1. Ashraf S, Eskander N, Ceren Amuk O, Patel RS. {{Do Demographics and Comorbidities Act as Predictors of Co-diagnosis of Attention-deficit/Hyperactivity Disorder in Autism Spectrum Disorder?}}. {Cureus};2020 (Apr 23);12(4):e7798.
Objective The study aims to determine the demographic predictors of attention-deficit/hyperactivity disorder (ADHD) in hospitalized children with autism spectrum disorder (ASD) and the impact of comorbidities on the length of stay (LOS). Methods A retrospective study was performed using a nationwide inpatient sample from US hospitals. All patients were ≤18 years in age with a primary diagnosis of ASD (n = 3,095) and grouped by co-diagnosis of ADHD based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Logistic regression was used to calculate the odds ratio (OR) and linear regression for estimated LOS. Results Male patients had a higher odds of comorbid ADHD (OR: 2.2). Age and race were not significant predictors of ADHD though the condition was found to be prevalent in adolescents and Caucasians. These children were mainly from the South (30.8%) and the Midwest (29.9%) regions of the US. Psychosis was seen in 37.3% of patients with ADHD and was more likely to be comorbid psychosis (OR: 1.8). Depression and ADHD increased the LOS in hospitals for ASD by 2.1 days and 0.9 days, respectively. Conclusion Our study led us to determine the demographic predictors of comorbid ADHD in patients with autism, and we believe that our findings can help to better serve these patients and their families. Comorbid ADHD and depression can prolong the length of hospitalization and they necessitate the need for acute inpatient care in such patients.
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2. Chatterjee M, Singh P, Xu J, Lombroso PJ, Kurup PK. {{Inhibition of Striatal-Enriched Protein Tyrosine Phosphatase (STEP) Activity Reverses Behavioral Deficits in a Rodent Model of Autism}}. {Behav Brain Res};2020 (May 24):112713.
Autism spectrum disorders (ASDs) are highly prevalent childhood illnesses characterized by impairments in communication, social behavior, and repetitive behaviors. Studies have found aberrant synaptic plasticity and neuronal connectivity during the early stages of brain development and have suggested that these contribute to an increased risk for ASD. STEP is a protein tyrosine phosphatase that regulates synaptic plasticity and is implicated in several cognitive disorders. Here we test the hypothesis that STEP may contribute to some of the aberrant behaviors present in the VPA-induced mouse model of ASD. In utero VPA exposure of pregnant dams results in autistic-like behavior in the pups, which is associated with a significant increase in the STEP expression in the prefrontal cortex. The elevated STEP protein levels are correlated with increased dephosphorylation of STEP substrates GluN2B, Pyk2 and ERK, suggesting upregulated STEP activity. Moreover, pharmacological inhibition of STEP rescues the sociability, repetitive and abnormal anxiety phenotypes commonly associated with ASD. These data suggest that STEP may play a role in the VPA model of ASD and STEP inhibition may have a potential therapeutic benefit in this model.
