1. Aishworiya R, Valica T, Hagerman R, Restrepo B. An Update on Psychopharmacological Treatment of Autism Spectrum Disorder. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2022.

While behavioral interventions remain the mainstay of treatment of autism spectrum disorder (ASD), several potential targeted treatments addressing the underlying neurophysiology of ASD have emerged in the last few years. These are promising for the potential to, in future, become part of the mainstay treatment in addressing the core symptoms of ASD. Although it is likely that the development of future targeted treatments will be influenced by the underlying heterogeneity in etiology, associated genetic mechanisms influencing ASD are likely to be the first targets of treatments and even gene therapy in the future for ASD. In this article, we provide a review of current psychopharmacological treatment in ASD including those used to address common comorbidities of the condition and upcoming new targeted approaches in autism management. Medications including metformin, arbaclofen, cannabidiol, oxytocin, bumetanide, lovastatin, trofinetide, and dietary supplements including sulforophane and N-acetylcysteine are discussed. Commonly used medications to address the comorbidities associated with ASD including atypical antipsychotics, serotoninergic agents, alpha-2 agonists, and stimulant medications are also reviewed. Targeted treatments in Fragile X syndrome (FXS), the most common genetic disorder leading to ASD, provide a model for new treatments that may be helpful for other forms of ASD.

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2. Al Tamimi MI, Alfawaz HA, Bhat RS, Arzoo S, Soliman DA, Al Khibary MAE, Hassan SA, El-Ansary A. Comparative Study on the Exacerbating Effects of Casein-Rich vs. Gluten-Rich Diets on Biochemical-Induced Features in Rodent Model of Autism. Journal of molecular neuroscience : MN. 2022; 72(2): 359-71.

In relation to dietary intervention in individuals with autism spectrum disorder (ASD), certain food constituents especially gluten and casein are recognized to be challenging and should be restricted. In this study, levels of glutathione S-transferase, glutathione, lipid peroxides, serotonin (5-HT), interleukin-6 (IL-6), glutamate, and gamma aminobutyric acid (GABA) were measured in the brain homogenates of ASD rodent model. Rats were treated either with single dose clindamycin (30 mg/kg) or with propionic acid (PPA) (250 mg/kg) for 3 days and then fed a standard diet, casein-rich diet (CRD), or gluten-rich diet (GRD). The obtained data demonstrates that clindamycin and PPA induced oxidative stress, which was slightly affected by CRD. A marked increase in the proinflammatory cytokine (IL-6) concentration found in clindamycin- and PPA-treated groups was lower in CRD fed rats. Both CRDs and GRDs produced similar trends in glutamate levels. 5-HT levels were higher in the clindamycin- and PPA-treated groups and increased with a GRD but were less affected by a CRD. CRD could be less deleterious compared to GRD. Although the underlying cause of gastrointestinal symptoms in patients with ASD is not exactly known, the most widely accepted one is the opioid theory which is related to GRD and CRD.

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3. Babu G, Scaria LM, Prasanna GL, Deepa B, Leena ML, Remadevi S. A Nine-Item Red Flag Sign Card for Identification of Autism Spectrum Disorder among Toddlers Aged 12 to 18 Months. Indian journal of pediatrics. 2022; 89(3): 288-90.

There is a dearth of validated red flags measures for early identification of autism spectrum disorder (ASD) among toddlers. Hence, a new screening measure was developed. Item generation was done through literature search. Content validity (CVI) assessment was done. Criterion validity was done using Diagnostic and Statistical Manual 5 (DSM-5) as reference standard, data were collected from the case records of children with ASD diagnosis at 2 y, and evaluated for developmental milestones between 12 and 18 mo in a tertiary care setting. Item reduction of the measure from 18 to 9 was done. The area under the curve in the receiver operating characteristic (ROC) curve for new measure was 0.81 (95% CI = 0.73, 0.87); z = 7.874; p < 0.001 against DSM-5 score of ≥ 2 in the new measure; achieved sensitivity of 93.42% (95% CI = 85.3, 97.8) and specificity of 60% (95% CI = 45.9, 73.0). Thus, new validated red flag sign card (Concern-9) can be used effectively for early screening and identification of ASD among children aged 12-18 mo.

