1. Arnold LE, Aman MG, Hollway J, Hurt E, Bates B, Li X, Farmer C, Anand R, Thompson S, Ramadan Y, Williams C. {{Placebo-Controlled Pilot Trial of Mecamylamine for Treatment of Autism Spectrum Disorders}}. {J Child Adolesc Psychopharmacol}. 2012.
Abstract Objective: To explore possible benefits of a nicotinic acetylcholine receptor (nAChR) agent for autistic symptoms based on postmortem observation of nAChR abnormalities (deficient alpha4beta2 nAChRs, excess alpha7 nAChRs) in brains of patients with autism. Method: Mecamylamine, because of its safety record in children with other disorders, was chosen for this first exploration. Twenty children with autism spectrum disorder age 4-12 years were randomly assigned for 14 weeks to placebo (n=8) or mecamylamine (n=12) in ascending fixed doses: 0.5 mg/day for 6 weeks, 2.5 mg for 2 weeks, then 5 mg/day for 6 weeks. Improvement was rated by a blinded independent evaluator. Because of small sample, data analysis was descriptive. Results: Eighteen participants (10 mecamylamine, 8 placebo) completed the study. All doses were well tolerated; the only side effect of note was constipation (50% compared with 25% of placebo group). Three children had clinically nonsignificant electrocardiographic QT prolongation. Both groups showed modest to moderate improvement, but differences between groups were negligible. On the primary outcome measure, the Ohio Autism Clinical Impressions Scale, 90% of the active treatment group showed improvement at some point (but only 40% sustained it), compared with 62% on placebo. Of the four in active treatment that sustained improvement, three had a maximum dose of 0.13-0.15 mg/kg/day, while those who regressed had doses >/=0.18 mg/kg/day. Graphed means suggested better outcome with lower mg/kg and longer medication duration. Four parents spontaneously reported reduced hyperactivity and irritability and better verbalization and continued mecamylamine at their own expense. Conclusion: Mecamylamine appeared to be safe, but not very effective in autism. The suggestion of better results at lower doses and longer exposure warrants consideration for future trials. The next step would be exploration of a more specific alpha4beta2 nAChR agonist, such as varenicline.
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2. Corley MJ, Meyza KZ, Blanchard DC, Blanchard RJ. {{Reduced sulfate plasma concentrations in the BTBR T+tf/J mouse model of autism}}. {Physiol Behav}. 2012.
Clinical studies have shown that children diagnosed with autism show abnormal sulfate chemistry, which is critical for cellular and metabolic processes. To determine if the inbred BTBR T+tf/J mouse shows autism-relevant aberrations in sulfate chemistry, the present study examined plasma sulfate concentrations in BTBR T+tf/J, inbred C57BL/6J, and outbred CD-1 mice. Results showed that the BTBR T+tf/J mouse exhibits significantly lower plasma sulfate concentrations in comparison to both C57BL/6J and CD-1 mice. These results suggest that the BTBR mouse shows autism-relevant abnormalities in sulfate chemistry and may serve additional utility in examining the role of sulfate and sulfate-dependent systems in relation to autism-relevant behavioral aberrations.
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3. Fung LK, Chahal L, Libove RA, Bivas R, Hardan AY. {{A Retrospective Review of the Effectiveness of Aripiprazole in the Treatment of Sensory Abnormalities in Autism}}. {J Child Adolesc Psychopharmacol}. 2012.
Abstract Although sensory deficits are frequently observed in autistic individuals, pharmacologic interventions targeting these abnormalities are lacking. The goal of this investigation was to assess the effectiveness of aripiprazole in targeting sensory deficits in children and adolescents with autism. Using an outpatient clinic registry for pervasive developmental disorder, 13 individuals who had received aripiprazole for treating disruptive behaviors and had completed behavioral rating scales (aberrant behavior checklist [ABC] and sensory profile questionnaire [SPQ]) were identified. Mean treatment duration was 24.4 weeks with a mean final aripiprazole dosage of 10.8 mg. Aripiprazole yielded improvements in the total ABC and in several items of the SPQ including registration, inattention/distractibility, auditory processing, and modulation of visual input affecting emotional responses and activity level, suggesting that aripiprazole might be beneficial in targeting sensory abnormalities in autism.
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4. Kalb LG, Cohen C, Lehmann H, Law P. {{Survey non-response in an internet-mediated, longitudinal autism research study}}. {J Am Med Inform Assoc}. 2012.
