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The Autism Diagnostic Interview-Revised is one of the ''gold standard'' diagnostic tools for autism spectrum disorders. It is traditionally administered face-to- face. Cost and geographical concerns constrain the employment of the ADI-R for large-scale research projects. The telephone interview is a reasonable alternative, but has not yet been examined for reliability with face-to-face administration. In this study, participants were interviewed both face-to-face and on the telephone using the complete ADI-R interview. Results indicate that there was no significant difference between the algorithm scores or the diagnoses arrived at for face-to-face and telephone administrations. Reliability statistics across the two modalities were very good and indicate that telephone interviews using the ADI-R are a viable option for researchers. [ABSTRACT FROM AUTHOR]

The PDD Behavior Inventory (PDDBI) is a rating scale filled out by parents and teachers that is designed to assess response to intervention in children with PDD. It consists of subscales that measure both maladaptive and adaptive behaviors and also provides a summary 'Autism Score' reflective of the severity of the condition. The scale has been shown to have very good internal consistency as well as developmental and construct validity. In this study, the PDDBI's criterion-related validity was assessed. Correlations with the Childhood Autism Rating Scale and the Autism Diagnostic Interview-Revised were good. Selected maladaptive scales from the PDDBI correlated well with comparable factors of the Nisonger Child Behavior Rating Form. The adaptive sections of the PDDBI correlated highly with the Griffiths Mental Development Scales and with the Vineland Adaptive Behavior Scales. These results confirm the validity of the PDDBI and suggest that the scale will have value in assessing treatment-related changes in maladaptive and adaptive behaviors associated with PDD. [ABSTRACT FROM AUTHOR]

The PDD Behavior Inventory (PDDBI) is a rating scale filled out by caregivers or teachers that was designed to assess children having a Pervasive Developmental Disorder (PDD; autism, Asperger disorder, PDD-NOS, or childhood disintegrative disorder). Both adaptive and maladaptive behaviors are assessed in the scale, making it useful for treatment studies in which decreases in maladaptive behaviors and improvements in adaptive social and language skills relevant to PDD are expected. The adaptive behaviors assessed include core features of the disorder such as joint attention skills, pretend play, and referential gesture. The maladaptive behaviors sample a wide variety of behaviors observed in both lower- and higher-functioning individuals and include stereotyped behaviors, fears, aggression, social interaction deficits, and aberrant language. The inventory was found to have a high degree of internal consistency. Inter-rater reliability was better for adaptive behaviors than for maladaptive behaviors. Factor analyses confirmed the structure of the PDDBI and indicated good construct validity. In a subsample of children between 3 and 6 years of age, raw scores for adaptive behaviors increased with age in the parent and teacher versions, as did measures of social pragmatic problems. It was concluded that the PDDBI is both reliable and valid and is useful in providing information not typically available in most instruments used to assess children with PDD. [ABSTRACT FROM AUTHOR]

A nonlinear pattern recognition system, neural network technology, was explored for its utility in assisting in the classification of autism. It was compared with a more traditional approach, simultaneous and stepwise linear discriminant analyses, in terms of the ability of each methodology to both classify and predict persons as having autism or mental retardation based on information obtained from a new structured parent interview: the Autistic Behavior Interview. The neural network methodology was superior to discriminant function analysis both in its ability to classify groups (92 vs. 85%) and to generalize to new cases that were not part of the training sample (92 vs. 82%). Interrater and test-retest reliabilities and measures of internal consistency were satisfactory for most of the subscales in the Autistic Behavior Interview. The implications of neural network technology for diagnosis, in general, and for understanding of possible core deficits in autism are discussed. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the cost-effectiveness of prolonged mechanical ventilation in patients 80 years of age and older in the intensive care unit (ICU).Design: A retrospective review of consecutive ICU patients requiring 3 or more days of mechanical ventilation. Cost-effectiveness analysis was performed by assessing incremental hospital charges from hospital billing records; charges were then related to years of life saved. A telephone survey was used to follow up hospital survivors for a minimum of 4 years after discharge.Setting: A 20-bed medical-surgical ICU in a 420-bed, tertiary-care community teaching hospital.Patients: The study included all patients aged 80 years or older taken from a comprehensive database of all patients admitted to the ICU requiring mechanical ventilation from April 1, 1985, through October 31, 1987 (n = 512). Of 59 potential candidates, 45 were found to have complete billing records and were the subject of further analysis.Results: Of the 45 patients in the group under analysis, 10 survived to leave the hospital. Of these, two were alive and one could not be located at the time of follow-up. The charge per year of life saved is estimated to between $51,854 and $75,090 in 1985-1987 dollars. Of 22 patients whose age in years plus duration of mechanical ventilation in days totaled 100 or greater, only two survived hospitalization and neither was alive at follow-up. The cost per year of life saved in this subset of patients was $1181,308 in 1985-1987 dollars. One of these patients was discharged to a nursing home and died there 4.5 years later, after multiple hospital readmissions. The other patient died at home 2 months after hospital discharge.Conclusion: Based on hospital charges and life expectancy, the cost-effectiveness of prolonged mechanical ventilation in ICU patients age 80 years and over was poor in our population when the combination of age and duration of mechanical ventilation exceeded 100. Further studies using this type of analysis may prove valuable in both clinical and administrative decision-making processes. [ABSTRACT FROM AUTHOR]

Aggressive behaviors in those with intellectual disability (ID) and autism (ASD) have been linked to a variety of factors including ID level, age, sex, psychiatric disorders, and medical conditions but these factors have not been studied, in large samples, in terms of how they affect the stimuli that trigger aggression. In this survey of 2243 adults, four triggers of aggression associated with frustration, discomfort, change in the physical/social environment, and defensive reactions were analyzed for their relation to ID level, ASD, age, sex, number of psychiatric diagnoses, sleeping problems, seizures, visual impairment, ear infections and gastrointestinal problems. All four triggers were associated with increasing number of psychiatric disorders, with frustration, discomfort, and change intolerance commonly linked to sleeping problems and ASD. Implications for assessment and intervention are discussed.