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4. Benevides TW, Tao S, Becker A, Verstreate K, Shea L. Occupational Therapy Service Delivery Among Medicaid-Enrolled Children and Adults on the Autism Spectrum and With Other Intellectual Disabilities. The American journal of occupational therapy : official publication of the American Occupational Therapy Association. 2022; 76(1).

IMPORTANCE: Rates of occupational therapy service utilization among people with autism spectrum disorder (ASD) or intellectual disability (ID) have not been explored in population-based samples. OBJECTIVE: To describe occupational therapy services delivered to Medicaid-eligible persons younger than age 65 yr identified as having ASD, ID, or both and to evaluate demographic factors associated with occupational therapy service utilization in this population. DESIGN: Retrospective, case-control, cohort study using claims records from Medicaid Analytic eXtract files (2009-2012). SETTING: Data from all 50 states and Washington, DC. PARTICIPANTS: Beneficiaries identified as having ASD only, ASD+ID, or ID only who were younger than age 18 yr (N = 664,214) and ages 18-64 yr (N = 702,338). Outcomes and Measures: We analyzed Current Procedural Terminology® and Healthcare Common Procedure Coding System procedure codes, Medicaid Statistical Information System type of service codes, and Center for Medicare & Medicaid Services provider specialty codes. RESULTS: Only 3.7% to 6.3% of eligible adult beneficiaries received occupational therapy; in contrast, 20.5% to 24.2% of children received occupational therapy. Significant predictors of service use varied by group; however, differences by race-ethnicity, eligibility on the basis of poverty, and geographic location were observed. Among children, the most frequent billing code was for « therapeutic activities » (43%-60%); among adults, it was « community/work reintegration training » (29%-39%). CONCLUSIONS AND RELEVANCE: Billed procedure code patterns do not consistently reflect the unique occupational focus that occupational therapy providers deliver to people with developmental disabilities. Disparities in occupational therapy receipt warrant further attention to understand the social and structural factors affecting service delivery. What This Article Adds: Occupational therapy services paid for by Medicaid are used more frequently by children with ASD and ID than by adults with these diagnoses. Greater understanding of the intersectional factors that drive service delivery and disparities is needed.

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5. Chung MK, Smith MR, Lin Y, Walker DI, Jones D, Patel CJ, Kong SW. Plasma metabolomics of autism spectrum disorder and influence of shared components in proband families. Exposome. 2021; 1(1): osab004.

Prevalence of autism spectrum disorder (ASD) has been increasing in the United States in the past decades. The exact mechanisms remain enigmatic, and diagnosis of the disease still relies primarily on assessment of behavior. We first used a case-control design (75 idiopathic cases and 29 controls, enrolled at Boston Children’s Hospital from 2007-2012) to identify plasma biomarkers of ASD through a metabolome-wide association study approach. Then we leveraged a family-based design (31 families) to investigate the influence of shared genetic and environmental components on the autism-associated features. Using untargeted high-resolution mass spectrometry metabolomics platforms, we detected 19 184 features. Of these, 191 were associated with ASD (false discovery rate < 0.05). We putatively annotated 30 features that had an odds ratio (OR) between <0.01 and 5.84. An identified endogenous metabolite, O-phosphotyrosine, was associated with an extremely low autism odds (OR 0.17; 95% confidence interval 0.06-0.39). We also found that glutathione metabolism was associated with ASD (P = 0.048). Correlations of the significant features between proband and parents were low (median = 0.09). Of the 30 annotated features, the median correlations within families (proband-parents) were -0.15 and 0.24 for the endogenous and exogenous metabolites, respectively. We hypothesize that, without feature identification, family-based correlation analysis of autism-associated features can be an alternative way to assist the prioritization of potentially diagnostic features. A panel of ASD diagnostic metabolic markers with high specificity could be derived upon further studies.

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6. Feldman JI, Thompson E, Davis H, Keceli-Kaysili B, Dunham K, Woynaroski T, Tharpe AM, Picou EM. Remote Microphone Systems Can Improve Listening-in-Noise Accuracy and Listening Effort for Youth With Autism. Ear and hearing. 2022; 43(2): 436-47.