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3. Deutsch SI, Burket JA. {{An Evolving Therapeutic Rationale for Targeting the α(7) Nicotinic Acetylcholine Receptor in Autism Spectrum Disorder}}. {Curr Top Behav Neurosci};2020 (May 29)
Abnormalities of cholinergic nuclei, cholinergic projections, and cholinergic receptors, as well as abnormalities of growth factors involved in the maturation and maintenance of cholinergic neurons, have been described in postmortem brains of persons with autism spectrum disorder (ASD). Further, microdeletions of the 15q13.3 locus that encompasses CHRNA7, the gene coding the α(7) nicotinic acetylcholine receptor (α(7) nAChR), are associated with a spectrum of neurodevelopmental disorders, including ASD. The heterozygous 15q13.3 microdeletion syndrome suggests that diminished or impaired transduction of the acetylcholine (ACh) signal by the α(7) nAChR can be a pathogenic mechanism of ASD. The α(7) nAChR has a role in regulating the firing and function of parvalbumin (PV)-expressing GABAergic projections, which synchronize the oscillatory output of assemblies of pyramidal neurons onto which they project. Synchronous oscillatory output is an electrophysiological substrate for higher executive functions, such as working memory, and functional connectivity between discrete anatomic areas of the brain. The α(7) nAChR regulates PV expression and works cooperatively with the co-expressed NMDA receptor in subpopulations of GABAergic interneurons in mouse models of ASD. An evolving literature supports therapeutic exploration of selectively targeted cholinergic interventions for the treatment of ASD, especially compounds that target the α(7) nAChR subtype. Importantly, development and availability of high-affinity, brain-penetrable, α(7) nAChR-selective agonists, partial agonists, allosteric agonists, and positive allosteric modulators (PAMs) should facilitate « proof-of-principle/concept » clinical trials. nAChRs are pentameric allosteric proteins that function as ligand-gated ion channel receptors constructed from five constituent polypeptide subunits, all of which share a common structural motif. Importantly, in addition to α(7) nAChR-gated Ca(2+) conductance causing membrane depolarization, there are emerging data consistent with possible metabotropic functions of this ionotropic receptor. The ability of α(7)-selective type II PAMs to « destabilize » the desensitized state and promote ion channel opening may afford them therapeutic advantages over orthosteric agonists. The current chapter reviews historic and recent literature supporting selective therapeutic targeting of the α(7) nAChR in persons affected with ASD.
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4. Hall DA, Nag S, Ouyang B, Bennett DA, Liu Y, Ali A, Zhou L, Berry-Kravis E. {{Fragile X Gray Zone Alleles Are Associated With Signs of Parkinsonism and Earlier Death}}. {Mov Disord};2020 (May 28)
BACKGROUND: Premutation size (55-199 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene cause fragile X-associated tremor/ataxia syndrome, but it is unclear whether smaller « gray » zone expansions of 41-54 repeats are also associated with movement disorders. The objectives of this study were to determine the association between the FMR1 gene gray zone expansions, AGG interspersions, and the presence of parkinsonism and motor and cognitive function in an elderly community-based population. METHODS: Automated FMR1 polymerase chain reaction was performed on existing samples from 2 longitudinal aging studies whose subjects agreed to brain donation. A detailed clinical evaluation including a modified Unified Parkinson’s Disease Rating Scale score, a composite score of global motor function, 17 cognitive tests summarized as a global measure of cognition, and neuropathological examination were obtained for genotyped participants. RESULTS: The average age of the population (n = 2362) was 85.9 ± 7.3 years, and average age at death was 88.6 ± 6.4 years (n = 1326), with 72% women. The prevalence of FMR1 gray zone alleles was 5.2% (122 of 2362). There was no difference between participants with gray zone expansions or those lacking AGG interspersions compared with normal participants in global cognition, global motor function, clinical diagnosis, or pathological changes. Gray zone alleles were associated with signs of parkinsonism in men (P = 0.01), and gray zone carrier men were more likely to die (hazard ratio, 2.34; 95% confidence interval, 1.31-4.16). CONCLUSIONS: This is the largest study to investigate gray zone alleles in a community population. The key findings are that in men, the gray zone allele is associated with signs of parkinsonism and higher risk of death, but not with intranuclear neuronal inclusions. © 2020 International Parkinson and Movement Disorder Society.
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5. Herrero MJ, Velmeshev D, Hernandez-Pineda D, Sethi S, Sorrells S, Banerjee P, Sullivan C, Gupta AR, Kriegstein AR, Corbin JG. {{Identification of amygdala-expressed genes associated with autism spectrum disorder}}. {Mol Autism};2020 (May 27);11(1):39.
