{"title":"揭示LILRB4基因型与帕金森病的关系：从临床特征到潜在病理","authors":"Yuting Zhou, Yaqing Li, Qiqing He, Zhen Kong, Ran Yu, Xin Yu, Anmu Xie","doi":"10.1111/cns.70522","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Leukocyte immunoglobulin-like receptor B4 (LILRB4) has been shown to be associated with susceptibility to neurodegenerative diseases. This study was aimed at investigating the relationships between <i>LILRB4</i> and the risk of developing PD, as well as its clinical characteristics and pathology.</p>\n </section>\n \n <section>\n \n <h3> Method</h3>\n \n <p>We analyzed 197 healthy controls and 606 PD patients from the Parkinson's Progression Marker Initiative (PPMI) study. The associations of <i>LILRB4</i> loci with image data, CSF biomarkers, and clinical scales at baseline were assessed using multiple linear models.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Dopamine transporter (DAT)-SPECT results showed that the striatal binding ratios (SBR) in the right caudate (<i>β</i> = 0.160, 95% CI = 0.076–0.244, <i>P</i><sub>c</sub> = 0.002), right putamen (<i>β</i> = 0.135, 95% CI = 0.057–0.214, <i>P</i><sub>c</sub> = 0.009), anterior right putamen (<i>β</i> = 0.156, 95% CI = 0.073–0.240, <i>P</i><sub>c</sub> = 0.003) and left caudate (<i>β</i> = 0.121, 95% CI = 0.038–0.2050, <i>P</i><sub>c</sub> = 0.048) were positively associated with <i>LILRB4</i>. Meanwhile, <i>LILRB4</i> was associated with reductions in semantic fluency (<i>β</i> = −2.135, 95% CI = −3.225 to 1.046, <i>P</i><sub>c</sub> = 0.001) and impairments in nigrostriatal white matter (WM) microstructure as assessed by diffusion tensor imaging (DTI) (right rostral of substantia nigra (SN), <i>β</i> = −0.026, 95% CI = −0.030 to 0.013, <i>P</i><sub>c</sub> = 0.002; right middle SN, <i>β</i> = −0.021, 95% CI = −0.033 to 0.009, <i>P</i><sub>c</sub> = 0.012). These associations were more prominent in females (DAT in right caudate, <i>β</i> = 0.246, 95% CI = 0.099–0.392, <i>P</i><sub>c</sub> = 0.013; DTI in right middle of SN, <i>β</i> = −0.025 95% CI = −0.040 to 0.010, <i>P</i><sub>c</sub> = 0.021), but less pronounced in males (DAT in right caudate, <i>p</i> = 0.036, <i>P</i><sub>c</sub> = 0.396; DTI in right rostral of SN, <i>β</i> = −0.025 95% CI = −0.041 to 0.008, <i>P</i><sub>c</sub> = 0.021). Interestingly, in females, we also observed associations between <i>LILRB4</i> and higher CSF α-synuclein levels (<i>β</i> = 0.177, 95% CI = 0.062–0.292, <i>p</i> = 3.280E−03, <i>P</i><sub>c</sub> = 0.036) and worse cognitive performance (Activity of Daily Living scale, <i>β</i> = −2.073, 95% CI = −3.446 to 0.699, <i>P</i><sub>c</sub> = 0.025; Semantic Fluency test, <i>β</i> = −2.508 95% CI = −4.255 to 0.761, <i>P</i><sub>c</sub> = 0.032). Although our results suggested that dopamine and its metabolites, astrocyte markers, and inflammation-related molecules were associated with <i>LILRB4</i>, these associations disappeared after false discovery rate (FDR) correction (<i>p</i> ≤ 0.05, but <i>P</i><sub>c</sub> > 0.05).</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>Our study supposes that LILRB4 may play a crucial role in modulating PD clinical characteristics by influencing nigrostriatal dopaminergic neuron function, Alzheimer's disease (AD)-related pathology, WM microstructural alterations, and astrocyte activation.</p>\n </section>\n </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 7","pages":""},"PeriodicalIF":5.0000,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70522","citationCount":"0","resultStr":"{\"title\":\"Uncovering the Associations of LILRB4 Genotypes With Parkinson's Disease: From Clinical Traits to Potential Pathologies\",\"authors\":\"Yuting Zhou, Yaqing Li, Qiqing He, Zhen Kong, Ran Yu, Xin Yu, Anmu Xie\",\"doi\":\"10.1111/cns.70522\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Leukocyte immunoglobulin-like receptor B4 (LILRB4) has been shown to be associated with susceptibility to neurodegenerative diseases. This study was aimed at investigating the relationships between <i>LILRB4</i> and the risk of developing PD, as well as its clinical characteristics and pathology.