1. Adornetti I, Chiera A, Deriu V, Altavilla D, Lucentini S, Marini A, Valeri G, Magni R, Vicari S, Ferretti F. {{An investigation of visual narrative comprehension in children with autism spectrum disorders}}. {Cognitive processing}. 2020.
The present study analyzed the comprehension of visual narrative in a group of twelve children with autism spectrum disorders (ASD). Their performances were compared to a control group of fifteen children with typical development (TD) matched for age, level of formal education, and IQ. Visual narrative comprehension was assessed by administering a task that required children to understand narrative’s global coherence by arranging in the correct order the constituent parts of stories presented in pictures. Specifically, the task evaluated children’s ability to grasp how single events connected (causally and temporally) each other and how these connections led to the ending of the story. Results showed that children with ASD obtained significantly lower scores than children with TD. These results open to alternative interpretations of narrative impairments often reported in individuals with ASD, which might not be restricted to the linguistic code but stem from a deeper deficit in narrative processing that is independent from the expressive modality.
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2. Ahn Y, Sabouny R, Villa BR, Yee NC, Mychasiuk R, Uddin GM, Rho JM, Shutt TE. {{Aberrant Mitochondrial Morphology and Function in the BTBR Mouse Model of Autism Is Improved by Two Weeks of Ketogenic Diet}}. {International journal of molecular sciences}. 2020; 21(9).
Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder that exhibits a common set of behavioral and cognitive impairments. Although the etiology of ASD remains unclear, mitochondrial dysfunction has recently emerged as a possible causative factor underlying ASD. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that augments mitochondrial function, and has been shown to reduce autistic behaviors in both humans and in rodent models of ASD. The aim of the current study was to examine mitochondrial bioenergetics in the BTBR mouse model of ASD and to determine whether the KD improves mitochondrial function. We also investigated changes in mitochondrial morphology, which can directly influence mitochondrial function. We found that BTBR mice had altered mitochondrial function and exhibited smaller more fragmented mitochondria compared to C57BL/6J controls, and that supplementation with the KD improved both mitochondrial function and morphology. We also identified activating phosphorylation of two fission proteins, pDRP1(S616) and pMFF(S146), in BTBR mice, consistent with the increased mitochondrial fragmentation that we observed. Intriguingly, we found that the KD decreased pDRP1(S616) levels in BTBR mice, likely contributing to the restoration of mitochondrial morphology. Overall, these data suggest that impaired mitochondrial bioenergetics and mitochondrial fragmentation may contribute to the etiology of ASD and that these alterations can be reversed with KD treatment.
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3. Cupaioli FA, Mosca E, Magri C, Gennarelli M, Moscatelli M, Raggi ME, Landini M, Galluccio N, Villa L, Bonfanti A, Renieri A, Fallerini C, Minelli A, Marabotti A, Milanesi L, Fasano A, Mezzelani A. {{Assessment of haptoglobin alleles in autism spectrum disorders}}. {Sci Rep}. 2020; 10(1): 7758.
Gene-environment interactions, by means of abnormal macromolecular intestinal adsorption, is one of the possible causes of autism spectrum disorders (ASD) predominantly in patients with gastrointestinal disorders. Pre-haptoglobin-2 (zonulin), encoded by the Haptoglobin (HP) allele-2 gene, enhances the intestinal permeability by modulation of intercellular tight junctions. The two alleles of HP, HP1 and HP2, differ for 2 extra exons in HP2 that result in exon duplication undetectable by classic genome-wide association studies. To evaluate the role of HP2 in ASD pathogenesis and to set up a method to discriminate HP alleles, Italian subjects with ASD (n = 398) and healthy controls (n = 379) were genotyped by PCR analysis; subsequently, the PCR results were integrated with microarray genotypes (Illumina Human Omni 1S-8), obtained using a subset from the same subjects, and then we developed a computational method to predict HP alleles. On the contrary to our expectations, there was no association between HP2 and ASD (P > 0.05), and there was no significant allele association in subjects with ASD with or without gastrointestinal disorders (P > 0.05). With the aid of bioinformatics analysis, from a window frame of ~2 Mb containing 314 SNPs, we obtain imputation accuracy (r(2)) between 0.4 and 0.9 (median 0.7) and correct predictions were between 70% and 100% (median 90%). The conclusions endorse that enhanced intestinal permeability in subjects with ASD should not be imputed to HP2 but to other members of the zonulin family and/or to environmental factors.
