1. Buxbaum JD, Betancur C, Bozdagi O, Dorr NP, Elder GA, Hof PR. {{Optimizing the phenotyping of rodent ASD models: Enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features}}. {Mol Autism};2012 (Feb 20);3(1):1.
ABSTRACT: BACKGROUND: There is interest in defining mouse neurobiological phenotypes useful for studying autism spectrum disorders (ASD) in both forward and reverse genetic approaches. A recurrent focus has been on high-order behavioral analyses, including learning and memory paradigms and social paradigms. However, well-studied mouse models, including for example Fmr1 knockout mice, do not show dramatic deficits in such high-order phenotypes, raising a question as to what constitute useful phenotypes in ASD models. METHODS: To address this, we made use of a list of 112 disease genes etiologically involved in ASD to survey, on a large scale and with unbiased methods as well as expert review, phenotypes associated with a targeted disruption of these genes in mice, using the Mammalian Phenotype Ontology database. In addition, we compared the results with similar analyses for human phenotypes. FINDINGS: We observed four classes of neurobiological phenotypes associated with disruption of a large proportion of ASD genes, including: (1) Changes in brain and neuronal morphology; (2) electrophysiological changes; (3) neurological changes; and (4) higher-order behavioral changes. Alterations in brain and neuronal morphology represent quantitative measures that can be more widely adopted in models of ASD to understand cellular and network changes. Interestingly, the electrophysiological changes differed across different genes, indicating that excitation/inhibition imbalance hypotheses for ASD would either have to be so non-specific as to be not falsifiable, or, if specific, would not be supported by the data. Finally, it was significant that in analyses of both mouse and human databases, many of the behavioral alterations were neurological changes, encompassing sensory alterations, motor abnormalities, and seizures, as opposed to higher-order behavioral changes in learning and memory and social behavior paradigms. CONCLUSIONS: The results indicated that mutations in ASD genes result in defined groups of changes in mouse models and support a broad neurobiological approach to phenotyping rodent models for ASD, with a focus on biochemistry and molecular biology, brain and neuronal morphology, and electrophysiology, as well as both neurological and additional behavioral analyses. Analysis of human phenotypes associated with these genes reinforced these conclusions, supporting face validity for these approaches to phenotyping of ASD models. Such phenotyping is consistent with the successes in Fmr1 knockout mice, in which morphological changes recapitulated human findings and electrophysiological deficits resulted in molecular insights that have since led to clinical trials. We propose both broad domains and, based on expert review of more than 50 publications in each of the four neurobiological domains, specific tests to be applied to rodent models of ASD.
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2. Eyler LT, Pierce K, Courchesne E. {{A failure of left temporal cortex to specialize for language is an early emerging and fundamental property of autism}}. {Brain};2012 (Feb 20)
Failure to develop normal language comprehension is an early warning sign of autism, but the neural mechanisms underlying this signature deficit are unknown. This is because of an almost complete absence of functional studies of the autistic brain during early development. Using functional magnetic resonance imaging, we previously observed a trend for abnormally lateralized temporal responses to language (i.e. greater activation on the right, rather than the expected left) in a small sample (n = 12) of sleeping 2-3 year olds with autism in contrast to typically developing children, a finding also reported in autistic adults and adolescents. It was unclear, however, if findings of atypical laterality would be observed in a larger sample, and at even earlier ages in autism, such as around the first birthday. Answers to these questions would provide the foundation for understanding how neurofunctional defects of autism unfold, and provide a foundation for studies using patterns of brain activation as a functional early biomarker of autism. To begin to examine these issues, a prospective, cross-sectional design was used in which brain activity was measured in a large sample of toddlers (n = 80) during the presentation of a bedtime story during natural sleep. Forty toddlers with autism spectrum disorder and 40 typically developing toddlers ranging in age between 12-48 months participated. Any toddler with autism who participated in the imaging experiment prior to final diagnosis was tracked and diagnoses confirmed at a later age. Results indicated that at-risk toddlers later diagnosed as autistic display deficient left hemisphere response to speech sounds and have abnormally right-lateralized temporal cortex response to language; this defect worsens with age, becoming most severe in autistic 3- and 4-year-olds. Typically developing children show opposite developmental trends with a tendency towards greater temporal cortex response with increasing age and maintenance of left-lateralized activation with age. We have now demonstrated lateralized abnormalities of temporal cortex processing of language in autism across two separate samples, including a large sample of young infants who later are diagnosed with autism, suggesting that this pattern may reflect a fundamental early neural developmental pathology in autism.
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3. Pedersen A, Pettygrove S, Meaney FJ, Mancilla K, Gotschall K, Kessler DB, Grebe TA, Cunniff C. {{Prevalence of Autism Spectrum Disorders in Hispanic and Non-Hispanic White Children}}. {Pediatrics};2012 (Feb 20)
OBJECTIVE:The number of individuals diagnosed with autism spectrum disorders (ASDs) continues to increase in the United States and other developed countries; however, ASD is diagnosed less commonly in Hispanic than in non-Hispanic white individuals. This report analyzes differences in ASD prevalence between Hispanic and non-Hispanic whites in a large, population-based sample of 8-year-old children, and explores how prevalence has changed over time.METHODS:Population-based surveillance of ASD was conducted on 142 717 8-year-old children. Evaluation of clinical and educational records resulted in 1212 children meeting the case definition criteria in 4 study years between 2000 and 2006.RESULTS:ASD prevalence in Hispanic children was lower than in non-Hispanic white children (P < .005) for all study years. More Hispanic than non-Hispanic white children met the case definition for intellectual disability (P < .05) in study years 2004 and 2006. Prevalence of ASD diagnosis increased in both groups; the Hispanic prevalence almost tripled, from 2.7 per 1000 in 2000 to 7.9 per 1000 in 2006. A comparison of prevalence ratios found that Hispanic and non-Hispanic white ASD prevalence became significantly more similar from 2000 to 2006 (chi(2) = 124.89, P < .001).CONCLUSIONS:The ASD prevalence for Hispanic individuals in this population-based sample is substantially higher than previously reported. Nonetheless, Hispanic children continue to have a significantly lower ASD prevalence in comparison with non-Hispanic whites. The prevalence of ASD is increasing in both populations, and results indicate that the gap in prevalence between groups is decreasing.
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4. van Alphen SP, Oude Voshaar RC. {{Screening of autism spectrum disorders in the elderly: a contribution to a psychometric approach}}. {Int Psychogeriatr};2012 (Feb 20):1-2.
