1. Bourque VR, Poulain C, Proulx C, Moreau CA, Joober R, Forgeot d’Arc B, Huguet G, Jacquemont S. Genetic and phenotypic similarity across major psychiatric disorders: a systematic review and quantitative assessment. Transl Psychiatry. 2024; 14(1): 171.

There is widespread overlap across major psychiatric disorders, and this is the case at different levels of observations, from genetic variants to brain structures and function and to symptoms. However, it remains unknown to what extent these commonalities at different levels of observation map onto each other. Here, we systematically review and compare the degree of similarity between psychiatric disorders at all available levels of observation. We searched PubMed and EMBASE between January 1, 2009 and September 8, 2022. We included original studies comparing at least four of the following five diagnostic groups: Schizophrenia, Bipolar Disorder, Major Depressive Disorder, Autism Spectrum Disorder, and Attention Deficit Hyperactivity Disorder, with measures of similarities between all disorder pairs. Data extraction and synthesis were performed by two independent researchers, following the PRISMA guidelines. As main outcome measure, we assessed the Pearson correlation measuring the degree of similarity across disorders pairs between studies and biological levels of observation. We identified 2975 studies, of which 28 were eligible for analysis, featuring similarity measures based on single-nucleotide polymorphisms, gene-based analyses, gene expression, structural and functional connectivity neuroimaging measures. The majority of correlations (88.6%) across disorders between studies, within and between levels of observation, were positive. To identify a consensus ranking of similarities between disorders, we performed a principal component analysis. Its first dimension explained 51.4% (95% CI: 43.2, 65.4) of the variance in disorder similarities across studies and levels of observation. Based on levels of genetic correlation, we estimated the probability of another psychiatric diagnosis in first-degree relatives and showed that they were systematically lower than those observed in population studies. Our findings highlight that genetic and brain factors may underlie a large proportion, but not all of the diagnostic overlaps observed in the clinic.

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2. Bradshaw J, O’Reilly C, Everhart KC, Dixon E, Vinyard A, Tavakoli A, Dail RB. Neonatal autonomic regulation as a predictor of autism symptoms in very preterm infants. J Perinatol. 2024.

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3. Brown DG, Murphy M, Cadeddu R, Bell R, Weis A, Chiaro T, Klag K, Morgan J, Coon H, Stephens WZ, Bortolato M, Round JL. Colitis reduces active social engagement in mice and is ameliorated by supplementation with human microbiota members. Nat Commun. 2024; 15(1): 2769.

Multiple neurological disorders are associated with gastrointestinal (GI) symptoms, including autism spectrum disorder (ASD). However, it is unclear whether GI distress itself can modify aspects of behavior. Here, we show that mice that experience repeated colitis have impaired active social engagement, as measured by interactions with a foreign mouse, even though signs of colitis were no longer present. We then tested the hypothesis that individuals with ASD harbor a microbiota that might differentially influence GI health by performing microbiota transplantation studies into male germfree animals, followed by induction of colitis. Animals that harbor a microbiota from ASD individuals have worsened gut phenotypes when compared to animals colonized with microbiotas from familial neurotypical (NT) controls. We identify the enrichment of Blautia species in all familial NT controls and observe an association between elevated abundance of Bacteroides uniformis and reductions in intestinal injury. Oral treatment with either of these microbes reduces colon injury in mice. Finally, provision of a Blautia isolate from a NT control ameliorates gut injury-associated active social engagement in mice. Collectively, our data demonstrate that past intestinal distress is associated with changes in active social behavior in mice that can be ameliorated by supplementation of members of the human microbiota.

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4. Du Z, Du P, Liu A. Likelihood ratio combination of multiple biomarkers via smoothing spline estimated densities. Stat Med. 2024; 43(7): 1372-83.

The diagnostic accuracy of multiple biomarkers in medical research is crucial for detecting diseases and predicting patient outcomes. An optimal method for combining these biomarkers is essential to maximize the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC). Although the optimality of the likelihood ratio has been proven by Neyman and Pearson, challenges persist in estimating the likelihood ratio, primarily due to the estimation of multivariate density functions. In this study, we propose a non-parametric approach for estimating multivariate density functions by utilizing Smoothing Spline density estimation to approximate the full likelihood function for both diseased and non-diseased groups, which compose the likelihood ratio. Simulation results demonstrate the efficiency of our method compared to other biomarker combination techniques under various settings for generated biomarker values. Additionally, we apply the proposed method to a real-world study aimed at detecting childhood autism spectrum disorder (ASD), showcasing its practical relevance and potential for future applications in medical research.

