阿尔茨海默病相关血液学标志物研究进展

doi:10.3969/j.issn.1673-8640.2020.04.019

摘要/Abstract

摘要：

阿尔茨海默病（AD）是一种中枢神经系统退行性疾病,主要临床表现为记忆、认知障碍以及后期的人格和行为改变等。有很多血液学指标和AD密切相关,如蛋白质、基因突变、微小RNA（miRNA）等,或可用于预测AD发生风险、反映疾病阶段及支持AD诊断。血液学标志物的检测简便、易行,因此,筛选理想的AD相关血液学标志物有利于AD的筛查与治疗。文章总结了AD相关血液学标志物的研究现状,并讨论其应用于临床的可能性和局限性。

关键词: 血液学标志物, 阿尔茨海默病, 筛查, 诊断

Abstract:

Alzheimer's disease（AD）is a degenerative disease of the central nervous system with clinical manifestations of memory impairment,cognitive impairment,later personality and behavioral changes. Recently,studies have shown that many blood markers are closely related to AD,like protein,gene mutation,microRNA（miRNA）,which may play a certain role in predicting the risk of AD,reflecting the stage of AD and supporting the diagnosis of AD. In addition,the determination method of blood markers is simple and easy,therefore screening ideal AD-related blood markers is beneficial to the screening and treatment of AD. In this review,the latest research status of AD-related blood markers is summarized,and the possibility and limitation of its clinical application are discussed.

Key words: Blood marker, Alzheimer's disease, Screening, Diagnosis

中图分类号:

R446.1

陈小童, 林勇. 阿尔茨海默病相关血液学标志物研究进展[J]. 检验医学, 2020, 35(4): 374-379.

CHEN Xiaotong, LIN Yong. Progressive research of Alzheimer's disease-related blood markers[J]. Laboratory Medicine, 2020, 35(4): 374-379.

参考文献 50.

