1. Aman MG, Findling RL, Hardan AY, Hendren RL, Melmed RD, Kehinde-Nelson O, Hsu HA, Trugman JM, Palmer RH, Graham SM, Gage AT, Perhach JL, Katz E. {{Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension}}. {J Child Adolesc Psychopharmacol};2016 (Mar 15)
OBJECTIVE: Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension. METHODS: A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day. RESULTS: There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks. CONCLUSIONS: This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.
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2. Casanova EL, Sharp JL, Chakraborty H, Sumi NS, Casanova MF. {{Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression}}. {Mol Autism};2016;7:18.
BACKGROUND: Intellectual disability (ID), autism, and epilepsy share frequent yet variable comorbidities with one another. In order to better understand potential genetic divergence underlying this variable risk, we studied genes responsible for monogenic IDs, grouped according to their autism and epilepsy comorbidities. METHODS: Utilizing 465 different forms of ID with known molecular origins, we accessed available genetic databases in conjunction with gene ontology (GO) to determine whether the genetics underlying ID diverge according to its comorbidities with autism and epilepsy and if genes highly penetrant for autism or epilepsy share distinctive features that set them apart from genes that confer comparatively variable or no apparent risk. RESULTS: The genetics of ID with autism are relatively enriched in terms associated with nervous system-specific processes and structural morphogenesis. In contrast, we find that ID with highly comorbid epilepsy (HCE) is modestly associated with lipid metabolic processes while ID without autism or epilepsy comorbidity (ID only) is enriched at the Golgi membrane. Highly comorbid autism (HCA) genes, on the other hand, are strongly enriched within the nucleus, are typically involved in regulation of gene expression, and, along with IDs with more variable autism, share strong ties with a core protein-protein interaction (PPI) network integral to basic patterning of the CNS. CONCLUSIONS: According to GO terminology, autism-related gene products are integral to neural development. While it is difficult to draw firm conclusions regarding IDs unassociated with autism, it is clear that the majority of HCA genes are tightly linked with general dysregulation of gene expression, suggesting that disturbances to the chronology of neural maturation and patterning may be key in conferring susceptibility to autism spectrum conditions.
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3. Falahpour M, Thompson WK, Abbott AE, Jahedi A, Mulvey ME, Datko M, Liu T, Muller RA. {{‘Underconnected’, but not broken? Dynamic fcMRI shows underconnectivity in autism is linked to increased intra-individual variability across time}}. {Brain Connect};2016 (Mar 14)
Autism spectrum disorder (ASD) is characterized by core sociocommunicative impairments. Atypical intrinsic functional connectivity (iFC) has been reported in numerous studies of ASD. A majority of findings has indicated long-distance underconnectivity. However, fMRI studies have thus far exclusively examined static iFC across several minutes of scanning. We examined temporal variability of iFC, using sliding window analyses in selected high-quality (low-motion) consortium datasets from 76 ASD and 76 matched typically developing (TD) participants (Study 1) and in-house data from 32 ASD and 32 TD participants. Mean iFC and standard deviation across time (SD-iFC) were computed for regions of interest from default mode and salience networks, as well as amygdalae and thalami. In both studies, ROI pairings with significant underconnectivity (ASD
4. Field SS. {{Nutrition and Autism: Intervention Compared with Identification}}. {Adv Nutr};2016 (Mar);7(2):420-421.
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5. Funabashi N, Takaoka H, Ozawa K, Tanabe N, Tatsumi K, Saeki N, Higashide T, Uno T, Kobayashi Y. {{Combined ostium secundum type ASD and pulmonary arterial thromboembolism causing pulmonary artery enlargement, pulmonary hypertension and recurrent paradoxical cerebral embolism due to deep venous thrombosis}}. {Int J Cardiol};2016 (Mar 15);207:303-307.
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6. Gangi DN, Messinger DS, Martin ER, Cuccaro ML. {{Dopaminergic variants in siblings at high risk for autism: Associations with initiating joint attention}}. {Autism Res};2016 (Mar 15)
Younger siblings of children with autism spectrum disorder (ASD; high-risk siblings) exhibit lower levels of initiating joint attention (IJA; sharing an object or experience with a social partner through gaze and/or gesture) than low-risk siblings of children without ASD. However, high-risk siblings also exhibit substantial variability in this domain. The neurotransmitter dopamine is linked to brain areas associated with reward, motivation, and attention, and common dopaminergic variants have been associated with attention difficulties. We examined whether these common dopaminergic variants, DRD4 and DRD2, explain variability in IJA in high-risk (n = 55) and low-risk (n = 38) siblings. IJA was assessed in the first year during a semi-structured interaction with an examiner. DRD4 and DRD2 genotypes were coded according to associated dopaminergic functioning to create a gene score, with higher scores indicating more genotypes associated with less efficient dopaminergic functioning. Higher dopamine gene scores (indicative of less efficient dopaminergic functioning) were associated with lower levels of IJA in the first year for high-risk siblings, while the opposite pattern emerged in low-risk siblings. Findings suggest differential susceptibility-IJA was differentially associated with dopaminergic functioning depending on familial ASD risk. Understanding genes linked to ASD-relevant behaviors in high-risk siblings will aid in early identification of children at greatest risk for difficulties in these behavioral domains, facilitating targeted prevention and intervention. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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7. Grabrucker S, Boeckers TM, Grabrucker AM. {{Gender Dependent Evaluation of Autism like Behavior in Mice Exposed to Prenatal Zinc Deficiency}}. {Front Behav Neurosci};2016;10:37.