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5. Khattab NA, El-Kadem AH, Elblehi SS, Ahmed El-Mahdy N, El-Shitany NA. The emerging role of α7nAChRs/caspase-3/Nrf-2 signaling pathway in citicoline improved autistic behavior induced by thimerosal in mice. Int Immunopharmacol. 2024; 130: 111736.

AIMS: Autism spectrum disorder (ASD) is a global concern,affecting around 75 million individuals.Various factors contribute to ASD,including mercury-containing preservatives like thimerosal (Thim) found in some vaccines.This study explored whether citicoline could be a therapeutic option for Thim-induced neuronal damage in a mouse model of ASD.Additionally,the study investigated the effects of citicoline on the α7nAChRs/Akt/Nrf2/caspase-3 pathway,which may be involved in the development of ASD. MATERIALS AND METHODS: The study separated newborn mice into four groups.The control group received saline injections,while the Thim group received intramuscular injections of 3000 μg Hg/kg Thim on days 7,9,11,and 15 after birth.The two citicoline groups were administered Thim followed by intraperitoneal injections of 250 mg/kg or 500 mg/kg citicoline for three weeks.Afterward,various parameters were assessed, including growth,behavior,brain histopathology,oxidative stress,apoptotic,and inflammatory markers. KEY FINDINGS: Untreated Thim-exposed mice exhibited significant brain damage,which was substantially alleviated by citicoline treatment.This beneficial effect was associated with increased expressions and concentrations of brain α7nAChRs and Akt, increased brain content of Nrf2, and the hippocampus contents of acetylcholine. Citicoline treatment decreased the brain levels of oxidative stress markers (MDA and NO),the apoptotic marker caspase-3,and pro-inflammatory markers (NF-κB,TNF-α,and IL-1β). The drug also increased the brain GPx activity. SIGNIFICANCE: Based on the results of this study,the α7nAChRs pathway appears to be essential for the therapeutic effectiveness of citicoline in treating Thim-induced ASD in mice.

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6. Kuo PL. Response to letter to the editor « Preterm birth and weight-for-gestational age for risks of autism spectrum disorder and intellectual disability: A nationwide population-based cohort study ». J Formos Med Assoc. 2024.

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7. Liang ZK, Xiong W, Wang C, Chen L, Zou X, Mai JW, Dong B, Guo C, Xin WJ, Luo DX, Xu T, Feng X. Resolving neuroinflammatory and social deficits in ASD model mice: Dexmedetomidine downregulates NF-κB/IL-6 pathway via α2AR. Brain Behav Immun. 2024.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that severely affects individuals’ daily life and social development. Unfortunately, there are currently no effective treatments for ASD. Dexmedetomidine (DEX) is a selective agonist of α2 adrenergic receptor (α2AR) and is widely used as a first-line medication for sedation and hypnosis in clinical practice. In recent years, there have been reports suggesting its potential positive effects on improving emotional and cognitive functions. However, whether dexmedetomidine has therapeutic effects on the core symptoms of ASD, namely social deficits and repetitive behaviors, remains to be investigated. In the present study, we employed various behavioral tests to assess the phenotypes of animals, including the three-chamber, self-grooming, marble burying, open field, and elevated plus maze. Additionally, electrophysiological recordings, western blotting, qPCR were mainly used to investigate and validate the potential mechanisms underlying the role of dexmedetomidine. We found that intraperitoneal injection of dexmedetomidine in ASD model mice-BTBR T(+) Itpr3(tf)/J (BTBR) mice could adaptively improve their social deficits. Further, we observed a significant reduction in c-Fos positive signals and interleukin-6 (IL-6) expression level in the prelimbic cortex (PrL) of the BTBR mice treated with dexmedetomidine. Enhancing or inhibiting the action of IL-6 directly affects the social behavior of BTBR mice. Mechanistically, we have found that NF-κB p65 is a key pathway regulating IL-6 expression in the PrL region. In addition, we have confirmed that the α2AR acts as a receptor switch mediating the beneficial effects of dexmedetomidine in improving social deficits. This study provides the first evidence of the beneficial effects of dexmedetomidine on core symptoms of ASD and offers a theoretical basis and potential therapeutic approach for the clinical treatment of ASD.

