1. Axelsson J, van Someren EJW, Balter LJT. Sleep profiles of different psychiatric traits. Transl Psychiatry;2024 (Jul 12);14(1):284.

Disturbed sleep comes in many forms. While the key role of sleep in mental health is undisputed, our understanding of the type of sleeping problems that manifest in the early stages of psychiatric disorders is limited. A sample without psychiatric diagnoses (N = 440, 341 women, 97 men, 2 non-binaries; M(age) = 32.1, SD = 9.4, range 18-77) underwent a comprehensive assessment, evaluating eight sleep features and 13 questionnaires on common psychiatric complaints. Results revealed that traits of affect disorders, generalized anxiety, and ADHD had the worst sleep profiles, while autism disorder, eating disorder, and impulsivity traits showed milder sleep issues. Mania was the only trait associated with an overall better sleep profile. Across traits, insomnia and fatigue dominated and sleep variability was least prominent. These findings provide support for both transdiagnostic and disorder-specific targets for prevention and treatment.

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2. Baldi S, Amer B, Alnadari F, Al-Mogahed M, Gao Y, Gamallat Y. The Prognostic and Therapeutic Potential of Fragile X Mental Retardation 1 (FMR1) Gene Expression in Prostate Adenocarcinoma: Insights into Survival Outcomes and Oncogenic Pathway Modulation. Int J Mol Sci;2024 (Jul 2);25(13)

Prostate adenocarcinoma (PRAD) is the second most common tumor associated with death. The role and mechanisms of the fragile X mental retardation 1 (FMR1) gene in PRAD remain unknown. We conducted an analysis of FMR1 expression in PRAD to determine its prognostic importance and connection to carcinogenic pathways such as PI3K_AKT_mTOR. Survival analyses were utilized to establish a correlation between FMR1 expression and patient outcomes. We used the integration of genomic data with bioinformatic predictions to predict the regulatory factors of the FMR1 gene in PRAD. Our data revealed that individuals with higher levels of FMR1 expression experience worse survival outcomes compared to those with lower expression (hazard ratio [HR] = 5.08, 95% confidence interval [CI] = 1.07 – 24, p = 0.0412). FMR1 expression was significantly higher in patients with advanced pathological tumor stages, particularly in the pT3 and pT4 combined stages and the pN1 nodal stage. Furthermore, patients with high Gleason scores (GSs) (combined GSs 8 and 9) exhibited increased levels of FMR1 expression. Our results further identify a possible regulatory link between FMR1 and key oncogenic pathways, including PI3K_AKT_mTOR, and predict the possible mechanism by which FMR1 is regulated in PRAD. Our data suggest that the FMR1 gene could serve as a biomarker for PRAD progression. However, in-depth investigations, including those with large patient samples and in vitro studies, are needed to validate this finding and understand the mechanisms involved.

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3. Bhat AN. Validating motor delays across the developmental coordination disorder-questionnaire and the Vineland adaptive behavior scales (VABS) in children with autism spectrum disorderASD: A SPARK dataset analysis. Autism Res;2024 (Jul 13)

Motor delays in children with autism spectrum disorder (ASD) are being increasingly recognized using a brief screening tool, called the Developmental Coordination Disorder-Questionnaire (DCD-Q). Further validation of these motor delays using a more robust normed, developmental measure is clearly warranted. In this analysis, a nationally representative sample from the SPARK study was used wherein parents completed the DCD-Q and a more widely used developmental/adaptive functioning measure, called the Vineland Adaptive Behavior Scales (VABS); which comprises of various developmental domains including the motor domain (N = 2,644 completed the DCD-Q and VABS). Eighty two percent children with ASD had a motor delay based on their DCD-Q scores whereas 77% children with ASD had a motor delay based on their VABS motor domain scores. Approximately 70% children with ASD had concurrent motor delay on the DCD-Q and the VABS (i.e., positive predictive value of DCD-Q). Furthermore, there was 81.2% accuracy in reporting a risk/no risk of motor delay across both measures. Overall, these statistics align with the recent reports on proportions of children with ASD having motor delays. Parents of ~70% children with ASD are reporting motor delays that are corroborated across two different motor measures. This not only validates the motor delays reported based on the DCD-Q but also indicates the need for concurrent motor screening using both DCD-Q and VABS for better detection of motor delays in children with ASD. Only 10%-32% of the current SPARK sample received any physical or recreational therapies. This mismatch between presence of motor delays and the lack of access to motor services highlights the need for more motor intervention referrals for children with ASD.

