Autism Diagnostic Interview-Revised Scores Research Articles

Association Study between DUF1220 Copy Number and Severity of Social Impairment in Sex-balanced Simplex Cases of Autism.

Copy number variations (CNVs), which are genetic factors responsible for human evolution, have emerged as underlying pathogenic factors for a number of diseases such as autism spectrum disorders (ASD). DUF1220 coding sequences have been shown to be positively associated with the severity of symptoms in familial/multiplex cases of autism. However, this association has not been confirmed in simplex autism, and the potential impact of gender/sex has not been studied. Using saliva samples taken from Iranian children with non-syndromic simplex autism, different ethnicity/race and genetic backgrounds from previous studies, we assessed the association between DUF1220 CNVs and Autism Diagnostic Interview-Revised (ADI-R) domain scores in both males and females. In the male and female combined group with autism, in line with previous reports, our findings showed that there were no significant associations between DUF1220 CNVs with either total ADI-R score, social, communication, or repetitive diagnostic scores in simplex autism cases. Interestingly, however, in sex classified groups, despite the insignificant results, our findings in girls with autism showed a negative trend between DUF1220 CNVs and severity of symptoms for the social interaction and communication domains. By contrast, in male children with autism, the results showed a positive trend. It seems that association of DUF1220 CNV with the severity of symptoms in simplex children with autism may follow a sexually dimorphic pattern that needs to be re-examined in prospective studies.

REM Sleep EEG Activity and Clinical Correlates in Adults With Autism.

We tested the hypothesis of an atypical scalp distribution of electroencephalography (EEG) activity during Rapid Eye Movement (REM) sleep in young autistic adults. EEG spectral activity and ratios along the anteroposterior axis and across hemispheres were compared in 16 neurotypical (NT) young adults and 17 individuals with autism spectrum disorder (ASD). EEG spectral power was lower in the ASD group over the bilateral central and right parietal (beta activity) as well as bilateral occipital (beta, theta, and total activity) recording sites. The NT group displayed a significant posterior polarity of intra-hemispheric EEG activity while EEG activity was more evenly or anteriorly distributed in ASD participants. No significant inter-hemispheric EEG lateralization was found. Correlations between EEG distribution and ASD symptoms using the Autism Diagnostic Interview-Revised (ADI-R) showed that a higher posterior ratio was associated with a better ADI-R score on communication skills, whereas a higher anterior ratio was related to more restricted interests and repetitive behaviors. EEG activity thus appears to be atypically distributed over the scalp surface in young adults with autism during REM sleep within cerebral hemispheres, and this correlates with some ASD symptoms. These suggests the existence in autism of a common substrate between some of the symptoms of ASD and an atypical organization and/or functioning of the thalamo-cortical loop during REM sleep.

The relationships between the topological properties of the whole-brain white matter network and the severity of autism spectrum disorder: A study from monozygotic twins

Twins provide a valuable perspective for exploring the pathological mechanism of autism spectrum disorder (ASD). We aim to analyze differences in the topological properties of the white matter (WM) network between monozygotic twins with ASD (MZCo-ASD) and children with typical development (TD). We enrolled 67 subjects aged 2–9 years. Twenty-three pairs of MZCo-ASD and 21 singleton children with TD completed clinical assessments and diffusion tensor imaging (DTI). Graph theory was used to compare the topological properties of the WM network between the two groups, and analyzed their correlations with the severity of clinical symptoms. We found that the global efficiency (Eg) of MZCo-ASD is weaker than that of TD children, while the shortest path length (Lp) of MZCo-ASD is longer than that of TD children, and MZCo-ASD have three unique hubs (the bilateral dorsolateral superior frontal gyrus and right insula). Eg and Lp were both correlated with the repetitive behavior scores of the Autism Diagnostic Interview-Revised (ADI-R) in the MZCo-ASD group, and the nodal efficiency of the dorsal superior frontal gyrus (SFGdor) was correlated with the ADI-R scores of repetitive behaviors. Left SFGdor nodal efficiency was correlated with Repetitive Behavior and Communication, two core symptoms of autism. The results implicated that MZCo-ASD had atypical brain structural network attributes and node distributions. Using MZCo-ASD, we found that the WM topological properties that correlate with the severity of ASD core symptoms were Eg, Lp, and the nodal efficiency of the SFGdor.

Alteration of TRIM33 Expression at Transcriptional and Translational Levels is Correlated with Autism Symptoms.

