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Clinical correlates of diagnostic certainty in children and youths with Autistic Disorder 自闭症儿童和青少年诊断确定性的临床相关性
IF 6.2 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-04-03 DOI: 10.1186/s13229-024-00592-7
Eya-Mist Rødgaard, Borja Rodríguez-Herreros, Abderrahim Zeribi, Kristian Jensen, Valérie Courchesne, Elise Douard, David Gagnon, Guillaume Huguet, Sebastien Jacquemont, Laurent Mottron
Clinicians diagnosing autism rely on diagnostic criteria and instruments in combination with an implicit knowledge based on clinical expertise of the specific signs and presentations associated with the condition. This implicit knowledge influences how diagnostic criteria are interpreted, but it cannot be directly observed. Instead, insight into clinicians’ understanding of autism can be gained by investigating their diagnostic certainty. Modest correlations between the certainty of an autism diagnosis and symptom load have been previously reported. Here, we investigated the associations of diagnostic certainty with specific items of the ADOS as well as other clinical features including head circumference. Phenotypic data from the Simons Simplex Collection was used to investigate clinical correlates of diagnostic certainty in individuals diagnosed with Autistic Disorder (n = 1511, age 4 to 18 years). Participants were stratified by the ADOS module used to evaluate them. We investigated how diagnostic certainty was associated with total ADOS scores, age, and ADOS module. We calculated the odds-ratios of being diagnosed with the highest possible certainty given the presence or absence of different signs during the ADOS evaluation. Associations between diagnostic certainty and other cognitive and clinical variables were also assessed. In each ADOS module, some items showed a larger association with diagnostic certainty than others. Head circumference was significantly higher for individuals with the highest certainty rating across all three ADOS modules. In turn, head circumference was positively correlated with some of the ADOS items that were associated with diagnostic certainty, and was negatively correlated with verbal/nonverbal IQ ratio among those assessed with ADOS module 2. The investigated cohort was heterogeneous, e.g. in terms of age, IQ, language level, and total ADOS score, which could impede the identification of associations that only exist in a subgroup of the population. The variability of the certainty ratings in the sample was low, limiting the power to identify potential associations with other variables. Additionally, the scoring of diagnostic certainty may vary between clinicians. Some ADOS items may better capture the signs that are most associated with clinicians’ implicit knowledge of Autistic Disorder. If replicated in future studies, new diagnostic instruments with differentiated weighting of signs may be needed to better reflect this, possibly resulting in better specificity in standardized assessments.
诊断自闭症的临床医生依赖于诊断标准和工具,以及基于临床专业知识的与自闭症相关的特殊体征和表现的隐性知识。这种隐性知识会影响诊断标准的解释,但无法直接观察到。相反,通过调查临床医生对自闭症诊断的确定性,可以深入了解他们对自闭症的理解。之前有报道称,自闭症诊断的确定性与症状负荷之间存在一定的相关性。在此,我们研究了诊断确定性与 ADOS 的特定项目以及包括头围在内的其他临床特征之间的关联。我们利用西蒙斯简易样本库(Simons Simplex Collection)中的表型数据调查了被诊断为自闭症患者(n = 1511,年龄在 4 至 18 岁之间)的诊断确定性的临床相关性。我们根据评估自闭症的 ADOS 模块对参与者进行了分层。我们研究了诊断确定性与 ADOS 总分、年龄和 ADOS 模块之间的关系。我们计算了在ADOS评估过程中出现或不出现不同体征时被诊断为最高确定性的几率比率。我们还评估了诊断确定性与其他认知和临床变量之间的关联。在 ADOS 的每个模块中,某些项目与诊断确定性的关系比其他项目更大。在所有三个 ADOS 模块中,确定性评级最高的个体的头围明显较高。反过来,头围与一些与诊断确定性相关的 ADOS 项目呈正相关,而在 ADOS 模块 2 的评估对象中,头围与言语/非言语智商比呈负相关。所调查的人群在年龄、智商、语言水平和 ADOS 总分等方面都是异质性的,这可能会妨碍识别仅存在于人口中某一亚群的关联。样本中确定性评分的变异性较低,这限制了识别与其他变量潜在关联的能力。此外,不同临床医生对诊断确定性的评分可能会有所不同。某些 ADOS 项目可能能更好地捕捉到与临床医生对自闭症的隐性认知最相关的体征。如果在未来的研究中得到验证,可能需要新的诊断工具对体征进行不同的加权,以更好地反映这一点,从而提高标准化评估的特异性。
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引用次数: 0
Neuroligin-2 shapes individual slow waves during slow-wave sleep and the response to sleep deprivation in mice 神经胶质蛋白-2塑造小鼠慢波睡眠期间的单个慢波以及对睡眠剥夺的反应
IF 6.2 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-04-03 DOI: 10.1186/s13229-024-00594-5
Tanya Leduc, Hiba El Alami, Khadija Bougadir, Erika Bélanger-Nelson, Valérie Mongrain
Sleep disturbances are a common comorbidity to most neurodevelopmental disorders and tend to worsen disease symptomatology. It is thus crucial to understand mechanisms underlying sleep disturbances to improve patients’ quality of life. Neuroligin-2 (NLGN2) is a synaptic adhesion protein regulating GABAergic transmission. It has been linked to autism spectrum disorders and schizophrenia in humans, and deregulations of its expression were shown to cause epileptic-like hypersynchronized cerebral activity in rodents. Importantly, the absence of Nlgn2 (knockout: KO) was previously shown to alter sleep-wake duration and quality in mice, notably increasing slow-wave sleep (SWS) delta activity (1–4 Hz) and altering its 24-h dynamics. This type of brain oscillation is involved in memory consolidation, and is also a marker of homeostatic sleep pressure. Sleep deprivation (SD) is notably known to impair cognition and the physiological response to sleep loss involves GABAergic transmission. Using electrocorticographic (ECoG) recordings, we here first aimed to verify how individual slow wave (SW; 0.5-4 Hz) density and properties (e.g., amplitude, slope, frequency) contribute to the higher SWS delta activity and altered 24-h dynamics observed in Nlgn2 KO mice. We further investigated the response of these animals to SD. Finally, we tested whether sleep loss affects the gene expression of Nlgn2 and related GABAergic transcripts in the cerebral cortex of wild-type mice using RNA sequencing. Our results show that Nlgn2 KO mice have both greater SW amplitude and density, and that SW density is the main property contributing to the altered 24-h dynamics. We also found the absence of Nlgn2 to accelerate paradoxical sleep recovery following SD, together with profound alterations in ECoG activity across vigilance states. Sleep loss, however, did not modify the 24-h distribution of the hypersynchronized ECoG events observed in these mice. Finally, RNA sequencing confirmed an overall decrease in cortical expression of Nlgn2 and related GABAergic transcripts following SD in wild-type mice. This work brings further insight into potential mechanisms of sleep duration and quality deregulation in neurodevelopmental disorders, notably involving NLGN2 and GABAergic neurotransmission.
睡眠障碍是大多数神经发育障碍的常见合并症,往往会加重疾病症状。因此,了解睡眠障碍的内在机制对改善患者的生活质量至关重要。神经胶质蛋白-2(NLGN2)是一种调节 GABA 能传导的突触粘附蛋白。它与人类自闭症谱系障碍和精神分裂症有关,其表达的失调已被证明会导致啮齿类动物癫痫样超同步化脑活动。重要的是,Nlgn2的缺失(基因敲除:KO)先前已被证明会改变小鼠的睡眠-觉醒持续时间和质量,特别是会增加慢波睡眠(SWS)的δ活动(1-4赫兹)并改变其24小时的动态变化。这种类型的大脑振荡参与记忆巩固,同时也是平衡睡眠压力的标志。众所周知,睡眠不足(SD)会损害认知能力,而对睡眠不足的生理反应涉及 GABA 能传递。在此,我们首先利用皮层电图(ECoG)记录来验证 Nlgn2 KO 小鼠的慢波(SW;0.5-4 Hz)密度和特性(如振幅、斜率、频率)是如何导致较高的 SWS 三角活动和 24 小时动态变化的。我们进一步研究了这些动物对 SD 的反应。最后,我们使用 RNA 测序法检测了睡眠丧失是否会影响野生型小鼠大脑皮层中 Nlgn2 及相关 GABA 能转录物的基因表达。我们的结果表明,Nlgn2 KO小鼠的SW振幅和密度都更大,SW密度是导致24小时动态变化的主要特性。我们还发现,缺失 Nlgn2 会加速自毁性睡眠后的矛盾性睡眠恢复,同时在各种警觉状态下的心电图活动也会发生深刻变化。然而,失眠并没有改变在这些小鼠身上观察到的超同步心电图事件的 24 小时分布。最后,RNA 测序证实,野生型小鼠在自毁睡眠后,大脑皮层中 Nlgn2 和相关 GABA 能转录物的表达量总体下降。这项研究进一步揭示了神经发育障碍中睡眠时间和质量失调的潜在机制,特别是涉及NLGN2和GABA能神经传递的机制。
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引用次数: 0
Fetal brain growth and infant autistic traits. 胎儿大脑发育与婴儿自闭症特征。
IF 6.2 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-02-28 DOI: 10.1186/s13229-024-00586-5
Ezra Aydin, Alex Tsompanidis, Daren Chaplin, Rebecca Hawkes, Carrie Allison, Gerald Hackett, Topun Austin, Eglė Padaigaitė, Lidia V Gabis, John Sucking, Rosemary Holt, Simon Baron-Cohen

