Pioglitazone is well-tolerated and shows a potential signal in measures of social withdrawal, repetitive, and externalizing behaviors. Randomized controlled trials using the confirmed dose are warranted. Trial registration: ClinicalTrials.gov, NCT01205282. Registration date: September 20, 2010. En ligne : https://dx.doi.org/10.1186/s13229-018-0241-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] A pilot dose finding study of pioglitazone in autistic children [Texte imprimé et/ou numérique] / L. CAPANO, Auteur ; A. DUPUIS, Auteur ; Jessica BRIAN, Auteur ; D. MANKAD, Auteur ; L. GENORE, Auteur ; R. HASTIE ADAMS, Auteur ; S. SMILE, Auteur ; T. LUI, Auteur ; D. ODROBINA, Auteur ; J. A. FOSTER, Auteur ; Evdokia ANAGNOSTOU, Auteur . - 59p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 59p. Mots-clés : Autism spectrum disorder  Clinical trial  Cytokines  Drug therapy  Efficacy  Inflammation  Maximum tolerated dose (MTD)  Physiological effects of drugs  Pioglitazone  Safety profile  Treatment Index. décimale : PER Périodiques Résumé : Background: Pioglitazone is a promising compound for treatment of core autism spectrum disorder (ASD) symptoms as it targets multiple relevant pathways, including immune system alterations. Objective: This pilot study aimed to elucidate the maximum tolerated dose, safety, preliminary evidence of efficacy, and appropriate outcome measures in autistic children ages 5-12 years old. Methods: We conducted a 16-week prospective cohort, single blind, single arm, 2-week placebo run-in, dose-finding study of pioglitazone. Twenty-five participants completed treatment. A modified dose finding method was used to determine safety and dose response among three dose levels: 0.25 mg/kg, 0.5 mg/kg, and 0.75 mg/kg once daily. Results: Maximum tolerated dose: there were no serious adverse events (SAEs) and as such the maximum tolerated dose within the range tested was 0.75 mg/Kg once daily.Safety: overall, pioglitazone was well tolerated. Two participants discontinued intervention due to perceived non-efficacy and one due to the inability to tolerate interim blood work. Three participants experienced mild neutropenia.Early evidence of efficacy: statistically significant improvement was observed in social withdrawal, repetitive behaviors, and externalizing behaviors as measured by the Aberrant Behavior Checklist (ABC), Child Yale-Brown Obsessive Compulsive Scale (CY-BOCS), and Repetitive Behavior Scale-Revised (RBS-R). Forty-six percent of those enrolled were deemed to be global responders. Conclusions and relevance: Pioglitazone is well-tolerated and shows a potential signal in measures of social withdrawal, repetitive, and externalizing behaviors. Randomized controlled trials using the confirmed dose are warranted. Trial registration: ClinicalTrials.gov, NCT01205282. Registration date: September 20, 2010. En ligne : https://dx.doi.org/10.1186/s13229-018-0241-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal differentiation in the SH-SY5Y neuronal cell model / D. HASLINGER in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 56p. Titre : Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal differentiation in the SH-SY5Y neuronal cell model Type de document : Texte imprimé et/ou numérique Auteurs : D. HASLINGER, Auteur ; R. WALTES, Auteur ; A. YOUSAF, Auteur ; S. LINDLAR, Auteur ; I. SCHNEIDER, Auteur ; C. K. LIM, Auteur ; M. M. TSAI, Auteur ; B. K. GARVALOV, Auteur ; A. ACKER-PALMER, Auteur ; N. KREZDORN, Auteur ; B. ROTTER, Auteur ; T. ACKER, Auteur ; G. J. GUILLEMIN, Auteur ; S. FULDA, Auteur ; C. M. FREITAG, Auteur ; Andreas G. CHIOCCHETTI, Auteur Article en page(s) : 56p. Langues : Anglais (eng) Mots-clés : 16p11.2  Autism  CRISPR/Cas9  Kynurenine  Quinolinate phosphoribosyltransferase  Quinolinic acid  Sholl analysis  has been positively reviewed by the ethic's committee Frankfurt (No 267/09).All  authors agree to publish the presented work.All authors declare that they have no  competing interests.Springer Nature remains neutral with regard to jurisdictional  claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Altered neuronal development is discussed as the underlying pathogenic mechanism of autism spectrum disorders (ASD). Copy number variations of 16p11.2 have recurrently been identified in individuals with ASD. Of the 29 genes within this region, quinolinate phosphoribosyltransferase (QPRT) showed the strongest regulation during neuronal differentiation of SH-SY5Y neuroblastoma cells. We hypothesized a causal relation between this tryptophan metabolism-related enzyme and neuronal differentiation. We thus analyzed the effect of QPRT on the differentiation of SH-SY5Y and specifically focused on neuronal morphology, metabolites of the tryptophan pathway, and the neurodevelopmental transcriptome. Methods: The gene dosage-dependent change of QPRT expression following Chr16p11.2 deletion was investigated in a lymphoblastoid cell line (LCL) of a deletion carrier and compared to his non-carrier parents. Expression of QPRT was tested for correlation with neuromorphology in SH-SY5Y cells. QPRT function was inhibited in SH-SY5Y neuroblastoma cells using (i) siRNA knockdown (KD), (ii) chemical mimicking of loss of QPRT, and (iii) complete CRISPR/Cas9-mediated knock out (KO). QPRT-KD cells underwent morphological analysis. Chemically inhibited and QPRT-KO cells were characterized using viability assays. Additionally, QPRT-KO cells underwent metabolite and whole transcriptome analyses. Genes differentially expressed upon KO of QPRT were tested for enrichment in biological processes and co-regulated gene-networks of the human brain. Results: QPRT expression was reduced in the LCL of the deletion carrier and significantly correlated with the neuritic complexity of SH-SY5Y. The reduction of QPRT altered neuronal morphology of differentiated SH-SY5Y cells. Chemical inhibition as well as complete KO of the gene were lethal upon induction of neuronal differentiation, but not proliferation. The QPRT-associated tryptophan pathway was not affected by KO. At the transcriptome level, genes linked to neurodevelopmental processes and synaptic structures were affected. Differentially regulated genes were enriched for ASD candidates, and co-regulated gene networks were implicated in the development of the dorsolateral prefrontal cortex, the hippocampus, and the amygdala. Conclusions: In this study, QPRT was causally related to in vitro neuronal differentiation of SH-SY5Y cells and affected the regulation of genes and gene networks previously implicated in ASD. Thus, our data suggest that QPRT may play an important role in the pathogenesis of ASD in Chr16p11.2 deletion carriers. En ligne : https://dx.doi.org/10.1186/s13229-018-0239-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal differentiation in the SH-SY5Y neuronal cell model [Texte imprimé et/ou numérique] / D. HASLINGER, Auteur ; R. WALTES, Auteur ; A. YOUSAF, Auteur ; S. LINDLAR, Auteur ; I. SCHNEIDER, Auteur ; C. K. LIM, Auteur ; M. M. TSAI, Auteur ; B. K. GARVALOV, Auteur ; A. ACKER-PALMER, Auteur ; N. KREZDORN, Auteur ; B. ROTTER, Auteur ; T. ACKER, Auteur ; G. J. GUILLEMIN, Auteur ; S. FULDA, Auteur ; C. M. FREITAG, Auteur ; Andreas G. CHIOCCHETTI, Auteur . - 56p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 56p. Mots-clés : 16p11.2  Autism  CRISPR/Cas9  Kynurenine  Quinolinate phosphoribosyltransferase  Quinolinic acid  Sholl analysis  has been positively reviewed by the ethic's committee Frankfurt (No 267/09).All  authors agree to publish the presented work.All authors declare that they have no  competing interests.Springer Nature remains neutral with regard to jurisdictional  claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Altered neuronal development is discussed as the underlying pathogenic mechanism of autism spectrum disorders (ASD). Copy number variations of 16p11.2 have recurrently been identified in individuals with ASD. Of the 29 genes within this region, quinolinate phosphoribosyltransferase (QPRT) showed the strongest regulation during neuronal differentiation of SH-SY5Y neuroblastoma cells. We hypothesized a causal relation between this tryptophan metabolism-related enzyme and neuronal differentiation. We thus analyzed the effect of QPRT on the differentiation of SH-SY5Y and specifically focused on neuronal morphology, metabolites of the tryptophan pathway, and the neurodevelopmental transcriptome. Methods: The gene dosage-dependent change of QPRT expression following Chr16p11.2 deletion was investigated in a lymphoblastoid cell line (LCL) of a deletion carrier and compared to his non-carrier parents. Expression of QPRT was tested for correlation with neuromorphology in SH-SY5Y cells. QPRT function was inhibited in SH-SY5Y neuroblastoma cells using (i) siRNA knockdown (KD), (ii) chemical mimicking of loss of QPRT, and (iii) complete CRISPR/Cas9-mediated knock out (KO). QPRT-KD cells underwent morphological analysis. Chemically inhibited and QPRT-KO cells were characterized using viability assays. Additionally, QPRT-KO cells underwent metabolite and whole transcriptome analyses. Genes differentially expressed upon KO of QPRT were tested for enrichment in biological processes and co-regulated gene-networks of the human brain. Results: QPRT expression was reduced in the LCL of the deletion carrier and significantly correlated with the neuritic complexity of SH-SY5Y. The reduction of QPRT altered neuronal morphology of differentiated SH-SY5Y cells. Chemical inhibition as well as complete KO of the gene were lethal upon induction of neuronal differentiation, but not proliferation. The QPRT-associated tryptophan pathway was not affected by KO. At the transcriptome level, genes linked to neurodevelopmental processes and synaptic structures were affected. Differentially regulated genes were enriched for ASD candidates, and co-regulated gene networks were implicated in the development of the dorsolateral prefrontal cortex, the hippocampus, and the amygdala. Conclusions: In this study, QPRT was causally related to in vitro neuronal differentiation of SH-SY5Y cells and affected the regulation of genes and gene networks previously implicated in ASD. Thus, our data suggest that QPRT may play an important role in the pathogenesis of ASD in Chr16p11.2 deletion carriers. En ligne : https://dx.doi.org/10.1186/s13229-018-0239-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

A cross-cultural study of autistic traits across India, Japan and the UK / S. CARRUTHERS in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 52p. Titre : A cross-cultural study of autistic traits across India, Japan and the UK Type de document : Texte imprimé et/ou numérique Auteurs : S. CARRUTHERS, Auteur ; E. KINNAIRD, Auteur ; A. RUDRA, Auteur ; P. SMITH, Auteur ; Carrie ALLISON, Auteur ; Bonnie AUYEUNG, Auteur ; Bhismadev CHAKRABARTI, Auteur ; A. WAKABAYASHI, Auteur ; Simon BARON-COHEN, Auteur ; I. BAKOLIS, Auteur ; R. A. HOEKSTRA, Auteur Article en page(s) : 52p. Langues : Anglais (eng) Mots-clés : Autism  Cross-cultural comparison  Culture  Positive predictive values  the original collection of data was obtained by ethics committees in India, Japan  and the UK for each country's data collection separately.Not applicable.The  authors declare that they have no competing interests.Springer Nature remains  neutral with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: There is a global need for brief screening instruments that can identify key indicators for autism to support frontline professionals in their referral decision-making. Although a universal set of conditions, there may be subtle differences in expression, identification and reporting of autistic traits across cultures. In order to assess the potential for any measure for cross-cultural screening use, it is important to understand the relative performance of such measures in different cultures. Our study aimed to identify the items on the Autism Spectrum Quotient (AQ)-Child that are most predictive of an autism diagnosis among children aged 4-9 years across samples from India, Japan and the UK. Methods: We analysed parent-reported AQ-Child data from India (73 children with an autism diagnosis and 81 neurotypical children), Japan (116 children with autism and 190 neurotypical children) and the UK (488 children with autism and 532 neurotypical children). None of the children had a reported existing diagnosis of intellectual disability. Discrimination indices (DI) and positive predictive values (PPV) were used to identify the most predictive items in each country. Results: Sixteen items in the Indian sample, 15 items in the Japanese sample and 28 items in the UK sample demonstrated excellent discriminatory power (DI >/= 0.5 and PPV >/= 0.7), suggesting these items represent the strongest indicators for predicting an autism diagnosis within these countries. Across cultures, good performing items were largely overlapping, with five key indicator items appearing across all three countries (can easily keep track of several different people's conversations, enjoys social chit-chat, knows how to tell if someone listening to him/her is getting bored, good at social chit-chat, finds it difficult to work out people's intentions). Four items indicated potential cultural differences. One item was highly discriminative in Japan but poorly discriminative (DI < 0.3) in the UK and India, and a further item had excellent discrimination properties in the UK but poorly discriminated in the Indian and Japanese samples. Two additional items were highly discriminative in two cultures but poor in the third. Conclusions: Cross-cultural overlap in the items most predictive of an autism diagnosis supports the general notion of universality in autistic traits whilst also highlighting that there can be cultural differences associated with certain autistic traits. These findings have the potential to inform the development of a brief global screening tool for autism. Further development and evaluation work is needed. En ligne : https://dx.doi.org/10.1186/s13229-018-0235-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] A cross-cultural study of autistic traits across India, Japan and the UK [Texte imprimé et/ou numérique] / S. CARRUTHERS, Auteur ; E. KINNAIRD, Auteur ; A. RUDRA, Auteur ; P. SMITH, Auteur ; Carrie ALLISON, Auteur ; Bonnie AUYEUNG, Auteur ; Bhismadev CHAKRABARTI, Auteur ; A. WAKABAYASHI, Auteur ; Simon BARON-COHEN, Auteur ; I. BAKOLIS, Auteur ; R. A. HOEKSTRA, Auteur . - 52p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 52p. Mots-clés : Autism  Cross-cultural comparison  Culture  Positive predictive values  the original collection of data was obtained by ethics committees in India, Japan  and the UK for each country's data collection separately.Not applicable.The  authors declare that they have no competing interests.Springer Nature remains  neutral with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: There is a global need for brief screening instruments that can identify key indicators for autism to support frontline professionals in their referral decision-making. Although a universal set of conditions, there may be subtle differences in expression, identification and reporting of autistic traits across cultures. In order to assess the potential for any measure for cross-cultural screening use, it is important to understand the relative performance of such measures in different cultures. Our study aimed to identify the items on the Autism Spectrum Quotient (AQ)-Child that are most predictive of an autism diagnosis among children aged 4-9 years across samples from India, Japan and the UK. Methods: We analysed parent-reported AQ-Child data from India (73 children with an autism diagnosis and 81 neurotypical children), Japan (116 children with autism and 190 neurotypical children) and the UK (488 children with autism and 532 neurotypical children). None of the children had a reported existing diagnosis of intellectual disability. Discrimination indices (DI) and positive predictive values (PPV) were used to identify the most predictive items in each country. Results: Sixteen items in the Indian sample, 15 items in the Japanese sample and 28 items in the UK sample demonstrated excellent discriminatory power (DI >/= 0.5 and PPV >/= 0.7), suggesting these items represent the strongest indicators for predicting an autism diagnosis within these countries. Across cultures, good performing items were largely overlapping, with five key indicator items appearing across all three countries (can easily keep track of several different people's conversations, enjoys social chit-chat, knows how to tell if someone listening to him/her is getting bored, good at social chit-chat, finds it difficult to work out people's intentions). Four items indicated potential cultural differences. One item was highly discriminative in Japan but poorly discriminative (DI < 0.3) in the UK and India, and a further item had excellent discrimination properties in the UK but poorly discriminated in the Indian and Japanese samples. Two additional items were highly discriminative in two cultures but poor in the third. Conclusions: Cross-cultural overlap in the items most predictive of an autism diagnosis supports the general notion of universality in autistic traits whilst also highlighting that there can be cultural differences associated with certain autistic traits. These findings have the potential to inform the development of a brief global screening tool for autism. Further development and evaluation work is needed. En ligne : https://dx.doi.org/10.1186/s13229-018-0235-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Does stereopsis account for the link between motor and social skills in adults? / D. SMITH in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 55p. Titre : Does stereopsis account for the link between motor and social skills in adults? Type de document : Texte imprimé et/ou numérique Auteurs : D. SMITH, Auteur ; D. ROPAR, Auteur ; H. A. ALLEN, Auteur Article en page(s) : 55p. Langues : Anglais (eng) Mots-clés : Depth perception  Factor analysis  Motor skills  Path analysis  Social skills  Stereoability  Stereopsis  accordance with the ethical standards of the institutional and/or national  research committee and with the 1964 Helsinki Declaration and its later  amendments or comparable ethical standards. Informed consent was obtained from  all individual participants included in the study.Not applicableThe authors  declare that they have no competing interests.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: Experimental and longitudinal evidence suggests that motor proficiency plays an important role in the development of social skills. However, stereopsis, or depth perception, may also play a fundamental role in social skill development either indirectly through its impact on motor skills or through a more direct route. To date, no systematic study has investigated the relationship between social skills and motor ability in the general adult population, and whether poor stereopsis may contribute to this association. This has implications for clinical populations since research has shown associations between motor abnormalities and social skills, as well as reduced depth perception in autism spectrum disorder and developmental coordination disorder. Methods: Six hundred fifty adults completed three validated questionnaires, the stereopsis screening inventory, the Adult Developmental Coordination Disorder Checklist, and the Autism Spectrum Quotient. Results: An exploratory factor analysis on pooled items across all measures revealed 10 factors that were largely composed of items from a single scale, indicating that any co-occurrence of poor stereopsis, reduced motor proficiency, and difficulties with social interaction cannot be attributed to a single underlying mechanism. Correlations between extracted factor scores found associations between motor skill and social skill. Conclusions: Mediation analyses suggested that whilst fine motor skill and coordination explained the relationship between stereopsis and social skill to some extent, stereopsis nonetheless exerted a substantial direct effect upon social skill. This is the first study to demonstrate that the functional significance of stereopsis is not limited to motor ability and may directly impact upon social functioning. En ligne : https://dx.doi.org/10.1186/s13229-018-0234-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Does stereopsis account for the link between motor and social skills in adults? [Texte imprimé et/ou numérique] / D. SMITH, Auteur ; D. ROPAR, Auteur ; H. A. ALLEN, Auteur . - 55p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 55p. Mots-clés : Depth perception  Factor analysis  Motor skills  Path analysis  Social skills  Stereoability  Stereopsis  accordance with the ethical standards of the institutional and/or national  research committee and with the 1964 Helsinki Declaration and its later  amendments or comparable ethical standards. Informed consent was obtained from  all individual participants included in the study.Not applicableThe authors  declare that they have no competing interests.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: Experimental and longitudinal evidence suggests that motor proficiency plays an important role in the development of social skills. However, stereopsis, or depth perception, may also play a fundamental role in social skill development either indirectly through its impact on motor skills or through a more direct route. To date, no systematic study has investigated the relationship between social skills and motor ability in the general adult population, and whether poor stereopsis may contribute to this association. This has implications for clinical populations since research has shown associations between motor abnormalities and social skills, as well as reduced depth perception in autism spectrum disorder and developmental coordination disorder. Methods: Six hundred fifty adults completed three validated questionnaires, the stereopsis screening inventory, the Adult Developmental Coordination Disorder Checklist, and the Autism Spectrum Quotient. Results: An exploratory factor analysis on pooled items across all measures revealed 10 factors that were largely composed of items from a single scale, indicating that any co-occurrence of poor stereopsis, reduced motor proficiency, and difficulties with social interaction cannot be attributed to a single underlying mechanism. Correlations between extracted factor scores found associations between motor skill and social skill. Conclusions: Mediation analyses suggested that whilst fine motor skill and coordination explained the relationship between stereopsis and social skill to some extent, stereopsis nonetheless exerted a substantial direct effect upon social skill. This is the first study to demonstrate that the functional significance of stereopsis is not limited to motor ability and may directly impact upon social functioning. En ligne : https://dx.doi.org/10.1186/s13229-018-0234-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Subcellular organization of UBE3A in human cerebral cortex / A. C. BURETTE in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 54p. Titre : Subcellular organization of UBE3A in human cerebral cortex Type de document : Texte imprimé et/ou numérique Auteurs : A. C. BURETTE, Auteur ; M. C. JUDSON, Auteur ; A. N. LI, Auteur ; E. F. CHANG, Auteur ; W. W. SEELEY, Auteur ; B. D. PHILPOT, Auteur ; R. J. WEINBERG, Auteur Article en page(s) : 54p. Langues : Anglais (eng) Mots-clés : Angelman syndrome  Axon terminal  e6-ap  Euchromatin  Mitochondria  UCSF Committee on Human Research and the University of Maryland Institutional  Review Board.All authors read and approved the final manuscript.The authors  declare that they have no competing interests.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: Loss of UBE3A causes Angelman syndrome, whereas excess UBE3A activity appears to increase the risk for autism. Despite this powerful association with neurodevelopmental disorders, there is still much to be learned about UBE3A, including its cellular and subcellular organization in the human brain. The issue is important, since UBE3A's localization is integral to its function. Methods: We used light and electron microscopic immunohistochemistry to study the cellular and subcellular distribution of UBE3A in the adult human cerebral cortex. Experiments were performed on multiple tissue sources, but our results focused on optimally preserved material, using surgically resected human temporal cortex of high ultrastructural quality from nine individuals. Results: We demonstrate that UBE3A is expressed in both glutamatergic and GABAergic neurons, and to a lesser extent in glial cells. We find that UBE3A in neurons has a non-uniform subcellular distribution. In somata, UBE3A preferentially concentrates in euchromatin-rich domains within the nucleus. Electron microscopy reveals that labeling concentrates in the head and neck of dendritic spines and is excluded from the PSD. Strongest labeling within the neuropil was found in axon terminals. Conclusions: By highlighting the subcellular compartments in which UBE3A is likely to function in the human neocortex, our data provide insight into the diverse functional capacities of this E3 ligase. These anatomical data may help to elucidate the role of UBE3A in Angelman syndrome and autism spectrum disorder. En ligne : https://dx.doi.org/10.1186/s13229-018-0238-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Subcellular organization of UBE3A in human cerebral cortex [Texte imprimé et/ou numérique] / A. C. BURETTE, Auteur ; M. C. JUDSON, Auteur ; A. N. LI, Auteur ; E. F. CHANG, Auteur ; W. W. SEELEY, Auteur ; B. D. PHILPOT, Auteur ; R. J. WEINBERG, Auteur . - 54p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 54p. Mots-clés : Angelman syndrome  Axon terminal  e6-ap  Euchromatin  Mitochondria  UCSF Committee on Human Research and the University of Maryland Institutional  Review Board.All authors read and approved the final manuscript.The authors  declare that they have no competing interests.