1.	SUGINO H,WATANABE A,AMADA N,et al.Global trends in alzheimer disease clinical development:increasing the probability of success[J]. Clin Ther,2015,37(8):1632-1642.
2.	FRICKER M,TOLKOVSKY A M,BORUTAITE V,et al.Neuronal cell death[J]. Physiol Rev,2018,98(2):813-880.
3.	DUBOIS B,FELDMAN H H,JACOVA C,et al.Research criteria for the diagnosis of Alzheimer's disease:revising the NINCDS-ADRDA criteria[J]. Lancet Neurol,2007,6(8):734-746.
4.	DUBOIS B,FELDMAN H H,JACOVA C,et al.Advancing research diagnostic criteria for Alzheimer's disease:the IWG-2 criteria[J]. Lancet Neurol,2014,13(6):614-629.
5.	JACK C R Jr,BENNETT D A,BLENNOW K,et al. NIA-AA research framework:toward a biological definition of Alzheimer's disease[J]. Alzheimers Dement,2018,14(4):535-562.
6.	JAGUST W.Imaging the evolution and pathophysiology of Alzheimer disease[J]. Nat Rev Neurosci,2018,19(11):687-700.
7.	SCHELTENS P,BLENNOW K,BRETELER M M,et al.Alzheimer's disease[J]. Lancet,2016,388(10043):505-517.
8.	WANG J,GU B J,MASTERS C L,et al.A systemic view of Alzheimer disease-insights from amyloid-β metabolism beyond the brain[J]. Nat Rev Neurol,2017,13(10):612-623.
9.	VERBERK I M W,SLOT R E,VERFAILLIE S C J,et al. Plasma amyloid as prescreener for the earliest Alzheimer pathological changes[J]. Ann Neurol,2018,84(5):648-658.
10.	NAKAMURA A,KANEKO N,VILLEMAGNE V L,et al.High performance plasma amyloid-β biomarkers for Alzheimer's disease[J]. Nature,2018,554(7691):249-254.
11.	NABERS A,PERNA L,LANGE J,et al.Amyloid blood biomarker detects Alzheimer's disease[J]. EMBO Mol Med,2018,10(5).
12.	VARMA V R,OOMMEN A M,VARMA S,et al.Brain and blood metabolite signatures of pathology and progression in Alzheimer disease:a targeted metabolomics study[J]. PLoS Med,2018,15(1):e1002482.
13.	SHEN Y,WANG H,SUN Q,et al.Increased plasma beta-secretase 1 may predict conversion to Alzheimer's disease dementia in individuals with mild cognitive impairment[J]. Biol Psych,2018,83(5):447-455.
14.	PEÑA-BAUTISTA C,VIGOR C,GALANO J M,et al. Plasma lipid peroxidation biomarkers for early and non-invasive Alzheimer disease detection[J]. Free Radic Biol Med,2018,124:388-394.
15.	TROUGAKOS I P.The molecular chaperone apolipoprotein J/clusterin as a sensor of oxidative stress:implications in therapeutic approaches-a mini-review[J]. Gerontology,2013,59(6):514-523.
16.	PERROTTE M,LE PAGE A,FOURNET M,et al.Blood-based redox-signature and their association to the cognitive scores in MCI and Alzheimer's disease patients[J]. Free Radic Biol Med,2019,130:499-511.
17.	PADURARIU M,CIOBICA A,HRITCU L,et al.Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer's disease[J]. Neurosci Lett,2010,469(1):6-10.
18.	HEPPNER F L,RANSOHOFF R M,BECHER B.Immune attack:the role of inflammation in Alzheimer disease[J]. Nat Rev Neurosci,2015,16(6):358-372.
19.	HENEKA M T,GOLENBOCK D T,LATZ E.Innate immunity in Alzheimer's disease[J]. Nat Immunol,2015,16(3):229-236.
20.	FORLENZA O V,DINIZ B S,TALIB L L,et al.Increased serum IL-1beta level in Alzheimer's disease and mild cognitive impairment[J]. Dement Geriatr Cogn Disord,2009,28(6):507-512.
21.	HARDY J,SELKOE D J.The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics[J]. Science,2002,297(5580):353-356.
22.	HEILIG E A,XIA W,SHEN J,et al.A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of gamma-secretase activity[J]. J Biol Chem,2010,285(29):22350-22359.
23.	VEUGELEN S,SAITO T,SAIDO T C,et al.Familial Alzheimer's disease mutations in presenilin generate amyloidogenic Aβ peptide seeds[J]. Neuron,2016,90(2):410-416.
24.	WANG Y,MANDELKOW E.Tau in physiology and pathology[J]. Nat Rev Neurosci,2016,17(1):5-21.
25.	MIELKE M M,HAGEN C E,XU J,et al.Plasma phospho-tau181 increases with Alzheimer's disease clinical severity and is associated with tau- and amyloid-positron emission tomography[J]. Alzheimers Dement,2018,14(8):989-997.
26.	OLSSON B,LAUTNER R,ANDREASSON U,et al.CSF and blood biomarkers for the diagnosis of Alzheimer's disease:a systematic review and meta-analysis[J]. Lancet Neurol,2016,15(7):673-684.
