Expediting clinician assessment in the diagnosis of autism spectrum disorder.
- 作者列表："Sanchez MJ","Constantino JN
AIM:To investigate a novel observational rating protocol designed to expedite clinical diagnosis of autism spectrum disorder (ASD). METHOD:Two hundred and forty patients referred to a tertiary autism center (median age 8y 9mo, 2y 6mo-34y 8mo; 188 males, 52 females) were rated using an adaptation of the Childhood Autism Rating Scale, Second Edition (CARS-2) based exclusively on patient observation (CARS-2obs ). Scores were compared to expert diagnosis of ASD, parent-reported Social Responsiveness Scale, Second Edition (SRS-2) and, in a selected subset of patients, the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). RESULTS:CARS-2obs distinguished patients with a clinical diagnosis of ASD from those with non-ASD neuropsychiatric disorders (mean score=18 vs 11.7, p<0.001). Severity ratings on the CARS-2obs correlated with the ADOS-2 (r=0.68, ρ=0.64) and SRS-2 (r=0.31, ρ=0.32). A CARS-2obs cutoff point equal to or greater than 16 demonstrated 95.8% specificity and 62.3% sensitivity in discriminating individuals with ASD from individuals without ASD. INTERPRETATION:The CARS-2obs allows the rapid acquisition of quantitative ratings of autistic severity by direct observation. Coupled with parent/teacher-reported symptoms and developmental history, the measure may contribute to a low-cost diagnostic paradigm in clinical and public health settings, where positive results might help reduce delays in diagnosis, and negative results could prompt further specialty assessment. What this paper adds The Childhood Autism Rating Scale, Second Edition based on patient observation distinguished individuals with versus without autism spectrum disorder (ASD). A score equal to or greater than 16 on this assessment showed high specificity for a diagnosis of ASD.
目的: 研究旨在加快自闭症谱系障碍 (ASD) 临床诊断的新型观察性评分方案。 方法: 188 名患者转诊到三级自闭症中心 (中位年龄 8y 9mo，2y 6mo-34y 8mo; 名男性，52 名女性) 完全基于患者观察 (CARS-2obs)，使用儿童自闭症评定量表第二版 (CARS-2) 的改编进行评级。将评分与 ASD 的专家诊断、父母报告的社会反应量表第二版 (SRS-2) 以及选定的患者子集中的自闭症诊断观察时间表进行比较,第二版 (ADOS-2)。 结果: CARS-2obs 将临床诊断为 ASD 的患者与非 ASD 神经精神疾病患者区分开来 (平均评分为 18 分 vs 11.7 分，p<0.001)。CARS-2obs 严重程度评分与 ADOS-2 (r = 0.68，ρ = 0.64) 和 SRS-2 (r = 0.31，ρ = 0.32) 相关。等于或大于 16 的 CARS-2obs 截断点在区分 ASD 个体和非 ASD 个体方面表现出 95.8% 的特异性和 62.3% 的敏感性。 解释: CARS-2obs 允许通过直接观察快速获得自闭症严重程度的定量评级。加上家长/教师报告的症状和发育史，该措施可能有助于临床和公共卫生环境中的低成本诊断范式，其中阳性结果可能有助于减少诊断延迟,阴性结果可能会促使进一步的专业评估。本文添加了基于患者观察的儿童孤独症评定量表第二版区分了患有与不患有孤独症谱系障碍 (ASD) 的个体。该评估的评分等于或大于 16 分对 ASD 的诊断显示出很高的特异性。
METHODS::The adipocyte-derived hormone adiponectin has a broad spectrum of functions beyond metabolic control. We previously reported that adiponectin acts in the brain to regulate depression-related behaviors. However, its underlying neural substrates have not been identified. Here we show that adiponectin receptor 1 (AdipoR1) is expressed in the dorsal raphe nucleus (DRN) and colocalized with tryptophan hydroxylase 2 (TPH2), a marker of serotonin (5-HT) neurons. Selective deletion of AdipoR1 in 5-HT neurons induced anhedonia in male mice, as indicated by reduced female urine sniffing time and saccharin preference, and behavioral despair in female mice and enhanced stress-induced decrease in sucrose preference in both sexes. The expression levels of TPH2 were downregulated with a concurrent reduction of 5-HT-immunoreactivity in the DRN and its two major projection regions, the hippocampus and medial prefrontal cortex (mPFC), in male but not female mice lacking AdipoR1 in 5-HT neurons. In addition, serotonin transporter (SERT) expression was upregulated in both DRN projection fields of male mice but only in the mPFC of female mice. These changes presumably lead to decreased 5-HT synthesis and/or increased 5-HT reuptake, thereby reducing 5-HT transmission. The augmented behavioral responses to the selective serotonin reuptake inhibitor fluoxetine but not desipramine, a selective norepinephrine reuptake inhibitor, observed in conditional knockout male mice supports deficient 5-HT transmission underlying depression-related phenotypes. Our results indicate that adiponectin acts on 5-HT neurons through AdipoR1 receptors to regulate depression-related behaviors in a sex-dependent manner.