Zinc deficiency has recently been linked to the etiology of autism spectrum disorders (ASD) as environmental risk factor. With an estimated 17% of the world population being at risk of zinc deficiency, especially zinc deficiency during pregnancy might be a common occurrence, also in industrialized nations. On molecular level, zinc deficiency has been shown to affect a signaling pathway at glutamatergic synapses that has previously been identified through genetic mutations in ASD patients, the Neurexin-Neuroligin-Shank pathway, via altering zinc binding Shank family members. In particular, prenatal zinc deficient but not acute zinc deficient animals have been reported to display autism like behavior in some behavioral tests. However, a full behavioral analysis of a possible autism like behavior has been lacking so far. Here, we performed an extensive behavioral phenotyping of mice born from mothers with mild zinc deficiency during all trimesters of pregnancy. Prenatal zinc deficient animals were investigated as adults and gender differences were assessed. Our results show that prenatal zinc deficient mice display increased anxiety, deficits in nest building and various social interaction paradigm, as well as mild alterations in ultrasonic vocalizations. A gender specific analysis revealed only few sex specific differences. Taken together, given that similar behavioral abnormalities as reported here are frequently observed in ASD mouse models, we conclude that prenatal zinc deficient animals even without specific genetic susceptibility for ASD, already show some features of ASD like behavior.
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8. Hedley D, Brewer N, Nevill R, Uljarevic M, Butter E, Mulick JA. {{The Relationship Between Clinicians’ Confidence and Accuracy, and the Influence of Child Characteristics, in the Screening of Autism Spectrum Disorder}}. {J Autism Dev Disord};2016 (Mar 15)
The study examined the confidence accuracy relationship, and the influence of child characteristics on clinician confidence, when predicting a diagnosis of Autism Spectrum Disorder during screening of 125 referred children aged under 3.5 years. The diagnostic process included observation, interview, language and developmental testing. Clinical judgement accuracy was compared against final diagnosis for high and low confidence levels (with confidence assessed on a 0-100 % scale). We identified a significant CA relationship with predictive accuracy highest at confidence levels of 90-100 %. Parent report of unusual behaviors was the only significant independent predictor of confidence. Clinicians’ confidence may be important when evaluating decisions to refer, or not to refer, children for further diagnostic assessment.
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9. Jones EJ, Venema K, Earl R, Lowy R, Barnes K, Estes A, Dawson G, Webb SJ. {{Reduced engagement with social stimuli in 6-month-old infants with later autism spectrum disorder: a longitudinal prospective study of infants at high familial risk}}. {J Neurodev Disord};2016;8:7.
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1 % of the population and close to 20 % of prospectively studied infants with an older sibling with ASD. Although significant progress has been made in characterizing the emergence of behavioral symptoms of ASD, far less is known about the underlying disruptions to early learning. Recent models suggest that core aspects of the causal path to ASD may only be apparent in early infancy. Here, we investigated social attention in 6- and 12-month-old infants who did and did not meet criteria for ASD at 24 months using both cognitive and electrophysiological methods. We hypothesized that a reduction in attention engagement to faces would be associated with later ASD. METHODS: In a prospective longitudinal design, we used measures of both visual attention (habituation) and brain function (event-related potentials to faces and objects) at 6 and 12 months and investigated the relationship to ASD outcome at 24 months. RESULTS: High-risk infants who met criteria for ASD at 24 months showed shorter epochs of visual attention, faster but less prolonged neural activation to faces, and delayed sensitization responses (increases in looking) to faces at 6 months; these differences were less apparent at 12 months. These findings are consistent with disrupted engagement of sustained attention to social stimuli. CONCLUSIONS: These findings suggest that there may be fundamental early disruptions to attention engagement that may have cascading consequences for later social functioning.