OBJECTIVES: This study examined whether remote microphone (RM) systems improved listening-in-noise performance in youth with autism. We explored effects of RM system use on both listening-in-noise accuracy and listening effort in a well-characterized sample of participants with autism. We hypothesized that listening-in-noise accuracy would be enhanced and listening effort reduced, on average, when participants used the RM system. Furthermore, we predicted that effects of RM system use on listening-in-noise accuracy and listening effort would vary according to participant characteristics. Specifically, we hypothesized that participants who were chronologically older, had greater nonverbal cognitive and language ability, displayed fewer features of autism, and presented with more typical sensory and multisensory profiles might exhibit greater benefits of RM system use than participants who were younger, had less nonverbal cognitive or language ability, displayed more features of autism, and presented with greater sensory and multisensory disruptions. DESIGN: We implemented a within-subjects design to investigate our hypotheses, wherein 32 youth with autism completed listening-in-noise testing with and without an RM system. Listening-in-noise accuracy and listening effort were evaluated simultaneously using a dual-task paradigm for stimuli varying in complexity (i.e., syllable-, word-, sentence-, and passage-level). In addition, several putative moderators of RM system effects (i.e., sensory and multisensory function, language, nonverbal cognition, and broader features of autism) on outcomes of interest were evaluated. RESULTS: Overall, RM system use resulted in higher listening-in-noise accuracy in youth with autism compared with no RM system use. The observed benefits were all large in magnitude, although the benefits on average were greater for more complex stimuli (e.g., key words embedded in sentences) and relatively smaller for less complex stimuli (e.g., syllables). Notably, none of the putative moderators significantly influenced the effects of the RM system on listening-in-noise accuracy, indicating that RM system benefits did not vary according to any of the participant characteristics assessed. On average, RM system use did not have an effect on listening effort across all youth with autism compared with no RM system use but instead yielded effects that varied according to participant profile. Specifically, moderated effects indicated that RM system use was associated with increased listening effort for youth who had (a) average to below-average nonverbal cognitive ability, (b) below-average language ability, and (c) reduced audiovisual integration. RM system use was also associated with decreased listening effort for youth with very high nonverbal cognitive ability. CONCLUSIONS: This study extends prior work by showing that RM systems have the potential to boost listening-in-noise accuracy for youth with autism. However, this boost in accuracy was coupled with increased listening effort, as indexed by longer reaction times while using an RM system, for some youth with autism, perhaps suggesting greater engagement in the listening-in-noise tasks when using the RM system for youth who had lower cognitive abilities, were less linguistically able, and/or have difficulty integrating seen and heard speech. These findings have important implications for clinical practice, suggesting RM system use in classrooms could potentially improve listening-in-noise performance for some youth with autism.

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7. Klusek J, Fairchild A, Moser C, Mailick MR, Thurman AJ, Abbeduto L. Family history of FXTAS is associated with age-related cognitive-linguistic decline among mothers with the FMR1 premutation. Journal of neurodevelopmental disorders. 2022; 14(1): 7.

BACKGROUND: Women who carry a premutation allele of the FMR1 gene are at increased vulnerability to an array of age-related symptoms and disorders, including age-related decline in select cognitive skills. However, the risk factors for age-related decline are poorly understood, including the potential role of family history and genetic factors. In other forms of pathological aging, early decline in syntactic complexity is observed and predicts the later onset of neurodegenerative disease. To shed light on the earliest signs of degeneration, the present study characterized longitudinal changes in the syntactic complexity of women with the FMR1 premutation across midlife, and associations with family history of fragile X-associated tremor/ataxia syndrome (FXTAS) and CGG repeat length. METHODS: Forty-five women with the FMR1 premutation aged 35-64 years at study entry participated in 1-5 longitudinal assessments spaced approximately a year apart (130 observations total). All participants were mothers of children with confirmed fragile X syndrome. Language samples were analyzed for syntactic complexity and participants provided information on family history of FXTAS. CGG repeat length was determined via molecular genetic testing. RESULTS: Hierarchical linear models indicated that women who reported a family history of FXTAS exhibited faster age-related decline in syntactic complexity than those without a family history, with that difference emerging as the women reached their mid-50 s. CGG repeat length was not a significant predictor of age-related change. CONCLUSIONS: Results suggest that women with the FMR1 premutation who have a family history of FXTAS may be at increased risk for neurodegenerative disease, as indicated by age-related loss of syntactic complexity. Thus, family history of FXTAS may represent a personalized risk factor for age-related disease. Follow-up study is needed to determine whether syntactic decline is an early indicator of FXTAS specifically, as opposed to being a more general age-related cognitive decline associated with the FMR1 premutation.