As a complex neurodevelopmental disorder, autism affects children in three major cognitive domains including social interactions, language learning and repetitive stereotyped behaviors. Abnormal regulation of cell proliferation in the brain during the embryonic period via the TGF-β signaling pathway and TRIM33 gene that encodes a protein with a corepressor and regulatory role in this pathway has been considered as an etiology for autism. Here, we investigated the association of a variation of TRIM33 with autism symptoms at levels of mRNA and protein expression. We used Autism Diagnostic Interview-Revised (ADI-R) and Childhood Autism Rating Scale (CARS) as behavioral diagnostic tools. Normal and autistic children were genotyped for a TRIM33 polymorphism (rs11102807), and then expression was assessed at transcriptional and translational levels. Results demonstrated that the frequency of the homozygous A allele (AA genotype of rs11102807) was significantly higher in children with autism (P < 0.001), whereas carriers of the G allele were mostly among healthy individuals. Children homozygous for the rs11102807 A allele were associated with an increase in CARS and ADI-R scores, indicating a significant correlation with autism symptoms. TRIM33 gene expression at both mRNA (P < 0.01) and protein (P < 0.001) levels was significantly higher in controls compared to autistic children. A remarkable association between higher TRIM33 gene expression at the transcriptional level and lower scores for both CARS and ADI-R was observed in non-autistic children. It seems that rs11102807 modulates the function and expression of the TRIM33 gene, implying that the A allele may increase the risk of autism in children by reducing gene expression and altering the TGF-β signaling pathway.

Increased plasma lipoprotein lipase activity in males with autism spectrum disorder

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder with complex genetics, characterized by impaired social communication and repetitive behaviors and interests. The involvement of lipid metabolism in ASD pathophysiology has been demonstrated in previous studies; however, the molecular mechanisms of abnormal lipid metabolism are not fully understood. A mutation in Lipoprotein lipase (LPL), which has central roles in lipid metabolism, has been identified in patients with ASD. We have reported that Lpl is downregulated in ASD model mice. Therefore, we explored the role of LPL in lipid metabolism in ASD patients. MethodsWe quantified LPL amount, LPL activity, and glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) amount in the plasma of ASD male subjects (n = 28) compared with typical development (TD) controls (n = 28), using enzyme-linked immunosorbent assay for LPL amount and fluorometric assays for LPL activity. We examined the correlations of plasma LPL with GPIHBP1 and clinical characteristic scores from the Autism Diagnostic Interview-Revised (ADI-R). ResultsThere was higher LPL activity, but not LPL amount, in the plasma of ASD subjects compared with controls. Receiver operating characteristics analysis also demonstrated that pure LPL activity (LPL activity/LPL amount) is a useful indicator to distinguish ASD from TD controls. There were no correlations between plasma LPL and ADI-R scores; however, LPL activity was negatively correlated with GPIHBP1 levels in the plasma of ASD subjects. ConclusionsOur results demonstrate increased activity of plasma LPL, regulated by GPIHBP1, in ASD, providing novel insights into the lipid metabolism associated with ASD pathophysiology.

Should autism spectrum disorder be considered part of CHARGE syndrome? A cross-sectional study of 46 patients

BackgroundBehavioral problems are an important issue for people with CHARGE syndrome. The similarity of their behavioral traits with those of people with autism raises questions. In a large national cross-sectional study, we used specific standardized tools for diagnosing autism (Autism Diagnostic Interview-Revised and Diagnostic and Statistical Manual of Mental Disorders, 5th edition, DSM-5) and evaluating behavioral disorders (Developmental Behavior Checklist-Parents, DBC-P) to investigate a series of individuals with CHARGE syndrome, defined by Verloes’s criteria. We evaluated their adaptive functioning level and sensory particularities and extracted several data items from medical files to assess as potential risk factors for autism and/or behavioral disorders.ResultsWe investigated 64 individuals with CHARGE syndrome (35 females; mean age 10.7 years, SD 7.1 years). Among 46 participants with complete results for the Autism Diagnostic Interview-Revised (ADI-R), 13 (28%) had a diagnosis of autism according to the ADI-R, and 25 (54%) had a diagnosis of autism spectrum disorder (ASD) according to the DSM-5 criteria. The frequency of autistic traits in the entire group was a continuum. We did not identify any risk factor for ASD but found a negative correlation between the ADI-R score and adaptive functioning level. Among 48 participants with data for the DBC-P, 26 (55%) had behavioral disorders, which were more frequent in patients with radiological brain anomalies, impaired adaptive functioning, later independent walking, and more sensory particularities.ConclusionsASD should be considered to be an independent risk requiring early screening and management in children born with CHARGE syndrome.