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: Loss of UBE3A causes Angelman syndrome, whereas excess UBE3A activity appears to increase the risk for autism. Despite this powerful association with neurodevelopmental disorders, there is still much to be learned about UBE3A, including its cellular and subcellular organization in the human brain. The issue is important, since UBE3A's localization is integral to its function. Methods: We used light and electron microscopic immunohistochemistry to study the cellular and subcellular distribution of UBE3A in the adult human cerebral cortex. Experiments were performed on multiple tissue sources, but our results focused on optimally preserved material, using surgically resected human temporal cortex of high ultrastructural quality from nine individuals. Results: We demonstrate that UBE3A is expressed in both glutamatergic and GABAergic neurons, and to a lesser extent in glial cells. We find that UBE3A in neurons has a non-uniform subcellular distribution. In somata, UBE3A preferentially concentrates in euchromatin-rich domains within the nucleus. Electron microscopy reveals that labeling concentrates in the head and neck of dendritic spines and is excluded from the PSD. Strongest labeling within the neuropil was found in axon terminals. Conclusions: By highlighting the subcellular compartments in which UBE3A is likely to function in the human neocortex, our data provide insight into the diverse functional capacities of this E3 ligase. These anatomical data may help to elucidate the role of UBE3A in Angelman syndrome and autism spectrum disorder. En ligne : https://dx.doi.org/10.1186/s13229-018-0238-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Savant syndrome has a distinct psychological profile in autism / J. E. A. HUGHES in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 53p. Titre : Savant syndrome has a distinct psychological profile in autism Type de document : Texte imprimé et/ou numérique Auteurs : J. E. A. HUGHES, Auteur ; J. WARD, Auteur ; E. GRUFFYDD, Auteur ; Simon BARON-COHEN, Auteur ; P. SMITH, Auteur ; Carrie ALLISON, Auteur ; J. SIMNER, Auteur Article en page(s) : 53p. Langues : Anglais (eng) Mots-clés : Autism spectrum conditions  Cognition  Perception  Savant syndrome  Sensory processing  Skill learning  Talent  Ethics Committee at the University of Sussex. Informed consent was gained from  all individual participants.Not applicable.The authors declare that they have no  competing interests.Springer Nature remains neutral with regard to jurisdictional  claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Savant syndrome is a condition where prodigious talent can co-occur with developmental conditions such as autism spectrum conditions (autism). It is not yet clear why some autistic people develop savant skills while others do not. Methods: We tested three groups of adults: autistic individuals who have savant skills, autistic individuals without savant skills, and typical controls without autism or savant syndrome. In experiment 1, we investigated the cognitive and behavioural profiles of these three groups by asking participants to complete a battery of self-report measures of sensory sensitivity, obsessional behaviours, cognitive styles, and broader autism-related traits including social communication and systemising. In experiment 2, we investigated how our three groups learned a novel savant skill-calendar calculation. Results: Heightened sensory sensitivity, obsessional behaviours, technical/spatial abilities, and systemising were all key aspects in defining the savant profile distinct from autism alone, along with a different approach to task learning. Conclusions: These results reveal a unique cognitive and behavioural profile in autistic adults with savant syndrome that is distinct from autistic adults without a savant skill. En ligne : https://dx.doi.org/10.1186/s13229-018-0237-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Savant syndrome has a distinct psychological profile in autism [Texte imprimé et/ou numérique] / J. E. A. HUGHES, Auteur ; J. WARD, Auteur ; E. GRUFFYDD, Auteur ; Simon BARON-COHEN, Auteur ; P. SMITH, Auteur ; Carrie ALLISON, Auteur ; J. SIMNER, Auteur . - 53p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 53p. Mots-clés : Autism spectrum conditions  Cognition  Perception  Savant syndrome  Sensory processing  Skill learning  Talent  Ethics Committee at the University of Sussex. Informed consent was gained from  all individual participants.Not applicable.The authors declare that they have no  competing interests.Springer Nature remains neutral with regard to jurisdictional  claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Savant syndrome is a condition where prodigious talent can co-occur with developmental conditions such as autism spectrum conditions (autism). It is not yet clear why some autistic people develop savant skills while others do not. Methods: We tested three groups of adults: autistic individuals who have savant skills, autistic individuals without savant skills, and typical controls without autism or savant syndrome. In experiment 1, we investigated the cognitive and behavioural profiles of these three groups by asking participants to complete a battery of self-report measures of sensory sensitivity, obsessional behaviours, cognitive styles, and broader autism-related traits including social communication and systemising. In experiment 2, we investigated how our three groups learned a novel savant skill-calendar calculation. Results: Heightened sensory sensitivity, obsessional behaviours, technical/spatial abilities, and systemising were all key aspects in defining the savant profile distinct from autism alone, along with a different approach to task learning. Conclusions: These results reveal a unique cognitive and behavioural profile in autistic adults with savant syndrome that is distinct from autistic adults without a savant skill. En ligne : https://dx.doi.org/10.1186/s13229-018-0237-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Links between looking and speaking in autism and first-degree relatives: insights into the expression of genetic liability to autism / K. NAYAR in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 51p. Titre : Links between looking and speaking in autism and first-degree relatives: insights into the expression of genetic liability to autism Type de document : Texte imprimé et/ou numérique Auteurs : K. NAYAR, Auteur ; P. C. GORDON, Auteur ; G. E. MARTIN, Auteur ; A. L. HOGAN, Auteur ; C. LA VALLE, Auteur ; W. MCKINNEY, Auteur ; M. LEE, Auteur ; E. S. NORTON, Auteur ; M. LOSH, Auteur Article en page(s) : 51p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Broad autism phenotype  Endophenotype  Eye movement  Eye-voice span  Gaze  Language  Rapid automatized naming  Restricted and repetitive behaviors  Social communication  standards of the institutional research committee and with the 1964 Helsinki  Declaration and its later amendments or comparable ethical standards. Informed  consent was obtained from all individual participants included in the study.Not  applicableThe authors declare that they have no competing interests.Springer  Nature remains neutral with regard to jurisdictional claims in published maps and  institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Rapid automatized naming (RAN; naming of familiar items presented in an array) is a task that taps fundamental neurocognitive processes that are affected in a number of complex psychiatric conditions. Deficits in RAN have been repeatedly observed in autism spectrum disorder (ASD), and also among first-degree relatives, suggesting that RAN may tap features that index genetic liability to ASD. This study used eye tracking to examine neurocognitive mechanisms related to RAN performance in ASD and first-degree relatives, and investigated links to broader language and clinical-behavioral features. Methods: Fifty-one individuals with ASD, biological parents of individuals with ASD (n = 133), and respective control groups (n = 45 ASD controls; 58 parent controls) completed RAN on an eye tracker. Variables included naming time, frequency of errors, and measures of eye movement during RAN (eye-voice span, number of fixations and refixations). Results: Both the ASD and parent-ASD groups showed slower naming times, more errors, and atypical eye-movement patterns (e.g., increased fixations and refixations), relative to controls, with differences persisting after accounting for spousal resemblance. RAN ability and associated eye movement patterns were correlated with increased social-communicative impairment and increased repetitive behaviors in ASD. Longer RAN times and greater refixations in the parent-ASD group were driven by the subgroup who showed clinical-behavioral features of the broad autism phenotype (BAP). Finally, parent-child dyad correlations revealed associations between naming time and refixations in parents with the BAP and increased repetitive behaviors in their child with ASD. Conclusions: Differences in RAN performance and associated eye movement patterns detected in ASD and in parents, and links to broader social-communicative abilities, clinical features, and parent-child associations, suggest that RAN-related abilities might constitute genetically meaningful neurocognitive markers that can help bridge connections between underlying biology and ASD symptomatology. En ligne : https://dx.doi.org/10.1186/s13229-018-0233-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Links between looking and speaking in autism and first-degree relatives: insights into the expression of genetic liability to autism [Texte imprimé et/ou numérique] / K. NAYAR, Auteur ; P. C. GORDON, Auteur ; G. E. MARTIN, Auteur ; A. L. HOGAN, Auteur ; C. LA VALLE, Auteur ; W. MCKINNEY, Auteur ; M. LEE, Auteur ; E. S. NORTON, Auteur ; M. LOSH, Auteur . - 51p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 51p. Mots-clés : Autism spectrum disorder  Broad autism phenotype  Endophenotype  Eye movement  Eye-voice span  Gaze  Language  Rapid automatized naming  Restricted and repetitive behaviors  Social communication  standards of the institutional research committee and with the 1964 Helsinki  Declaration and its later amendments or comparable ethical standards. Informed  consent was obtained from all individual participants included in the study.Not  applicableThe authors declare that they have no competing interests.Springer  Nature remains neutral with regard to jurisdictional claims in published maps and  institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Rapid automatized naming (RAN; naming of familiar items presented in an array) is a task that taps fundamental neurocognitive processes that are affected in a number of complex psychiatric conditions. Deficits in RAN have been repeatedly observed in autism spectrum disorder (ASD), and also among first-degree relatives, suggesting that RAN may tap features that index genetic liability to ASD. This study used eye tracking to examine neurocognitive mechanisms related to RAN performance in ASD and first-degree relatives, and investigated links to broader language and clinical-behavioral features. Methods: Fifty-one individuals with ASD, biological parents of individuals with ASD (n = 133), and respective control groups (n = 45 ASD controls; 58 parent controls) completed RAN on an eye tracker. Variables included naming time, frequency of errors, and measures of eye movement during RAN (eye-voice span, number of fixations and refixations). Results: Both the ASD and parent-ASD groups showed slower naming times, more errors, and atypical eye-movement patterns (e.g., increased fixations and refixations), relative to controls, with differences persisting after accounting for spousal resemblance. RAN ability and associated eye movement patterns were correlated with increased social-communicative impairment and increased repetitive behaviors in ASD. Longer RAN times and greater refixations in the parent-ASD group were driven by the subgroup who showed clinical-behavioral features of the broad autism phenotype (BAP). Finally, parent-child dyad correlations revealed associations between naming time and refixations in parents with the BAP and increased repetitive behaviors in their child with ASD. Conclusions: Differences in RAN performance and associated eye movement patterns detected in ASD and in parents, and links to broader social-communicative abilities, clinical features, and parent-child associations, suggest that RAN-related abilities might constitute genetically meaningful neurocognitive markers that can help bridge connections between underlying biology and ASD symptomatology. En ligne : https://dx.doi.org/10.1186/s13229-018-0233-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Alterations in electrophysiological indices of perceptual processing and discrimination are associated with co-occurring emotional and behavioural problems in adolescents with autism spectrum disorder / Virginia CARTER LENO in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 50p. Titre : Alterations in electrophysiological indices of perceptual processing and discrimination are associated with co-occurring emotional and behavioural problems in adolescents with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Virginia CARTER LENO, Auteur ; S. CHANDLER, Auteur ; P. WHITE, Auteur ; I. YORKE, Auteur ; Tony CHARMAN, Auteur ; A. PICKLES, Auteur ; E. SIMONOFF, Auteur Article en page(s) : 50p. Langues : Anglais (eng) Mots-clés : asd  Comorbidity  eeg  erp  IAMHealth  Perceptual processing  Psychopathology  Sensory  approved by Camden and King's Cross Ethics Sub-Committee (14/LO/2098).Not  applicable.AP receives royalties from the Social Communication Questionnaire. The  other authors declare that they have no competing interests.Springer Nature  remains neutral with regard to jurisdictional claims in published maps and  institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Many young people with autism spectrum disorder (ASD) experience emotional and behavioural problems. However, the causes of these co-occurring difficulties are not well understood. Perceptual processing atypicalities are also often reported in individuals with ASD, but how these relate to co-occurring emotional and behavioural problems remains unclear, and few studies have used objective measurement of perceptual processing. Methods: Event-related potentials (ERPs) were recorded in response to both standard and deviant stimuli (which varied in pitch) in an auditory oddball paradigm in adolescents (mean age of 13.56 years, SD = 1.12, range = 11.40-15.70) with ASD (n = 43) with a wide range of IQ (mean IQ of 84.14, SD = 24.24, range 27-129). Response to deviant as compared to standard stimuli (as indexed by the mismatch negativity (MMN)) and response to repeated presentations of standard stimuli (habituation) were measured. Multivariate regression tested the association between neural indices of perceptual processing and co-occurring emotional and behavioural problems. Results: Greater sensitivity to changes in pitch in incoming auditory information (discrimination), as indexed by increased MMN amplitude, was associated with higher levels of parent-rated behaviour problems. MMN amplitude also showed a trend positive correlation with parent-rated sensory hyper-sensitivity. Conversely, greater habituation at the later N2 component was associated with higher levels of emotional problems. Upon more detailed analyses, this appeared to be driven by a selectively greater ERP response to the first (but not the second or third) standard stimuli that followed deviant stimuli. A similar pattern of association was found with other measures of anxiety. All results remained in covariation analyses controlling for age, sex and IQ, although the association between MMN amplitude and behaviour problems became non-significant when controlling for ASD severity. Conclusions: Findings suggest that alterations in mechanisms of perceptual processing and discrimination may be important for understanding co-occurring emotional and behavioural problems in young people with ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0236-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Alterations in electrophysiological indices of perceptual processing and discrimination are associated with co-occurring emotional and behavioural problems in adolescents with autism spectrum disorder [Texte imprimé et/ou numérique] / Virginia CARTER LENO, Auteur ; S. CHANDLER, Auteur ; P. WHITE, Auteur ; I. YORKE, Auteur ; Tony CHARMAN, Auteur ; A. PICKLES, Auteur ; E. SIMONOFF, Auteur . - 50p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 50p. Mots-clés : asd  Comorbidity  eeg  erp  IAMHealth  Perceptual processing  Psychopathology  Sensory  approved by Camden and King's Cross Ethics Sub-Committee (14/LO/2098).Not  applicable.AP receives royalties from the Social Communication Questionnaire. The  other authors declare that they have no competing interests.Springer Nature  remains neutral with regard to jurisdictional claims in published maps and  institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Many young people with autism spectrum disorder (ASD) experience emotional and behavioural problems. However, the causes of these co-occurring difficulties are not well understood. Perceptual processing atypicalities are also often reported in individuals with ASD, but how these relate to co-occurring emotional and behavioural problems remains unclear, and few studies have used objective measurement of perceptual processing. Methods: Event-related potentials (ERPs) were recorded in response to both standard and deviant stimuli (which varied in pitch) in an auditory oddball paradigm in adolescents (mean age of 13.56 years, SD = 1.12, range = 11.40-15.70) with ASD (n = 43) with a wide range of IQ (mean IQ of 84.14, SD = 24.24, range 27-129). Response to deviant as compared to standard stimuli (as indexed by the mismatch negativity (MMN)) and response to repeated presentations of standard stimuli (habituation) were measured. Multivariate regression tested the association between neural indices of perceptual processing and co-occurring emotional and behavioural problems. Results: Greater sensitivity to changes in pitch in incoming auditory information (discrimination), as indexed by increased MMN amplitude, was associated with higher levels of parent-rated behaviour problems. MMN amplitude also showed a trend positive correlation with parent-rated sensory hyper-sensitivity. Conversely, greater habituation at the later N2 component was associated with higher levels of emotional problems. Upon more detailed analyses, this appeared to be driven by a selectively greater ERP response to the first (but not the second or third) standard stimuli that followed deviant stimuli. A similar pattern of association was found with other measures of anxiety. All results remained in covariation analyses controlling for age, sex and IQ, although the association between MMN amplitude and behaviour problems became non-significant when controlling for ASD severity. Conclusions: Findings suggest that alterations in mechanisms of perceptual processing and discrimination may be important for understanding co-occurring emotional and behavioural problems in young people with ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0236-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

The effect of age on vertex-based measures of the grey-white matter tissue contrast in autism spectrum disorder / C. MANN in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 49p. Titre : The effect of age on vertex-based measures of the grey-white matter tissue contrast in autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : C. MANN, Auteur ; Anke BLETSCH, Auteur ; D. ANDREWS, Auteur ; Eileen DALY, Auteur ; C. MURPHY, Auteur ; D. MURPHY, Auteur ; C. ECKER, Auteur Article en page(s) : 49p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Brain anatomy  Neurodevelopment  Neuroimaging  Structural MRI  Psychosomatics and Psychotherapy, University Hospital, Goethe-University  Frankfurt am Main, Deutschordenstrasse 50, 60528 Frankfurt, Germany  DA, PhD, The  Medical Investigation of Neurodevelopmental Disorders (MIND) Institute and  Department of Psychiatry and Behavioural Sciences, UC Davis School of Medicine,  University of California Davis, Sacramento, CA, USA  ED, PhD and CM, PhD,  Department of Forensic and Neurodevelopmental Sciences, and the Sackler Institute  for Translational Neurodevelopmental Sciences, Institute of Psychiatry,  Psychology & Neuroscience (IoPPN), King's College London, London SE5 8AF, United  Kingdom  DM, Professor, Head of Department of Forensic and Neurodevelopmental  Sciences, and the Sackler Institute for Translational Neurodevelopmental  Sciences, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's  College London, London SE5 8AF, United Kingdom  CE, Professor, Department of  Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University  Hospital, Goethe-University Frankfurt am Main, Deutschordenstrasse 50, 60528  Frankfurt, Germany and Department of Forensic and Neurodevelopmental Sciences,  and the Sackler Institute for Translational Neurodevelopmental Sciences,  Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College  London, London SE5 8AF, United Kingdom.All participants gave informed written  consent in accordance with the ethics approval by the National Research Ethics  Committee, Suffolk, England.Not applicable.The authors declare that they have no  competing interests.Springer Nature remains neutral with regard to jurisdictional  claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Histological evidence suggests that autism spectrum disorder (ASD) is accompanied by a reduced integrity of the grey-white matter boundary. This has also recently been confirmed by a structural neuroimaging study in vivo reporting significantly reduced grey-white matter tissue contrast (GWC) in adult individuals (18-42 years of age) with ASD relative to typically developing (TD) controls. However, it remains unknown whether the neuroanatomical differences in ASD at the grey-white matter boundary are stable across development or are age-dependent. Methods: Here, we examined differences in the neurodevelopmental trajectories of GWC in a cross-sectional sample of 77 male ASD individuals and 76 typically developing (TD) controls across childhood and early adulthood (from 7 to 25 years). Results: Using nested model comparisons, we first established that the developmental trajectory of GWC is complex in many regions across the cortex and includes linear and non-linear effects of age. Second, while ASD individuals have significantly reduced GWC overall, these differences are age-dependent and are most prominent during childhood (< 15 years). Conclusions: Taken together, our findings suggest that differences in GWC in ASD are unlikely to reflect atypical grey matter cytoarchitecture alone, but may also represent other aspects of the cortical architecture such as age-dependent variability in myelin integrity. En ligne : https://dx.doi.org/10.1186/s13229-018-0232-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] The effect of age on vertex-based measures of the grey-white matter tissue contrast in autism spectrum disorder [Texte imprimé et/ou numérique] / C. MANN, Auteur ; Anke BLETSCH, Auteur ; D. ANDREWS, Auteur ; Eileen DALY, Auteur ; C. MURPHY, Auteur ; D. MURPHY, Auteur ; C. ECKER, Auteur . - 49p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 49p. Mots-clés : Autism spectrum disorder  Brain anatomy  Neurodevelopment  Neuroimaging  Structural MRI  Psychosomatics and Psychotherapy, University Hospital, Goethe-University  Frankfurt am Main, Deutschordenstrasse 50, 60528 Frankfurt, Germany  DA, PhD, The  Medical Investigation of Neurodevelopmental Disorders (MIND) Institute and  Department of Psychiatry and Behavioural Sciences, UC Davis School of Medicine,  University of California Davis, Sacramento, CA, USA  ED, PhD and CM, PhD,  Department of Forensic and Neurodevelopmental Sciences, and the Sackler Institute  for Translational Neurodevelopmental Sciences, Institute of Psychiatry,  Psychology & Neuroscience (IoPPN), King's College London, London SE5 8AF, United  Kingdom  DM, Professor, Head of Department of Forensic and Neurodevelopmental  Sciences, and the Sackler Institute for Translational Neurodevelopmental  Sciences, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's  College London, London SE5 8AF, United Kingdom  CE, Professor, Department of  Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University  Hospital, Goethe-University Frankfurt am Main, Deutschordenstrasse 50, 60528  Frankfurt, Germany and Department of Forensic and Neurodevelopmental Sciences,  and the Sackler Institute for Translational Neurodevelopmental Sciences,  Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College  London, London SE5 8AF, United Kingdom.All participants gave informed written  consent in accordance with the ethics approval by the National Research Ethics  Committee, Suffolk, England.Not applicable.The authors declare that they have no  competing interests.Springer Nature remains neutral with regard to jurisdictional  claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Histological evidence suggests that autism spectrum disorder (ASD) is accompanied by a reduced integrity of the grey-white matter boundary. This has also recently been confirmed by a structural neuroimaging study in vivo reporting significantly reduced grey-white matter tissue contrast (GWC) in adult individuals (18-42 years of age) with ASD relative to typically developing (TD) controls. However, it remains unknown whether the neuroanatomical differences in ASD at the grey-white matter boundary are stable across development or are age-dependent. Methods: Here, we examined differences in the neurodevelopmental trajectories of GWC in a cross-sectional sample of 77 male ASD individuals and 76 typically developing (TD) controls across childhood and early adulthood (from 7 to 25 years). Results: Using nested model comparisons, we first established that the developmental trajectory of GWC is complex in many regions across the cortex and includes linear and non-linear effects of age. Second, while ASD individuals have significantly reduced GWC overall, these differences are age-dependent and are most prominent during childhood (< 15 years). Conclusions: Taken together, our findings suggest that differences in GWC in ASD are unlikely to reflect atypical grey matter cytoarchitecture alone, but may also represent other aspects of the cortical architecture such as age-dependent variability in myelin integrity. En ligne : https://dx.doi.org/10.1186/s13229-018-0232-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Clustering the autisms using glutamate synapse protein interaction networks from cortical and hippocampal tissue of seven mouse models / E. A. BROWN in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 48p. Titre : Clustering the autisms using glutamate synapse protein interaction networks from cortical and hippocampal tissue of seven mouse models Type de document : Texte imprimé et/ou numérique Auteurs : E. A. BROWN, Auteur ; J. D. LAUTZ, Auteur ; T. R. DAVIS, Auteur ; E. P. GNIFFKE, Auteur ; A. A. W. VANSCHOIACK, Auteur ; S. C. NEIER, Auteur ; N. TASHBOOK, Auteur ; C. NICOLINI, Auteur ; M. FAHNESTOCK, Auteur ; A. G. SCHRUM, Auteur ; S. E. P. SMITH, Auteur Article en page(s) : 48p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorders (ASDs) are a heterogeneous group of behaviorally defined disorders and are associated with hundreds of rare genetic mutations and several environmental risk factors. Mouse models of specific risk factors have been successful in identifying molecular mechanisms associated with a given factor. However, comparisons among different models to elucidate underlying common pathways or to define clusters of biologically relevant disease subtypes have been complicated by different methodological approaches or different brain regions examined by the labs that developed each model. Here, we use a novel proteomic technique, quantitative multiplex co-immunoprecipitation or QMI, to make a series of identical measurements of a synaptic protein interaction network in seven different animal models. We aim to identify molecular disruptions that are common to multiple models. Methods: QMI was performed on 92 hippocampal and cortical samples taken from seven mouse models of ASD: Shank3B, Shank3Deltaex4-9, Ube3a(2xTG), TSC2, FMR1, and CNTNAP2 mutants, as well as E12.5 VPA (maternal valproic acid injection on day 12.5 post-conception). The QMI panel targeted a network of 16 interacting, ASD-linked, synaptic proteins, probing 240 potential co-associations. A custom non-parametric statistical test was used to call significant differences between ASD models and littermate controls, and Hierarchical Clustering by Principal Components was used to cluster the models using mean log2 fold change values. Results: Each model displayed a unique set of disrupted interactions, but some interactions were disrupted in multiple models. These tended to be interactions that are known to change with synaptic activity. Clustering revealed potential relationships among models and suggested deficits in AKT signaling in Ube3a(2xTG) mice, which were confirmed by phospho-western blots. Conclusions: These data highlight the great heterogeneity among models, but suggest that high-dimensional measures of a synaptic protein network may allow differentiation of subtypes of ASD with shared molecular pathology. En ligne : https://dx.doi.org/10.1186/s13229-018-0229-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Clustering the autisms using glutamate synapse protein interaction networks from cortical and hippocampal tissue of seven mouse models [Texte imprimé et/ou numérique] / E. A. BROWN, Auteur ; J. D. LAUTZ, Auteur ; T. R. DAVIS, Auteur ; E. P. GNIFFKE, Auteur ; A. A. W. VANSCHOIACK, Auteur ; S. C. NEIER, Auteur ; N. TASHBOOK, Auteur ; C. NICOLINI, Auteur ; M. FAHNESTOCK, Auteur ; A. G. SCHRUM, Auteur ; S. E. P. SMITH, Auteur . - 48p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 48p. Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorders (ASDs) are a heterogeneous group of behaviorally defined disorders and are associated with hundreds of rare genetic mutations and several environmental risk factors. Mouse models of specific risk factors have been successful in identifying molecular mechanisms associated with a given factor. However, comparisons among different models to elucidate underlying common pathways or to define clusters of biologically relevant disease subtypes have been complicated by different methodological approaches or different brain regions examined by the labs that developed each model. Here, we use a novel proteomic technique, quantitative multiplex co-immunoprecipitation or QMI, to make a series of identical measurements of a synaptic protein interaction network in seven different animal models. We aim to identify molecular disruptions that are common to multiple models. Methods: QMI was performed on 92 hippocampal and cortical samples taken from seven mouse models of ASD: Shank3B, Shank3Deltaex4-9, Ube3a(2xTG), TSC2, FMR1, and CNTNAP2 mutants, as well as E12.5 VPA (maternal valproic acid injection on day 12.5 post-conception). The QMI panel targeted a network of 16 interacting, ASD-linked, synaptic proteins, probing 240 potential co-associations. A custom non-parametric statistical test was used to call significant differences between ASD models and littermate controls, and Hierarchical Clustering by Principal Components was used to cluster the models using mean log2 fold change values. Results: Each model displayed a unique set of disrupted interactions, but some interactions were disrupted in multiple models. These tended to be interactions that are known to change with synaptic activity. Clustering revealed potential relationships among models and suggested deficits in AKT signaling in Ube3a(2xTG) mice, which were confirmed by phospho-western blots. Conclusions: These data highlight the great heterogeneity among models, but suggest that high-dimensional measures of a synaptic protein network may allow differentiation of subtypes of ASD with shared molecular pathology. En ligne : https://dx.doi.org/10.1186/s13229-018-0229-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

