阿尔茨海默病常规临床诊断与淀粉样蛋白PET诊断的一致性研究
|
摘要
目的:评估阿尔茨海默病(Alzheimer’s disease,AD)临床诊断与~(11)C-PiB示踪的正电子发射断层显像(positron emission tomography,PET)神经影像学诊断的一致性,探讨脑内Aβ沉积的影响因素。方法:纳入AD患者48例,MCI患者14例。收集患者年龄、性别、文化程度、神经心理学量表评分、血管危险因素(vascular risk factors,VRF)(包括高血压、糖尿病、高血脂、冠心病、卒中史)等信息,对患者做PiB-PET检查及APOE基因型测序。分析AD临床诊断与PET病理诊断的符合率,PET阳性组与PET阴性组神经心理学量表评分差异及各类危险因素与脑内Aβ沉积的相关性。结果:AD组患者临床诊断与PET诊断的阳性一致率达77.1%,MCI组阳性一致率仅为21.4%;AD患者PET阳性组MMSE量表评分低于PET阴性组(P=0.004),CDR量表评分(P=0.012)和ADL量表评分(P=0.034)高于PET阴性组;各类危险因素中仅APOE基因与Aβ沉积相关,即APOE ε4携带者的Aβ沉积风险更高(OR=4.913,P=0.049)。结论:当前AD临床诊断准确性不高,有必要纳入更多的生物标志物、影像学检测、遗传基因指标辅助诊断;APOE作为AD的重要危险基因,对临床AD的诊断、评估、预防及治疗有重要意义。
Objective Evaluate the consistency between clinical diagnosis and the diagnosis based on ~(11)C-Pittsburgh Compound B-positron emission tomography(PiB-PET) for Alzheimer’s disease(AD), and discuss the factors that may influence brain Aβ deposition. Methods 48 AD and 14 mild cognitive impairment(MCI)patients were enrolled in our study. The information of age, sex, education level, Neuropsychological assessment and vascular risk factors(VRF)(including hypertension, diabetes, hyperlipemia, coronary heart disease and stroke history) were collected and PiB-PET scanning and APOE gene sequencing were carried out on all subjects. We compared the consistency of AD clinical diagnosis and PiB-PET based diagnosis, analysed the neuropsychological test scores differences between PET positive and negative subjects, and discuss the correlation between VRF, education lever, APOE genotype and brain Aβ deposition. Results The consistency between AD clinical diagnosis and PiB-PET based diagnosis were 77.1%, while PET positive subjects only cover 21.4% in MCI patients. The MMSE scores of PET positive subjects were lower than PET negative subjects(t=-3.232, P=0.004), and CDR(t=2.727, P=0.012)and ADL(t=2.261, P=0.034)scores were higher. Among all these risk factors, APOE genotype was the only significant one(OR=4.913, P=0.049) that can affect the brain Aβ deposition. Conclusions Misdiagnose exists and can hardly be avoided in clinical diagnosis, it is necessary to bring into more assistance tools like biological biomarkers, neuroimaging and hereditary factor for a more precise clinical diagnosis. As the most important gene of AD, APOE perform well at AD diagnosis,evaluation,prevention and treatment.
Objective Evaluate the consistency between clinical diagnosis and the diagnosis based on ~(11)C-Pittsburgh Compound B-positron emission tomography(PiB-PET) for Alzheimer’s disease(AD), and discuss the factors that may influence brain Aβ deposition. Methods 48 AD and 14 mild cognitive impairment(MCI)patients were enrolled in our study. The information of age, sex, education level, Neuropsychological assessment and vascular risk factors(VRF)(including hypertension, diabetes, hyperlipemia, coronary heart disease and stroke history) were collected and PiB-PET scanning and APOE gene sequencing were carried out on all subjects. We compared the consistency of AD clinical diagnosis and PiB-PET based diagnosis, analysed the neuropsychological test scores differences between PET positive and negative subjects, and discuss the correlation between VRF, education lever, APOE genotype and brain Aβ deposition. Results The consistency between AD clinical diagnosis and PiB-PET based diagnosis were 77.1%, while PET positive subjects only cover 21.4% in MCI patients. The MMSE scores of PET positive subjects were lower than PET negative subjects(t=-3.232, P=0.004), and CDR(t=2.727, P=0.012)and ADL(t=2.261, P=0.034)scores were higher. Among all these risk factors, APOE genotype was the only significant one(OR=4.913, P=0.049) that can affect the brain Aβ deposition. Conclusions Misdiagnose exists and can hardly be avoided in clinical diagnosis, it is necessary to bring into more assistance tools like biological biomarkers, neuroimaging and hereditary factor for a more precise clinical diagnosis. As the most important gene of AD, APOE perform well at AD diagnosis,evaluation,prevention and treatment.
