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验证 LUMIPULSE 自动化免疫分析系统在脑脊液中核心 AD 生物标志物测量中的应用。

Validation of the LUMIPULSE automated immunoassay for the measurement of core AD biomarkers in cerebrospinal fluid.

机构信息

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

出版信息

Clin Chem Lab Med. 2021 Nov 15;60(2):207-219. doi: 10.1515/cclm-2021-0651. Print 2022 Jan 27.

DOI:10.1515/cclm-2021-0651

PMID:34773730

Abstract

OBJECTIVES

The core cerebrospinal fluid (CSF) biomarkers; total tau (tTau), phospho-tau (pTau), amyloid β 1-42 (Aβ 1-42), and the Aβ 1-42/Aβ 1-40 ratio have transformed Alzheimer's disease (AD) research and are today increasingly used in clinical routine laboratories as diagnostic tools. Fully automated immunoassay instruments with ready-to-use assay kits and calibrators has simplified their analysis and improved reproducibility of measurements. We evaluated the analytical performance of the fully automated immunoassay instrument LUMIPULSE G (Fujirebio) for measurement of the four core AD CSF biomarkers and determined cutpoints for AD diagnosis.

METHODS

Comparison of the LUMIPULSE G assays was performed with the established INNOTEST ELISAs (Fujirebio) for hTau Ag, pTau 181, β-amyloid 1-42, and with V-PLEX Plus Aβ Peptide Panel 1 (6E10) (Meso Scale Discovery) for Aβ 1-42/Aβ 1-40, as well as with a LC-MS reference method for Aβ 1-42. Intra- and inter-laboratory reproducibility was evaluated for all assays. Clinical cutpoints for Aβ 1-42, tTau, and pTau was determined by analysis of three cohorts of clinically diagnosed patients, comprising 651 CSF samples. For the Aβ 1-42/Aβ 1-40 ratio, the cutpoint was determined by mixture model analysis of 2,782 CSF samples.

RESULTS

The LUMIPULSE G assays showed strong correlation to all other immunoassays (r>0.93 for all assays). The repeatability (intra-laboratory) CVs ranged between 2.0 and 5.6%, with the highest variation observed for β-amyloid 1-40. The reproducibility (inter-laboratory) CVs ranged between 2.1 and 6.5%, with the highest variation observed for β-amyloid 1-42. The clinical cutpoints for AD were determined to be 409 ng/L for total tau, 50.2 ng/L for pTau 181, 526 ng/L for β-amyloid 1-42, and 0.072 for the Aβ 1-42/Aβ 1-40 ratio.

CONCLUSIONS

Our results suggest that the LUMIPULSE G assays for the CSF AD biomarkers are fit for purpose in clinical laboratory practice. Further, they corroborate earlier presented reference limits for the biomarkers.

摘要

目的

核心脑脊髓液（CSF）生物标志物；总 tau（tTau）、磷酸化 tau（pTau）、淀粉样β 1-42（Aβ 1-42）和 Aβ 1-42/Aβ 1-40 比值已经改变了阿尔茨海默病（AD）的研究，并且今天越来越多地作为诊断工具在临床常规实验室中使用。具有即用型检测试剂盒和校准品的全自动免疫分析仪器简化了它们的分析，并提高了测量的可重复性。我们评估了全自动免疫分析仪器 LUMIPULSE G（富士瑞必欧）用于测量四个核心 AD CSF 生物标志物的分析性能，并确定了 AD 诊断的切点。

方法

比较了 LUMIPULSE G 检测与 INNOTEST ELISA（富士瑞必欧）用于 hTau Ag、pTau 181、β-淀粉样蛋白 1-42 的检测，以及与 V-PLEX Plus Aβ 肽谱 1（6E10）（Meso Scale Discovery）用于 Aβ 1-42/Aβ 1-40 的检测，以及与 LC-MS 参考方法用于 Aβ 1-42 的检测。评估了所有检测的室内和室间重复性。通过分析由 651 份 CSF 样本组成的三个临床诊断患者队列，确定了 Aβ 1-42、tTau 和 pTau 的临床切点。对于 Aβ 1-42/Aβ 1-40 比值，通过 2782 份 CSF 样本的混合模型分析确定了切点。

结果

LUMIPULSE G 检测与所有其他免疫检测具有很强的相关性（所有检测的相关性>0.93）。重复性（室内）CV 范围为 2.0%至 5.6%，β-淀粉样蛋白 1-40 的变异最大。重现性（室间）CV 范围为 2.1%至 6.5%，β-淀粉样蛋白 1-42 的变异最大。AD 的临床切点确定为总 tau 409ng/L、pTau 181 50.2ng/L、β-淀粉样蛋白 1-42 526ng/L 和 Aβ 1-42/Aβ 1-40 比值 0.072。