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4. Biswal SR, Kumar A, Muthuswamy S, Kumar S. Genetic components of microdeletion syndromes and their role in determining schizophrenia traits. Mol Biol Rep;2024 (Jul 13);51(1):804.

Schizophrenia is a neuropsychiatric disorder characterized by various symptoms such as hallucinations, delusions, and disordered thinking. The etiology of this disease is unknown; however, it has been linked to many microdeletion syndromes that are likely to contribute to the pathology of schizophrenia. In this review we have comprehensively analyzed the role of various microdeletion syndromes, like 3q29, 15q13.3, and 22q11.2, which are known to be involved with schizophrenia. A variety of factors lead to schizophrenia phenotypes, but copy number variants that disrupt gene regulation and impair brain function and cognition are one of the causes that have been identified. Multiple case studies have shown that loss of one or more genes in the microdeletion regions lead to brain activity defects. In this article, we present a coherent paradigm that connects copy number variations (CNVs) to numerous neurological and behavioral abnormalities associated with schizophrenia. It would be helpful in understanding the different aspects of the microdeletions and how they contribute in the pathophysiology of schizophrenia.

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5. Hrnciarova J, Kubelkova K, Bostik V, Rychlik I, Karasova D, Babak V, Datkova M, Simackova K, Macela A. Modulation of Gut Microbiome and Autism Symptoms of ASD Children Supplemented with Biological Response Modifier: A Randomized, Double-Blinded, Placebo-Controlled Pilot Study. Nutrients;2024 (Jun 21);16(13)

The etiology and mechanisms of autism and autism spectrum disorder (ASD) are not yet fully understood. There is currently no treatment for ASD for providing significant improvement in core symptoms. Recent studies suggest, however, that ASD is associated with gut dysbiosis, indicating that modulation of gut microbiota in children with ASD may thus reduce the manifestation of ASD symptoms. The aim of this pilot study (prospective randomized, double-blinded, placebo-controlled) was to evaluate efficacy of the biological response modifier Juvenil in modulating the microbiome of children with ASD and, in particular, whether Juvenil is able to alleviate the symptoms of ASD. In total, 20 children with ASD and 12 neurotypical children were included in our study. Supplementation of ASD children lasted for three months. To confirm Juvenil’s impact on the gut microbiome, stool samples were collected from all children and the microbiome’s composition was analyzed. This pilot study demonstrated that the gut microbiome of ASD children differed significantly from that of healthy controls and was converted by Juvenil supplementation toward a more neurotypical microbiome that positively modulated children’s autism symptoms.

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6. Kim SY, Lecavalier L. Stability and Validity of Self-Reported Depression and Anxiety in Autistic Youth. J Autism Dev Disord;2024 (Jul 13)

The aim of this study was to assess test-retest reliability and diagnostic validity of self-report instruments of depression and anxiety in autistic youth. Participants were 55 autistic youth aged 8-17 years presenting with depressive or anxiety symptoms. They were interviewed with the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS-PL) and completed the Children’s Depression Inventory, Second Edition – Self Report Short (CDI 2:SR[S]) and the Revised Child Anxiety and Depression Scale (RCADS) twice, separated by a two-week interval. Test-retest reliability was measured with intraclass correlation coefficients (ICCs), and diagnostic validity was assessed using receiver operating characteristic (ROC) curves with the summary ratings on the K-SADS-PL as the criterion. The effect of participant characteristics was analyzed through a moderation analysis. Generalized anxiety (GAD) and social anxiety disorder (SOC) were the two most prevalent disorders in the sample. Test-retest reliability for most of the subscales was good (ICC = 0.74 - 0.87), with the exception of the RCADS obsessive-compulsive disorder (OCD) and GAD. The Adaptive Behavior conceptual score was a significant moderator of the reliability of the CDI 2:SR[S]. The ROC analysis suggested the RCADS SOC and the CDI 2:SR[S] to be good screening tools with inadequate specificity when appropriately sensitive cutoff scores are used. Optimal cutoff scores in this sample were lower than originally published. The findings suggest that autistic youth can provide stable reports of anxiety and depressive symptoms over time. Diagnostic validity varied according to the construct and instrument.

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7. Li M, Izumoto M, Wang Y, Kato Y, Iwatani Y, Hirata I, Mizuno Y, Tachibana M, Mohri I, Kagitani-Shimono K. Altered white matter connectivity of ventral language networks in autism spectrum disorder: An automated fiber quantification analysis with multi-site datasets. Neuroimage;2024 (Jul 13);297:120731.

