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1.  Decreased Epidermal Growth Factor (EGF) Associated with HMGB1 and Increased Hyperactivity in Children with Autism 
Biomarker Insights  2013;8:35-41.
Background
Autism spectrum disorders (ASDs), characterized by impaired social interactions and deficits in verbal and nonverbal communication, are thought to affect 1 in 88 children in the United States. There is much support for the role of growth factors in the etiology of autism. Recent research has shown that epithelial growth factor (EGF) is decreased in young autistic children (2–4 years of age). This study was designed to determine plasma levels of EGF in an older group of autistic children (mean age 10.6 years) and to correlate these EGF levels with putative biomarkers HGF, uPA, uPAR, GAD2, MPO GABA, and HMGB1, as well as symptom severity of 19 different symptoms.
Subjects and methods
Plasma from 38 autistic children, 11 children with pervasive developmental disorder (PDD-NOS) and 40 neurotypical, age and gender similar controls was assessed for EGF concentration using ELISAs. Severity of 19 symptoms (awareness, expressive language, receptive language, (conversational) pragmatic language, focus/attention, hyperactivity, impulsivity, perseveration, fine motor skills, gross motor skills, hypotonia (low muscle tone), tiptoeing, rocking/pacing, stimming, obsessions/fixations, eye contact, sound sensitivity, light sensitivity, and tactile sensitivity) was assessed and then compared to EGF concentrations.
Results
In this study, we found EGF levels in autistic children and those with PDD-NOS to be significantly lower when compared with neurotypical controls. EGF levels correlated with HMGB1 levels but not the other tested putative biomarkers, and EGF correlated negatively with hyperactivity, gross motor skills, and tiptoeing but not other symptoms.
Conclusions
These results suggest an association between decreased plasma EGF levels and selected symptom severity. We also found a strong correlation between plasma EGF and HMGB1, suggesting inflammation is associated with decreased EGF.
doi:10.4137/BMI.S11270
PMCID: PMC3623607  PMID: 23645980
EGF; HMGB1; GABA; autism; PDD; symptom severity
2.  Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders 
Journal of neuroimmunology  2010;232(1-2):196-199.
A role for immune dysfunction has been suggested in autism spectrum disorders (ASD). Elevated levels of chemokines have been detected in the brain and CSF of individuals with ASD but, to date, no study has examined chemokine levels in the plasma of children with this disorder. In the current study, we determined whether there were differential profiles of chemokines in the plasma of children with ASD compared to age-matched typically developing controls and children with developmental disabilities other than ASD. Increased MCP-1, RANTES and eotaxin levels were observed in ASD children compared with both control groups (p<0.03), and increased chemokine production was associated with higher aberrant behavior scores and more impaired developmental and adaptive function.. Elevated MCP-1, RANTES and eotaxin in some ASD children and their association with more impaired behaviors may have etiological significance. Chemokines and their receptors might provide unique targets for future therapies in ASD.
doi:10.1016/j.jneuroim.2010.10.025
PMCID: PMC3053074  PMID: 21095018
3.  DECREASED TRANSFORMING GROWTH FACTOR BETA1 IN AUTISM: A POTENTIAL LINK BETWEEN IMMUNE DYSREGULATION AND IMPAIRMENT IN CLINICAL BEHAVIORAL OUTCOMES 
Journal of neuroimmunology  2008;204(1-2):149-153.
Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. There is evidence of both immune dysregulation and autoimmune phenomena in autism. We examined the regulatory cytokine transforming growth factor beta-1 (TGFβ1) because of its role in controlling immune responses. Plasma levels of active TGFβ1 were evaluated in 75 children with ASD compared with 96 controls. Children with ASD had significantly lower plasma TGFβ1 levels compared with typically developing controls (p=0.0017) and compared with children with developmental disabilities other than ASD (p=0.0037) but not siblings, after adjusting for age and gender. In addition, there were significant correlations between psychological measures and TGFβ1 levels, such that lower TGFβ1 levels were associated with lower adaptive behaviors and worse behavioral symptoms. The data suggest that immune responses in autism may be inappropriately regulated due to reductions in TGFβ1. Such immune dysregulation may predispose to the development of possible autoimmune responses and/or adverse neuroimmune interactions during critical windows in development.
doi:10.1016/j.jneuroim.2008.07.006
PMCID: PMC2615583  PMID: 18762342
4.  Increased Anti-Phospholipid Antibodies in Autism Spectrum Disorders 
Mediators of Inflammation  2013;2013:935608.
