Department of Pharmacology and Hypoxia-related Disease Research Center, College of Medicine, Inha University, Room 1015, 60th Anniversary Hall, 100, Inha-ro, Nam-gu, Incheon, 22212, South Korea.
Department of Kinesiology, Inha University, Incheon, 22212, South Korea.
Alzheimers Res Ther. 2021 Jan 12;13(1):22. doi: 10.1186/s13195-020-00767-3.
BACKGROUND: Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker cutoffs from immunoassays with low interlaboratory variability in diverse ethnic groups are necessary for their use in clinics and clinical trials. With lack of cutoffs from fully automated immunoassay platforms in diverse races, the aim of this study is to evaluate the clinical utility of CSF AD biomarkers from the Lumipulse fully automated immunoassay based on β-amyloid (Aβ) positron emission tomography (PET) status comparing with these from two manual immunoassays, in Koreans. METHODS: Among 331 Korean participants enrolled from a prospective, 3-year longitudinal observational study of the validation cohort of Korean Brain Aging Study for the Early Diagnosis and Prediction of AD, 139 (29 CN, 58 SCD, 29 MCI, and 23 AD) provided CSF and 271 underwent baseline amyloid PET (n = 128 with overlapping CSF and Aβ-PET, and 143 without CSFs). Three annual cognitive and neuropsychiatric function tests were conducted. Aβ42, Aβ40, total-tau, and phosphorylated-tau were measured by Lumipulse fully automated immunoassay and two manual immunoassays (INNO-BIA AlzBio3, INNOTEST). Clinical utility of CSF biomarker cutoffs, based on 128 participants with Aβ-PET, was evaluated. RESULTS: Cognitive and neuropsychological scores differed significantly among the groups, with descending performance among CN>SCD>MCI>AD. Biomarker levels among immunoassays were strongly intercorrelated. We determined the Aβ-PET status in a subgroup without CSF (n = 143), and then when we applied CSF biomarker cutoffs determined based on the Aβ-PET status, the CSF biomarkers (cutoffs of 642.1 pg/mL for Aβ42, 0.060 for Aβ42/Aβ40, 0.315 for t-tau/Aβ42, and 0.051 for p-tau/Aβ42, respectively) showed good agreement with Aβ-PET (overall AUC ranges of 0.840-0.898). Use of the Aβ-PET-based CSF cutoffs showed excellent diagnostic discrimination between AD and CN (Aβ42, Aβ42/Aβ40, t-tau/Aβ42, and p-tau/Aβ42) with overall AUC ranges of 0.876-0.952. During follow-up, participants with AD-like CSF signature determined by Aβ-PET-based cutoffs from Lumipulse showed rapid progression of cognitive decline in 139 subjects, after adjustment for potential confounders, compared with those with a normal CSF signature. CONCLUSION: CSF AD biomarkers measured by different immunoassay platforms show strong intercorrelated agreement with Aβ-PET in Koreans. The Korean-specific Aβ-PET-based CSF biomarker cutoffs measured by the Lumipulse assay strongly predicts progression of cognitive decline. The clinical utility of CSF biomarkers from fully-automated immunoassay platforms should be evaluated in larger, more diverse cohorts.
背景：在不同种族群体中，具有较低实验室间变异性的阿尔茨海默病（AD）脑脊液（CSF）生物标志物免疫测定的 cutoff 值对于其在临床和临床试验中的应用是必要的。由于缺乏来自不同种族的全自动免疫测定平台的 cutoff 值，本研究旨在评估基于 Lumipulse 全自动免疫测定的 CSF AD 生物标志物的临床效用，该测定基于 β-淀粉样蛋白（Aβ）正电子发射断层扫描（PET）状态，与来自两种手动免疫测定的结果进行比较，对象为韩国人。
方法：在韩国大脑衰老研究的前瞻性、3 年纵向观察性验证队列中，共招募了 331 名韩国参与者，其中 139 名（29 名认知正常、58 名轻度认知障碍、29 名轻度认知障碍和 23 名 AD）提供了 CSF，271 名参与者进行了基线淀粉样蛋白 PET（n=128 名重叠 CSF 和 Aβ-PET，143 名无 CSF）。进行了 3 次年度认知和神经心理学功能测试。通过 Lumipulse 全自动免疫测定和两种手动免疫测定（INNO-BIA AlzBio3、INNOTEST）测量 Aβ42、Aβ40、总 tau 和磷酸化 tau。基于 128 名接受 Aβ-PET 的参与者，评估 CSF 生物标志物 cutoff 值的临床效用。
结果：在各组中，认知和神经心理学评分存在显著差异，表现为 CN>SCD>MCI>AD。免疫测定中的生物标志物水平具有很强的相关性。我们在没有 CSF 的亚组（n=143）中确定了 Aβ-PET 状态，然后应用基于 Aβ-PET 状态的 CSF 生物标志物 cutoff 值时，CSF 生物标志物（Aβ42 的 cutoff 值为 642.1 pg/mL，Aβ42/Aβ40 的 cutoff 值为 0.060，t-tau/Aβ42 的 cutoff 值为 0.315，p-tau/Aβ42 的 cutoff 值为 0.051）与 Aβ-PET 具有良好的一致性（整体 AUC 范围为 0.840-0.898）。使用基于 Aβ-PET 的 CSF cutoff 值在 AD 和 CN 之间表现出极好的诊断区分（Aβ42、Aβ42/Aβ40、t-tau/Aβ42 和 p-tau/Aβ42），整体 AUC 范围为 0.876-0.952。在随访期间，与具有正常 CSF 特征的参与者相比，在 139 名参与者中，基于 Lumipulse 基于 Aβ-PET 的 cutoff 值确定具有 AD 样 CSF 特征的参与者在调整了潜在混杂因素后，认知能力下降的进展更快。
结论：在韩国人中，不同免疫测定平台测量的 CSF AD 生物标志物与 Aβ-PET 具有很强的相关性。基于 Lumipulse 测定的韩国特异性 Aβ-PET 基于 CSF 生物标志物 cutoff 值强烈预测认知下降的进展。应在更大、更多样化的队列中评估全自动免疫测定平台的 CSF 生物标志物的临床效用。
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