A recent cross-sectional analysis of PDD Behavior Inventory (PDDBI) data, analyzed with a classification and regression tree algorithm, yielded a decision tree (the Autism Spectrum Disorder-Decision Tree or ASD-DT) that detected three behaviorally distinct ASD subgroups: minimally verbal, verbal, and atypical. These subgroups differed in PDDBI profiles and in factors previously reported to be predictors of autism severity and adaptive behavior trajectories. We retrospectively analyzed trajectories of adaptive skills and autism severity in these subgroups, defined by ASD-DTs calculated from initial evaluation PDDBIs. Results confirmed predictions that each subgroup had distinct trajectories that varied with the type of adaptive behavior assessed suggesting that the ASD-DT has prognostic value that could be helpful for both clinical and research applications.

Folate deficiency can affect fetal and neonatal brain development Considering the reported association of Folate receptor alpha (FRα) autoantibodies (Abs) with autism and developmental disorders, we sought to confirm this in families of 82 children with ASD, 53 unaffected siblings, 65 fathers, and 70 mothers, along with 52 unrelated normal controls. Overall, 76% of the affected children, 75% of the unaffected siblings, 69% of fathers and 59% of mothers were positive for either blocking or binding Ab, whereas the prevalence of this Ab in the normal controls was 29%. The Ab was highly prevalent in affected families including unaffected siblings. The appearance of these antibodies may have a familial origin but the risk of developing ASD is likely influenced by other mitigating factors since some siblings who had the antibodies were not affected. The antibody response appears heritable with the blocking autoantibody in the parents and affected child increasing the risk of ASD. Autism Res 2018, 11: 707-712. © 2018 International Society for Autism Research, Wiley Periodicals, Inc., Lay Summary: Folate is an essential nutrient during fetal and infant development. Autoantibodies against the folate receptor alpha can block folate transport from the mother to the fetus and to the brain in infants. Children diagnosed with autism and their immediate family members were evaluated for the prevalence of folate receptor autoantibodies. The autoantibody was highly prevalent in affected families with similar distribution in parents, normal siblings and affected children. The presence of these antibodies appears to have a familial origin and may contribute to developmental deficits when combined with other factors., (© 2018 International Society for Autism Research, Wiley Periodicals, Inc.)

In order to improve discrimination accuracy between Autism Spectrum Disorder (ASD) and similar neurodevelopmental disorders, a data mining procedure, Classification and Regression Trees (CART), was used on a large multi-site sample of PDD Behavior Inventory (PDDBI) forms on children with and without ASD. Discrimination accuracy exceeded 80 %, generalized to an independent validation set, and generalized across age groups and sites, and agreed well with ADOS classifications. Parent PDDBIs yielded better results than teacher PDDBIs but, when CART predictions agreed across informants, sensitivity increased. Results also revealed three subtypes of ASD: minimally verbal, verbal, and atypical; and two, relatively common subtypes of non-ASD children: social pragmatic problems and good social skills. These subgroups corresponded to differences in behavior profiles and associated bio-medical findings.

Objective: Younger siblings of children with autism spectrum disorder (ASD) are at high risk (HR) for developing ASD as well as features of the broader autism phenotype. Although this complicates early diagnostic considerations in this cohort, it also provides an opportunity to examine patterns of behavior associated specifically with ASD compared to other developmental outcomes., Method: We applied Classification and Regression Trees (CART) analysis to individual items of the Autism Diagnostic Observation Schedule (ADOS) in 719 HR siblings to identify behavioral features at 18 months that were predictive of diagnostic outcomes (ASD, atypical development, and typical development) at 36 months., Results: Three distinct combinations of features at 18 months were predictive of ASD outcome: poor eye contact combined with lack of communicative gestures and giving; poor eye contact combined with a lack of imaginative play; and lack of giving and presence of repetitive behaviors, but with intact eye contact. These 18-month behavioral profiles predicted ASD versus non-ASD status at 36 months with 82.7% accuracy in an initial test sample and 77.3% accuracy in a validation sample. Clinical features at age 3 years among children with ASD varied as a function of their 18-month symptom profiles. Children with ASD who were misclassified at 18 months were higher functioning, and their autism symptoms increased between 18 and 36 months., Conclusion: These findings suggest the presence of different developmental pathways to ASD in HR siblings. Understanding such pathways will provide clearer targets for neural and genetic research and identification of developmentally specific treatments for ASD., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: A total of 38 brain cytoarchitectonic subdivisions, representing subcortical and cortical structures, cerebellum, and brainstem, were examined in 4- to 60-year-old subjects diagnosed with autism and control subjects (a) to detect a global pattern of developmental abnormalities and (b) to establish whether the function of developmentally modified structures matches the behavioral alterations that are diagnostic for autism. The volume of cytoarchitectonic subdivisions, neuronal numerical density, and total number of neurons per region of interest were determined in 14 subjects with autism and 14 age-matched controls by using unbiased stereological methods., Results: The study revealed that significant differences between the group of subjects with autism and control groups are limited to a few brain regions, including the cerebellum and some striatum and amygdala subdivisions. In the group of individuals with autism, the total number and numerical density of Purkinje cells in the cerebellum were reduced by 25% and 24%, respectively. In the amygdala, significant reduction of neuronal density was limited to the lateral nucleus (by 12%). Another sign of the topographic selectivity of developmental alterations in the brain of individuals with autism was an increase in the volumes of the caudate nucleus and nucleus accumbens by 22% and 34%, respectively, and the reduced numerical density of neurons in the nucleus accumbens and putamen by 15% and 13%, respectively., Conclusions: The observed pattern of developmental alterations in the cerebellum, amygdala and striatum is consistent with the results of magnetic resonance imaging studies and their clinical correlations, and of some morphometric studies that indicate that detected abnormalities may contribute to the social and communication deficits, and repetitive and stereotypical behaviors observed in individuals with autism.