Autism spectrum disorders (ASD) are characterized by impairments in communication, social interactions, and repetitive behaviors. While the etiology of ASD is complex and likely involves the interplay of genetic and environmental factors, growing evidence suggests that immune dysfunction and the presence of autoimmune responses including autoantibodies may play a role in ASD. Anti-phospholipid antibodies are believed to occur from both genetic and environmental factors and have been linked to a number of neuropsychiatric symptoms such as cognitive impairments, anxiety, and repetitive behaviors. In the current study, we investigated whether there were elevated levels of anti-phospholipid antibodies in a cross-sectional analysis of plasma of young children with ASD compared to age-matched typically developing (TD) controls and children with developmental delays (DD) other than ASD. We found that levels of anti-cardiolipin, β2-glycoprotein 1, and anti-phosphoserine antibodies were elevated in children with ASD compared with age-matched TD and DD controls. Further, the increase in antibody levels was associated with more impaired behaviors reported by parents. This study provides the first evidence for elevated production of anti-phospholipid antibodies in young children with ASD and provides a unique avenue for future research into determining possible pathogenic mechanisms that may underlie some cases of ASD.
doi:10.1155/2013/935608
PMCID: PMC3794552  PMID: 24174712
5.  High Complement Factor I Activity in the Plasma of Children with Autism Spectrum Disorders 
Autism Research and Treatment  2011;2012:868576.
Autism spectrum disorders (ASDs) are neurodevelopmental and behavioural syndromes affecting social orientation, behaviour, and communication that can be classified as developmental disorders. ASD is also associated with immune system abnormality. Immune system abnormalities may be caused partly by complement system factor I deficiency. Complement factor I is a serine protease present in human plasma that is involved in the degradation of complement protein C3b, which is a major opsonin of the complement system. Deficiency in factor I activity is associated with an increased incidence of infections in humans. In this paper, we show that the mean level of factor I activity in the ASD group is significantly higher than in the control group of typically developed and healthy children, suggesting that high activity of complement factor I might have an impact on the development of ASD.
doi:10.1155/2012/868576
PMCID: PMC3420436  PMID: 22928102
6.  Autism-Associated Gene Expression in Peripheral Leucocytes Commonly Observed between Subjects with Autism and Healthy Women Having Autistic Children 
PLoS ONE  2011;6(9):e24723.
Autism spectrum disorder (ASD) is a severe neuropsychiatric disorder which has complex pathobiology with profound influences of genetic factors in its development. Although the numerous autism susceptible genes were identified, the etiology of autism is not fully explained. Using DNA microarray, we examined gene expression profiling in peripheral blood from 21 individuals in each of the four groups; young adults with ASD, age- and gender-matched healthy subjects (ASD control), healthy mothers having children with ASD (asdMO), and asdMO control. There was no blood relationship between ASD and asdMO. Comparing the ASD group with control, 19 genes were found to be significantly changed. These genes were mainly involved in cell morphology, cellular assembly and organization, and nerve system development and function. In addition, the asdMO group possessed a unique gene expression signature shown as significant alterations of protein synthesis despite of their nonautistic diagnostic status. Moreover, an ASD-associated gene expression signature was commonly observed in both individuals with ASD and asdMO. This unique gene expression profiling detected in peripheral leukocytes from affected subjects with ASD and unaffected mothers having ASD children suggest that a genetic predisposition to ASD may be detectable even in peripheral cells. Altered expression of several autism candidate genes such as FMR-1 and MECP2, could be detected in leukocytes. Taken together, these findings suggest that the ASD-associated genes identified in leukocytes are informative to explore the genetic, epigenetic, and environmental background of ASD and might become potential tools to assess the crucial factors related to the clinical onset of the disorder.
doi:10.1371/journal.pone.0024723
PMCID: PMC3174190  PMID: 21935445
7.  Attentional networks in children and adolescents with autism spectrum disorder 
Background
Individuals diagnosed with autism spectrum disorder (ASD) exhibit lifelong abnormalities in the adaptive allocation of visual attention. The ubiquitous nature of attentional impairments in ASD has led some authors to hypothesize that atypical attentional modulation may be a factor in the development of higher-level sociocommunicative deficits.
Method
Participants were 20 children with ASD and 20 age- and Nonverbal IQ-matched typically developing (TD) children. We used the Attention Network Test (ANT) to investigate the efficiency and independence of three discrete attentional networks: alerting, orienting, and executive control. Additionally, we sought to investigate the relationship between each attentional network and measures of sociocommunicative symptom severity in children with ASD.
Results
Results indicate that the orienting, but not alerting or executive control, networks may be impaired in children with ASD. In contrast to TD children, correlational analyses suggest that the alerting and executive control networks may not function as independently in children with ASD. Additionally, an association was found between the alerting network and social impairment and between the executive control network and IQ in children with ASD.
Conclusions
The results provide further evidence of an impairment in the visuospatial orienting network in ASD and suggest that there may be greater interdependence of alerting and executive control networks in ASD. Furthermore, decreased ability to efficiently modulate levels of alertness was related to increased sociocommunicative deficits, suggesting that domain-general attentional function may be associated with ASD symptomatology.
doi:10.1111/j.1469-7610.2010.02257.x
PMCID: PMC3145814  PMID: 20456535
Autism; reaction time; visual attention; alerting; orienting; executive control
8.  DETECTION OF PLASMA AUTOANTIBODIES TO BRAIN TISSUE IN YOUNG CHILDREN WITH AND WITHOUT AUTISM SPECTRUM DISORDERS 
Brain, Behavior, and Immunity  2011;25(6):1123-1135.