ObjectiveTo evaluate non-response rates to follow-up online surveys using a prospective cohort of parents raising at least one child with an autism spectrum disorder. A secondary objective was to investigate predictors of non-response over time.Materials and MethodsData were collected from a US-based online research database, the Interactive Autism Network (IAN). A total of 19 497 youths, aged 1.9-19 years (mean 9 years, SD 3.94), were included in the present study. Response to three follow-up surveys, solicited from parents after baseline enrollment, served as the outcome measures. Multivariate binary logistic regression models were then used to examine predictors of non-response.Results31 216 survey instances were examined, of which 8772 or 28.1% were partly or completely responded to. Results from the multivariate model found non-response of baseline surveys (OR 28.0), years since enrollment in the online protocol (OR 2.06), and numerous sociodemographic characteristics were associated with non-response to follow-up surveys (all p<0.05).DiscussionConsistent with the current literature, response rates to online surveys were somewhat low. While many demographic characteristics were associated with non-response, time since registration and participation at baseline played the greatest role in predicting follow-up survey non-response.ConclusionAn important hazard to the generalizability of findings from research is non-response bias; however, little is known about this problem in longitudinal internet-mediated research (IMR). This study sheds new light on important predictors of longitudinal response rates that should be considered before launching a prospective IMR study.
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5. Mellios N, Sur M. {{The Emerging Role of microRNAs in Schizophrenia and Autism Spectrum Disorders}}. {Front Psychiatry}. 2012; 3: 39.
MicroRNAs (miRNAs) are small non-coding RNAs conserved throughout evolution whose perceived importance for brain development and maturation is increasingly being understood. Although a plethora of new discoveries have provided novel insights into miRNA-mediated molecular mechanisms that influence brain plasticity, their relevance for neuropsychiatric diseases with known deficits in synaptic plasticity, such as schizophrenia and autism, has not been adequately explored. In this review we discuss the intersection between current and old knowledge on the role of miRNAs in brain plasticity and function with a focus in the potential involvement of brain expressed miRNAs in the pathophysiology of neuropsychiatric disorders.
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6. Naber FB, Poslawsky IE, van Ijzendoorn MH, van Engeland H, Bakermans-Kranenburg MJ. {{Brief Report: Oxytocin Enhances Paternal Sensitivity to a Child with Autism: A Double-Blind Within-Subject Experiment with Intranasally Administered Oxytocin}}. {J Autism Dev Disord}. 2012.
Oxytocin seems associated with parenting style, and experimental work showed positive effects of intranasally administered oxytocin on parenting style of fathers. Here, the first double-blind, placebo-controlled, within-subject experiment with intranasal oxytocin administration to fathers of children with autism spectrum disorder (ASD) is presented. Fathers with their typically developing toddler (n = 18), and fathers of toddlers diagnosed with ASD (n = 14), were observed in two play sessions of 15 min each with an intervening period of 1 week. In all fathers oxytocin elevated the quality of paternal sensitive play: fathers stimulated their child in a more optimal way, and they showed less hostility which suggests the positive effects of oxytocin on paternal sensitive play irrespective of clinical status of their child.
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7. Niere F, Wilkerson JR, Huber KM. {{Evidence for a fragile x mental retardation protein-mediated translational switch in metabotropic glutamate receptor-triggered arc translation and long-term depression}}. {J Neurosci}. 2012; 32(17): 5924-36.
Group 1 metabotropic glutamate receptor (mGluR)-stimulated protein synthesis and long-term synaptic depression (mGluR-LTD) are altered in the mouse model of fragile X syndrome, Fmr1 knock-out (KO) mice. Fmr1 encodes fragile X mental retardation protein (FMRP), a dendritic RNA binding protein that functions, in part, as a translational suppressor. It is unknown whether and how FMRP acutely regulates LTD and/or the rapid synthesis of new proteins required for LTD, such as the activity-regulated cytoskeletal-associated protein (Arc). The protein phosphatase PP2A dephosphorylates FMRP, which contributes to translational activation of some target mRNAs. Here, we report that PP2A and dephosphorylation of FMRP at S500 are required for an mGluR-induced, rapid (5 min) increase in dendritic Arc protein and LTD in rat and mouse hippocampal neurons. In Fmr1 KO neurons, basal, dendritic Arc protein levels and mGluR-LTD are enhanced, but mGluR-triggered Arc synthesis is absent. Lentiviral-mediated expression of wild-type FMRP in Fmr1 KO neurons suppresses basal dendritic Arc levels and mGluR-LTD, and restores rapid mGluR-triggered Arc synthesis. A phosphomimic of FMRP (S500D) suppresses steady-state dendritic Arc levels but does not rescue mGluR-induced Arc synthesis. A dephosphomimic of FMRP (S500A) neither suppresses dendritic Arc nor supports mGluR-induced Arc synthesis. Accordingly, S500D-FMRP expression in Fmr1 KO neurons suppresses mGluR-LTD, whereas S500A-FMRP has no effect. These data support a model in which phosphorylated FMRP functions to suppress steady-state translation of Arc and LTD. Upon mGluR activation of PP2A, FMRP is rapidly dephosphorylated, which contributes to rapid new synthesis of Arc and mGluR-LTD.