BACKGROUND: Studies of individuals with autism spectrum disorder (ASD) have revealed a strong multigenic basis with the identification of hundreds of ASD susceptibility genes. ASD is characterized by social deficits and a range of other phenotypes, implicating complex genetics and involvement of a variety of brain regions. However, how mutations and mis-expression of select gene sets are associated with the behavioral components of ASD remains unknown. We reasoned that for genes to be associated with ASD core behaviors they must be: (1) expressed in brain regions relevant to ASD social behaviors and (2) expressed during the ASD susceptible window of brain development. METHODS: Focusing on the amygdala, a brain region whose dysfunction has been highly implicated in the social component of ASD, we mined publicly available gene expression databases to identify ASD-susceptibility genes expressed during human and mouse amygdala development. We found that a large cohort of known ASD susceptibility genes is expressed in the developing human and mouse amygdala. We further performed analysis of single-nucleus RNA-seq (snRNA-seq) data from microdissected amygdala tissue from five ASD and five control human postmortem brains ranging in age from 4 to 20 years to elucidate cell type specificity of amygdala-expressed genes and their dysregulation in ASD. RESULTS: Our analyses revealed that of the high-ranking ASD susceptibility genes, 80 are expressed in both human and mouse amygdala during fetal to early postnatal stages of development. Our human snRNA-seq analyses revealed cohorts of genes with altered expression in the ASD amygdala postnatally, especially within excitatory neurons, with dysregulated expression of seven genes predicted from our datamining pipeline. LIMITATIONS: We were limited by the ages for which we were able to obtain human tissue; therefore, the results from our datamining pipeline approach will require validation, to the extent possible, in human tissue from earlier developmental stages. CONCLUSIONS: Our pipeline narrows down the number of amygdala-expressed genes possibly involved in the social pathophysiology of ASD. Our human single-nucleus gene expression analyses revealed that ASD is characterized by changes in gene expression in specific cell types in the early postnatal amygdala.
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6. Kuo HY, Liu FC. {{Pathological alterations in striatal compartments in the human brain of autism spectrum disorder}}. {Mol Brain};2020 (May 27);13(1):83.
The striatum comprises a mosaic structure of striosomal and matrix compartments. Imbalanced neuronal activity between striosomes and matrix is implicated in neurological deficits in psychomotor and limbic functions. Because patients with autism spectrum disorder (ASD) are impaired in social communication and psychomotor function, it raises the possibility that abnormal striatal compartments may contribute to ASD pathogenesis. Here, we provide pathological evidence from human postmortem brains to support this hypothesis. Because ASD is a neurodevelopmental disease that emerges early in childhood, we analyzed juvenile and adolescent brains. Distinct patterns of PRODYNORPHIN-positive and calbindin-poor striosomes were detected in the caudate nucleus of control brains by in situ hybridization and immunohistochemistry. By contrast, PRODYNORPHIN-positive and calbindin-poor striosomes were decreased in the caudate nucleus of young ASD brains. Moreover, calbindin, a matrix marker, was aberrantly increased in the striosomal compartment, obscuring the boundaries between calbindin-poor striosomes and calbindin-rich matrix in ASD caudate nucleus. Calbindin-positive cells were decreased in the ASD matrix compartment. Collectively, our study has uncovered for the first time that aberrant striatal compartments occur in the caudate nucleus of human ASD brains, which suggests abnormal striatal compartmentation as a pathological signature that has previously been underestimated in ASD pathogenesis.
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7. LaBianca S, LaBianca J, Pagsberg AK, Jakobsen KD, Appadurai V, Buil A, Werge T. {{Copy Number Variants and Polygenic Risk Scores Predict Need of Care in Autism and/or ADHD Families}}. {J Autism Dev Disord};2020 (May 27)
Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are highly heritable neurodevelopmental disorders that frequently co-occur. Both rare and common genetic variants are important for ASD and ADHD risk but their combined contribution to clinical heterogeneity is unclear. In a sample of 39 ASD and/or ADHD families we estimated the overall variance explained by known rare copy number variants (CNVs) and polygenic risk score (PRS) from common variants to be 10% in comorbid ASD/ADHD, 4% in ASD and 2% in ADHD. We show that burden of large, rare CNVs and PRS is significantly higher in adult ASD and/or ADHD patients with sustained need for specialist care compared to their unaffected relatives, while affected relatives fall in-between the two.
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8. Liao X, Li Y. {{Nuclear Factor Kappa B in Autism Spectrum Disorder: A Systematic Review}}. {Pharmacol Res};2020 (May 24):104918.