引文
[1]Kidd,M.Paired helical filaments in electron microscopy of Alzheimer’s disease.Nature 1963;197:192-3.
[2]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 AgingAlzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.Alzheimers Dement2011;7:270-9.
[3]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.
[4]Beach,T.G.,S.E.Monsell,L.E.Phillips,and W.Kukull.Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers,2005-2010.J Neuropathol Exp Neurol2012;71:266-73.
[5]Toledo,J.B.,E.Toledo,M.W.Weiner,C.R.Jack,Jr.,W.Jagust,V.M.Lee,et al.Cardiovascular risk factors,cortisol,and amyloid-beta deposition in Alzheimer’s Disease Neuroimaging Initiative.Alzheimers Dement2012;8:483-9.
[6]Willette,A.A.,S.C.Johnson,A.C.Birdsill,M.A.Sager,B.Christian,L.D.Baker,et al.Insulin resistance predicts brain amyloid deposition in late middle-aged adults.Alzheimers Dement 2015;11:504-510 e1.
[7]Nagga,K.,A.M.Gustavsson,E.Stomrud,D.Lindqvist,D.van Westen,K.Blennow,et al.Increased midlife triglycerides predict brain beta-amyloid and tau pathology 20 years later.Neurology 2018;90:e73-e81.
[8]Schreiner,S.J.,T.Kirchner,A.Narkhede,M.Wyss,J.M.G.Van Bergen,S.C.Steininger,et al.Brain amyloid burden and cerebrovascular disease are synergistically associated with neurometabolism in cognitively unimpaired older adults.Neurobiol Aging 2018;63:152-161.
[9]Vemuri,P.,T.G.Lesnick,S.A.Przybelski,D.S.Knopman,V.J.Lowe,J.Graff-Radford,et al.Age,vascular health,and Alzheimer disease biomarkers in an elderly sample.Ann Neurol 2017;82:706-718.
[10]Arenaza-Urquijo,E.M.,A.Bejanin,J.Gonneaud,M.Wirth,R.La Joie,J.Mutlu,et al.Association between educational attainment and amyloid deposition across the spectrum from normal cognition to dementia:neuroimaging evidence for protection and compensation.Neurobiol Aging 2017;59:72-79.
[11]Farrer,L.A.,L.A.Cupples,J.L.Haines,B.Hyman,W.A.Kukull,R.Mayeux,et al.Effects of age,sex,and ethnicity on the association between apolipoprotein Egenotype and Alzheimer disease.A meta-analysis.APOE and Alzheimer Disease Meta Analysis Consortium.JAMA 1997;278:1349-56.
[12]Caselli,R.J.,A.C.Dueck,D.Osborne,M.N.Sabbagh,D.J.Connor,G.L.Ahern,et al.Longitudinal modeling of age-related memory decline and the APOE epsilon4effect.N Engl J Med 2009;361:255-63.
[13]Lautenschlager,N.T.,K.L.Cox,L.Flicker,J.K.Foster,F.M.van Bockxmeer,J.Xiao,et al.Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease:a randomized trial.JAMA 2008;300:1027-37.
[14]Dore,G.A.,M.F.Elias,M.A.Robbins,P.K.Elias,and Z.Nagy.Presence of the APOE epsilon4 allele modifies the relationship between type 2 diabetes and cognitive performance:the Maine-Syracuse Study.Diabetologia2009;52:2551-60.
[15]Hall,K.,J.Murrell,A.Ogunniyi,M.Deeg,O.Baiyewu,S.Gao,et al.Cholesterol,APOE genotype,and Alzheimer disease:an epidemiologic study of Nigerian Yoruba.Neurology 2006;66:223-7.
[16]Brookmeyer,R.,E.Johnson,K.Ziegler-Graham,and H.M.Arrighi.Forecasting the global burden of Alzheimer’s disease.Alzheimers Dement 2007;3:186-91.
[17]Hejl,A.,P.Hogh,and G.Waldemar.Potentially reversible conditions in 1000 consecutive memory clinic patients.J Neurol Neurosurg Psychiatry 2002;73:390-4.