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4. Dawson PA, Lee S, Ewing AD, Prins JB, Heussler HS. {{Whole genome investigation of an atypical autism case identifies a novel ANOS1 mutation with subsequent diagnosis of Kallmann syndrome}}. {Molecular genetics and metabolism reports}. 2020; 23: 100593.
We report an actionable secondary finding from whole-genome sequencing (WGS) of a 10-year-old boy with autism. WGS identified non-synonymous variants in several genes, including a nonsense mutation in the ANOS1 gene which is an X-linked cause of Kallmann syndrome. WGS can provide insights into complex genetic disorders such as autism, and actionable incidental findings can offer the potential for therapeutic interventions.
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5. Dietz PM, Rose CE, McArthur D, Maenner M. {{National and State Estimates of Adults with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2020.
U.S. national and state population-based estimates of adults living with autism spectrum disorder (ASD) are nonexistent due to the lack of existing surveillance systems funded to address this need. Therefore, we estimated national and state prevalence of adults 18-84 years living with ASD using simulation in conjunction with Bayesian hierarchal models. In 2017, we estimated that approximately 2.21% (95% simulation interval (SI) 1.95%, 2.45%) or 5,437,988 U.S. adults aged 18 and older have ASD, with state prevalence ranging from 1.97% (95% SI 1.55%, 2.45%) in Louisiana to 2.42% (95% SI 1.93%, 2.99%) in Massachusetts. Prevalence and case estimates of adults living with ASD (diagnosed and undiagnosed) can help states estimate the need for diagnosing and providing services to those unidentified.
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6. Exley C, Clarkson E. {{Aluminium in human brain tissue from donors without neurodegenerative disease: A comparison with Alzheimer’s disease, multiple sclerosis and autism}}. {Sci Rep}. 2020; 10(1): 7770.
A burgeoning number of studies are demonstrating aluminium in human brain tissue. While research has both quantified and imaged aluminium in human brain tissue in neurodegenerative and neurodevelopmental disease there are few similar data for brain tissue from non-neurologically impaired donors. We have used microwave assisted acid digestion and transversely heated graphite furnace atomic absorption spectrometry to measure aluminium in twenty brains from donors without recognisable neurodegenerative disease. The aluminium content of 191 tissue samples was invariably low with over 80% of tissues having an aluminium content below 1.0 mug/g dry weight of tissue. The data for these control tissues were compared with data (measured using identical procedures) for sporadic Alzheimer’s disease, familial Alzheimer’s disease, autism spectrum disorder and multiple sclerosis. Detailed statistical analyses showed that aluminium was significantly increased in each of these disease groups compared to control tissues. We have confirmed previous conclusions that the aluminium content of brain tissue in Alzheimer’s disease, autism spectrum disorder and multiple sclerosis is significantly elevated. Further research is required to understand the role played by high levels of aluminium in the aetiology of human neurodegenerative and neurodevelopmental disease.
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7. Frasca A, Spiombi E, Palmieri M, Albizzati E, Valente MM, Bergo A, Leva B, Kilstrup-Nielsen C, Bianchi F, Di Carlo V, Di Cunto F, Landsberger N. {{MECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disorders}}. {EMBO molecular medicine}. 2020: e10270.
Mutations in MECP2 cause several neurological disorders of which Rett syndrome (RTT) represents the best-defined condition. Although mainly working as a transcriptional repressor, MeCP2 is a multifunctional protein revealing several activities, the involvement of which in RTT remains obscure. Besides being mainly localized in the nucleus, MeCP2 associates with the centrosome, an organelle from which primary cilia originate. Primary cilia function as « sensory antennae » protruding from most cells, and a link between primary cilia and mental illness has recently been reported. We herein demonstrate that MeCP2 deficiency affects ciliogenesis in cultured cells, including neurons and RTT fibroblasts, and in the mouse brain. Consequently, the cilium-related Sonic Hedgehog pathway, which is essential for brain development and functioning, is impaired. Microtubule instability participates in these phenotypes that can be rescued by HDAC6 inhibition together with the recovery of RTT-related neuronal defects. Our data indicate defects of primary cilium as a novel pathogenic mechanism that by contributing to the clinical features of RTT might impact on proper cerebellum/brain development and functioning, thus providing a novel therapeutic target.
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8. Geryk J, Krsicka D, Vlckova M, Havlovicova M, Macek M, Jr., Kremlikova Pourova R. {{The Key Role of Purine Metabolism in the Folate-Dependent Phenotype of Autism Spectrum Disorders: An In Silico Analysis}}. {Metabolites}. 2020; 10(5).