What is the association between ADI-R scores and final diagnosis of autism in an all IQ adult autism diagnostic service?

PurposeThe diagnosis of autism in adults often involves the use of tools recommended by NICE guidance but which are validated in children. The purpose of the paper is to establish the strength of the association between the Autism Diagnostic Interview-Revised (ADI-R) scores and the final clinical outcome in an all intellectual quotients adult autism diagnostic service and to establish if this in any way relates with gender and intellectual ability.Design/methodology/approachThe sample includes referrals to Leeds Autism Diagnostic Service in 2015 that received a clinical outcome. Sensitivity, specificity and positive and negative predictive values were calculated to evaluate ADI-R and final clinical outcomes. Logistic regression model was used to predict the effect of the scores in all the domains of ADI-R and the two-way interactions with gender and intellectual ability.FindingsADI-R has a high sensitivity and low specificity and is useful to rule out the presence of autism, but if used alone, it can over diagnose. Restricted stereotyped behaviours are the strongest predictor for autism and suggests that the threshold should be increased to enhance its specificity.Research limitations/implicationsThis is a single site study with small effect size, so results may not be replicable. It supports the combined use of ADI-R and Autism Diagnostic Observation Schedule and suggests increasing ADI-R cut-offs to increase the specificity.Practical implicationsThe clinical team may consider piloting a modified ADI-R as suggested by the results.Originality/valueTo the authors’ knowledge this is the only study of ADI-R in an adult population of all intellectual abilities.

The influence of parental concern on the utility of autism diagnostic instruments.

The parental report-based Autism Diagnostic Interview-Revised (ADI-R) and the clinician observation-based Autism Diagnostic Observation Schedule (ADOS) have been validated primarily in U.S. clinics specialized in autism spectrum disorder (ASD), in which most children are referred by their parents because of ASD concern. This study assessed diagnostic agreement of the ADOS-2 and ADI-R toddler algorithms in a more broadly based sample of 679 toddlers (age 35-47 months) from the Norwegian Mother and Child Cohort. We also examined whether parental concern about ASD influenced instrument performance, comparing toddlers identified based on parental ASD concern (n = 48) and parent-reported signs of developmental problems (screening) without a specific concern about ASD (n = 400). The ADOS cutoffs showed consistently well-balanced sensitivity and specificity. The ADI-R cutoffs demonstrated good specificity, but reduced sensitivity, missing 43% of toddlers whose parents were not specifically concerned about ASD. The ADI-R and ADOS dimensional scores agreed well with clinical diagnoses (area under the curve ≥ 0.85), contributing additively to their prediction. On the ADI-R, different cutoffs were needed according to presence or absence of parental ASD concern, in order to achieve comparable balance of sensitivity and specificity. These results highlight the importance of taking parental concern about ASD into account when interpreting scores from parental report-based instruments such as the ADI-R. While the ADOS cutoffs performed consistently well, the additive contributions of ADI-R and ADOS scores to the prediction of ASD diagnosis underscore the value of combining instruments based on parent accounts and clinician observation in evaluation of ASD. Autism Res 2017, 10: 1672-1686. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