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Method</h3>\\n \\n <p>We analyzed 197 healthy controls and 606 PD patients from the Parkinson's Progression Marker Initiative (PPMI) study. The associations of <i>LILRB4</i> loci with image data, CSF biomarkers, and clinical scales at baseline were assessed using multiple linear models.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Dopamine transporter (DAT)-SPECT results showed that the striatal binding ratios (SBR) in the right caudate (<i>β</i> = 0.160, 95% CI = 0.076–0.244, <i>P</i><sub>c</sub> = 0.002), right putamen (<i>β</i> = 0.135, 95% CI = 0.057–0.214, <i>P</i><sub>c</sub> = 0.009), anterior right putamen (<i>β</i> = 0.156, 95% CI = 0.073–0.240, <i>P</i><sub>c</sub> = 0.003) and left caudate (<i>β</i> = 0.121, 95% CI = 0.038–0.2050, <i>P</i><sub>c</sub> = 0.048) were positively associated with <i>LILRB4</i>. Meanwhile, <i>LILRB4</i> was associated with reductions in semantic fluency (<i>β</i> = −2.135, 95% CI = −3.225 to 1.046, <i>P</i><sub>c</sub> = 0.001) and impairments in nigrostriatal white matter (WM) microstructure as assessed by diffusion tensor imaging (DTI) (right rostral of substantia nigra (SN), <i>β</i> = −0.026, 95% CI = −0.030 to 0.013, <i>P</i><sub>c</sub> = 0.002; right middle SN, <i>β</i> = −0.021, 95% CI = −0.033 to 0.009, <i>P</i><sub>c</sub> = 0.012). These associations were more prominent in females (DAT in right caudate, <i>β</i> = 0.246, 95% CI = 0.099–0.392, <i>P</i><sub>c</sub> = 0.013; DTI in right middle of SN, <i>β</i> = −0.025 95% CI = −0.040 to 0.010, <i>P</i><sub>c</sub> = 0.021), but less pronounced in males (DAT in right caudate, <i>p</i> = 0.036, <i>P</i><sub>c</sub> = 0.396; DTI in right rostral of SN, <i>β</i> = −0.025 95% CI = −0.041 to 0.008, <i>P</i><sub>c</sub> = 0.021). Interestingly, in females, we also observed associations between <i>LILRB4</i> and higher CSF α-synuclein levels (<i>β</i> = 0.177, 95% CI = 0.062–0.292, <i>p</i> = 3.280E−03, <i>P</i><sub>c</sub> = 0.036) and worse cognitive performance (Activity of Daily Living scale, <i>β</i> = −2.073, 95% CI = −3.446 to 0.699, <i>P</i><sub>c</sub> = 0.025; Semantic Fluency test, <i>β</i> = −2.508 95% CI = −4.255 to 0.761, <i>P</i><sub>c</sub> = 0.032). Although our results suggested that dopamine and its metabolites, astrocyte markers, and inflammation-related molecules were associated with <i>LILRB4</i>, these associations disappeared after false discovery rate (FDR) correction (<i>p</i> ≤ 0.05, but <i>P</i><sub>c</sub> > 0.05).</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusion</h3>\\n \\n <p>Our study supposes that LILRB4 may play a crucial role in modulating PD clinical characteristics by influencing nigrostriatal dopaminergic neuron function, Alzheimer's disease (AD)-related pathology, WM microstructural alterations, and astrocyte activation.</p>\\n </section>\\n </div>\",\"PeriodicalId\":154,\"journal\":{\"name\":\"CNS Neuroscience & Therapeutics\",\"volume\":\"31 7\",\"pages\":\"\"},\"PeriodicalIF\":5.0000,\"publicationDate\":\"2025-07-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70522\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"CNS Neuroscience & Therapeutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/cns.70522\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"CNS Neuroscience & Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cns.70522","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
摘要
