Zhou Yuting, Li Yaqing, He Qiqing, Kong Zhen, Yu Ran, Yu Xin, Xie Anmu
Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China.
Cerebral Vascular Disease Institute, Affiliated Hospital of Qingdao University, Qingdao, China.
CNS Neurosci Ther. 2025 Jul;31(7):e70522. doi: 10.1111/cns.70522.
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.
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.
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, P = 0.002), right putamen (β = 0.135, 95% CI = 0.057-0.214, P = 0.009), anterior right putamen (β = 0.156, 95% CI = 0.073-0.240, P = 0.003) and left caudate (β = 0.121, 95% CI = 0.038-0.2050, P = 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, P = 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, P = 0.002; right middle SN, β = -0.021, 95% CI = -0.033 to 0.009, P = 0.012). These associations were more prominent in females (DAT in right caudate, β = 0.246, 95% CI = 0.099-0.392, P = 0.013; DTI in right middle of SN, β = -0.025 95% CI = -0.040 to 0.010, P = 0.021), but less pronounced in males (DAT in right caudate, p = 0.036, P = 0.396; DTI in right rostral of SN, β = -0.025 95% CI = -0.041 to 0.008, P = 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, P = 0.036) and worse cognitive performance (Activity of Daily Living scale, β = -2.073, 95% CI = -3.446 to 0.699, P = 0.025; Semantic Fluency test, β = -2.508 95% CI = -4.255 to 0.761, P = 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 P > 0.05).
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.
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有关。本研究旨在探讨LILRB4与帕金森病（PD）发病风险之间的关系，以及其临床特征和病理学。
我们分析了帕金森病进展标记物倡议（PPMI）研究中的197名健康对照者和606名PD患者。使用多元线性模型评估LILRB4基因座与基线时的图像数据、脑脊液生物标志物和临床量表之间的关联。
多巴胺转运体（DAT）-单光子发射计算机断层扫描（SPECT）结果显示，右侧尾状核（β = 0.160，95%可信区间[CI] = 0.076 - 0.244，P = 0.002）、右侧壳核（β = 0.135，95% CI = 0.057 - 0.214，P = 0.009）、右侧壳核前部（β = 0.156，95% CI = 0.073 - 0.240，P = 0.003）和左侧尾状核（β = 0.121，95% CI = 0.038 - 0.2050，P = 0.048）的纹状体结合率（SBR）与LILRB4呈正相关。同时，LILRB4与语义流畅性降低（β = -2.135，95% CI = -3.225至1.046，P = 0.001）以及通过扩散张量成像（DTI）评估的黑质纹状体白质（WM）微观结构损伤有关（右侧黑质（SN）头端，β = -0.026，95% CI = -0.030至0.013，P = 0.002；右侧SN中部，β = -0.021，95% CI = -0.033至0.009，P = 0.012）。这些关联在女性中更为显著（右侧尾状核的DAT，β = 0.246，95% CI = 0.099 - 0.392，P = 0.013；右侧SN中部的DTI，β = -0.025，95% CI = -0.040至0.010，P = 0.021），而在男性中则不太明显（右侧尾状核的DAT，P = 0.036，P = 0.396；右侧SN头端的DTI，β = -0.025，95% CI = -0.041至0.008，P = 0.021）。有趣的是，在女性中，我们还观察到LILRB4与脑脊液α-突触核蛋白水平升高（β = 0.177，95% CI = 0.062 - 0.292，P = 3.280E - 03，P = 0.036）以及较差的认知表现有关（日常生活活动量表，β = -2.073，95% CI = -3.446至0.699，P = 0.025；语义流畅性测试，β = -2.508，95% CI = -4.255至0.761，P = 0.032）。尽管我们的结果表明多巴胺及其代谢产物、星形胶质细胞标志物和炎症相关分子与LILRB4有关，但在错误发现率（FDR）校正后这些关联消失（P≤0.05，但P>0.05）。
我们的研究推测，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）相关病理学、WM微观结构改变和星形胶质细胞激活，在调节PD临床特征中发挥关键作用。