Background: Structural differences exist in the brains of autistic individuals. To date only a few studies have explored the relationship between fetal brain growth and later infant autistic traits, and some have used fetal head circumference (HC) as a proxy for brain development. These findings have been inconsistent. Here we investigate whether fetal subregional brain measurements correlate with autistic traits in toddlers.

Methods: A total of 219 singleton pregnancies (104 males and 115 females) were recruited at the Rosie Hospital, Cambridge, UK. 2D ultrasound was performed at 12-, 20- and between 26 and 30 weeks of pregnancy, measuring head circumference (HC), ventricular atrium (VA) and transcerebellar diameter (TCD). A total of 179 infants were followed up at 18-20 months of age and completed the quantitative checklist for autism in toddlers (Q-CHAT) to measure autistic traits.

Results: Q-CHAT scores at 18-20 months of age were positively associated with TCD size at 20 weeks and with HC at 28 weeks, in univariate analyses, and in multiple regression models which controlled for sex, maternal age and birth weight.

Limitations: Due to the nature and location of the study, ascertainment bias could also have contributed to the recruitment of volunteer mothers with a higher than typical range of autistic traits and/or with a significant interest in the neurodevelopment of their children.

Conclusion: Prenatal brain growth is associated with toddler autistic traits and this can be ascertained via ultrasound starting at 20 weeks gestation.