A behavioral test battery for mouse models of Angelman syndrome: a powerful tool for testing drugs and novel Ube3a mutants / M. SONZOGNI in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 47p. Titre : A behavioral test battery for mouse models of Angelman syndrome: a powerful tool for testing drugs and novel Ube3a mutants Type de document : Texte imprimé et/ou numérique Auteurs : M. SONZOGNI, Auteur ; I. WALLAARD, Auteur ; S. S. SANTOS, Auteur ; J. KINGMA, Auteur ; D. DU MEE, Auteur ; G. M. VAN WOERDEN, Auteur ; Y. ELGERSMA, Auteur Article en page(s) : 47p. Langues : Anglais (eng) Mots-clés : Angelman syndrome  Mouse model, behavior, drug screening  UBE3A Index. décimale : PER Périodiques Résumé : Background: Angelman syndrome (AS) is a neurodevelopmental disorder caused by mutations affecting UBE3A function. AS is characterized by intellectual disability, impaired motor coordination, epilepsy, and behavioral abnormalities including autism spectrum disorder features. The development of treatments for AS heavily relies on the ability to test the efficacy of drugs in mouse models that show reliable, and preferably clinically relevant, phenotypes. We previously described a number of behavioral paradigms that assess phenotypes in the domains of motor performance, repetitive behavior, anxiety, and seizure susceptibility. Here, we set out to evaluate the robustness of these phenotypes when tested in a standardized test battery. We then used this behavioral test battery to assess the efficacy of minocycline and levodopa, which were recently tested in clinical trials of AS. Methods: We combined data of eight independent experiments involving 111 Ube3a mice and 120 wild-type littermate control mice. Using a meta-analysis, we determined the statistical power of the subtests and the effect of putative confounding factors, such as the effect of sex and of animal weight on rotarod performance. We further assessed the robustness of these phenotypes by comparing Ube3a mutants in different genetic backgrounds and by comparing the behavioral phenotypes of independently derived Ube3a-mutant lines. In addition, we investigated if the test battery allowed re-testing the same animals, which would allow a within-subject testing design. Results: We find that the test battery is robust across different Ube3a-mutant lines, but confirm and extend earlier studies that several phenotypes are very sensitive to genetic background. We further found that the audiogenic seizure susceptibility phenotype is fully reversible upon pharmacological treatment and highly suitable for dose-finding studies. In agreement with the clinical trial results, we found that minocycline and levodopa treatment of Ube3a mice did not show any sign of improved performance in our test battery. Conclusions: Our study provides a useful tool for preclinical drug testing to identify treatments for Angelman syndrome. Since the phenotypes are observed in several independently derived Ube3a lines, the test battery can also be employed to investigate the effect of specific Ube3a mutations on these phenotypes. En ligne : https://dx.doi.org/10.1186/s13229-018-0231-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] A behavioral test battery for mouse models of Angelman syndrome: a powerful tool for testing drugs and novel Ube3a mutants [Texte imprimé et/ou numérique] / M. SONZOGNI, Auteur ; I. WALLAARD, Auteur ; S. S. SANTOS, Auteur ; J. KINGMA, Auteur ; D. DU MEE, Auteur ; G. M. VAN WOERDEN, Auteur ; Y. ELGERSMA, Auteur . - 47p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 47p. Mots-clés : Angelman syndrome  Mouse model, behavior, drug screening  UBE3A Index. décimale : PER Périodiques Résumé : Background: Angelman syndrome (AS) is a neurodevelopmental disorder caused by mutations affecting UBE3A function. AS is characterized by intellectual disability, impaired motor coordination, epilepsy, and behavioral abnormalities including autism spectrum disorder features. The development of treatments for AS heavily relies on the ability to test the efficacy of drugs in mouse models that show reliable, and preferably clinically relevant, phenotypes. We previously described a number of behavioral paradigms that assess phenotypes in the domains of motor performance, repetitive behavior, anxiety, and seizure susceptibility. Here, we set out to evaluate the robustness of these phenotypes when tested in a standardized test battery. We then used this behavioral test battery to assess the efficacy of minocycline and levodopa, which were recently tested in clinical trials of AS. Methods: We combined data of eight independent experiments involving 111 Ube3a mice and 120 wild-type littermate control mice. Using a meta-analysis, we determined the statistical power of the subtests and the effect of putative confounding factors, such as the effect of sex and of animal weight on rotarod performance. We further assessed the robustness of these phenotypes by comparing Ube3a mutants in different genetic backgrounds and by comparing the behavioral phenotypes of independently derived Ube3a-mutant lines. In addition, we investigated if the test battery allowed re-testing the same animals, which would allow a within-subject testing design. Results: We find that the test battery is robust across different Ube3a-mutant lines, but confirm and extend earlier studies that several phenotypes are very sensitive to genetic background. We further found that the audiogenic seizure susceptibility phenotype is fully reversible upon pharmacological treatment and highly suitable for dose-finding studies. In agreement with the clinical trial results, we found that minocycline and levodopa treatment of Ube3a mice did not show any sign of improved performance in our test battery. Conclusions: Our study provides a useful tool for preclinical drug testing to identify treatments for Angelman syndrome. Since the phenotypes are observed in several independently derived Ube3a lines, the test battery can also be employed to investigate the effect of specific Ube3a mutations on these phenotypes. En ligne : https://dx.doi.org/10.1186/s13229-018-0231-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

The impact of robotic intervention on joint attention in children with autism spectrum disorders / H. KUMAZAKI in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 46p. Titre : The impact of robotic intervention on joint attention in children with autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : H. KUMAZAKI, Auteur ; Y. YOSHIKAWA, Auteur ; Y. YOSHIMURA, Auteur ; T. IKEDA, Auteur ; C. HASEGAWA, Auteur ; Daisuke N. SAITO, Auteur ; S. TOMIYAMA, Auteur ; Kyung-Min AN, Auteur ; J. SHIMAYA, Auteur ; H. ISHIGURO, Auteur ; Y. MATSUMOTO, Auteur ; Y. MINABE, Auteur ; M. KIKUCHI, Auteur Article en page(s) : 46p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorders  Intervention  Joint attention  Robot  Typical development Index. décimale : PER Périodiques Résumé : Background: A growing body of anecdotal evidence indicates that the use of robots may provide unique opportunities for assisting children with autism spectrum disorders (ASD). However, previous studies investigating the effects of interventions using robots on joint attention (JA) in children with ASD have shown insufficient results. The robots used in these studies could not turn their eyes, which was a limitation preventing the robot from resembling a human agent. Methods: We compared the behavior of children with ASD with that of children with typical development (TD) during a JA elicitation task while the children interacted with either a human or a robotic agent. We used the robot "CommU," which has clear eyes and can turn its eyes, for the robotic intervention. The age range of the participants was limited to 5-6 years. Results: Sixty-eight participants participated in this study, including 30 (10 females and 20 males) children with ASD and 38 (13 females and 25 males) children with TD. The participants were randomly assigned to one of the following two groups: the robotic intervention group or the control group. JA in the children with ASD was better during the robotic intervention than during the human agent intervention. These children exhibited improved performance in the JA task with human after interacting with the robot CommU. JA was differentially facilitated by the human and robotic agents between the ASD and TD children. Conclusions: The findings of this study significantly contribute to the literature on the impact of robots on JA and provide information regarding the suitability of specific robot types for therapeutic use. En ligne : https://dx.doi.org/10.1186/s13229-018-0230-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] The impact of robotic intervention on joint attention in children with autism spectrum disorders [Texte imprimé et/ou numérique] / H. KUMAZAKI, Auteur ; Y. YOSHIKAWA, Auteur ; Y. YOSHIMURA, Auteur ; T. IKEDA, Auteur ; C. HASEGAWA, Auteur ; Daisuke N. SAITO, Auteur ; S. TOMIYAMA, Auteur ; Kyung-Min AN, Auteur ; J. SHIMAYA, Auteur ; H. ISHIGURO, Auteur ; Y. MATSUMOTO, Auteur ; Y. MINABE, Auteur ; M. KIKUCHI, Auteur . - 46p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 46p. Mots-clés : Autism spectrum disorders  Intervention  Joint attention  Robot  Typical development Index. décimale : PER Périodiques Résumé : Background: A growing body of anecdotal evidence indicates that the use of robots may provide unique opportunities for assisting children with autism spectrum disorders (ASD). However, previous studies investigating the effects of interventions using robots on joint attention (JA) in children with ASD have shown insufficient results. The robots used in these studies could not turn their eyes, which was a limitation preventing the robot from resembling a human agent. Methods: We compared the behavior of children with ASD with that of children with typical development (TD) during a JA elicitation task while the children interacted with either a human or a robotic agent. We used the robot "CommU," which has clear eyes and can turn its eyes, for the robotic intervention. The age range of the participants was limited to 5-6 years. Results: Sixty-eight participants participated in this study, including 30 (10 females and 20 males) children with ASD and 38 (13 females and 25 males) children with TD. The participants were randomly assigned to one of the following two groups: the robotic intervention group or the control group. JA in the children with ASD was better during the robotic intervention than during the human agent intervention. These children exhibited improved performance in the JA task with human after interacting with the robot CommU. JA was differentially facilitated by the human and robotic agents between the ASD and TD children. Conclusions: The findings of this study significantly contribute to the literature on the impact of robots on JA and provide information regarding the suitability of specific robot types for therapeutic use. En ligne : https://dx.doi.org/10.1186/s13229-018-0230-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Modeling the neuropsychiatric manifestations of Lowe syndrome using induced pluripotent stem cells: defective F-actin polymerization and WAVE-1 expression in neuronal cells / J. BARNES in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 44p. Titre : Modeling the neuropsychiatric manifestations of Lowe syndrome using induced pluripotent stem cells: defective F-actin polymerization and WAVE-1 expression in neuronal cells Type de document : Texte imprimé et/ou numérique Auteurs : J. BARNES, Auteur ; F. SALAS, Auteur ; R. MOKHTARI, Auteur ; H. DOLSTRA, Auteur ; E. PEDROSA, Auteur ; H. M. LACHMAN, Auteur Article en page(s) : 44p. Langues : Anglais (eng) Mots-clés : Autism  Cataract  Dent disease  Developmental  inpp5b  Induced pluripotent stem cells  Intellectual  Lowe syndrome  ocrl  Renal Index. décimale : PER Périodiques Résumé : Background: Lowe syndrome (LS) is a rare genetic disorder caused by loss of function mutations in the X-linked gene, OCRL, which codes for inositol polyphosphate 5-phosphatase. LS is characterized by the triad of congenital cataracts, neurodevelopmental impairment (primarily intellectual and developmental disabilities [IDD]), and renal proximal tubular dysfunction. Studies carried out over the years have shown that hypomorphic mutations in OCRL adversely affect endosome recycling and actin polymerization in kidney cells and patient-derived fibroblasts. The renal problem has been traced to an impaired recycling of megalin, a multi-ligand receptor that plays a key role in the reuptake of lipoproteins, amino acids, vitamin-binding proteins, and hormones. However, the neurodevelopmental aspects of the disorder have been difficult to study because the mouse knockout (KO) model does not display LS-related phenotypes. Fortunately, the discovery of induced pluripotent stem (iPS) cells has provided an opportunity to grow patient-specific neurons, which can be used to model neurodevelopmental disorders in vitro, as demonstrated in the many studies that have been published in the past few years in autism spectrum disorders (ASD), schizophrenia (SZ), bipolar disorder (BD), and IDD. Methods: We now report the first findings in neurons and neural progenitor cells (NPCs) generated from iPS cells derived from patients with LS and their typically developing male siblings, as well as an isogenic line in which the OCRL gene has been incapacitated by a null mutation generated using CRISPR-Cas9 gene editing. Results: We show that neuronal cells derived from patient-specific iPS cells containing hypomorphic variants are deficient in their capacity to produce F-filamentous actin (F-actin) fibers. Abnormalities were also found in the expression of WAVE-1, a component of the WAVE regulatory complex (WRC) that regulates actin polymerization. Curiously, neuronal cells carrying the engineered OCRL null mutation, in which OCRL protein is not expressed, did not show similar defects in F-actin and WAVE-1 expression. This is similar to the apparent lack of a phenotype in the mouse Ocrl KO model, and suggests that in the complete absence of OCRL protein, as opposed to producing a dysfunctional protein, as seen with the hypomorphic variants, there is partial compensation for the F-actin/WAVE-1 regulating function of OCRL. Conclusions: Alterations in F-actin polymerization and WRC have been found in a number of genetic subgroups of IDD and ASD. Thus, LS, a very rare genetic condition, is linked to a more expansive family of genes responsible for neurodevelopmental disorders that have shared pathogenic features. En ligne : https://dx.doi.org/10.1186/s13229-018-0227-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Modeling the neuropsychiatric manifestations of Lowe syndrome using induced pluripotent stem cells: defective F-actin polymerization and WAVE-1 expression in neuronal cells [Texte imprimé et/ou numérique] / J. BARNES, Auteur ; F. SALAS, Auteur ; R. MOKHTARI, Auteur ; H. DOLSTRA, Auteur ; E. PEDROSA, Auteur ; H. M. LACHMAN, Auteur . - 44p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 44p. Mots-clés : Autism  Cataract  Dent disease  Developmental  inpp5b  Induced pluripotent stem cells  Intellectual  Lowe syndrome  ocrl  Renal Index. décimale : PER Périodiques Résumé : Background: Lowe syndrome (LS) is a rare genetic disorder caused by loss of function mutations in the X-linked gene, OCRL, which codes for inositol polyphosphate 5-phosphatase. LS is characterized by the triad of congenital cataracts, neurodevelopmental impairment (primarily intellectual and developmental disabilities [IDD]), and renal proximal tubular dysfunction. Studies carried out over the years have shown that hypomorphic mutations in OCRL adversely affect endosome recycling and actin polymerization in kidney cells and patient-derived fibroblasts. The renal problem has been traced to an impaired recycling of megalin, a multi-ligand receptor that plays a key role in the reuptake of lipoproteins, amino acids, vitamin-binding proteins, and hormones. However, the neurodevelopmental aspects of the disorder have been difficult to study because the mouse knockout (KO) model does not display LS-related phenotypes. Fortunately, the discovery of induced pluripotent stem (iPS) cells has provided an opportunity to grow patient-specific neurons, which can be used to model neurodevelopmental disorders in vitro, as demonstrated in the many studies that have been published in the past few years in autism spectrum disorders (ASD), schizophrenia (SZ), bipolar disorder (BD), and IDD. Methods: We now report the first findings in neurons and neural progenitor cells (NPCs) generated from iPS cells derived from patients with LS and their typically developing male siblings, as well as an isogenic line in which the OCRL gene has been incapacitated by a null mutation generated using CRISPR-Cas9 gene editing. Results: We show that neuronal cells derived from patient-specific iPS cells containing hypomorphic variants are deficient in their capacity to produce F-filamentous actin (F-actin) fibers. Abnormalities were also found in the expression of WAVE-1, a component of the WAVE regulatory complex (WRC) that regulates actin polymerization. Curiously, neuronal cells carrying the engineered OCRL null mutation, in which OCRL protein is not expressed, did not show similar defects in F-actin and WAVE-1 expression. This is similar to the apparent lack of a phenotype in the mouse Ocrl KO model, and suggests that in the complete absence of OCRL protein, as opposed to producing a dysfunctional protein, as seen with the hypomorphic variants, there is partial compensation for the F-actin/WAVE-1 regulating function of OCRL. Conclusions: Alterations in F-actin polymerization and WRC have been found in a number of genetic subgroups of IDD and ASD. Thus, LS, a very rare genetic condition, is linked to a more expansive family of genes responsible for neurodevelopmental disorders that have shared pathogenic features. En ligne : https://dx.doi.org/10.1186/s13229-018-0227-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Characterization and structure-activity relationships of indenoisoquinoline-derived topoisomerase I inhibitors in unsilencing the dormant Ube3a gene associated with Angelman syndrome / H. M. LEE in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 45p. Titre : Characterization and structure-activity relationships of indenoisoquinoline-derived topoisomerase I inhibitors in unsilencing the dormant Ube3a gene associated with Angelman syndrome Type de document : Texte imprimé et/ou numérique Auteurs : H. M. LEE, Auteur ; E. P. CLARK, Auteur ; M. B. KUIJER, Auteur ; M. CUSHMAN, Auteur ; Y. POMMIER, Auteur ; B. D. PHILPOT, Auteur Article en page(s) : 45p. Langues : Anglais (eng) Mots-clés : Angelman syndrome  Indenoisoquinoline  Indotecan  Topoisomerase I  Topoisomerase inhibitor  Topotecan  UBE3A Index. décimale : PER Périodiques Résumé : Background: Angelman syndrome (AS) is a severe neurodevelopmental disorder lacking effective therapies. AS is caused by mutations in ubiquitin protein ligase E3A (UBE3A), which is genomically imprinted such that only the maternally inherited copy is expressed in neurons. We previously demonstrated that topoisomerase I (Top1) inhibitors could successfully reactivate the dormant paternal allele of Ube3a in neurons of a mouse model of AS. We also previously showed that one such Top1 inhibitor, topotecan, could unsilence paternal UBE3A in induced pluripotent stem cell-derived neurons from individuals with AS. Although topotecan has been well-studied and is FDA-approved for cancer therapy, its limited CNS bioavailability will likely restrict the therapeutic use of topotecan in AS. The goal of this study was to identify additional Top1 inhibitors with similar efficacy as topotecan, with the expectation that these could be tested in the future for safety and CNS bioavailability to assess their potential as AS therapeutics. Methods: We tested 13 indenoisoquinoline-derived Top1 inhibitors to identify compounds that unsilence the paternal allele of Ube3a in mouse neurons. Primary cortical neurons were isolated from embryonic day 14.5 (E14.5) mice with a Ube3a-YFP fluorescent tag on the paternal allele (Ube3a(m+/pYFP) mice) or mice that lack the maternal Ube3a allele and hence model AS (Ube3a(m-/p+) mice). Neurons were cultured for 7 days, treated with drug for 72 h, and examined for paternal UBE3A protein expression by Western blot or fluorescence immunostaining. Dose responses of the compounds were determined across a log range of drug treatments, and cytotoxicity was tested using a luciferase-based assay. Results: All 13 indenoisoquinoline-derived Top1 inhibitors unsilenced paternal Ube3a. Several compounds exhibited favorable paternal Ube3a unsilencing properties, similar to topotecan, and of these, indotecan (LMP400) was the most effective based on estimated Emax (maximum response of unsilencing paternal Ube3a) and EC50 (half maximal effective concentration). Conclusions: We provide pharmacological profiles of indenoisoquinoline-derived Top1 inhibitors as paternal Ube3a unsilencers. All 13 tested compounds were effective at unsilencing paternal Ube3a, although with variable efficacy and potency. Indotecan (LMP400) demonstrated a better pharmacological profile of Ube3a unsilencing compared to our previous lead compound, topotecan. Taken together, indotecan and its structural analogues are potential AS therapeutics whose translational potential in AS treatment should be further assessed. En ligne : https://dx.doi.org/10.1186/s13229-018-0228-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Characterization and structure-activity relationships of indenoisoquinoline-derived topoisomerase I inhibitors in unsilencing the dormant Ube3a gene associated with Angelman syndrome [Texte imprimé et/ou numérique] / H. M. LEE, Auteur ; E. P. CLARK, Auteur ; M. B. KUIJER, Auteur ; M. CUSHMAN, Auteur ; Y. POMMIER, Auteur ; B. D. PHILPOT, Auteur . - 45p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 45p. Mots-clés : Angelman syndrome  Indenoisoquinoline  Indotecan  Topoisomerase I  Topoisomerase inhibitor  Topotecan  UBE3A Index. décimale : PER Périodiques Résumé : Background: Angelman syndrome (AS) is a severe neurodevelopmental disorder lacking effective therapies. AS is caused by mutations in ubiquitin protein ligase E3A (UBE3A), which is genomically imprinted such that only the maternally inherited copy is expressed in neurons. We previously demonstrated that topoisomerase I (Top1) inhibitors could successfully reactivate the dormant paternal allele of Ube3a in neurons of a mouse model of AS. We also previously showed that one such Top1 inhibitor, topotecan, could unsilence paternal UBE3A in induced pluripotent stem cell-derived neurons from individuals with AS. Although topotecan has been well-studied and is FDA-approved for cancer therapy, its limited CNS bioavailability will likely restrict the therapeutic use of topotecan in AS. The goal of this study was to identify additional Top1 inhibitors with similar efficacy as topotecan, with the expectation that these could be tested in the future for safety and CNS bioavailability to assess their potential as AS therapeutics. Methods: We tested 13 indenoisoquinoline-derived Top1 inhibitors to identify compounds that unsilence the paternal allele of Ube3a in mouse neurons. Primary cortical neurons were isolated from embryonic day 14.5 (E14.5) mice with a Ube3a-YFP fluorescent tag on the paternal allele (Ube3a(m+/pYFP) mice) or mice that lack the maternal Ube3a allele and hence model AS (Ube3a(m-/p+) mice). Neurons were cultured for 7 days, treated with drug for 72 h, and examined for paternal UBE3A protein expression by Western blot or fluorescence immunostaining. Dose responses of the compounds were determined across a log range of drug treatments, and cytotoxicity was tested using a luciferase-based assay. Results: All 13 indenoisoquinoline-derived Top1 inhibitors unsilenced paternal Ube3a. Several compounds exhibited favorable paternal Ube3a unsilencing properties, similar to topotecan, and of these, indotecan (LMP400) was the most effective based on estimated Emax (maximum response of unsilencing paternal Ube3a) and EC50 (half maximal effective concentration). Conclusions: We provide pharmacological profiles of indenoisoquinoline-derived Top1 inhibitors as paternal Ube3a unsilencers. All 13 tested compounds were effective at unsilencing paternal Ube3a, although with variable efficacy and potency. Indotecan (LMP400) demonstrated a better pharmacological profile of Ube3a unsilencing compared to our previous lead compound, topotecan. Taken together, indotecan and its structural analogues are potential AS therapeutics whose translational potential in AS treatment should be further assessed. En ligne : https://dx.doi.org/10.1186/s13229-018-0228-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation / W. XIE in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 43p. Titre : Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation Type de document : Texte imprimé et/ou numérique Auteurs : W. XIE, Auteur ; X. GE, Auteur ; L. LI, Auteur ; A. YAO, Auteur ; X. WANG, Auteur ; M. LI, Auteur ; X. GONG, Auteur ; Z. CHU, Auteur ; Z. LU, Auteur ; X. HUANG, Auteur ; Y. JIAO, Auteur ; Y. WANG, Auteur ; M. XIAO, Auteur ; H. CHEN, Auteur ; W. XIANG, Auteur ; P. YAO, Auteur Article en page(s) : 43p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Estrogen receptor beta  Lipid metabolism  Mitochondria  Oxidative stress  Progestin  Resveratrol Index. décimale : PER Périodiques Résumé : Background: Recent literatures indicate that maternal hormone exposure is a risk factor for autism spectrum disorder (ASD). We hypothesize that prenatal progestin exposure may counteract the neuroprotective effect of estrogen and contribute to ASD development, and we aim to develop a method to ameliorate prenatal progestin exposure-induced autism-like behavior. Methods: Experiment 1: Prenatal progestin exposure-induced offspring are treated with resveratrol (RSV) through either prenatal or postnatal exposure and then used for autism-like behavior testing and other biomedical analyses. Experiment 2: Prenatal norethindrone (NET) exposure-induced offspring are treated with ERbeta knockdown lentivirus together with RSV for further testing. Experiment 3: Pregnant dams are treated with prenatal NET exposure together with RSV, and the offspring are used for further testing. Results: Eight kinds of clinically relevant progestins were used for prenatal exposure in pregnant dams, and the offspring showed decreased ERbeta expression in the amygdala with autism-like behavior. Oral administration of either postnatal or prenatal RSV treatment significantly reversed this effect with ERbeta activation and ameliorated autism-like behavior. Further investigation showed that RSV activates ERbeta and its target genes by demethylation of DNA and histone on the ERbeta promoter, and then minimizes progestin-induced oxidative stress as well as the dysfunction of mitochondria and lipid metabolism in the brain, subsequently ameliorating autism-like behavior. Conclusions: We conclude that resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation. Our data suggest that prenatal progestin exposure is a strong risk factor for autism-like behavior. Many potential clinical progestin applications, including oral contraceptive pills, preterm birth drugs, and progestin-contaminated drinking water or seafood, may be risk factors for ASD. In addition, RSV may be a good candidate for clinically rescuing or preventing ASD symptoms in humans, while high doses of resveratrol used