Pubmed du 15/08/23
1. Brown RL, Epel EE, Lin J, Dubal DB, Prather AA. Associations between klotho and telomere biology in high stress caregivers. Aging (Albany NY);2023 (Aug 14);15(15):7381-7396.
Aging biomarkers may be related to each other through direct co-regulation and/or through being regulated by common processes associated with chronological aging or stress. Klotho is an aging regulator that acts as a circulating hormone with critical involvement in regulating insulin signaling, phosphate homeostasis, oxidative stress, and age-related inflammatory functioning. Both klotho and telomere length are biomarkers of biological aging and decrease with age; however, the relationship between them is not well understood. Here we test the association between klotho levels and the telomere length of specific sorted immune cells among a healthy sample of mothers caregiving for a child with autism spectrum disorder (ASD; i.e., experiencing higher caregiving stress) or a child without ASD, covarying age and body mass index, in order to understand if high stress associated with caregiving for a child with an ASD may be involved in any association between these aging biomarkers. In 178 caregiving women (n = 90 high-stress mothers of children with ASD, n = 88 low-stress mothers of neurotypical children), we found that klotho levels were positively associated with telomere length in PBMCs (an effect driven by CD4+ and CD8+CD28- T cells) among high-stress mothers of children with an ASD but not among low-stress mothers of neurotypical children. There were no significant associations between klotho and telomerase activity in either group, across cell types assessed here. Our results suggest that klotho levels and telomere length may be associated through a coordinated downregulation of longevity factors occurring under higher stress caregiving conditions.
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2. Chavoshnejad P, Vallejo L, Zhang S, Guo Y, Dai W, Zhang T, Razavi MJ. Mechanical hierarchy in the formation and modulation of cortical folding patterns. Sci Rep;2023 (Aug 14);13(1):13177.
The important mechanical parameters and their hierarchy in the growth and folding of the human brain have not been thoroughly understood. In this study, we developed a multiscale mechanical model to investigate how the interplay between initial geometrical undulations, differential tangential growth in the cortical plate, and axonal connectivity form and regulate the folding patterns of the human brain in a hierarchical order. To do so, different growth scenarios with bilayer spherical models that features initial undulations on the cortex and uniform or heterogeneous distribution of axonal fibers in the white matter were developed, statistically analyzed, and validated by the imaging observations. The results showed that the differential tangential growth is the inducer of cortical folding, and in a hierarchal order, high-amplitude initial undulations on the surface and axonal fibers in the substrate regulate the folding patterns and determine the location of gyri and sulci. The locations with dense axonal fibers after folding settle in gyri rather than sulci. The statistical results also indicated that there is a strong correlation between the location of positive (outward) and negative (inward) initial undulations and the locations of gyri and sulci after folding, respectively. In addition, the locations of 3-hinge gyral folds are strongly correlated with the initial positive undulations and locations of dense axonal fibers. As another finding, it was revealed that there is a correlation between the density of axonal fibers and local gyrification index, which has been observed in imaging studies but not yet fundamentally explained. This study is the first step in understanding the linkage between abnormal gyrification (surface morphology) and disruption in connectivity that has been observed in some brain disorders such as Autism Spectrum Disorder. Moreover, the findings of the study directly contribute to the concept of the regularity and variability of folding patterns in individual human brains.
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3. Hyassat M, Al-Makahleh A, Rahahleh Z, Al-Zyoud N. The Diagnostic Process for Children with Autism Spectrum Disorder: A Preliminary Study of Jordanian Parents’ Perspectives. Children (Basel);2023 (Aug 15);10(8)
Although extensive research has been conducted worldwide to investigate the diagnostic process of Autism Spectrum Disorder (ASD), Jordanian parents’ experiences have been overlooked. This study explored parents’ journeys toward receiving diagnoses for their children with ASD. In particular, it aimed to provide a clear picture of the process for obtaining these diagnoses for children in Jordan. METHODS: Eighteen semi-structured interviews were carried out with 12 mothers and six fathers of children with ASD aged 5 to 11 years old. RESULTS: The coding process was based on a thematic analysis method and resulted in the identification of three overlapping themes: dissatisfaction with professionals’ abilities to approach parents, an unstructured diagnostic process, and perspectives on diagnosis tools. CONCLUSIONS: Our data upheld the idea that parental satisfaction with the diagnostic process is influenced by the duration of the process, the information provided, the support offered, and the communication approach used by professionals. Within the local cultural context, parents were significantly impacted by the societal stigma associated with disability when they sought diagnoses for their children with ASD.
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4. Kaminski VL, Kulmann-Leal B, Tyska-Nunes GL, Beltrame BP, Riesgo RDS, Schüler-Faccini L, Roman T, Schuch JB, Chies JAB. Association between NKG2/KLR gene variants and epilepsy in Autism Spectrum Disorder. J Neuroimmunol;2023 (Aug 15);381:578132.
Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders mainly characterized by repetitive, restrictive and stereotypical behaviors, and impaired communication skills. Several lines of evidence indicate that alterations of the immune system account for ASD development, including the presence of brain-reactive antibodies, abnormal T cell activation, altered cytokine levels in brain, cerebrospinal fluid and peripheral blood circulation, increased levels of circulating monocytes, and dysregulation in Natural Killer (NK) cells activity. Regarding NK cells, a lower cytotoxic activity, a higher level of activation and an increased number of these cells in individuals with ASD have been described. In 2019, a study showed that NK cells derived from patients with ASD show a characteristic pattern of NKG2C overexpression, highlighting the importance of the NK cell pathway in ASD. In fact, the study of genes related to NK cell activity has proven to be an excellent research target, both in terms of susceptibility as well as a marker for the different clinical manifestations observed in ASD individuals. Here, we evaluated the influence of KLRC2 gene deletion as well as KLRK1 rs1049174 and rs2255336 variants in a cohort of 185 children diagnosed with ASD and their respective biological parents in southern Brazil. Of note, this is the first study concerning genetic variants of the KLRC2 and KLRK1 genes in an ASD sample. The KLRC2 gene deletion (p = 0.001; pc = 0.009), KLRK1 rs1049174 (p = 0.005; pc = 0.045) and KLRK1 rs2255336 (p = 0.001; pc = 0.009) were associated with epilepsy in ASD patients. The results indicate that KLRC2 deletion, KLRK1 rs2255336, and KLRK1 rs1049174 could be involved in epilepsy manifestation in ASD patients, possibly impacting the NK dysregulation already described in ASD and epileptic patients.
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5. Kaneko T, Nakamura T, Ryokawa A, Washizuka S, Kitoh Y, Fujinaga Y. Connective differences between patients with depression with and without ASD: A case-control study. PLoS One;2023;18(8):e0289735.
BACKGROUND: Researchers find it difficult to distinguish between depression with ASD (Depress-wASD) and without ASD (Depression) in adult patients. We aimed to clarify the differences in brain connectivity between patients with depression with ASD and without ASD. METHODS: From April 2017 to February 2019, 22 patients with suspected depression were admitted to the hospital for diagnosis or follow-up and met the inclusion criteria. The diagnosis was determined according to the Diagnostic and Statistical Manual of Mental Disorders-5 by skilled psychiatrists. The Hamilton Depression Rating Scale (HAM-D), Young Mania Raging Scale (YMRS), Mini-International Neuropsychiatric Interview, Parent-interview ASD Rating Scale-Text Revision (PARS-TR), and Autism-Spectrum Quotient-Japanese version (AQ-J) were used to assess the patients’ background and help with diagnosis. Resting-state functional magnetic resonance imaging (rs-fMRI) was performed using the 3-T-MRI system. rs-fMRI was processed using the CONN functional connectivity toolbox. Voxel-based morphometry was performed using structural images. RESULTS: No significant difference was observed between the Depress-wASD and Depression groups using the HAM-D, YMRS, AQ-J, Intelligence Quotient (IQ), and verbal IQ results. rs-fMRI for the Depress-wASD group indicated a positive connection between the salience network (SN) and right supramarginal gyrus (SMG) and a negative connection between the SN and hippocampus and para-hippocampus than that for the Depression group. No significant structural differences were observed between the groups. CONCLUSIONS: We identified differences in the SN involving the SMG and hippocampal regions between the Depress-wASD and Depression groups.
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6. Kanina A, Larsson H, Sjölander A, Butwicka A, Taylor MJ, Martini MI, Lichtenstein P, Lundberg FE, Onofrio BM, Rosenqvist MA. Association between cumulative psychosocial adversity in the family and ADHD and autism: a family-based cohort study. Transl Psychiatry;2023 (Aug 14);13(1):282.