The pathological role of autoantibodies in development of CNS disorders is a new idea with growing interest among neuroscientists. The involvement of autoimmune response in the pathogenesis of autism spectrum disorders (ASD) has been suggested by the presence of multiple brain-specific autoantibodies in children with ASD and in their mothers. The possibility of the effect of autoimmunity on neurogenesis and postnatal brain plasticity has not been determined. The presence of autoantibodies against human neuronal progenitor cells (NPCs) stimulated for neuronal differentiation in culture was tested in sera from children with autism (n=20) and age-matched controls (n=18) by immunoblotting and immunocytochemistry. Immunoreactivity against multiple NPCs proteins of molecular sizes of approximately 55 kDa, 105 kDa, 150 kDa, and 210 kDa in sera from individuals with autism had a higher incidence and was stronger than in control sera which immunoreacted mainly with a 150 kDa protein. The sera from children with autism immunoreacted the strongest with NPCs expressing neuronal markers Tuj1 and doublecortin, but not astrocyte marker GFAP. The epitopes recognized by antibodies from sera were not human-specific because they detected also NPCs in situ in murine hippocampus. The autoimmune reactions against NPCs suggest an impaired tolerance to neural antigens in autism. These autoantibodies may be symptomatic for autism and furthermore, their presence suggests that autoimmunity may affect postnatal neuronal plasticity particularly after impairment of blood-brain barrier. Future studies will determine the diagnostic value of the presence of autoantibodies in autism and the therapeutic value of prevention of autoimmunity in autism., (Published by Elsevier B.V.)

Several morphometric studies have revealed smaller than normal neurons in the neocortex of autistic subjects. To test the hypothesis that abnormal neuronal growth is a marker of an autism-associated global encephalopathy, neuronal volumes were estimated in 16 brain regions, including various subcortical structures, Ammon's horn, archicortex, cerebellum, and brainstem in 14 brains from individuals with autism 4 to 60 years of age and 14 age-matched control brains. This stereological study showed a significantly smaller volume of neuronal soma in 14 of 16 regions in the 4- to 8-year-old autistic brains than in the controls. Arbitrary classification revealed a very severe neuronal volume deficit in 14.3% of significantly altered structures, severe in 50%, moderate in 21.4%, and mild in 14.3% structures. This pattern suggests desynchronized neuronal growth in the interacting neuronal networks involved in the autistic phenotype. The comparative study of the autistic and control subject brains revealed that the number of structures with a significant volume deficit decreased from 14 in the 4- to 8-year-old autistic subjects to 4 in the 36- to 60-year-old. Neuronal volumes in 75% of the structures examined in the older adults with autism are comparable to neuronal volume in age-matched controls. This pattern suggests defects of neuronal growth in early childhood and delayed up-regulation of neuronal growth during adolescence and adulthood reducing neuron soma volume deficit in majority of examined regions. However, significant correction of neuron size but limited clinical improvements suggests that delayed correction does not restore functional deficits.

Background: Children with Autism Spectrum Disorder (ASD) show unusual social behaviors and repetitive behaviors. Some of these behaviors, e.g., time spent in an area or turning rate/direction, can be automatically tracked. Automated tracking has several advantages over subjective ratings including reliability, amount of information provided, and consistency across laboratories, and is potentially of importance for diagnosis, animal models and objective assessment of treatment efficacy. However, its validity for ASD has not been examined. In this exploratory study, we examined associations between rating scale data with automated tracking of children's movements using the Noldus EthoVision XT system; i.e., tracking not involving a human observer. Based on our observations and previous research, we predicted that time spent in the periphery of the room would be associated with autism severity and that rate and direction of turning would be associated with stereotypies., Methods: Children with and without ASD were observed in a free-play situation for 3 min before and 3 min after Autism Diagnostic Observation Scale - Generic (ADOS-G) testing. The Noldus system provided measures of the rate and direction of turning, latency to approach and time spend near the periphery or the parent., Results: Ratings of the severity of maladaptive social behaviors, stereotypies, autism severity, and arousal problems were positively correlated with increases in percent time spent in the periphery in the total sample and in the ASD subset. Adaptive social communication skills decreased with increases in the percentage of time spent in the periphery and increases in the latency to approach the parent in the ASD group. The rate and direction of turning was linked with stereotypies only in the group without ASD (the faster the rate of a turn to the left, the worse the rating). In the ASD group, there was a shift from a neutral turning bias prior to the ADOS assessment to a strong left turn bias after the ADOS assessment. In the entire sample, this left turn bias was associated with measures of autism severity., Conclusion: Results suggest that automated tracking yields valid and unbiased information for assessing children with autism. Turning bias is an interesting and unexplored measure related to autism.

Individuals with autism demonstrate atypical gaze, impairments in smooth pursuit, altered movement perception and deficits in facial perception. The olivofloccular neuronal circuit is a major contributor to eye movement control. This study of the cerebellum in 12 autistic and 10 control subjects revealed dysplastic changes in the flocculus of eight autistic (67%) and two control (20%) subjects. Defects of the oculomotor system, including avoidance of eye contact and poor or no eye contact, were reported in 88% of autistic subjects with postmortem-detected floccular dysplasia. Focal disorganization of the flocculus cytoarchitecture with deficit, altered morphology, and spatial disorientation of Purkinje cells (PCs); deficit and abnormalities of granule, basket, stellate and unipolar brush cells; and structural defects and abnormal orientation of Bergmann glia are indicators of profound disruption of flocculus circuitry in a dysplastic area. The average volume of PCs was 26% less in the dysplastic region than in the unaffected region of the flocculus (p<0.01) in autistic subjects. Moreover, the average volume of PCs in the entire cerebellum was 25% less in the autistic subjects than in the control subjects (p<0.001). Findings from this study and a parallel study of the inferior olive (IO) suggest that focal floccular dysplasia combined with IO neurons and PC developmental defects may contribute to oculomotor system dysfunction and atypical gaze in autistic subjects., (Published by Elsevier B.V.)

The use of psychotropics by categories and the reason for their prescription was investigated in a large scale study of 4,069 adults with ID, including those with autism spectrum disorder, in New York State. Similar to other studies it was found that 58 % (2,361/4,069) received one or more psychotropics. Six percent received typical, while 39 % received atypical antipsychotics [corrected]. There was greater use of antidepressants (23 %), mood stabilizers (19 %), and antianxiety agents (16 %) relative to other studies. The use of anti-impulsives, stimulants and hypnotics was rare (1-2 %). Half of the psychotropics were prescribed for treatment of major psychiatric disorders, 13 % for control of challenging behaviors, and 38 % for both. Results indicated that the major psychiatric disorders, except anxiety disorder and autism, influenced the use of psychotropics and the number of medication used. These findings imply that although practitioners still rely too heavily on the use of antipsychotics in this population, there is a welcome shift in the prescription patterns relative to other studies. The practitioners appeared to use psychotropics primarily to treat diagnosed psychiatric disorders and not just to control aggressive behavior which suggests that evidence-based practice of psychiatry is playing an increasing role in the ID population.

