1. Bernhardt BC, Di Martino A, Valk SL, Wallace GL. {{Neuroimaging-Based Phenotyping of the Autism Spectrum}}. {Curr Top Behav Neurosci};2016 (Mar 6)
Recent advances in neuroimaging have offered a rich array of structural and functional markers to probe the organization of regional and large-scale brain networks. The current chapter provides a brief introduction into these techniques and overviews their contribution to the understanding of autism spectrum disorder (ASD), a neurodevelopmental condition associated with atypical social cognition, language function, and repetitive behaviors/interests. While it is generally recognized that ASD relates to structural and functional network anomalies, the extent and overall pattern of reported findings have been rather heterogeneous. Indeed, while several attempts have been made to label the main neuroimaging phenotype of ASD (e.g., ‘early brain overgrowth hypothesis’, ‘amygdala theory’, ‘disconnectivity hypothesis’), none of these frameworks has been without controversy. Methodological sources of inconsistent results may include differences in subject inclusion criteria, variability in image processing, and analysis methodology. However, inconsistencies may also relate to high heterogeneity across the autism spectrum itself. It, therefore, remains to be investigated whether a consistent imaging phenotype that adequately describes the entire autism spectrum can, in fact, be established. On the other hand, as previous findings clearly emphasize the value of neuroimaging in identifying atypical brain morphology, function, and connectivity, they ultimately support its high potential to identify biologically and clinically relevant endophenotypes.
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2. Goin-Kochel RP, Mire SS, Dempsey AG, Fein RH, Guffey D, Minard CG, Cunningham RM, Sahni LC, Boom JA. {{Parental report of vaccine receipt in children with autism spectrum disorder: Do rates differ by pattern of ASD onset?}}. {Vaccine};2016 (Mar 8);34(11):1335-1342.
A contentious theory espoused by some parents is that regressive-onset of autism spectrum disorder (ASD) is triggered by vaccines. If this were true, then vaccine receipt should be higher in children with regressive-onset ASD compared with other patterns of onset. Parental report of rate of receipt for six vaccines (DPT/DTaP, HepB, Hib, polio, MMR, varicella) was examined in children with ASD (N=2755) who were categorized by pattern of ASD onset (early onset, plateau, delay-plus-regression, regression). All pairwise comparisons were significantly equivalent within a 10% margin for all vaccines except varicella, for which the delay-plus-regression group had lower rates of receipt (81%) than the early-onset (87%) and regression (87%) groups. Findings do not support a connection between regressive-onset ASD and vaccines in this cohort.
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3. Kwok YK, Wong KM, Lo FM, Kong GW, Moore JK, Wu S, Lam ST, Schermer M, Leung TY, Kwong WC. {{Validation of a robust PCR-based assay for quantifying fragile X CGG repeats}}. {Clin Chim Acta};2016 (Mar 3)
BACKGROUND: Sizing of FMR1 trinucleotide repeats in the clinical laboratory requires the use of capillary sequencer by PCR, or by a labor intensive measurement using Southern blot method. Our aim was to validate an accurate and robust PCR assay for quantification of CGG repeats. METHODS: We performed an analytical and clinical validation of a new PCR-based method that utilizes a low-cost capillary electrophoresis instrument and the FragilEase reagent kit. First, analytical performance was demonstrated on 12 Coriell reference samples comprising normal through full mutations. Subsequently, a cohort of 112 archived clinical DNA samples, enriched for premutation and full mutations, was analyzed. RESULTS: All samples were amplified successfully. Quantification of repeat numbers was interpreted by the use of standards with known repeats. Twenty-five full-mutation samples were successfully amplified with the largest allele size measured at 1380 repeats. The repeat numbers from the new assay were concordant with those obtained with the reference method. The intra-assay (CV<2.5%) and inter-assay imprecision was within 1 CGG repeat. CONCLUSION: This new PCR-based method is reproducible and capable of identifying all Fragile X alleles. It is an accurate and robust method that facilitates Fragile X testing in a broader spectrum of clinical laboratories.
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4. Li J, Ma Z, Shi M, Malty RH, Aoki H, Minic Z, Phanse S, Jin K, Wall DP, Zhang Z, Urban AE, Hallmayer J, Babu M, Snyder M. {{Identification of Human Neuronal Protein Complexes Reveals Biochemical Activities and Convergent Mechanisms of Action in Autism Spectrum Disorders}}. {Cell Syst};2015 (Nov 25);1(5):361-374.
The prevalence of autism spectrum disorders (ASDs) is rapidly growing, yet its molecular basis is poorly understood. We used a systems approach in which ASD candidate genes were mapped onto the ubiquitous human protein complexes and the resulting complexes were characterized. The studies revealed the role of histone deacetylases (HDAC1/2) in regulating the expression of ASD orthologs in the embryonic mouse brain. Proteome-wide screens for the co-complexed subunits with HDAC1 and six other key ASD proteins in neuronal cells revealed a protein interaction network, which displayed preferential expression in fetal brain development, exhibited increased deleterious mutations in ASD cases, and were strongly regulated by FMRP and MECP2 causal for Fragile X and Rett syndromes, respectively. Overall, our study reveals molecular components in ASD, suggests a shared mechanism between the syndromic and idiopathic forms of ASDs, and provides a systems framework for analyzing complex human diseases.