Cumulative exposure to psychosocial adversity at an early age has been shown to be a risk factor for attention-deficit hyperactivity disorder (ADHD) and autism that often co-occur. However, it is not clear if this association reflects a causal effect or familial confounding. We aimed to assess whether cumulative psychosocial adversity in the family increases the risk for ADHD and autism in offspring while accounting for unmeasured familial confounding. We used a population-based cohort of 1,877,901 individuals born in Sweden between 1990 and 2009. Participants were followed from the age of 3 until 2013, with a median follow up time of 13.8 years. We created a cumulative index based on 7 psychosocial adversity factors. We used Cox regression to estimate the hazard ratios (HRs) relating neurodevelopmental conditions to cumulative psychosocial adversity. To address familial confounding, the analyses were repeated in groups of relatives of different kinship: siblings and half-siblings and cousins. A dose-response relationship was observed between cumulative exposure to psychosocial adversity and ADHD at a general population level (covariate adjusted HRs (aHRs) with 95% confidence intervals ranged from 1.55 [one adversity; 1.53-1.58] to 2.65 [ ≥ 4 adversities; 1.98-3.54]). No clear dose-response relation was seen for autism (aHRs ranged from 1.04 [.59-1.84] to 1.37 [1.30-1.45]). HRs of ADHD and autism decreased with increasing level of kinship in the analysis of relatives. Cumulative exposure to psychosocial adversity was associated with both ADHD and autism in the general population, these associations were partly explained by unmeasured familial confounding between relatives. This highlights the need for using family-based designs in studies of psychosocial adversity and ADHD and autism.
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7. Ko C, Kang S, Hong SB, Park YR. Protocol for the development of joint attention-based subclassification of autism spectrum disorder and validation using multi-modal data. BMC Psychiatry;2023 (Aug 15);23(1):589.
BACKGROUND: Heterogeneity in clinical manifestation and underlying neuro-biological mechanisms are major obstacles to providing personalized interventions for individuals with autism spectrum disorder (ASD). Despite various efforts to unify disparate data modalities and machine learning techniques for subclassification, replicable ASD clusters remain elusive. Our study aims to introduce a novel method, utilizing the objective behavioral biomarker of gaze patterns during joint attention, to subclassify ASD. We will assess whether behavior-based subgrouping yields clinically, genetically, and neurologically distinct ASD groups. METHODS: We propose a study involving 60 individuals with ASD recruited from a specialized psychiatric clinic to perform joint attention tasks. Through the examination of gaze patterns in social contexts, we will conduct a semi-supervised clustering analysis, yielding two primary clusters: good gaze response group and poor gaze response group. Subsequent comparison will occur across these clusters, scrutinizing neuroanatomical structure and connectivity using structural as well as functional brain imaging studies, genetic predisposition through single nucleotide polymorphism data, and assorted socio-demographic and clinical information. CONCLUSIONS: The aim of the study is to investigate the discriminative properties and the validity of the joint attention-based subclassification of ASD using multi-modality data. TRIAL REGISTRATION: Clinical trial, KCT0008530, Registered 16 June 2023, https://cris.nih.go.kr/cris/index/index.do .
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8. Ollà I, Pardiñas AF, Parras A, Hernández IH, Santos-Galindo M, Picó S, Callado LF, Elorza A, Rodríguez-López C, Fernández-Miranda G, Belloc E, Walters JTR, O’Donovan MC, Méndez R, Toma C, Meana JJ, Owen MJ, Lucas JJ. Pathogenic Mis-splicing of CPEB4 in Schizophrenia. Biol Psychiatry;2023 (Aug 15);94(4):341-351.
BACKGROUND: Schizophrenia (SCZ) is caused by an interplay of polygenic risk and environmental factors, which may alter regulators of gene expression leading to pathogenic misexpression of SCZ risk genes. The CPEB family of RNA-binding proteins (CPEB1-4) regulates translation of target RNAs (approximately 40% of overall genes). We previously identified CPEB4 as a key dysregulated translational regulator in autism spectrum disorder (ASD) because its neuronal-specific microexon (exon 4) is mis-spliced in ASD brains, causing underexpression of numerous ASD risk genes. The genetic factors and pathogenic mechanisms shared between SCZ and ASD led us to hypothesize CPEB4 mis-splicing in SCZ leading to underexpression of multiple SCZ-related genes. METHODS: We performed MAGMA-enrichment analysis on Psychiatric Genomics Consortium genome-wide association study data and analyzed RNA sequencing data from the PsychENCODE Consortium. Reverse transcriptase polymerase chain reaction and Western blot were performed on postmortem brain tissue, and the presence/absence of antipsychotics was assessed through toxicological analysis. Finally, mice with mild overexpression of exon 4-lacking CPEB4 (CPEB4Δ4) were generated and analyzed biochemically and behaviorally. RESULTS: First, we found enrichment of SCZ-associated genes for CPEB4-binder transcripts. We also found decreased usage of CPEB4 microexon in SCZ probands, which was correlated with decreased protein levels of CPEB4-target SCZ-associated genes only in antipsychotic-free individuals. Interestingly, differentially expressed genes fit those reported for SCZ, specifically in the SCZ probands with decreased CPEB4-microexon inclusion. Finally, we demonstrated that mice with mild overexpression of CPEB4Δ4 showed decreased protein levels of CPEB4-target SCZ genes and SCZ-linked behaviors. CONCLUSIONS: We identified aberrant CPEB4 splicing and downstream misexpression of SCZ risk genes as a novel etiological mechanism in SCZ.