T8. GLUTAMATERGIC SIGNALLING AND AUTISM: A FAMILY BASED ASSOCIATION STUDY ON THE GLUTAMATERGIC NEUROTRANSMITTER SYSTEM

Background Common single nucleotide polymorphisms (SNPs) explain around 50% of genetic risk underlying Autism-Spectrum-Disorder (ASD). In a previous study we showed that common functional SNPs of genes implicated in Fragile X Syndrome (FXS) were associated with ASD (Waltes et al., 2014). The FXS associated protein FMRP is regulated by the glutamatergic system, a patho-mechanism discussed for ASD. Objective We tested if functional common SNPs of glutamatergic genes were associated with ASD or ASD specific symptoms in two large ASD family cohorts (Autism Genome Project/AGP set, N=2734 families; German data set N=578 families). Since the genetic architecture between individuals with High IQ (HIQ= IQ>70) and Low IQ (LIQ= IQ≤70) differs (Vieland et al., 2010), we also split the two cohorts into high and low functioning (HIQ, LIQ) individuals. Methods 207 functional SNPs of 124 glutamatergic genes with a minor allele frequency over 5% were tested using Plink v 1.9 (DFAM) in the cohort with HIQ, LIQ and the combined cohorts, respectively. Phenotype association was studied by logistic ordinal regression correcting for gender, IQ, clinical site and population stratification. Phenotype measures were taken from the Autism Diagnostic Interview-Revised (ADI-R) scores for Social Interaction (Domain A), Verbal Communication (B1-B4; verbal individuals only), Non-Verbal Communication (Domain B2; B3; all individuals) and Repetitive Behavior (Domain C). Variants significant in both cohorts with effect sizes in the same direction were considered as replicated. Similarly, genes with any nominal significant variant in both cohorts were considered as replicated hits. Results We identified nominal significant associations of variants rs7206796 and rs3790112 (GNAO1) as well as rs3742926 (AKAP6) in both the German and the AGP LIQ cohort. In addition, significant but not overlapping SNPs of AKAP2 were identified (LIQ only). rs731826 (AKT1S1) was associated with Non Verbal Communication in the HIQ cohorts. In addition, we report 24 variants that were nominally associated with ADI-R scores in both cohorts. Genes that were involved in all five phenotypes tested were strongly related to the mTOR Pathway (e.g. genes MTOR and TSC2) or the second messenger system (e.g. G-proteins GNAS, phospholipases PLCB, protein phosphatases PPP1CA). A subset of genes was specific to each phenotype or significant in one of the subgroups (HIQ and LIQ) only. For example AKAP13 or RPS6K are associated with Verbal Communication in Low Functioning Individuals. Discussion Replication and extending previous findings we found that variants of genes that are associated with glutamate signaling, and specifically the mTOR pathway are modulators of ASD symptoms. Genes such as TSC1 or RPS6K are known to mediate glutamatergic signaling through mTOR, whereas AKAP proteins are important interactors of glutamate receptors (Sanderson et al., 2011). Both, the mTOR pathways and AKAP proteins have previously been associated with ASD (Chen et al ., 2014; Poelmans et al., 2013). Further functional analyses of glutamatergic variants are thus recommended to elucidate ASD etiology.

Sex chromosomes and the brain: a study of neuroanatomy in XYY syndrome

To assess global and regional brain matter variations associated with XYY syndrome by comparison with Klinefelter syndrome and typical development. We used two conceptually distinct voxel-based magnetic resonance imaging methods to examine brain structure in young males with XYY syndrome: (1) volumetric comparison to assess global grey and white matter volumes and (2) support vector machine-based multivariate pattern classification analysis to assess regional neuroanatomy. We assessed verbal, non-verbal, and spatial abilities with the Differential Ability Scales (DAS), and we measured autism diagnostic criteria in eight males with XYY syndrome using the Social Responsiveness Scale and the Autism Diagnostic Interview-Revised (ADI-R). A comparison of 36 typically developing males (mean age 11 y, SD 1 y 9 mo), 31 males with Klinefelter syndrome (mean age 9 y 8 mo, SD 1 y 8 mo), and eight males with XYY syndrome (mean age 11 y 6 mo, SD 1 y 11 mo) showed that total white and grey matter volumes were significantly, or nearly significantly, higher in males with XYY syndrome than in males belonging to the other two groups (grey matter: XYY males vs typically developing males, p<0.006; XYY vs males with Klinefelter syndrome, p<0.001; white matter: XYY males vs typically developing males, p=0.061; XYY males vs males with Klinefelter syndrome, p=0.004). Voxel-based multivariate pattern classification analysis indicates that, after controlling for global volumes, regional brain variations in XYY syndrome are more like those found in Klinefelter syndrome than those occurring in typical development. Further, visualization of classification parameters suggests that insular and frontotemporal grey matter and white matter, including known language areas, are reduced in males with XYY syndrome, similar to what is seen in Klinefelter syndrome. In males with XYY syndrome, DAS verbal and non-verbal scores were significantly lower than in typically developing participants (both p<0.001). DAS scores were not significantly different between XYY and Klinefelter syndrome groups. In five of eight males with XYY syndrome, the Social Responsiveness Scale score exceeded the cut-off for a likely diagnosis of autism spectrum disorder (ASD). In three of eight males with XYY syndrome, the ADI-R score met the cut-off for ASD diagnosis; in another two, ADI-R scores within the social and communication domains met the cut-off values for a diagnosis of ASD. The results suggest that genetic variations associated with XYY syndrome result in increased brain matter volumes, a finding putatively related to the increased frequency of ASDs in individuals with this condition. In addition, frontotemporal grey and white matter reductions in XYY syndrome provide a likely neuroanatomical correlate for observed language impairments.