The authors evaluated the contribution of initially abnormal neonatal auditory brainstem responses (ABRs) and 4-month arousal-modulated attention visual preference to later autism spectrum disorder (ASD) behaviors in neonatal intensive care unit (NICU) graduates. A longitudinal study design was used to compare NICU graduates with normal ABRs (n = 28) to those with initially abnormal ABRs (n = 46) that later resolved. At 4 months postterm age, visual preference (measured after feeding) for a random check pattern flashing at 1, 3, or 8 Hz and gestational age (GA) served as additional predictors. Outcome measures were PDD Behavior Inventory (PDDBI) scores at 3.4 years (standard deviation = 1.2), and developmental quotients (DQ) obtained around the same age with the Griffiths Mental Development Scales (GMDS). Preferences for higher rates of stimulation at 4 months were highly correlated with PDDBI scores (all P-values < 0.01) and the GMDS Hearing and Speech DQ, but only in those with initially abnormal ABRs. Effects were strongest for a PDDBI social competence measure most associated with a diagnosis of autism. For those with abnormal ABRs, increases in preference for higher rates of stimulation as infants were linked to nonlinear increases in severity of ASD at 3 years and to an ASD diagnosis. Abnormal ABRs were associated with later reports of repetitive and ritualistic behaviors irrespective of 4-month preference for stimulation. The joint occurrence of initially abnormal neonatal ABRs and preference for more stimulation at 4 months, both indices of early brainstem dysfunction, may be a marker for the development of autism in this cohort., (© 2012 International Society for Autism Research, Wiley Periodicals, Inc.)

Duplications of 7q11.23, deleted in Williams-Beuren Syndrome, have been implicated in autism spectrum disorders (ASDs). A 1.5 Mb duplication was identified in one girl with severe expressive language deficits and anxiety among 1,142 ASD individuals screened for this duplication. Family-based association studies of Tag-SNPs in three genes (STX1A , CYLN2 and GTF2i) in two multiplex autism family cohorts revealed strong association of two GTF2i SNPs and their haplotype in Cohort 1 and the combined families. The risk alleles and haplotype were associated with severe problems in social interaction and excessive repetitive behaviors. Our findings suggest the GTF2i gene is important in the etiology of autism in individuals with this duplication and in non-duplication cases with severe social interaction problems and repetitive behaviors.

Background: The neurotransmitter dopamine (DA) modulates executive functions, learning, and emotional processing, all of which are impaired in individuals with autism spectrum disorders (ASDs). Our previous findings suggest a role for dopamine-related genes in families with only affected males., Methods: We examined two additional genes which affect DA function, the DRD2 and PPP1R1B (DARPP-32) genes, in a cohort of 112 male-only affected sib-pair families. Selected polymorphisms spanning these genes were genotyped and both family-based and population-based tests were carried out for association analysis. General discriminant analysis was used to examine the gene-gene interactions in predicting autism susceptibility., Results: There was a significantly increased frequency of the DRD2 rs1800498TT genotype (P = 0.007) in affected males compared to the comparison group, apparently due to over-transmission of the T allele (P = 0.0003). The frequency of the PPP1R1B rs1495099CC genotype in affected males was also higher than that in the comparison group (P = 0.002) due to preferential transmission of the C allele from parents to affected children (P = 0.0009). Alleles rs1800498T and rs1495099C were associated with more severe problems in social interaction (P = 0.0002 and P = 0.0016, respectively) and communication (P = 0.0004 and P = 0.0046), and increased stereotypic behaviours (P = 0.0021 and P = 0.00072). General discriminant analysis found that the DRD2 and PPP1R1B genes additively predicted ASDs (P = 0.00011; Canonical R = 0.26) and explain ~7% of the variance in our families. All findings remained significant following corrections for multiple testing., Conclusion: Our findings support a role for the DRD2 and PPP1R1B genes in conferring risk for autism in families with only affected males and show an additive effect of these genes towards prediction of affected status in our families.

The purposes of this study were to identify differences in patterns of developmental abnormalities between the brains of individuals with autism of unknown etiology and those of individuals with duplications of chromosome 15q11.2-q13 (dup[15]) and autism and to identify alterations that may contribute to seizures and sudden death in the latter. Brains of 9 subjects with dup(15), 10 with idiopathic autism, and 7 controls were examined. In the dup(15) cohort, 7 subjects (78%) had autism, 7 (78%) had seizures, and 6 (67%) had experienced sudden unexplained death. Subjects with dup(15) autism were microcephalic, with mean brain weights 300 g less (1,177 g) than those of subjects with idiopathic autism (1,477 g; p<0.001). Heterotopias in the alveus, CA4, and dentate gyrus and dysplasia in the dentate gyrus were detected in 89% of dup(15) autism cases but in only 10% of idiopathic autism cases (p < 0.001). By contrast, cerebral cortex dysplasia was detected in 50% of subjects with idiopathic autism and in no dup(15) autism cases (p<0.04). The different spectrum and higher prevalence of developmental neuropathologic findings in the dup(15) cohort than in cases with idiopathic autism may contribute to the high risk of early onset of seizures and sudden death.

