自闭症患者的大脑成熟模式及其分子关联。

IF 22.5 1区 医学 Q1 PSYCHIATRY JAMA Psychiatry Pub Date : 2024-10-16 DOI:10.1001/jamapsychiatry.2024.3194
Charlotte M Pretzsch,Martina Arenella,Jason P Lerch,Michael V Lombardo,Christian Beckmann,Tim Schaefer,Johanna Leyhausen,Caroline Gurr,Anke Bletsch,Lisa M Berg,Hanna Seelemeyer,Dorothea L Floris,Bethany Oakley,Eva Loth,Thomas Bourgeron,Tony Charman,Jan Buitelaar,Grainne McAlonan,Declan Murphy,Christine Ecker,
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引用次数: 0

摘要

重要性在神经畸形的大脑中,各区域以协调的模式发育,为大脑功能和行为提供了一个基本支架。目的研究自闭症患者的大脑区域是否以不同的方式相互发育,以及这些差异与分子/基因组机制和症状学的关系。设计、设置和参与者本研究分析了最大的深度表型、病例对照、纵向(两次评估相隔约 12-24 个月)结构磁共振成像和认知行为自闭症数据集(EU-AIMS 欧洲自闭症纵向项目 [LEAP];研究日期:2014 年 2 月至 2017 年 11 月)之一,以及脑发育成像研究(BrainMapASD)独立队列的样本外验证。分析在 2022 年至 2023 年期间进行。这项多中心研究包括自闭症和神经畸形儿童、青少年和成人。如果自闭症患者已被诊断为自闭症(DSM-IV/《疾病和相关健康问题国际统计分类》第十版或 DSM-5 标准),则将其纳入研究范围。结果LEAP队列中共有386人(首次就诊时年龄为6-31岁;自闭症患者214人,平均[标码]年龄为17.3[5.4]岁;154 名男性[72.0%]和 172 名神经畸形患者,平均[标码]年龄为 16.35 [5.7]岁;108 名男性[62.8%]),以及 BrainMapASD 队列中的 146 名患者(初诊时年龄为 11-18 岁;49 名自闭症患者,平均[标码]年龄为 14.31 [2.4]岁;42 名男性[85.7%]和 97 名神经畸形患者,平均[标码]年龄为 14.10 [2.5]岁;58 名男性[59.8%])。皮质厚度和表面积的成熟期组间差异已经确定,这些差异主要由感觉运动区驱动(例如,在不同特征中,早期视觉皮质的绝对负荷从 0.07 到 0.11 不等,而背外侧前额叶皮质的绝对负荷从 0.005 到 0.06 不等)。神经发育差异在转录组学上富集了在几种细胞类型和不同神经发育阶段表达的基因以及自闭症候选基因(例如,自闭症中下调的基因,包括那些调节突触传递的基因;富集几率比 =3.7;P =2.6 × -10)。更神经质、更不像自闭症的成熟特征与更少的社交障碍和更典型的感觉处理有关(误发现率 P <.05;Pearson r ≥0.17)。这项病例对照研究的结果表明,自闭症患者大脑区域的协调发育发生了改变,涉及时间敏感性分子机制的复杂相互作用,并可能与自闭症的低阶(如感觉)和高阶(如社交)临床特征有关。因此,研究成熟模式可以为研究神经发育/精神健康状况临床特征的神经生物学起源提供一个分析框架。
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Patterns of Brain Maturation in Autism and Their Molecular Associations.
Importance In the neurotypical brain, regions develop in coordinated patterns, providing a fundamental scaffold for brain function and behavior. Whether altered patterns contribute to clinical profiles in neurodevelopmental conditions, including autism, remains unclear. Objectives To examine if, in autism, brain regions develop differently in relation to each other and how these differences are associated with molecular/genomic mechanisms and symptomatology. Design, Setting, and Participants This study was an analysis of one the largest deep-phenotyped, case-control, longitudinal (2 assessments separated by approximately 12-24 months) structural magnetic resonance imaging and cognitive-behavioral autism datasets (EU-AIMS Longitudinal European Autism Project [LEAP]; study dates, February 2014-November 2017) and an out-of-sample validation in the Brain Development Imaging Study (BrainMapASD) independent cohort. Analyses were performed during the 2022 to 2023 period. This multicenter study included autistic and neurotypical children, adolescents, and adults. Autistic participants were included if they had an existing autism diagnosis (DSM-IV/International Statistical Classification of Diseases and Related Health Problems, Tenth Revision or DSM-5 criteria). Autistic participants with co-occurring psychiatric conditions (except psychosis/bipolar disorder) and those taking regular medications were included. Exposures Neuroanatomy of neurotypical and autistic participants. Main Outcomes and Measures Intraindividual changes in surface area and cortical thickness over time, analyzed via surface-based morphometrics. Results A total of 386 individuals in the LEAP cohort (6-31 years at first visit; 214 autistic individuals, mean [SD] age, 17.3 [5.4] years; 154 male [72.0%] and 172 neurotypical individuals, mean [SD] age, 16.35 [5.7] years; 108 male [62.8%]) and 146 individuals in the BrainMapASD cohort (11-18 years at first visit; 49 autistic individuals, mean [SD] age, 14.31 [2.4] years; 42 male [85.7%] and 97 neurotypical individuals, mean [SD] age, 14.10 [2.5] years; 58 male [59.8%]). Maturational between-group differences in cortical thickness and surface area were established that were mostly driven by sensorimotor regions (eg, across features, absolute loadings for early visual cortex ranged from 0.07 to 0.11, whereas absolute loadings for dorsolateral prefrontal cortex ranged from 0.005 to 0.06). Neurodevelopmental differences were transcriptomically enriched for genes expressed in several cell types and during various neurodevelopmental stages, and autism candidate genes (eg, downregulated genes in autism, including those regulating synaptic transmission; enrichment odds ratio =3.7; P =2.6 × -10). A more neurotypical, less autismlike maturational profile was associated with fewer social difficulties and more typical sensory processing (false discovery rate P <.05; Pearson r ≥0.17). Results were replicated in the independently collected BrainMapASD cohort. Conclusions and Relevance Results of this case-control study suggest that the coordinated development of brain regions was altered in autism, involved a complex interplay of temporally sensitive molecular mechanisms, and may be associated with both lower-order (eg, sensory) and higher-order (eg, social) clinical features of autism. Thus, examining maturational patterns may provide an analytic framework to study the neurobiological origins of clinical profiles in neurodevelopmental/mental health conditions.
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来源期刊
JAMA Psychiatry
JAMA Psychiatry PSYCHIATRY-
CiteScore
30.60
自引率
1.90%
发文量
233
期刊介绍: JAMA Psychiatry is a global, peer-reviewed journal catering to clinicians, scholars, and research scientists in psychiatry, mental health, behavioral science, and related fields. The Archives of Neurology & Psychiatry originated in 1919, splitting into two journals in 1959: Archives of Neurology and Archives of General Psychiatry. In 2013, these evolved into JAMA Neurology and JAMA Psychiatry, respectively. JAMA Psychiatry is affiliated with the JAMA Network, a group of peer-reviewed medical and specialty publications.
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