白细胞免疫球蛋白样受体B4 （LILRB4）已被证明与神经退行性疾病的易感性相关。本研究旨在探讨LILRB4与PD发生风险的关系，以及其临床特征和病理。方法对197名健康对照者和606名帕金森病进展标志物倡议（PPMI）研究的PD患者进行分析。使用多重线性模型评估LILRB4位点与图像数据、脑脊液生物标志物和基线临床量表的相关性。结果多巴胺转运体(DAT)-SPECT结果显示，右侧尾状核纹状体结合率（SBR） （β = 0.160, 95% CI = 0.076 ~ 0.244, Pc = 0.002）、右侧壳核（β = 0.135, 95% CI = 0.057 ~ 0.214, Pc = 0.009）、右侧壳核前部（β = 0.156, 95% CI = 0.073 ~ 0.240, Pc = 0.003）和左侧尾状核（β = 0.121, 95% CI = 0.038 ~ 0.2050, Pc = 0.048）与LILRB4呈正相关。同时，LILRB4与语义流畅性降低（β = - 2.135, 95% CI = - 3.225 ~ 1.046, Pc = 0.001）和扩散张量成像（DTI）评估的黑质纹状体白质（SN）右吻侧黑质（SN）， β = - 0.026, 95% CI = - 0.030 ~ 0.013, Pc = 0.002；对SN,β=−0.021,95% CI =−0.033至0.009,电脑= 0.012)。这些相关性在女性中更为显著(右侧尾状核DAT， β = 0.246, 95% CI = 0.099 ~ 0.392, Pc = 0.013；右侧尾状核中部DTI， β = - 0.025 95% CI = - 0.040 ~ 0.010, Pc = 0.021)，但男性较不明显(右侧尾状核DAT， p = 0.036, Pc = 0.396；SN右吻侧DTI， β = - 0.025 95% CI = - 0.041 ~ 0.008, Pc = 0.021)。有趣的是，在女性中，我们还观察到LILRB4与较高的CSF α-突触核蛋白水平（β = 0.177, 95% CI = 0.062-0.292, p = 3.280E - 03, Pc = 0.036）和较差的认知能力(日常生活活动量表，β = - 2.073, 95% CI = - 3.446 - 0.699, Pc = 0.025；语义流畅性测试，β = - 2.508 95% CI = - 4.255 ~ 0.761, Pc = 0.032)。虽然我们的研究结果表明，多巴胺及其代谢物、星形胶质细胞标志物和炎症相关分子与LILRB4相关，但这些关联在错误发现率（FDR）校正后消失（p≤0.05，但Pc >； 0.05）。结论本研究认为，LILRB4可能通过影响黑质纹状体多巴胺能神经元功能、阿尔茨海默病（AD）相关病理、WM微结构改变和星形胶质细胞活化，在PD临床特征调节中发挥重要作用。
Uncovering the Associations of LILRB4 Genotypes With Parkinson's Disease: From Clinical Traits to Potential Pathologies
Background
Leukocyte immunoglobulin-like receptor B4 (LILRB4) has been shown to be associated with susceptibility to neurodegenerative diseases. This study was aimed at investigating the relationships between LILRB4 and the risk of developing PD, as well as its clinical characteristics and pathology.
Method
We analyzed 197 healthy controls and 606 PD patients from the Parkinson's Progression Marker Initiative (PPMI) study. The associations of LILRB4 loci with image data, CSF biomarkers, and clinical scales at baseline were assessed using multiple linear models.
Results
Dopamine transporter (DAT)-SPECT results showed that the striatal binding ratios (SBR) in the right caudate (β = 0.160, 95% CI = 0.076–0.244, Pc = 0.002), right putamen (β = 0.135, 95% CI = 0.057–0.214, Pc = 0.009), anterior right putamen (β = 0.156, 95% CI = 0.073–0.240, Pc = 0.003) and left caudate (β = 0.121, 95% CI = 0.038–0.2050, Pc = 0.048) were positively associated with LILRB4. Meanwhile, LILRB4 was associated with reductions in semantic fluency (β = −2.135, 95% CI = −3.225 to 1.046, Pc = 0.001) and impairments in nigrostriatal white matter (WM) microstructure as assessed by diffusion tensor imaging (DTI) (right rostral of substantia nigra (SN), β = −0.026, 95% CI = −0.030 to 0.013, Pc = 0.002; right middle SN, β = −0.021, 95% CI = −0.033 to 0.009, Pc = 0.012). These associations were more prominent in females (DAT in right caudate, β = 0.246, 95% CI = 0.099–0.392, Pc = 0.013; DTI in right middle of SN, β = −0.025 95% CI = −0.040 to 0.010, Pc = 0.021), but less pronounced in males (DAT in right caudate, p = 0.036, Pc = 0.396; DTI in right rostral of SN, β = −0.025 95% CI = −0.041 to 0.008, Pc = 0.021). Interestingly, in females, we also observed associations between LILRB4 and higher CSF α-synuclein levels (β = 0.177, 95% CI = 0.062–0.292, p = 3.280E−03, Pc = 0.036) and worse cognitive performance (Activity of Daily Living scale, β = −2.073, 95% CI = −3.446 to 0.699, Pc = 0.025; Semantic Fluency test, β = −2.508 95% CI = −4.255 to 0.761, Pc = 0.032). Although our results suggested that dopamine and its metabolites, astrocyte markers, and inflammation-related molecules were associated with LILRB4, these associations disappeared after false discovery rate (FDR) correction (p ≤ 0.05, but Pc > 0.05).
Conclusion
Our study supposes that LILRB4 may play a crucial role in modulating PD clinical characteristics by influencing nigrostriatal dopaminergic neuron function, Alzheimer's disease (AD)-related pathology, WM microstructural alterations, and astrocyte activation.
期刊介绍：
CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.
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