阿尔茨海默病血液标志物与淀粉样蛋白PET诊断的相关性研究
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摘要
目的:探讨阿尔茨海默病(Alzheimer’s disease, AD)血液标志物Aβ42、P-tau与淀粉样蛋白PET诊断相关性。方法:纳入我院做了以~(11)C-PiB示踪的正电子发射断层显像(positron emission tomography,PET)检查的患者,包括PET阳性患者30例,PET阴性患者18例。另从我院体检中心选入认知正常者30例。收集患者临床诊断、年龄、性别、文化程度、APOE基因型信息,测量患者血液Aβ42和P-tau浓度。分析各组间血液Aβ42、P-tau和Aβ42/P-tau的差异,对各指标进行年龄相关性分析。结果:PET阳性患者与PET阴性患者血液Aβ42、P-tau、Aβ42/P-tau无显著性差异,临床诊断的AD患者血液Aβ42、P-tau浓度显著高于认知正常者(P<0.05)。在APOEε4携带者中,PET阳性患者血液Aβ42、P-tau和Aβ42/P-tau低于PET阴性患者;在APOEε4非携带者中,PET阳性患者血液Aβ42和P-tau浓度高于PET阴性患者,Aβ42/P-tau相反,但差异无统计学意义。各指标无年龄相关性。结论:血液标志物Aβ42和P-tau可区分临床诊断的AD患者与认知正常者,并具有脑内Aβ沉积的预测潜力,值得进一步研究。
Objective To investigate the correlation between blood biomarkers Aβ42,P-tau and PET-amyloid imaging of Alzheimer's disease(AD). Methods Subjects who have got 11C-Pittsburgh Compound B-positron emission tomography(~(11)C-PiB-PET) scanning were enrolled in our study, includ-ing 30 PET positive subjects and 18 PET negative subjects, another 30 cognitively normal(CN) subjects were also selected from health examination center. The information of clinical diagnosis, age, sex, education level and APOE genotype were collected. Blood Aβ42 and P-tau were measured and analysed within each group, and analysis for age correlation of these biomarkers were also performed. Results No significant difference was found between PET positive subjects and negative subjects, while clinical diagnosis based AD patients have higher blood Aβ42 and P-tau than cognitively normal(CN) subjects(P<0.05). Within APOE ε4 carriers, the blood Aβ42, P-tau and Aβ42/P-tau of PET positive subjects were relatively lower than PET negative subjects, The trend was opposite in APOE ε4 non-carriers except for Aβ42/P-tau, though significance was deficient(P>0.05). Age has no correlation with any of these biomarkers in our study. Conclusions To some extent, blood biomarkers Aβ42 and P-tau can distinguish clinical diagnosis based AD patients from cognitively normal subjects, and have the potential to predict brain Aβ deposition, which is worth to be further researched.
Objective To investigate the correlation between blood biomarkers Aβ42,P-tau and PET-amyloid imaging of Alzheimer's disease(AD). Methods Subjects who have got 11C-Pittsburgh Compound B-positron emission tomography(~(11)C-PiB-PET) scanning were enrolled in our study, includ-ing 30 PET positive subjects and 18 PET negative subjects, another 30 cognitively normal(CN) subjects were also selected from health examination center. The information of clinical diagnosis, age, sex, education level and APOE genotype were collected. Blood Aβ42 and P-tau were measured and analysed within each group, and analysis for age correlation of these biomarkers were also performed. Results No significant difference was found between PET positive subjects and negative subjects, while clinical diagnosis based AD patients have higher blood Aβ42 and P-tau than cognitively normal(CN) subjects(P<0.05). Within APOE ε4 carriers, the blood Aβ42, P-tau and Aβ42/P-tau of PET positive subjects were relatively lower than PET negative subjects, The trend was opposite in APOE ε4 non-carriers except for Aβ42/P-tau, though significance was deficient(P>0.05). Age has no correlation with any of these biomarkers in our study. Conclusions To some extent, blood biomarkers Aβ42 and P-tau can distinguish clinical diagnosis based AD patients from cognitively normal subjects, and have the potential to predict brain Aβ deposition, which is worth to be further researched.
引文
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[22]Chiu,M.J.,Y.F.Chen,T.F.Chen,S.Y.Yang,F.P.Yang,T.W.Tseng,et al.Plasma tau as a window to the brain-negative associations with brain volume and memory function in mild cognitive impairment and early Alzheimer’s disease.Hum Brain Mapp 2014;35:3132-42.
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[25]Burnham,S.C.,N.G.Faux,W.Wilson,S.M.Laws,D.Ames,J.Bedo,et al.A blood-based predictor for neocortical Abeta burden in Alzheimer’s disease:results from the AIBL study.2014;19:1476-5578
[2]Kidd,M.Paired helical filaments in electron microscopy of Alzheimer’s disease.Nature 1963;197:192-3.
[3]Yang,L.,D.Rieves,and C.Ganley.Brain amyloid imaging--FDA approval of florbetapir F18 injection.NEngl J Med 2012;367:885-7.
[4]Villemagne,V.L.,K.E.Pike,G.Chetelat,K.A.Ellis,R.S.Mulligan,P.Bourgeat,et al.Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease.Ann Neurol 2011;69:181-92.
[5]Scheltens,P.,K.Blennow,M.M.Breteler,B.de Strooper,G.B.Frisoni,S.Salloway,et al.Alzheimer’s disease.Lancet 2016;388:505-17.