Folate deficiency in the critical developmental period has been repeatedly associated with an increased risk of Autism spectrum disorders (ASD), but the key pathophysiological mechanism has not yet been identified. In this work, we focused on identifying genes whose defect has similar consequences to folate depletion in the metabolic network. Within the Flux Balance Analysis (FBA) framework, we developed a method of blocked metabolites that allowed us to define the metabolic consequences of various gene defects and folate depletion. We identified six genes (GART, PFAS, PPAT, PAICS, ATIC, and ADSL) whose blocking results in nearly the same effect in the metabolic network as folate depletion. All of these genes form the purine biosynthetic pathway. We found that, just like folate depletion, the blockade of any of the six genes mentioned above results in a blockage of purine metabolism. We hypothesize that this can lead to decreased adenosine triphosphate (ATP) and subsequently, an S-adenosyl methionine (SAM) pool in neurons in the case of rapid cell division. Based on our results, we consider the methylation defect to be a potential cause of ASD, due to the depletion of purine, and consequently S-adenosyl methionine (SAM), biosynthesis.
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9. Jalambadani Z. {{Art therapy based on painting therapy on the improvement of autistic children’s social interactions in Iran}}. {Indian journal of psychiatry}. 2020; 62(2): 218-9.
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10. Kanne SM, Bishop SL. {{Editorial Perspective: The autism waitlist crisis and remembering what families need}}. {J Child Psychol Psychiatry}. 2020.
Differential diagnosis of autism is very complex. Best practice guidelines in the US encourage the use of specialized tools by a highly trained provider. The need for this comprehensive evaluation, coupled with the increase in autism prevalence and awareness, has led to alarmingly long wait times for diagnostic evaluations. Several solutions are currently being researched to remedy this problem and relieve the pressure, including testing new devices or procedures that can speed up the diagnostic process. Creative solutions are welcomed; however, we urge caution in the use of new devices and methods without being fully vetted. Moreover, a quality assessment provides much more than just a designation of whether or not autism is present. Thus, even in cases when alternative means could be used to more quickly arrive at a diagnosis, a comprehensive assessment with a trained clinician is needed to guide recommendations and ongoing care.
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11. Pangrazzi L, Balasco L, Bozzi Y. {{Oxidative Stress and Immune System Dysfunction in Autism Spectrum Disorders}}. {International journal of molecular sciences}. 2020; 21(9).
Autism Spectrum Disorders (ASDs) represent a group of neurodevelopmental disorders associated with social and behavioral impairments. Although dysfunctions in several signaling pathways have been associated with ASDs, very few molecules have been identified as potentially effective drug targets in the clinic. Classically, research in the ASD field has focused on the characterization of pathways involved in neural development and synaptic plasticity, which support the pathogenesis of this group of diseases. More recently, immune system dysfunctions have been observed in ASD. In addition, high levels of reactive oxygen species (ROS), which cause oxidative stress, are present in ASD patients. In this review, we will describe the major alterations in the expression of genes coding for enzymes involved in the ROS scavenging system, in both ASD patients and ASD mouse models. In addition, we will discuss, in the context of the most recent literature, the possibility that oxidative stress, inflammation and immune system dysfunction may be connected to, and altogether support, the pathogenesis and/or severity of ASD. Finally, we will discuss the possibility of novel treatments aimed at counteracting the interplay between ROS and inflammation in people with ASD.
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12. Qureshi F, Adams J, Coleman D, Quig D, Hahn J. {{Urinary Essential Elements of Young Children with Autism Spectrum Disorder and their Mothers}}. {Res Autism Spectr Disord}. 2020; 72.
Background: Even though the cause of autism spectrum disorders (ASD) remains unknown, the current understanding points towards complex interactions between environmental and genetic factors. One important environmental factor to consider is intake of toxic and essential elements, and their role in metabolism. Essential elements have received considerably less attention in the literature than the presence of toxins in urine. Method: The purpose of this investigation is to comprehensively assess the association between urinary element compositions of 28 mothers who had young children with ASD and 29 mothers who had young typically developing (TD) children, and in a subset of their children (21 with ASD and 26 TD). Results: The results show that there are significant differences between the ASD and TD children cohorts’ concentrations for four specific elements (sulfur, phosphorous, molybdenum, and tin). Utilizing multivariate statistical techniques (Fisher’s discriminant analysis and support vector machines), it was possible to distinguish the ASD from the TD children groups with an 81% accuracy after cross-validation utilizing the four significantly different elements. However, among the mother cohorts assessed, there were no significant differences between those that had children with ASD and those with TD children. There was a significant correlation of levels of phosphorus and sulfur in the children with ASD (r = 0.63, p = 3.0E-3) and in the TD children (r = 0.47, p = 0.02). Conclusions: Notable differences were observed between the elemental concentration in urine of children with ASD and their TD peers. Analyzing cellular pathways related to these elements are promising areas of future research.
