Plasma Oxytocin and Arginine-Vasopressin Levels in Children with Autism Spectrum Disorder in China: Associations with Symptoms

Autism spectrum disorder(ASD) is defined by impairments of social interaction and the presence of obsessive behaviors. The ‘‘twin' nonapeptides oxytocin(OXT) and arginine-vasopressin(AVP) are known to play regulatory roles in social behaviors. However, the plasma levels and behavioral relevance of OXT and AVP in children with ASD have seldom been investigated. It is also unknown whether their mothers have abnormal plasma peptide levels. Here, using well-established methods of neuropeptide measurement and a relatively large sample size, we determined the plasma levels of the two neuropeptides in 85 normal children, 84 children with ASD, and 31 mothers from each group of children.As expected, children with ASD had lower plasma OXT levels than gender-matched controls(P = 0.028). No such difference was found for plasma AVP concentrations. Correlation analysis showed that ASD children with higher plasma OXT concentrations tended to have less impairment of verbal communication(Rho =-0.22,P = 0.076), while those with higher plasma AVP levels tended to have lower levels of repetitive use of objects(Rho =-0.231, P = 0.079). Unlike the findings in children, maternal plasma OXT levels showed no group difference. However, plasma AVP levels in the mothers of ASD children tended to be lower than in the mothers of normal children(P = 0.072). In conclusion, our results suggest that the OXT system is dysregulated in children with ASD, and that OXT and AVP levels in plasma seem to be associated with specific autistic symptoms. The plasma levels of OXT or AVP in mothers and their ASD children did not seem to change in the same direction.     

A Replication and Extension of the PEERS® for Young Adults Social Skills Intervention: Examining Effects on Social Skills and Social Anxiety in Young Adults with Autism Spectrum Disorder

Young adults with ASD experience difficulties with social skills, empathy, loneliness, and social anxiety. One intervention, PEERS® for Young Adults, shows promise in addressing these challenges. The present study replicated and extended the original study by recruiting a larger sample (N?=?56), employing a gold standard ASD assessment tool, and examining changes in social anxiety utilizing a randomized controlled trial design. Results indicated improvements in social responsiveness (SSIS-RS SS, p?=?.006 and CPB, p?=?.005; SRS, p?=?.004), PEERS® knowledge (TYASSK, p?=?.001), empathy (EQ, p?=?.044), direct interactions (QSQ-YA, p?=?.059), and social anxiety (LSAS-SR, p?=?.019). Findings demonstrate further empirical support for the intervention for individuals with ASD.     

Genetic Factors Affecting Late-Onset Alzheimer’s Disease Susceptibility

Alzheimer’s disease is considered a progressive brain disease in the older population. Late-onset Alzheimer’s disease (LOAD) as a multifactorial dementia has a polygenic inheritance. Age, environment, and lifestyle along with a growing number of genetic factors have been reported as risk factors for LOAD. Our aim was to present results of LOAD association studies that have been done in northwestern Iran, and we also explored possible interactions with apolipoprotein E (APOE) status. We re-evaluated the association of these markers in dominant, recessive, and additive models. In all, 160 LOAD and 163 healthy control subjects of Azeri Turkish ethnicity were studied. The Chi-square test with Yates’ correction and Fisher’s exact test were used for statistical analysis. A Bonferroni-corrected p value, based on the number of statistical tests, was considered significant. Our results confirmed that chemokine receptor type 2 (CCR2), estrogen receptor 1 (ESR1), toll-like receptor 2 (TLR2), tumor necrosis factor alpha (TNF α), APOE, bridging integrator 1 (BIN1), and phosphatidylinositol-binding clathrin assembly protein (PICALM) are LOAD susceptibility loci in Azeri Turk ancestry populations. Among them, variants of CCR2, ESR1, TNF α, and APOE revealed associations in three different genetic models. After adjusting for APOE, the association (both allelic and genotypic) with CCR2, BIN1, and ESRα (PvuII) was evident only among subjects without the APOE ε4, whereas the association with CCR5, without Bonferroni correction, was significant only among subjects carrying the APOE ε4 allele. This result is an evidence of a synergistic and antagonistic effect of APOE on variant associations with LOAD.     