Autism spectrum disorders (ASDs) are characterized by impaired language and social skills, often with restricted interests and stereotyped behaviors. A previous investigation of blood plasma from children with ASDs (mean age = 5½ years) demonstrated that 21% of samples contained autoantibodies that reacted intensely with GABAergic Golgi neurons of the cerebellum while no samples from non-sibling, typically developing children showed similar staining (Wills et al., 2009). In order to characterize the clinical features of children positive for these autoantibodies, we analyzed plasma samples from children enrolled in the Autism Phenome Project, a multidisciplinary project aimed at identifying subtypes of ASD. Plasma from male and female children (mean age = 3.2 years) was analyzed immunohistochemically for the presence of autoantibodies using histological sections of macaque monkey brain. Immunoreactivity to cerebellar Golgi neurons and other presumed interneurons was observed for some samples but there was no difference in the rate of occurrence of these autoantibodies between children with ASD and their typically developing peers. Staining of neurons, punctate profiles in the molecular layer of the dentate gyrus, and neuronal nuclei were also observed. Taken together, 42% of controls and subjects with ASD demonstrated immunoreactivity to some neural element. Interestingly, children whose plasma reacted to brain tissue had scores on the Child Behavior Checklist (CBCL) that indicated increased behavioral and emotional problems. Children whose plasma was immunoreactive with neuronal cell bodies scored higher on multiple CBCL scales. These studies indicate that additional research into the genesis and prevalence of brain-directed autoantibodies is warranted.
doi:10.1016/j.bbi.2011.02.011
PMCID: PMC3313674  PMID: 21420487
Autism; autoantibody; interneurons; immunohistochemistry; Child Behavior Checklist
9.  Blood Mercury Concentrations in CHARGE Study Children with and without Autism 
Environmental Health Perspectives  2009;118(1):161-166.
Background
Some authors have reported higher blood mercury (Hg) levels in persons with autism, relative to unaffected controls.
Objectives
We compared blood total Hg concentrations in children with autism or autism spectrum disorder (AU/ASD) and typically developing (TD) controls in population-based samples, and determined the role of fish consumption in differences observed.
Methods
The Childhood Autism Risk from Genetics and the Environment (CHARGE) Study enrolled children 2–5 years of age. After diagnostic evaluation, we analyzed three groups: AU/ASD, non-AU/ASD with developmental delay (DD), and population-based TD controls. Mothers were interviewed about household, medical, and dietary exposures. Blood Hg was measured by inductively coupled plasma mass spectrometry. Multiple linear regression analysis was conducted (n = 452) to predict blood Hg from diagnostic status controlling for Hg sources.
Results
Fish consumption strongly predicted total Hg concentration. AU/ASD children ate less fish. After adjustment for fish and other Hg sources, blood Hg levels in AU/ASD children were similar to those of TD children (p = 0.75); this was also true among non-fish eaters (p = 0.73). The direct effect of AU/ASD diagnosis on blood Hg not through the indirect pathway of altered fish consumption was a 12% reduction. DD children had lower blood Hg concentrations in all analyses. Dental amalgams in children with gum-chewing or teeth-grinding habits predicted higher levels.
Conclusions
After accounting for dietary and other differences in Hg exposures, total Hg in blood was neither elevated nor reduced in CHARGE Study preschoolers with AU/ASD compared with unaffected controls, and resembled those of nationally representative samples.
doi:10.1289/ehp.0900736
PMCID: PMC2831962  PMID: 20056569
autism; autism spectrum disorders; child development; dental amalgams; developmental delay; fish; mercury; metabolism; metals
10.  Attention deficit/hyperactivity disorder symptoms moderate cognition and behavior in children with autism spectrum disorders 
Recent estimates suggest that over 30% of children with autism spectrum disorders (ASD) meet diagnostic criteria for attention deficit/hyperactivity disorder (ADHD), and another 20% of children with ASD exhibit subthreshold clinical ADHD symptoms. Presence of ADHD symptoms in the context of ASD could have a variety of effects on cognition, autistic traits, and adaptive/maladaptive behaviors including: exacerbating core ASD impairments; adding unique impairments specific to ADHD; producing new problems unreported in ASD or ADHD; having no clear impact; or producing some combination of these scenarios. Children with ASD and co-morbid ADHD symptoms (ASD+ADHD; n=21), children with ASD without ADHD (ASD; n=28), and a typically developing control group (n=21) were included in the study; all groups were matched on age, gender-ratio, IQ, and socioeconomic status. Data were collected on verbal and spatial working memory, response inhibition, global executive control, autistic traits, adaptive functioning, and maladaptive behavior problems. In this sample, the presence of ADHD symptoms in ASD exacerbated impairments in executive control and adaptive behavior and resulted in higher autistic trait, and externalizing behavior ratings. ADHD symptoms were also associated with greater impairments on a lab measure of verbal working memory. These findings suggest that children with ASD+ADHD symptoms present with exacerbated impairments in some but not all domains of functioning relative to children with ASD, most notably in adaptive behavior and working memory. Therefore, ADHD may moderate the expression of components of the ASD cognitive and behavioral phenotype, but ASD+ADHD may not represent an etiologically distinct phenotype from ASD alone.
doi:10.1002/aur.103
PMCID: PMC3012375  PMID: 19998356
11.  Parenting-related stress and psychological distress in mothers of toddlers with autism spectrum disorders 
Brain & development  2012;35(2):133-138.