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13. Sandbank M, Bottema-Beutel K, Crowley S, Cassidy M, Feldman JI, Canihuante M, Woynaroski T. {{Intervention Effects on Language in Children With Autism: A Project AIM Meta-Analysis}}. {Journal of speech, language, and hearing research : JSLHR}. 2020: 1-24.
Purpose This study synthesized effects of interventions on language outcomes of young children (ages 0-8 years) with autism and evaluated the extent to which summary effects varied by intervention, participant, and outcome characteristics. Method A subset of effect sizes gathered for a larger meta-analysis (the Autism Intervention Meta-analysis or Project AIM) examining the effects of interventions for young children with autism, which were specific to language outcomes, was analyzed. Robust variance estimation and metaregression were used to calculate summary and moderated effects while controlling for intercorrelation among outcomes within studies. Results A total of 221 outcomes were gathered from 60 studies. The summary effect of intervention on language outcomes was small but significant. Summary effects were larger for expressive and composite language outcomes compared to receptive language outcomes. Interventions implemented by clinicians, or by clinicians and caregivers together, had summary effects that were significantly larger than interventions implemented by caregivers alone. Participants’ pretreatment language age equivalent scores positively and significantly moderated intervention effects, such that effects were significantly larger on average when samples of children had higher pretreatment language levels. Effects were not moderated by cumulative intervention intensity, intervention type, autism symptomatology, chronological age, or the proximity or boundedness of outcomes. Study quality concerns were apparent for a majority of included outcomes. Conclusions We found evidence that intervention can facilitate improvements in language outcomes for young children with autism. Effects were largest for expressive and composite language outcomes, for children with initially higher language abilities, and for interventions implemented by clinicians or by caregivers and clinicians combined. However, quality concerns of included studies and borderline significance of some results temper our conclusions regarding intervention effectiveness and corresponding moderators.
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14. Sutantio JD, Pusponegoro HD, Sekartini R. {{Validity of Telemedicine for Diagnosing Autism Spectrum Disorder: Protocol-Guided Video Recording Evaluation}}. {Telemedicine journal and e-health : the official journal of the American Telemedicine Association}. 2020.
Background: Delayed diagnosis of autism spectrum disorder (ASD) remains a persistent pediatric health problem, due to limited access to competent diagnosticians and tertiary health care. A telemedicine method using a store-and-forward approach presents an opportunity to facilitate early identification and referral for intervention. This study aimed to evaluate the validity of protocol-guided video recording compared with direct assessment (DA) for diagnosing ASD. Materials and Methods: Children aged 18-30 months with chief complaints of delayed speech or social indifference, and Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) score of more than two were included. Parents were instructed to video record certain scenarios, which were assessed by an experienced professional based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) checklist for ASD. DAs using DSM-5 criteria were considered to be the gold standard of diagnosis. Diagnostic agreement, sensitivity, specificity, predictive values, and likelihood ratios were calculated to measure diagnostic validity. Results: The diagnostic agreement between the two methods was 82.5%. The sensitivity of video recording for diagnosing ASD was 91.3% (95% confidence interval [CI] [79.7%-100%]), while the specificity was 70.6% (95% CI [48.9%-92.2%]). The positive predictive value was 80.7% (95% CI [65.6%-95.9%]), while the negative predictive value was 85.7% (95% CI [67.4%-100%]). The positive likelihood ratio was 3.1 (95% CI [1.47-6.5]), while the negative likelihood ratio was 0.16 (95% CI [0.03-0.47]). Conclusions: A telemedicine approach using protocol-guided video recording evaluation has substantial validity compared with DA for diagnosing ASD.
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15. van Noordt S, Desjardins JA, Huberty S, Abou-Abbas L, Webb SJ, Levin AR, Segalowitz SJ, Evans AC, Elsabbagh M. {{EEG-IP: an international infant EEG data integration platform for the study of risk and resilience in autism and related conditions}}. {Molecular medicine (Cambridge, Mass)}. 2020; 26(1): 40.