BACKGROUND: The nuclear factor kappa B (NF-κB) is composed of a series of transcription factors, which are involved in the expression of a plethora of target genes, many of these genes contributing to the regulation of inflammatory responses. Consistent with its central role in inflammatory responses, existing studies of the neurobiological basis for ASD propose the involvement of NF-κB in the etiology of this disorder. OBJECTIVES: The present review aimed to systematically characterize extant literatures regarding the role of NF-κB in the etiology of ASD through data derived from both human studies and animal models. METHODS: A systematic electronic search was conducted for records indexed within Pubmed, EMBASE, or Web of Science to identify potentially eligible studies. Study inclusion and data extraction was agreed by two independent authors after reviewing the abstract and full text. RESULTS: Among the 586 articles identified in the initial screening, 18 articles met the eligibility criteria for this review, including 14 human case-control studies compared the expression or activation of NF-κB between ASD cases and controls as well as 4 animal studies used mouse model of ASD to examine the level of NF-κB and further evaluate its changes after different drug treatments. These included 18 studies, although relatively small in quantity, appear to support the role of NF-κB in the etiology of ASD. CONCLUSIONS: Evidence generated from both human studies and animal models supported the involvement of NF-κB in the neurobiological basis of ASD, despite some concern about whether it functions as a primary contributor causes ASD onset or rather an ancillary factor regulates ASD pathogenesis. The increased understanding of NF-κB in the neurobiological basis of ASD could aid the emergence of clinically relevant diagnostic biomarkers and novel therapeutic strategies acting on the underlying disease pathogenesis. These results suggested that potential methodological differences between studies need to be accounted for and keep open the discussion over the existence of aberrantly NF-κB signaling in ASD subjects.
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9. Lo LH, Lai KO. {{Dysregulation of protein synthesis and dendritic spine morphogenesis in ASD: studies in human pluripotent stem cells}}. {Mol Autism};2020 (May 27);11(1):40.
Autism spectrum disorder (ASD) is a brain disorder that involves changes in neuronal connections. Abnormal morphology of dendritic spines on postsynaptic neurons has been observed in ASD patients and transgenic mice that model different monogenetic causes of ASD. A number of ASD-associated genetic variants are known to disrupt dendritic local protein synthesis, which is essential for spine morphogenesis, synaptic transmission, and plasticity. Most of our understanding on the molecular mechanism underlying ASD depends on studies using rodents. However, recent advance in human pluripotent stem cells and their neural differentiation provides a powerful alternative tool to understand the cellular aspects of human neurological disorders. In this review, we summarize recent progress on studying mRNA targeting and local protein synthesis in stem cell-derived neurons, and discuss how perturbation of these processes may impact synapse development and functions that are relevant to cognitive deficits in ASD.
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10. Lord C. {{The future of autism: Global & local achievements & challenges}}. {Indian J Med Res};2020 (Apr);151(4):263-265.
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11. Mano-Sousa BJ, Pedrosa AM, Alves BC, Galduróz JCF, Belo VS, Chaves VE, Duarte-Almeida JM. {{Effects of risperidone in autistic children and young adults: A Systematic Review and Meta-Analysis}}. {Curr Neuropharmacol};2020 (May 29)
There are several studies investigating the effects of risperidone in autism, but many of these studies are contradictory or inconclusive. This systematic review and meta-analysis investigated the effects of risperidone on five domains of Aberrant Behaviour Checklist (ABC) scale on Autism Spectrum Disorder (ASD), as well as weight gain and waist circumference. The protocol for the present systematic review and meta-analysis was registered on International Prospective Register of Systematic Reviews (PROSPERO). For this study, we analysed articles (2,459), selecting them according to the PICOS strategy (Population, Intervention, Comparison, Outcome, Study design). Although risperidone is effective for the treatment of lethargy and inadequate speech, concerns about the association between weight gain, waist circumference and risperidone require a need to evaluation of the risk-benefit ratio in its use. There was a significant association between weight gain, waist circumference and risperidone. In Conclusion, it was possible to suggest the efficacy of risperidone for the treatment of lethargy and inadequate speech. Finally, we emphasize that the risk-benefit in its use should be evaluated. Protocol number CRD42019122316.