METHODS::Multiple schizophrenia (SCZ) risk loci may be involved in gene co-regulation mechanisms, and analysis of coexpressed gene networks may help to clarify SCZ molecular basis. We have previously identified a dopamine D2 receptor (DRD2) coexpression module enriched for SCZ risk genes and associated with cognitive and neuroimaging phenotypes of SCZ, as well as with response to treatment with antipsychotics. Here we aimed to identify regulatory factors modulating this coexpression module and their relevance to SCZ. We performed motif enrichment analysis to identify transcription factor (TF) binding sites in human promoters of genes coexpressed with DRD2. Then, we measured transcript levels of a group of these genes in primary mouse cortical neurons in basal conditions and upon overexpression and knockdown of predicted TFs. Finally, we analyzed expression levels of these TFs in dorsolateral prefrontal cortex (DLPFC) of SCZ patients. Our in silico analysis revealed enrichment for NURR1 and ERR1 binding sites. In neuronal cultures, the expression of genes either relevant to SCZ risk (Drd2, Gatad2a, Slc28a1, Cnr1) or indexing coexpression in our module (Btg4, Chit1, Osr1, Gpld1) was significantly modified by gain and loss of Nurr1 and Err1. Postmortem DLPFC expression data analysis showed decreased expression levels of NURR1 and ERR1 in patients with SCZ. For NURR1 such decreased expression is associated with treatment with antipsychotics. Our results show that NURR1 and ERR1 modulate the transcription of DRD2 coexpression partners and support the hypothesis that NURR1 is involved in the response to SCZ treatment.SIGNIFICANCE STATEMENT In the present study, we provide in silico and experimental evidence for a role of the TFs NURR1 and ERR1 in modulating the expression pattern of genes coexpressed with DRD2 in human DLPFC. Notably, genetic variations in these genes is associated with SCZ risk and behavioral and neuroimaging phenotypes of the disease, as well as with response to treatment. Furthermore, this study presents novel findings on a possible interplay between D2 receptor-mediated dopamine signaling involved in treatment with antipsychotics and the transcriptional regulation mechanisms exerted by NURR1. Our results suggest that coexpression and co-regulation mechanisms may help to explain some of the complex biology of genetic associations with SCZ.
METHODS::Abnormal neurotransmission is central to schizophrenia (SZ). Alterations across multiple neurotransmitter systems in SZ suggest that this illness may be associated with dysregulation of core intracellular processes such as signaling pathways that underlie the regulation and integration of these systems. The AKT-mTOR signaling cascade has been implicated in SZ by gene association, postmortem brain and animal studies. AKT and mTOR are serine/threonine kinases which play important roles in cell growth, proliferation, survival, and differentiation. Both AKT and mTOR require phosphorylation at specific sites for their complete activation. mTOR forms two functionally distinct multiprotein complexes, mTOR Complex 1 (mTORC1) and Complex 2 (mTORC2). mTORC1 mediates ribosome biogenesis, protein translation, and autophagy, whereas mTORC2 contributes to actin dynamics. Altered protein synthesis and actin dynamics can lead to an abnormal neuronal morphology resulting in deficits in learning and memory. Currently, there is a lack of direct evidence to support the hypothesis of disrupted mTOR signaling in SZ, and we have addressed this by characterizing this signaling pathway in SZ brain. We found a reduction in AKT and mTOR protein expression and/or phosphorylation state in dorsolateral prefrontal cortex (DLPFC) from 22 pairs of SZ and matched comparison subjects. We also found reduced protein expression of GβL, a subunit protein common to both mTOR complexes. We further investigated mTOR complex-specific subunit composition and phosphorylation state, and found abnormal mTOR expression in both complexes in SZ DLPFC. These findings provide evidence that proteins associated with the AKT-mTOR signaling cascade are downregulated in SZ DLPFC.