[18]Hyman,B.T.,C.H.Phelps,T.G.Beach,E.H.Bigio,N.J.Cairns,M.C.Carrillo,et al.National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease.Alzheimers Dement 2012;8:1-13.
[19]Boxer,A.L.and B.F.Boeve.Frontotemporal dementia treatment:current symptomatic therapies and implications of recent genetic,biochemical,and neuroimaging studies.Alzheimer Dis Assoc Disord 2007;21:S79-87.
[20]McKeith,I.,J.Mintzer,D.Aarsland,D.Burn,H.Chiu,J.Cohen-Mansfield,et al.Dementia with Lewy bodies.Lancet Neurol 2004;3:19-28.
[21]Gaugler,J.E.,H.Ascher-Svanum,D.L.Roth,T.Fafowora,A.Siderowf,and T.G.Beach.Characteristics of patients misdiagnosed with Alzheimer’s disease and their medication use:an analysis of the NACC-UDSdatabase.BMC Geriatr 2013;13:137.
[22]Valenti,R.,L.Pantoni,and H.S.Markus.Treatment of vascular risk factors in patients with a diagnosis of Alzheimer’s disease:a systematic review.BMC Med2014;12:160.
[23]Hess,N.C.and N.A.Smart.Isometric Exercise Training for Managing Vascular Risk Factors in Mild Cognitive Impairment and Alzheimer’s Disease.Front Aging Neurosci 2017;9:48.
[24]Noh,Y.,S.W.Seo,S.Jeon,J.M.Lee,J.S.Kim,J.H.Lee,et al.The Role of Cerebrovascular Disease in Amyloid Deposition.J Alzheimers Dis 2016;54:1015-1026.
[25]Shpanskaya,K.S.,K.R.Choudhury,C.Hostage,Jr.,K.R.Murphy,J.R.Petrella,P.M.Doraiswamy,et al.Educational attainment and hippocampal atrophy in the Alzheimer’s disease neuroimaging initiative cohort.JNeuroradiol 2014;41:350-7.
[26]Kemppainen,N.,J.Johansson,J.Teuho,R.Parkkola,J.Joutsa,T.Ngandu,et al.Brain amyloid load and its associations with cognition and vascular risk factors in FINGER Study.Neurology 2018;90:e206-e213.
[27]Yu,J.T.,L.Tan,and J.Hardy.Apolipoprotein E in Alzheimer’s disease:an update.Annu Rev Neurosci2014;37:79-100.
[2]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 AgingAlzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.Alzheimers Dement2011;7:270-9.
[3]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.
[4]Beach,T.G.,S.E.Monsell,L.E.Phillips,and W.Kukull.Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers,2005-2010.J Neuropathol Exp Neurol2012;71:266-73.
[5]Toledo,J.B.,E.Toledo,M.W.Weiner,C.R.Jack,Jr.,W.Jagust,V.M.Lee,et al.Cardiovascular risk factors,cortisol,and amyloid-beta deposition in Alzheimer’s Disease Neuroimaging Initiative.Alzheimers Dement2012;8:483-9.
[6]Willette,A.A.,S.C.Johnson,A.C.Birdsill,M.A.Sager,B.Christian,L.D.Baker,et al.Insulin resistance predicts brain amyloid deposition in late middle-aged adults.Alzheimers Dement 2015;11:504-510 e1.
[7]Nagga,K.,A.M.Gustavsson,E.Stomrud,D.Lindqvist,D.van Westen,K.Blennow,et al.Increased midlife triglycerides predict brain beta-amyloid and tau pathology 20 years later.Neurology 2018;90:e73-e81.
[8]Schreiner,S.J.,T.Kirchner,A.Narkhede,M.Wyss,J.M.G.Van Bergen,S.C.Steininger,et al.Brain amyloid burden and cerebrovascular disease are synergistically associated with neurometabolism in cognitively unimpaired older adults.Neurobiol Aging 2018;63:152-161.
[9]Vemuri,P.,T.G.Lesnick,S.A.Przybelski,D.S.Knopman,V.J.Lowe,J.Graff-Radford,et al.Age,vascular health,and Alzheimer disease biomarkers in an elderly sample.Ann Neurol 2017;82:706-718.
[10]Arenaza-Urquijo,E.M.,A.Bejanin,J.Gonneaud,M.Wirth,R.La Joie,J.Mutlu,et al.Association between educational attainment and amyloid deposition across the spectrum from normal cognition to dementia:neuroimaging evidence for protection and compensation.Neurobiol Aging 2017;59:72-79.