Background
Parents of children with autism spectrum disorders (ASDs) are at risk for higher stress levels than parents of children with other developmental disabilities and typical development. Recent advances in early diagnosis have resulted in younger children being diagnosed with ASDs but factors associated with parent stress in this age group are not well understood.
Aims
The present study examined parenting-related stress and psychological distress in mothers of toddlers with ASD, developmental delay without ASD (DD), and typical development. The impact of child problem behavior and daily living skills on parenting-stress and psychological distress were further investigated.
Methods
Participants were part of a larger research study on early ASD intervention. Parent self-report of parenting-related stress and psychological distress was utilized.
Results
Parents of toddlers with ASD demonstrated increased parenting-related stress compared with parents of toddlers with DD and typical development. However, psychological distress did not differ significantly between the groups. Child behavior problems, but not daily living skills emerged as a significant predictor of parenting-related stress and psychological distress. This was true for both mothers of children with ASD and DD.
Conclusions
These finding suggest that parents’ abilities to manage and reduce behavior problems is a critical target for interventions for young children with ASD and DD in order to improve child functioning and decrease parenting-related stress.
doi:10.1016/j.braindev.2012.10.004
PMCID: PMC3552060  PMID: 23146332
Autism Spectrum Disorder; parents; distress; toddlers; parenting-stress
12.  ANS: Aberrant Neurodevelopment of the Social Cognition Network in Adolescents with Autism Spectrum Disorders 
PLoS ONE  2011;6(4):e18905.
Background
Autism spectrum disorders (ASD) are characterized by aberrant neurodevelopment. Although the ASD brain undergoes precocious growth followed by decelerated maturation during early postnatal period of childhood, the neuroimaging approach has not been empirically applied to investigate how the ASD brain develops during adolescence.
Methodology/Principal Findings
We enrolled 25 male adolescents with high functioning ASD and 25 typically developing controls for voxel-based morphometric analysis of structural magnetic resonance image. Results indicate that there is an imbalance of regional gray matter volumes and concentrations along with no global brain enlargement in adolescents with high functioning ASD relative to controls. Notably, the right inferior parietal lobule, a role in social cognition, have a significant interaction of age by groups as indicated by absence of an age-related gain of regional gray matter volume and concentration for neurodevelopmental maturation during adolescence.
Conclusions/Significance
The findings indicate the neural correlates of social cognition exhibits aberrant neurodevelopment during adolescence in ASD, which may cast some light on the brain growth dysregulation hypothesis. The period of abnormal brain growth during adolescence may be characteristic of ASD. Age effects must be taken into account while measures of structural neuroimaging have been clinically put forward as potential phenotypes for ASD.
doi:10.1371/journal.pone.0018905
PMCID: PMC3082537  PMID: 21541322
13.  Altered Gene Expression and Function of Peripheral Blood Natural Killer Cells in Children with Autism 
Brain, behavior, and immunity  2008;23(1):124-133.
Immune related abnormalities have repeatedly been reported in autism spectrum disorders (ASD), including evidence of immune dysregulation and autoimmune phenomena. NK cells may play an important role in neurodevelopmental disorders such as ASD. Here we performed a gene expression screen and cellular functional analysis on peripheral blood obtained from 52 children with ASD and 27 typically developing control children enrolled in the case-control CHARGE study. RNA expression of NK cell receptors and effector molecules were significantly upregulated in ASD. Flow cytometric analysis of NK cells demonstrated increased production of perforin, granzyme B, and interferon gamma (IFNγ) under resting conditions in children with ASD (p<0.01). Following NK cell stimulation in the presence of K562 target cells, the cytotoxicity of NK cells was significantly reduced in ASD compared with controls (p<0.02). Furthermore, under similar stimulation conditions the presence of perforin, granzyme B, and IFNγ in NK cells from ASD children was significantly lower compared with controls (p<0.001). These findings suggest possible dysfunction of NK cells in children with ASD. Abnormalities in NK cells may represent a susceptibility factor in ASD and may predispose to the development of autoimmunity and/or adverse neuroimmune interactions during critical periods of development.
doi:10.1016/j.bbi.2008.08.001
PMCID: PMC2636576  PMID: 18762240
14.  Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome 
Brain, behavior, and immunity  2010;25(1):40-45.
Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. A potential role for immune dysfunction has been suggested in ASD. To test this hypothesis, we investigated evidence of differential cytokine release in plasma samples obtained from 2-5 year-old children with ASD compared with age-matched typically developing (TD) children and children with developmental disabilities other than autism (DD). Participants were recruited as part of the population based case-control CHARGE (Childhood Autism Risks from Genetics and Environment) study and included: 97 participants with a confirmed diagnosis of ASD using standard assessments (DSM IV criteria and ADOS, ADI-R), 87 confirmed TD controls, and 39 confirmed DD controls. Plasma was isolated and cytokine production was assessed by multiplex Luminex™ analysis. Observations indicate significant increases in plasma levels of a number of cytokines, including IL-1β, IL-6, IL-8 and IL-12p40 in the ASD group compared with TD controls (p < 0.04). Moreover, when the ASD group was separated based on the onset of symptoms, it was noted that the increased cytokine levels were predominantly in ASD children who had a regressive form of ASD. In addition, increasing cytokine levels were associated with more impaired communication and aberrant behaviors. In conclusion, using larger number of participants than previous studies, we report significantly shifted cytokine profiles in ASD. These findings suggest that ongoing inflammatory responses may be linked to disturbances in behavior and require confirmation in larger replication studies. The characterization of immunological parameters in ASD has important implications for diagnosis, and should be considered when designing therapeutic strategies to treat core symptoms and behavioral impairments of ASD.
doi:10.1016/j.bbi.2010.08.003
PMCID: PMC2991432  PMID: 20705131
15.  Visual attention to dynamic faces and objects is linked to face processing skills: a combined study of children with autism and controls 
Although the extant literature on face recognition skills in Autism Spectrum Disorder (ASD) shows clear impairments compared to typically developing controls (TDC) at the group level, the distribution of scores within ASD is broad. In the present research, we take a dimensional approach and explore how differences in social attention during an eye tracking experiment correlate with face recognition skills across ASD and TDC. Emotional discrimination and person identity perception face processing skills were assessed using the Let's Face It! Skills Battery in 110 children with and without ASD. Social attention was assessed using infrared eye gaze tracking during passive viewing of movies of facial expressions and objects displayed together on a computer screen. Face processing skills were significantly correlated with measures of attention to faces and with social skills as measured by the Social Communication Questionnaire (SCQ). Consistent with prior research, children with ASD scored significantly lower on face processing skills tests but, unexpectedly, group differences in amount of attention to faces (vs. objects) were not found. We discuss possible methodological contributions to this null finding. We also highlight the importance of a dimensional approach for understanding the developmental origins of reduced face perception skills, and emphasize the need for longitudinal research to truly understand how social motivation and social attention influence the development of social perceptual skills.
doi:10.3389/fpsyg.2013.00185
PMCID: PMC3622030  PMID: 23596436
autism; eye tracking; face processing; eyetracking; autism spectrum disorder; ASD
16.  Brain hyper-connectivity in children with autism and its links to social deficits 
Cell reports  2013;5(3):738-747.
Summary
Autism spectrum disorder (ASD), a neurodevelopmental disorder affecting nearly 1 in 88 children, is thought to result from aberrant brain connectivity. Remarkably, there have been no systematic attempts to characterize whole-brain connectivity in children with ASD. Here, we use neuroimaging to show there are more instances of greater functional connectivity in the brains of children with ASD compared with typically developing children. Hyper-connectivity in ASD was observed at the whole-brain and subsystems level, across long- and short-range connections, and was associated with higher levels of fluctuations in regional brain signals. Brain hyper-connectivity predicted symptom severity in ASD such that children with greater functional connectivity exhibited more severe social deficits. We replicated these findings in two additional independent cohorts, demonstrating again that at earlier ages, the brain in ASD is largely functionally hyper-connected in ways that contribute to social dysfunction. Our findings provide novel insights into brain mechanisms underlying childhood autism.
doi:10.1016/j.celrep.2013.10.001
PMCID: PMC3894787  PMID: 24210821
17.  Abnormality in face scanning by children with autism spectrum disorder is limited to the eye region: Evidence from multi-method analyses of eye tracking data 
Journal of Vision  2013;13(10):5.
There has been considerable controversy regarding whether children with autism spectrum disorder (ASD) and typically developing children (TD) show different eye movement patterns when processing faces. We investigated ASD and age- and IQ-matched TD children's scanning of faces using a novel multi-method approach. We found that ASD children spent less time looking at the whole face generally. After controlling for this difference, ASD children's fixations of the other face parts, except for the eye region, and their scanning paths between face parts were comparable either to the age-matched or IQ-matched TD groups. In contrast, in the eye region, ASD children's scanning differed significantly from that of both TD groups: (a) ASD children fixated significantly less on the right eye (from the observer's view); (b) ASD children's fixations were more biased towards the left eye region; and (c) ASD children fixated below the left eye, whereas TD children fixated on the pupil region of the eye. Thus, ASD children do not have a general abnormality in face scanning. Rather, their abnormality is limited to the eye region, likely due to their strong tendency to avoid eye contact.