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12. Merritt JK, Collins BE, Erickson KR, Dong H, Neul JL. {{Pharmacological readthrough of R294X Mecp2 in a novel mouse model of Rett Syndrome}}. {Hum Mol Genet};2020 (May 29)
Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). More than 35% of affected individuals have nonsense mutations in MECP2. For these individuals, nonsense suppression has been suggested as a possible therapeutic approach. To assess the viability of this strategy, we created and characterized a mouse model with the common p.R294X mutation introduced into the endogenous Mecp2 locus (Mecp2R294X). Mecp2R294X mice exhibit phenotypic abnormalities similar to those seen in complete Null mouse models, however, these occur at a later time point consistent with the reduced phenotypic severity seen in affected individuals containing this specific mutation. The delayed onset of severe phenotypes is likely due to the presence of truncated MeCP2 in Mecp2R294X mice. Supplying the MECP2 transgene in Mecp2R294X mice rescued phenotypic abnormalities including early death and demonstrated that the presence of truncated MeCP2 in these mice does not interfere with wild-type MeCP2. In vitro treatment of a cell line derived from Mecp2R294X mice with the nonsense suppression agent G418 resulted in full-length MeCP2 protein production, demonstrating feasibility of this therapeutic approach. Intraperitoneal administration of G418 in Mecp2R294X mice was sufficient to elicit full-length MeCP2 protein expression in peripheral tissues. Finally, intracranial ventricular injection of G418 in Mecp2R294X mice induced expression of full-length MeCP2 protein in the mouse brain. These experiments demonstrate that translational read-through drugs are able to suppress the Mecp2 p.R294X mutation in vivo and provide a proof-of-concept for future preclinical studies of nonsense suppression agents in RTT.
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13. Meyer AT, Moody EJ, Keefer A, O’Kelley S, Duncan A, Blakeley-Smith A, Reaven J. {{Effect of Co-occurring Psychiatric Disorders on Treatment of Children with Autism Spectrum Disorder and Anxiety}}. {J Autism Dev Disord};2020 (May 27)
Co-occurring psychiatric diagnoses are very common in individuals with ASD. Little is known about the effect that co-occurring psychiatric conditions may have on treatment response to CBT for children with ASD and anxiety. The present study examined the relationship between co-occurring psychiatric diagnoses and response to CBT for anxiety in ninety youth with ASD. Psychiatric complexity did not appear to differentially impact treatment response. A notable portion of youth with anxiety and externalizing disorders such as ADHD, no longer met criteria for those externalizing diagnoses following intervention. Results indicate that youth with ASD and anxiety present with complex psychiatric profiles and CBT for anxiety may positively affect co-occurring diagnoses. In addition, thorough and nuanced assessment of psychiatric symptoms in youth with ASD is needed to ensure the differentiation between diagnoses of anxiety and other co-occurring psychiatric symptoms.
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14. Niesler B, Rappold GA. {{Emerging evidence for gene mutations driving both brain and gut dysfunction in autism spectrum disorder}}. {Mol Psychiatry};2020 (May 27)
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15. Schallmo MP, Kolodny T, Kale AM, Millin R, Flevaris AV, Edden RAE, Gerdts J, Bernier RA, Murray SO. {{Weaker neural suppression in autism}}. {Nat Commun};2020 (May 29);11(1):2675.
Abnormal sensory processing has been observed in autism, including superior visual motion discrimination, but the neural basis for these sensory changes remains unknown. Leveraging well-characterized suppressive neural circuits in the visual system, we used behavioral and fMRI tasks to demonstrate a significant reduction in neural suppression in young adults with autism spectrum disorder (ASD) compared to neurotypical controls. MR spectroscopy measurements revealed no group differences in neurotransmitter signals. We show how a computational model that incorporates divisive normalization, as well as narrower top-down gain (that could result, for example, from a narrower window of attention), can explain our observations and divergent previous findings. Thus, weaker neural suppression is reflected in visual task performance and fMRI measures in ASD, and may be attributable to differences in top-down processing.
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16. Tanet A, Hubert-Barthelemy A, Clément MN, Soumille F, Crespin GC, Pellerin H, Allaert FA, Cohen D, Saint-Georges C. {{Developmental and sequenced one-to-one educational intervention (DS1-EI) for autism spectrum disorder and intellectual disability: a two-year interim report of a randomized single-blind multicenter controlled trial}}. {BMC Pediatr};2020 (May 29);20(1):263.