Comprehension and pragmatic deficits are prevalent in autism spectrum disorder (ASD) and are potentially linked to altered connectivity in the ventral language networks. However, previous magnetic resonance imaging studies have not sufficiently explored the microstructural abnormalities in the ventral fiber tracts underlying comprehension dysfunction in ASD. Additionally, the precise locations of white matter (WM) changes in the long tracts of patients with ASD remain poorly understood. In the current study, we applied the automated fiber-tract quantification (AFQ) method to investigate the fine-grained WM properties of the ventral language pathway and their relationships with comprehension and symptom manifestation in ASD. The analysis included diffusion/T1 weighted imaging data of 83 individuals with ASD and 83 age-matched typically developing (TD) controls. Case-control comparisons were performed on the diffusion metrics of the ventral tracts at both the global and point-wise levels. We also explored correlations between diffusion metrics, comprehension performance, and ASD traits, and conducted subgroup analyses based on age range to examine developmental moderating effects. Individuals with ASD exhibited remarkable hypoconnectivity in the ventral tracts, particularly in the temporal portions of the left inferior longitudinal fasciculus (ILF) and the inferior fronto-occipital fasciculus (IFOF). These WM abnormalities were associated with poor comprehension and more severe ASD symptoms. Furthermore, WM alterations in the ventral tract and their correlation with comprehension dysfunction were more prominent in younger children with ASD than in adolescents. These findings indicate that WM disruptions in the temporal portions of the left ILF/IFOF are most notable in ASD, potentially constituting the core neurological underpinnings of comprehension and communication deficits in autism. Moreover, impaired WM connectivity and comprehension ability in patients with ASD appear to improve with age.

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8. Lumsden DE. What you see is what you get? Eye gaze as a window to vocabulary in Rett Syndrome. Eur J Paediatr Neurol;2024 (Jul 10)

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9. Montanaro FAM, Alfieri P, Caciolo C, Brunetti A, Airoldi A, de Florio A, Tinella L, Bosco A, Vicari S. Fragile X Syndrome and FMR1 premutation: results from a survey on associated conditions and treatment priorities in Italy. Orphanet J Rare Dis;2024 (Jul 12);19(1):264.

BACKGROUND AND OBJECTIVES: Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability, caused by CGG-repeat expansions (> 200) in the FMR1 gene leading to lack of expression. Espansion between 55 and 200 triplets fall within the premutation range (PM) and can lead to different clinical conditions, including fragile X- primary ovarian insufficiency (FXPOI), fragile X-associated neuropsychiatric disorders (FXAND) and fragile X-associated tremor/ataxia syndrome (FXTAS). Although there is not a current cure for FXS and for the Fragile X-PM associated conditions (FXPAC), timely diagnosis as well as the implementation of treatment strategies, psychoeducation and behavioral intervention may improve the quality of life (QoL) of people with FXS or FXPAC. With the aim to investigate the main areas of concerns and the priorities of treatment in these populations, the Italian National Fragile X Association in collaboration with Bambino Gesù Children’s Hospital, conducted a survey among Italian participants. METHOD: Here, we present a survey based on the previous study that Weber and colleagues conducted in 2019 and that aimed to investigate the main symptoms and challenges in American individuals with FXS. The survey has been translated into Italian language to explore FXS needs of treatment also among Italian individuals affected by FXS, family members, caretakers, and professionals. Furthermore, we added a section designated only to people with PM, to investigate the main symptoms, daily living challenges and treatment priorities. RESULTS: Anxiety, challenging behaviors, language difficulties and learning disabilities were considered the major areas of concern in FXS, while PM was reported as strongly associated to cognitive problems, social anxiety, and overthinking. Anxiety was reported as a treatment priority in both FXS and PM. CONCLUSION: FXS and PM can be associated with a range of cognitive, affective, and physical health complications. Taking a patient-first perspective may help clinicians to better characterize the cognitive-behavioral phenotype associated to these conditions, and eventually to implement tailored therapeutic approaches.