Comparing oxytocin and cortisol regulation in a double-blind,placebo-controlled,hydrocortisone challenge pilot study in children with autism and typical development

Background

Children with autism spectrum disorder (ASD) show marked impairment in social functioning and poor adaptation to new and changing contexts, which may be influenced by underlying regulatory processes. Oxytocin (OT) and cortisol are key neuromodulators of biological and behavioral responses, show a synergistic effect, and have been implicated in the neuropathological profile in ASD. However, they are rarely investigated together. The purpose of the pilot study was to evaluate the relationship between cortisol and OT in children with ASD under baseline and physiological stress (hydrocortisone challenge) conditions. Arginine vasopressin (AVP), structurally similar to OT, was also examined.

Methods

A double-blind, placebo-controlled, randomly assigned, crossover design was employed in 25 children 8-to-12 years with ASD (N?=?14) or typical development (TD, N?=?11). A low dose of hydrocortisone and placebo were administered via liquid suspension. Analysis of variance (ANOVA) was used to examine the within-subject factor “Condition” (hydrocortisone/placebo) and “Time” (pre and post) and the between-subject factor “Group” (ASD vs. TD). Pearson correlations examined the relationship between hormone levels and clinical profile.

Results

There was a significant Time × Condition × Group interaction F (1.23)?=?4.18, p?=?0.05 showing a rise in OT during the experimental condition (hydrocortisone) and a drop during the placebo condition for the TD group but not the ASD group. There were no group differences for AVP. Hormone levels were associated with social profiles.

Conclusions

For the TD group, an inverse relationship was observed. OT increased during physiological challenge suggesting that OT played a stress-buffering role during cortisol administration. In contrast for the ASD group, OT remained unchanged or decreased during both the physiological challenge and the placebo condition, suggesting that OT failed to serve as a stress buffer under conditions of physiological stress.While OT has been tied to the social ability of children with ASD, the diminished moderating effect of OT on cortisol may also play a contributory role in the heightened stress often observed in children with ASD. These results contribute to our understanding of the growing complexity of the effects of OT on social behavior as well as the functional interplay and differential regulation OT may have on stress modulation.

     

Neurodevelopmental Disorders Affecting Sociability: Recent Research Advances and Future Directions in Autism Spectrum Disorder and Williams Syndrome

Purpose of Review

In this review, we summarize current knowledge and hypotheses on the nature of social abnormalities in autism spectrum disorder (ASD) and Williams syndrome (WS).

Recent Findings

Social phenotypes in ASD and WS appear to reflect analogous disruptions in social cognition, and distinct patterns of social motivation, which appears to be reduced in ASD and enhanced in WS. These abnormalities likely originate from heterogeneous vulnerabilities that disrupt the interplay between domain-general and social domain-specific cognitive and motivational processes during early development. Causal pathways remain unclear.

Summary

Advances and research gaps in our understanding of the social phenotypes in ASD and WS highlight the importance of (1) parsing the construct of sociability, (2) adopting a developmental perspective, (3) including samples that are representative of the spectrum of severity within ASD and WS in neuroscientific research, and (4) adopting transdiagnostic treatment approaches to target shared areas of impairment across diagnostic boundaries.

     

Stranger Fear and Early Risk for Social Anxiety in Preschoolers with Fragile X Syndrome Contrasted to Autism Spectrum Disorder

This study investigated behavioral indicators of social fear in preschool boys with fragile X syndrome (FXS) with a low degree of autism spectrum disorder (ASD) symptoms (FXS-Low; n?=?29), FXS with elevated ASD symptoms (FXS-High; n?=?25), idiopathic ASD (iASD; n?=?11), and typical development (TD; n?=?36). Gaze avoidance, escape behaviors, and facial fear during a stranger approach were coded. Boys with elevated ASD symptoms displayed more avoidant gaze, looking less at the stranger and parent than those with low ASD symptoms across etiologies. The iASD group displayed more facial fear than the other groups. Results suggest etiologically distinct behavioral patterns of social fear in preschoolers with elevated ASD symptoms.     