Background: It has been shown that amyloid ß (Aβ), a product of proteolytic cleavage of the amyloid β precursor protein (APP), accumulates in neuronal cytoplasm in non-affected individuals in a cell type-specific amount., Methodology/principal Findings: In the present study, we found that the percentage of amyloid-positive neurons increases in subjects diagnosed with idiopathic autism and subjects diagnosed with duplication 15q11.2-q13 (dup15) and autism spectrum disorder (ASD). In spite of interindividual differences within each examined group, levels of intraneuronal Aβ load were significantly greater in the dup(15) autism group than in either the control or the idiopathic autism group in 11 of 12 examined regions (p<0.0001 for all comparisons; Kruskall-Wallis test). In eight regions, intraneuronal Aβ load differed significantly between idiopathic autism and control groups (p<0.0001). The intraneuronal Aβ was mainly N-terminally truncated. Increased intraneuronal accumulation of Aβ(17-40/42) in children and adults suggests a life-long enhancement of APP processing with α-secretase in autistic subjects. Aβ accumulation in neuronal endosomes, autophagic vacuoles, Lamp1-positive lysosomes and lipofuscin, as revealed by confocal microscopy, indicates that products of enhanced α-secretase processing accumulate in organelles involved in proteolysis and storage of metabolic remnants. Diffuse plaques containing Aβ(1-40/42) detected in three subjects with ASD, 39 to 52 years of age, suggest that there is an age-associated risk of alterations of APP processing with an intraneuronal accumulation of a short form of Aβ and an extracellular deposition of full-length Aβ in nonfibrillar plaques., Conclusions/significance: The higher prevalence of excessive Aβ accumulation in neurons in individuals with early onset of intractable seizures, and with a high risk of sudden unexpected death in epilepsy in autistic subjects with dup(15) compared to subjects with idiopathic ASD, supports the concept of mechanistic and functional links between autism, epilepsy and alterations of APP processing leading to neuronal and astrocytic Aβ accumulation and diffuse plaque formation.

Reports of unrelated individuals with autism spectrum disorder (ASD) and similar clinical features having overlapping de novo interstitial deletions at 2p15-p16.1 suggest that this region harbors a gene(s) important to the development of autism. We molecularly characterized two such deletions, selecting two genes in this region, exportin 1 (XPO1) and orthodenticle homolog 1 (OTX1) for association studies in three North American cohorts (Autism Spectrum Disorder - Canadian American Research Consortium (ASD-CARC), New York, and Autism Genetic Resource Exchange (AGRE)) and one Italian cohort (Società Italiana per la Ricerca e la Formazione sull'Autismo (SIRFA)) of families with ASD. In XPO1, rs6735330 was associated with autism in all four cohorts (P<0.05), being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing (P(FDR))=1.29 × 10(-5)), the AGRE cohort (P(FDR)=0.0011) and the combined families (P(FDR)=2.34 × 10(-9)). Similarly, in OTX1, rs2018650 and rs13000344 were associated with autism in ASD-CARC cohorts (P(FDR)=8.65 × 10(-7) and 6.07 × 10(5), respectively), AGRE cohort (P(FDR)=0.0034 and 0.015, respectively) and the combined families (P(FDR)=2.34 × 10(-9) and 0.00017, respectively); associations were marginal or insignificant in the New York and SIRFA cohorts. A significant association (P(FDR)=2.63 × 10(-11)) was found for the rs2018650G-rs13000344C haplotype. The above three SNPs were associated with severity of social interaction and verbal communication deficits and repetitive behaviors (P-values <0.01). No additional deletions were identified following screening of 798 ASD individuals. Our results indicate that deletion 2p15-p16.1 is not commonly associated with idiopathic ASD, but represents a novel contiguous gene syndrome associated with a constellation of phenotypic features (autism, intellectual disability, craniofacial/CNS dysmorphology), and that XPO1 and OXT1 may contribute to ASD in 2p15-p16.1 deletion cases and non-deletion cases of ASD mapping to this chromosome region.

Two methylenetetrahydrofolate reductase gene (MTHFR) functional polymorphisms were studied in 205 North American simplex (SPX) and 307 multiplex (MPX) families having one or more children with an autism spectrum disorder. Case-control comparisons revealed a significantly higher frequency of the low-activity 677T allele, higher prevalence of the 677TT genotype and higher frequencies of the 677T-1298A haplotype and double homozygous 677TT/1298AA genotype in affected individuals relative to controls. Family-based association testing demonstrated significant preferential transmission of the 677T and 1298A alleles and the 677T-1298A haplotype to affected offspring. The results were not replicated in MPX families. The results associate the MTHFR gene with autism in SPX families only, suggesting that reduced MTHFR activity is a risk factor for autism in these families.

Background: The link between aggression and mental disorders has been the focus of diverse studies in persons with and without intellectual disabilities (ID). Because of discrepancies in the finding of studies in persons with ID to date, and because of differences in research design, instruments used and the population studied, more research is needed. The purpose of this study was to delineate any significant association between certain psychiatric disorders and specific domains of aggressive behaviours in a large sample of persons with ID controlling for sex, age, autism and degree of ID., Method: Data from the present study were obtained from 47% of all persons with ID receiving services from New York State agencies, using the Institute for Basic Research - Modified Overt Aggression Scale (IBR-MOAS between 2006 and 2007). The IBR-MOAS was completed by the chief psychologists of 14 agencies based on information from the participants' files. Demographic information obtained included the psychiatric diagnosis made by the treating psychiatrist as well as information on age, sex and degree of ID. Data from 4069 participants were analysed., Results: Impulse control disorder and bipolar disorder were strongly associated with all five domains of aggressive behaviour in the IBR-MOAS. Psychotic disorder was highly associated with four domains except for physical aggression against self (PASLF), which was of borderline significance. Anxiety was most associated with PASLF and verbal aggression against self (VASLF); depression with VASLF; obsessive compulsive disorder with physical aggression against objects (PAOBJ); personality disorders with verbal aggression against others (VAOTH), VASLF and PASLF; and autism with physical aggression against others (PAOTH), PAOBJ and PASLF. Mild to moderate ID was associated with VAOTH and VASLF and severe to profound ID with PAOBJ and PASLF. Female sex was most associated with VASLF., Conclusions: Impulse control, mood dysregulation and perceived threat appear to underlie most of the aggressive behaviours reported. Psychosis and depression appeared to have been over-diagnosed in persons with mild to moderate ID and under-diagnosed in persons with severe and profound ID. These findings replicate and extend findings from previous studies. The pattern of associations reported can be used as helpful indicators by professionals involved in the treatment of aggressive behaviours in persons with ID., (© 2011 The Authors. Journal of Intellectual Disability Research © 2011 Blackwell Publishing Ltd.)