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10. Mouat JS, Krigbaum NY, Hakam S, Thrall E, Mellis J, Yasui DH, Cirillo PM, Ludena Y, Schmidt RJ, La Merrill MA, Hertz-Picciotto I, Cohn BA, LaSalle JM. Females with autism spectrum disorders show stronger DNA methylation signatures than males in perinatal tissues. bioRxiv;2024 (Jul 13)

Autism spectrum disorder (ASD) comprises a group of neurodevelopmental conditions currently diagnosed by behavioral assessment in childhood, with reported underdiagnosis in females. Though diagnosis in early life is linked to improved outcomes, we currently lack objective screening tools for newborns. To address this gap, we sought to identify a sex-specific DNA methylation signature for ASD using perinatal tissues that reflect dysregulation in the brain. DNA methylation was assayed from ASD and typically developing (TD) newborn blood, umbilical cord blood, placenta, and post-mortem cortex samples using whole genome bisulfite sequencing (WGBS) in a total of 511 samples. We found that methylation levels of differentially methylated regions (DMRs) differentiated samples by ASD diagnosis in females more than males across the perinatal tissues. We tested three theories for ASD sex differences in newborn blood, finding epigenetic support for an X chromosome-related female protective effect, as well as a high replication rate of DMRs (48.1%) in females across two independent cohorts. In our pan-tissue analysis, three genes (X-linked BCOR , GALNT9 , OPCML ) mapped to ASD DMRs replicated in all four female tissues. ASD DMRs from all tissues were enriched for neuro-related processes (females) and SFARI ASD-risk genes (females and males). Overall, we found a highly replicated methylation signature of ASD in females across perinatal tissues that reflected dysregulation in the brain and involvement of X chromosome epigenetics. This comparative study of perinatal tissues shows the promise of newborn blood DNA methylation biomarkers for early detection of females at risk for ASD and emphasizes the importance of sex-stratification in ASD studies.

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11. Tsotsokou G, Miliou A, Trompoukis G, Leontiadis LJ, Papatheodoropoulos C. Region-Related Differences in Short-Term Synaptic Plasticity and Synaptotagmin-7 in the Male and Female Hippocampus of a Rat Model of Fragile X Syndrome. Int J Mol Sci;2024 (Jun 26);25(13)

Fragile X syndrome (FXS) is an intellectual developmental disorder characterized, inter alia, by deficits in the short-term processing of neural information, such as sensory processing and working memory. The primary cause of FXS is the loss of fragile X messenger ribonucleoprotein (FMRP), which is profoundly involved in synaptic function and plasticity. Short-term synaptic plasticity (STSP) may play important roles in functions that are affected by FXS. Recent evidence points to the crucial involvement of the presynaptic calcium sensor synaptotagmin-7 (Syt-7) in STSP. However, how the loss of FMRP affects STSP and Syt-7 have been insufficiently studied. Furthermore, males and females are affected differently by FXS, but the underlying mechanisms remain elusive. The aim of the present study was to investigate possible changes in STSP and the expression of Syt-7 in the dorsal (DH) and ventral (VH) hippocampus of adult males and females in a Fmr1-knockout (KO) rat model of FXS. We found that the paired-pulse ratio (PPR) and frequency facilitation/depression (FF/D), two forms of STSP, as well as the expression of Syt-7, are normal in adult KO males, but the PPR is increased in the ventral hippocampus of KO females (6.4 ± 3.7 vs. 18.3 ± 4.2 at 25 ms in wild type (WT) and KO, respectively). Furthermore, we found no gender-related differences, but did find robust region-dependent difference in the STSP (e.g., the PPR at 50 ms: 50.0 ± 5.5 vs. 17.6 ± 2.9 in DH and VH of WT male rats; 53.1 ± 3.6 vs. 19.3 ± 4.6 in DH and VH of WT female rats; 48.1 ± 2.3 vs. 19.1 ± 3.3 in DH and VH of KO male rats; and 51.2 ± 3.3 vs. 24.7 ± 4.3 in DH and VH of KO female rats). AMPA receptors are similarly expressed in the two hippocampal segments of the two genotypes and in both genders. Also, basal excitatory synaptic transmission is higher in males compared to females. Interestingly, we found more than a twofold higher level of Syt-7, not synaptotagmin-1, in the dorsal compared to the ventral hippocampus in the males of both genotypes (0.43 ± 0.1 vs. 0.16 ± 0.02 in DH and VH of WT male rats, and 0.6 ± 0.13 vs. 0.23 ± 0.04 in DH and VH of KO male rats) and in the WT females (0.97 ± 0.23 vs. 0.31 ± 0.09 in DH and VH). These results point to the susceptibility of the female ventral hippocampus to FMRP loss. Importantly, the different levels of Syt-7, which parallel the higher score of the dorsal vs. ventral hippocampus on synaptic facilitation, suggest that Syt-7 may play a pivotal role in defining the striking differences in STSP along the long axis of the hippocampus.

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12. Wieting J, Baumann MV, Deest-Gaubatz S, Bleich S, Eberlein CK, Frieling H, Deest M. Structured neurological soft signs examination reveals motor coordination deficits in adults diagnosed with high-functioning autism. Sci Rep;2024 (Jul 12);14(1):16123.