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8. Salgueiro E, Nunes L, Barros A, Maroco J, Salgueiro AI, Dos Santos ME. {{Effects of a dolphin interaction program on children with autism spectrum disorders – an exploratory research}}. {BMC Res Notes}. 2012; 5(1): 199.
ABSTRACT: BACKGROUND: Interaction programs involving dolphins and patients with various pathologies or developmental disorders (e.g., cerebral palsy, intellectual impairment, autism, atopic dermatitis, post-traumatic stress disorder, depression) have stimulated interest in their beneficial effects and therapeutic potential. However, the true effects observed in different clinical and psycho-educational setups are still controversial. RESULTS: An evaluation protocol consisting of the Childhood Autism Rating Scale (CARS), Psychoeducational Profile-Revised (PEP-R), Autism Treatment Evaluation Checklist (ATEC), Theory of Mind Tasks (ToM Tasks) and a custom-made Interaction Evaluation Grid (IEG) to evaluate behavioural complexity during in-pool interactions was applied to 10 children diagnosed with Autism Spectrum Disorders. The ATEC, ToM Tasks and CARS results show no benefits of the dolphin interaction program. Interestingly, the PEP-R suggests some statistically significant effects on ‘Overall development score’, as well as on their ‘Fine motor development’, ‘Cognitive performance’ and ‘Cognitive verbal development’. Also, a significant evolution in behavioural complexity was shown by the IEG. CONCLUSIONS: This study does not support significant developmental progress resulting from the dolphin interaction program.
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9. Silverman JL, Smith DG, Rizzo SJ, Karras MN, Turner SM, Tolu SS, Bryce DK, Smith DL, Fonseca K, Ring RH, Crawley JN. {{Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism}}. {Sci Transl Med}. 2012; 4(131): 131ra51.
Neurodevelopmental disorders such as autism and fragile X syndrome were long thought to be medically untreatable, on the assumption that brain dysfunctions were immutably hardwired before diagnosis. Recent revelations that many cases of autism are caused by mutations in genes that control the ongoing formation and maturation of synapses have challenged this dogma. Antagonists of metabotropic glutamate receptor subtype 5 (mGluR5), which modulate excitatory neurotransmission, are in clinical trials for fragile X syndrome, a major genetic cause of intellectual disabilities. About 30% of patients with fragile X syndrome meet the diagnostic criteria for autism. Reasoning by analogy, we considered the mGluR5 receptor as a potential target for intervention in autism. We used BTBR T+tf/J (BTBR) mice, an established model with robust behavioral phenotypes relevant to the three diagnostic behavioral symptoms of autism-unusual social interactions, impaired communication, and repetitive behaviors-to probe the efficacy of a selective negative allosteric modulator of the mGluR5 receptor, GRN-529. GRN-529 reduced repetitive behaviors in three cohorts of BTBR mice at doses that did not induce sedation in control assays of open field locomotion. In addition, the same nonsedating doses reduced the spontaneous stereotyped jumping that characterizes a second inbred strain of mice, C58/J. Further, GRN-529 partially reversed the striking lack of sociability in BTBR mice on some parameters of social approach and reciprocal social interactions. These findings raise the possibility that a single targeted pharmacological intervention may alleviate multiple diagnostic behavioral symptoms of autism.
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10. Smith M, Flodman PL, Gargus JJ, Simon MT, Verrell K, Haas R, Reiner GE, Naviaux R, Osann K, Spence MA, Wallace DC. {{Mitochondrial and ion channel gene alterations in autism}}. {Biochim Biophys Acta}. 2012.
