{"title":"淀粉样蛋白-β在阿尔茨海默病和伴路易体痴呆患者苍白球血脑屏障渗漏与食欲素- a关系中的潜在作用","authors":"Jinghuan Gan, Ziming Xu, Chen Wen, Hao Wu, Zhichao Chen, Zhihong Shi, Hao Lu, Yajie Wang, Shuai Liu, Yong Ji","doi":"10.1186/s13195-025-01770-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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<sup>trans</sup> or Vp values).</p><p><strong>Results: </strong>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<sup>trans</sup> for left GP and average left-right K<sup>trans</sup> than both HC and DLB (all p < 0.05). K<sup>trans</sup> 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<sup>trans</sup> for left GP in HC. Aβ1-40 (Beta = -1.845, p = 0.042) partially mediated the link between orexin-A and K<sup>trans</sup> for right GP in DLB. No significant mediation was found in AD or across all participants.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"128"},"PeriodicalIF":7.6000,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128392/pdf/","citationCount":"0","resultStr":"{\"title\":\"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.\",\"authors\":\"Jinghuan Gan, Ziming Xu, Chen Wen, Hao Wu, Zhichao Chen, Zhihong Shi, Hao Lu, Yajie Wang, Shuai Liu, Yong Ji\",\"doi\":\"10.1186/s13195-025-01770-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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<sup>trans</sup> or Vp values).</p><p><strong>Results: </strong>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<sup>trans</sup> for left GP and average left-right K<sup>trans</sup> than both HC and DLB (all p < 0.05). K<sup>trans</sup> 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<sup>trans</sup> for left GP in HC. Aβ1-40 (Beta = -1.845, p = 0.042) partially mediated the link between orexin-A and K<sup>trans</sup> for right GP in DLB. No significant mediation was found in AD or across all participants.</p><p><strong>Conclusion: </strong>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. 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引用次数: 0
摘要
背景：越来越多的证据表明，在运动障碍中，白球（GP）功能可以通过食欲素- a调节，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。我们发现GP患者血脑屏障（BBB）通透性升高，AD和DLB患者血浆orexin-A水平分别与血浆淀粉样蛋白-β (Aβ)水平相关。然而，这些因素之间的相互作用及其潜在机制尚不清楚。方法：在这项研究中，我们在2020年12月至2022年4月期间，通过动态对比增强MRI测量了20名健康对照（HC）、25名AD患者和16名DLB患者的血浆食欲素- a、Aβ1-40和Aβ1-42水平，以及GP血脑屏障通透性。收集了人口学、临床和神经心理学数据。采用中介分析模型计算Aβ在GP中orexin-A与血脑屏障通透性之间的中介作用（通过Ktrans或Vp值反映）。结果：AD患者血浆食欲素- a明显高于DLB （p = 0.047）和HC（左GP的p反式和平均左-右Ktrans均高于HC和DLB （GP的p反式和Vp值均与AD和DLB患者MoCA、CDR、HAMD和NPI评分相关），HC患者血浆食欲素- a、Aβ1-40和Aβ1-42相关）。在调整混杂因素后，Aβ1-40 （Beta = -0.864, p = 0.021）和Aβ1-42 （Beta = -0.875, p = 0.039）部分介导了HC左GP orexin-A与Ktrans之间的联系。Aβ1-40 （β = -1.845, p = 0.042）在DLB中部分介导了食欲素- a和Ktrans对右侧GP的联系。在AD或所有参与者中没有发现显著的中介作用。结论：本研究阐明了GP在AD和DLB中血脑屏障通透性的临床作用，强调了Aβ在食欲素a与血脑屏障渗漏之间的部分介导作用。这些发现为衰老和神经退行性变过程中血脑屏障功能障碍提供了机制见解。
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.
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 Ktrans 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 Ktrans for left GP and average left-right Ktrans than both HC and DLB (all p < 0.05). Ktrans 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 Ktrans for left GP in HC. Aβ1-40 (Beta = -1.845, p = 0.042) partially mediated the link between orexin-A and Ktrans 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.
期刊介绍：
Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.
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