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8. Palmer M, Tarver J, Carter Leno V, Paris Perez J, Frayne M, Slonims V, Pickles A, Scott S, Charman T, Simonoff E. Parent, Teacher and Observational Reports of Emotional and Behavioral Problems in Young Autistic Children. Journal of autism and developmental disorders. 2022.

Emotional and behavioral problems (EBPs) frequently occur in young autistic children. Discrepancies between parents and other informants are common but can lead to uncertainty in formulation, diagnosis and care planning. This study aimed to explore child and informant characteristics are associated with reported child EBPs across settings. Participants were 83 4-8-year-old autistic children and their parents and teachers in the Autism Spectrum Treatment and Resilience (ASTAR) study. Questionnaires of child EBPs were completed by parents and teachers, and self-reported parenting stress and wellbeing measures were obtained. An observation of parent-child/researcher-child interaction was also completed. Parents reported more EBPs than teachers and parent-teacher agreement was low, particularly for emotional problems. Greater parenting stress and being verbal was associated with more parent- but not teacher-reported EBPs. More observed behaviors that challenge were displayed by minimally verbal children. More parenting stress could be associated with the presence of more EBPs in the home; alternatively, parenting stress may confound reports. It is essential for assessments of EBPs in autistic children to take a multi-informant approach. Better understanding of the associations between informant characteristics and informant discrepancies of EBPs is needed.

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9. Shojaeian N, Li Z, Kaurav RPS, Salem A. Theory of Mind Among Swedish Children with ASD, Down Syndrome and Typically Developing Group. Journal of autism and developmental disorders. 2022.

The present study examined the role of IQ and the Theory of Mind understanding in children with an autism spectrum disorder and down syndrome. Sixty-six Swedish children with ASD (n = 26), DS (n = 18), and typically developed group (n = 22) ranged between 6 and 12 years old were compared on ToM tasks consisted of standard ToM and IQ tasks. SPSS 25 program was used to analyze data. The results indicated that individuals with ASD reach a better understanding of first-order ToM tasks than children with DS. This picture was the same in the TD group to show better ability than children with ASD and DS on first-order tasks, except one task which was not found significant differences. To employ second-order TD performed better than clinical groups, while, there was no significant difference between ASD and DS. The scores for the third-order task in children with ASD were significantly better than children with DS.

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10. Yu H, Niu Y, Jia G, Liang Y, Chen B, Sun R, Wang M, Huang S, Zeng J, Lu J, Li L, Guo X, Yao P. Maternal diabetes-mediated RORA suppression in mice contributes to autism-like offspring through inhibition of aromatase. Communications biology. 2022; 5(1): 51.

Retinoic acid-related orphan receptor alpha (RORA) suppression is associated with autism spectrum disorder (ASD) development, although the mechanism remains unclear. In this study, we aim to investigate the potential effect and mechanisms of RORA suppression on autism-like behavior (ALB) through maternal diabetes-mediated mouse model. Our in vitro study in human neural progenitor cells shows that transient hyperglycemia induces persistent RORA suppression through oxidative stress-mediated epigenetic modifications and subsequent dissociation of octamer-binding transcription factor 3/4 from the RORA promoter, subsequently suppressing the expression of aromatase and superoxide dismutase 2. The in vivo mouse study shows that prenatal RORA deficiency in neuron-specific RORA null mice mimics maternal diabetes-mediated ALB; postnatal RORA expression in the amygdala ameliorates, while postnatal RORA knockdown mimics, maternal diabetes-mediated ALB in offspring. In addition, RORA mRNA levels in peripheral blood mononuclear cells decrease to 34.2% in ASD patients (n = 121) compared to the typically developing group (n = 118), and the related Receiver Operating Characteristic curve shows good sensitivity and specificity with a calculated 84.1% of Area Under the Curve for ASD diagnosis. We conclude that maternal diabetes contributes to ALB in offspring through suppression of RORA and aromatase, RORA expression in PBMC could be a potential marker for ASD screening.

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