BACKGROUND: Children with autism spectrum disorder (ASD) and moderate to severe intellectual disability (ID) face many challenges. There is little evidence-based research into educational settings for children with ID and ASD and in France. Little is known about how this unserved population could benefit from intervention and education. This study assessed the feasibility and efficacy of a new intervention model using an individualized educational approach. METHODS: We conducted a randomized, single-blind controlled trial to assess a novel intervention: the « Developmental and Sequenced One-to-One Intervention (DS1-EI) ». In DS1-EI, trained teachers worked one-to-one with each child in a small classroom setting, offering 10 h per week of the intervention. The focus was on encouraging spontaneous communication, promoting skills through play with peers, supporting positive interactions, and developmental and sequenced learning. We enrolled 5- to 9-year-old children with ASD and ID across 11 French child care institutions for children with co-occurring ASD and ID. Participants were matched in dyads by developmental quotient and randomized to the treatment-as-usual (TAU) group or the DS1-EI group. Independent raters blindly assessed the primary variables: The Childhood Autism Rating scale (CARS) and the Psychoeducational Profile, third edition (PEP-3). The secondary variables included the Vineland Adaptive Behavior Scale II (VABS-II) and the Clinical Global Assessment Scale (CGAS). Here we perform interim analyses at 24 months. RESULTS: At baseline, 72 participants were randomized. Nine patients (5 in the DS1-EI group and 4 in the TAU group) dropped out of the study. Using linear mixed models, both intent-to-treat (ITT) and per-protocol (PP) analyses at the 12-, 18- and 24-month outcomes showed no significant group nor group-by-time interaction effects. However, we found significant improvements in most primary and secondary variables over time in both groups. CONCLUSIONS: The study did not show that DS1-EI was superior to TAU in treating children with ASD and ID over 24 months. However, the low dropout rate shows that DS1-EI is feasible, and well accepted. As the study is still ongoing, we need to wait for data at 36 months to ensure whether DS1-EI could be recommended. TRIAL REGISTRATION: ANSM130282B-31 (April 16, 2013) and ACTRN12616000592448. Registered 6 May 2016, retrospectively registered, http://www.anzctr.org.au/.
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17. Tripathi MK, Kartawy M, Amal H. {{The role of nitric oxide in brain disorders: Autism spectrum disorder and other psychiatric, neurological, and neurodegenerative disorders}}. {Redox Biol};2020 (May 15);34:101567.
Nitric oxide (NO) is a multifunctional signalling molecule and a neurotransmitter that plays an important role in physiological and pathophysiological processes. In physiological conditions, NO regulates cell survival, differentiation and proliferation of neurons. It also regulates synaptic activity, plasticity and vesicle trafficking. NO affects cellular signalling through protein S-nitrosylation, the NO-mediated posttranslational modification of cysteine thiols (SNO). SNO can affect protein activity, protein-protein interaction and protein localization. Numerous studies have shown that excessive NO and SNO can lead to nitrosative stress in the nervous system, contributing to neuropathology. In this review, we summarize the role of NO and SNO in the progression of neurodevelopmental, psychiatric and neurodegenerative disorders, with special attention to autism spectrum disorder (ASD). We provide mechanistic insights into the contribution of NO in diverse brain disorders. Finally, we suggest that pharmacological agents that can inhibit or augment the production of NO as well as new approaches to modulate the formation of SNO-proteins can serve as a promising approach for the treatment of diverse brain disorders.
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18. Tubul-Lavy G, Jokel A, Leon-Attia O, Gabis LV. {{Content Words in Child-Directed Speech of Mothers Toward Children With Autism Spectrum Disorder}}. {Am J Speech Lang Pathol};2020 (May 28):1-14.
Purpose Our study aimed to analyze the characteristics of content word usage in mother’s child-directed speech ( CDS) toward children with autism spectrum disorder compared to mother’s CDS toward typically developing children. Method We analyzed the lexical characteristics of CDS of mothers of children with autism (16 dyads) and compared them from a language developmental perspective to mothers of 20 typical children at the same level of expressive language development. Results Results suggest that mothers of children with autism use equal amounts of content words at the same language level, but the content consists of significantly more concrete nouns and active verbs and rarely the use of abstract nouns, stative verbs, adjectives, and adverbs. Conclusion This study suggests that professionals and parents of children with autism should be aware of the importance of varying their language use of content words.