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8. Longhurst P, Todd J, Aspell JE, Swami V. Psychometric evaluation of a revised version of the body appreciation scale-2 for autistic adults (BAS-2A). Body Image. 2024; 49: 101706.

Emerging evidence points to unique conceptualisations of positive body image in autistic individuals. However, there are no existing measures of positive body image that have been developed or validated for use with autistic adults. To rectify this, we developed a revised version of the BAS-2 – the BAS-2A – and examined its factorial validity and psychometric properties in a sample of autistic adults from the United Kingdom. Based on the results of exploratory factor analysis and scale purification, we extracted a 12-item, unidimensional model of BAS-2A scores in a first split-subsample (n = 273). Confirmatory factor analysis supported the unidimensional model of BAS-2A scores in a second split-subsample (n = 277). BAS-2A scores presented adequate composite reliability, measurement invariance across gender identity, and patterns of construct validity. For both women and men, BAS-2A scores correlated positively with self-esteem, well-being, quality of life, and adaptive coping, and inversely with dietary restraint, weight/shape overvaluation, body dissatisfaction, and depression. Finally, BAS-2A scores demonstrated incremental validity, predicting self-esteem over-and-above body dissatisfaction. However, temporal stability of the BAS-2A over three weeks was not supported. These results support the BAS-2A as a psychometrically robust measure of body appreciation for use in autistic adults from the United Kingdom.

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9. Lyvers M, Dark S, Jaguru I, Thorberg FA. Adult Symptoms of ASD and ADHD in Relation to Alcohol Use: Potential Roles of Transdiagnostic Features. Alcohol. 2024.

Attention Deficit Hyperactivity Disorder (ADHD) is the most common comorbidity in Autism Spectrum Disorder (ASD). ADHD is a risk factor for alcohol misuse whereas ASD is often regarded as protective; however, research on ASD and alcohol use has yielded conflicting findings, sometimes implicating the role of comorbid ADHD. The possibility that certain transdiagnostic features (i.e., characteristics associated with multiple disorders) may underlie relationships of both disorders to alcohol use in adults was examined in the present study. A nonclinical young adult sample of 248 alcohol users (117 men, 131 women) completed validated self-report measures of ASD and ADHD symptoms as well as the transdiagnostic features alexithymia, impulsivity, and negative moods. ASD and ADHD symptoms were normally distributed, suggesting that the respective disorders represent extreme, dysfunctional ends of population distributions of symptoms. Path analysis indicated that the significant positive association between ASD and ADHD symptom measures was fully mediated by alexithymia, impulsivity, and negative moods. Hierarchical regression and path analysis indicated that the positive relationship between ADHD symptoms and alcohol use severity was fully mediated by transdiagnostic features, particularly alexithymia and impulsivity, whereas the relationship between ASD and alcohol use severity was positively mediated by these features (especially alexithymia), with a highly significant and negative direct effect. Present findings may help reconcile previous conflicting evidence on the relationship of ASD to alcohol use, and the role of comorbid ADHD, by emphasizing the roles of alexithymia and impulsivity in both ASD and ADHD as transdiagnostic traits promoting excessive drinking.

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10. Niimi T, Inaba Y, Honda H. Developmental changes in prefrontal cortex activation in children with or without autism spectrum traits on near-infrared spectroscopy. Brain Dev. 2024.

BACKGROUND: Autism spectrum disorder (ASD) ranges from mild to severe symptoms, with autistic traits possibly distributed throughout the population. However, the precise neurodevelopmental differences in children with autistic traits remain unknown. SUBJECTS AND METHODS: Fifty-three healthy volunteers (32 male and 21 female, mean [standard deviation] age: 12.9 [2.5] years) having a normal intelligence quotient and without social impairment were divided into two groups according to scores of the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS). Subjects with or without autistic traits were placed into the high-PARS (n = 14) or low-PARS (n = 39) group, respectively. Activation of the prefrontal cortex was estimated using change in hemoglobin oxygenation concentration (Δ[oxy-Hb]) on near-infrared spectroscopy (NIRS) during a verbal fluency test. Age-related changes in prefrontal cortex activation were first assessed for each group. Then, the effects of age (elementary school age or junior/senior high school age) and PARS score on Δ[oxy-Hb] in the task were analyzed by two-way analysis of variance. RESULTS: We observed significant positive correlations between mean Δ[oxy-Hb] and age in the prefrontal cortex region in the low-PARS group. Mean Δ[oxy-Hb] in the low-PARS group was significantly higher than in the high-PARS group. Task performance results were comparable between the groups. CONCLUSION: In PARS-determined typically developed children, prefrontal cortex activation on NIRS correlated positively with age. In healthy volunteers without ASD but harboring autistic traits, prefrontal cortex activation was markedly lower than in normal counterparts. Our results provide biological evidence that ASD may be a pervasively distributed disorder.

