PDF(Pubmed)
Abstract：
Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson\'s disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49-87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41-88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain\'s structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer\'s disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain\'s structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer\'s disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks.
摘要：
孤立的快速眼动睡眠行为障碍（iRBD）是一种睡眠障碍，其特征是在快速眼动睡眠过程中快速眼动睡眠肌肉失功的丧失以及异常运动和发声的出现。它是早期突触核蛋白病的强烈标志，如路易体痴呆和帕金森病。iRBD患者已经表现出大脑变化，让人想起明显的突触核蛋白病，包括脑萎缩。然而,这种萎缩发展的潜在机制仍然知之甚少。在这项研究中,我们对171例多导睡眠图证实的iRBD患者(67.7±6.6(49~87)岁;83%为男性)和238例健康对照(66.6±7.9(41~88)岁;77%为男性)的T1加权MRI进行了尖端成像转录组学和综合空间定位分析,以调查与iRBD皮质厚度和表面积变化相关的基因表达和连接模式.进行偏最小二乘回归以鉴定iRBD中皮层变化的基因表达模式。然后进行基因集富集分析和虚拟组织学以评估生物学过程，细胞成分，人类疾病基因术语，和富含这些基因表达模式的细胞类型。然后，我们使用结构和功能邻域分析来评估iRBD的萎缩模式是否受到大脑结构和功能连接体的限制。此外，我们使用全面的空间映射分析来评估特定的神经递质系统，功能网络，细胞建筑学类，和与iRBD皮质变化相关的认知脑系统。所有比较均针对保留脑区之间空间自相关性的空模型进行测试，并与阿尔茨海默病进行比较，以评估发现对突触核蛋白病的特异性。我们发现，参与线粒体功能和巨自噬的基因是iRBD中皮质变薄的最强贡献者。此外，我们证明，皮质变薄受到大脑结构和功能连接体的限制，并映射到涉及运动和计划功能的特定网络上。与皮质厚度相反，皮质表面积的变化与不同的基因有关，即参与炎症反应的基因，以及不同的空间映射模式。与iRBD相关的基因表达和连接模式都与阿尔茨海默病中观察到的不同。总之,这项研究表明，突触核蛋白病中脑萎缩的发展受到特定基因和网络的限制。