Inhibin B and anti-Müllerian hormone/Müllerian-inhibiting substance may contribute to the male bias in autism

The autistic spectrum disorders have a significant male bias in incidence, which is unexplained. The Sertoli cells of the immature testes secrete supra-adult levels of Müllerian-inhibiting substance/anti-Müllerian hormone (AMH) and inhibin B (InhB), with both hormones being putative regulators of brain development. We report here, that 82 boys with an autism spectrum disorder have normal levels of InhB and AMH. However, the boys' level of InhB correlated with their autism diagnostic interview—revised (ADI-R) scores for the social interaction (R=0.29, P=0.009, N=82) and communication domains (R=0.29, P=0.022, N=63), and with the number of autistic traits the boys exhibited (R=0.34 and 0.27, respectively). The strengths of the abovementioned correlates were stronger in the boys with milder autism (R=0.42 and 0.50, respectively), with AMH exhibiting a significant negative correlation to the ADI-R score in these boys (R=−0.44 and R=−0.39, respectively). Neither hormone correlated to the incidence of stereotyped and repetitive behaviours. This suggests that the male bias in the autistic spectrum has multiple determinants, which modulate the effects of an otherwise non-dimorphic pathology. Furthermore, AMH and InhB have opposing effects on the SMAD1/5/8 pathway, and opposing correlates to autistic traits, implicating the SMAD pathways as a putative point of molecular convergence for the autistic spectrum.

Self-Reported Autism Symptoms in Adults with Autism Spectrum Disorders

Scores on the autism spectrum quotient (AQ) were examined in 65 adults with ASD. Maternal reports of symptoms were collected simultaneously using the autism diagnostic interview-revised (ADI-R) and the Vineland Screener. A slightly revised AQ administration procedure was used to accommodate adults with below average IQ. AQ scores were lower than in the original validation study, with only 11 adults (17%) scoring above the proposed diagnostic cut-off and 24 (27%) exceeding the screening cut-off. Adults with higher IQs endorsed more symptoms than those with below average intelligence, but even when analyses were restricted to the 39 adults with at least average IQ, only 44% met the screening cut-off. AQ scores were not significantly correlated with ADI-R or Vineland scores.

Signes neurologiques mineurs et troubles envahissants du développement

Many studies have focused on specific motor signs in autism and Asperger's syndrome, but few has been published on the complete range of neurological soft signs (NSS) in children with pervasive developmental disorder (PDD). Scarce are the studies evaluating NSS in children suffering from PDD not otherwise specified (PDDNOS). This study compared performance of 11 autistic children (AD) and 10 children with PDDNOS, with controls matched on age, sex and cognitive performance on Krebs et al.'s NSS scale. Because of the duration of the assessments and specific difficulties encountered in managing some items, an adaptation of the scale had to be made during a pilot study with the agreement of the author. To be eligible, patients had to meet the following inclusion criteria: an age range of 6-16 years, a diagnosis of autistic disorder or PDDNOS based on the DSMIV criteria (American Psychiatric Association 1994). The autism diagnostic interview-revised (ADI-R) was used in order to confirm the diagnosis and to evaluate the association of the symptoms to the severity of the NSS. The childhood autism rating scale (CARS) was completed for the patients in order to evaluate symptoms at the time of the NSS examination. Cognitive ability was assessed with Raven's progressive matrices. Were excluded patients with: history of cerebral palsy, congenital anomaly of the central nervous system, epilepsy, known genetic syndrome, tuberous sclerosis, neurofibromatosis, antecedent of severe head trauma, Asperger's syndrome, obvious physical deformities or sensory deficits that would interfere with neurological assessment, deep mental retardation and recent or chronic substance use or abuse. Healthy controls shared the same exclusion criteria, with no personal history of neurological, psychiatric disorder or substance abuse, no family history of psychiatric disorder and normal or retardation in schooling. All study procedures were approved by the local Ethics Committee (Comité d'éthique, Razi Hospital), according to the declaration of Helsinki. There was no difference between patients and controls with respect to sex, age and cognitive function. All children had an IQ higher than 81. Significant differences were found between AD children and control group in the motor integration function and sensory integration function. Different NSS scores were significantly higher in the PDDNOS group than in controls: the total scores, motor coordination, motor integration function, sensory integration and abnormal movements. Lower performance in motor coordination skills was associated with higher ADI-R communication score in the AD group. No relationship was found between NSS and CARS' total sore. This study confirms the impaired neurological functioning in autistic as well as PDDNOS children. The association of motor impairment with autistic symptoms highlights the argument that motor control problems can be part of the autism spectrum disorders. The lack of relationship between NSS and intellectual aptitude in the clinical sample provides new elements for the neurodevelopment model of the autism spectrum.