Neurological soft signs (NSS), discrete deficits in motor coordination and sensory integration, have shown promise as markers in autism diagnosis. While motor impairments, partly associated with core behavioral features, are frequently found in children with autism, there is limited evidence in adults. In this study, NSS were assessed in adults undergoing initial diagnosis of high-functioning autism (HFA), a subgroup difficult to diagnose due to social adaptation and psychiatric comorbidity. Adults with HFA (n = 34) and 1:1 sex-, age-, and intelligence-matched neurotypical controls were administered a structured NSS examination including motor, sensory, and visuospatial tasks. We showed that adults with HFA have significantly increased motor coordination deficits compared with controls. Using hierarchical cluster analysis within the HFA group, we also identified a subgroup that was particularly highly affected by NSS. This subgroup differed from the less affected by intelligence level, but not severity of autism behavioral features nor global psychological distress. It remains questionable whether motor impairment represents a genuinely autistic trait or is more a consequence of factors such as intelligence. Nevertheless, we conclude that examining NSS in terms of motor coordination may help diagnose adults with HFA and identify HFA individuals who might benefit from motor skills interventions.

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13. Xing Y, Liu H, Wu X. Acquisition and Retention Effects of Fundamental Movement Skills on Physical Activity and Health-Related Fitness of Children with Autism Spectrum Disorder. Healthcare (Basel);2024 (Jun 29);12(13)

This study adopted a quasi-experimental design to explore the effects of fundamental movement skill intervention on the acquisition and retention of physical activity levels and health-related fitness in children with autism spectrum disorder (ASD). In the experiments, 11 children received fundamental motor skill training (12 weeks, 60 min/session, 4 times/week), and 10 children maintained traditional physical activity. Assessments were performed using an ActiGraph GT3X+ accelerometer, health-related fitness pre-post intervention, and 1-month follow-up tests. The sedentary time during physical activity was significantly decreased (p = 0.01), and there were large changes in health-related physical fitness indicators, including significantly improved body composition (body mass index, F(1,19) = 8.631, p = 0.03, partial η(2) = 0.312), muscle strength and endurance (sit-ups, F(1,19) = 3.376, p = 0.02, partial η(2) = 0.151 and vertical jumps, F(1,19) = 5.309, p = 0.04, partial η(2) = 0.218), and flexibility (sit and reach, F(1,19) = 36.228, p = 0.02, partial η(2) = 0.656). Moreover, the follow-up tests showed that the children’s sedentary time continued to reduce, and the muscle strength and endurance (sit-ups, F(1,19) = 4.215, p = 0.01, partial η(2) = 0.426) improved continuously after the intervention. Based on this study, actionable and regular fundamental movement skill programs can be provided in the future as an effective way to achieve the healthy development goals of children with ASD.

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14. Zhou D, Hua T, Tang H, Yang R, Huang L, Gong Y, Zhang L, Tang G. Gender and age related brain structural and functional alterations in children with autism spectrum disorder. Cereb Cortex;2024 (Jul 3);34(7)

To explore the effects of age and gender on the brain in children with autism spectrum disorder using magnetic resonance imaging. 185 patients with autism spectrum disorder and 110 typically developing children were enrolled. In terms of gender, boys with autism spectrum disorder had increased gray matter volumes in the insula and superior frontal gyrus and decreased gray matter volumes in the inferior frontal gyrus and thalamus. The brain regions with functional alterations are mainly distributed in the cerebellum, anterior cingulate gyrus, postcentral gyrus, and putamen. Girls with autism spectrum disorder only had increased gray matter volumes in the right cuneus and showed higher amplitude of low-frequency fluctuation in the paracentral lobule, higher regional homogeneity and degree centrality in the calcarine fissure, and greater right frontoparietal network-default mode network connectivity. In terms of age, preschool-aged children with autism spectrum disorder exhibited hypo-connectivity between and within auditory network, somatomotor network, and visual network. School-aged children with autism spectrum disorder showed increased gray matter volumes in the rectus gyrus, superior temporal gyrus, insula, and suboccipital gyrus, as well as increased amplitude of low-frequency fluctuation and regional homogeneity in the calcarine fissure and precentral gyrus and decreased in the cerebellum and anterior cingulate gyrus. The hyper-connectivity between somatomotor network and left frontoparietal network and within visual network was found. It is essential to consider the impact of age and gender on the neurophysiological alterations in autism spectrum disorder children when analyzing changes in brain structure and function.

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