中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (8): 2373-2381.doi: 10.4103/NRR.NRR-D-23-01983

• 原著:退行性病与再生 • 上一篇    下一篇

长期保存的血浆样品中神经退行性疾病生物标志物浓度和诊断效能可受到影响

  

  • 出版日期:2025-08-15 发布日期:2024-12-14

Storage time affects the level and diagnostic efficacy of plasma biomarkers for neurodegenerative diseases

Lifang Zhao1, 2, #, Mingkai Zhang3, #, Qimeng Li1, 2, Xuemin Wang1, 2, Jie Lu4, 5, 6, *, Ying Han3, 7, 8, 9, 10, *, Yanning Cai1, 2, 6, 11, *   

  1. 1 Department of Clinical Biobank, Xuanwu Hospital, Capital Medical University, Beijing, China;  2 Beijing Geriatric Medical Research Center, Beijing, China;  3 Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China;  4 Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China;  5 Beijing Key Laboratory of Magnetic Resonance Imaging and Brain Informatics, Beijing, China;  6 Key Laboratory of Neurodegenerative diseases, Ministry of Education, Beijing, China;  7 School of Biomedical Engineering, Hainan University, Haikou, Hainan Province, China;  8 Center of Alzheimer’s Disease, Beijing Institute for Brain Disorders, Beijing, China;  9 National Clinical Research Center for Geriatric Diseases, Beijing, China;  10Institute of Biomedical Engineering, Shenzhen Bay Laboratory, Gaoke Innovation Center, Shenzhen, Guangdong Province, China;  11Department of Neurobiology, Xuanwu Hospital, Capital Medical University, Beijing, China
  • Online:2025-08-15 Published:2024-12-14
  • Contact: Jie Lu, MD, PhD, imaginglu@hotmail.com; Ying Han, MD, PhD, hanying@xwh.ccmu.edu.cn; Yanning Cai, Ph.D, yanningcaimailbox@163.com.
  • Supported by:
    The study was supported by the National Key Research & Development Program of China, Nos. 2021YFC2501205 (to YC), 2022YFC24069004 (to JL), the STI2030-Major Project, Nos. 2021ZD0201101 (to YC), 2022ZD0211800 (to YH); the National Natural Science Foundation of China (Major International Joint Research Project), No. 82020108013 (to YH), the Sino-German Center for Research Promotion, No. M-0759 (to YH); and a grant from Beijing Municipal Science & Technology Commission (Beijing Brain Initiative), No. Z201100005520018 (to JL).

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摘要：

多种血浆生物标志物，如淀粉样蛋白β（Aβ）、tau、神经丝轻链蛋白和胶质纤维酸性蛋白广泛用于阿尔茨海默病等神经退行性疾病的诊断。然而，对储存在-80℃下的血浆样品中这些生物标志物的长期稳定性尚知之甚少。为了解大型队列研究储存时间如何影响这些生物标志物的诊断准确性，试验从SILCODE实验中纳入229例认知正常者（CU）（包括健康对照组和主观认知能力下降）和99名认知受损者（CI）（包括轻度认知障碍和痴呆）的血浆样本，这些样本在-80℃下存储1个月至6年。结果显示，所有受试者血浆中Aβ42、Aβ40、神经丝轻链蛋白和胶质纤维酸性蛋白的浓度与存储时间没有显著相关性，而总tau浓度与存储时间呈显著负相关。有趣的是，在认知正常组中血浆总蛋白浓度和磷酸化tau181浓度与存储时间呈负相关，但这一现象未出现在认知受损人群。因此，血浆磷酸化tau181以及磷酸化tau181/tau的诊断能力可能会受到样本储存时间的影响，使用长期存储血浆样本中这些血浆生物标志物识别阿尔茨海默病等神经退行性疾病潜在患者时需要谨慎，且队列研究需要充分考虑存储时间这一变量对结果的影响。

https://orcid.org/0000-0003-0425-3921 (Jie Lu); https://orcid.org/0000-0003-0377-7424 (Ying Han); 

https://orcid.org/0000-0003-0879-9809 (Yanning Cai)

关键词: 储存时间,  诊断能力,  血浆生物标志物,  淀粉样蛋白β,  tau,  神经丝轻链蛋白,  胶质纤维酸性蛋白,  阿尔茨海默病,  神经退行性变,  单分子阵列

Abstract: Several promising plasma biomarker proteins, such as amyloid-β (Aβ), tau, neurofilament light chain, and glial fibrillary acidic protein, are widely used for the diagnosis of neurodegenerative diseases. However, little is known about the long-term stability of these biomarker proteins in plasma samples stored at –80°C. We aimed to explore how storage time would affect the diagnostic accuracy of these biomarkers using a large cohort. Plasma samples from 229 cognitively unimpaired individuals, encompassing healthy controls and those experiencing subjective cognitive decline, as well as 99 patients with cognitive impairment, comprising those with mild cognitive impairment and dementia, were acquired from the Sino Longitudinal Study on Cognitive Decline project. These samples were stored at –80°C for up to 6 years before being used in this study. Our results showed that plasma levels of Aβ42, Aβ40, neurofilament light chain, and glial fibrillary acidic protein were not significantly correlated with sample storage time. However, the level of total tau showed a negative correlation with sample storage time. Notably, in individuals without cognitive impairment, plasma levels of total protein and tau phosphorylated protein threonine 181 (p-tau181) also showed a negative correlation with sample storage time. This was not observed in individuals with cognitive impairment. Consequently, we speculate that the diagnostic accuracy of plasma p-tau181 and the p-tau181 to total tau ratio may be influenced by sample storage time. Therefore, caution is advised when using these plasma biomarkers for the identification of neurodegenerative diseases, such as Alzheimer’s disease. Furthermore, in cohort studies, it is important to consider the impact of storage time on the overall results.

Key words: Alzheimer’s disease,  amyloid-β,  diagnostic ability,  glial fibrillary acidic protein,  neurodegeneration,  neurofilament light chain,   plasma biomarkers,  single molecule array,  storage time, tau