in the animals may be a potential limitation for human application. En ligne : https://dx.doi.org/10.1186/s13229-018-0225-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation [Texte imprimé et/ou numérique] / W. XIE, Auteur ; X. GE, Auteur ; L. LI, Auteur ; A. YAO, Auteur ; X. WANG, Auteur ; M. LI, Auteur ; X. GONG, Auteur ; Z. CHU, Auteur ; Z. LU, Auteur ; X. HUANG, Auteur ; Y. JIAO, Auteur ; Y. WANG, Auteur ; M. XIAO, Auteur ; H. CHEN, Auteur ; W. XIANG, Auteur ; P. YAO, Auteur . - 43p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 43p. Mots-clés : Autism spectrum disorder  Estrogen receptor beta  Lipid metabolism  Mitochondria  Oxidative stress  Progestin  Resveratrol Index. décimale : PER Périodiques Résumé : Background: Recent literatures indicate that maternal hormone exposure is a risk factor for autism spectrum disorder (ASD). We hypothesize that prenatal progestin exposure may counteract the neuroprotective effect of estrogen and contribute to ASD development, and we aim to develop a method to ameliorate prenatal progestin exposure-induced autism-like behavior. Methods: Experiment 1: Prenatal progestin exposure-induced offspring are treated with resveratrol (RSV) through either prenatal or postnatal exposure and then used for autism-like behavior testing and other biomedical analyses. Experiment 2: Prenatal norethindrone (NET) exposure-induced offspring are treated with ERbeta knockdown lentivirus together with RSV for further testing. Experiment 3: Pregnant dams are treated with prenatal NET exposure together with RSV, and the offspring are used for further testing. Results: Eight kinds of clinically relevant progestins were used for prenatal exposure in pregnant dams, and the offspring showed decreased ERbeta expression in the amygdala with autism-like behavior. Oral administration of either postnatal or prenatal RSV treatment significantly reversed this effect with ERbeta activation and ameliorated autism-like behavior. Further investigation showed that RSV activates ERbeta and its target genes by demethylation of DNA and histone on the ERbeta promoter, and then minimizes progestin-induced oxidative stress as well as the dysfunction of mitochondria and lipid metabolism in the brain, subsequently ameliorating autism-like behavior. Conclusions: We conclude that resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation. Our data suggest that prenatal progestin exposure is a strong risk factor for autism-like behavior. Many potential clinical progestin applications, including oral contraceptive pills, preterm birth drugs, and progestin-contaminated drinking water or seafood, may be risk factors for ASD. In addition, RSV may be a good candidate for clinically rescuing or preventing ASD symptoms in humans, while high doses of resveratrol used in the animals may be a potential limitation for human application. En ligne : https://dx.doi.org/10.1186/s13229-018-0225-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Risk markers for suicidality in autistic adults / Sarah A. CASSIDY in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 42p. Titre : Risk markers for suicidality in autistic adults Type de document : Texte imprimé et/ou numérique Auteurs : Sarah A. CASSIDY, Auteur ; Louise BRADLEY, Auteur ; R. SHAW, Auteur ; Simon BARON-COHEN, Auteur Article en page(s) : 42p. Langues : Anglais (eng) Mots-clés : Anxiety  Autism spectrum condition  Autistic traits  Depression  Mental health  nssi  nssi-at  Non-suicidal self-injury  Risk markers  sbq-r  Suicidality Index. décimale : PER Périodiques Résumé : Background: Research has shown high rates of suicidality in autism spectrum conditions (ASC), but there is lack of research into why this is the case. Many common experiences of autistic adults, such as depression or unemployment, overlap with known risk markers for suicide in the general population. However, it is unknown whether there are risk markers unique to ASC that require new tailored suicide prevention strategies. Methods: Through consultation with a steering group of autistic adults, a survey was developed aiming to identify unique risk markers for suicidality in this group. The survey measured suicidality (SBQ-R), non-suicidal self-injury (NSSI-AT), mental health problems, unmet support needs, employment, satisfaction with living arrangements, self-reported autistic traits (AQ), delay in ASC diagnosis, and 'camouflaging' ASC. One hundred sixty-four autistic adults (65 male, 99 female) and 169 general population adults (54 males, 115 females) completed the survey online. Results: A majority of autistic adults (72%) scored above the recommended psychiatric cut-off for suicide risk on the SBQ-R; significantly higher than general population (GP) adults (33%). After statistically controlling for a range of demographics and diagnoses, ASC diagnosis and self-reported autistic traits in the general population significantly predicted suicidality. In autistic adults, non-suicidal self-injury, camouflaging, and number of unmet support needs significantly predicted suicidality. Conclusions: Results confirm previously reported high rates of suicidality in ASC, and demonstrate that ASC diagnosis, and self-reported autistic traits in the general population are independent risk markers for suicidality. This suggests there are unique factors associated with autism and autistic traits that increase risk of suicidality. Camouflaging and unmet support needs appear to be risk markers for suicidality unique to ASC. Non-suicidal self-injury, employment, and mental health problems appear to be risk markers shared with the general population that are significantly more prevalent in the autistic community. Implications for understanding and prevention of suicide in ASC are discussed. En ligne : https://dx.doi.org/10.1186/s13229-018-0226-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Risk markers for suicidality in autistic adults [Texte imprimé et/ou numérique] / Sarah A. CASSIDY, Auteur ; Louise BRADLEY, Auteur ; R. SHAW, Auteur ; Simon BARON-COHEN, Auteur . - 42p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 42p. Mots-clés : Anxiety  Autism spectrum condition  Autistic traits  Depression  Mental health  nssi  nssi-at  Non-suicidal self-injury  Risk markers  sbq-r  Suicidality Index. décimale : PER Périodiques Résumé : Background: Research has shown high rates of suicidality in autism spectrum conditions (ASC), but there is lack of research into why this is the case. Many common experiences of autistic adults, such as depression or unemployment, overlap with known risk markers for suicide in the general population. However, it is unknown whether there are risk markers unique to ASC that require new tailored suicide prevention strategies. Methods: Through consultation with a steering group of autistic adults, a survey was developed aiming to identify unique risk markers for suicidality in this group. The survey measured suicidality (SBQ-R), non-suicidal self-injury (NSSI-AT), mental health problems, unmet support needs, employment, satisfaction with living arrangements, self-reported autistic traits (AQ), delay in ASC diagnosis, and 'camouflaging' ASC. One hundred sixty-four autistic adults (65 male, 99 female) and 169 general population adults (54 males, 115 females) completed the survey online. Results: A majority of autistic adults (72%) scored above the recommended psychiatric cut-off for suicide risk on the SBQ-R; significantly higher than general population (GP) adults (33%). After statistically controlling for a range of demographics and diagnoses, ASC diagnosis and self-reported autistic traits in the general population significantly predicted suicidality. In autistic adults, non-suicidal self-injury, camouflaging, and number of unmet support needs significantly predicted suicidality. Conclusions: Results confirm previously reported high rates of suicidality in ASC, and demonstrate that ASC diagnosis, and self-reported autistic traits in the general population are independent risk markers for suicidality. This suggests there are unique factors associated with autism and autistic traits that increase risk of suicidality. Camouflaging and unmet support needs appear to be risk markers for suicidality unique to ASC. Non-suicidal self-injury, employment, and mental health problems appear to be risk markers shared with the general population that are significantly more prevalent in the autistic community. Implications for understanding and prevention of suicide in ASC are discussed. En ligne : https://dx.doi.org/10.1186/s13229-018-0226-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Event-related potential (ERP) correlates of face processing in verbal children with autism spectrum disorders (ASD) and their first-degree relatives: a family study / O. V. SYSOEVA in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 41p. Titre : Event-related potential (ERP) correlates of face processing in verbal children with autism spectrum disorders (ASD) and their first-degree relatives: a family study Type de document : Texte imprimé et/ou numérique Auteurs : O. V. SYSOEVA, Auteur ; John N. CONSTANTINO, Auteur ; Andrey P. ANOKHIN, Auteur Article en page(s) : 41p. Langues : Anglais (eng) Mots-clés : Adolescent  Adult  Autism Spectrum Disorder/physiopathology  Child  Electroencephalography  Evoked Potentials  Face  Fathers  Humans  Male  Middle Aged  Pattern Recognition, Visual  Siblings  Young Adult  Autistic disorder  erp  Electrophysiology  Endophenotype  N170 Index. décimale : PER Périodiques Résumé : Background: Inherited abnormalities of perception, recognition, and attention to faces have been implicated in the etiology of autism spectrum disorders (ASD) including abnormal components of event-related brain potentials (ERP) elicited by faces. Methods: We examined familial aggregation of face processing ERP abnormalities previously implicated in ASD in 49 verbal individuals with ASD, 36 unaffected siblings (US), 18 unaffected fathers (UF), and 53 unrelated controls (UC). The ASD, US, and UC groups ranged in age from 12 to 21 years, the UF group ranged in age from 30 to 56 years. ERP responses to images of upright and inverted faces and houses were analyzed under disparate EEG reference schemes. Results: Face-sensitive features of N170 and P1 were readily observed in all groups. Differences between ASD and control groups depended upon the EEG reference scheme. Notably, the superiority of face over object for N170 latency was attenuated in ASD subjects, but not their relatives; this occurred exclusively with the average reference. The difference in N170 amplitude between inverted and upright faces was reduced in both ASD and US groups relative to UC, but this effect was significant only with the vertex reference. Furthermore, similar group differences were observed for both inverted faces and inverted houses, suggesting a lack of face specificity for the attenuation of the N170 inversion effect in ASD. Conclusion: The present findings refine understanding of face processing ERPs in ASD. These data provide only modest evidence for highly-selective ASD-sensitive ERP features, and underscore the sensitivity of these biomarkers to ERP reference scheme. These schemes have varied across published studies and must be accounted for in future studies of the relationship between these commonly acquired ERP characteristics, genotype, and ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0220-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Event-related potential (ERP) correlates of face processing in verbal children with autism spectrum disorders (ASD) and their first-degree relatives: a family study [Texte imprimé et/ou numérique] / O. V. SYSOEVA, Auteur ; John N. CONSTANTINO, Auteur ; Andrey P. ANOKHIN, Auteur . - 41p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 41p. Mots-clés : Adolescent  Adult  Autism Spectrum Disorder/physiopathology  Child  Electroencephalography  Evoked Potentials  Face  Fathers  Humans  Male  Middle Aged  Pattern Recognition, Visual  Siblings  Young Adult  Autistic disorder  erp  Electrophysiology  Endophenotype  N170 Index. décimale : PER Périodiques Résumé : Background: Inherited abnormalities of perception, recognition, and attention to faces have been implicated in the etiology of autism spectrum disorders (ASD) including abnormal components of event-related brain potentials (ERP) elicited by faces. Methods: We examined familial aggregation of face processing ERP abnormalities previously implicated in ASD in 49 verbal individuals with ASD, 36 unaffected siblings (US), 18 unaffected fathers (UF), and 53 unrelated controls (UC). The ASD, US, and UC groups ranged in age from 12 to 21 years, the UF group ranged in age from 30 to 56 years. ERP responses to images of upright and inverted faces and houses were analyzed under disparate EEG reference schemes. Results: Face-sensitive features of N170 and P1 were readily observed in all groups. Differences between ASD and control groups depended upon the EEG reference scheme. Notably, the superiority of face over object for N170 latency was attenuated in ASD subjects, but not their relatives; this occurred exclusively with the average reference. The difference in N170 amplitude between inverted and upright faces was reduced in both ASD and US groups relative to UC, but this effect was significant only with the vertex reference. Furthermore, similar group differences were observed for both inverted faces and inverted houses, suggesting a lack of face specificity for the attenuation of the N170 inversion effect in ASD. Conclusion: The present findings refine understanding of face processing ERPs in ASD. These data provide only modest evidence for highly-selective ASD-sensitive ERP features, and underscore the sensitivity of these biomarkers to ERP reference scheme. These schemes have varied across published studies and must be accounted for in future studies of the relationship between these commonly acquired ERP characteristics, genotype, and ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0220-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Case-control meta-analysis of blood DNA methylation and autism spectrum disorder / S. V. ANDREWS in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 40p. Titre : Case-control meta-analysis of blood DNA methylation and autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : S. V. ANDREWS, Auteur ; B. SHEPPARD, Auteur ; G. C. WINDHAM, Auteur ; Laura A. SCHIEVE, Auteur ; Diana SCHENDEL, Auteur ; Lisa A. CROEN, Auteur ; P. CHOPRA, Auteur ; R. S. ALISCH, Auteur ; C. J. NEWSCHAFFER, Auteur ; S. T. WARREN, Auteur ; A. P. FEINBERG, Auteur ; M. D. FALLIN, Auteur ; Christine LADD-ACOSTA, Auteur Article en page(s) : 40p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/blood/genetics  Case-Control Studies  Child, Preschool  CpG Islands  DNA Methylation  Epigenesis, Genetic  Female  Genome-Wide Association Study  Humans  Male  Autism spectrum disorders  Epigenome  Peripheral blood  Simons Simplex Collection  Study to Explore Early Development Index. décimale : PER Périodiques Résumé : Background: Several reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies. Methods: DNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample. Findings: In this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p < 1.12 x 10(- 7). Seven CpGs showed differences at p < 1 x 10(- 5) and 48 at 1 x 10(- 4). Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance (r = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpG hits, which was consistent across EWAS and meQTL discovery p value thresholds. Conclusions: No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the seven sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0224-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Case-control meta-analysis of blood DNA methylation and autism spectrum disorder [Texte imprimé et/ou numérique] / S. V. ANDREWS, Auteur ; B. SHEPPARD, Auteur ; G. C. WINDHAM, Auteur ; Laura A. SCHIEVE, Auteur ; Diana SCHENDEL, Auteur ; Lisa A. CROEN, Auteur ; P. CHOPRA, Auteur ; R. S. ALISCH, Auteur ; C. J. NEWSCHAFFER, Auteur ; S. T. WARREN, Auteur ; A. P. FEINBERG, Auteur ; M. D. FALLIN, Auteur ; Christine LADD-ACOSTA, Auteur . - 40p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 40p. Mots-clés : Autism Spectrum Disorder/blood/genetics  Case-Control Studies  Child, Preschool  CpG Islands  DNA Methylation  Epigenesis, Genetic  Female  Genome-Wide Association Study  Humans  Male  Autism spectrum disorders  Epigenome  Peripheral blood  Simons Simplex Collection  Study to Explore Early Development Index. décimale : PER Périodiques Résumé : Background: Several reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies. Methods: DNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample. Findings: In this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p < 1.12 x 10(- 7). Seven CpGs showed differences at p < 1 x 10(- 5) and 48 at 1 x 10(- 4). Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance (r = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpG hits, which was consistent across EWAS and meQTL discovery p value thresholds. Conclusions: No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the seven sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0224-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Symptom severity in autism spectrum disorder is related to the frequency and severity of nausea and vomiting during pregnancy: a retrospective case-control study / Andrew J. O. WHITEHOUSE in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 37p. Titre : Symptom severity in autism spectrum disorder is related to the frequency and severity of nausea and vomiting during pregnancy: a retrospective case-control study Type de document : Texte imprimé et/ou numérique Auteurs : Andrew J. O. WHITEHOUSE, Auteur ; Gail A. ALVARES, Auteur ; D. CLEARY, Auteur ; A. HARUN, Auteur ; A. STOJANOSKA, Auteur ; L. J. TAYLOR, Auteur ; Kandice J. VARCIN, Auteur ; M. MAYBERY, Auteur Article en page(s) : 37p. Langues : Anglais (eng) Mots-clés : Adolescent  Autism Spectrum Disorder/epidemiology  Case-Control Studies  Child  Child, Preschool  Female  Humans  Male  Morning Sickness/epidemiology  Nausea/epidemiology  Pregnancy Index. décimale : PER Périodiques Résumé : Background: Nausea and vomiting during pregnancy (NVP) is thought to be caused by changes in maternal hormones during pregnancy. Differences in hormone exposure during prenatal life have been implicated in the causal pathways for some cases of autism spectrum disorder (ASD). However, no study has investigated whether the presence and severity of NVP may be related to symptom severity in offspring with ASD. Methods: A large sample of children with ASD (227 males and 60 females, aged 2 to 18 years) received a clinical assessment, during which parents completed questionnaires regarding their child's social (Social Responsiveness Scale, SRS) and communication (Children's Communication Checklist-2nd edition, CCC-2) symptoms. Parents also reported on a 5-point scale the frequency and severity of NVPs during the pregnancy of the child being assessed: (1) no NVP during the pregnancy, (2) occasional nausea, but no vomiting, (3) daily nausea, but no vomiting, (4) occasional vomiting, with or without nausea, and (5) daily nausea and vomiting. Results: Impairments in social responsiveness in offspring, as indexed by SRS total score, significantly increased as a function of the frequency and severity of their mothers' NVP, as did the level of language difficulties as indexed by the Global Communication Composite of the CCC-2. Conclusions: The strong, positive association between increasing frequency and severity of NVP and ASD severity in offspring provides further evidence that exposure to an atypical hormonal environment during prenatal life may affect neurodevelopment and contribute to the ASD phenotype. Given that the measure of NVP symptoms in the current study was based on retrospective recall, replication of this finding is required before strong conclusions can be drawn. En ligne : https://dx.doi.org/10.1186/s13229-018-0223-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Symptom severity in autism spectrum disorder is related to the frequency and severity of nausea and vomiting during pregnancy: a retrospective case-control study [Texte imprimé et/ou numérique] / Andrew J. O. WHITEHOUSE, Auteur ; Gail A. ALVARES, Auteur ; D. CLEARY, Auteur ; A. HARUN, Auteur ; A. STOJANOSKA, Auteur ; L. J. TAYLOR, Auteur ; Kandice J. VARCIN, Auteur ; M. MAYBERY, Auteur . - 37p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 37p. Mots-clés : Adolescent  Autism Spectrum Disorder/epidemiology  Case-Control Studies  Child  Child, Preschool  Female  Humans  Male  Morning Sickness/epidemiology  Nausea/epidemiology  Pregnancy Index. décimale : PER Périodiques Résumé : Background: Nausea and vomiting during pregnancy (NVP) is thought to be caused by changes in maternal hormones during pregnancy. Differences in hormone exposure during prenatal life have been implicated in the causal pathways for some cases of autism spectrum disorder (ASD). However, no study has investigated whether the presence and severity of NVP may be related to symptom severity in offspring with ASD. Methods: A large sample of children with ASD (227 males and 60 females, aged 2 to 18 years) received a clinical assessment, during which parents completed questionnaires regarding their child's social (Social Responsiveness Scale, SRS) and communication (Children's Communication Checklist-2nd edition, CCC-2) symptoms. Parents also reported on a 5-point scale the frequency and severity of NVPs during the pregnancy of the child being assessed: (1) no NVP during the pregnancy, (2) occasional nausea, but no vomiting, (3) daily nausea, but no vomiting, (4) occasional vomiting, with or without nausea, and (5) daily nausea and vomiting. Results: Impairments in social responsiveness in offspring, as indexed by SRS total score, significantly increased as a function of the frequency and severity of their mothers' NVP, as did the level of language difficulties as indexed by the Global Communication Composite of the CCC-2. Conclusions: The strong, positive association between increasing frequency and severity of NVP and ASD severity in offspring provides further evidence that exposure to an atypical hormonal environment during prenatal life may affect neurodevelopment and contribute to the ASD phenotype. Given that the measure of NVP symptoms in the current study was based on retrospective recall, replication of this finding is required before strong conclusions can be drawn. En ligne : https://dx.doi.org/10.1186/s13229-018-0223-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Role of miR-146a in neural stem cell differentiation and neural lineage determination: relevance for neurodevelopmental disorders / L. S. NGUYEN in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 38p. Titre : Role of miR-146a in neural stem cell differentiation and neural lineage determination: relevance for neurodevelopmental disorders Type de document : Texte imprimé et/ou numérique Auteurs : L. S. NGUYEN, Auteur ; J. FREGEAC, Auteur ; C. BOLE-FEYSOT, Auteur ; N. CAGNARD, Auteur ; A. IYER, Auteur ; J. ANINK, Auteur ; E. ARONICA, Auteur ; O. ALIBEU, Auteur ; P. NITSCHKE, Auteur ; L. COLLEAUX, Auteur Article en page(s) : 38p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/genetics/metabolism  Cell Line  Cell Lineage  Child  Female  Humans  Male  MicroRNAs/genetics/metabolism  Neural Stem Cells/cytology/metabolism  Neurogenesis  Temporal Lobe/cytology/metabolism  Up-Regulation  Autism spectrum disorders  Human neural stem cell  Transcriptome  microRNA Index. décimale : PER Périodiques Résumé : Background: MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. miRNAs have emerged as important modulators of brain development and neuronal function and are implicated in several neurological diseases. Previous studies found miR-146a upregulation is the most common miRNA deregulation event in neurodevelopmental disorders such as autism spectrum disorder (ASD), epilepsy, and intellectual disability (ID). Yet, how miR-146a upregulation affects the developing fetal brain remains unclear. Methods: We analyzed the expression of miR-146a in the temporal lobe of ASD children using Taqman assay. To assess the role of miR-146a in early brain development, we generated and characterized stably induced H9 human neural stem cell (H9 hNSC) overexpressing miR-146a using various cell and molecular biology techniques. Results: We first showed that miR-146a upregulation occurs early during childhood in the ASD brain. In H9 hNSC, miR-146a overexpression enhances neurite outgrowth and branching and favors differentiation into neuronal like cells. Expression analyses revealed that 10% of the transcriptome was deregulated and organized into two modules critical for cell cycle control and neuronal differentiation. Twenty known or predicted targets of miR-146a were significantly deregulated in the modules, acting as potential drivers. The two modules also display distinct transcription profiles during human brain development, affecting regions relevant for ASD including the neocortex, amygdala, and hippocampus. Cell type analyses indicate markers for pyramidal, and interneurons are highly enriched in the deregulated gene list. Up to 40% of known markers of newly defined neuronal lineages were deregulated, suggesting that miR-146a could participate also in the acquisition of neuronal identities. Conclusion: Our results demonstrate the dynamic roles of miR-146a in early neuronal development and provide new insight into the molecular events that link miR-146a overexpression to impaired neurodevelopment. This, in turn, may yield new therapeutic targets and strategies. En ligne : https://dx.doi.org/10.1186/s13229-018-0219-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Role of miR-146a in neural stem cell differentiation and neural lineage determination: relevance for neurodevelopmental disorders [Texte imprimé et/ou numérique] / L. S. NGUYEN, Auteur ; J. FREGEAC, Auteur ; C. BOLE-FEYSOT, Auteur ; N. CAGNARD, Auteur ; A. IYER, Auteur ; J. ANINK, Auteur ; E. ARONICA, Auteur ; O. ALIBEU, Auteur ; P. NITSCHKE, Auteur ; L. COLLEAUX, Auteur . - 38p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 38p. Mots-clés : Autism Spectrum Disorder/genetics/metabolism  Cell Line  Cell Lineage  Child  Female  Humans  Male  MicroRNAs/genetics/metabolism  Neural Stem Cells/cytology/metabolism  Neurogenesis  Temporal Lobe/cytology/metabolism  Up-Regulation  Autism spectrum disorders  Human neural stem cell  Transcriptome  microRNA Index. décimale : PER Périodiques Résumé : Background: MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. miRNAs have emerged as important modulators of brain development and neuronal function and are implicated in several neurological diseases. Previous studies found miR-146a upregulation is the most common miRNA deregulation event in neurodevelopmental disorders such as autism spectrum disorder (ASD), epilepsy, and intellectual disability (ID). Yet, how miR-146a upregulation affects the developing fetal brain remains unclear. Methods: We analyzed the expression of miR-146a in the temporal lobe of ASD children using Taqman assay. To assess the role of miR-146a in early brain development, we generated and characterized stably induced H9 human neural stem cell (H9 hNSC) overexpressing miR-146a using various cell and molecular biology techniques. Results: We first showed that miR-146a upregulation occurs early during childhood in the ASD brain. In H9 hNSC, miR-146a overexpression enhances neurite outgrowth and branching and favors differentiation into neuronal like cells. Expression analyses revealed that 10% of the transcriptome was deregulated and organized into two modules critical for cell cycle control and neuronal differentiation. Twenty known or predicted targets of miR-146a were significantly deregulated in the modules, acting as potential drivers. The two modules also display distinct transcription profiles during human brain development, affecting regions relevant for ASD including the neocortex, amygdala, and hippocampus. Cell type analyses indicate markers for pyramidal, and interneurons are highly enriched in the deregulated gene list. Up to 40% of known markers of newly defined neuronal lineages were deregulated, suggesting that miR-146a could participate also in the acquisition of neuronal identities. Conclusion: Our results demonstrate the dynamic roles of miR-146a in early neuronal development and provide new insight into the molecular events that link miR-146a overexpression to impaired neurodevelopment. This, in turn, may yield new therapeutic targets and strategies. En ligne : https://dx.doi.org/10.1186/s13229-018-0219-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Autism spectrum disorder: prospects for treatment using gene therapy / M. BENGER in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 39p. Titre : Autism spectrum disorder: prospects for treatment using gene therapy Type de document : Texte imprimé et/ou numérique Auteurs : M. BENGER, Auteur ; M. KINALI, Auteur ; N. D. MAZARAKIS, Auteur Article en page(s) : 39p. Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics/therapy  Genetic Therapy/methods  ASD models  Autistic spectrum disorder  Gene therapy  Synaptic dysfunction  Viral vector Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is characterised by the concomitant occurrence of impaired social interaction; restricted, perseverative and stereotypical behaviour; and abnormal communication skills. Recent epidemiological studies have reported a dramatic increase in the prevalence of ASD with as many as 1 in every 59 children being diagnosed with ASD. The fact that ASD appears to be principally genetically driven, and may be reversible postnatally, has raised the exciting possibility of using gene therapy as a disease-modifying treatment. Such therapies have already started to seriously impact on human disease and particularly monogenic disorders (e.g. metachromatic leukodystrophy, SMA type 1). In regard to ASD, technical advances in both our capacity to model the disorder in animals and also our ability to deliver genes to the central nervous system (CNS) have led to the first preclinical studies in monogenic ASD, involving both gene replacement and silencing. Furthermore, our increasing awareness and understanding of common dysregulated pathways in ASD have broadened gene therapy's potential scope to include various polygenic ASDs. As this review highlights, despite a number of outstanding challenges, gene therapy has excellent potential to address cognitive dysfunction in ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0222-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Autism spectrum disorder: prospects for treatment using gene therapy [Texte imprimé et/ou numérique] / M. BENGER, Auteur ; M. KINALI, Auteur ; N. D. MAZARAKIS, Auteur . - 39p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 39p. Mots-clés : Animals  Autism Spectrum Disorder/genetics/therapy  Genetic Therapy/methods  ASD models  Autistic spectrum disorder  Gene therapy  Synaptic dysfunction  Viral vector Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is characterised by the concomitant occurrence of impaired social interaction; restricted, perseverative and stereotypical behaviour; and abnormal communication skills. Recent epidemiological studies have reported a dramatic increase in the prevalence of ASD with as many as 1 in every 59 children being diagnosed with ASD. The fact that ASD appears to be principally genetically driven, and may be reversible postnatally, has raised the exciting possibility of using gene therapy as a disease-modifying treatment. Such therapies have already started to seriously impact on human disease and particularly monogenic disorders (e.g. metachromatic leukodystrophy, SMA type 1). In regard to ASD, technical advances in both our capacity to model the disorder in animals and also our ability to deliver genes to the central nervous system (CNS) have led to the first preclinical studies in monogenic ASD, involving both gene replacement and silencing. Furthermore, our increasing awareness and understanding of common dysregulated pathways in ASD have broadened gene therapy's potential scope to include various polygenic ASDs. As this review highlights, despite a number of outstanding challenges, gene therapy has excellent potential to address cognitive dysfunction in ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0222-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Sociability deficits after prenatal exposure to valproic acid are rescued by early social enrichment / M. CAMPOLONGO in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 36p. Titre : Sociability deficits after prenatal exposure to valproic acid are rescued by early social enrichment Type de document : Texte imprimé et/ou numérique Auteurs : M. CAMPOLONGO, Auteur ; N. KAZLAUSKAS, Auteur ; G. FALASCO, Auteur ; L. URRUTIA, Auteur ; N. SALGUEIRO, Auteur ; C. HOCHT, Auteur ; Amaicha Mara DEPINO, Auteur Article en page(s) : 36p. Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/etiology/therapy  Brain/diagnostic imaging  Female  Male  Mice  Pregnancy  Prenatal Exposure Delayed Effects/drug therapy/etiology  Social Behavior  Socioenvironmental Therapy/methods  Valproic Acid/administration & dosage/toxicity  Autism spectrum disorder  Dopamine  Piriform cortex  Sociability Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is characterized by impaired social interactions and repetitive patterns of behavior. Symptoms appear in early life and persist throughout adulthood. Early social stimulation can help reverse some of the symptoms, but the biological mechanisms of these therapies are unknown. By analyzing the effects of early social stimulation on ASD-related behavior in the mouse, we aimed to identify brain structures that contribute to these behaviors. Methods: We injected pregnant mice with 600-mg/kg valproic acid (VPA) or saline (SAL) at gestational day 12.5 and evaluated the effect of weaning their offspring in cages containing only VPA animals, only SAL animals, or mixed. We analyzed juvenile play at PD21 and performed a battery of behavioral tests in adulthood. We then used preclinical PET imaging for an unbiased analysis of the whole brain of these mice and studied the function of the piriform cortex by c-Fos immunoreactivity and HPLC. Results: Compared to control animals, VPA-exposed animals play less as juveniles and exhibit a lower frequency of social interaction in adulthood when reared with other VPA mice. In addition, these animals were less likely to investigate social odors in the habituation/dishabituation olfactory test. However, when VPA animals were weaned with control animals, these behavioral alterations were not observed. Interestingly, repetitive behaviors and depression-related behaviors were not affected by social enrichment. We also found that VPA animals present high levels of glucose metabolism bilaterally in the piriform cortex (Pir), a region known to be involved in social behaviors. Moreover, we found alterations in the somatosensory, motor, and insular cortices. Remarkably, these effects were mostly reversed after social stimulation. To evaluate if changes in glucose metabolism in the Pir correlated with changes in neuronal activity, we measured c-Fos immunoreactivity in the Pir and found it increased in animals prenatally exposed to VPA. We further found increased dopamine turnover in the Pir. Both alterations were largely reversed by social enrichment. Conclusions: We show that early social enrichment can specifically rescue social deficits in a mouse model of ASD. Our results identified the Pir as a structure affected by VPA-exposure and social enrichment, suggesting that it could be a key component of the social brain circuitry. En ligne : https://dx.doi.org/10.1186/s13229-018-0221-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Sociability deficits after prenatal exposure to valproic acid are rescued by early social enrichment [Texte imprimé et/ou numérique] / M. CAMPOLONGO, Auteur ; N. KAZLAUSKAS, Auteur ; G. FALASCO, Auteur ; L. URRUTIA, Auteur ; N. SALGUEIRO, Auteur ; C. HOCHT, Auteur ; Amaicha Mara DEPINO, Auteur . - 36p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 36p. Mots-clés : Animals  Autism Spectrum Disorder/etiology/therapy  Brain/diagnostic imaging  Female  Male  Mice  Pregnancy  Prenatal Exposure Delayed Effects/drug therapy/etiology  Social Behavior  Socioenvironmental Therapy/methods  Valproic Acid/administration & dosage/toxicity  Autism spectrum disorder  Dopamine  Piriform cortex  Sociability Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is characterized by impaired social interactions and repetitive patterns of behavior. Symptoms appear in early life and persist throughout adulthood. Early social stimulation can help reverse some of the symptoms, but the biological mechanisms of these therapies are unknown. By analyzing the effects of early social stimulation on ASD-related behavior in the mouse, we aimed to identify brain structures that contribute to these behaviors. Methods: We injected pregnant mice with 600-mg/kg valproic acid (VPA) or saline (SAL) at gestational day 12.5 and evaluated the effect of weaning their offspring in cages containing only VPA animals, only SAL animals, or mixed. We analyzed juvenile play at PD21 and performed a battery of behavioral tests in adulthood. We then used preclinical PET imaging for an unbiased analysis of the whole brain of these mice and studied the function of the piriform cortex by c-Fos immunoreactivity and HPLC. Results: Compared to control animals, VPA-exposed animals play less as juveniles and exhibit a lower frequency of social interaction in adulthood when reared with other VPA mice. In addition, these animals were less likely to investigate social odors in the habituation/dishabituation olfactory test. However, when VPA animals were weaned with control animals, these behavioral alterations were not observed. Interestingly, repetitive behaviors and depression-related behaviors were not affected by social enrichment. We also found that VPA animals present high levels of glucose metabolism bilaterally in the piriform cortex (Pir), a region known to be involved in social behaviors. Moreover, we found alterations in the somatosensory, motor, and insular cortices. Remarkably, these effects were mostly reversed after social stimulation. To evaluate if changes in glucose metabolism in the Pir correlated with changes in neuronal activity, we measured c-Fos immunoreactivity in the Pir and found it increased in animals prenatally exposed to VPA. We further found increased dopamine turnover in the Pir. Both alterations were largely reversed by social enrichment. Conclusions: We show that early social enrichment can specifically rescue social deficits in a mouse model of ASD. Our results identified the Pir as a structure affected by VPA-exposure and social enrichment, suggesting that it could be a key component of the social brain circuitry. En ligne : https://dx.doi.org/10.1186/s13229-018-0221-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli / Stephen BENT in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 35p. Titre : Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli Type de document : Texte imprimé et/ou numérique Auteurs : Stephen BENT, Auteur ; B. LAWTON, Auteur ; T. WARREN, Auteur ; F. WIDJAJA, Auteur ; K. DANG, Auteur ; J. W. FAHEY, Auteur ; Brian CORNBLATT, Auteur ; J. M. KINCHEN, Auteur ; K. DELUCCHI, Auteur ; R. L. HENDREN, Auteur Article en page(s) : 35p. Langues : Anglais (eng) Mots-clés : Adolescent  Antioxidants/administration & dosage/analysis/therapeutic use  Autistic Disorder/drug therapy/urine  Biomarkers/urine  Brassica/chemistry  Child  Female  Humans  Isothiocyanates/administration & dosage/analysis/therapeutic use  Male  Metabolome  Social Behavior  Young Adult  Antioxidant  Autism  Biomarker  Metabolomics Index. décimale : PER Périodiques Résumé : Background: Children with autism spectrum disorder (ASD) have urinary metabolites suggesting impairments in several pathways, including oxidative stress, inflammation, mitochondrial dysfunction, and gut microbiome alterations. Sulforaphane, a supplement with indirect antioxidant effects that are derived from broccoli sprouts and seeds, was recently shown to lead to improvements in behavior and social responsiveness in children with ASD. We conducted the current open-label study to determine if we could identify changes in urinary metabolites that were associated with clinical improvements with the goal of identifying a potential mechanism of action. Methods: Children and young adults enrolled in a school for children with ASD and related neurodevelopmental disorders were recruited to participate in a 12-week, open-label study of sulforaphane. Fasting urinary metabolites and measures of behavior (Aberrant Behavior Checklist-ABC) and social responsiveness (Social Responsiveness Scale-SRS) were measured at baseline and at the end of the study. Pearson's correlation coefficient was calculated for the pre- to post-intervention change in each of the two clinical scales (ABS and SRS) versus the change in each metabolite. Results: Fifteen children completed the 12-week study. Mean scores on both symptom measures showed improvements (decreases) over the study period, but only the change in the SRS was significant. The ABC improved - 7.1 points (95% CI - 17.4 to 3.2), and the SRS improved - 9.7 points (95% CI - 18.7 to - 0.8). We identified 77 urinary metabolites that were correlated with changes in symptoms, and they clustered into pathways of oxidative stress, amino acid/gut microbiome, neurotransmitters, hormones, and sphingomyelin metabolism. Conclusions: Urinary metabolomics analysis is a useful tool to identify pathways that may be involved in the mechanism of action of treatments targeting abnormal physiology in ASD. Trial registration: This study was prospectively registered at clinicaltrials.gov (NCT02654743) on January 11, 2016. En ligne : https://dx.doi.org/10.1186/s13229-018-0218-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli [Texte imprimé et/ou numérique] / Stephen BENT, Auteur ; B. LAWTON, Auteur ; T. WARREN, Auteur ; F. WIDJAJA, Auteur ; K. DANG, Auteur ; J. W. FAHEY, Auteur ; Brian CORNBLATT, Auteur ; J. M. KINCHEN, Auteur ; K. DELUCCHI, Auteur ; R. L. HENDREN, Auteur . - 35p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 35p. Mots-clés : Adolescent  Antioxidants/administration & dosage/analysis/therapeutic use  Autistic Disorder/drug therapy/urine  Biomarkers/urine  Brassica/chemistry  Child  Female  Humans  Isothiocyanates/administration & dosage/analysis/therapeutic use  Male  Metabolome  Social Behavior  Young Adult  Antioxidant  Autism  Biomarker  Metabolomics Index. décimale : PER Périodiques Résumé : Background: Children with autism spectrum disorder (ASD) have urinary metabolites suggesting impairments in several pathways, including oxidative stress, inflammation, mitochondrial dysfunction, and gut microbiome alterations. Sulforaphane, a supplement with indirect antioxidant effects that are derived from broccoli sprouts and seeds, was recently shown to lead to improvements in behavior and social responsiveness in children with ASD. We conducted the current open-label study to determine if we could identify changes in urinary metabolites that were associated with clinical improvements with the goal of identifying a potential mechanism of action. Methods: Children and young adults enrolled in a school for children with ASD and related neurodevelopmental disorders were recruited to participate in a 12-week, open-label study of sulforaphane. Fasting urinary metabolites and measures of behavior (Aberrant Behavior Checklist-ABC) and social responsiveness (Social Responsiveness Scale-SRS) were measured at baseline and at the end of the study. Pearson's correlation coefficient was calculated for the pre- to post-intervention change in each of the two clinical scales (ABS and SRS) versus the change in each metabolite. Results: Fifteen children completed the 12-week study. Mean scores on both symptom measures showed improvements (decreases) over the study period, but only the change in the SRS was significant. The ABC improved - 7.1 points (95% CI - 17.4 to 3.2), and the SRS improved - 9.7 points (95% CI - 18.7 to - 0.8). We identified 77 urinary metabolites that were correlated with changes in symptoms, and they clustered into pathways of oxidative stress, amino acid/gut microbiome, neurotransmitters, hormones, and sphingomyelin metabolism. Conclusions: Urinary metabolomics analysis is a useful tool to identify pathways that may be involved in the mechanism of action of treatments targeting abnormal physiology in ASD. Trial registration: This study was prospectively registered at clinicaltrials.gov (NCT02654743) on January 11, 2016. En ligne : https://dx.doi.org/10.1186/s13229-018-0218-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Robot-based intervention may reduce delay in the production of intransitive gestures in Chinese-speaking preschoolers with autism spectrum disorder / W. C. SO in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 34p. Titre : Robot-based intervention may reduce delay in the production of intransitive gestures in Chinese-speaking preschoolers with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : W. C. SO, Auteur ; M. K. WONG, Auteur ; W. Y. LAM, Auteur ; C. H. CHENG, Auteur ; J. H. YANG, Auteur ; Y. HUANG, Auteur ; P. NG, Auteur ; W. L. WONG, Auteur ; C. L. HO, Auteur ; K. L. YEUNG, Auteur ; C. C. LEE, Auteur Article en page(s) : 34p. Langues : Anglais (eng) Mots-clés : Asian Continental Ancestry Group  Autism Spectrum Disorder/ethnology/rehabilitation  Child  Child Development  Child, Preschool  Early Intervention (Education)/methods  Female  Gestures  Humans  Language  Male  Robotics/methods  Autism spectrum disorder  Early childhood  Gesture  Robot-based intervention Index. décimale : PER Périodiques Résumé : Background: Past studies have shown that robot-based intervention was effective in improving gestural use in children with autism spectrum disorders (ASD). The present study examined whether children with ASD could catch up to the level of gestural production found in age-matched children with typical development and whether they showed an increase in verbal imitation after the completion of robot-based training. We also explored the cognitive and motor skills associated with gestural learning. Methods: Children with ASD were randomly assigned to two groups. Four- to 6-year-old children with ASD in the intervention group (N = 15) received four 30-min robot-based gestural training sessions. In each session, a social robot, NAO, narrated five stories and gestured (e.g., both hands clapping for an awesome expression). Children with ASD were told to imitate the gestures during training. Age-matched children with ASD in the wait-list control group (N = 15) and age-matched children with typical development (N = 15) received the gestural training after the completion of research. Standardized pretests and posttests (both immediate and delayed) were administered to assess the accuracy and appropriateness of gestural production in both training and novel stories. Children's language and communication abilities, gestural recognition skills, fine motor proficiencies, and attention skills were also examined. Results: Children with ASD in the intervention condition were more likely to produce accurate or appropriate intransitive gestures in training and novel stories than those in the wait-list control. The positive learning outcomes were maintained in the delayed posttests. The level of gestural production accuracy in children with ASD in the delayed posttest of novel stories was comparable to that in children with typical development, suggesting that children with ASD could catch up to the level of gestural production found in children with typical development. Children with ASD in the intervention condition were also more likely to produce verbal markers while gesturing than those in the wait-list control. Gestural recognition skills were found to significantly predict the learning of gestural production accuracy in the children with ASD, with such relation partially mediated via spontaneous imitation. Conclusions: Robot-based intervention may reduce the gestural delay in children with ASD in their early childhood. En ligne : https://dx.doi.org/10.1186/s13229-018-0217-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Robot-based intervention may reduce delay in the production of intransitive gestures in Chinese-speaking preschoolers with autism spectrum disorder [Texte imprimé et/ou numérique] / W. C. SO, Auteur ; M. K. WONG, Auteur ; W. Y. LAM, Auteur ; C. H. CHENG, Auteur ; J. H. YANG, Auteur ; Y. HUANG, Auteur ; P. NG, Auteur ; W. L. WONG, Auteur ; C. L. HO, Auteur ; K. L. YEUNG, Auteur ; C. C. LEE, Auteur . - 34p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 34p. Mots-clés : Asian Continental Ancestry Group  Autism Spectrum Disorder/ethnology/rehabilitation  Child  Child Development  Child, Preschool  Early Intervention (Education)/methods  Female  Gestures  Humans  Language  Male  Robotics/methods  Autism spectrum disorder  Early childhood  Gesture  Robot-based intervention Index. décimale : PER Périodiques Résumé : Background: Past studies have shown that robot-based intervention was effective in improving gestural use in children with autism spectrum disorders (ASD). The present study examined whether children with ASD could catch up to the level of gestural production found in age-matched children with typical development and whether they showed an increase in verbal imitation after the completion of robot-based training. We also explored the cognitive and motor skills associated with gestural learning. Methods: Children with ASD were randomly assigned to two groups. Four- to 6-year-old children with ASD in the intervention group (N = 15) received four 30-min robot-based gestural training sessions. In each session, a social robot, NAO, narrated five stories and gestured (e.g., both hands clapping for an awesome expression). Children with ASD were told to imitate the gestures during training. Age-matched children with ASD in the wait-list control group (N = 15) and age-matched children with typical development (N = 15) received the gestural training after the completion of research. Standardized pretests and posttests (both immediate and delayed) were administered to assess the accuracy and appropriateness of gestural production in both training and novel stories. Children's language and communication abilities, gestural recognition skills, fine motor proficiencies, and attention skills were also examined. Results: Children with ASD in the intervention condition were more likely to produce accurate or appropriate intransitive gestures in training and novel stories than those in the wait-list control. The positive learning outcomes were maintained in the delayed posttests. The level of gestural production accuracy in children with ASD in the delayed posttest of novel stories was comparable to that in children with typical development, suggesting that children with ASD could catch up to the level of gestural production found in children with typical development. Children with ASD in the intervention condition were also more likely to produce verbal markers while gesturing than those in the wait-list control. Gestural recognition skills were found to significantly predict the learning of gestural production accuracy in the children with ASD, with such relation partially mediated via spontaneous imitation. Conclusions: Robot-based intervention may reduce the gestural delay in children with ASD in their early childhood. En ligne : https://dx.doi.org/10.1186/s13229-018-0217-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Self-reported sex differences in high-functioning adults with autism: a meta-analysis / R. L. MOSELEY in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 33p. Titre : Self-reported sex differences in high-functioning adults with autism: a meta-analysis Type de document : Texte imprimé et/ou numérique Auteurs : R. L. MOSELEY, Auteur ; R. HITCHINER, Auteur ; J. A. KIRKBY, Auteur Article en page(s) : 33p. Langues : Anglais (eng) Mots-clés : Adult  Autistic Disorder/diagnosis/epidemiology  Female  Humans  Language Development  Male  Self Report  Sensorimotor Cortex/growth & development/physiopathology  Sex Factors  Sexual Development  Gender  raads-r  Self-report  Sex Index. décimale : PER Périodiques Résumé : Background: Sex differences in autistic symptomatology are believed to contribute to the mis- and missed diagnosis of many girls and women with an autism spectrum condition (ASC). Whilst recent years have seen the emergence of clinical and empirical reports delineating the profile of young autistic girls, recognition of sex differences in symptomatology in adulthood is far more limited. Methods: We chose here to focus on symptomatology as reported using a screening instrument, the Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R). In a meta-analysis, we pooled and analysed RAADS-R data from a number of experimental groups. Analysis of variance (ANOVA) searched for the presence of main effects of Sex and Diagnosis and for interactions between these factors in our sample of autistic and non-autistic adults. Results: In social relatedness and circumscribed interests, main effects of Diagnosis revealed that as expected, autistic adults reported significantly greater lifetime prevalence of symptoms in these domains; an effect of Sex, in circumscribed interests, also suggested that males generally reported more prevalent symptoms than females. An interaction of Sex and Diagnosis in language symptomatology revealed that a normative sex difference in language difficulties was attenuated in autism. An interaction of Sex and Diagnosis in the sensorimotor domain revealed the opposite picture: a lack of sex differences between typically developing men and women and a greater prevalence of sensorimotor symptoms in autistic women than autistic men. Conclusions: We discuss the literature on childhood sex differences in relation to those which emerged in our adult sample. Where childhood sex differences fail to persist in adulthood, several interpretations exist, and we discuss, for example, an inherent sampling bias that may mean that only autistic women most similar to the male presentation are diagnosed. The finding that sensorimotor symptomatology is more highly reported by autistic women is a finding requiring objective confirmation, given its potential importance in diagnosis. En ligne : https://dx.doi.org/10.1186/s13229-018-0216-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Self-reported sex differences in high-functioning adults with autism: a meta-analysis [Texte imprimé et/ou numérique] / R. L. MOSELEY, Auteur ; R. HITCHINER, Auteur ; J. A. KIRKBY, Auteur . - 33p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 33p. Mots-clés : Adult  Autistic Disorder/diagnosis/epidemiology  Female  Humans  Language Development  Male  Self Report  Sensorimotor Cortex/growth & development/physiopathology  Sex Factors  Sexual Development  Gender  raads-r  Self-report  Sex Index. décimale : PER Périodiques Résumé : Background: Sex differences in autistic symptomatology are believed to contribute to the mis- and missed diagnosis of many girls and women with an autism spectrum condition (ASC). Whilst recent years have seen the emergence of clinical and empirical reports delineating the profile of young autistic girls, recognition of sex differences in symptomatology in adulthood is far more limited. Methods: We chose here to focus on symptomatology as reported using a screening instrument, the Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R). In a meta-analysis, we pooled and analysed RAADS-R data from a number of experimental groups. Analysis of variance (ANOVA) searched for the presence of main effects of Sex and Diagnosis and for interactions between these factors in our sample of autistic and non-autistic adults. Results: In social relatedness and circumscribed interests, main effects of Diagnosis revealed that as expected, autistic adults reported significantly greater lifetime prevalence of symptoms in these domains; an effect of Sex, in circumscribed interests, also suggested that males generally reported more prevalent symptoms than females. An interaction of Sex and Diagnosis in language symptomatology revealed that a normative sex difference in language difficulties was attenuated in autism. An interaction of Sex and Diagnosis in the sensorimotor domain revealed the opposite picture: a lack of sex differences between typically developing men and women and a greater prevalence of sensorimotor symptoms in autistic women than autistic men. Conclusions: We discuss the literature on childhood sex differences in relation to those which emerged in our adult sample. Where childhood sex differences fail to persist in adulthood, several interpretations exist, and we discuss, for example, an inherent sampling bias that may mean that only autistic women most similar to the male presentation are diagnosed. The finding that sensorimotor symptomatology is more highly reported by autistic women is a finding requiring objective confirmation, given its potential