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19. Varderidou-Minasian S, Hinz L, Hagemans D, Posthuma D, Altelaar M, Heine VM. {{Quantitative proteomic analysis of Rett iPSC-derived neuronal progenitors}}. {Mol Autism};2020 (May 27);11(1):38.
BACKGROUND: Rett syndrome (RTT) is a progressive neurodevelopmental disease that is characterized by abnormalities in cognitive, social, and motor skills. RTT is often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanism by which impaired MeCP2 induces the pathological abnormalities in the brain is not understood. Both patients and mouse models have shown abnormalities at molecular and cellular level before typical RTT-associated symptoms appear. This implies that underlying mechanisms are already affected during neurodevelopmental stages. METHODS: To understand the molecular mechanisms involved in disease onset, we used an RTT patient induced pluripotent stem cell (iPSC)-based model with isogenic controls and performed time-series of proteomic analysis using in-depth high-resolution quantitative mass spectrometry during early stages of neuronal development. RESULTS: We provide mass spectrometry-based quantitative proteomic data, depth of about 7000 proteins, at neuronal progenitor developmental stages of RTT patient cells and isogenic controls. Our data gives evidence of proteomic alteration at early neurodevelopmental stages, suggesting alterations long before the phase that symptoms of RTT syndrome become apparent. Significant changes are associated with the GO enrichment analysis in biological processes cell-cell adhesion, actin cytoskeleton organization, neuronal stem cell population maintenance, and pituitary gland development, next to protein changes previously associated with RTT, i.e., dendrite morphology and synaptic deficits. Differential expression increased from early to late neural stem cell phases, although proteins involved in immunity, metabolic processes, and calcium signaling were affected throughout all stages analyzed. LIMITATIONS: The limitation of our study is the number of RTT patients analyzed. As the aim of our study was to investigate a large number of proteins, only one patient was considered, of which 3 different RTT iPSC clones and 3 isogenic control iPSC clones were included. Even though this approach allowed the study of mutation-induced alterations due to the usage of isogenic controls, results should be validated on different RTT patients to suggest common disease mechanisms. CONCLUSIONS: During early neuronal differentiation, there are consistent and time-point specific proteomic alterations in RTT patient cells carrying exons 3-4 deletion in MECP2. We found changes in proteins involved in pathway associated with RTT phenotypes, including dendrite morphology and synaptogenesis. Our results provide a valuable resource of proteins and pathways for follow-up studies, investigating common mechanisms involved during early disease stages of RTT syndrome.
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20. Walker SC, Williams K, Moore DJ. {{Superior Identification of Component Odors in a Mixture Is Linked to Autistic Traits in Children and Adults}}. {Chem Senses};2020 (May 29);45(5):391-399.
Most familiar odors are complex mixtures of volatile molecules, which the olfactory system automatically synthesizes into a perceptual whole. However, odors are rarely encountered in isolation; thus, the brain must also separate distinct odor objects from complex and variable backgrounds. In vision, autistic traits are associated with superior performance in tasks that require focus on the local features of a perceptual scene. The aim of the present study was to determine whether the same advantage was observed in the analysis of olfactory scenes. To do this, we compared the ability of 1) 40 young adults (aged 16-35) with high (n = 20) and low levels of autistic traits and 2) 20 children (aged 7-11), with (n = 10) and without an autism spectrum disorder diagnosis, to identify individual odor objects presented within odor mixtures. First, we used a 4-alternative forced choice task to confirm that both adults and children were able to reliably identify 8 blended fragrances, representing food-related odors, when presented individually. We then used the same forced choice format to test participants’ ability to identify the odors when they were combined in either binary or ternary mixtures. Adults with high levels of autistic traits showed superior performance on binary but not ternary mixture trials, whereas children with an autism spectrum disorder diagnosis outperformed age-matched neurotypical peers, irrespective of mixture complexity. These findings indicate that the local processing advantages associated with high levels of autistic traits in visual tasks are also apparent in a task requiring analytical processing of odor mixtures.