BACKGROUND: Establishing reliable predictive and diganostic biomarkers of autism would enhance early identification and facilitate targeted intervention during periods of greatest plasticity in early brain development. High impact research on biomarkers is currently limited by relatively small sample sizes and the complexity of the autism phenotype. METHODS: EEG-IP is an International Infant EEG Data Integration Platform developed to advance biomarker discovery by enhancing the large scale integration of multi-site data. Currently, this is the largest multi-site standardized dataset of infant EEG data. RESULTS: First, multi-site data from longitudinal cohort studies of infants at risk for autism was pooled in a common repository with 1382 EEG longitudinal recordings, linked behavioral data, from 432 infants between 3- to 36-months of age. Second, to address challenges of limited comparability across independent recordings, EEG-IP applied the Brain Imaging Data Structure (BIDS)-EEG standard, resulting in a harmonized, extendable, and integrated data state. Finally, the pooled and harmonized raw data was preprocessed using a common signal processing pipeline that maximizes signal isolation and minimizes data reduction. With EEG-IP, we produced a fully standardized data set, of the pooled, harmonized, and pre-processed EEG data from multiple sites. CONCLUSIONS: Implementing these integrated solutions for the first time with infant data has demonstrated success and challenges in generating a standardized multi-site data state. The challenges relate to annotation of signal sources, time, and ICA analysis during pre-processing. A number of future opportunities also emerge, including validation of analytic pipelines that can replicate existing findings and/or test novel hypotheses.
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16. Wilder DA, Ertel H, Thomas R. {{Further analysis of modifications to the three-step guided compliance procedure to enhance compliance among children with autism}}. {Journal of applied behavior analysis}. 2020.
Three-step guided compliance (vocal prompt, vocal plus model prompt, vocal prompt plus physical guidance) is a commonly used procedure to increase compliance among children with intellectual disabilities. Previous research has suggested that under some conditions, slight modifications to the three-step procedure may enhance its effectiveness. These modifications include omitting the model prompt and decreasing the interprompt interval. In the current study, we evaluated another modification to the procedure: the delivery of a high-preference item contingent upon compliance with the first vocal prompt (i.e., differential reinforcement). For 2 participants with autism, compliance remained low when we implemented differential reinforcement and the guided compliance procedure in isolation. However, compliance improved when we combined differential reinforcement and the three-step guided procedure, suggesting that for at least some children, the combination of contingent access to a high-preference item and the guided compliance procedure is more effective than either intervention alone.
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17. Wong NML, Findon JL, Wichers RH, Giampietro V, Stoencheva V, Murphy CM, Blainey S, Ecker C, Murphy DG, McAlonan GM, Daly E. {{Serotonin differentially modulates the temporal dynamics of the limbic response to facial emotions in male adults with and without autism spectrum disorder (ASD): a randomised placebo-controlled single-dose crossover trial}}. {Neuropsychopharmacology}. 2020.
Emotion processing-including signals from facial expressions-is often altered in individuals with autism spectrum disorder (ASD). The biological basis of this is poorly understood but may include neurochemically mediated differences in the responsivity of key ‘limbic’ regions (including amygdala, ventromedial prefrontal cortex (vmPFC) and nucleus accumbens (NAc)). Emerging evidence also suggests that ASD may be a disorder of brain temporal dynamics. Moreover, serotonin (5-HT) has been shown to be a key regulator of both facial-emotion processing and brain dynamics, and 5-HT abnormalities have been consistently implicated in ASD. To date, however, no one has examined how 5-HT influences the dynamics of facial-emotion processing in ASD. Therefore, we compared the influence of 5-HT on the responsivity of brain dynamics during facial-emotion processing in individuals with and without ASD. Participants completed a facial-emotion processing fMRI task at least 8 days apart using a randomised double-blind crossover design. At each visit they received either a single 20-mg oral dose of the selective serotonin reuptake inhibitor (SSRI) citalopram or placebo. We found that citalopram (which increases levels of 5-HT) caused sustained activation in key limbic regions during processing of negative facial emotions in adults with ASD-but not in neurotypical adults. The neurotypical adults’ limbic response reverted more rapidly to baseline following a 5-HT-challenge. Our results suggest that serotonergic homoeostatic control of the temporal dynamics in limbic regions is altered in adults with ASD, and provide a fresh perspective on the biology of ASD.