importance in diagnosis. En ligne : https://dx.doi.org/10.1186/s13229-018-0216-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Abnormal coherence and sleep composition in children with Angelman syndrome: a retrospective EEG study / H. DEN BAKKER in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 32p. Titre : Abnormal coherence and sleep composition in children with Angelman syndrome: a retrospective EEG study Type de document : Texte imprimé et/ou numérique Auteurs : H. DEN BAKKER, Auteur ; M. S. SIDOROV, Auteur ; Z. FAN, Auteur ; D. J. LEE, Auteur ; L. M. BIRD, Auteur ; C. J. CHU, Auteur ; B. D. PHILPOT, Auteur Article en page(s) : 32p. Langues : Anglais (eng) Mots-clés : Angelman Syndrome/physiopathology  Case-Control Studies  Child  Delta Rhythm  Female  Gamma Rhythm  Humans  Male  Sleep Stages  Angelman syndrome  Biomarker  Coherence  eeg  Spindles  UBE3A Index. décimale : PER Périodiques Résumé : Background: Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, speech and motor impairments, epilepsy, abnormal sleep, and phenotypic overlap with autism. Individuals with AS display characteristic EEG patterns including high-amplitude rhythmic delta waves. Here, we sought to quantitatively explore EEG architecture in AS beyond known spectral power phenotypes. We were motivated by studies of functional connectivity and sleep spindles in autism to study these EEG readouts in children with AS. Methods: We analyzed retrospective wake and sleep EEGs from children with AS (age 4-11) and age-matched neurotypical controls. We assessed long-range and short-range functional connectivity by measuring coherence across multiple frequencies during wake and sleep. We quantified sleep spindles using automated and manual approaches. Results: During wakefulness, children with AS showed enhanced long-range EEG coherence across a wide range of frequencies. During sleep, children with AS showed increased long-range EEG coherence specifically in the gamma band. EEGs from children with AS contained fewer sleep spindles, and these spindles were shorter in duration than their neurotypical counterparts. Conclusions: We demonstrate two quantitative readouts of dysregulated sleep composition in children with AS-gamma coherence and spindles-and describe how functional connectivity patterns may be disrupted during wakefulness. Quantitative EEG phenotypes have potential as biomarkers and readouts of target engagement for future clinical trials and provide clues into how neural circuits are dysregulated in children with AS. En ligne : https://dx.doi.org/10.1186/s13229-018-0214-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Abnormal coherence and sleep composition in children with Angelman syndrome: a retrospective EEG study [Texte imprimé et/ou numérique] / H. DEN BAKKER, Auteur ; M. S. SIDOROV, Auteur ; Z. FAN, Auteur ; D. J. LEE, Auteur ; L. M. BIRD, Auteur ; C. J. CHU, Auteur ; B. D. PHILPOT, Auteur . - 32p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 32p. Mots-clés : Angelman Syndrome/physiopathology  Case-Control Studies  Child  Delta Rhythm  Female  Gamma Rhythm  Humans  Male  Sleep Stages  Angelman syndrome  Biomarker  Coherence  eeg  Spindles  UBE3A Index. décimale : PER Périodiques Résumé : Background: Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, speech and motor impairments, epilepsy, abnormal sleep, and phenotypic overlap with autism. Individuals with AS display characteristic EEG patterns including high-amplitude rhythmic delta waves. Here, we sought to quantitatively explore EEG architecture in AS beyond known spectral power phenotypes. We were motivated by studies of functional connectivity and sleep spindles in autism to study these EEG readouts in children with AS. Methods: We analyzed retrospective wake and sleep EEGs from children with AS (age 4-11) and age-matched neurotypical controls. We assessed long-range and short-range functional connectivity by measuring coherence across multiple frequencies during wake and sleep. We quantified sleep spindles using automated and manual approaches. Results: During wakefulness, children with AS showed enhanced long-range EEG coherence across a wide range of frequencies. During sleep, children with AS showed increased long-range EEG coherence specifically in the gamma band. EEGs from children with AS contained fewer sleep spindles, and these spindles were shorter in duration than their neurotypical counterparts. Conclusions: We demonstrate two quantitative readouts of dysregulated sleep composition in children with AS-gamma coherence and spindles-and describe how functional connectivity patterns may be disrupted during wakefulness. Quantitative EEG phenotypes have potential as biomarkers and readouts of target engagement for future clinical trials and provide clues into how neural circuits are dysregulated in children with AS. En ligne : https://dx.doi.org/10.1186/s13229-018-0214-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations / S. DE RUBEIS in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 31p. Titre : Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations Type de document : Texte imprimé et/ou numérique Auteurs : S. DE RUBEIS, Auteur ; P. M. SIPER, Auteur ; A. DURKIN, Auteur ; J. WEISSMAN, Auteur ; F. MURATET, Auteur ; Danielle B. HALPERN, Auteur ; M. D. P. TRELLES, Auteur ; Y. FRANK, Auteur ; R. LOZANO, Auteur ; A. Ting WANG, Auteur ; J. L. HOLDER, Auteur ; Catalina BETANCUR, Auteur ; Joseph D. BUXBAUM, Auteur ; A. KOLEVZON, Auteur Article en page(s) : 31p. Langues : Anglais (eng) Mots-clés : Adolescent  Adult  Child  Child, Preschool  Chromosome Deletion  Chromosome Disorders/genetics/pathology  Chromosomes, Human, Pair 22/genetics  Female  Haploinsufficiency  Humans  Male  Nerve Tissue Proteins/genetics  Phenotype  Point Mutation  22q13 deletion syndrome  Autism spectrum disorder  Intellectual disability  Phelan-McDermid syndrome  shank3  Sequence variants Index. décimale : PER Périodiques Résumé : Background: Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in SHANK3 has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking. Methods: We provide detailed clinical and genetic data on 17 individuals carrying mutations in SHANK3. We also review 60 previously reported patients with pathogenic or likely pathogenic SHANK3 variants, often lacking detailed phenotypic information. Results: SHANK3 mutations in our cohort and in previously reported cases were distributed throughout the protein; the majority were truncating and all were compatible with de novo inheritance. Despite substantial allelic heterogeneity, four variants were recurrent (p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A), suggesting that these are hotspots for de novo mutations. All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). Severe speech deficits were common, but in contrast to individuals with 22q13.3 deletions, the majority developed single words, including 41% with at least phrase speech. Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems. Conclusions: Haploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS. Our findings expand the molecular and phenotypic spectrum of PMS caused by SHANK3 point mutations and suggest that, in general, speech impairment and motor deficits are more severe in the case of deletions. In contrast, renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3. En ligne : https://dx.doi.org/10.1186/s13229-018-0205-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations [Texte imprimé et/ou numérique] / S. DE RUBEIS, Auteur ; P. M. SIPER, Auteur ; A. DURKIN, Auteur ; J. WEISSMAN, Auteur ; F. MURATET, Auteur ; Danielle B. HALPERN, Auteur ; M. D. P. TRELLES, Auteur ; Y. FRANK, Auteur ; R. LOZANO, Auteur ; A. Ting WANG, Auteur ; J. L. HOLDER, Auteur ; Catalina BETANCUR, Auteur ; Joseph D. BUXBAUM, Auteur ; A. KOLEVZON, Auteur . - 31p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 31p. Mots-clés : Adolescent  Adult  Child  Child, Preschool  Chromosome Deletion  Chromosome Disorders/genetics/pathology  Chromosomes, Human, Pair 22/genetics  Female  Haploinsufficiency  Humans  Male  Nerve Tissue Proteins/genetics  Phenotype  Point Mutation  22q13 deletion syndrome  Autism spectrum disorder  Intellectual disability  Phelan-McDermid syndrome  shank3  Sequence variants Index. décimale : PER Périodiques Résumé : Background: Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in SHANK3 has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking. Methods: We provide detailed clinical and genetic data on 17 individuals carrying mutations in SHANK3. We also review 60 previously reported patients with pathogenic or likely pathogenic SHANK3 variants, often lacking detailed phenotypic information. Results: SHANK3 mutations in our cohort and in previously reported cases were distributed throughout the protein; the majority were truncating and all were compatible with de novo inheritance. Despite substantial allelic heterogeneity, four variants were recurrent (p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A), suggesting that these are hotspots for de novo mutations. All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). Severe speech deficits were common, but in contrast to individuals with 22q13.3 deletions, the majority developed single words, including 41% with at least phrase speech. Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems. Conclusions: Haploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS. Our findings expand the molecular and phenotypic spectrum of PMS caused by SHANK3 point mutations and suggest that, in general, speech impairment and motor deficits are more severe in the case of deletions. In contrast, renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3. En ligne : https://dx.doi.org/10.1186/s13229-018-0205-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Prenatal mercury exposure and features of autism: a prospective population study / J. GOLDING in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 30p. Titre : Prenatal mercury exposure and features of autism: a prospective population study Type de document : Texte imprimé et/ou numérique Auteurs : J. GOLDING, Auteur ; D. RAI, Auteur ; S. GREGORY, Auteur ; G. ELLIS, Auteur ; A. EMOND, Auteur ; Y. ILES-CAVEN, Auteur ; J. HIBBELN, Auteur ; C. TAYLOR, Auteur Article en page(s) : 30p. Langues : Anglais (eng) Mots-clés : Adult  Autistic Disorder/epidemiology  Child  Female  Fish Products/standards  Food Contamination  Humans  Male  Maternal Nutritional Physiological Phenomena  Mercury/blood  Pregnancy  Prenatal Exposure Delayed Effects/epidemiology  alspac  Autism  Autistic traits  Dental amalgam  Fish consumption  Prenatal mercury  Social cognition Index. décimale : PER Périodiques Résumé : Background: Mercury (Hg) has been suspected of causing autism in the past, especially a suspected link with vaccinations containing thiomersal, but a review of the literature shows that has been largely repudiated. Of more significant burden is the total quantity of Hg in the environment. Here, we have used the Avon Longitudinal Study of Parents and Children (ALSPAC) to test whether prenatal exposure from total maternal blood Hg in the first half of pregnancy is associated with the risk of autism or of extreme levels of autistic traits. This is the largest longitudinal study to date to have tested this hypothesis and the only one to have considered early pregnancy. Methods: We have used three strategies: (1) direct comparison of 45 pregnancies resulting in children with diagnosed autism from a population of 3840, (2) comparison of high scores on each of the four autistic traits within the population at risk (n~2800), and (3) indirect measures of association of these outcomes with proxies for increased Hg levels such as frequency of fish consumption and exposure to dental amalgam (n > 8000). Logistic regression adjusted for social conditions including maternal age, housing circumstances, maternal education, and parity. Interactions were tested between risks to offspring of fish and non-fish eaters. Results: There was no suggestion of an adverse effect of total prenatal blood Hg levels on diagnosed autism (AOR 0.89; 95% CI 0.65, 1.22) per SD of Hg (P = 0.485). The only indication of adverse effects concerned a measure of poor social cognition when the mother ate no fish, where the AOR was 1.63 [95% CI 1.02, 2.62] per SD of Hg (P = 0.041), significantly different from the association among the offspring of fish-eaters (AOR = 0.74 [95% CI 0.41, 1.35]). Conclusion: In conclusion, our study identifies no adverse effect of prenatal total blood Hg on autism or autistic traits provided the mother ate fish. Although these results should be confirmed in other populations, accumulating evidence substantiates the recommendation to eat fish during pregnancy. En ligne : https://dx.doi.org/10.1186/s13229-018-0215-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Prenatal mercury exposure and features of autism: a prospective population study [Texte imprimé et/ou numérique] / J. GOLDING, Auteur ; D. RAI, Auteur ; S. GREGORY, Auteur ; G. ELLIS, Auteur ; A. EMOND, Auteur ; Y. ILES-CAVEN, Auteur ; J. HIBBELN, Auteur ; C. TAYLOR, Auteur . - 30p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 30p. Mots-clés : Adult  Autistic Disorder/epidemiology  Child  Female  Fish Products/standards  Food Contamination  Humans  Male  Maternal Nutritional Physiological Phenomena  Mercury/blood  Pregnancy  Prenatal Exposure Delayed Effects/epidemiology  alspac  Autism  Autistic traits  Dental amalgam  Fish consumption  Prenatal mercury  Social cognition Index. décimale : PER Périodiques Résumé : Background: Mercury (Hg) has been suspected of causing autism in the past, especially a suspected link with vaccinations containing thiomersal, but a review of the literature shows that has been largely repudiated. Of more significant burden is the total quantity of Hg in the environment. Here, we have used the Avon Longitudinal Study of Parents and Children (ALSPAC) to test whether prenatal exposure from total maternal blood Hg in the first half of pregnancy is associated with the risk of autism or of extreme levels of autistic traits. This is the largest longitudinal study to date to have tested this hypothesis and the only one to have considered early pregnancy. Methods: We have used three strategies: (1) direct comparison of 45 pregnancies resulting in children with diagnosed autism from a population of 3840, (2) comparison of high scores on each of the four autistic traits within the population at risk (n~2800), and (3) indirect measures of association of these outcomes with proxies for increased Hg levels such as frequency of fish consumption and exposure to dental amalgam (n > 8000). Logistic regression adjusted for social conditions including maternal age, housing circumstances, maternal education, and parity. Interactions were tested between risks to offspring of fish and non-fish eaters. Results: There was no suggestion of an adverse effect of total prenatal blood Hg levels on diagnosed autism (AOR 0.89; 95% CI 0.65, 1.22) per SD of Hg (P = 0.485). The only indication of adverse effects concerned a measure of poor social cognition when the mother ate no fish, where the AOR was 1.63 [95% CI 1.02, 2.62] per SD of Hg (P = 0.041), significantly different from the association among the offspring of fish-eaters (AOR = 0.74 [95% CI 0.41, 1.35]). Conclusion: In conclusion, our study identifies no adverse effect of prenatal total blood Hg on autism or autistic traits provided the mother ate fish. Although these results should be confirmed in other populations, accumulating evidence substantiates the recommendation to eat fish during pregnancy. En ligne : https://dx.doi.org/10.1186/s13229-018-0215-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Hans Asperger, National Socialism, and "race hygiene" in Nazi-era Vienna / H. CZECH in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 29p. Titre : Hans Asperger, National Socialism, and "race hygiene" in Nazi-era Vienna Type de document : Texte imprimé et/ou numérique Auteurs : H. CZECH, Auteur Article en page(s) : 29p. Langues : Anglais (eng) Mots-clés : Asperger Syndrome/diagnosis  Austria  Eugenics/history  History, 20th Century  National Socialism/history  Psychiatry/history  Asperger's syndrome  Autism  Biography  Child psychiatry  Hans Asperger  History  National Socialism  Pediatrics  Therapeutic pedagogy (Heilpadagogik)  Vienna/Austria  World War II Index. décimale : PER Périodiques Résumé : Background: Hans Asperger (1906-1980) first designated a group of children with distinct psychological characteristics as 'autistic psychopaths' in 1938, several years before Leo Kanner's famous 1943 paper on autism. In 1944, Asperger published a comprehensive study on the topic (submitted to Vienna University in 1942 as his postdoctoral thesis), which would only find international acknowledgement in the 1980s. From then on, the eponym 'Asperger's syndrome' increasingly gained currency in recognition of his outstanding contribution to the conceptualization of the condition. At the time, the fact that Asperger had spent pivotal years of his career in Nazi Vienna caused some controversy regarding his potential ties to National Socialism and its race hygiene policies. Documentary evidence was scarce, however, and over time a narrative of Asperger as an active opponent of National Socialism took hold. The main goal of this paper is to re-evaluate this narrative, which is based to a large extent on statements made by Asperger himself and on a small segment of his published work. Methods: Drawing on a vast array of contemporary publications and previously unexplored archival documents (including Asperger's personnel files and the clinical assessments he wrote on his patients), this paper offers a critical examination of Asperger's life, politics, and career before and during the Nazi period in Austria. Results: Asperger managed to accommodate himself to the Nazi regime and was rewarded for his affirmations of loyalty with career opportunities. He joined several organizations affiliated with the NSDAP (although not the Nazi party itself), publicly legitimized race hygiene policies including forced sterilizations and, on several occasions, actively cooperated with the child 'euthanasia' program. The language he employed to diagnose his patients was often remarkably harsh (even in comparison with assessments written by the staff at Vienna's notorious Spiegelgrund 'euthanasia' institution), belying the notion that he tried to protect the children under his care by embellishing their diagnoses. Conclusion: The narrative of Asperger as a principled opponent of National Socialism and a courageous defender of his patients against Nazi 'euthanasia' and other race hygiene measures does not hold up in the face of the historical evidence. What emerges is a much more problematic role played by this pioneer of autism research. Future use of the eponym should reflect the troubling context of its origins in Nazi-era Vienna. En ligne : https://dx.doi.org/10.1186/s13229-018-0208-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Hans Asperger, National Socialism, and "race hygiene" in Nazi-era Vienna [Texte imprimé et/ou numérique] / H. CZECH, Auteur . - 29p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 29p. Mots-clés : Asperger Syndrome/diagnosis  Austria  Eugenics/history  History, 20th Century  National Socialism/history  Psychiatry/history  Asperger's syndrome  Autism  Biography  Child psychiatry  Hans Asperger  History  National Socialism  Pediatrics  Therapeutic pedagogy (Heilpadagogik)  Vienna/Austria  World War II Index. décimale : PER Périodiques Résumé : Background: Hans Asperger (1906-1980) first designated a group of children with distinct psychological characteristics as 'autistic psychopaths' in 1938, several years before Leo Kanner's famous 1943 paper on autism. In 1944, Asperger published a comprehensive study on the topic (submitted to Vienna University in 1942 as his postdoctoral thesis), which would only find international acknowledgement in the 1980s. From then on, the eponym 'Asperger's syndrome' increasingly gained currency in recognition of his outstanding contribution to the conceptualization of the condition. At the time, the fact that Asperger had spent pivotal years of his career in Nazi Vienna caused some controversy regarding his potential ties to National Socialism and its race hygiene policies. Documentary evidence was scarce, however, and over time a narrative of Asperger as an active opponent of National Socialism took hold. The main goal of this paper is to re-evaluate this narrative, which is based to a large extent on statements made by Asperger himself and on a small segment of his published work. Methods: Drawing on a vast array of contemporary publications and previously unexplored archival documents (including Asperger's personnel files and the clinical assessments he wrote on his patients), this paper offers a critical examination of Asperger's life, politics, and career before and during the Nazi period in Austria. Results: Asperger managed to accommodate himself to the Nazi regime and was rewarded for his affirmations of loyalty with career opportunities. He joined several organizations affiliated with the NSDAP (although not the Nazi party itself), publicly legitimized race hygiene policies including forced sterilizations and, on several occasions, actively cooperated with the child 'euthanasia' program. The language he employed to diagnose his patients was often remarkably harsh (even in comparison with assessments written by the staff at Vienna's notorious Spiegelgrund 'euthanasia' institution), belying the notion that he tried to protect the children under his care by embellishing their diagnoses. Conclusion: The narrative of Asperger as a principled opponent of National Socialism and a courageous defender of his patients against Nazi 'euthanasia' and other race hygiene measures does not hold up in the face of the historical evidence. What emerges is a much more problematic role played by this pioneer of autism research. Future use of the eponym should reflect the troubling context of its origins in Nazi-era Vienna. En ligne : https://dx.doi.org/10.1186/s13229-018-0208-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Did Hans Asperger actively assist the Nazi euthanasia program? / Simon BARON-COHEN in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 28p. Titre : Did Hans Asperger actively assist the Nazi euthanasia program? Type de document : Texte imprimé et/ou numérique Auteurs : Simon BARON-COHEN, Auteur ; A. KLIN, Auteur ; S. SILBERMAN, Auteur ; Joseph D. BUXBAUM, Auteur Article en page(s) : 28p. Langues : Anglais (eng) Mots-clés : Eugenics  Euthanasia  Humans  National Socialism Index. décimale : PER Périodiques En ligne : https://dx.doi.org/10.1186/s13229-018-0209-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Did Hans Asperger actively assist the Nazi euthanasia program? [Texte imprimé et/ou numérique] / Simon BARON-COHEN, Auteur ; A. KLIN, Auteur ; S. SILBERMAN, Auteur ; Joseph D. BUXBAUM, Auteur . - 28p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 28p. Mots-clés : Eugenics  Euthanasia  Humans  National Socialism Index. décimale : PER Périodiques En ligne : https://dx.doi.org/10.1186/s13229-018-0209-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Integrated genome-wide Alu methylation and transcriptome profiling analyses reveal novel epigenetic regulatory networks associated with autism spectrum disorder / T. SAELIW in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 27p. Titre : Integrated genome-wide Alu methylation and transcriptome profiling analyses reveal novel epigenetic regulatory networks associated with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : T. SAELIW, Auteur ; C. TANGSUWANSRI, Auteur ; S. THONGKORN, Auteur ; W. CHONCHAIYA, Auteur ; K. SUPHAPEETIPORN, Auteur ; A. MUTIRANGURA, Auteur ; T. TENCOMNAO, Auteur ; V. W. HU, Auteur ; T. SARACHANA, Auteur Article en page(s) : 27p. Langues : Anglais (eng) Mots-clés : Alu Elements  Autism Spectrum Disorder/genetics  Case-Control Studies  Cells, Cultured  DNA Methylation  Epigenesis, Genetic  Female  Gene Regulatory Networks  Genome, Human  Humans  Male  Transcriptome  Autism spectrum disorder  Epigenetic regulation  Gene expression profiles  Lymphoblastoid cell lines  Neuroinflammation  Retrotransposon  Sex bias  Subgrouping Index. décimale : PER Périodiques Résumé : Background: Alu elements are a group of repetitive elements that can influence gene expression through CpG residues and transcription factor binding. Altered gene expression and methylation profiles have been reported in various tissues and cell lines from individuals with autism spectrum disorder (ASD). However, the role of Alu elements in ASD remains unclear. We thus investigated whether Alu elements are associated with altered gene expression profiles in ASD. Methods: We obtained five blood-based gene expression profiles from the Gene Expression Omnibus database and human Alu-inserted gene lists from the TranspoGene database. Differentially expressed genes (DEGs) in ASD were identified from each study and overlapped with the human Alu-inserted genes. The biological functions and networks of Alu-inserted DEGs were then predicted by Ingenuity Pathway Analysis (IPA). A combined bisulfite restriction analysis of lymphoblastoid cell lines (LCLs) derived from 36 ASD and 20 sex- and age-matched unaffected individuals was performed to assess the global DNA methylation levels within Alu elements, and the Alu expression levels were determined by quantitative RT-PCR. Results: In ASD blood or blood-derived cells, 320 Alu-inserted genes were reproducibly differentially expressed. Biological function and pathway analysis showed that these genes were significantly associated with neurodevelopmental disorders and neurological functions involved in ASD etiology. Interestingly, estrogen receptor and androgen signaling pathways implicated in the sex bias of ASD, as well as IL-6 signaling and neuroinflammation signaling pathways, were also highlighted. Alu methylation was not significantly different between the ASD and sex- and age-matched control groups. However, significantly altered Alu methylation patterns were observed in ASD cases sub-grouped based on Autism Diagnostic Interview-Revised scores compared with matched controls. Quantitative RT-PCR analysis of Alu expression also showed significant differences between ASD subgroups. Interestingly, Alu expression was correlated with methylation status in one phenotypic ASD subgroup. Conclusion: Alu methylation and expression were altered in LCLs from ASD subgroups. Our findings highlight the association of Alu elements with gene dysregulation in ASD blood samples and warrant further investigation. Moreover, the classification of ASD individuals into subgroups based on phenotypes may be beneficial and could provide insights into the still unknown etiology and the underlying mechanisms of ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0213-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Integrated genome-wide Alu methylation and transcriptome profiling analyses reveal novel epigenetic regulatory networks associated with autism spectrum disorder [Texte imprimé et/ou numérique] / T. SAELIW, Auteur ; C. TANGSUWANSRI, Auteur ; S. THONGKORN, Auteur ; W. CHONCHAIYA, Auteur ; K. SUPHAPEETIPORN, Auteur ; A. MUTIRANGURA, Auteur ; T. TENCOMNAO, Auteur ; V. W. HU, Auteur ; T. SARACHANA, Auteur . - 27p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 27p. Mots-clés : Alu Elements  Autism Spectrum Disorder/genetics  Case-Control Studies  Cells, Cultured  DNA Methylation  Epigenesis, Genetic  Female  Gene Regulatory Networks  Genome, Human  Humans  Male  Transcriptome  Autism spectrum disorder  Epigenetic regulation  Gene expression profiles  Lymphoblastoid cell lines  Neuroinflammation  Retrotransposon  Sex bias  Subgrouping Index. décimale : PER Périodiques Résumé : Background: Alu elements are a group of repetitive elements that can influence gene expression through CpG residues and transcription factor binding. Altered gene expression and methylation profiles have been reported in various tissues and cell lines from individuals with autism spectrum disorder (ASD). However, the role of Alu elements in ASD remains unclear. We thus investigated whether Alu elements are associated with altered gene expression profiles in ASD. Methods: We obtained five blood-based gene expression profiles from the Gene Expression Omnibus database and human Alu-inserted gene lists from the TranspoGene database. Differentially expressed genes (DEGs) in ASD were identified from each study and overlapped with the human Alu-inserted genes. The biological functions and networks of Alu-inserted DEGs were then predicted by Ingenuity Pathway Analysis (IPA). A combined bisulfite restriction analysis of lymphoblastoid cell lines (LCLs) derived from 36 ASD and 20 sex- and age-matched unaffected individuals was performed to assess the global DNA methylation levels within Alu elements, and the Alu expression levels were determined by quantitative RT-PCR. Results: In ASD blood or blood-derived cells, 320 Alu-inserted genes were reproducibly differentially expressed. Biological function and pathway analysis showed that these genes were significantly associated with neurodevelopmental disorders and neurological functions involved in ASD etiology. Interestingly, estrogen receptor and androgen signaling pathways implicated in the sex bias of ASD, as well as IL-6 signaling and neuroinflammation signaling pathways, were also highlighted. Alu methylation was not significantly different between the ASD and sex- and age-matched control groups. However, significantly altered Alu methylation patterns were observed in ASD cases sub-grouped based on Autism Diagnostic Interview-Revised scores compared with matched controls. Quantitative RT-PCR analysis of Alu expression also showed significant differences between ASD subgroups. Interestingly, Alu expression was correlated with methylation status in one phenotypic ASD subgroup. Conclusion: Alu methylation and expression were altered in LCLs from ASD subgroups. Our findings highlight the association of Alu elements with gene dysregulation in ASD blood samples and warrant further investigation. Moreover, the classification of ASD individuals into subgroups based on phenotypes may be beneficial and could provide insights into the still unknown etiology and the underlying mechanisms of ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0213-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