背景:自闭症患者的大脑存在结构性差异。迄今为止,只有少数研究探讨了胎儿大脑发育与婴儿日后自闭症特征之间的关系,其中一些研究使用胎儿头围(HC)作为大脑发育的替代指标。这些研究结果并不一致。在此,我们研究了胎儿亚区域脑部测量是否与幼儿的自闭症特征相关:方法:英国剑桥罗西医院共招募了 219 名单胎孕妇(104 名男性和 115 名女性)。在怀孕 12 周、20 周和 26-30 周时进行二维超声波检查,测量头围 (HC)、心室心房 (VA) 和跨小脑直径 (TCD)。共有 179 名婴儿在 18-20 个月大时接受了随访,并填写了幼儿自闭症定量检查表(Q-CHAT)以测量自闭症特征:在单变量分析和控制性别、母亲年龄和出生体重的多元回归模型中,18-20个月大时的Q-CHAT得分与20周时的TCD大小和28周时的HC呈正相关:由于研究的性质和地点,招募的志愿者母亲中自闭症特质和/或对其子女的神经发育有浓厚兴趣的比例高于典型范围,这也可能导致确认偏差:结论:产前脑部发育与幼儿的自闭症特征有关,这可以通过从妊娠 20 周开始的超声波检查来确定。
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引用次数: 0
Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokines 粒细胞巨噬细胞集落刺激因子诱导的自闭症谱系障碍患者巨噬细胞通过分泌促炎细胞因子对神经元树突产生不利影响
IF 6.2 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-02-21 DOI: 10.1186/s13229-024-00589-2
Ryohei Takada, Michihiro Toritsuka, Takahira Yamauchi, Rio Ishida, Yoshinori Kayashima, Yuki Nishi, Mitsuru Ishikawa, Kazuhiko Yamamuro, Minobu Ikehara, Takashi Komori, Yuki Noriyama, Kohei Kamikawa, Yasuhiko Saito, Hideyuki Okano, Manabu Makinodan
A growing body of evidence suggests that immune dysfunction and inflammation in the peripheral tissues as well as the central nervous system are associated with the neurodevelopmental deficits observed in autism spectrum disorder (ASD). Elevated expression of pro-inflammatory cytokines in the plasma, serum, and peripheral blood mononuclear cells of ASD has been reported. These cytokine expression levels are associated with the severity of behavioral impairments and symptoms in ASD. In a prior study, our group reported that tumor necrosis factor-α (TNF-α) expression in granulocyte–macrophage colony-stimulating factor-induced macrophages (GM-CSF MΦ) and the TNF-α expression ratio in GM-CSF MΦ/M-CSF MΦ (macrophage colony-stimulating factor-induced macrophages) was markedly higher in individuals with ASD than in typically developed (TD) individuals. However, the mechanisms of how the macrophages and the highly expressed cytokines affect neurons remain to be addressed. To elucidate the effect of macrophages on human neurons, we used a co-culture system of control human-induced pluripotent stem cell-derived neurons and differentiated macrophages obtained from the peripheral blood mononuclear cells of five TD individuals and five individuals with ASD. All participants were male and ethnically Japanese. Our results of co-culture experiments showed that GM-CSF MΦ affect the dendritic outgrowth of neurons through the secretion of pro-inflammatory cytokines, interleukin-1α and TNF-α. Macrophages derived from individuals with ASD exerted more severe effects than those derived from TD individuals. The main limitations of our study were the small sample size with a gender bias toward males, the use of artificially polarized macrophages, and the inability to directly observe the interaction between neurons and macrophages from the same individuals. Our co-culture system revealed the non-cell autonomous adverse effects of GM-CSF MΦ in individuals with ASD on neurons, mediated by interleukin-1α and TNF-α. These results may support the immune dysfunction hypothesis of ASD, providing new insights into its pathology.
越来越多的证据表明,外周组织和中枢神经系统的免疫功能障碍和炎症与自闭症谱系障碍(ASD)的神经发育缺陷有关。据报道,自闭症谱系障碍患者的血浆、血清和外周血单核细胞中促炎细胞因子的表达水平升高。这些细胞因子的表达水平与 ASD 行为障碍和症状的严重程度有关。在之前的一项研究中,我们小组报告了粒细胞-巨噬细胞集落刺激因子诱导的巨噬细胞(GM-CSF MΦ)中肿瘤坏死因子-α(TNF-α)的表达以及GM-CSF MΦ/M-CSF MΦ(巨噬细胞集落刺激因子诱导的巨噬细胞)中TNF-α的表达比率,ASD患者明显高于典型发育(TD)患者。然而,巨噬细胞和高表达细胞因子如何影响神经元的机制仍有待研究。为了阐明巨噬细胞对人类神经元的影响,我们使用了一种人类诱导多能干细胞衍生神经元与从五名TD患者和五名ASD患者外周血单核细胞中获得的分化巨噬细胞的共培养系统。所有参与者均为男性,日裔。我们的共培养实验结果表明,GM-CSF MΦ通过分泌促炎细胞因子(白细胞介素-1α和TNF-α)影响神经元树突的生长。来自ASD患者的巨噬细胞比来自TD患者的巨噬细胞产生的影响更严重。我们研究的主要局限性在于样本量较小,且性别偏向男性;使用了人工极化的巨噬细胞;无法直接观察来自同一个体的神经元和巨噬细胞之间的相互作用。我们的共培养系统揭示了在白细胞介素-1α和TNF-α的介导下,GM-CSF MΦ对ASD患者神经元的非细胞自主不良影响。这些结果可能支持了ASD的免疫功能紊乱假说,为了解其病理提供了新的视角。
{"title":"Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokines","authors":"Ryohei Takada, Michihiro Toritsuka, Takahira Yamauchi, Rio Ishida, Yoshinori Kayashima, Yuki Nishi, Mitsuru Ishikawa, Kazuhiko Yamamuro, Minobu Ikehara, Takashi Komori, Yuki Noriyama, Kohei Kamikawa, Yasuhiko Saito, Hideyuki Okano, Manabu Makinodan","doi":"10.1186/s13229-024-00589-2","DOIUrl":"https://doi.org/10.1186/s13229-024-00589-2","url":null,"abstract":"A growing body of evidence suggests that immune dysfunction and inflammation in the peripheral tissues as well as the central nervous system are associated with the neurodevelopmental deficits observed in autism spectrum disorder (ASD). Elevated expression of pro-inflammatory cytokines in the plasma, serum, and peripheral blood mononuclear cells of ASD has been reported. These cytokine expression levels are associated with the severity of behavioral impairments and symptoms in ASD. In a prior study, our group reported that tumor necrosis factor-α (TNF-α) expression in granulocyte–macrophage colony-stimulating factor-induced macrophages (GM-CSF MΦ) and the TNF-α expression ratio in GM-CSF MΦ/M-CSF MΦ (macrophage colony-stimulating factor-induced macrophages) was markedly higher in individuals with ASD than in typically developed (TD) individuals. However, the mechanisms of how the macrophages and the highly expressed cytokines affect neurons remain to be addressed. To elucidate the effect of macrophages on human neurons, we used a co-culture system of control human-induced pluripotent stem cell-derived neurons and differentiated macrophages obtained from the peripheral blood mononuclear cells of five TD individuals and five individuals with ASD. All participants were male and ethnically Japanese. Our results of co-culture experiments showed that GM-CSF MΦ affect the dendritic outgrowth of neurons through the secretion of pro-inflammatory cytokines, interleukin-1α and TNF-α. Macrophages derived from individuals with ASD exerted more severe effects than those derived from TD individuals. The main limitations of our study were the small sample size with a gender bias toward males, the use of artificially polarized macrophages, and the inability to directly observe the interaction between neurons and macrophages from the same individuals. Our co-culture system revealed the non-cell autonomous adverse effects of GM-CSF MΦ in individuals with ASD on neurons, mediated by interleukin-1α and TNF-α. These results may support the immune dysfunction hypothesis of ASD, providing new insights into its pathology.","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"28 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139919973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Naturally occurring low sociality in female rhesus monkeys: A tractable model for autism or not? 雌性恒河猴天生社交能力低下:自闭症的可控模型?
IF 6.3 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-01-31 DOI: 10.1186/s13229-024-00588-3
Ozge Oztan, Laura A Del Rosso, Sierra M Simmons, Duyen K K Nguyen, Catherine F Talbot, John P Capitanio, Joseph P Garner, Karen J Parker