Broad Autism Phenotypic Traits and the Relationship to Sexual Orientation and Sexual Behavior

Individuals with higher levels of the broad autism phenotype (BAP) have some symptoms of autism spectrum disorder (ASD). Like individuals with ASD, people with higher-BAP may have fewer sexual experiences and may experience more same-sex attraction. This study measured BAP traits, sexual experiences, and sexual orientation in typically developing (TD) individuals to see if patterns of sexual behavior and sexual orientation in higher-BAP resemble those in ASD. Although BAP characteristics did not predict sexual experiences, one BAP measure significantly predicted sexual orientation, β?=?0.22, t?=?2.72, p?=?.007, controlling for demographic variables (R² change?=?.04, F?=?7.41, p?=?.007), showing individuals with higher-BAP also reported increased same-sex attraction. This finding supports the hypothesis that individuals with higher-BAP resemble ASD individuals in being more likely than TD individuals to experience same-sex attraction.     

Monogenic disorders that mimic the phenotype of Rett syndrome

Rett syndrome (RTT) is caused by mutations in methyl-CpG-binding protein 2 (MECP2), but defects in a handful of other genes (e.g., CDKL5, FOXG1, MEF2C) can lead to presentations that resemble, but do not completely mirror, classical RTT. In this study, we attempted to identify other monogenic disorders that share features with RTT. We performed a retrospective chart review on n?=?319 patients who had undergone clinical whole exome sequencing (WES) for further etiological evaluation of neurodevelopmental diagnoses that remained unexplained despite extensive prior workup. From this group, we characterized those who (1) possessed features that were compatible with RTT based on clinical judgment, (2) subsequently underwent MECP2 sequencing and/or MECP2 deletion/duplication analysis with negative results, and (3) ultimately arrived at a diagnosis other than RTT with WES. n?=?7 patients had clinical features overlapping RTT with negative MECP2 analysis but positive WES providing a diagnosis. These seven patients collectively possessed pathogenic variants in six different genes: two in KCNB1 and one each in FOXG1, IQSEC2, MEIS2, TCF4, and WDR45. n?=?2 (both with KCNB1 variants) fulfilled criteria for atypical RTT. RTT-associated features included the following: loss of hand or language skills (n?=?3; IQSEC2, KCNB1 x 2); disrupted sleep (n?=?4; KNCB1, MEIS2, TCF4, WDR45); stereotyped hand movements (n?=?5; FOXG1, KNCB1 x 2, MEIS2, TCF4); bruxism (n?=?3; KCNB1 x 2; TCF4); and hypotonia (n?=?7). Clinically based diagnoses can be misleading, evident by the increasing number of genetic conditions associated with features of RTT with negative MECP2 mutations.     

The complete chloroplast genome of the dove tree <Emphasis Type="Italic">Davidia involucrata</Emphasis> (Nyssaceae), a relict species endemic to China

The dove tree, Davidia involucrate, with its distinguishing pair of white bracts, is endemic to China. Here, we reported the complete chloroplast (cp) genome sequence and the cp genomic features of D. involucrata. The D. involucrata cp genome was 169,196 bp long, with 129 genes comprising 83 protein-coding genes (PCG), 40 tRNA genes, and six rRNA genes. The majority of the gene species occurred as a single-copy, while 18 gene species occurred in double copies, including six PCG species (ndhB, rpl2, rpl23, rps7, rps15, and ycf2), eight tRNA species (trnH-GTG, trnL-CAA, trnI-CAT, trnV-GAC, trnL-GAV, trnA-UGC, trnN-GTT, and trnR-ACG) and all four rRNA species (rrn4.5, rrn5, rrn16, and rrn23). A neighbor-joining (NJ) phylogenetic tree was reconstructed with sequences of complete cp, revealing that D. involucrata belongs to the asterids. The complete cp genome of D. involucrata will be useful for further investigations and the conservation of this endemic relict woody plant.     