EU-AIMS Longitudinal European Autism Project (LEAP): the autism twin cohort / J. ISAKSSON in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 26p. Titre : EU-AIMS Longitudinal European Autism Project (LEAP): the autism twin cohort Type de document : Texte imprimé et/ou numérique Auteurs : J. ISAKSSON, Auteur ; K. TAMMIMIES, Auteur ; J. NEUFELD, Auteur ; Elodie CAUVET, Auteur ; K. LUNDIN, Auteur ; Jan K. BUITELAAR, Auteur ; E. LOTH, Auteur ; D. G. M. MURPHY, Auteur ; W. SPOOREN, Auteur ; Sven BÖLTE, Auteur Article en page(s) : 26p. Langues : Anglais (eng) Mots-clés : Adolescent  Autistic Disorder/diagnosis/epidemiology/genetics  Child  Cohort Studies  Europe  Female  Humans  Longitudinal Studies  Male  Phenotype  Twins, Dizygotic/statistics & numerical data  Twins, Monozygotic/statistics & numerical data  adhd  Autism spectrum disorder  Biomarkers  Brain  Cognition  Genetics  Intervention  Twins Index. décimale : PER Périodiques Résumé : EU-AIMS is the largest European research program aiming to identify stratification biomarkers and novel interventions for autism spectrum disorder (ASD). Within the program, the Longitudinal European Autism Project (LEAP) has recruited and comprehensively phenotyped a rare sample of 76 monozygotic and dizygotic twins, discordant, or concordant for ASD plus 30 typically developing twins. The aim of this letter is to complete previous descriptions of the LEAP case-control sample, clinically characterize, and investigate the suitability of the sample for ASD twin-control analyses purposes and share some 'lessons learnt.' Among the twins, a diagnosis of ASD is associated with increased symptom levels of ADHD, higher rates of intellectual disability, and lower family income. For the future, we conclude that the LEAP twin cohort offers multiple options for analyses of genetic and shared and non-shared environmental factors to generate new hypotheses for the larger cohort of LEAP singletons, but particularly cross-validate and refine evidence from it. En ligne : https://dx.doi.org/10.1186/s13229-018-0212-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] EU-AIMS Longitudinal European Autism Project (LEAP): the autism twin cohort [Texte imprimé et/ou numérique] / J. ISAKSSON, Auteur ; K. TAMMIMIES, Auteur ; J. NEUFELD, Auteur ; Elodie CAUVET, Auteur ; K. LUNDIN, Auteur ; Jan K. BUITELAAR, Auteur ; E. LOTH, Auteur ; D. G. M. MURPHY, Auteur ; W. SPOOREN, Auteur ; Sven BÖLTE, Auteur . - 26p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 26p. Mots-clés : Adolescent  Autistic Disorder/diagnosis/epidemiology/genetics  Child  Cohort Studies  Europe  Female  Humans  Longitudinal Studies  Male  Phenotype  Twins, Dizygotic/statistics & numerical data  Twins, Monozygotic/statistics & numerical data  adhd  Autism spectrum disorder  Biomarkers  Brain  Cognition  Genetics  Intervention  Twins Index. décimale : PER Périodiques Résumé : EU-AIMS is the largest European research program aiming to identify stratification biomarkers and novel interventions for autism spectrum disorder (ASD). Within the program, the Longitudinal European Autism Project (LEAP) has recruited and comprehensively phenotyped a rare sample of 76 monozygotic and dizygotic twins, discordant, or concordant for ASD plus 30 typically developing twins. The aim of this letter is to complete previous descriptions of the LEAP case-control sample, clinically characterize, and investigate the suitability of the sample for ASD twin-control analyses purposes and share some 'lessons learnt.' Among the twins, a diagnosis of ASD is associated with increased symptom levels of ADHD, higher rates of intellectual disability, and lower family income. For the future, we conclude that the LEAP twin cohort offers multiple options for analyses of genetic and shared and non-shared environmental factors to generate new hypotheses for the larger cohort of LEAP singletons, but particularly cross-validate and refine evidence from it. En ligne : https://dx.doi.org/10.1186/s13229-018-0212-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Operationalizing atypical gaze in toddlers with autism spectrum disorders: a cohesion-based approach / Q. WANG in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 25p. Titre : Operationalizing atypical gaze in toddlers with autism spectrum disorders: a cohesion-based approach Type de document : Texte imprimé et/ou numérique Auteurs : Q. WANG, Auteur ; Daniel J. CAMPBELL, Auteur ; S. L. MACARI, Auteur ; Katarzyna CHAWARSKA, Auteur ; F. SHIC, Auteur Article en page(s) : 25p. Langues : Anglais (eng) Mots-clés : Attention  Autism Spectrum Disorder/diagnosis/physiopathology  Case-Control Studies  Child, Preschool  Female  Fixation, Ocular  Humans  Infant  Male  Social Behavior  Visual Perception  asd  Attentional synchrony  Atypicality  Autism  Cohesion  Eye tracking  Visual attention Index. décimale : PER Périodiques Résumé : Background: Multiple eye-tracking studies have highlighted the "atypical" nature of social attention in autism. However, it is unclear how "atypical" or "typical" should be quantified. Methods: We developed a method for identifying moments when members of a group looked at similar places (High-Cohesion Time Frames; HCTFs). We defined typicality as the proximity of gaze points to typically developing (TD) gaze points during TD HCTFs. Comparing toddlers with ASD (n = 112) to developmentally delayed (DD, n = 36) and TD (n = 163) toddlers during a video with Dyadic Bid, Sandwich-Making, Joint Attention, and Animated Toys conditions, we examined (a) individual typicality scores, (b) the relationship between typicality and symptom severity, and (c) HCTF distributions associated with each diagnostic group. Results: The ASD group had lower gaze typicality scores compared to the TD and DD groups in the Dyadic Bid and Sandwich-Making conditions but not during Animated Toys. The DD and TD groups did not differ in any condition. Correlational analyses indicated that higher typicality scores were associated with increased looking at pre-planned locations of the scene indexed by each experimental condition. In the ASD group, lower gaze typicality was associated with more severe autism symptoms. Examining ASD HCTFs, the gaze of toddlers with ASD was least cohesive during Dyadic Bid and most cohesive during Animated Toys. Conclusion: In contrast to non-ASD groups, toddlers with ASD show high cohesion during salient nonsocial events, suggesting that consistency in looking strategies may depend more on perceptual features. These findings are consequential for understanding individual differences in visual attention in ASD and for the design of more sensitive biomarker tasks for stratification, between-group differentiation, and measuring response to treatment. En ligne : https://dx.doi.org/10.1186/s13229-018-0211-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Operationalizing atypical gaze in toddlers with autism spectrum disorders: a cohesion-based approach [Texte imprimé et/ou numérique] / Q. WANG, Auteur ; Daniel J. CAMPBELL, Auteur ; S. L. MACARI, Auteur ; Katarzyna CHAWARSKA, Auteur ; F. SHIC, Auteur . - 25p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 25p. Mots-clés : Attention  Autism Spectrum Disorder/diagnosis/physiopathology  Case-Control Studies  Child, Preschool  Female  Fixation, Ocular  Humans  Infant  Male  Social Behavior  Visual Perception  asd  Attentional synchrony  Atypicality  Autism  Cohesion  Eye tracking  Visual attention Index. décimale : PER Périodiques Résumé : Background: Multiple eye-tracking studies have highlighted the "atypical" nature of social attention in autism. However, it is unclear how "atypical" or "typical" should be quantified. Methods: We developed a method for identifying moments when members of a group looked at similar places (High-Cohesion Time Frames; HCTFs). We defined typicality as the proximity of gaze points to typically developing (TD) gaze points during TD HCTFs. Comparing toddlers with ASD (n = 112) to developmentally delayed (DD, n = 36) and TD (n = 163) toddlers during a video with Dyadic Bid, Sandwich-Making, Joint Attention, and Animated Toys conditions, we examined (a) individual typicality scores, (b) the relationship between typicality and symptom severity, and (c) HCTF distributions associated with each diagnostic group. Results: The ASD group had lower gaze typicality scores compared to the TD and DD groups in the Dyadic Bid and Sandwich-Making conditions but not during Animated Toys. The DD and TD groups did not differ in any condition. Correlational analyses indicated that higher typicality scores were associated with increased looking at pre-planned locations of the scene indexed by each experimental condition. In the ASD group, lower gaze typicality was associated with more severe autism symptoms. Examining ASD HCTFs, the gaze of toddlers with ASD was least cohesive during Dyadic Bid and most cohesive during Animated Toys. Conclusion: In contrast to non-ASD groups, toddlers with ASD show high cohesion during salient nonsocial events, suggesting that consistency in looking strategies may depend more on perceptual features. These findings are consequential for understanding individual differences in visual attention in ASD and for the design of more sensitive biomarker tasks for stratification, between-group differentiation, and measuring response to treatment. En ligne : https://dx.doi.org/10.1186/s13229-018-0211-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging / J. ELLEGOOD in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 24p. Titre : Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging Type de document : Texte imprimé et/ou numérique Auteurs : J. ELLEGOOD, Auteur ; Y. YEE, Auteur ; T. M. KERR, Auteur ; C. L. MULLER, Auteur ; R. D. BLAKELY, Auteur ; R. M. HENKELMAN, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur ; J. P. LERCH, Auteur Article en page(s) : 24p. Langues : Anglais (eng) Mots-clés : Animals  Brain/diagnostic imaging/metabolism  Female  Magnetic Resonance Imaging  Male  Mice  Mice, Inbred C57BL  Mutation  Neurons/metabolism  Serotonin/metabolism  Serotonin Plasma Membrane Transport Proteins/genetics/metabolism  5-ht  5htt  Brain  Dorsal raphe  Magnetic resonance imaging  Neurodevelopment  Serotonin  Slc6a4 Index. décimale : PER Périodiques Résumé : Background: The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects of brain development, but systematic neuroimaging studies have not previously been reported. In particular, the 5-HT transporter (serotonin transporter, SERT; 5-HTT) gene, Slc6a4, has been extensively studied. Methods: Using a 7-T MRI and deformation-based morphometry, we assessed neuroanatomical differences in an Slc6a4 knockout mouse on a C57BL/6 genetic background, along with an Slc6a4 Ala56 knockin mouse on two different genetic backgrounds (129S and C57BL/6). Results: Individually (same sex, same background, same genotype), the only differences found were in the female Slc6a4 knockout mouse; all the others had no significant differences. However, an analysis of variance across the whole study sample revealed a significant effect of Slc6a4 on the amygdala, thalamus, dorsal raphe nucleus, and lateral and frontal cortices. Conclusions: This work shows that an increase or decrease in SERT function has a significant effect on the neuroanatomy in 5-HT relevant regions, particularly the raphe nuclei. Notably, the Slc6a4 Ala56 knockin alone appears to have an insignificant, but suggestive, effect compared to the KO, which is consistent with Slc6a4 function. Despite the small number of 5-HT neurons and their localization to the brainstem, it is clear that 5-HT plays an important role in neuroanatomical organization. En ligne : https://dx.doi.org/10.1186/s13229-018-0210-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging [Texte imprimé et/ou numérique] / J. ELLEGOOD, Auteur ; Y. YEE, Auteur ; T. M. KERR, Auteur ; C. L. MULLER, Auteur ; R. D. BLAKELY, Auteur ; R. M. HENKELMAN, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur ; J. P. LERCH, Auteur . - 24p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 24p. Mots-clés : Animals  Brain/diagnostic imaging/metabolism  Female  Magnetic Resonance Imaging  Male  Mice  Mice, Inbred C57BL  Mutation  Neurons/metabolism  Serotonin/metabolism  Serotonin Plasma Membrane Transport Proteins/genetics/metabolism  5-ht  5htt  Brain  Dorsal raphe  Magnetic resonance imaging  Neurodevelopment  Serotonin  Slc6a4 Index. décimale : PER Périodiques Résumé : Background: The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects of brain development, but systematic neuroimaging studies have not previously been reported. In particular, the 5-HT transporter (serotonin transporter, SERT; 5-HTT) gene, Slc6a4, has been extensively studied. Methods: Using a 7-T MRI and deformation-based morphometry, we assessed neuroanatomical differences in an Slc6a4 knockout mouse on a C57BL/6 genetic background, along with an Slc6a4 Ala56 knockin mouse on two different genetic backgrounds (129S and C57BL/6). Results: Individually (same sex, same background, same genotype), the only differences found were in the female Slc6a4 knockout mouse; all the others had no significant differences. However, an analysis of variance across the whole study sample revealed a significant effect of Slc6a4 on the amygdala, thalamus, dorsal raphe nucleus, and lateral and frontal cortices. Conclusions: This work shows that an increase or decrease in SERT function has a significant effect on the neuroanatomy in 5-HT relevant regions, particularly the raphe nuclei. Notably, the Slc6a4 Ala56 knockin alone appears to have an insignificant, but suggestive, effect compared to the KO, which is consistent with Slc6a4 function. Despite the small number of 5-HT neurons and their localization to the brainstem, it is clear that 5-HT plays an important role in neuroanatomical organization. En ligne : https://dx.doi.org/10.1186/s13229-018-0210-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Functional MRI connectivity of children with autism and low verbal and cognitive performance / T. P. GABRIELSEN in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 67 p. Titre : Functional MRI connectivity of children with autism and low verbal and cognitive performance Type de document : Texte imprimé et/ou numérique Auteurs : T. P. GABRIELSEN, Auteur ; Jeffrey S. ANDERSON, Auteur ; K. G. STEPHENSON, Auteur ; J. BECK, Auteur ; J. B. KING, Auteur ; R. KELLEMS, Auteur ; D. N. TOP, Auteur ; N. C. C. RUSSELL, Auteur ; Emily I. ANDERBERG, Auteur ; R. A. LUNDWALL, Auteur ; B. HANSEN, Auteur ; M. SOUTH, Auteur Article en page(s) : 67 p. Langues : Anglais (eng) Mots-clés : Adolescent  Autistic Disorder/*diagnostic imaging/physiopathology  Case-Control Studies  Child  *Cognition  Female  Humans  Intelligence  *Language Development  Magnetic Resonance Imaging  Male  *Autism spectrum disorder  *Functional connectivity  *Imaging methodology  *Intelligence  *Language  Institutional Review Board, protocol #F25403. Written informed consent was  obtained from parents, with assent obtained from participants following video  review of procedures.The boy who modeled the MRI procedures in the video modeling  procedure was filmed, and the final video was shared, with written permission of  both of his parents and with his own assent.The authors declare that they have no  competing interests.Springer Nature remains neutral with regard to jurisdictional  claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Functional neuroimaging research in autism spectrum disorder has reported patterns of decreased long-range, within-network, and interhemispheric connectivity. Research has also reported increased corticostriatal connectivity and between-network connectivity for default and attentional networks. Past studies have excluded individuals with autism and low verbal and cognitive performance (LVCP), so connectivity in individuals more significantly affected with autism has not yet been studied. This represents a critical gap in our understanding of brain function across the autism spectrum. Methods: Using behavioral support procedures adapted from Nordahl, et al. (J Neurodev Disord 8:20-20, 2016), we completed non-sedated structural and functional MRI scans of 56 children ages 7-17, including LVCP children (n = 17, mean IQ = 54), children with autism and higher performance (HVCP, n = 20, mean IQ = 106), and neurotypical children (NT, n = 19, mean IQ = 111). Preparation included detailed intake questionnaires, video modeling, behavioral and anxiety reduction techniques, active noise-canceling headphones, and in-scan presentation of the Inscapes movie paradigm from Vanderwal et al. (Neuroimage 122:222-32, 2015). A high temporal resolution multiband echoplanar fMRI protocol analyzed motion-free time series data, extracted from concatenated volumes to mitigate the influence of motion artifact. All participants had > 200 volumes of motion-free fMRI scanning. Analyses were corrected for multiple comparisons. Results: LVCP showed decreased within-network connectivity in default, salience, auditory, and frontoparietal networks (LVCP < HVCP) and decreased interhemispheric connectivity (LVCP < HVCP=NT). Between-network connectivity was higher for LVCP than NT between default and dorsal attention and frontoparietal networks. Lower IQ was associated with decreased connectivity within the default network and increased connectivity between default and dorsal attention networks. Conclusions: This study demonstrates that with moderate levels of support, including readily available techniques, information about brain similarities and differences in LVCP individuals can be further studied. This initial study suggested decreased network segmentation and integration in LVCP individuals. Further imaging studies of LVCP individuals with larger samples will add to understanding of origins and effects of autism on brain function and behavior. En ligne : https://dx.doi.org/10.1186/s13229-018-0248-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] Functional MRI connectivity of children with autism and low verbal and cognitive performance [Texte imprimé et/ou numérique] / T. P. GABRIELSEN, Auteur ; Jeffrey S. ANDERSON, Auteur ; K. G. STEPHENSON, Auteur ; J. BECK, Auteur ; J. B. KING, Auteur ; R. KELLEMS, Auteur ; D. N. TOP, Auteur ; N. C. C. RUSSELL, Auteur ; Emily I. ANDERBERG, Auteur ; R. A. LUNDWALL, Auteur ; B. HANSEN, Auteur ; M. SOUTH, Auteur . - 67 p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 67 p. Mots-clés : Adolescent  Autistic Disorder/*diagnostic imaging/physiopathology  Case-Control Studies  Child  *Cognition  Female  Humans  Intelligence  *Language Development  Magnetic Resonance Imaging  Male  *Autism spectrum disorder  *Functional connectivity  *Imaging methodology  *Intelligence  *Language  Institutional Review Board, protocol #F25403. Written informed consent was  obtained from parents, with assent obtained from participants following video  review of procedures.The boy who modeled the MRI procedures in the video modeling  procedure was filmed, and the final video was shared, with written permission of  both of his parents and with his own assent.The authors declare that they have no  competing interests.Springer Nature remains neutral with regard to jurisdictional  claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Functional neuroimaging research in autism spectrum disorder has reported patterns of decreased long-range, within-network, and interhemispheric connectivity. Research has also reported increased corticostriatal connectivity and between-network connectivity for default and attentional networks. Past studies have excluded individuals with autism and low verbal and cognitive performance (LVCP), so connectivity in individuals more significantly affected with autism has not yet been studied. This represents a critical gap in our understanding of brain function across the autism spectrum. Methods: Using behavioral support procedures adapted from Nordahl, et al. (J Neurodev Disord 8:20-20, 2016), we completed non-sedated structural and functional MRI scans of 56 children ages 7-17, including LVCP children (n = 17, mean IQ = 54), children with autism and higher performance (HVCP, n = 20, mean IQ = 106), and neurotypical children (NT, n = 19, mean IQ = 111). Preparation included detailed intake questionnaires, video modeling, behavioral and anxiety reduction techniques, active noise-canceling headphones, and in-scan presentation of the Inscapes movie paradigm from Vanderwal et al. (Neuroimage 122:222-32, 2015). A high temporal resolution multiband echoplanar fMRI protocol analyzed motion-free time series data, extracted from concatenated volumes to mitigate the influence of motion artifact. All participants had > 200 volumes of motion-free fMRI scanning. Analyses were corrected for multiple comparisons. Results: LVCP showed decreased within-network connectivity in default, salience, auditory, and frontoparietal networks (LVCP < HVCP) and decreased interhemispheric connectivity (LVCP < HVCP=NT). Between-network connectivity was higher for LVCP than NT between default and dorsal attention and frontoparietal networks. Lower IQ was associated with decreased connectivity within the default network and increased connectivity between default and dorsal attention networks. Conclusions: This study demonstrates that with moderate levels of support, including readily available techniques, information about brain similarities and differences in LVCP individuals can be further studied. This initial study suggested decreased network segmentation and integration in LVCP individuals. Further imaging studies of LVCP individuals with larger samples will add to understanding of origins and effects of autism on brain function and behavior. En ligne : https://dx.doi.org/10.1186/s13229-018-0248-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

Neuroglia in the autistic brain: evidence from a preclinical model / M. R. BRONZUOLI in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 66 p. Titre : Neuroglia in the autistic brain: evidence from a preclinical model Type de document : Texte imprimé et/ou numérique Auteurs : M. R. BRONZUOLI, Auteur ; R. FACCHINETTI, Auteur ; D. INGRASSIA, Auteur ; M. SARVADIO, Auteur ; S. SCHIAVI, Auteur ; L. STEARDO, Auteur ; A. VERKHRATSKY, Auteur ; V. TREZZA, Auteur ; C. SCUDERI, Auteur Article en page(s) : 66 p. Langues : Anglais (eng) Mots-clés : Animals  Autistic Disorder/etiology/*pathology/physiopathology  Brain/drug effects/*pathology  Female  Male  Neuroglia/drug effects/*pathology  Rats  Rats, Wistar  Stereotyped Behavior  Valproic Acid/pharmacology/toxicity  Vocalization, Animal  *Astrocyte  *Autism spectrum disorder  *Microglia  *Oligodendrocyte  *Valproic acid  of the Italian Ministry of Health (D.L. 26/2014) and with the European Parliament  directive 2010/63/EU.Not applicable.The authors declare that they have no  competing interests.Springer Nature remains neutral with regard to jurisdictional  claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Neuroglial cells that provide homeostatic support and form defence of the nervous system contribute to all neurological disorders. We analyzed three major types of neuroglia, astrocytes, oligodendrocytes, and microglia in the brains of an animal model of autism spectrum disorder, in which rats were exposed prenatally to antiepileptic and mood stabilizer drug valproic acid; this model being of acknowledged clinical relevance. Methods: We tested the autistic-like behaviors of valproic acid-prenatally exposed male rats by performing isolation-induced ultrasonic vocalizations, the three-chamber test, and the hole board test. To account for human infancy, adolescence, and adulthood, such tasks were performed at postnatal day 13, postnatal day 35, and postnatal day 90, respectively. After sacrifice, we examined gene and protein expression of specific markers of neuroglia in hippocampus, prefrontal cortex, and cerebellum, these brain regions being associated with autism spectrum disorder pathogenesis. Results: Infant offspring of VPA-exposed dams emitted less ultrasonic vocalizations when isolated from their mothers and siblings and, in adolescence and adulthood, they showed altered sociability in the three chamber test and increased stereotypic behavior in the hole board test. Molecular analyses indicate that prenatal valproic acid exposure affects all types of neuroglia, mainly causing transcriptional modifications. The most prominent changes occur in prefrontal cortex and in the hippocampus of autistic-like animals; these changes are particularly evident during infancy and adolescence, while they appear to be mitigated in adulthood. Conclusions: Neuroglial pathological phenotype in autism spectrum disorder rat model appears to be rather mild with little signs of widespread and chronic neuroinflammation. En ligne : https://dx.doi.org/10.1186/s13229-018-0254-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] Neuroglia in the autistic brain: evidence from a preclinical model [Texte imprimé et/ou numérique] / M. R. BRONZUOLI, Auteur ; R. FACCHINETTI, Auteur ; D. INGRASSIA, Auteur ; M. SARVADIO, Auteur ; S. SCHIAVI, Auteur ; L. STEARDO, Auteur ; A. VERKHRATSKY, Auteur ; V. TREZZA, Auteur ; C. SCUDERI, Auteur . - 66 p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 66 p. Mots-clés : Animals  Autistic Disorder/etiology/*pathology/physiopathology  Brain/drug effects/*pathology  Female  Male  Neuroglia/drug effects/*pathology  Rats  Rats, Wistar  Stereotyped Behavior  Valproic Acid/pharmacology/toxicity  Vocalization, Animal  *Astrocyte  *Autism spectrum disorder  *Microglia  *Oligodendrocyte  *Valproic acid  of the Italian Ministry of Health (D.L. 26/2014) and with the European Parliament  directive 2010/63/EU.Not applicable.The authors declare that they have no  competing interests.Springer Nature remains neutral with regard to jurisdictional  claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Neuroglial cells that provide homeostatic support and form defence of the nervous system contribute to all neurological disorders. We analyzed three major types of neuroglia, astrocytes, oligodendrocytes, and microglia in the brains of an animal model of autism spectrum disorder, in which rats were exposed prenatally to antiepileptic and mood stabilizer drug valproic acid; this model being of acknowledged clinical relevance. Methods: We tested the autistic-like behaviors of valproic acid-prenatally exposed male rats by performing isolation-induced ultrasonic vocalizations, the three-chamber test, and the hole board test. To account for human infancy, adolescence, and adulthood, such tasks were performed at postnatal day 13, postnatal day 35, and postnatal day 90, respectively. After sacrifice, we examined gene and protein expression of specific markers of neuroglia in hippocampus, prefrontal cortex, and cerebellum, these brain regions being associated with autism spectrum disorder pathogenesis. Results: Infant offspring of VPA-exposed dams emitted less ultrasonic vocalizations when isolated from their mothers and siblings and, in adolescence and adulthood, they showed altered sociability in the three chamber test and increased stereotypic behavior in the hole board test. Molecular analyses indicate that prenatal valproic acid exposure affects all types of neuroglia, mainly causing transcriptional modifications. The most prominent changes occur in prefrontal cortex and in the hippocampus of autistic-like animals; these changes are particularly evident during infancy and adolescence, while they appear to be mitigated in adulthood. Conclusions: Neuroglial pathological phenotype in autism spectrum disorder rat model appears to be rather mild with little signs of widespread and chronic neuroinflammation. En ligne : https://dx.doi.org/10.1186/s13229-018-0254-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons / Q. XU in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 65 p. Titre : Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons Type de document : Texte imprimé et/ou numérique Auteurs : Q. XU, Auteur ; Y. Y. LIU, Auteur ; X. WANG, Auteur ; G. H. TAN, Auteur ; H. P. LI, Auteur ; S. W. HULBERT, Auteur ; C. Y. LI, Auteur ; C. C. HU, Auteur ; Z. Q. XIONG, Auteur ; X. XU, Auteur ; Y. H. JIANG, Auteur Article en page(s) : 65 p. Langues : Anglais (eng) Mots-clés : Animals  Autistic Disorder/*genetics/pathology  Cells, Cultured  Cerebral Cortex/cytology/growth & development  DNA-Binding Proteins/*genetics/metabolism  Humans  Mice  Mice, Inbred C57BL  *Neurogenesis  Neurons/cytology/*metabolism/physiology  *Autism spectrum disorder (ASD)  *chd8  *Chromatin remodeling  *Neurite growth  *Neurodevelopment  Animal Care and Use Committee-approved protocols both at Children's Hospital of  Fudan University ethics approval ID: 2015-87 and Duke University. Human  postmortem brain tissues: The use of archived human postmortem brain tissues is  approved by Institute Review Board at Duke University.Not applicableThe authors  declare that they have no competing interests.