To evaluate the potential importance in autistic subjects of copy number variants (CNVs) that alter genes of relevance to bioenergetics, ionic metabolism, and synaptic function, we conducted a detailed microarray analysis of 69 autism probands and 35 parents, compared to 89 CEU HapMap controls. This revealed that the frequency CNVs of>/=100kb and CNVs of>/=10 Kb were markedly increased in probands over parents and in probands and parents over controls. Evaluation of CNVs>/=1Mb by chromosomal FISH confirmed the molecular identity of a subset of the CNVs, some of which were associated with chromosomal rearrangements. In a number of the cases, CNVs were found to alter the copy number of genes that are important in mitochondrial oxidative phosphorylation (OXPHOS), ion and especially calcium transport, and synaptic structure. Hence, autism might result from alterations in multiple bioenergetic and metabolic genes required for mental function. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012).
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11. Testa C, Nuti F, Hayek J, De Felice C, Chelli M, Rovero P, Latini G, Papini AM. {{Di(2-ethylhexyl)phthalate and Autism Spectrum Disorders}}. {ASN Neuro}. 2012.
Autism spectrum disorders (ASDs) are a complex group of neurodevelopment disorders, still poorly understood, steadily rising in frequency, and treatment-refractory. Extensive research has been so far unable to explain the aetiology of this condition, whereas a growing body of evidence suggests the involvement of environmental factors. Phthalates, given their extensive use and their persistence, are ubiquitous environmental contaminants. They are endocrine-disrupting chemicals suspected to interfere with neurodevelopment. Therefore, they represent interesting candidate risk factors for ASDs pathogenesis. Aim of this study was to evaluate the levels of the primary and secondary metabolites of the di(2-ethylhexyl)phthalate (DEHP) in children with ASDs. A total of 48 children with ASDs [M: 36, F: 12; mean age: 11 years +/- 5 years] and 45 age and sex comparable healthy controls (HCs, M: 25, F: 20; mean age: 12 years+/- 5 years) were enrolled. A diagnostic methodology, based on the determination of urinary concentrations of DEHP metabolites by HPLC-ESI-MS, was applied to urine spot samples. MEHP, 6-OH-MEHP, 5-OH-MEHP, and 5-oxo-MEHP were measured and compared to unequivocally characterised, pure synthetic compounds (<98%) taken as standards. In ASDs patients, significantly increased 5-OH-MEHP (52.1%, median 0.18) and 5-oxo-MEHP (46.0%, median 0.096) urinary concentrations were detected, with a significant positive correlation between 5-OH-MEHP and 5-oxo-MEHP (rs = 0.668, p < 0.0001). The fully oxidised form 5-oxo-MEHP showed 91.1% specificity in identifying patients with ASDs. Our findings, demonstrate for the first time an association between phthalates exposure and ASDs, thus suggesting a previously unrecognized role for these ubiquitous environmental contaminants in the pathogenesis of autism.
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12. van Steijn DJ, Richards JS, Oerlemans AM, de Ruiter SW, van Aken MA, Franke B, Buitelaar JK, Rommelse NN. {{The co-occurrence of autism spectrum disorder and attention-deficit/hyperactivity disorder symptoms in parents of children with ASD or ASD with ADHD}}. {J Child Psychol Psychiatry}. 2012.
Background: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) share about 50-72% of their genetic factors, which is the most likely explanation for their frequent co-occurrence within the same patient or family. An additional or alternative explanation for the co-occurrence may be (cross-)assortative mating, e.g., the tendency to choose a partner that is similar or dissimilar to oneself. Another issue is that of parent-of-origin effect which refers to the possibility of parents differing in the relative quantity of risk factors they transmit to the offspring. The current study sets out to examine (cross-)assortative mating and (cross-)parent-of-origin effects of ASD and ADHD in parents of children with either ASD or ASD with ADHD diagnosis. Methods: In total, 121 families were recruited in an ongoing autism-ADHD family genetics project. Participating families consisted of parents and at least one child aged between 2 and 20 years, with either autistic disorder, Asperger disorder or PDD-NOS, and one or more biological siblings. All children and parents were carefully screened for the presence of ASD and ADHD. Results: No correlations were found between maternal and paternal ASD and ADHD symptoms. Parental ASD and ADHD symptoms were predictive for similar symptoms in the offspring, but with maternal hyperactive-impulsive symptoms, but not paternal symptoms, predicting similar symptoms in daughters. ASD pathology in the parents was not predictive for ADHD pathology in the offspring, but mother’s ADHD pathology was predictive for offspring ASD pathology even when corrected for maternal ASD pathology. Conclusions: Cross-assortative mating for ASD and ADHD does not form an explanation for the frequent co-occurrence of these disorders within families. Given that parental ADHD is predictive of offspring’ ASD but not vice versa, risk factors underlying ASD may overlap to a larger degree with risk factors underlying ADHD than vice versa. However, future research is needed to clarify this issue.
