中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (5): 1154-1160.doi: 10.4103/1673-5374.355764

• 原著:退行性病与再生 • 上一篇    

认知相关单核苷酸多态性对帕金森病患者脑表型的影响

  

  • 出版日期:2023-05-15 发布日期:2022-11-01
  • 基金资助:
    国家自然科学基金；国家重点研发计划；浙江省重点研发计划；浙江省实验室重点项目；中央高校基本科研业务费；浙江省博士后优选基金

Impact of cognition-related single nucleotide polymorphisms on brain imaging phenotype in Parkinson’s disease

Ting Shen1, 2, #, Jia-Li Pu1, #, Ya-Si Jiang1, 2, Yu-Mei Yue3, Ting-Ting He2, 4, Bo-Yi Qu2, 4, Shuai Zhao1, Ya-Ping Yan1, Hsin-Yi Lai2, 3, 4, *, Bao-Rong Zhang1, *#br#   

  1. 1Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China;  2Department of Neurology of the Second Affiliated Hospital, Interdisciplinary Institute of Neuroscience and Technology, Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China;  3Department of Neurology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China;  4College of Biomedical Engineering and Instrument Science, Key Laboratory for Biomedical Engineering of Ministry of Education, Zhejiang University, Hangzhou, Zhejiang Province, China
  • Online:2023-05-15 Published:2022-11-01
  • Contact: Bao-Rong Zhang, MD, PhD, brzhang@zju.edu.cn; Hsin-Yi Lai, PhD, laihy@zju.edu.cn.
  • Supported by:
    This work was supported by grants from the National Natural Science Foundation of China, Nos. 81771216 (to JLP), 81520108010 (to BRZ), and 82101323 (to TS), the National Key R&D Program of China, No. 2018YFA0701400 (to HYL), the Primary Research and Development Plan of Zhejiang Province, No. 2020C03020 (to BRZ), the Key Project of Zhejiang Laboratory, No. 2018EB0ZX01 (to HYL), the Fundamental Research Funds for the Central Universities, No. 2019XZZX001-01-21 (to HYL), and Preferred Foundation of Zhejiang Postdoctors, No. ZJ2021152 (to TS).

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摘要：

多种单核苷酸多态性（SNPs）可能与帕金森病（PD）的认知能力下降有关；然而，这些SNPs改变大脑表型的机制仍不清楚。为了解多个SNPs对帕金森病的大脑表型的潜在影响，研究纳入48例PD患者和与之匹配39名的健康对照者，通过采集多模态7.0T超高场强磁共振数据，利用其高分辨率、高信噪比和高检测力的特点，揭示与SNP相关的大脑表型变化。通过建立认知加权的多基因风险评分（PRS）模型，发现多个SNP对脑表型存在累积效应，主要表现为该PRS评分与海马、海马旁回和梭状回的神经活动，海马-前额叶功能连接和梭状回-颞叶功能连接，以及眶额皮层的灰质体积改变有关。同时，还进行了个体SNP分析，以探讨基因型的主要影响及其与PD诊断的交互作用。研究发现，α-synuclein 基因（SNCA）的SNP与上放射冠、胼胝体和外囊等的白质纤维微结构变化相关。儿茶酚-o-甲基转移酶（COMT）基因的SNP与舌回、梭状回等视觉认知功能相关脑区的神经活动有关。此外，多巴胺D3受体（DRD3）基因的SNP与额叶和颞叶的功能及结构都存在一定的相关性。研究结果表明，神经影像学特征、遗传信息和临床数据可以互相补充，从多个角度阐述帕金森病认知功能减退的神经退行性变相关的神经机制。

https://orcid.org/0000-0002-8099-7407 (Bao-Rong Zhang); https://orcid.org/0000-0001-6413-0179 (Hsin-Yi Lai)

Abstract: Multiple single nucleotide polymorphisms may contribute to cognitive decline in Parkinson’s disease. However, the mechanism by which these single nucleotide polymorphisms modify brain imaging phenotype remains unclear. The aim of this study was to investigate the potential effects of multiple single nucleotide polymorphisms on brain imaging phenotype in Parkinson’s disease. Forty-eight Parkinson’s disease patients and 39 matched healthy controls underwent genotyping and 7T magnetic resonance imaging. A cognitive-weighted polygenic risk score model was designed, in which the effect sizes were determined individually for 36 single nucleotide polymorphisms. The correlations between polygenic risk score, neuroimaging features, and clinical data were analyzed. Furthermore, individual single nucleotide polymorphism analysis was performed to explore the main effects of genotypes and their interactive effects with Parkinson’s disease diagnosis. We found that, in Parkinson’s disease, the polygenic risk score was correlated with the neural activity of the hippocampus, parahippocampus, and fusiform gyrus, and with hippocampal-prefrontal and fusiform-temporal connectivity, as well as with gray matter alterations in the orbitofrontal cortex. In addition, we found that single nucleotide polymorphisms in α-synuclein (SNCA) were associated with white matter microstructural changes in the superior corona radiata, corpus callosum, and external capsule. A single nucleotide polymorphism in catechol-O-methyltransferase was associated with the neural activities of the lingual, fusiform, and occipital gyri, which are involved in visual cognitive dysfunction. Furthermore, DRD3 was associated with frontal and temporal lobe function and structure. In conclusion, imaging genetics is useful for providing a better understanding of the genetic pathways involved in the pathophysiologic processes underlying Parkinson’s disease. This study provides evidence of an association between genetic factors, cognitive functions, and multi-modality neuroimaging biomarkers in Parkinson’s disease.

Key words: cognition, imaging genetics, magnetic resonance imaging, multi-modality, Parkinson’s disease, polygenic risk score, single nucleotide polymorphism, ultra-high field