轻度认知障碍患者的血液生物标志物：分析物与向阿尔茨海默病痴呆进展的关系。

Blood biomarkers in mild cognitive impairment patients: Relationship between analytes and progression to Alzheimer disease dementia.

机构信息

Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.

Center for Informatics and Systems, Department of Informatics Engineering, University of Coimbra, Coimbra, Portugal.

出版信息

Eur J Neurol. 2023 Jun;30(6):1565-1573. doi: 10.1111/ene.15762. Epub 2023 Mar 20.

DOI:10.1111/ene.15762

PMID:36880887

Abstract

BACKGROUND AND PURPOSE

Blood-based biomarkers are promising tools for the diagnosis of Alzheimer disease (AD) at prodromal stages (mild cognitive impairment [MCI]) and are hoped to be implemented as screening tools for patients with cognitive complaints. In this work, we evaluated the potential of peripheral neurological biomarkers to predict progression to AD dementia and the relation between blood and cerebrospinal fluid (CSF) AD markers in MCI patients referred from a general neurological department.

METHODS

A group of 106 MCI patients followed at the Neurology Department of Coimbra University Hospital was included. Data regarding baseline neuropsychological evaluation, CSF levels of amyloid β 42 (Aβ42), Aβ40, total tau (t-Tau), and phosphorylated tau 181 (p-Tau181) were available for all the patients. Aβ42, Aβ40, t-Tau, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) levels were determined in baseline stored serum and plasma samples by commercial SiMoA (Single Molecule Array) assays. Progression from MCI to AD dementia was assessed at follow-up (mean = 5.8 ± 3.4 years).

RESULTS

At baseline, blood markers NfL, GFAP, and p-Tau181 were significantly increased in patients who progressed to AD at follow-up (p < 0.001). In contrast, plasma Aβ42/40 ratio and t-Tau showed no significant differences between groups. NfL, GFAP, and p-Tau181 demonstrated good diagnostic accuracy to identify progression to AD dementia (area under the curve [AUC] = 0.81, 0.80, and 0.76, respectively), which improved when combined (AUC = 0.89). GFAP and p-Tau181 were correlated with CSF Aβ42. Association of p-Tau181 with NfL was mediated by GFAP, with a significant indirect association of 88% of the total effect.

CONCLUSIONS

Our findings highlight the potential of combining blood-based GFAP, NfL, and p-Tau181 to be applied as a prognostic tool in MCI.

摘要

背景与目的

基于血液的生物标志物是在前驱期（轻度认知障碍[MCI]）诊断阿尔茨海默病（AD）的有前途的工具，有望作为有认知主诉的患者的筛查工具。在这项工作中，我们评估了外周神经生物标志物预测进展为 AD 痴呆的潜力，以及 MCI 患者从一般神经科转介时血液和脑脊液（CSF）AD 标志物之间的关系。

方法

纳入了一组在科英布拉大学医院神经内科就诊的 106 名 MCI 患者。所有患者均有基线神经心理学评估、CSF 中淀粉样蛋白β 42（Aβ42）、Aβ40、总 tau（t-Tau）和磷酸化 tau 181（p-Tau181）水平的数据。通过商业 SiMoA（单分子阵列）测定，在基线储存的血清和血浆样本中测定 Aβ42、Aβ40、t-Tau、p-Tau181、神经胶质纤维酸性蛋白（GFAP）和神经丝轻链（NfL）的水平。在随访时（平均=5.8±3.4 年）评估从 MCI 进展为 AD 痴呆的情况。

结果

在基线时，与随访时进展为 AD 的患者相比，血液标志物 NfL、GFAP 和 p-Tau181 显著升高（p<0.001）。相比之下，血浆 Aβ42/40 比值和 t-Tau 在组间无显著差异。NfL、GFAP 和 p-Tau181 对识别向 AD 痴呆进展具有良好的诊断准确性（曲线下面积[AUC]分别为 0.81、0.80 和 0.76），当联合使用时（AUC=0.89）则有所提高。GFAP 和 p-Tau181 与 CSF Aβ42 相关。p-Tau181 与 NfL 的关联由 GFAP 介导，总效应的 88%为显著间接关联。