doi:10.1167/13.10.5
PMCID: PMC3739407  PMID: 23929830
autism spectrum disorder; face processing; face recognition; eye movements; eye tracking
18.  Genetic Evidence Implicating Multiple Genes in the MET Receptor Tyrosine Kinase Pathway in Autism Spectrum Disorder 
A functional promoter variant of the gene encoding the MET receptor tyrosine kinase alters SP1 and SUB1 transcription factor binding, and is associated with autism spectrum disorder (ASD). Recent analyses of postmortem cerebral cortex from ASD patients revealed altered expression of MET protein and three transcripts encoding proteins that regulate MET signaling, hepatocyte growth factor (HGF), urokinase plasminogen activator receptor (PLAUR) and plasminogen activator inhibitor-1 (SERPINE1). To address potential risk conferred by multiple genes in the MET signaling pathway, we screened all exons and 5′ promoter regions for variants in the five genes encoding proteins that regulate MET expression and activity. Identified variants were genotyped in 664 families (2,712 individuals including 1,228 with ASD) and 312 unrelated controls. Replicating our initial findings, family-based association test (FBAT) analyses demonstrated that the MET promoter variant rs1858830 C allele was associated with ASD in 101 new families (P=0.033). Two other genes in the MET signaling pathway also may confer risk. A haplotype of the SERPINE1 gene exhibited significant association. In addition, the PLAUR promoter variant rs344781 T allele was associated with ASD by both FBAT (P=0.006) and case-control analyses (P=0.007). The PLAUR promoter rs344781 relative risk was 1.93 (95% Confidence Interval [CI]: 1.12−3.31) for genotype TT and 2.42 (95% CI: 1.38−4.25) for genotype CT compared to genotype CC. Gene-gene interaction analyses suggested a significant interaction between MET and PLAUR. These data further support our hypothesis that genetic susceptibility impacting multiple components of the MET signaling pathway contributes to ASD risk.
doi:10.1002/aur.27
PMCID: PMC2678909  PMID: 19360663
Genetic; Association; Plasminogen; PLAUR; uPAR; SERPINE1; Brain; Cerebral Cortex
19.  Di-(2-ethylhexyl) phthalate and autism spectrum disorders 
ASN NEURO  2012;4(4):e00089.
ASDs (autism spectrum disorders) are a complex group of neurodevelopment disorders, still poorly understood, steadily rising in frequency and treatment refractory. Extensive research has been so far unable to explain the aetiology of this condition, whereas a growing body of evidence suggests the involvement of environmental factors. Phthalates, given their extensive use and their persistence, are ubiquitous environmental contaminants. They are EDs (endocrine disruptors) suspected to interfere with neurodevelopment. Therefore they represent interesting candidate risk factors for ASD pathogenesis. The aim of this study was to evaluate the levels of the primary and secondary metabolites of DEHP [di-(2-ethylhexyl) phthalate] in children with ASD. A total of 48 children with ASD (male: 36, female: 12; mean age: 11±5 years) and age- and sex-comparable 45 HCs (healthy controls; male: 25, female: 20; mean age: 12±5 years) were enrolled. A diagnostic methodology, based on the determination of urinary concentrations of DEHP metabolites by HPLC-ESI-MS (HPLC electrospray ionization MS), was applied to urine spot samples. MEHP [mono-(2-ethylhexenyl) 1,2-benzenedicarboxylate], 6-OH-MEHP [mono-(2-ethyl-6-hydroxyhexyl) 1,2-benzenedicarboxylate], 5-OH-MEHP [mono-(2-ethyl-5-hydroxyhexyl) 1,2-benzenedicarboxylate] and 5-oxo-MEHP [mono-(2-ethyl-5-oxohexyl) 1,2-benzenedicarboxylate] were measured and compared with unequivocally characterized, pure synthetic compounds (>98%) taken as standard. In ASD patients, significant increase in 5-OH-MEHP (52.1%, median 0.18) and 5-oxo-MEHP (46.0%, median 0.096) urinary concentrations were detected, with a significant positive correlation between 5-OH-MEHP and 5-oxo-MEHP (rs = 0.668, P<0.0001). The fully oxidized form 5-oxo-MEHP showed 91.1% specificity in identifying patients with ASDs. Our findings demonstrate for the first time an association between phthalates exposure and ASDs, thus suggesting a previously unrecognized role for these ubiquitous environmental contaminants in the pathogenesis of autism.
doi:10.1042/AN20120015
PMCID: PMC3363982  PMID: 22537663
autism; di-(2-ethylhexyl) phthalate; endocrine disrupters; HPLC-ESI-MS urine analysis; secondary metabolites; ASD, autism spectrum disorder; CARS, childhood autism rating scale; CI, confidence interval; DEHP, di-(2-ethylhexyl) phthalate; ED, endocrine disruptor; HC, healthy control; HPLC-ESI-MS, HPLC electrospray ionization MS; MEHP, mono-(2-ethylhexenyl) 1,2-benzenedicarboxylate; 5-OH-MEHP, mono-(2-ethyl-5-hydroxyhexyl) 1,2-benzenedicarboxylate; 6-OH-MEHP, mono-(2-ethyl-6-hydroxyhexyl) 1,2-benzenedicarboxylate; OS, oxidative stress; 5-oxo-MEHP, mono-(2-ethyl-5-oxohexyl) 1,2-benzenedicarboxylate; QC, quality control; RP-HPLC-ESI-MS, reverse-phase HPLC-ESI-MS; ROC, receiver operating characteristic; SPE, solid phase extraction; PPARα, peroxisome-proliferator-activated receptor α; TH, thyroid hormone
20.  Altered Metabolites in the Plasma of Autism Spectrum Disorder: A Capillary Electrophoresis Time-of-Flight Mass Spectroscopy Study 
PLoS ONE  2013;8(9):e73814.