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10. Kugelberg E. {{Neuroimmunology: IL-17A mediates a path to autism}}. {Nat Rev Immunol};2016 (Mar 14)
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11. Ruparelia K, Abubakar A, Badoe E, Bakare M, Visser K, Chugani DC, Chugani HT, Donald KA, Wilmshurst JM, Shih A, Skuse D, Newton CR. {{Autism Spectrum Disorders in Africa: Current Challenges in Identification, Assessment, and Treatment: A Report on the International Child Neurology Association Meeting on ASD in Africa, Ghana, April 3-5, 2014}}. {J Child Neurol};2016 (Mar 15)
Prevalence of autism spectrum disorders has increased over recent years, however, little is known about the identification and management of autism spectrum disorder in Africa. This report summarizes a workshop on autism spectrum disorder in Africa under the auspices of the International Child Neurology Association and the African Child Neurology Association through guided presentations and working group reports, focusing on identification, diagnosis, management, and community support. A total of 47 delegates participated from 14 African countries. Although there was a huge variability in services across the countries represented, numbers of specialists assessing and managing autism spectrum disorder was small relative to populations served. Strategies were proposed to improve identification, diagnosis, management and support delivery for individuals with autism spectrum disorder across Africa in these culturally diverse, low-resource settings. Emphasis on raising public awareness through community engagement and improving access to information and training in autism spectrum disorder. Special considerations for the cultural, linguistic, and socioeconomic factors within Africa are discussed.
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12. Shireman ML, Lerman DC, Hillman CB. {{Teaching social play skills to adults and children with autism as an approach to building rapport}}. {J Appl Behav Anal};2016 (Mar 15)
Adults with autism spectrum disorder (ASD) and no intellectual disabilities were taught to increase the social play skills of children with ASD as part of a vocational training program. Participants included 3 adults, aged 21 to 27 years, and 6 children with ASD. Probes conducted throughout the study evaluated whether play skills training affected a measure of rapport between the adult and child. Results demonstrated the effectiveness of behavioral skills training for teaching the adult participants the appropriate play skills. In addition, the children’s social engagement increased. Finally, rapport probes showed that play skills training increased levels of proximity, our measure of rapport, between the adults and children.
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13. Takechi K, Suemaru K, Kiyoi T, Tanaka A, Araki H. {{The alpha4beta2 nicotinic acetylcholine receptor modulates autism-like behavioral and motor abnormalities in pentylenetetrazol-kindled mice}}. {Eur J Pharmacol};2016 (Mar 15);775:57-66.
Epilepsy is associated with several psychiatric disorders, including cognitive impairment, autism and attention deficit/hyperactivity disorder (ADHD). However, the psychopathology of epilepsy is frequently unrecognized and untreated in patients. In the present study, we investigated the effects of ABT-418, a neuronal nicotinic acetylcholine receptor agonist, on pentylenetetrazol (PTZ)-kindled mice with behavioral and motor abnormalities. PTZ-kindled mice displayed impaired motor coordination (in the rotarod test), anxiety (in the elevated plus maze test) and social approach impairment (in the three-chamber social test) compared with control mice. ABT-418 treatment (0.05mg/kg, intraperitoneally) alleviated these behavioral abnormalities in PTZ-kindled mice. Immunolabeling of tissue sections demonstrated that expression of the alpha4 nicotinic acetylcholine receptor subunit in the medial habenula was similar in control and PTZ-kindled mice. However, expression was significantly decreased in the piriform cortex in PTZ-kindled mice. In addition, we examined the expression of the synaptic adhesion molecule neuroligin 3 (NLG3). NLG3 expression in the piriform cortex was significantly higher in PTZ-kindled mice compared with control mice. Collectively, our findings suggest that ADHD-like or autistic-like behavioral abnormalities associated with epilepsy are closely related to the downregulation of the alpha4 nicotinic receptor and the upregulation of NLG3 in the piriform cortex. In summary, this study indicates that ABT-418 might have therapeutic potential for attentional impairment in epileptic patients with psychiatric disorders such as autism and ADHD.
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14. Zafar R, Hsiao EY, Botteron KN, McKinstry RC, Gutmann DH. {{De novo development of gliomas in a child with neurofibromatosis type 1, fragile X and previously normal brain magnetic resonance imaging}}. {Radiol Case Rep};2016 (Mar);11(1):33-35.
Fifteen to 20% of children with neurofibromatosis type 1 develop low-grade glial neoplasms. However, since neuroimaging is not routinely obtained until a child is clinically symptomatic, little is known about presymptomatic radiographic characteristics of gliomas in this at-risk population. Herein, we describe a child with neurofibromatosis type 1 who initially had normal brain imaging before the development of multifocal gliomas. Comparison of these serial images demonstrated that brain tumors can arise de novo in children with this cancer predisposition syndrome, further underscoring the limited prognostic value of normal baseline magnetic resonance imaging.
