1. Cooper SA, Henderson A, Kinnear D, Mackay D, Fleming M, Smith GS, Hughes-McCormack LA, Rydzewska E, Dunn K, Pell JP, Melville C. Cohort profile: Scotland’s record-linkage e-cohorts of people with intellectual disabilities, and autistic people (SCIDA). BMJ Open;2022 (May 13);12(5):e057230.

PURPOSE: To investigate health, mortality and healthcare inequalities experienced by people with intellectual disabilities, and autistic people, and their determinants; an important step towards identifying and implementing solutions to reduce inequalities. This paper describes the cohorts, record-linkages and variables that will be used. PARTICIPANTS: Scotland’s Census, 2011 was used to identify Scotland’s citizens with intellectual disabilities, and autistic citizens, and representative general population samples with neither. Using Scotland’s community health index, the Census data (demography, household, employment, long-term conditions) were linked with routinely collected health, death and healthcare data: Scotland’s register of deaths, Scottish morbidity data 06 (SMR06: cancer incidence, mortality, treatments), Prescribing Information System (identifying asthma/chronic obstructive pulmonary disease; angina/congestive heart failure/hypertension; peptic ulcer/reflux; constipation; diabetes; thyroid disorder; depression; bipolar disorders; anxiety/sleep; psychosis; attention deficit hyperactivity disorder; epilepsy; glaucoma), SMR01 (general/acute hospital admissions and causes, ambulatory care sensitive admissions), SMR04 (mental health admissions and causes), Scottish Care Information-Diabetes Collaboration (diabetic care quality, diabetic outcomes), national bowel screening programme and cervical screening. FINDINGS TO DATE: Of the whole population, 0.5% had intellectual disabilities, and 0.6% were autistic. Linkage was successful for >92%. The resultant e-cohorts include: (1) 22 538 people with intellectual disabilities (12 837 men and 9701 women), 4509 of whom are children <16 years, (2) 27 741 autistic people (21 390 men and 6351 women), 15 387 of whom are children <16 years and (3) representative general population samples with neither condition. Very good general health was reported for only 3389 (15.0%) people with intellectual disabilities, 10 510 (38.0%) autistic people, compared with 52.4% general population. Mental health conditions were reported for 4755 (21.1%) people with intellectual disabilities, 3998 (14.4%) autistic people, compared with 4.2% general population. FUTURE PLANS: Analyses will determine the extent of premature mortality, causes of death, and avoidable deaths, profile of health conditions and cancers, healthcare quality and screening and determinants of mortality and healthcare.

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2. Javadi S, Li Y, Sheng J, Zhao L, Fu Y, Wang D, Zhao X. Sustained correction of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mouse model of fragile X syndrome. BMC Med;2022 (May 13);20(1):163.

BACKGROUND: Fragile X syndrome (FXS), the most prevalent inherited intellectual disability and one of the most common monogenic forms of autism, is caused by a loss of fragile X messenger ribonucleoprotein 1 (FMR1). We have previously shown that FMR1 represses the levels and activities of ubiquitin ligase MDM2 in young adult FMR1-deficient mice, and treatment by a MDM2 inhibitor Nutlin-3 rescues both hippocampal neurogenic and cognitive deficits in FMR1-deficient mice when analyzed shortly after the administration. However, it is unknown whether Nutlin-3 treatment can have long-lasting therapeutic effects. METHODS: We treated 2-month-old young adult FMR1-deficient mice with Nutlin-3 for 10 days and then assessed the persistent effect of Nutlin-3 on both cognitive functions and adult neurogenesis when mice were 6-month-old mature adults. To investigate the mechanisms underlying the persistent effects of Nutlin-3, we analyzed the proliferation and differentiation of neural stem/progenitor cells isolated from these mice and assessed the transcriptome of the hippocampal tissues of treated mice. RESULTS: We found that transient treatment with Nutlin-3 of 2-month-old young adult FMR1-deficient mice prevents the emergence of neurogenic and cognitive deficits in mature adult FXS mice at 6 months of age. We further found that the long-lasting restoration of neurogenesis and cognitive function might not be mediated by changing intrinsic properties of adult neural stem cells. Transcriptomic analysis of the hippocampal tissue demonstrated that transient Nultin-3 treatment leads to significant expression changes in genes related to the extracellular matrix, secreted factors, and cell membrane proteins in the FMR1-deficient hippocampus. CONCLUSIONS: Our data indicates that transient Nutlin-3 treatment in young adults leads to long-lasting neurogenic and behavioral changes likely through modulating adult neurogenic niche that impact adult neural stem cells. Our results demonstrate that cognitive impairments in FXS may be prevented by an early intervention through Nutlin-3 treatment.