Clinical diagnosis and severity of autism spectrum disorders (ASD) are determined by trained clinicians based on clinical evaluations of observed behaviors. As such, this approach is inevitably dependent on the expertise and subjective assessment of those administering the clinical evaluations. There is a need to identify objective biological markers associated with diagnosis or clinical severity of the disorder. To identify novel candidate metabolites as potential biomarkers for ASD, the current study applied capillary electrophoresis time-of-flight mass spectroscopy (CE-TOFMS) for high-throughput profiling of metabolite levels in the plasma of 25 psychotropic-naïve adult males with high-functioning ASD and 28 age-matched typically-developed control subjects. Ten ASD participants and ten age-matched controls were assigned in the first exploration set, while 15 ASD participants and 18 controls were included in the second replication set. By CE-TOFMS analysis, a total of 143 metabolites were detected in the plasma of the first set. Of these, 17 metabolites showed significantly different relative areas between the ASD participants and the controls (p<0.05). Of the 17 metabolites, we consistently found that the ASD participants had significantly high plasma levels of arginine (p = 0.024) and taurine (p = 0.018), and significantly low levels of 5-oxoproline (p<0.001) and lactic acid (p = 0.031) compared with the controls in the second sample set. Further confirmatory analysis using quantification of absolute metabolite concentrations supported the robustness of high arginine (p = 0.001) and low lactic acid (p = 0.003) in the combined sample (n = 53). The present study identified deviated plasma metabolite levels associated with oxidative stress and mitochondrial dysfunction in individuals with ASD.
doi:10.1371/journal.pone.0073814
PMCID: PMC3776798  PMID: 24058493
21.  fMRI activation during a language task in adolescents with ASD 
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by language and communication impairments, social impairments, and repetitive behaviors or restricted interests. Previous studies of semantic functions have found differences in semantic processing and differences in the activation of the language network in adults with ASD compared to controls. The goal of this study is to examine semantic functions in adolescents with ASD compared to typically developing adolescents. We utilized fMRI with a reading version of a response-naming task to investigate activation in 12 right-handed adolescent boys with ASD and 12 typically developing boys. Both groups performed the task at ceiling levels. Boys with ASD had significantly stronger activation than controls in Broca's area, which was less left lateralized in ASD individuals. Controls had a significant correlation between frontal and temporal language area activation in the left hemisphere, whereas ASD adolescents did not. Direct group comparisons revealed additional regions activated in the ASD group relative to the control group. These results suggest differences in semantic organization, approaches to the semantic task, or efficiency in semantic processing in ASD adolescents relative to typically developing adolescents.
doi:10.1017/S1355617708081216
PMCID: PMC2747321  PMID: 18954477
Autistic disorder; Functional MRI; Broca's area; Wernicke's area; Semantics; Asymmetry
22.  Exploring the Ability to Deceive in Children with Autism Spectrum Disorders 
The present study explored the relations among lie-telling ability, false belief understanding, and verbal mental age. We found that children with autism spectrum disorder (ASD), like typically developing children, can and do tell antisocial lies (to conceal a transgression) and white lies (in politeness settings). However, children with ASD were less able than typically developing children to cover up their initial lie; that is, children with ASD had difficulty exercising semantic leakage control—the ability to maintain consistency between their initial lie and subsequent statements. Furthermore, unlike in typically developing children, lie-telling ability in children with ASD was not found to be related to their false belief understanding. Future research should examine the underlying processes by which children with ASD tell lies.
doi:10.1007/s10803-010-1045-4
PMCID: PMC3482107  PMID: 20556501
Autism; Lie-telling; Deception; False belief; Theory of mind
23.  Relationship between postural control and restricted, repetitive behaviors in autism spectrum disorders 
Restricted, repetitive behaviors (RRBs) are one of the core diagnostic criteria of autism spectrum disorders (ASD), and include simple repetitive motor behaviors and more complex cognitive behaviors, such as compulsions and restricted interests. In addition to the core symptoms, impaired movement is often observed in ASD. Research suggests that the postural system in individuals with ASD is immature and may never reach adult levels. RRBs have been related to postural sway in individuals with mental retardation. Our goals were to determine whether subjects with ASD had greater postural sway and whether RBS-R scores were related to the magnitude of postural sway. We compared the center of pressure (COP) sway area during quiet stance with scores on the Repetitive Behavior Scale-Revised (RBS-R) in children with ASD and typically developing (TD) controls ages 3–16. All subjects had Non-verbal IQ > 70. Subjects performed four quiet stance trials at a self-selected stance width for 20 s. Subjects with ASD had greater postural sway area compared to controls. Not surprisingly, subjects with ASD exhibited greater frequencies and intensities of RRBs overall and on all six subscales. Further, there was a positive correlation between postural sway area and presence of RRBs. Interestingly, results of the postural sway area for the ASD group suggests that roughly half of the ASD subjects scored comparable to TD controls, whereas the other half scored >2 SD worse. Motor impaired children did not have significantly worse IQ scores, but were younger and had more RRBs. Results support previous findings of relationships between RRBs and postural control. It appears that motor control impairments may characterize a subset of individuals with ASD. Better delineation of motor control abilities in individuals with ASD will be important to help explain variations of abilities in ASD, inform treatment, and guide examination of underlying neural involvement in this very diverse disorder.