[11]Farrer,L.A.,L.A.Cupples,J.L.Haines,B.Hyman,W.A.Kukull,R.Mayeux,et al.Effects of age,sex,and ethnicity on the association between apolipoprotein Egenotype and Alzheimer disease.A meta-analysis.APOE and Alzheimer Disease Meta Analysis Consortium.JAMA 1997;278:1349-56.
[12]Caselli,R.J.,A.C.Dueck,D.Osborne,M.N.Sabbagh,D.J.Connor,G.L.Ahern,et al.Longitudinal modeling of age-related memory decline and the APOE epsilon4effect.N Engl J Med 2009;361:255-63.
[13]Lautenschlager,N.T.,K.L.Cox,L.Flicker,J.K.Foster,F.M.van Bockxmeer,J.Xiao,et al.Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease:a randomized trial.JAMA 2008;300:1027-37.
[14]Dore,G.A.,M.F.Elias,M.A.Robbins,P.K.Elias,and Z.Nagy.Presence of the APOE epsilon4 allele modifies the relationship between type 2 diabetes and cognitive performance:the Maine-Syracuse Study.Diabetologia2009;52:2551-60.
[15]Hall,K.,J.Murrell,A.Ogunniyi,M.Deeg,O.Baiyewu,S.Gao,et al.Cholesterol,APOE genotype,and Alzheimer disease:an epidemiologic study of Nigerian Yoruba.Neurology 2006;66:223-7.
[16]Brookmeyer,R.,E.Johnson,K.Ziegler-Graham,and H.M.Arrighi.Forecasting the global burden of Alzheimer’s disease.Alzheimers Dement 2007;3:186-91.
[17]Hejl,A.,P.Hogh,and G.Waldemar.Potentially reversible conditions in 1000 consecutive memory clinic patients.J Neurol Neurosurg Psychiatry 2002;73:390-4.
[18]Hyman,B.T.,C.H.Phelps,T.G.Beach,E.H.Bigio,N.J.Cairns,M.C.Carrillo,et al.National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease.Alzheimers Dement 2012;8:1-13.
[19]Boxer,A.L.and B.F.Boeve.Frontotemporal dementia treatment:current symptomatic therapies and implications of recent genetic,biochemical,and neuroimaging studies.Alzheimer Dis Assoc Disord 2007;21:S79-87.
[20]McKeith,I.,J.Mintzer,D.Aarsland,D.Burn,H.Chiu,J.Cohen-Mansfield,et al.Dementia with Lewy bodies.Lancet Neurol 2004;3:19-28.
[21]Gaugler,J.E.,H.Ascher-Svanum,D.L.Roth,T.Fafowora,A.Siderowf,and T.G.Beach.Characteristics of patients misdiagnosed with Alzheimer’s disease and their medication use:an analysis of the NACC-UDSdatabase.BMC Geriatr 2013;13:137.
[22]Valenti,R.,L.Pantoni,and H.S.Markus.Treatment of vascular risk factors in patients with a diagnosis of Alzheimer’s disease:a systematic review.BMC Med2014;12:160.
[23]Hess,N.C.and N.A.Smart.Isometric Exercise Training for Managing Vascular Risk Factors in Mild Cognitive Impairment and Alzheimer’s Disease.Front Aging Neurosci 2017;9:48.
[24]Noh,Y.,S.W.Seo,S.Jeon,J.M.Lee,J.S.Kim,J.H.Lee,et al.The Role of Cerebrovascular Disease in Amyloid Deposition.J Alzheimers Dis 2016;54:1015-1026.
[25]Shpanskaya,K.S.,K.R.Choudhury,C.Hostage,Jr.,K.R.Murphy,J.R.Petrella,P.M.Doraiswamy,et al.Educational attainment and hippocampal atrophy in the Alzheimer’s disease neuroimaging initiative cohort.JNeuroradiol 2014;41:350-7.
[26]Kemppainen,N.,J.Johansson,J.Teuho,R.Parkkola,J.Joutsa,T.Ngandu,et al.Brain amyloid load and its associations with cognition and vascular risk factors in FINGER Study.Neurology 2018;90:e206-e213.
[27]Yu,J.T.,L.Tan,and J.Hardy.Apolipoprotein E in Alzheimer’s disease:an update.Annu Rev Neurosci2014;37:79-100.