结构性病变和转录组特化形成了威尔逊病的梯度扰动。

IF 4.1 Q1 CLINICAL NEUROLOGY
Brain communications Pub Date : 2024-09-24 eCollection Date: 2024-01-01 DOI:10.1093/braincomms/fcae329
Sheng Hu, Chuanfu Li, Yanming Wang, Taohua Wei, Xiaoxiao Wang, Ting Dong, Yulong Yang, Yufeng Ding, Bensheng Qiu, Wenming Yang
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引用次数: 0

摘要

威尔逊病(WD)患者脑内铜的过度沉积会导致多个区域的功能失调。WD的遗传机制被认为与肝脏中ATP7B的异常表达有关,而大脑中功能失调所涉及的生物和分子过程仍未得到探索。本研究的目的是揭示WD结构性病变和转录组特化背后的功能梯度扰动的基础。在这项研究中,我们纳入了 105 名 WD 患者和 93 名健康对照者,对他们进行了结构和功能磁共振成像评估。我们利用扩散图谱嵌入模型得出了功能连接组梯度,并进一步利用灰质体积揭示了 WD 的结构-功能解耦。然后,我们利用Neurosynth、临床数据和全脑基因表达数据,对与WD梯度改变相关的认知功能、临床表型和转录组特化进行了荟萃分析。与对照组相比,WD 患者的主要颅内-脑内梯度表现出全球性的地形变化。在运动相关处理、高阶认知、神经症状和年龄方面,元分析术语和临床特征与这些梯度改变相关。空间相关性揭示了多个网络的结构-功能解耦,尤其是皮层下和视觉网络。在皮层内,梯度改变与基因表达谱之间的空间关联揭示了 WD 中转录组的特异性,这些特异性显示了离子平衡、神经发育和运动控制的特性。此外,我们还首次确定了 ATP7B 基因在影响皮层下功能方面的作用。WD 的转录组特异性还与其他神经和精神疾病有关。最后,我们发现结构性病变和梯度扰动可能在 WD 中具有类似的转录组特异性。总之,这些发现将功能梯度扰动与 WD 患者的结构病变和基因表达谱联系起来,可能会促进我们对复杂的神经和精神表型出现的神经生物学机制的理解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Structural lesions and transcriptomic specializations shape gradient perturbations in Wilson disease.

Functional dysregulations in multiple regions are caused by excessive copper deposition in the brain in Wilson disease (WD) patients. The genetic mechanism of WD is thought to involve the abnormal expression of ATP7B in the liver, whereas the biological and molecular processes involved in functional dysregulation within the brain remain unexplored. The objective of this study was to unravel the underpinnings of functional gradient perturbations underlying structural lesions and transcriptomic specializations in WD. In this study, we included 105 WD patients and 93 healthy controls who underwent structural and functional MRI assessments. We used the diffusion mapping embedding model to derive the functional connectome gradient and further employed gray matter volume to uncover structure-function decoupling for WD. Then, we used Neurosynth, clinical data, and whole-brain gene expression data to examine the meta-analytic cognitive function, clinical phenotypes, and transcriptomic specializations related to WD gradient alterations. Compared with controls, WD patients exhibited global topographic changes in the principal pramary-to-transmodal gradient. Meta-analytic terms and clinical characteristics were correlated with these gradient alterations in motor-related processing, higher-order cognition, neurological symptoms, and age. Spatial correlations revealed structure-function decoupling in multiple networks, especially in subcortical and visual networks. Within the cortex, the spatial association between gradient alterations and gene expression profiles has revealed transcriptomic specilizations in WD that display properties indicative of ion homeostasis, neural development, and motor control. Furthermore, for the first time, we characterized the role of the ATP7B gene in impacting subcortical function. The transcriptomic specializations of WD were also associated with other neurological and psychiatric disorders. Finally, we revealed that structural lesions and gradient perturbations may share similar transcriptomic specializations in WD. In conclusion, these findings bridged functional gradient perturbations to structural lesions and gene expression profiles in WD patients, possibly promoting our understanding of the neurobiological mechanisms underlying the emergence of complex neurological and psychiatric phenotypes.

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