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5. Lu C, Qi Z, Harris A, Weil LW, Han M, Halverson K, Perrachione TK, Kjelgaard M, Wexler K, Tager-Flusberg H, Gabrieli JD. {{Shared neuroanatomical substrates of impaired phonological working memory across reading disability and autism}}. {Biol Psychiatry Cogn Neurosci Neuroimaging};2016 (Mar 1);1(2):169-177.
BACKGROUND: Individuals with reading disability or individuals with autism spectrum disorder (ASD) are characterized, respectively, by their difficulties in reading or social communication, but both groups often have impaired phonological working memory (PWM). It is not known whether the impaired PWM reflects distinct or shared neuroanatomical abnormalities in these two diagnostic groups. METHODS: White-matter structural connectivity via diffusion weighted imaging was examined in sixty-four children, ages 5-17 years, with reading disability, ASD, or typical development (TD), who were matched in age, gender, intelligence, and diffusion data quality. RESULTS: Children with reading disability and children with ASD exhibited reduced PWM compared to children with TD. The two diagnostic groups showed altered white-matter microstructure in the temporo-parietal portion of the left arcuate fasciculus (AF) and in the temporo-occipital portion of the right inferior longitudinal fasciculus (ILF), as indexed by reduced fractional anisotropy and increased radial diffusivity. Moreover, the structural integrity of the right ILF was positively correlated with PWM ability in the two diagnostic groups, but not in the TD group. CONCLUSIONS: These findings suggest that impaired PWM is transdiagnostically associated with shared neuroanatomical abnormalities in ASD and reading disability. Microstructural characteristics in left AF and right ILF may play important roles in the development of PWM. The right ILF may support a compensatory mechanism for children with impaired PWM.
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6. Packer A. {{Neocortical Neurogenesis and the Etiology of Autism Spectrum Disorder}}. {Neurosci Biobehav Rev};2016 (Mar 3)
Researchers have now identified many highly penetrant genetic risk factors for autism spectrum disorder (ASD). Some of these genes encode synaptic proteins, lending support to the hypothesis that ASD is a disorder of synaptic homeostasis. Less attention, however, has been paid to the genetic risk factors that converge on events that precede synaptogenesis, including the proliferation of neural progenitor cells and the migration of neurons to the appropriate layers of the developing neocortex. Here I review this evidence, focusing on studies of mutant mouse phenotypes, human postmortem data, systems biological analyses, and non-genetic risk factors. These findings highlight embryonic neurogenesis as a potentially important locus of pathology in ASD. In some instances, this pathology may be driven by alterations in chromatin biology and canonical Wnt signaling, which in turn affect fundamental cellular processes such as cell-cycle length and cell migration. This view of ASD suggests the need for a better understanding of the relationship between variation in neuron number, laminar composition, and the neural circuitry most relevant to the disorder.
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7. Walch TJ, Tinkelman A. {{Selective Serotonin Reuptake Inhibitors and Autism}}. {Am J Ther};2016 (Mar-Apr);23(2):e325.
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8. Yasuda Y, Hashimoto R, Nakae A, Kang H, Ohi K, Yamamori H, Fujimoto M, Hagihira S, Takeda M. {{Sensory cognitive abnormalities of pain in autism spectrum disorder: a case-control study}}. {Ann Gen Psychiatry};2016;15:8.
BACKGROUND: The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) recently included sensory processing abnormalities in the diagnostic criteria for individuals with autism spectrum disorder (ASD). However, there is no standard method for evaluating sensory abnormalities in individuals with ASD. METHODS: Fifteen individuals with ASD and 15 age- and sex-matched controls were enrolled in this study. We compared objective pain sensitivity by measuring the pain detection threshold and pain tolerance to three different stimuli (electricity, heat, and cold). Then, we compared both subjective pain sensitivity, assessed by the visual analog scale (VAS), and quality of pain, assessed by the short-form McGill Pain Questionnaire (SF-MPQ), to determine the maximum tolerable pain intensities of each stimulation. RESULTS: The pain detection threshold and pain tolerance of individuals with ASD were not impaired, indicating that there were no differences in the somatic perception of pain between groups. However, individuals with ASD were hyposensitive to subjective pain intensity compared to controls (VAS; electrical: p = 0.044, cold: p = 0.011, heat: p = 0.042) and hyposensitive to affective aspects of pain sensitivity (SF-MPQ; electrical: p = 0.0071, cold: p = 0.042). CONCLUSIONS: Our results suggest that the cognitive pathways for pain processing are impaired in ASD and, furthermore, that our methodology can be used to assess pain sensitivity in individuals with ASD. Further investigations into sensory abnormalities in individuals with ASD are needed to clarify the pathophysiologic processes that may alter sensory processing in this disorder.