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: Mutations in CHD8, chromodomain helicase DNA-binding protein 8, are among the most replicated and common findings in genetic studies of autism spectrum disorder (ASD). The CHD8 protein is believed to act as a transcriptional regulator by remodeling chromatin structure and recruiting histone H1 to target genes. The mechanism by which deficiency of CHD8 causes ASD has not been fully elucidated. Methods: We examined the expression of CHD8 in human and mouse brains using both immunohistochemistry and RNA in situ hybridization. We performed in utero electroporation, neuronal culture, and biochemical analysis using RNAi to examine the functional consequences of CHD8 deficiency. Results: We discovered that CHD8 is expressed highly in neurons and at low levels in glia cells in both humans and mice. Specifically, CHD8 is localized predominately in the nucleus of both MAP2 and parvalbumin-positive neurons. In the developing mouse brain, expression of Chd8 peaks from E16 to E18 and then decreases significantly at P14 to adulthood. Knockdown of Chd8 results in reduced axon and dendritic growth, disruption of axon projections to the contralateral cortex, and delayed neuronal migration at E18.5 which recovers by P3 and P7. Conclusion: Our findings indicate an important role for CHD8 in dendritic and axon development and neuronal migration and thus offer novel insights to further dissect the underlying molecular and circuit mechanisms of ASD caused by CHD8 deficiency. En ligne : https://dx.doi.org/10.1186/s13229-018-0244-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons [Texte imprimé et/ou numérique] / Q. XU, Auteur ; Y. Y. LIU, Auteur ; X. WANG, Auteur ; G. H. TAN, Auteur ; H. P. LI, Auteur ; S. W. HULBERT, Auteur ; C. Y. LI, Auteur ; C. C. HU, Auteur ; Z. Q. XIONG, Auteur ; X. XU, Auteur ; Y. H. JIANG, Auteur . - 65 p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 65 p. Mots-clés : Animals  Autistic Disorder/*genetics/pathology  Cells, Cultured  Cerebral Cortex/cytology/growth & development  DNA-Binding Proteins/*genetics/metabolism  Humans  Mice  Mice, Inbred C57BL  *Neurogenesis  Neurons/cytology/*metabolism/physiology  *Autism spectrum disorder (ASD)  *chd8  *Chromatin remodeling  *Neurite growth  *Neurodevelopment  Animal Care and Use Committee-approved protocols both at Children's Hospital of  Fudan University ethics approval ID: 2015-87 and Duke University. Human  postmortem brain tissues: The use of archived human postmortem brain tissues is  approved by Institute Review Board at Duke University.Not applicableThe authors  declare that they have no competing interests.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: Mutations in CHD8, chromodomain helicase DNA-binding protein 8, are among the most replicated and common findings in genetic studies of autism spectrum disorder (ASD). The CHD8 protein is believed to act as a transcriptional regulator by remodeling chromatin structure and recruiting histone H1 to target genes. The mechanism by which deficiency of CHD8 causes ASD has not been fully elucidated. Methods: We examined the expression of CHD8 in human and mouse brains using both immunohistochemistry and RNA in situ hybridization. We performed in utero electroporation, neuronal culture, and biochemical analysis using RNAi to examine the functional consequences of CHD8 deficiency. Results: We discovered that CHD8 is expressed highly in neurons and at low levels in glia cells in both humans and mice. Specifically, CHD8 is localized predominately in the nucleus of both MAP2 and parvalbumin-positive neurons. In the developing mouse brain, expression of Chd8 peaks from E16 to E18 and then decreases significantly at P14 to adulthood. Knockdown of Chd8 results in reduced axon and dendritic growth, disruption of axon projections to the contralateral cortex, and delayed neuronal migration at E18.5 which recovers by P3 and P7. Conclusion: Our findings indicate an important role for CHD8 in dendritic and axon development and neuronal migration and thus offer novel insights to further dissect the underlying molecular and circuit mechanisms of ASD caused by CHD8 deficiency. En ligne : https://dx.doi.org/10.1186/s13229-018-0244-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 64 p. Titre : Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Type de document : Texte imprimé et/ou numérique Article en page(s) : 64 p. Langues : Anglais (eng) Mots-clés : Adult  Autism Spectrum Disorder/*genetics  Child  Female  Humans  Male  *Models, Genetic  *Multifactorial Inheritance  *Mutation  Pedigree  Quantitative Trait Loci  *Autism spectrum disorders  *De novo mutations  *Genotype-phenotype relationship  *Multifactorial model  *Multiple hit  *Targeted sequencing  Institutional Review Board of the School of Life Sciences at Central South  University (CSU), Changsha, Hunan, China. Informed consent was obtained from the  parents or legal guardians of all study participants.Written informed consent for  publication was obtained from the parents or legal guardians.EEE is on the  scientific advisory board (SAB) of DNAnexus, Inc.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: We previously performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China (ACGC) (phase I). Here, we expand this analysis to a larger cohort of patients (ACGC phase II) to better understand the prevalence, inheritance, and genotype-phenotype correlations of likely gene-disrupting (LGD) mutations for autism candidate genes originally identified in cohorts of European descent. Methods: We sequenced 187 autism candidate genes in an additional 784 probands and 85 genes in 599 probands using single-molecule molecular inversion probes. We tested the inheritance of potentially pathogenic mutations, performed a meta-analysis of phase I and phase II data and combined our results with existing exome sequence data to investigate the phenotypes of carrier parents and patients with multiple hits in different autism risk genes. Results: We validated recurrent, LGD, de novo mutations (DNMs) in 13 genes. We identified a potential novel risk gene (ZNF292), one novel gene with recurrent LGD DNMs (RALGAPB), as well as genes associated with macrocephaly (GIGYF2 and WDFY3). We identified the transmission of private LGD mutations in genes predominantly associated with DNMs and showed that parental carriers tended to share milder autism-related phenotypes. Patients that carried DNMs in two or more candidate genes show more severe phenotypes. Conclusions: We identify new risk genes and transmission of deleterious mutations in genes primarily associated with DNMs. The fact that parental carriers show milder phenotypes and patients with multiple hits are more severe supports a multifactorial model of risk. En ligne : https://dx.doi.org/10.1186/s13229-018-0247-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model [Texte imprimé et/ou numérique] . - 64 p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 64 p. Mots-clés : Adult  Autism Spectrum Disorder/*genetics  Child  Female  Humans  Male  *Models, Genetic  *Multifactorial Inheritance  *Mutation  Pedigree  Quantitative Trait Loci  *Autism spectrum disorders  *De novo mutations  *Genotype-phenotype relationship  *Multifactorial model  *Multiple hit  *Targeted sequencing  Institutional Review Board of the School of Life Sciences at Central South  University (CSU), Changsha, Hunan, China. Informed consent was obtained from the  parents or legal guardians of all study participants.Written informed consent for  publication was obtained from the parents or legal guardians.EEE is on the  scientific advisory board (SAB) of DNAnexus, Inc.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: We previously performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China (ACGC) (phase I). Here, we expand this analysis to a larger cohort of patients (ACGC phase II) to better understand the prevalence, inheritance, and genotype-phenotype correlations of likely gene-disrupting (LGD) mutations for autism candidate genes originally identified in cohorts of European descent. Methods: We sequenced 187 autism candidate genes in an additional 784 probands and 85 genes in 599 probands using single-molecule molecular inversion probes. We tested the inheritance of potentially pathogenic mutations, performed a meta-analysis of phase I and phase II data and combined our results with existing exome sequence data to investigate the phenotypes of carrier parents and patients with multiple hits in different autism risk genes. Results: We validated recurrent, LGD, de novo mutations (DNMs) in 13 genes. We identified a potential novel risk gene (ZNF292), one novel gene with recurrent LGD DNMs (RALGAPB), as well as genes associated with macrocephaly (GIGYF2 and WDFY3). We identified the transmission of private LGD mutations in genes predominantly associated with DNMs and showed that parental carriers tended to share milder autism-related phenotypes. Patients that carried DNMs in two or more candidate genes show more severe phenotypes. Conclusions: We identify new risk genes and transmission of deleterious mutations in genes primarily associated with DNMs. The fact that parental carriers show milder phenotypes and patients with multiple hits are more severe supports a multifactorial model of risk. En ligne : https://dx.doi.org/10.1186/s13229-018-0247-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

Diffusional kurtosis imaging of the corpus callosum in autism / Y. V. SUI in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 62 p. Titre : Diffusional kurtosis imaging of the corpus callosum in autism Type de document : Texte imprimé et/ou numérique Auteurs : Y. V. SUI, Auteur ; J. DONALDSON, Auteur ; L. MILES, Auteur ; James S. BABB, Auteur ; Francisco Xavier CASTELLANOS, Auteur ; M. LAZAR, Auteur Article en page(s) : 62 p. Langues : Anglais (eng) Mots-clés : Adolescent  Adult  Autistic Disorder/*diagnostic imaging/physiopathology  Case-Control Studies  Corpus Callosum/*diagnostic imaging  Humans  Magnetic Resonance Imaging  Wechsler Scales  White Matter/diagnostic imaging  *Autism  *Corpus callosum  *Diffusional kurtosis imaging  *Interhemispheric connectivity  *Processing speed  Medicine. All participants provided informed consent at the time of their  visit.The authors give consent for this manuscript to be published.The authors  declare that they have no competing interests.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: The corpus callosum is implicated in the pathophysiology of autism spectrum disorder (ASD). However, specific structural deficits and underlying mechanisms are yet to be well defined. Methods: We employed diffusional kurtosis imaging (DKI) metrics to characterize white matter properties within five discrete segments of the corpus callosum in 17 typically developing (TD) adults and 16 age-matched participants with ASD without co-occurring intellectual disability (ID). The DKI metrics included axonal water fraction (f axon) and intra-axonal diffusivity (D axon), which reflect axonal density and caliber, and extra-axonal radial (RDextra) and axial (ADextra) diffusivities, which reflect myelination and microstructural organization of the extracellular space. The relationships between DKI metrics and processing speed, a cognitive feature known to be impaired in ASD, were also examined. Results: ASD group had significantly decreased callosal f axon and D axon (p = .01 and p = .045), particularly in the midbody, isthmus, and splenium. Regression analysis showed that variation in DKI metrics, primarily in the mid and posterior callosal regions explained up to 70.7% of the variance in processing speed scores for TD (p = .001) but not for ASD (p > .05). Conclusion: Decreased DKI metrics suggested that ASD may be associated with axonal deficits such as reduced axonal caliber and density in the corpus callosum, especially in the mid and posterior callosal areas. These data suggest that impaired interhemispheric connectivity may contribute to decreased processing speed in ASD participants. En ligne : https://dx.doi.org/10.1186/s13229-018-0245-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] Diffusional kurtosis imaging of the corpus callosum in autism [Texte imprimé et/ou numérique] / Y. V. SUI, Auteur ; J. DONALDSON, Auteur ; L. MILES, Auteur ; James S. BABB, Auteur ; Francisco Xavier CASTELLANOS, Auteur ; M. LAZAR, Auteur . - 62 p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 62 p. Mots-clés : Adolescent  Adult  Autistic Disorder/*diagnostic imaging/physiopathology  Case-Control Studies  Corpus Callosum/*diagnostic imaging  Humans  Magnetic Resonance Imaging  Wechsler Scales  White Matter/diagnostic imaging  *Autism  *Corpus callosum  *Diffusional kurtosis imaging  *Interhemispheric connectivity  *Processing speed  Medicine. All participants provided informed consent at the time of their  visit.The authors give consent for this manuscript to be published.The authors  declare that they have no competing interests.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: The corpus callosum is implicated in the pathophysiology of autism spectrum disorder (ASD). However, specific structural deficits and underlying mechanisms are yet to be well defined. Methods: We employed diffusional kurtosis imaging (DKI) metrics to characterize white matter properties within five discrete segments of the corpus callosum in 17 typically developing (TD) adults and 16 age-matched participants with ASD without co-occurring intellectual disability (ID). The DKI metrics included axonal water fraction (f axon) and intra-axonal diffusivity (D axon), which reflect axonal density and caliber, and extra-axonal radial (RDextra) and axial (ADextra) diffusivities, which reflect myelination and microstructural organization of the extracellular space. The relationships between DKI metrics and processing speed, a cognitive feature known to be impaired in ASD, were also examined. Results: ASD group had significantly decreased callosal f axon and D axon (p = .01 and p = .045), particularly in the midbody, isthmus, and splenium. Regression analysis showed that variation in DKI metrics, primarily in the mid and posterior callosal regions explained up to 70.7% of the variance in processing speed scores for TD (p = .001) but not for ASD (p > .05). Conclusion: Decreased DKI metrics suggested that ASD may be associated with axonal deficits such as reduced axonal caliber and density in the corpus callosum, especially in the mid and posterior callosal areas. These data suggest that impaired interhemispheric connectivity may contribute to decreased processing speed in ASD participants. En ligne : https://dx.doi.org/10.1186/s13229-018-0245-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice / R. T. MOLENHUIS in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 63 p. Titre : Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice Type de document : Texte imprimé et/ou numérique Auteurs : R. T. MOLENHUIS, Auteur ; Hilgo BRUINING, Auteur ; M. J. V. BRANDT, Auteur ; P. E. VAN SOLDT, Auteur ; H. J. ABU-TOAMIH ATAMNI, Auteur ; J. P. H. BURBACH, Auteur ; F. A. IRAQI, Auteur ; R. F. MOTT, Auteur ; M. J. H. KAS, Auteur Article en page(s) : 63 p. Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/*genetics  Genetics, Behavioral/*methods/standards  Genome-Wide Association Study/*methods/standards  Male  Mice  Mice, Inbred C57BL  Multifactorial Inheritance  Quantitative Trait Loci  Reference Standards  *Animal models  *Autism  *Behavioral neuroscience  *Genetic reference population  *Histamine 3 receptor  *Neurodevelopmental disorders  *Quantitative genetics  *Repetitive behavior  Care and Use Committee of Tel Aviv University.Not applicable.The authors declare  that they have no competing interests.Springer Nature remains neutral with regard  to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Animal models for neurodevelopmental disorders (NDD) generally rely on a single genetic mutation on a fixed genetic background. Recent human genetic studies however indicate that a clinical diagnosis with ASDAutism Spectrum Disorder (ASD) is almost always associated with multiple genetic fore- and background changes. The translational value of animal model studies would be greatly enhanced if genetic insults could be studied in a more quantitative framework across genetic backgrounds. Methods: We used the Collaborative Cross (CC), a novel mouse genetic reference population, to investigate the quantitative genetic architecture of mouse behavioral phenotypes commonly used in animal models for NDD. Results: Classical tests of social recognition and grooming phenotypes appeared insufficient for quantitative studies due to genetic dilution and limited heritability. In contrast, digging, locomotor activity, and stereotyped exploratory patterns were characterized by continuous distribution across our CC sample and also mapped to quantitative trait loci containing genes associated with corresponding phenotypes in human populations. Conclusions: These findings show that the CC can move animal model studies beyond comparative single gene-single background designs, and point out which type of behavioral phenotypes are most suitable to quantify the effect of developmental etiologies across multiple genetic backgrounds. En ligne : https://dx.doi.org/10.1186/s13229-018-0252-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice [Texte imprimé et/ou numérique] / R. T. MOLENHUIS, Auteur ; Hilgo BRUINING, Auteur ; M. J. V. BRANDT, Auteur ; P. E. VAN SOLDT, Auteur ; H. J. ABU-TOAMIH ATAMNI, Auteur ; J. P. H. BURBACH, Auteur ; F. A. IRAQI, Auteur ; R. F. MOTT, Auteur ; M. J. H. KAS, Auteur . - 63 p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 63 p. Mots-clés : Animals  Autism Spectrum Disorder/*genetics  Genetics, Behavioral/*methods/standards  Genome-Wide Association Study/*methods/standards  Male  Mice  Mice, Inbred C57BL  Multifactorial Inheritance  Quantitative Trait Loci  Reference Standards  *Animal models  *Autism  *Behavioral neuroscience  *Genetic reference population  *Histamine 3 receptor  *Neurodevelopmental disorders  *Quantitative genetics  *Repetitive behavior  Care and Use Committee of Tel Aviv University.Not applicable.The authors declare  that they have no competing interests.Springer Nature remains neutral with regard  to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Animal models for neurodevelopmental disorders (NDD) generally rely on a single genetic mutation on a fixed genetic background. Recent human genetic studies however indicate that a clinical diagnosis with ASDAutism Spectrum Disorder (ASD) is almost always associated with multiple genetic fore- and background changes. The translational value of animal model studies would be greatly enhanced if genetic insults could be studied in a more quantitative framework across genetic backgrounds. Methods: We used the Collaborative Cross (CC), a novel mouse genetic reference population, to investigate the quantitative genetic architecture of mouse behavioral phenotypes commonly used in animal models for NDD. Results: Classical tests of social recognition and grooming phenotypes appeared insufficient for quantitative studies due to genetic dilution and limited heritability. In contrast, digging, locomotor activity, and stereotyped exploratory patterns were characterized by continuous distribution across our CC sample and also mapped to quantitative trait loci containing genes associated with corresponding phenotypes in human populations. Conclusions: These findings show that the CC can move animal model studies beyond comparative single gene-single background designs, and point out which type of behavioral phenotypes are most suitable to quantify the effect of developmental etiologies across multiple genetic backgrounds. En ligne : https://dx.doi.org/10.1186/s13229-018-0252-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

The valproic acid rat model of autism presents with gut bacterial dysbiosis similar to that in human autism / F. LIU in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 61 p. Titre : The valproic acid rat model of autism presents with gut bacterial dysbiosis similar to that in human autism Type de document : Texte imprimé et/ou numérique Auteurs : F. LIU, Auteur ; K. HORTON-SPARKS, Auteur ; V. HULL, Auteur ; R. W. LI, Auteur ; V. MARTINEZ-CERDENO, Auteur Article en page(s) : 61 p. Langues : Anglais (eng) Mots-clés : Animals  Autistic Disorder/etiology/*microbiology  Bacterial Typing Techniques  Disease Models, Animal  Dysbiosis/etiology/*microbiology  *Gastrointestinal Microbiome  Rats  Rats, Sprague-Dawley  Valproic Acid/administration & dosage/toxicity Index. décimale : PER Périodiques Résumé : Background: Gut microbiota has the capacity to impact the regular function of the brain, which can in turn affect the composition of microbiota. Autism spectrum disorder (ASD) patients suffer from gastrointestinal problems and experience changes in gut microbiota; however, it is not yet clear whether the change in the microbiota associated with ASD is a cause or a consequence of the disease. Methods: We have investigated the species richness and microbial composition in a valproic acid (VPA)-induced rat model autism. Fecal samples from the rectum were collected at necropsy, microbial total DNA was extracted, 16 rRNA genes sequenced using Illumina, and the global microbial co-occurrence network was constructed using a random matrix theory-based pipeline. Collected rat microbiome data were compared to available data derived from cases of autism. Results: We found that VPA administration during pregnancy reduced fecal microbial richness, changed the gut microbial composition, and altered the metabolite potential of the fecal microbial community in a pattern similar to that seen in patients with ASD. However, the global network property and network composition as well as microbial co-occurrence patterns were largely preserved in the offspring of rats exposed to prenatal administration of VPA. Conclusions: Our data on the microbiota of the VPA rat model of autism indicate that this model, in addition to behaviorally and anatomically mimicking the autistic brain as previously shown, also mimics the microbiome features of autism, making it one of the best-suited rodent models for the study of autism and ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0251-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] The valproic acid rat model of autism presents with gut bacterial dysbiosis similar to that in human autism [Texte imprimé et/ou numérique] / F. LIU, Auteur ; K. HORTON-SPARKS, Auteur ; V. HULL, Auteur ; R. W. LI, Auteur ; V. MARTINEZ-CERDENO, Auteur . - 61 p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 61 p. Mots-clés : Animals  Autistic Disorder/etiology/*microbiology  Bacterial Typing Techniques  Disease Models, Animal  Dysbiosis/etiology/*microbiology  *Gastrointestinal Microbiome  Rats  Rats, Sprague-Dawley  Valproic Acid/administration & dosage/toxicity Index. décimale : PER Périodiques Résumé : Background: Gut microbiota has the capacity to impact the regular function of the brain, which can in turn affect the composition of microbiota. Autism spectrum disorder (ASD) patients suffer from gastrointestinal problems and experience changes in gut microbiota; however, it is not yet clear whether the change in the microbiota associated with ASD is a cause or a consequence of the disease. Methods: We have investigated the species richness and microbial composition in a valproic acid (VPA)-induced rat model autism. Fecal samples from the rectum were collected at necropsy, microbial total DNA was extracted, 16 rRNA genes sequenced using Illumina, and the global microbial co-occurrence network was constructed using a random matrix theory-based pipeline. Collected rat microbiome data were compared to available data derived from cases of autism. Results: We found that VPA administration during pregnancy reduced fecal microbial richness, changed the gut microbial composition, and altered the metabolite potential of the fecal microbial community in a pattern similar to that seen in patients with ASD. However, the global network property and network composition as well as microbial co-occurrence patterns were largely preserved in the offspring of rats exposed to prenatal administration of VPA. Conclusions: Our data on the microbiota of the VPA rat model of autism indicate that this model, in addition to behaviorally and anatomically mimicking the autistic brain as previously shown, also mimics the microbiome features of autism, making it one of the best-suited rodent models for the study of autism and ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0251-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

Assessing subtypes of restricted and repetitive behaviour using the Adult Repetitive Behaviour Questionnaire-2 in autistic adults / Sarah L. BARRETT in Molecular Autism, 9 (2018)  

Public ISBD [article]  Titre : Assessing subtypes of restricted and repetitive behaviour using the Adult Repetitive Behaviour Questionnaire-2 in autistic adults Type de document : Texte imprimé et/ou numérique Auteurs : Sarah L. BARRETT, Auteur ; M. ULJAREVIC, Auteur ; Catherine R. G. JONES, Auteur ; S. R. LEEKAM, Auteur Article en page(s) : 58 p. Langues : Anglais (eng) Mots-clés : Adolescent  Adult  Aged  Autistic Disorder/classification/*diagnosis  Female  Humans  Male  Middle Aged  *Stereotyped Behavior  Surveys and Questionnaires/*standards  *Adults  *Insistence on sameness  *Principal components analysis  *Questionnaire  *Repetitive behaviours  *Repetitive sensory and motor behaviours  the Cardiff University School of Psychology Research Ethics Committee  (EC.14.04.08.3784R2A3). All participants provided informed electronic consent  before taking part in the study.Not applicableThe authors declare that they have  no competing interests.Springer Nature remains neutral with regard to  jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: The majority of previous research into restricted and repetitive behaviours (RRBs) has focussed on children, partly due to a lack of suitable measures for RRBs in adults. This study aimed to explore the psychometric properties of the Adult Repetitive Behaviour Questionnaire-2 (RBQ-2A) in a large sample of autistic adults using a self-report questionnaire method. Methods: The RBQ-2A and Autism-Spectrum Quotient (AQ) were administered online. Data from 275 autistic adults aged 18-66 (M = 36.56, SD = 12.24; 100 men and 171 women) were analysed using polychoric principal components analysis (PCA). Reliability and validity were assessed using Cro