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9. Ortega DP, Walsh K, Bődi CB, Hawkins LB, Bright MA. School-based prevention education for children and youth with intellectual developmental disabilities. Child Abuse Negl;2023 (Aug 15);145:106397.
Children with intellectual developmental disabilities (IDD) are at a heightened risk of experiencing child maltreatment (CM) when compared to their peers without IDD. Despite expanding evidence supporting the efficacy of school-based CM prevention programs, there are limited programs that tailor their lessons to the unique needs of children with IDD. This discussion first presents information regarding the prevalence and risk factors of CM among children with IDD. We then present existing peer-reviewed CM programs that have been developed for children with IDD. Finally, based on the latest research of CM prevention and special education, we present our considerations for a comprehensive school-based CM prevention program for children with IDD. Prevention programs for children with IDD may increase risk awareness among children with IDD and their parents, equip children with IDD with the protective skills necessary to navigate unsafe situations, and decrease the overall incidence of CM against this population.
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10. Woods R, Williams K, Watts C. « Profound autism »: The dire consequences of diagnostic overshadowing. Autism Res;2023 (Aug 15)
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11. Zhang J, Fang S, Yao Y, Li F, Luo Q. Parsing the heterogeneity of brain-symptom associations in autism spectrum disorder via random forest with homogeneous canonical correlation. J Affect Disord;2023 (Aug 15);335:36-43.
BACKGROUND: Autism spectrum disorder (ASD) is a highly heterogeneous developmental disorder, but the neuroimaging substrates of its heterogeneity remain unknown. The difficulty lies mainly on the significant individual variability in the brain-symptom association. METHODS: T1-weighted magnetic resonance imaging data from the Autism Brain Imaging Database Exchange (ABIDE) (N(TDC) = 1146) were used to generate a normative model to map brain structure deviations of cases (N(ASD) = 571). Voxel-based morphometry (VBM) was used to compute gray matter volume (GMV). Singular Value Decomposition (SVD) was employed to perform dimensionality reduction. A tree-based algorithm was proposed to identify the ASD subtypes according to the pattern of brain-symptom association as assessed by a homogeneous canonical correlation. RESULTS: We identified 4 ASD subtypes with distinct association patterns between residual volumes and a social symptom score. More severe the social symptom was associated with greater GMVs in both the frontoparietal regions for the subtype1 (r = 0.29-0.44) and the ventral visual pathway for the subtype3 (r = 0.19-0.23), but lower GMVs in both the right anterior cingulate cortex for the subtype4 (r = -0.25) and a few subcortical regions for the subtype2 (r = -0.31 to -0.20). The subtyping significantly improved the classification accuracy between cases and controls from 0.64 to 0.75 (p < 0.05, permutation test), which was also better than the accuracy of 0.68 achieved by the k-means-based subtyping (p < 0.01). LIMITATIONS: Sample size limited the study due to the missing data. CONCLUSIONS: These findings suggest that the heterogeneity of ASD might reflect changes in different subsystems of the social brain, especially including social attention, motivation, perceiving and evaluation.
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12. Zhao W, Liu Q, Zhang X, Song X, Zhang Z, Qing P, Liu X, Zhu S, Yang W, Kendrick KM. Differential responses in the mirror neuron system during imitation of individual emotional facial expressions and association with autistic traits. Neuroimage;2023 (Aug 15);277:120263.
The mirror neuron system (MNS), including the inferior frontal gyrus (IFG), inferior parietal lobule (IPL) and superior temporal sulcus (STS) plays an important role in action representation and imitation and may be dysfunctional in autism spectrum disorder (ASD). However, it’s not clear how these three regions respond and interact during the imitation of different basic facial expressions and whether the pattern of responses is influenced by autistic traits. Thus, we conducted a natural facial expression (happiness, angry, sadness and fear) imitation task in 100 healthy male subjects where expression intensity was measured using facial emotion recognition software (FaceReader) and MNS responses were recorded using functional near-infrared spectroscopy (fNIRS). Autistic traits were measured using the Autism Spectrum Quotient questionnaire. Results showed that imitation of happy expressions produced the highest expression intensity but a small deactivation in MNS responses, suggesting a lower processing requirement compared to other expressions. A cosine similarity analysis indicated a distinct pattern of MNS responses during imitation of each facial expression with functional intra-hemispheric connectivity between the left IPL and left STS being significantly higher during happy compared to other expressions, while inter-hemispheric connectivity between the left and right IPL differed between imitation of fearful and sad expressions. Furthermore, functional connectivity changes during imitation of each different expression could reliably predict autistic trait scores. Overall, the results provide evidence for distinct patterns of functional connectivity changes between MNS regions during imitation of different emotions which are also associated with autistic traits.