Objectives: Recent evidence suggests higher prevalence of autism spectrum disorder (ASD) in NICU graduates. This aim of this study was to identify retrospectively early behaviors found more frequently in NICU infants who went on to develop ASD., Methods: Twenty-eight NICU graduates who later received a diagnosis of ASD were compared with 2169 other NICU graduates recruited from 1994 to 2005. They differed in gender, gestational age, and birth cohort. These characteristics were used to draw a matched control sample (n=112) to determine which, if any, early behaviors discriminated subsequent ASD diagnosis. Behavioral testing at targeted ages (adjusted for gestation) included the Rapid Neonatal Neurobehavioral Assessment (hospital discharge, 1 month), Arousal-Modulated Attention (hospital discharge, 1 and 4 months), and Bayley Scales of Infant Development (multiple times, 4-25 months)., Results: At 1 month, children with ASD but not control children had persistent neurobehavioral abnormalities and higher incidences of asymmetric visual tracking and arm tone deficits. At 4 months, children with ASD had continued visual preference for higher amounts of stimulation than did control children, behaving more like newborns. Unlike control children, children with ASD had declining mental and motor performance by 7 to 10 months, resembling infants with severe central nervous system involvement., Conclusions: Differences in specific behavior domains between NICU graduates who later receive a diagnosis of ASD and matched NICU control children may be identified in early infancy. Studies with this cohort may provide insights to help understand and detect early disabilities, including ASD.

Autism is characterized by a broad spectrum of clinical manifestations including qualitative impairments in social interactions and communication, and repetitive and stereotyped patterns of behavior. Abnormal acceleration of brain growth in early childhood, signs of slower growth of neurons, and minicolumn developmental abnormalities suggest multiregional alterations. The aim of this study was to detect the patterns of focal qualitative developmental defects and to identify brain regions that are prone to developmental alterations in autism. Formalin-fixed brain hemispheres of 13 autistic (4-60 years of age) and 14 age-matched control subjects were embedded in celloidin and cut into 200-mum-thick coronal sections, which were stained with cresyl violet and used for neuropathological evaluation. Thickening of the subependymal cell layer in two brains and subependymal nodular dysplasia in one brain is indicative of active neurogenesis in two autistic children. Subcortical, periventricular, hippocampal and cerebellar heterotopias detected in the brains of four autistic subjects (31%) reflect abnormal neuronal migration. Multifocal cerebral dysplasia resulted in local distortion of the cytoarchitecture of the neocortex in four brains (31%), of the entorhinal cortex in two brains (15%), of the cornu Ammonis in four brains and of the dentate gyrus in two brains. Cerebellar flocculonodular dysplasia detected in six subjects (46%), focal dysplasia in the vermis in one case, and hypoplasia in one subject indicate local failure of cerebellar development in 62% of autistic subjects. Detection of flocculonodular dysplasia in only one control subject and of a broad spectrum of focal qualitative neuropathological developmental changes in 12 of 13 examined brains of autistic subjects (92%) reflects multiregional dysregulation of neurogenesis, neuronal migration and maturation in autism, which may contribute to the heterogeneity of the clinical phenotype.

The psychometric characteristics of the IBR Modified Overt Aggression Scale were studied in over 2,000 people with Intellectual Disability (ID). Reliability ranged from good to excellent. Aggression toward others and objects was highest in the youngest adults, in those in the moderate to severe range of ID, and in those with an autism spectrum diagnosis. Self-injury was highest in those in the severe to profound range of ID and in those with autism, particularly the females. Females with autism were also more likely to make the most self-deprecating statements. Our data suggest that adult females with autism are a unique group and support the notion that mood and anxiety disorders play a role in self-destructive behaviors in this population.

Quantitative variations in score profiles from the parent version of the PDD Behavior Inventory (PDDBI) were examined in young Autism and PDD-NOS groups defined by ADOS-G and ADI-R criteria, relative to a not spectrum (NS) group of similar age. Both the Autism and the PDD-NOS group profiles markedly differed from the NS group. The most sensitive measures of group differences were those domain and composite scores that assessed social communication competence, as well as the overall Autism Composite score. Sensitivity, specificity and positive and negative predictability measures were quite good for these measures. It was concluded that the PDDBI is useful in assisting in the differential diagnosis of autism spectrum disorder.

Altered brain development during embryogenesis and early postnatal life has been hypothesized to be responsible for the abnormal behaviors of people with autism. The specific genetic background that alters vulnerability to some environmental insults has been suggested in the etiology of autism; however, the specific pathomechanisms have not been identified. Recently, we showed that sera from children with autism alter the maturation of human neuronal progenitor cells (NPCs) in culture. Results suggest that pre-programmed neurogenesis, i.e., neuronal proliferation, migration, differentiation, growth, and circuit organization, can be affected differently by factors present in autistic sera. In this report, we tested the effect of autistic sera on the vulnerability of NPCs to oxidative stress-a recognized risk factor of autism. We found that mild oxidative stress reduced proliferation of differentiating NPCs but not immature NPCs. This decrease of proliferation was less prominent in cultures treated with sera from children with autism than from age-matched controls. These results suggest that altered response of NPCs to oxidative stress may play a role in the etiology of autism.

An imbalance between excitation and inhibition in the cerebral cortex has been suggested as a possible etiology of autism. The DLX genes encode homeodomain-containing transcription factors controlling the generation of GABAergic cortical interneurons. The DLX1 and DLX2 genes lie head-to-head in 2q32, a region associated with autism susceptibility. We investigated 6 Tag SNPs within the DLX1/2 genes in two cohorts of multiplex (MPX) and one of simplex (SPX) families for association with autism. Family-based association tests showed strong association with five of the SNPs. The common alleles of rs743605 and rs4519482 were significantly associated with autism (P<0.012) in the first sample of 138 MPX families, with the latter remaining significant after correction for multiple testing (P(cor)=0.0046). Findings in a second sample of 169 MPX families not only confirmed the association at rs4519482 (P=0.034) but also showed strong allelic association of the common alleles at rs788172, rs788173 and rs813720 (P(cor)=0.0003-0.04). In the combined MPX families, the common alleles were all significantly associated with autism (P(cor)=0.0005-0.016). The GGGTG haplotype was over transmitted in the two MPX cohorts and the combined samples [P(cor)<0.05: P(cor)=0.00007 for the combined MPX families, Odds Ratio: 1.75 (95% CI: 1.33-2.30)]. Further testing in 306 SPX families replicated the association at rs4519482 (P=0.033) and the over transmission of the haplotype GGGTG (P=0.012) although P-values were not significant after correction for multiple testing. The findings support the presence of two functional polymorphisms, one in or near each of the DLX genes that increase susceptibility to, or cause, autism in MPX families where there is a greater genetic component for these conditions.