27.	CORSI M M,LICASTRO F,PORCELLINI E,et al.Reduced plasma levels of P-selectin and L-selectin in a pilot study from Alzheimer disease:relationship with neuro-degeneration[J]. Biogerontology,2011,12(5):451-454.
28.	丁冰玉,林萍,李擎天. 植物血凝素刺激外周血单个核细胞Th1/Th2细胞因子分泌对阿尔茨海默病的诊断价值[J]. 检验医学,2018,33(4):290-294.
29.	D'ANNA L,ABU-RUMEILEH S,FABRIS M,et al. Serum interleukin-10 levels correlate with cerebrospinal fluid amyloid beta deposition in Alzheimer disease patients[J]. Neurodegener Dis,2017,17(4-5):227-234.
30.	TOGO T,AKIYAMA H,KONDO H,et al.Expression of CD40 in the brain of Alzheimer's disease and other neurological diseases[J]. Brain Res,2000,885(1):117-121.
31.	MOCALI A,CEDROLA S,DELLA MALVA N,et al.Increased plasma levels of soluble CD40,together with the decrease of TGF beta 1,as possible differential markers of Alzheimer disease[J]. Exp Gerontol,2004,39(10):1555-1561.
32.	BROSSERON F,KRAUTHAUSEN M,KUMMER M,et al.Body fluid cytokine levels in mild cognitive impairment and Alzheimer's disease:a comparative overview[J]. Mol Neurobiol,2014,50(2):534-544.
33.	TRAMUTOLA A,ABATE G,LANZILLOTTA C,et al.Protein nitration profile of CD3+:lymphocytes from Alzheimer disease patients:novel hints on immunosenescence and biomarker detection[J]. Free Radic Biol Med,2018,129:430-439.
34.	BHATNAGAR S,CHERTKOW H,SCHIPPER H M,et al.Increased microRNA-34c abundance in Alzheimer's disease circulating blood plasma[J]. Front Mol Neurosci,2014,7:2.
35.	AYBEK H,ERCAN F,ASLAN D,et al.Determination of malondialdehyde,reduced glutathione levels and APOE4 allele frequency in late-onset Alzheimer's disease in Denizli,Turkey[J]. Clin Biochem,2007,40(3-4):172-176.
36.	FIANDACA M S,KAPOGIANNIS D,MAPSTONE M,et al.Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes:a case-control study[J]. Alzheimers Dement,2015,11(6):600-607.e1.
37.	HARA N,KIKUCHI M,MIYASHITA A,et al.Serum microRNA miR-501-3p as a potential biomarker related to the progression of Alzheimer's disease[J]. Acta Neuropathol Commun,2017,5(1):10.
38.	YANG T T,LIU C G,GAO S C,et al.The serum exosome derived microRNA-135a,-193b,and -384 were potential Alzheimer's disease biomarkers[J]. Biomed Environ Sci,2018,31(2):87-96.
39.	HONG S,BEJA-GLASSER V FNFONOYIM B M,et al.Complement and microglia mediate early synapse loss in Alzheimer mouse models[J]. Science,2016,352(6286):712-716.
40.	ZHOU X,CHEN Y,MOK K Y,et al.Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer's disease pathogenesis[J]. Proc Natl Acad Sci U S A,2018,115(8):1697-1706.
41.	WENDELN A C,DEGENHARDT K,KAURANI L,et al.Innate immune memory in the brain shapes neurological disease hallmarks[J]. Nature,2018,556(7701):332-338.
42.	SNYDER H M,CARRILLO M C,GRODSTEIN F,et al.Developing novel blood-based biomarkers for Alzheimer's disease[J]. Alzheimers Dement,2014,10(1):109-114.
43.	FIORINI M,BONGIANNI M,BENEDETTI M D,et al.Reappraisal of Aβ40 and Aβ42 peptides measurements in cerebrospinal fluid of patients with Alzheimer's disease[J]. J Alzheimers Dis,2018,66(1):219-227.
44.	SWEENEY M D,SAGARE A P,ZLOKOVIC B V.Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders[J]. Nat Rev Neurol,2018,14(3):133-150.
45.	HENRIKSEN K,O'BRYANT S E,HAMPEL H,et al. The future of blood-based biomarkers for Alzheimer's disease[J]. Alzheimers Dement,2014,10(1):115-131.
46.	THAMBISETTY M,LOVESTONE S.Blood-based biomarkers of Alzheimer's disease:challenging but feasible[J]. Biomark Med,2010,4(1):65-79.
47.	O'BRYANT S E,EDWARDS M,JOHNSON L,et al. A blood screening test for Alzheimer's disease[J]. Alzheimer's Dementia(Amst),2016,3:83-90.
48.	WOOD H.Alzheimer disease:localized proteomics distinguishes AD subtypes[J]. Nat Rev Neurol,2017,13(5):260.
49.	ROSENBERG R N,LAMBRACHT-WASHINGTON D,YU G,et al.Genomics of Alzheimer disease:a review[J]. JAMA Neurol,2016,73(7):867-874.
50.	XIANG Y,LAM S M,SHUI G.What can lipidomics tell us about the pathogenesis of Alzheimer disease?[J]. Biol Chem,2015,396(12):1281-1291.

