理清三级记忆诊所患者中阿尔茨海默病血浆生物标志物与既定生物标志物之间的关系。

Disentangling relationships between Alzheimer's disease plasma biomarkers and established biomarkers in patients of tertiary memory clinics.

作者信息

Bluma Marina, Chiotis Konstantinos, Bucci Marco, Savitcheva Irina, Matton Anna, Kivipelto Miia, Jeromin Andreas, De Santis Giovanni, Di Molfetta Guglielmo, Ashton Nicholas J, Blennow Kaj, Zetterberg Henrik, Nordberg Agneta

机构信息

Center of Alzheimer Research, Division of Clinical Geriatrics, Department of Neurobiology, Karolinska Institutet, Care Sciences and Society, Stockholm, Sweden.

Center of Alzheimer Research, Division of Clinical Geriatrics, Department of Neurobiology, Karolinska Institutet, Care Sciences and Society, Stockholm, Sweden; Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.

出版信息

EBioMedicine. 2025 Feb;112:105504. doi: 10.1016/j.ebiom.2024.105504. Epub 2024 Dec 18.

DOI:10.1016/j.ebiom.2024.105504

PMID:39701863

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11873569/

Abstract

BACKGROUND

Several plasma biomarkers for Alzheimer's disease (AD) have demonstrated diagnostic and analytical robustness. Yet, contradictory results have been obtained regarding their association with standard diagnostic markers of AD. This study aims to investigate the specific relationship between the AD biomarkers currently used in clinical practice and the plasma biomarkers.

METHODS

In a memory clinic cohort, we analysed plasma pTau181, pTau217, pTau231, respectively, GFAP, NfL, CSF pTau181, Aβ-PET scans, and MRI/CT visual read of atrophy. We utilized methods based on multiple linear regression to evaluate the specific associations between clinically used and recently developed plasma biomarkers, while also considering demographic variables such as age and sex.

FINDINGS

Although plasma pTau181, pTau217, pTau231, and GFAP were significantly associated with both Aβ-PET and CSF pTau181, Aβ-PET explained more variance in the levels of these biomarkers. The effect of CSF pTau181 on plasma GFAP and pTau181 was completely attenuated by Aβ-PET, whereas pTau231 and pTau217 were affected by both Aβ-PET and CSF pTau181 levels. Unlike these biomarkers, increased NfL was rather indicative of brain atrophy and older age. Based on the effect sizes, plasma pTau217 emerged as highly effective in distinguishing between A+ and A-, and T+ and T- individuals, with 60% of variance in plasma pTau217 explained by clinical AD biomarkers.

INTERPRETATION

Amyloid burden primarily drives the changes in plasma pTau181, pTau217, pTau231, and GFAP. In contrast to plasma pTau217, a significant portion of variance in plasma pTau181, pTau231, GFAP, NfL remains unexplained by clinical AD biomarkers.

FUNDING

This research is supported by the Swedish Research Council VR: 2017-06086, 2020-4-3018, 2024-2027; Swedish Brain Foundation, Swedish Alzhzeimer Foundation, CIMED Region Stockholm/Karolinska Institutet; the Region Stockholm - Karolinska Institutet regional agreement on medical training and clinical research (ALF), Fondation Recherche sur Alzheimer (France).

摘要

背景

几种用于阿尔茨海默病（AD）的血浆生物标志物已显示出诊断和分析的稳健性。然而，关于它们与AD标准诊断标志物的关联，却得到了相互矛盾的结果。本研究旨在探讨目前临床实践中使用的AD生物标志物与血浆生物标志物之间的具体关系。

方法

在一个记忆门诊队列中，我们分别分析了血浆pTau181、pTau217、pTau231、胶质纤维酸性蛋白（GFAP）、神经丝轻链（NfL）、脑脊液pTau181、淀粉样蛋白正电子发射断层扫描（Aβ-PET）以及磁共振成像/计算机断层扫描（MRI/CT）对萎缩的视觉判读。我们采用基于多元线性回归的方法来评估临床使用的和最近开发的血浆生物标志物之间的具体关联，同时还考虑了年龄和性别等人口统计学变量。

研究结果

尽管血浆pTau181、pTau217、pTau231和GFAP与Aβ-PET及脑脊液pTau181均显著相关，但Aβ-PET解释了这些生物标志物水平中更多的变异。脑脊液pTau181对血浆GFAP和pTau181的影响被Aβ-PET完全减弱，而pTau231和pTau217则受到Aβ-PET和脑脊液pTau181水平的共同影响。与这些生物标志物不同，NfL升高更表明脑萎缩和年龄较大。基于效应量，血浆pTau217在区分A+和A-以及T+和T-个体方面表现出高效性，临床AD生物标志物解释了血浆pTau217中60%的变异。

解读

淀粉样蛋白负荷主要驱动血浆pTau181、pTau217、pTau231和GFAP的变化。与血浆pTau217不同，血浆pTau181、pTau231、GFAP、NfL中相当一部分变异无法由临床AD生物标志物解释。

资金来源

本研究由瑞典研究理事会VR资助：2017 - 06086、2020 - 4 - 3018、2024 - 2027；瑞典脑基金会、瑞典阿尔茨海默病基金会、斯德哥尔摩地区CIMED/卡罗林斯卡学院；斯德哥尔摩地区 - 卡罗林斯卡学院关于医学培训和临床研究的区域协议（ALF）、法国阿尔茨海默病研究基金会。