淀粉样β蛋白在阿茨海默病和路易体痴呆中对食欲素A与苍白球血脑屏障渗漏之间关联的潜在作用。

Potential role of Amyloid-β on the association between Orexin-A and blood-brain barrier leakage of globus pallidus in Alzheimer's disease and dementia with lewy bodies.

作者信息

Gan Jinghuan, Xu Ziming, Wen Chen, Wu Hao, Chen Zhichao, Shi Zhihong, Lu Hao, Wang Yajie, Liu Shuai, Ji Yong

机构信息

Department of Neurology, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing, 100050, China.

Center for Biomedical Imaging Research, School of Biomedical Engineering, Tsinghua University, No.30 Shuangqing Road, Haidian District, Beijing, 100084, China.

出版信息

Alzheimers Res Ther. 2025 Jun 2;17(1):128. doi: 10.1186/s13195-025-01770-2.

DOI:10.1186/s13195-025-01770-2

PMID:40457423

Abstract

BACKGROUND

Emerging evidence indicates that globus pallidus (GP) function can be modulated by orexin-A in movement disorders, while its role in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) remains unclear. We have ever found the increased blood-brain barrier (BBB) permeability in GP and plasma orexin-A level were respectively correlated with plasma amyloid-β (Aβ) levels in AD and DLB. However, the interplay among these factors and their underlying mechanisms is poorly understood.

METHODS

In this study, we measured plasma orexin-A, Aβ1-40, and Aβ1-42 levels, along with BBB permeability in GP via dynamic contrast-enhanced MRI, in 20 healthy controls (HC), 25 patients with AD, and 16 patients with DLB from December 2020 to April 2022. Demographic, clinical, and neuropsychological data were collected. The mediation analysis models were used to calculate the mediating effect of Aβ on the associations between orexin-A and BBB permeability in GP (reflected by K or Vp values).

RESULTS

Patients with AD had significantly higher plasma orexin-A than DLB (p = 0.047) and HC (p < 0.001), while DLB showed elevated Aβ1-40 and Aβ1-42 versus AD and HC (all p < 0.05). HC had higher Vp values of right GP than AD (p = 0.037). Patients with AD displayed higher K for left GP and average left-right K than both HC and DLB (all p < 0.05). K and Vp values for GP correlated with MoCA, CDR, HAMD, and NPI scores in patients with AD and DLB, and with plasma orexin-A, Aβ1-40, and Aβ1-42 in HC. After adjusting for confounders, Aβ1-40 (Beta = -0.864, p = 0.021) and Aβ1-42 (Beta = -0.875, p = 0.039) partially mediated the link between orexin-A and K for left GP in HC. Aβ1-40 (Beta = -1.845, p = 0.042) partially mediated the link between orexin-A and K for right GP in DLB. No significant mediation was found in AD or across all participants.

CONCLUSION

This study elucidates the clinical role of BBB permeability in GP in AD and DLB, highlights the partial mediating effect of Aβ on the association between orexin-A and BBB leakage. These findings provide mechanistic insights into BBB dysfunction during aging and neurodegeneration.

摘要

背景

新出现的证据表明，在运动障碍中，食欲素-A可调节苍白球（GP）功能，而其在阿尔茨海默病（AD）和路易体痴呆（DLB）中的作用尚不清楚。我们曾发现，AD和DLB患者中，GP处血脑屏障（BBB）通透性增加以及血浆食欲素-A水平分别与血浆淀粉样β蛋白（Aβ）水平相关。然而，这些因素之间的相互作用及其潜在机制仍知之甚少。

方法

在本研究中，我们于2020年12月至2022年4月期间，测量了20名健康对照者（HC）、25例AD患者和16例DLB患者的血浆食欲素-A、Aβ1-40和Aβ1-42水平，以及通过动态对比增强磁共振成像测量的GP处BBB通透性。收集了人口统计学、临床和神经心理学数据。采用中介分析模型计算Aβ对食欲素-A与GP处BBB通透性（由K或Vp值反映）之间关联的中介作用。

结果

AD患者的血浆食欲素-A显著高于DLB患者（p = 0.047）和HC（p < 0.001），而DLB患者的Aβ1-40和Aβ1-42水平高于AD患者和HC（所有p < 0.05）。HC右侧GP的Vp值高于AD患者（p = 0.037）。AD患者左侧GP的K值以及左右侧平均K值高于HC和DLB（所有p < 0.05）。AD和DLB患者中，GP的K值和Vp值与蒙特利尔认知评估量表（MoCA）、临床痴呆评定量表（CDR）、汉密尔顿抑郁量表（HAMD）和神经精神症状问卷（NPI）评分相关，HC中的这些值与血浆食欲素-A、Aβ1-40和Aβ1-42相关。在调整混杂因素后，Aβ1-40（β = -0.864，p = 0.021）和Aβ1-42（β = -0.875，p = 0.039）部分介导了HC中食欲素-A与左侧GP的K值之间的联系。Aβ1-40（β = -1.845，p = 0.042）部分介导了DLB中食欲素-A与右侧GP的K值之间的联系。在AD患者或所有参与者中未发现显著的中介作用。