The functional impact of cognition in adults with autism spectrum disorders.
- 作者列表："Nyrenius J","Billstedt E
:Purpose and aim: The overall aim of this study was to examine the relationship between adaptive function and cognitive factors in young adults diagnosed with autism spectrum disorder (ASD) in adult age.Methods: The study included 30 adults (age 18-30) diagnosed with ASD in adulthood. All participants were clinically referred to an adult psychiatric clinic for assessment. Adaptive functioning was measured with Adaptive Behavior Assessment System - 2nd edition (parent version). Wechsler scales of intelligence and Delis-Kaplan Executive Function System were used to measure intelligence and executive function.Results: We found considerable adaptive functioning deficits regardless of Full Scale Intelligence Quotient (FSIQ) level. FSIQ, working memory and processing speed were positively associated with adaptive functioning. No associations were found between adaptive functioning and cognitive flexibility, inhibition, word generation or shifting. Regression analysis showed that working memory and processing speed predicted 23% of the variance in adaptive functioning in this group.Conclusions: The results suggest that cognitive dysfunction could be an important area for intervention to improve adaptive functioning in ASD.
: 目的和目的: 本研究的总体目的是检查成年后诊断为自闭症谱系障碍 (ASD) 的年轻人的适应功能和认知因素之间的关系。方法: 该研究包括 30 名成人 (年龄 18-30) 在成年期被诊断为 ASD。所有参与者均被临床转诊到成人精神病诊所进行评估。用适应性行为评估系统-第2 版 (父版) 测量适应性功能。采用韦氏智力量表和德利斯-卡普兰执行功能系统测量智力和执行功能。结果: 无论全量表智商 (FSIQ) 水平如何，我们都发现了相当大的适应性功能缺陷。FSIQ 、工作记忆和加工速度与适应性功能呈正相关。未发现适应性功能与认知灵活性、抑制、单词生成或移位之间存在关联。回归分析显示，工作记忆和加工速度预测了该组适应性功能方差的 23%。结论: 研究结果表明，认知功能障碍可能是改善 ASD 适应性功能的重要干预领域。
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.