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11. Ramazani Z, Nakhaee S, Sharafi K, Rezaei Z, Mansouri B. Autism spectrum disorder: Cadmium and mercury concentrations in different biological samples, a systematic literature review and meta-analysis of human studies. Heliyon. 2024; 10(6): e27789.

The present study was conducted to investigate the differences in cadmium (Cd) and mercury (Hg) concentrations between children with autism spectrum disorder (ASD) and controls. In this systematic review and meta-analysis study, three thousand one hundred forty-five studies were collected from scientific databases including Web of Science, Scopus, PubMed, and Google Scholar from January 2000 to October 2022 and were investigated for eligibility. As a result, 37 studies published in the period from 2003 to 2022 met our inclusion criteria and were considered in the meta-analysis. The heterogeneity assumption was evaluated using the Chi-squared-based Q-test and I-squared (I(2)) statistics. The pooled estimates were shown in the forest plots with Hedges’ g (95% confidence interval) values. The random effects model demonstrated that there is no significant difference in the blood (Hedges’ g: 0.14, 95% CI: 0.45, 0.72, p > 0.05), hair (Hedges’ g: 0.12, 95% CI: 0.26, 0.50, p > 0.05), and urinary (Hedges’ g: 0.05, 95% CI: 0.86, 0.76, p > 0.05) Cd levels of the case group versus control subjects. Moreover, the pooled findings of studies showed no significant difference in the blood (Hedges’ g: 1.69, 95% CI: 0.09, 3.48, p > 0.05), hair (Hedges’ g: 3.42, 95% CI: 1.96, 8.80, p > 0.05), and urinary (Hedges’ g: 0.49, 95% CI: 1.29 – 0.30, p > 0.05) Hg concentrations. The results demonstrated no significant differences in Hg and Cd concentrations in different biological samples of children with ASD compared to control subjects.

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12. Zheng X, Zhou F, Fu M, Xu L, Wang J, Li J, Li K, Sindermann C, Montag C, Becker B, Zhan Y, Kendrick KM. Patterns of neural activity in response to threatening faces are predictive of autistic traits: modulatory effects of oxytocin receptor genotype. Transl Psychiatry. 2024; 14(1): 168.

Autistic individuals generally demonstrate impaired emotion recognition but it is unclear whether effects are emotion-specific or influenced by oxytocin receptor (OXTR) genotype. Here we implemented a dimensional approach using an implicit emotion recognition task together with functional MRI in a large cohort of neurotypical adult participants (N = 255, male = 131, aged 17-29 years) to establish associations between autistic traits and neural and behavioral responses to specific face emotions, together with modulatory effects of OXTR genotype. A searchlight-based multivariate pattern analysis (MVPA) revealed an extensive network of frontal, basal ganglia, cingulate and limbic regions exhibiting significant predictability for autistic traits from patterns of responses to angry relative to neutral expression faces. Functional connectivity analyses revealed a genotype interaction (OXTR SNPs rs2254298, rs2268491) for coupling between the orbitofrontal cortex and mid-cingulate during angry expression processing, with a negative association between coupling and autistic traits in the risk-allele group and a positive one in the non-risk allele group. Overall, results indicate extensive emotion-specific associations primarily between patterns of neural responses to angry faces and autistic traits in regions processing motivation, reward and salience but not in early visual processing. Functional connections between these identified regions were not only associated with autistic traits but also influenced by OXTR genotype. Thus, altered patterns of neural responses to threatening faces may be a potential biomarker for autistic symptoms although modulatory influences of OXTR genotype need to be taken into account.

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