Serum levels of platelet-derived growth factor BB homodimers are increased in male children with autism

The neurobiological basis of autism remains poorly understood. To examine the role played by serum cytokines in brain development, we hypothesized that Platelet-Derived Growth Factor (PDGF) and Vascular Endothelial Growth Factor (VEGF) may be associated with pathophysiology of autism. In this study, we screened serum levels of these growth factors in young male subjects with autism. We measured serum levels of PDGF subtypes and VEGF in the 31 male children with autism (6-19 years old) and 31 healthy age- and gender-matched subjects. The serum levels of PDGF-BB in male children with autism (N=31, 5624.5+/-1651.8 pg/mL [mean+/-SD]) were significantly higher (two-tailed Student's t-test: p=0.0188) than those of normal control subjects (N=31, 4758.2+/-1521.5 pg/mL [mean+/-SD]). There was a significant and positive correlation (Pearson's r=0.5320, p=0.0010) between the serum levels of PDGF-BB and the Autism Diagnostic Interview-Revised (ADI-R) domain C scores, which represent stereotyped patterns of behavior in the children with autism. However, there were no marked or significant correlations between serum PDGF-BB levels and clinical variables, including the other ADI-R scores and Intellectual Quotient (IQ) scores by WAIS-R. There were no significant change and correlations with clinical variables in serum PDGF-AA, PDGF-AB, and VEGF levels in the children with autism. Increased levels of serum PDGF-BB homodimers might be implicated in the pathophysiology of autism.

Twins with KBG Syndrome and Autism

Twins with KBG Syndrome and Autism

The structure of the Autism Diagnostic Interview‐Revised: diagnostic and phenotypic implications

Multivariate statistics can assist in refining the nosology and diagnosis of pervasive developmental disorders (PDD) and also contribute important information for genetic studies. The Autism Diagnostic Interview-Revised (ADI-R) is one of the most widely used assessment instruments in the field of PDD. The current study investigated its factor structure and convergence with measures of adaptive, language, and intellectual functioning. Analyses were conducted on 1,861 individuals with PDD between the ages of 4 and 18 years (mean = 8.3, SD = 3.2). ADI-R scores were submitted to confirmatory factor analysis (CFA) and exploratory factor analysis (EFA). Analyses were conducted according to verbal status (n = 1,329 verbal, n = 532 nonverbal) and separately for algorithm items only and for all items. ADI-R scores were correlated with scores on measures of adaptive, language, and intellectual functioning. Several factor solutions were examined and compared. CFAs suggested that two- and three-factor solutions were similar, and slightly superior to a one-factor solution. EFAs and measures of internal consistency provided some support for a two-factor solution consisting of social and communication behaviors and restricted and repetitive behaviors. Measures of functioning were not associated with ADI-R domain scores in nonverbal children, but negatively correlated in verbal children. Overall, data suggested that autism symptomatology can be explained statistically with a two-domain model. It also pointed to different symptoms susceptible to be helpful in linkage analyses. Implications of a two-factor model are discussed.

Novel clustering of items from the Autism Diagnostic Interview‐Revised to define phenotypes within autism spectrum disorders

Heterogeneity in phenotypic presentation of Autism spectrum disorders has been cited as one explanation for the difficulty in pinpointing specific genes involved in autism. Recent studies have attempted to reduce the "noise" in genetic and other biological data by reducing the phenotypic heterogeneity of the sample population. The current study employs multiple clustering algorithms on 123 item scores from the Autism Diagnostic Interview-Revised (ADI-R) diagnostic instrument of nearly 2,000 autistic individuals to identify subgroups of autistic probands with clinically relevant behavioral phenotypes in order to isolate more homogeneous groups of subjects for gene expression analyses. Our combined cluster analyses suggest optimal division of the autistic probands into four phenotypic clusters based on similarity of symptom severity across the 123 selected item scores. One cluster is characterized by severe language deficits, while another exhibits milder symptoms across the domains. A third group possesses a higher frequency of savant skills while the fourth group exhibited intermediate severity across all domains. Grouping autistic individuals by multivariate cluster analysis of ADI-R scores reveals meaningful phenotypes of subgroups within the autistic spectrum, which we show, in a related (accompanying) study, to be associated with distinct gene expression profiles.