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3. Junnarkar VS, Tong HJ, Hanna KMB, Aishworiya R, Duggal M. Occupational and speech therapists’ perceptions of their role in dental care for children with autism spectrum disorder: A qualitative exploration. Int J Paediatr Dent;2022 (May 13)

BACKGROUND: Children with autism spectrum disorders (ASD) have challenges in home oral care, accessing a dentist and accepting dental treatment. Occupational therapists (OTs) and speech therapists (STs) are likely to be involved earlier in managing communication, behavioural and sensory processing issues. AIM: To determine the perceived barriers and potential solutions to dental care for children with ASD in Singapore from the perspective of OTs and STs. DESIGN: Semi-structured interviews and a focus group discussion involving OTs and STs who treat children with ASD were conducted. Audio-recordings were transcribed and coded into themes using NVivo 12 software. RESULTS: Emergent themes indicated that: 1) OTs and STs have important roles in recognition of issues with toothbrushing, oral pathology and harmful oral habits 2) OTs and STs were able to identify reasons for difficulties in oral home care for children with ASD and offer helpful strategies 3) OTs and STs can play a role in pre-dental visit preparations, but lack a clear dental referral pathway. CONCLUSION: OTs and STs are in a unique position to assist in early identification and dental referrals of children with ASD. Interprofessional collaboration with dentists should be further explored to aid in provision of preventive dental advice.

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4. Kang LRJ, Barlott T, Turpin M, Urbanowicz A. A trial of the AASPIRE healthcare toolkit with Australian adults on the autism spectrum. Aust J Prim Health;2022 (May 13)

BACKGROUND: Autistic adults experience barriers to accessing health care, such as service provider communication not meeting their needs, healthcare facilities causing sensory discomfort and feeling fear or anxiety regarding their healthcare visit. The Academic Autism Spectrum Partnership in Research and Education (AASPIRE) developed and trialled an online healthcare toolkit to reduce such barriers and improve healthcare interactions between autistic adults and their primary care providers in the United States. This preliminary study aimed to explore experiences of autistic adults using the AASPIRE Healthcare Toolkit in Australia. METHODS: Semi-structured interviews were conducted with six autistic adults about their experiences and perceptions of utilising the toolkit in an Australian healthcare setting. RESULTS: Participants identified that the toolkit facilitated their interactions with health professionals by providing structure to appointments, supplementing new knowledge and increasing individual confidence. They also offered suggestions to tailor the toolkit for use in Australia. CONCLUSIONS: Future research should seek to explore the experiences of autistic adults using a version of the toolkit adapted for Australian use, as well as exploring the views of health professionals utilising it.

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5. Lassen J, Oranje B, Vestergaard M, Foldager M, Kjaer TW, Arnfred S, Aggernaes B. Reduced mismatch negativity in children and adolescents with autism spectrum disorder is associated with their impaired adaptive functioning. Autism Res;2022 (May 12)