Changes of brain structure and functions in people with autism may result from altered neuronal development, however, no adequate cellular or animal models are available to study neurogenesis in autism. Neuronal development can be modeled in culture of neuronal progenitor cells (NPCs) stimulated with serum to differentiate into neurons. Because sera from people with autism and age-matched controls contain different levels of numerous biologically active factors, we hypothesized that development of human NPCs induced to differentiate into neurons with sera from children with autism reflects the altered early neuronal development that leads to autism. The control and autistic sera were collected from siblings aged below 6 years that lived in the same environment. The effect of sera on differentiation of NPC neurospheres into neuronal colonies was tested in 72-h-long cultures by morphometry, immunocytochemistry and immunoblotting. We found that sera from children with autism significantly reduced NPCs' proliferation, but stimulated cell migration, development of small neurons with processes, length of processes and synaptogenesis. These results suggest that development of network of processes and synaptogenesis--the specific events in the brain during postnatal ontogenesis--are altered in autism. Further studies in this cell culture model may explain some of the cellular alterations described in autistic patients.

A quantitative examination was made of the association of parental mood and anxiety disorders with severity of disability within a large sample of young children with Pervasive Developmental Disorder (PDD). Maternal recurrent mood disorders were associated with elevated cognitive and adaptive functioning in their affected children, parent reports of increased behavior problems and teacher reports of an internalizing behavioral style. Maternal histories of anxiety disorders and paternal depression or anxiety disorders were not associated with levels of adaptive/cognitive functioning or levels of maladaptive behaviors in the children. Various genetic models are discussed. It is hypothesized that genes associated with recurrent depression in women may exert a "protective" effect on cognition and adaptive functioning in children with PDD.

Currently, there is no biochemical test to assist in the behavioral diagnosis of autism. We observed that levels of phosphatidylethanolamine (PE) were decreased while phosphatidylserine (PS) were increased in the erythrocyte membranes of children with autism as compared to their non-autistic developmentally normal siblings. A new method using Trinitrobenezene sulfonic acid (TNBS) for the quantification of PE and PS (amino-glycerophospholipids, i.e., AGP) in the plasma of children was developed and standardized. Wavelength scans of TNBS-PE and TNBS-PS complexes gave two peaks at 320 nm and 410 nm. When varying concentrations of PS and PE were used, a linear regression line was observed at 410 nm with TNBS. Using this assay, the levels of AGP were found to be significantly increased in the plasma of children with autism as compared to their non-autistic normal siblings. It is proposed that plasma AGP levels may function as a potential diagnostic marker for autism.

Background: Self-injurious behavior (SIB) is one of the most common challenging behaviors in persons with autistic disorder or severe/profound mental retardation. Many psychotropic drugs have been evaluated for their effectiveness in SIB. Results have varied, and no one psychotropic drug has been indicated for SIB. In this prospective, open clinical study, psychotropic drugs were used to treat the previously undiagnosed psychiatric disorder in persons exhibiting SIB., Method: Data were collected from 26 individuals with mental retardation (14 males, 12 females), 7 to 45 years of age (mean = 30.3 years), who exhibited SIB. Psychiatric diagnosis was made according to DSM-III-R and DSM-IV criteria. The Behavior Problem Inventory, Yudofsky's Overt Aggression Scale, repeated direct observation, and information on use of protective devices and Likert scales from log books were used to evaluate degree of SIB. Most of the patients were treated with different psychotropic drugs and behavior modification before they were evaluated for this study, but only 7 of them carried a psychiatric diagnosis. Data were collected between 1987 and 1997., Results: Depressive disorders, impulse-control disorder, and anxiety disorder were the most common final diagnoses. Neuroleptics were discontinued in 5 patients and tapered by 50% to 75% in 14 patients. Antidepressants were added in 12 patients. Treatment of psychiatric disorders produced significant (p < .001) decrease in the severity of SIB in the 26 patients, and SIB was eliminated in 12 patients. The severity of SIB decreased to mild from a moderate, severe, or extreme degree in 11 patients and from an extreme to a severe degree in 3 patients., Conclusion: The most effective treatment for SIB that is resistant to environment changes and behavior modification in persons with developmental disabilities is the treatment of their psychiatric disorders with the appropriate psychotropics.

Using single subject research design, we performed pilot research to evaluate the safety and efficacy of famotidine for the treatment of children with autistic spectrum disorders. We studied 9 Caucasian boys, 3.8-8.1 years old, with a DSM-IV diagnosis of a pervasive developmental disorder, living with their families, receiving no chronic medications, and without significant gastrointestinal symptoms. The dose of oral famotidine was 2 mg/kg/day (given in two divided doses); the maximum total daily dose was 100 mg. Using single-subject research analysis and medication given in a randomized, double-blind, placebo-controlled, cross-over design, 4 of 9 children randomized (44%) had evidence of behavioral improvement. Primary efficacy was based on data kept by primary caregivers, including a daily diary; daily visual analogue scales of affection, reciting, or aspects of social interaction; Aberrant Behavior Checklists (ABC, Aman); and Clinical Global Improvement scales. Children with marked stereotypy (meaningless, repetitive behaviors) did not respond. Our subjects did not have prominent gastrointestinal symptoms and endoscopy was not part of our protocol; thus, we cannot exclude the possibility that our subjects improved due to the effective treatment of asymptomatic esophagitis. The use of famotidine for the treatment of children with autistic spectrum disorders warrants further investigation.