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21. Wang Y, Xu Q, Zuo C, Zhao L, Hao L. {{Longitudinal Changes of Cerebellar Thickness in Autism Spectrum Disorder}}. {Neurosci Lett};2020 (May 29);728:134949.
Many studies have reported abnormal cerebellar volume in patients with autism spectrum disorder (ASD) and that this abnormal volume can change with age. In the present study, we used CERES, an automated and reliable quantitative analysis tool, and adopted a longitudinal design to examine developmental changes in the cerebellar lobular thickness in ASD and quantified the relationship between cerebellar thickness development and clinical symptoms. Nineteen individuals with ASD (16 males; age, 12.53 ± 2.34 years at baseline, interval: 2.33 years) and 14 typically developing controls (TD; 12 males; age, 13.50 ± 1.77 years at baseline, interval: 2.31 years) underwent T1-weighted magnetic resonance imaging at two time points. To explore the relationship between cerebellar lobular thickness and the symptoms of ASD, the correlation of Autism Diagnostic Observation Schedule (ADOS) score with lobular thickness data was calculated. The cerebellar lobule thickness decreased in the right Crus II and the Crus II asymmetry was reduced in individuals with ASD. The reduction in lobular thickness and the asymmetry in Crus II were associated with the severity of stereotyped behavior symptoms. Structural differences and behavioral correlations were concentrated in the right cerebellar Crus II. These results emphasize the importance of the potential functional effect of structural differences in cerebellar subregions on ASD and suggest that the changes of thickness in the right cerebellar Crus II are related to the core profile of ASD.
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22. Wang Z, Li J, Zhang T, Lu T, Wang H, Jia M, Liu J, Xiong J, Zhang D, Wang L. {{Family-based association study identifies SNAP25 as a susceptibility gene for autism in the Han Chinese population}}. {Prog Neuropsychopharmacol Biol Psychiatry};2020 (May 29):109985.
Autism is a neurodevelopmental disorder with high heritability. Synaptosome associated protein 25 (SNAP25) encodes a presynaptic membrane-binding protein. It plays a crucial role in neurotransmission and may be involved in the pathogenesis of autism. However, the association between SNAP25 and autism in the Han Chinese population remains unclear. To investigate whether single nucleotide polymorphisms (SNPs) in SNAP25 contribute to the risk of autism, we performed a family-based association study of 14 tagSNPs in SNAP25 in 640 Han Chinese autism trios. Our results demonstrated that rs363018 in SNAP25 was significantly associated with autism under both additive (A > G, Z = 3.144, P = .0017) and recessive models (A > G, Z = 3.055, P = .0023) after Bonferroni correction (P < .0036). An additional SNP, rs8636, was nominally associated with autism under the recessive model (C > T, Z = 1.972, P = .0487). Haplotype-based association test revealed that haplotypes A-T (Z = 2.038, P = .0415) and G-T (Z = -3.114, P = .0018) of rs363018-rs362582 were significantly associated with autism after the permutation test (P = .0158). These findings suggest that SNAP25 may represent a susceptibility gene for autism in the Han Chinese population.
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23. Yildiz GY, Vilsten JS, Millard AS, Chouinard PA. {{Grey-Matter Thickness of the Left But Not the Right Primary Visual Area Correlates with Autism Traits in Typically Developing Adults}}. {J Autism Dev Disord};2020 (May 29)
We examined whether functional and structural variability in the primary visual area (V1) correlated with autism traits. Twenty-nine participants (16 males; M(Age) = 26.4 years, SD(Age) = 4.0 years) completed the autism-spectrum quotient (AQ) questionnaire prior to a magnetic resonance imaging session. The total AQ scores was used to assess the degree of self-reported autism traits. The average functional activation in V1 to visual stimulation and its average grey-matter thickness were calculated. There were no correlations between functional activation in V1 and autism traits. Conversely, grey-matter thickness of the left but not the right V1 correlated with autism traits. We conclude that structural changes in the left V1 could be a marker for the presence of autism traits.