Autistic Traits and Symptoms of Social Anxiety are Differentially Related to Attention to Others’ Eyes in Social Anxiety Disorder

Autism spectrum disorder (ASD) and social anxiety disorder (SAD) have partly overlapping symptoms. Gaze avoidance has been linked to both SAD and ASD, but little is known about differences in social attention between the two conditions. We studied eye movements in a group of treatment-seeking adolescents with SAD (N?=?25), assessing SAD and ASD dimensionally. The results indicated a double dissociation between two measures of social attention and the two symptom dimensions. Controlling for social anxiety, elevated autistic traits were associated with delayed orienting to eyes presented among distractors. In contrast, elevated social anxiety levels were associated with faster orienting away from the eyes, when controlling for autistic traits. This distinction deepens our understanding of ASD and SAD.     

The Orphan Nuclear Receptor TLX/NR2E1 in Neural Stem Cells and Diseases

The human TLX gene encodes an orphan nuclear receptor predominantly expressed in the central nervous system. Tailess and Tlx, the TLX homologues in Drosophila and mouse, play essential roles in body-pattern formation and neurogenesis during early embryogenesis and perform crucial functions in maintaining stemness and controlling the differentiation of adult neural stem cells in the central nervous system, especially the visual system. Multiple target genes and signaling pathways are regulated by TLX and its homologues in specific tissues during various developmental stages. This review aims to summarize previous studies including many recent updates from different aspects concerning TLX and its homologues in Drosophila and mouse.     

How ‘core’ are motor timing difficulties in ADHD? A latent class comparison of pure and comorbid ADHD classes

Children with attention-deficit/hyperactivity disorder (ADHD) have motor timing difficulties. This study examined whether affected motor timing accuracy and variability are specific for ADHD, or that comorbidity with autism spectrum disorders (ASD) contributes to these motor timing difficulties. An 80-trial motor timing task measuring accuracy (μ), variability (σ) and infrequent long response times (τ) in estimating a 1-s interval was administered to 283 children and adolescents (8–17 years) from both a clinic and population based sample. They were divided into four latent classes based on the SCQ and CPRS-R:L data. These classes were: without behavioral problems ‘Normal-class’ (n = 154), with only ADHD symptoms ‘ADHD-class’ (n = 49), and two classes with both ASD and ADHD symptoms; ADHD(+ASD)-class (n = 39) and ASD(+ADHD)-class (n = 41). The pure ADHD-class did not deviate from the Normal class on any of the motor timing measures (mean RTs 916 and 925 ms, respectively). The comorbid ADHD(+ASD) and ASD(+ADHD) classes were significantly less accurate (more time underestimations) compared to the Normal class (mean RTs 847 and 870 ms, respectively). Variability in motor timing was reduced in the younger children in the ADHD(+ASD) class, which may reflect a tendency to rush the tedious task. Only patients with more severe behavioral symptoms show motor timing deficiencies. This cannot merely be explained by high ADHD severity with ASD playing no role, as ADHD symptom severity in the pure ADHD-class and the ASD(+ADHD) class was highly similar, with the former class showing no motor timing deficits.     

Psychosexual Functioning of Cognitively-able Adolescents with Autism Spectrum Disorder Compared to Typically Developing Peers: The Development and Testing of the Teen Transition Inventory- a Self- and Parent Report Questionnaire on Psychosexual Functioning

To gain further insight into psychosexual functioning, including behaviors, intrapersonal and interpersonal aspects, in adolescents with Autism Spectrum Disorder (ASD), comprehensive, multi-informant measures are needed. This study describes (1) the development of a new measure of psychosexual functioning in both parent- and self-reports (Teen Transition Inventory; TTI) covering all three domains of psychosexual functioning (i.e. psychosexual socialization, psychosexual selfhood, and sexual/intimate behavior). And (2) the initial testing of this instrument, comparing adolescents with ASD (n?=?79 parent-report; n?=?58 self-report) to Typically Developing (TD) adolescents (n?=?131 parent-report; n?=?91 self-report) while taking into account gender as a covariate. Results from both informants indicate more difficulties regarding psychosexual socialization and psychosexual selfhood in the ASD group. With regard to sexual/intimate behavior, only parents reported significantly more problems in adolescents with ASD.     