Studies of immune function during depression in persons without intellectual disability (ID) have revealed elevated levels of alpha2 macroglobulin (alpha2M) and an acute phase protein (APP) response. Clinical observation suggests that people with Down's syndrome (DS) may have associated genetic abnormalities in their immune systems. The APP response and alpha2M changes in depressed versus non-depressed adults with DS was the subject of the present study. The serum pan-proteinase inhibitor alpha2M, and the AP proteins c-reactive protein (CRP), alpha1 antitrypsin (alpha1AT), ceruloplasmin (Cp), beta2 Macroglobulin (beta2M), transthyretin (Trans), serum amyloid protein (SAP), and albumin (Alb) were measured in 38 adults with DS, 19 of whom were diagnosed with and 19 without depression using a sandwich enzyme-linked immunosorbent assay (ELISA). The DSM-IV criteria were used for diagnoses. Medical and neurological examinations excluded medical disorders associated with APP response. Only alpha2M and CRP were significantly different in the depressed versus non-depressed groups. The alpha2M was higher, a response similar to one observed in depressed people without ID, but the CRP was lower in the depressed group, especially in those subjects not on psychotropic medications, contrary to the expected APP response to depression. The results suggest that alpha2M elevation in depressed adults with DS is independent of the APP response. An alternative explanation for its elevation is proposed linking the core symptom of depression with the mammalian dormancy/hibernation process. Further studies are needed to confirm that alpha2M elevation is specific to depression and that it might provide a helpful marker for the diagnosis of depression in people with ID.

Objective: To analyze the costs and discharge status for patients with prolonged mechanical ventilation undergoing tracheostomy., Design: Retrospective analysis of a statewide database., Patients: All patients (n = 37,573) >18 yrs of age who had prolonged mechanical ventilation (procedure code 96.72) and were discharged from the hospital between 1992 and 1996 with a final DRG code of 483., Interventions: None., Measurements and Main Results: Rates of change in discharges and hospital reimbursements and the cost per survivor were examined by case payment groups and discharge year. A direct relation between volume and reimbursement rate was seen over time, although the patient age distributions remained relatively stable. The greatest increase in volume was from 1995 to 1996. For most years, there was a consistent inverse relation between age and survival, with older survivors being more likely to be discharged to residential healthcare facilities and younger patients more likely to be discharged home. There was a consistent direct relation between age and cost per survivor, mainly the result of improved survival rather than decreased reimbursements in later years., Conclusions: More controlled reimbursements and improved overall survival rates for DRG 483 have contributed to the improved cost per survivor among all age groups over the period. Given the greater proportion of elderly that do not survive or who are placed into residential healthcare facilities, more scrutiny is needed concerning the use of DRG 483 resources so that care is better coordinated for these patients in the inpatient and postacute care settings.

Study Objectives: To examine and describe the relationship between age and disposition in patients undergoing mechanical ventilation., Design: Retrospective analysis of a statewide database., Setting: All acute-care hospitals in New York State., Patients: All patients (n=10,473) aged > or = 18 years discharged from hospital during 1993 with a final diagnosis related group (DRG) coding of 475., Interventions: None., Measurements and Results: The final disposition, according to six codes (other acute-care facility, residential health-care facility, other health-care facility, home, home health-care services, and death) were examined for the whole population. Cost per case was assumed to equal the average statewide Medicaid rate. An inverse relationship between survival rate and age was observed and this resulted in an age-related increased cost per survivor. Also, survivors in older age groups have an increasing rate of hospital discharge to residential health-care facilities., Conclusion: Patients who undergo mechanical ventilation are expensive to care for. The older they are, the less satisfactory is the outcome both from clinical and economic perspectives.

Objective: To present guidelines for writing admission and discharge policies for adult intermediate care units., Data Sources: Opinion of practitioners with experience and expertise in managing critical and intermediate care units., Data Synthesis: Consensus was reached regarding the characteristics of patients best suited for management in an intermediate care unit, as supported by a literature review., Conclusion: Criteria were developed that define patients who are optimal candidates for management in an intermediate care unit.

Patients with prolonged intensive care unit (ICU) length of stay, though few in number, consume as much as 50% of ICU resources. With increasing pressures for cost containment in health care, the availability of ICU beds may be jeopardized. To improve the efficiency of care for patients requiring a surgical intensive care unit (SICU) stay of 3 or more days, a multidisciplinary, highly "protocolized," Progressive Care Area was developed within the existing SICU environment. Entry into this area is limited to patients whose acuity level is not high by ICU standards, but too high for a general surgical floor. In designing the Progressive Care Area, we drew on a number of published management strategies-including total quality management concepts and our prior experience in establishing ventilator management teams. The Progressive Care Area has resulted in a reduction in both the frequency and variation of resources used. A Progressive Care Area within an existing ICU is a viable alternative for the care of the patients who have prolonged lengths of stay and are less acutely ill, and it significantly improves ICU efficiency.

Objective: To examine and describe the relation between age and disposition in patients undergoing tracheostomy., Design: Retrospective analysis of a statewide database., Setting: All acute care hospitals in New York state., Patients: All patients (n = 6,353) > or = 18 yrs of age who were discharged from the hospital during 1993 with a final diagnosis-related groups code of 483., Interventions: None., Measurements and Main Results: The final disposition, according to six disposition codes (other acute care facility, residential healthcare facility, other healthcare facility, home, home healthcare services, and death) was examined for the entire population. Cost per case was assumed to equal the average statewide Medicaid rate. An inverse relation between survival rate and age was observed, which resulted in an age-related increased cost per survivor. Also, survivors in older age groups had an increased rate of discharge to residential healthcare facilities. There was a negative, albeit less marked, effect of older age on the rates of survivors discharged to home and to other healthcare facilities., Conclusions: Care of patients who undergo tracheostomy for prolonged mechanical ventilation is expensive. The older the patient, the less satisfactory the outcome from an economic, clinical, and possibly social perspective.

Fragile X syndrome is one of the most common forms of inherited mental retardation, and the first of a new class of genetic disorders associated with expanded trinucleotide repeats. Previously, we found that about 41% of affected males are mosaic for this mutation in that some of their blood cells have an active fragile X gene and others do not. It has been hypothesized that these mosaic cases should show higher levels of functioning than those who have only the inactive full mutation gene, but previous studies have provided negative or equivocal results. In the present study, the cross-sectional development of communication, self-care, socialization, and motor skills was studied in 46 males with fragile X syndrome under age 20 years as a function of two variables: age and the presence or absence of mosaicism. The rate of adaptive skills development was 2-4 times as great in mosaic cases as in full mutation cases. There was also a trend for cases with autism to be more prevalent in the full-mutation group. These results have implications for prognosis, for the utility of gene or protein replacement therapies for this disorder, and for understanding the association between mental retardation, developmental disorders, and fragile X syndrome.