Background: Autism spectrum disorder (ASD) is characterized by persistent social interaction impairments and is male-biased in prevalence. We have established naturally occurring low sociality in male rhesus monkeys as a model for the social features of ASD. Low-social male monkeys exhibit reduced social interactions and increased autistic-like trait burden, with both measures highly correlated and strongly linked to low cerebrospinal fluid (CSF) arginine vasopressin (AVP) concentration. Little is known, however, about the behavioral and neurochemical profiles of female rhesus monkeys, and whether low sociality in females is a tractable model for ASD.

Methods: Social behavior assessments (ethological observations; a reverse-translated autistic trait measurement scale, the macaque Social Responsiveness Scale-Revised [mSRS-R]) were completed on N = 88 outdoor-housed female rhesus monkeys during the non-breeding season. CSF and blood samples were collected from a subset of N = 16 monkeys across the frequency distribution of non-social behavior, and AVP and oxytocin (OXT) concentrations were quantified. Data were analyzed using general linear models.

Results: Non-social behavior frequency and mSRS-R scores were continuously distributed across the general female monkey population, as previously found for male monkeys. However, dominance rank significantly predicted mSRS-R scores in females, with higher-ranking individuals showing fewer autistic-like traits, a relationship not previously observed in males from this colony. Females differed from males in several other respects: Social behavior frequencies were unrelated to mSRS-R scores, and AVP concentration was unrelated to any social behavior measure. Blood and CSF concentrations of AVP were positively correlated in females; no significant relationship involving any OXT measure was found.

Limitations: This study sample was small, and did not consider genetic, environmental, or other neurochemical measures that may be related to female mSRS-R scores.

Conclusions: Dominance rank is the most significant predictor of autistic-like traits in female rhesus monkeys, and CSF neuropeptide concentrations are unrelated to measures of female social functioning (in contrast to prior CSF AVP findings in male rhesus monkeys and male and female autistic children). Although preliminary, this evidence suggests that the strong matrilineal organization of this species may limit the usefulness of low sociality in female rhesus monkeys as a tractable model for ASD.

背景:自闭症谱系障碍(ASD)的特点是持续的社会交往障碍,并且男性偏多。我们已在雄性恒河猴中建立了自然发生的低社交性模型,作为自闭症社交特征的模型。社会性低的雄性恒河猴表现出社会交往减少和自闭症样特征负荷增加,这两种测量结果高度相关,并与脑脊液(CSF)精氨酸加压素(AVP)浓度低密切相关。然而,人们对雌性恒河猴的行为和神经化学特征知之甚少,也不知道雌性恒河猴的低社会性是否是自闭症的一个可控模型:方法:在非繁殖季节对N = 88只室外饲养的雌性恒河猴进行了社会行为评估(伦理观察;反向翻译的自闭症特质测量量表--猕猴社会反应性量表-修订版[mSRS-R])。从N = 16只猴子的非社会行为频率分布中收集了脑脊液和血液样本,并对AVP和催产素(OXT)的浓度进行了量化。数据采用一般线性模型进行分析:结果:非社会行为频率和 mSRS-R 评分在整个雌猴群体中呈连续分布,这与之前在雄猴群体中发现的情况相同。然而,雌猴的优势等级能显著预测mSRS-R得分,等级越高的个体表现出的类似自闭症的特征越少,这种关系以前在该猴群的雄猴身上没有观察到。雌猴在其他几个方面也与雄猴不同:社会行为频率与 mSRS-R 评分无关,AVP 浓度与任何社会行为测量值无关。雌性动物血液和脑脊液中的 AVP 浓度呈正相关,但没有发现任何与 OXT 测量相关的显著关系:该研究样本较小,且未考虑可能与女性 mSRS-R 评分相关的遗传、环境或其他神经化学指标:优势等级是预测雌性恒河猴自闭症样特征的最重要因素,而 CSF 神经肽浓度与雌性社会功能测量无关(这与之前在雄性恒河猴和男女自闭症儿童中发现的 CSF AVP 形成鲜明对比)。尽管是初步研究,但这些证据表明,该物种强大的母系组织可能会限制雌性恒河猴的低社会性作为自闭症模型的有用性。
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引用次数: 0
Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs 自闭症相关 Shank3 突变体犬前额叶皮层锥体神经元的突触功能受损和兴奋性过高
IF 6.2 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-01-31 DOI: 10.1186/s13229-024-00587-4
Feipeng Zhu, Qi Shi, Yong-hui Jiang, Yong Q. Zhang, Hui Zhao
SHANK3 gene is a highly replicated causative gene for autism spectrum disorder and has been well characterized in multiple Shank3 mutant rodent models. When compared to rodents, domestic dogs are excellent animal models in which to study social cognition as they closely interact with humans and exhibit similar social behaviors. Using CRISPR/Cas9 editing, we recently generated a dog model carrying Shank3 mutations, which displayed a spectrum of autism-like behaviors, such as social impairment and heightened anxiety. However, the neural mechanism underlying these abnormal behaviors remains to be identified. We used Shank3 mutant dog models to examine possible relationships between Shank3 mutations and neuronal dysfunction. We studied electrophysiological properties and the synaptic transmission of pyramidal neurons from acute brain slices of the prefrontal cortex (PFC). We also examined dendrite elaboration and dendritic spine morphology in the PFC using biocytin staining and Golgi staining. We analyzed the postsynaptic density using electron microscopy. We established a protocol for the electrophysiological recording of canine brain slices and revealed that excitatory synaptic transmission onto PFC layer 2/3 pyramidal neurons in Shank3 heterozygote dogs was impaired, and this was accompanied by reduced dendrite complexity and spine density when compared to wild-type dogs. Postsynaptic density structures were also impaired in Shank3 mutants; however, pyramidal neurons exhibited hyperexcitability. Causal links between impaired PFC pyramidal neuron function and behavioral alterations remain unclear. Further experiments such as manipulating PFC neuronal activity or restoring synaptic transmission in Shank3 mutant dogs are required to assess PFC roles in altered social behaviors. Our study demonstrated the feasibility of using canine brain slices as a model system to study neuronal circuitry and disease. Shank3 haploinsufficiency causes morphological and functional abnormalities in PFC pyramidal neurons, supporting the notion that Shank3 mutant dogs are new and valid animal models for autism research.
SHANK3 基因是自闭症谱系障碍的一个高度复制的致病基因,在多个 Shank3 突变啮齿动物模型中都得到了很好的表征。与啮齿类动物相比,家犬是研究社会认知的绝佳动物模型,因为它们与人类有着密切的互动关系,并表现出类似的社会行为。利用 CRISPR/Cas9 编辑技术,我们最近生成了一种携带 Shank3 突变的狗模型,它表现出一系列类似自闭症的行为,如社交障碍和焦虑症。然而,这些异常行为背后的神经机制仍有待确定。我们利用 Shank3 突变狗模型来研究 Shank3 突变与神经元功能障碍之间可能存在的关系。我们研究了前额叶皮层(PFC)急性脑切片中锥体神经元的电生理特性和突触传递。我们还使用生物细胞素染色法和高尔基染色法检测了前额叶皮质的树突细化和树突棘形态。我们使用电子显微镜分析了突触后密度。我们建立了一套犬脑切片电生理记录方案,结果发现,与野生型犬相比,Shank3杂合子犬PFC第2/3层锥体神经元的兴奋性突触传递受损,同时树突复杂性和棘突密度降低。突触后密度结构在 Shank3 突变体中也受到损害,但锥体神经元表现出过度兴奋。PFC锥体神经元功能受损与行为改变之间的因果关系尚不清楚。要评估 PFC 在社会行为改变中的作用,还需要进一步的实验,如操纵 PFC 神经元的活动或恢复 Shank3 突变体犬的突触传递。我们的研究证明了将犬脑片作为研究神经元回路和疾病的模型系统的可行性。Shank3单倍体缺陷会导致PFC锥体神经元的形态和功能异常,这支持了Shank3突变狗是研究自闭症的新型有效动物模型的观点。
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引用次数: 0
Cortico-basal ganglia white matter microstructure is linked to restricted repetitive behavior in autism spectrum disorder. 皮层-基底节白质微结构与自闭症谱系障碍的局限性重复行为有关。
IF 6.3 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-01-23 DOI: 10.1186/s13229-023-00581-2
Bradley J Wilkes, Derek B Archer, Anna L Farmer, Carly Bass, Hannah Korah, David E Vaillancourt, Mark H Lewis