doi:10.3389/fnint.2013.00028
PMCID: PMC3646241  PMID: 23675326
autism spectrum disorders (ASD); center of pressure (COP); repetitive behavior; posture; stability
24.  Broader Autism Phenotype in Iranian Parents of Children with Autism Spectrum Disorders vs. Normal Children 
Iranian Journal of Psychiatry  2012;7(4):157-163.
Objective
The aim of the present study was to compare the broader autism phenotype in Iranian parents of children with autism spectrum disorders and parents of typically developing children.
Method
Parents of children with ASD and parents of typically developing children were asked to complete the Persian version of the Autism Spectrum Quotient (AQ). In the ASD group, families included 204 parents (96 fathers and 108 mothers) of children diagnosed as having autism (Autistic Disorder, or AD) (n=124), Asperger Syndrome (AS) or High Functioning Autism (HFA) (n=48) and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) (n=32) by psychiatrists based on the Diagnostic and Statistical Manual of Mental Disorders-4thedition (DSM-IV-TR) criteria. In the control group, 210 (108 fathers and 102 mothers) parents of typically developing children. Parents of typically developing children were selected from four primary schools. Based on family reports, their children did not have any psychiatric problems. Total AQ score and each of the 5 subscales were analyzed using two-way ANOVAs with sex and group as factors.
Results
The mean age of ASD fathers was 40.6 years (SD=5.96; range 31-54), and of ASD mothers was 34.7 years (SD=4.55; range 28-45). The mean age of control fathers was 37 years (SD=4.6; range 29-45) and of control mothers was 34.11 years (SD=4.86; range 28-45). Group differences were found in age (p ‹ 0/001). On total AQ, a main effect for group and sex was found. ASD parents scored higher than controls (F(1,410)=77.876, P ‹ 0/001) and males scored higher than females (F(1,410)=23.324, P ‹ 0/001). Also, Group by Sex interaction was significant (F(1,410)=4.986, P ‹ 0/05). Results of MANOVA analysis displayed significant differences between ASD's subgroups on total AQ and subscales scores (F (15, 1121)=13.924, p < 0.0005; Wilk's Lambda= 0.624, partial =0.145). Pairwise comparisons between ASD's subgroups and Normal group showed that mean scores for the Asperger group are significantly more than other groups in total AQ, attention switching and communication subscales (p < 0.05). The frequencies of BAP (X^2=52.721 (DF=1), P ‹ 0/001), MAP (X^2=17.133 (DF=1), P ‹ 0/001) and NAP (X^2=12.722 (DF=1), P ‹ 0/001) in ASD parents were significantly more than control parents. The frequencies of Broader Autism Phenotype (BAP) (X^2=3.842 (DF=1), P›0/05) and Medium Autism phenotype (MAP) (X^2=0.060 (DF=1), P›0/05) did not significantly differ in ASD fathers and mothers, but the proportion of fathers in Narrow Autism Phenotype(NAP) range was more than mothers (X2=14.344, P ‹ 0/001).
Conclusion
Results of the present study revealed that parents of children with ASD scored significantly higher than control parents on total AQ and its subscales and the rates of BAP, MAP and NAP were higher in ASD parents than in controls. In addition, in ASD's subgroups, the parents of Asperger children scored significantly more than other subgroups (Autism and PDD-nos) and the normal group on total AQ and some subscales.
PMCID: PMC3570573  PMID: 23408558
Autistic disorder; Child; Iran; Parents
25.  Impaired Eye Region Search Accuracy in Children with Autistic Spectrum Disorders 
PLoS ONE  2013;8(3):e58167.
To explore mechanisms underlying reduced fixation of eyes in autism, children with Autistic Spectrum Disorders (ASD) and typically developing children were tested in five visual search experiments: simple color feature; color-shape conjunction; face in non-face objects; mouth region; and eye region. No group differences were found for reaction time profile shapes in any of the five experiments, suggesting intact basic search mechanics in children with ASD. Contrary to early reports in the literature, but consistent with other more recent findings, we observed no superiority for conjunction search in children with ASD. Importantly, children with ASD did show reduced accuracy for eye region search (p = .005), suggesting that eyes contribute less to high-level face representations in ASD or that there is an eye region-specific disruption to attentional processes engaged by search in ASD.
doi:10.1371/journal.pone.0058167
PMCID: PMC3597629  PMID: 23516446

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