[6]Albert,M.S.,S.T.DeKosky,D.Dickson,B.Dubois,H.H.Feldman,N.C.Fox,et al.The diagnosis of mild cognitive impairment due to Alzheimer’s disease:recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.Alzheimers Dement2011;7:270-9.
[7]McKhann,G.M.,D.S.Knopman,H.Chertkow,B.T.Hyman,C.R.Jack,Jr.,C.H.Kawas,et al.The diagnosis of dementia due to Alzheimer’s disease:recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.Alzheimers Dement 2011;7:263-9.
[8]Ovod,V.,K.N.Ramsey,K.G.Mawuenyega,J.G.Bollinger,T.Hicks,T.Schneider,et al.Amyloid beta concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis.Alzheimers Dement 2017;13:841-849.
[9]Tzen,K.Y.,S.Y.Yang,T.F.Chen,T.W.Cheng,H.E.Horng,H.P.Wen,et al.Plasma Abeta but not tau is related to brain PiB retention in early Alzheimer’s disease.ACS Chem Neurosci 2014;5:830-6.
[10]Mattsson,N.,H.Zetterberg,S.Janelidze,P.S.Insel,U.Andreasson,E.Stomrud,et al.Plasma tau in Alzheimer disease.Neurology 2016;87:1827-1835.
[11]Freeman,S.H.,S.Raju,B.T.Hyman,M.P.Frosch,and M.C.Irizarry.Plasma Abeta levels do not reflect brain Abeta levels.J Neuropathol Exp Neurol 2007;66:264-71.
[12]Kuo,Y.M.,T.A.Kokjohn,M.D.Watson,A.S.Woods,R.J.Cotter,L.I.Sue,et al.Elevated abeta42 in skeletal muscle of Alzheimer disease patients suggests peripheral alterations of AbetaPP metabolism.Am J Pathol2000;156:797-805.
[13]Li,Q.X.,S.Whyte,J.E.Tanner,G.Evin,K.Beyreuther,and C.L.Masters.Secretion of Alzheimer’s disease Abeta amyloid peptide by activated human platelets.Lab Invest 1998;78:461-9.
[14]Van Nostrand,W.E.and J.P.Melchor.Disruption of pathologic amyloid beta-protein fibril assembly on the surface of cultured human cerebrovascular smooth muscle cells.Amyloid 2001;8 Suppl 1:20-7.
[15]Ghiso,J.,M.Shayo,M.Calero,D.Ng,Y.Tomidokoro,S.Gandy,et al.Systemic catabolism of Alzheimer’s Abeta40 and Abeta42.J Biol Chem 2004;279:45897-908.
[16]Kuo,Y.M.,M.R.Emmerling,H.C.Lampert,S.R.Hempelman,T.A.Kokjohn,A.S.Woods,et al.High levels of circulating Abeta42 are sequestered by plasma proteins in Alzheimer’s disease.Biochem Biophys Res Commun1999;257:787-91.
[17]Kuo,Y.M.,T.A.Kokjohn,W.Kalback,D.Luehrs,D.R.Galasko,N.Chevallier,et al.Amyloid-beta peptides interact with plasma proteins and erythrocytes:implications for their quantitation in plasma.Biochem Biophys Res Commun 2000;268:750-6.
[18]O’Bryant,S.E.,V.Gupta,K.Henriksen,M.Edwards,A.Jeromin,S.Lista,et al.Guidelines for the standardization of preanalytic variables for blood-based biomarker studies in Alzheimer’s disease research.Alzheimers Dement 2015;11:549-60.
[19]Andreasson,U.,K.Blennow,and H.Zetterberg.Update on ultrasensitive technologies to facilitate research on blood biomarkers for central nervous system disorders.Alzheimers Dement(Amst)2016;3:98-102.
[20]Deane,R.,A.Sagare,K.Hamm,M.Parisi,S.Lane,M.B.Finn,et al.apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain.J Clin Invest 2008;118:4002-13.
[21]Sharman,M.J.,M.Morici,E.Hone,T.Berger,K.Taddei,I.J.Martins,et al.APOE genotype results in differential effects on the peripheral clearance of amyloid-beta42 in APOE knock-in and knock-out mice.JAlzheimers Dis 2010;21:403-9.
[22]Chiu,M.J.,Y.F.Chen,T.F.Chen,S.Y.Yang,F.P.Yang,T.W.Tseng,et al.Plasma tau as a window to the brain-negative associations with brain volume and memory function in mild cognitive impairment and early Alzheimer’s disease.Hum Brain Mapp 2014;35:3132-42.
[23]Koyama,A.,O.I.Okereke,T.Yang,D.Blacker,D.J.Selkoe,and F.Grodstein.Plasma amyloid-beta as a predictor of dementia and cognitive decline:a systematic review and meta-analysis.Arch Neurol 2012;69:824-31.
[24]Jansen,W.J.,R.Ossenkoppele,D.L.Knol,B.M.Tijms,P.Scheltens,F.R.Verhey,et al.Prevalence of cerebral amyloid pathology in persons without dementia:a meta-analysis.JAMA 2015;313:1924-38.
[25]Burnham,S.C.,N.G.Faux,W.Wilson,S.M.Laws,D.Ames,J.Bedo,et al.A blood-based predictor for neocortical Abeta burden in Alzheimer’s disease:results from the AIBL study.2014;19:1476-5578