Background: Restricted repetitive behavior (RRB) is one of two behavioral domains required for the diagnosis of autism spectrum disorder (ASD). Neuroimaging is widely used to study brain alterations associated with ASD and the domain of social and communication deficits, but there has been less work regarding brain alterations linked to RRB.

Methods: We utilized neuroimaging data from the National Institute of Mental Health Data Archive to assess basal ganglia and cerebellum structure in a cohort of children and adolescents with ASD compared to typically developing (TD) controls. We evaluated regional gray matter volumes from T1-weighted anatomical scans and assessed diffusion-weighted scans to quantify white matter microstructure with free-water imaging. We also investigated the interaction of biological sex and ASD diagnosis on these measures, and their correlation with clinical scales of RRB.

Results: Individuals with ASD had significantly lower free-water corrected fractional anisotropy (FAT) and higher free-water (FW) in cortico-basal ganglia white matter tracts. These microstructural differences did not interact with biological sex. Moreover, both FAT and FW in basal ganglia white matter tracts significantly correlated with measures of RRB. In contrast, we found no significant difference in basal ganglia or cerebellar gray matter volumes.

Limitations: The basal ganglia and cerebellar regions in this study were selected due to their hypothesized relevance to RRB. Differences between ASD and TD individuals that may occur outside the basal ganglia and cerebellum, and their potential relationship to RRB, were not evaluated.

Conclusions: These new findings demonstrate that cortico-basal ganglia white matter microstructure is altered in ASD and linked to RRB. FW in cortico-basal ganglia and intra-basal ganglia white matter was more sensitive to group differences in ASD, whereas cortico-basal ganglia FAT was more closely linked to RRB. In contrast, basal ganglia and cerebellar volumes did not differ in ASD. There was no interaction between ASD diagnosis and sex-related differences in brain structure. Future diffusion imaging investigations in ASD may benefit from free-water estimation and correction in order to better understand how white matter is affected in ASD, and how such measures are linked to RRB.