Obstetric and Parental Psychiatric Variables as Potential Predictors of Autism Severity

Associations between obstetric and parental psychiatric variables and subjects' Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) domain scores were examined using linear mixed effects models. Data for the 228 families studied were provided by the Autism Genetic Resource Exchange. Hypertension (P = 0.002), preeclampsia (P = 0.021) and generalized edema (P = 0.011) were associated with higher ADI-R communication scores. Hypertension (P = 0.011), albuminuria (P = 0.039) and generalized edema (P = 0.009) were associated with higher ADI-R repetitive behaviors scores. Parent depression was associated with higher ADI-R repetitive behaviors scores (P = 0.005), and parent anxiety with lower ADOS social/communication composite scores (P = 0.025). The associations between hypertension-related obstetric conditions and autistic severity warrant further investigation and raise intriguing questions regarding potential causal and modifying factors in autism.

Administration of secretin for autism alters dopamine metabolism in the central nervous system

We evaluated the clinical effects of intravenously administered secretin in 12 children with autism (age range: 4–6 years, median age: 9 years, boy:girl=8:4). In addition, we investigated the association between improvement in symptoms and changes in the cerebrospinal fluid (CSF) homovanillic acid (HVA),5-hydroxyindole-3-acetic acid (5-HIAA), and 6R-5,6,7,8-tetrahydro-L-biopterin (BH 4) levels after administration. After administration of secretin, the Autism Diagnostic Interview-Revised (ADI-R) score improved in 7 of the 12 children. However, the score deteriorated in 2 of the 12 children (in the item of ‘restricted and repetitive, stereotyped interests and behaviors’). The HVA and BH 4 levels in CSF were increased in all children with improvement in the ADI-R score. In contrast, no patient without the elevation of the BH 4 level showed improvement in the score. These findings suggest that secretin activated metabolic turnover of dopamine in the central nervous system via BH 4, improving symptoms.

Survival in senile and presenile Alzheimer's disease : ∗L. Bracco, A. Lippi, L. Amaducci, Department of Neurologic and Psychiatric Sciences, University of Florence; R. Gallato, F. Grigoletto, Fidia Research Laboratories, Abano Terme; D. Pedone, P. Livrea, Department of Neurology, University of Bari; G. Bino, M. Tabaton, C. Moretti, C. Loeb, Department of Neurology, University of Genoa; M.L. Bonatti, F. Campanozzi,

Twins provide a valuable perspective for exploring the pathological mechanism of autism spectrum disorder (ASD). We aim to analyze differences in the topological properties of the white matter (WM) network between monozygotic twins with ASD (MZCo-ASD) and children with typical development (TD). We enrolled 67 subjects aged 2–9 years. Twenty-three pairs of MZCo-ASD and 21 singleton children with TD completed clinical assessments and diffusion tensor imaging (DTI). Graph theory was used to compare the topological properties of the WM network between the two groups, and analyzed their correlations with the severity of clinical symptoms. We found that the global efficiency (Eg) of MZCo-ASD is weaker than that of TD children, while the shortest path length (Lp) of MZCo-ASD is longer than that of TD children, and MZCo-ASD have three unique hubs (the bilateral dorsolateral superior frontal gyrus and right insula). Eg and Lp were both correlated with the repetitive behavior scores of the Autism Diagnostic Interview-Revised (ADI-R) in the MZCo-ASD group, and the nodal efficiency of the dorsal superior frontal gyrus (SFGdor) was correlated with the ADI-R scores of repetitive behaviors. Left SFGdor nodal efficiency was correlated with Repetitive Behavior and Communication, two core symptoms of autism. The results implicated that MZCo-ASD had atypical brain structural network attributes and node distributions. Using MZCo-ASD, we found that the WM topological properties that correlate with the severity of ASD core symptoms were Eg, Lp, and the nodal efficiency of the SFGdor.