Are Anxiety Disorders in Children and Adolescents Less Impairing Than ADHD and Autism Spectrum Disorders? Associations with Child Quality of Life and Parental Stress and Psychopathology

We compared clinically referred children with anxiety disorders (AD; n?=?63) to children with autism spectrum disorder (ASD; n?=?39), ADHD Combined (ADHD-C; n?=?62), ADHD Predominantly Inattentive (ADHD-I; n?=?64), and typically developing children (n?=?42) on child quality of life (QOL), paternal and maternal psychopathology and parental stress. Diagnoses were based on DSM-IV-TR criteria. Multilevel analyses showed that QOL in AD was higher on school and social functioning, compared to respectively ADHD and ASD, and lower compared to normal controls on all five domains. Fathers reported their AD children higher QOL than mothers. Also, AD appeared to be associated with less parental stress and parental psychopathology than other child psychopathology. Therefore, parental factors may need to be considered more in treatment of children with ADHD/ASD than AD.     

Motor Coordination in Autism Spectrum Disorders: A Synthesis and Meta-Analysis

Are motor coordination deficits an underlying cardinal feature of Autism Spectrum Disorders (ASD)? Database searches identified 83 ASD studies focused on motor coordination, arm movements, gait, or postural stability deficits. Data extraction involved between-group comparisons for ASD and typically developing controls (N = 51). Rigorous meta-analysis techniques including random effects models, forest and funnel plots, I ², publication bias, fail-safe analysis, and moderator variable analyses determined a significant standardized mean difference effect equal to 1.20 (SE = 0.144; p < 0.0001; Z = 10.49). This large effect indicated substantial motor coordination deficits in the ASD groups across a wide range of behaviors. The current overall findings portray motor coordination deficits as pervasive across diagnoses, thus, a cardinal feature of ASD.     

Amygdala Volume Differences in Autism Spectrum Disorder Are Related to Anxiety

Recent studies suggest that longstanding findings of abnormal amygdala morphology in ASD may be related to symptoms of anxiety. To test this hypothesis, fifty-three children with ASD (mean age?=?11.9) underwent structural MRI and were divided into subgroups to compare those with at least one anxiety disorder diagnosis (n?=?29) to those without (n?=?24) and to a typically developing control group (TDC; n?=?37). Groups were matched on age and intellectual level. The ASD and anxiety group showed decreased right amygdala volume (controlled for total brain volume) relative to ASD without anxiety (p?=?.04) and TDCs (p?=?.068). Results suggest that youth with ASD and co-occurring anxiety have a distinct neurodevelopmental trajectory.     

Synaptosome-Associated Protein 25 (<Emphasis Type="Italic">SNAP25</Emphasis>) Gene Association Analysis Revealed Risk Variants for ASD,in Iranian Population

Autism spectrum disorder (ASD) is a common, complex neurological condition, affecting approximately 1% of people worldwide. Monogenic neurodevelopmental disorders which showed autistic behavior patterns have suggested synaptic dysfunction, as a key mechanism in the pathophysiology of ASD. Subsequently, genes involved in synaptic signaling have been investigated with a priority for candidate gene studies. A synaptosomal-associated protein 25 (SNAP25) gene plays a crucial role in the central nervous system, contributing to exocytosis by targeting and fusion of vesicles to the cell membrane. Studies have shown a correlation between aberrant expression of the SNAP25 and a variety of brain diseases. Single nucleotide polymorphisms (SNPs) in this gene are associated with several psychiatric diseases, such as bipolar, schizophrenia, and attention-deficit/hyperactivity disorder. The aim of the present study was to investigate whether polymorphisms (rs3746544 and rs1051312) in the regulatory 3′-untranslated region (3′UTR) of the SNAP25 gene have an association with ASD in unrelated Iranian case (N = 524)-control (N = 472) samples. We observed robust association of the rs3746544 SNP and ASD patients, in both allele and haplotype-based analyses. Our results supported the previous observations and indicated a possible role for SNAP25 polymorphisms as susceptibility genetic factors involved in developing ASD.