背景:限制性重复行为(RRB)是诊断自闭症谱系障碍(ASD)所需的两个行为领域之一。神经影像学被广泛用于研究与自闭症谱系障碍以及社交和沟通障碍领域相关的大脑改变,但与 RRB 相关的大脑改变研究却较少:我们利用美国国家心理健康研究所数据档案中的神经影像学数据,评估了一组患有 ASD 的儿童和青少年的基底节和小脑结构,并与发育正常(TD)的对照组进行了比较。我们通过T1加权解剖扫描评估了区域灰质体积,并通过自由水成像评估了扩散加权扫描以量化白质微观结构。我们还研究了生理性别和ASD诊断对这些测量结果的交互作用,以及它们与RRB临床量表的相关性:结果:ASD患者的自由水校正分数各向异性(FAT)明显较低,皮质-基底节白质束的自由水(FW)较高。这些微观结构上的差异与生理性别无关。此外,基底节白质束中的 FAT 和 FW 都与 RRB 的测量结果显著相关。相比之下,我们发现基底节或小脑灰质体积没有明显差异:局限性:本研究选择基底节和小脑区域是因为假设它们与RRB相关。没有评估 ASD 和 TD 患者在基底节和小脑以外区域的差异及其与 RRB 的潜在关系:这些新发现表明,皮质-基底节白质微结构在 ASD 中发生改变,并与 RRB 有关。皮质-基底节和基底节内白质的FW对ASD的群体差异更为敏感,而皮质-基底节FAT与RRB的关系更为密切。相比之下,基底节和小脑体积在ASD中没有差异。ASD诊断与大脑结构中与性别相关的差异之间没有相互作用。未来的ASD扩散成像研究可能会受益于自由水估计和校正,以便更好地了解ASD患者的白质是如何受到影响的,以及这些测量结果是如何与RRB相关联的。
{"title":"Cortico-basal ganglia white matter microstructure is linked to restricted repetitive behavior in autism spectrum disorder.","authors":"Bradley J Wilkes, Derek B Archer, Anna L Farmer, Carly Bass, Hannah Korah, David E Vaillancourt, Mark H Lewis","doi":"10.1186/s13229-023-00581-2","DOIUrl":"10.1186/s13229-023-00581-2","url":null,"abstract":"<p><strong>Background: </strong>Restricted repetitive behavior (RRB) is one of two behavioral domains required for the diagnosis of autism spectrum disorder (ASD). Neuroimaging is widely used to study brain alterations associated with ASD and the domain of social and communication deficits, but there has been less work regarding brain alterations linked to RRB.</p><p><strong>Methods: </strong>We utilized neuroimaging data from the National Institute of Mental Health Data Archive to assess basal ganglia and cerebellum structure in a cohort of children and adolescents with ASD compared to typically developing (TD) controls. We evaluated regional gray matter volumes from T1-weighted anatomical scans and assessed diffusion-weighted scans to quantify white matter microstructure with free-water imaging. We also investigated the interaction of biological sex and ASD diagnosis on these measures, and their correlation with clinical scales of RRB.</p><p><strong>Results: </strong>Individuals with ASD had significantly lower free-water corrected fractional anisotropy (FA<sub>T</sub>) and higher free-water (FW) in cortico-basal ganglia white matter tracts. These microstructural differences did not interact with biological sex. Moreover, both FA<sub>T</sub> and FW in basal ganglia white matter tracts significantly correlated with measures of RRB. In contrast, we found no significant difference in basal ganglia or cerebellar gray matter volumes.</p><p><strong>Limitations: </strong>The basal ganglia and cerebellar regions in this study were selected due to their hypothesized relevance to RRB. Differences between ASD and TD individuals that may occur outside the basal ganglia and cerebellum, and their potential relationship to RRB, were not evaluated.</p><p><strong>Conclusions: </strong>These new findings demonstrate that cortico-basal ganglia white matter microstructure is altered in ASD and linked to RRB. FW in cortico-basal ganglia and intra-basal ganglia white matter was more sensitive to group differences in ASD, whereas cortico-basal ganglia FA<sub>T</sub> was more closely linked to RRB. In contrast, basal ganglia and cerebellar volumes did not differ in ASD. There was no interaction between ASD diagnosis and sex-related differences in brain structure. Future diffusion imaging investigations in ASD may benefit from free-water estimation and correction in order to better understand how white matter is affected in ASD, and how such measures are linked to RRB.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"15 1","pages":"6"},"PeriodicalIF":6.3,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10804694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139521298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pharmacological and non-pharmacological interventions for irritability in autism spectrum disorder: a systematic review and meta-analysis with the GRADE assessment. 针对自闭症谱系障碍易激惹性的药物和非药物干预:采用 GRADE 评估方法进行的系统综述和荟萃分析。
IF 6.3 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-01-23 DOI: 10.1186/s13229-024-00585-6
Hangnyoung Choi, Jae Han Kim, Hee Sang Yang, Jong Yeob Kim, Samuele Cortese, Lee Smith, Ai Koyanagi, Elena Dragioti, Joaquim Radua, Paolo Fusar-Poli, Jae Il Shin, Keun-Ah Cheon, Marco Solmi

Background: Numerous interventions for irritability in autism spectrum disorder (ASD) have been investigated. We aimed to appraise the magnitude of pharmacological and non-pharmacological interventions for irritability in ASD without any restrictions in terms of eligible interventions.

Methods: We systematically searched PubMed/MEDLINE, Scopus, and Web of Science until April 15, 2023. We included randomized controlled trials (RCTs) with a parallel design that examined the efficacy of interventions for the treatment of irritability in patients of any age with ASD without any restrictions in terms of eligible interventions. We performed a random-effects meta-analysis by pooling effect sizes as Hedges' g. We classified assessed interventions as follows: pharmacological monotherapy, risperidone plus adjuvant therapy versus risperidone monotherapy, non-pharmacological intervention, and dietary intervention. We utilized the Cochrane tool to evaluate the risk of bias in each study and the GRADE approach to assess the certainty of evidence for each meta-analyzed intervention.

Results: Out of 5640 references, we identified 60 eligible articles with 45 different kinds of interventions, including 3531 participants, of which 80.9% were males (mean age [SD] = 8.79 [3.85]). For pharmacological monotherapy, risperidone (Hedges' g - 0.857, 95% CI - 1.263 to - 0.451, certainty of evidence: high) and aripiprazole (Hedges' g - 0.559, 95% CI - 0.767 to - 0.351, certainty of evidence: high) outperformed placebo. Among the non-pharmacological interventions, parent training (Hedges' g - 0.893, 95% CI - 1.184 to - 0.602, certainty of evidence: moderate) showed a significant result. None of the meta-analyzed interventions yielded significant effects among risperidone + adjuvant therapy and dietary supplementation. However, several novel molecules in augmentation to risperidone outperformed risperidone monotherapy, yet from one RCT each.

Limitations: First, various tools have been utilized to measure the irritability in ASD, which may contribute to the heterogeneity of the outcomes. Second, meta-analyses for each intervention included only a small number of studies and participants.