Children and adolescents on the autism spectrum display sensory disturbances, rigid and repetitive behavior, social communication problems and a high prevalence of impaired adaptive functioning. Autism is associated with slowed behavioral and neural habituation to repeated sensory input and decreased responses to sensory deviations. Mismatch negativity (MMN) reflects a pre-attentive difference in the neural response to sensory deviations relative to regularities and studies overall suggest that children and adolescents with autism tend to have smaller MMN. However, it remains unclear whether reduced MMN in autism is coupled to severity of specific autistic symptoms or more generally to lower level of adaptive functioning. To address these questions, the present study used electroencephalography (EEG) to assess whether auditory MMN in 59 children and adolescents with autism aged 7-14 years compared to 59 typically developing children and adolescents were related to specific autistic symptoms or level in adaptive functioning. As hypothesized, the autism group had a lower MMN amplitude than controls. Smaller MMN amplitudes were specifically associated with lower adaptive functioning in the autistic subjects but not in controls while no apparent relationships were observed with autistic-like social interaction and communication problems, atypical language, rigidity, stereotypy or sensory sensitivity symptoms. Our findings indicate that a blunted response to changes in sensory input may underlie or contribute to the generalized difficulties with adapting to daily life circumstances seen in children and adolescents with autism. LAY SUMMARY: Children and adolescents on the autism spectrum have a high prevalence of impaired adaptive functioning. Neuroimaging studies have reported that children and adolescents with autism display attenuated brain activity when discriminating sensory input. However, it is unknown whether this attenuation is related to autistic symptoms and/or adaptive functioning. The present study used electroencephalogram (EEG) to show that attenuated brain response in discrimination of novel compared to repetitive sounds in children and adolescents with autism is related to their impaired adaptive functioning.

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6. Lin YJ, Chiu YN, Wu YY, Tsai WC, Gau SS. Correction to: Developmental Changes of Autistic Symptoms, ADHD Symptoms, and Attentional Performance in Children and Adolescents with Autism Spectrum Disorder. J Autism Dev Disord;2022 (May 13)

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7. Saha S, Chatterjee M, Dutta N, Sinha S, Mukhopadhyay K. GABA Receptor SNPs and Elevated Plasma GABA Levels Affect the Severity of the Indian ASD Probands. J Mol Neurosci;2022 (May 13)

Altered signaling of the chief inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), has been speculated in the etiology of autism spectrum disorder (ASD). We have investigated the association of six GABA(A)-receptor genetic variants and plasma GABA levels with ASD. Subjects were recruited based on the DSM, and CARS2-ST and ADI-R assessed disease severity. Peripheral blood was collected from the ASD probands (N = 251), their parents, and ethnically matched controls (N = 347). A positive correlation between the CARS2-ST and ADI-R scores was observed; domain scores of ADI-R were higher in the severe group categorized by the CARS2-ST. GABRB3 rs1432007 « A, » GABRG3 rs897173 « A, » and GABRA5 rs140682 « T » showed significant association with ASD. Trait scores were influenced by rs1432007 « AA » and rs140682 « TT. » GABA level was significantly higher in the probands than the age-matched controls. Our findings indicate an influence of GABA in the etiology of ASD in the Indian probands.

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8. Shih PY, Fang YL, Shankar S, Lee SP, Hu HT, Chen H, Wang TF, Hsia KC, Hsueh YP. Phase separation and zinc-induced transition modulate synaptic distribution and association of autism-linked CTTNBP2 and SHANK3. Nat Commun;2022 (May 13);13(1):2664.

Many synaptic proteins form biological condensates via liquid-liquid phase separation (LLPS). Synaptopathy, a key feature of autism spectrum disorders (ASD), is likely relevant to the impaired phase separation and/or transition of ASD-linked synaptic proteins. Here, we report that LLPS and zinc-induced liquid-to-gel phase transition regulate the synaptic distribution and protein-protein interaction of cortactin-binding protein 2 (CTTNBP2), an ASD-linked protein. CTTNBP2 forms self-assembled condensates through its C-terminal intrinsically disordered region and facilitates SHANK3 co-condensation at dendritic spines. Zinc binds the N-terminal coiled-coil region of CTTNBP2, promoting higher-order assemblies. Consequently, it leads to reduce CTTNBP2 mobility and enhance the stability and synaptic retention of CTTNBP2 condensates. Moreover, ASD-linked mutations alter condensate formation and synaptic retention of CTTNBP2 and impair mouse social behaviors, which are all ameliorated by zinc supplementation. Our study suggests the relevance of condensate formation and zinc-induced phase transition to the synaptic distribution and function of ASD-linked proteins.

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