[1]	王慧英, 汤昱, 董利利, 王静. 肺炎支原体RNA检测用于肺炎患儿疾病诊断和疗效监测[J]. 检验医学, 2023, 38(9): 865-869.
[2]	孙信林, 叶星明, 李倩, 赵丽君. 支气管镜检查联合痰TB-RNA、血清TB-SA检测诊断菌阴肺结核[J]. 检验医学, 2023, 38(9): 870-873.
[3]	冯暄, 张庆华, 王兴, 何静, 梁济慈, 贾春暘, 蔺朋武, 朱韶华, 郝胜菊. 扩展性无创产前筛查技术在染色体拷贝数变异检测中的临床应用效果评价[J]. 检验医学, 2023, 38(8): 730-737.
[4]	韩雪, 闻柳, 宛杨. 唐氏筛查临界或高风险孕妇羊水染色体核型和基因组拷贝数变异结果分析[J]. 检验医学, 2023, 38(6): 548-552.
[5]	张楚, 王建红, 李瑞, 肖艳华, 王恒, 张品肖, 徐凝馨, 夏半半. 5 696例孕妇拓展性无创产前基因检测结果[J]. 检验医学, 2023, 38(6): 553-558.
[6]	张敏, 王彬宇, 迟伟群, 刘禹. 外泌体非编码RNA作为疾病诊断生物标志物的研究进展[J]. 检验医学, 2023, 38(6): 594-598.
[7]	张国良, 刘鷖雯, 何怡青, 许静, 杨翠霞, 高锋, 刘华. 血清HYAL1、HA在结直肠癌辅助诊断和疗效监测中的价值[J]. 检验医学, 2023, 38(4): 313-319.
[8]	陈慧, 陈光辉, 梁映亮, 王万党, 尹志军. 基于GEO数据库筛选妊娠糖尿病关键基因及其诊断价值分析[J]. 检验医学, 2023, 38(3): 276-281.
[9]	郁婷婷, 王剑. 罕见病诊疗进展与挑战[J]. 检验医学, 2023, 38(2): 103-105.
[10]	蔡潇艺, 娄丹, 杨兴鸽, 王剑. 15例疑似假肥大性肌营养不良患儿遗传学分析[J]. 检验医学, 2023, 38(2): 106-111.
[11]	王东江, 郭建. 侵袭性真菌感染实验室诊断研究进展[J]. 检验医学, 2023, 38(2): 179-185.
[12]	池锐彬, 周卉芬, 叶铨秋, 李超锋. NGS快速诊断疑难鹦鹉热衣原体重症肺炎合并脓毒症休克1例报道[J]. 检验医学, 2023, 38(12): 1211-1212.
[13]	杨丹平, 王宏, 王灿, 陈卫, 杨爱平. 新型冠状病毒抗原检测诊断效能和临床应用评价[J]. 检验医学, 2023, 38(1): 28-31.
[14]	姚晓宾, 许青霞, 王桢, 魏丹丹, 郑培明, 李刚. 新型冠状病毒区域筛查实验室结果上报经验分享[J]. 检验医学, 2023, 38(1): 76-77.
[15]	温静, 史瑞, 谢佳, 刘锋, 李光, 任婧婧, 雷小茹, 郭晓波, 宋艳萍. 宏基因组二代测序在粒细胞缺乏伴发热患者病原菌检测中的价值[J]. 检验医学, 2022, 37(9): 855-859.