Conclusions: Only risperidone, aripiprazole among pharmacological interventions, and parent training among non-pharmacological interventions can be recommended for irritability in ASD. As an augmentation to risperidone, several novel treatments show promising effects, but further RCTs are needed to replicate findings. Trial registration PROSPERO, CRD42021243965.

背景:针对自闭症谱系障碍(ASD)易激惹性的许多干预措施已得到研究。我们的目的是评估针对自闭症谱系障碍易激惹性的药物和非药物干预措施的效果,对符合条件的干预措施不作任何限制:我们系统地检索了 PubMed/MEDLINE、Scopus 和 Web of Science,直至 2023 年 4 月 15 日。我们纳入了采用平行设计的随机对照试验(RCT),这些试验研究了治疗任何年龄段 ASD 患者易激惹性的干预措施的疗效,对符合条件的干预措施没有任何限制。我们将评估的干预措施分为以下几类:药物单一疗法、利培酮加辅助疗法与利培酮单一疗法、非药物干预和饮食干预。我们使用 Cochrane 工具评估了每项研究的偏倚风险,并使用 GRADE 方法评估了每项荟萃分析干预措施的证据确定性:在 5640 篇参考文献中,我们发现了 60 篇符合条件的文章,涉及 45 种不同的干预措施,包括 3531 名参与者,其中 80.9% 为男性(平均年龄 [SD] = 8.79 [3.85])。在单一药物疗法中,利培酮(Hedges' g - 0.857,95% CI - 1.263 to - 0.451,证据确定性:高)和阿立哌唑(Hedges' g - 0.559,95% CI - 0.767 to - 0.351,证据确定性:高)的疗效优于安慰剂。在非药物干预中,家长培训(Hedges' g - 0.893,95% CI - 1.184 to - 0.602,证据确定性:中)的效果显著。在利培酮+辅助疗法和膳食补充剂中,没有一项荟萃分析干预措施产生了显著效果。然而,在利培酮的辅助治疗中,几种新型分子药物的疗效优于利培酮单药治疗,但每种药物均来自一项研究:局限性:首先,测量ASD易激惹性的工具多种多样,这可能会导致结果的异质性。其次,每种干预措施的荟萃分析仅包括少量研究和参与者:结论:药物干预中只有利培酮、阿立哌唑和非药物干预中的家长培训可用于治疗ASD的易激惹性。作为利培酮的辅助治疗,几种新型疗法显示出了良好的效果,但还需要进一步的RCT研究来验证研究结果。试验注册PROSPERO,CRD42021243965。
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引用次数: 0
Clinical impact and in vitro characterization of ADNP variants in pediatric patients. ADNP 变异体对儿科患者的临床影响和体外特征。
IF 6.3 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-01-22 DOI: 10.1186/s13229-024-00584-7
Chuanhui Ge, Yuxin Tian, Chunchun Hu, Lianni Mei, Dongyun Li, Ping Dong, Ying Zhang, Huiping Li, Daijing Sun, Wenzhu Peng, Xiu Xu, Yan Jiang, Qiong Xu

Background: Helsmoortel-Van der Aa syndrome (HVDAS) is a rare genetic disorder caused by variants in the activity-dependent neuroprotector homeobox (ADNP) gene; hence, it is also called ADNP syndrome. ADNP is a multitasking protein with the function as a transcription factor, playing a critical role in brain development. Furthermore, ADNP variants have been identified as one of the most common single-gene causes of autism spectrum disorder (ASD) and intellectual disability.

Methods: We assembled a cohort of 15 Chinese pediatric patients, identified 13 variants in the coding region of ADNP gene, and evaluated their clinical phenotypes. Additionally, we constructed the corresponding ADNP variants and performed western blotting and immunofluorescence analysis to examine their protein expression and subcellular localization in human HEK293T and SH-SY5Y cells.

Results: Our study conducted a thorough characterization of the clinical manifestations in 15 children with ADNP variants, and revealed a broad spectrum of symptoms including global developmental delay, intellectual disability, ASD, facial abnormalities, and other features. In vitro studies were carried out to check the expression of ADNP with identified variants. Two cases presented missense variants, while the remainder exhibited nonsense or frameshift variants, leading to truncated mutants in in vitro overexpression systems. Both overexpressed wildtype ADNP and all the different mutants were found to be confined to the nuclei in HEK293T cells; however, the distinctive pattern of nuclear bodies formed by the wildtype ADNP was either partially or entirely disrupted by the mutant proteins. Moreover, two variants of p.Y719* on the nuclear localization signal (NLS) of ADNP disrupted the nuclear expression pattern, predominantly manifesting in the cytoplasm in SH-SY5Y cells.

Limitations: Our study was limited by a relatively small sample size and the absence of a longitudinal framework to monitor the progression of patient conditions over time. Additionally, we lacked in vivo evidence to further indicate the causal implications of the identified ADNP variants.

Conclusions: Our study reported the first cohort of HVDAS patients in the Chinese population and provided systematic clinical presentations and laboratory examinations. Furthermore, we identified multiple genetic variants and validated them in vitro. Our findings offered valuable insights into the diverse genetic variants associated with HVDAS.

背景:Helsmoortel-Van der Aa 综合征(HVDAS)是一种罕见的遗传性疾病,由活动依赖性神经保护基因(ADNP)变异引起,因此也被称为 ADNP 综合征。ADNP 是一种多任务蛋白,具有转录因子的功能,在大脑发育过程中起着至关重要的作用。此外,ADNP变异已被确定为自闭症谱系障碍(ASD)和智力障碍最常见的单基因病因之一:方法:我们收集了15名中国儿童患者,鉴定了ADNP基因编码区的13个变体,并评估了他们的临床表型。此外,我们还构建了相应的ADNP变体,并对其在人HEK293T和SH-SY5Y细胞中的蛋白表达和亚细胞定位进行了Western印迹和免疫荧光分析:我们的研究对15名ADNP变异型患儿的临床表现进行了全面分析,发现了包括全面发育迟缓、智力障碍、ASD、面部畸形和其他特征在内的广泛症状。研究人员还进行了体外研究,以检测ADNP变异体的表达情况。两个病例出现了错义变异,其余病例则出现了无义或框移位变异,导致体外过表达系统中出现截短突变体。在 HEK293T 细胞中,过表达的野生型 ADNP 和所有不同的突变体都被限制在细胞核中;然而,野生型 ADNP 形成的独特核体模式被突变体蛋白部分或完全破坏。此外,ADNP核定位信号(NLS)上p.Y719*的两个变体破坏了核表达模式,在SH-SY5Y细胞中主要表现为胞质表达:我们的研究受到样本量相对较小以及缺乏纵向框架来监测患者病情随时间推移的进展等因素的限制。此外,我们缺乏体内证据来进一步说明已确定的 ADNP 变异的因果影响:我们的研究报告了中国人群中首个 HVDAS 患者队列,并提供了系统的临床表现和实验室检查。此外,我们还发现了多种基因变异,并在体外进行了验证。我们的研究结果为了解与 HVDAS 相关的多种基因变异提供了宝贵的见解。
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引用次数: 0
The search for gastrointestinal inflammation in autism: a systematic review and meta-analysis of non-invasive gastrointestinal markers 寻找自闭症的胃肠道炎症:非侵入性胃肠道标记物的系统回顾和荟萃分析
IF 6.2 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-01-17 DOI: 10.1186/s13229-023-00575-0
Nisha E. Mathew, Delyse McCaffrey, Adam K. Walker, Kylie-Ann Mallitt, Anne Masi, Margaret J. Morris, Chee Y. Ooi
Gastrointestinal symptoms and inflammatory gastrointestinal diseases exist at higher rates in the autistic population. It is not clear however whether autism is associated with elevated gastrointestinal inflammation as studies examining non-invasive faecal biomarkers report conflicting findings. To understand the research landscape and identify gaps, we performed a systematic review and meta-analysis of studies measuring non-invasive markers of gastrointestinal inflammation in autistic and non-autistic samples. Our examination focused on faecal biomarkers as sampling is non-invasive and these markers are a direct reflection of inflammatory processes in the gastrointestinal tract. We extracted data from case–control studies examining faecal markers of gastrointestinal inflammation. We searched PubMed, Embase, Cochrane CENTRAL, CINAHL, PsycINFO, Web of Science Core Collection and Epistemonikos and forward and backwards citations of included studies published up to April 14, 2023 (PROSPERO CRD42022369279). There were few studies examining faecal markers of gastrointestinal inflammation in the autistic population, and many established markers have not been studied. Meta-analyses of studies examining calprotectin (n = 9) and lactoferrin (n = 3) were carried out. A total of 508 autistic children and adolescents and 397 non-autistic children and adolescents were included in the meta-analysis of calprotectin studies which found no significant group differences (ROM: 1.30 [0.91, 1.86]). Estimated differences in calprotectin were lower in studies with siblings and studies which did not exclude non-autistic controls with gastrointestinal symptoms. A total of 139 autistic participants and 75 non-autistic controls were included in the meta-analysis of lactoferrin studies which found no significant group differences (ROM: 1.27 [0.79, 2.04]). All studies included in this systematic review and meta-analysis examined children and adolescents. Many studies included non-autistic controls with gastrointestinal symptoms which limit the validity of their findings. The majority of studies of gastrointestinal inflammation focused on children under 12 with few studies including adolescent participants. Most studies that included participants aged four or under did not account for the impact of age on calprotectin levels. Future studies should screen for relevant confounders, include larger samples and explore gastrointestinal inflammation in autistic adolescents and adults. There is no evidence to suggest higher levels of gastrointestinal inflammation as measured by calprotectin and lactoferrin are present in autistic children and adolescents at the population level. Preliminary evidence suggests however that higher calprotectin levels may be present in a subset of autistic participants, who may be clinically characterised by more severe gastrointestinal symptoms and higher levels of autistic traits.
在自闭症人群中,胃肠道症状和炎症性胃肠道疾病的发病率较高。然而,自闭症是否与胃肠道炎症升高有关尚不清楚,因为检查非侵入性粪便生物标志物的研究结果相互矛盾。为了了解研究现状并找出差距,我们对自闭症和非自闭症样本中测量非侵入性胃肠道炎症标志物的研究进行了系统回顾和荟萃分析。我们的研究重点是粪便生物标记物,因为取样是非侵入性的,而且这些标记物能直接反映胃肠道的炎症过程。我们从检查胃肠道炎症粪便标记物的病例对照研究中提取了数据。我们检索了 PubMed、Embase、Cochrane CENTRAL、CINAHL、PsycINFO、Web of Science Core Collection 和 Epistemonikos,以及截至 2023 年 4 月 14 日发表的纳入研究的正向和反向引文(PROSPERO CRD42022369279)。针对自闭症人群胃肠道炎症的粪便标记物的研究很少,许多已确定的标记物也未进行过研究。我们对检测钙蛋白(9 个)和乳铁蛋白(3 个)的研究进行了元分析。共有 508 名自闭症儿童和青少年以及 397 名非自闭症儿童和青少年被纳入钙蛋白研究的元分析中,结果发现各组间无显著差异(ROM:1.30 [0.91, 1.86])。在有兄弟姐妹的研究和未排除有胃肠道症状的非自闭症对照组的研究中,估计的犊牛蛋白差异较低。乳铁蛋白研究的荟萃分析共纳入了 139 名自闭症参与者和 75 名非自闭症对照者,结果发现没有明显的群体差异(ROM:1.27 [0.79, 2.04])。本系统综述和荟萃分析所纳入的所有研究均针对儿童和青少年。许多研究纳入了有胃肠道症状的非自闭症对照组,这限制了研究结果的有效性。大多数有关胃肠道炎症的研究都集中在 12 岁以下的儿童身上,很少有研究包括青少年参与者。大多数包含 4 岁或 4 岁以下参与者的研究并未考虑年龄对钙粘蛋白水平的影响。未来的研究应筛查相关的混杂因素,纳入更多样本,并探讨自闭症青少年和成人的胃肠道炎症。目前还没有证据表明,在人群水平上,自闭症儿童和青少年的胃肠道炎症水平较高,这可以通过钙蛋白和乳铁蛋白来衡量。不过,初步证据表明,部分自闭症患者的钙黏蛋白水平可能较高,他们的临床特征可能是胃肠道症状更严重、自闭症特征更明显。
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Molecular Autism
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