神经科学进展认知功能障碍.pptx

会计学1神经科学进展神经科学进展(jnzhn)认知功能障碍认知功能障碍第一页，共98页。2第2页/共98页第二页，共98页。3n n痴呆是一种获得性多认知障碍疾病，通常包含记忆损害以及非谵妄条件(tiojin)下的至少其他一种认知功能损害失语、失用、失认和执行功能受损（归纳、计划、启动、排序、跟踪、终止）。第3页/共98页第三页，共98页。4第4页/共98页第四页，共98页。5Wimo A,et al.Alzheimers Disease International World Alzheimer Report 2010.第5页/共98页第五页，共98页。6修改(xigi)至Cummings JL.Primary Psychiatry.Vol 15,No 2.2008第6页/共98页第六页，共98页。7n n阿尔茨海默病（Alzheimers disease）n nAD(AD-P&AD-C)的新理念、诊断新指南NIA2011n nAD研究热点n nAD治疗及预防(yfng)新进展n n血管性认知功能障碍（Vascular Cognitive Impairment）n nFTDP-17病例报道第7页/共98页第七页，共98页。8第8页/共98页第八页，共98页。9第9页/共98页第九页，共98页。10Alois Alzheimer，1864-1915，德国神经病理学家、精神病学家。1906年11月3日，第一次定义了阿尔茨海默病。1901年，Alzheimer在Frankfurt Asylum遇见患者Mrs.Auguste Deter，一位有着短期记忆(jy)丧失在内的各种奇怪行为症状的患者。随后，Alzheimer对其进行了随访。1906年，Mrs.Deter去世，她的脑组织与病史被送往Munich的Kraepelin实验室。于是，Alzheimer与两位意大利同事通过组织染色发现了淀粉样斑块和神经纤维缠结。最后于1906年11月3日，Alzheimer进行了第一次早老性痴呆临床与病理特征的报道。第10页/共98页第十页，共98页。11A,Tau内侧颞叶萎缩、颞顶叶内侧颞叶萎缩、颞顶叶(dn y)低代谢低代谢记忆记忆(jy)认知行为障认知行为障碍碍第11页/共98页第十一页，共98页。12第12页/共98页第十二页，共98页。13第13页/共98页第十三页，共98页。14AD(AD-P&AD-C)的新的新理念、诊断理念、诊断(zhndun)新新指南指南NIA2011 第14页/共98页第十四页，共98页。15Lancet Neurol 2010;9:111827The International Working GroupHoward H FeldmanJeff rey L CummingsPhilip ScheltensNew research criteria第15页/共98页第十五页，共98页。16Diagnosis of AD:High accuracy,at earliest stagen nRevising AD definition“dual clinicopathological entity”Revising AD definition“dual clinicopathological entity”n n(1)(1)临床表型：临床表型：临床表型：临床表型：a progressive dementia a progressive dementia n nepisodic memory impairment as a defining feature and involvement of episodic memory impairment as a defining feature and involvement of other cognitive domains or skills,other cognitive domains or skills,n n(2)(2)特异的神经病理改变特异的神经病理改变特异的神经病理改变特异的神经病理改变(g(g ibin)ibin)n nintraneuronal(neurofibrillary tangles),extracellular parenchymal intraneuronal(neurofibrillary tangles),extracellular parenchymal lesions(senile plaques),lesions(senile plaques),n nsynaptic loss and vascular amyloid deposits.synaptic loss and vascular amyloid deposits.n nAD“AD“双重临床生物学实体双重临床生物学实体双重临床生物学实体双重临床生物学实体”:”:n nin-vivo biological evidence of Alzheimers pathologyin-vivo biological evidence of Alzheimers pathology第16页/共98页第十六页，共98页。17病理病理(bngl)(bngl)生理升级模式生理升级模式P Tau分子(fnz)病理变化地形学变化(binhu)临床表型个体易感性Co-morbidity病理损害和生物标记物密切相关病理损害和生物标记物密切相关病理损害和生物标记物密切相关病理损害和生物标记物密切相关第17页/共98页第十七页，共98页。18ADAD的病理级联动态的病理级联动态(dngti)(dngti)生物标志物模型生物标志物模型生物标记生物标记(bioj)(bioj)物和临床表型密物和临床表型密切相关切相关Extentofbiomarkers第18页/共98页第十八页，共98页。19ADAD两个临床两个临床两个临床两个临床(ln chun(ln chun)阶段阶段阶段阶段:AD-P and AD-C:AD-P and AD-Cn nAD-P:AD-P:AD-pathophysiological processAD-pathophysiological process n nAD-C:AD-C:Clinical phases of AD as“AD-Clinical”Clinical phases of AD as“AD-Clinical”n nincluding not only including not only AD dementiaAD dementia,but also,but also MCI due to AD-PMCI due to AD-Pn nBetween AD-P and Between AD-P and AD-CAD-Cn nTime lagTime lag:10 yrs or more(evidence:genetic at-risk and aging cohorts):10 yrs or more(evidence:genetic at-risk and aging cohorts)n nExtentExtent of biomarkers as predictor?of biomarkers as predictor?n nModulateModulate the relationship between AD-P and the relationship between AD-P and AD-CAD-Cn n“a specific“a specific threshold threshold or regional or regional distribution of AD pathologydistribution of AD pathology,and/or a specific,and/or a specific combinationcombination of biomarker abnormalities”remains unknown of biomarker abnormalities”remains unknownn nTo be clarifiedTo be clarifiedn nAD could one day be AD could one day be diagnosed preclinicallydiagnosed preclinically by the presence of biomarker evidence of by the presence of biomarker evidence of AD-P,which may eventually AD-P,which may eventually guide therapyguide therapy before the onset of symptoms.before the onset of symptoms.n nThe hypothesis that many individuals with laboratory evidence of AD-P are The hypothesis that many individuals with laboratory evidence of AD-P are indeed in the preclinical stages of AD,and determine indeed in the preclinical stages of AD,and determine which biomarkerwhich biomarker and and cognitive profilescognitive profiles are most predictive of subsequent clinical decline and emergence are most predictive of subsequent clinical decline and emergence of AD-C.of AD-C.第19页/共98页第十九页，共98页。20New Research Criteria framework for the Diagnosis of ADn n新：病理生理标记物适用于各阶段的新：病理生理标记物适用于各阶段的ADADn n新：新：ADAD传统的单一的临床传统的单一的临床(ln chun(ln chun)实体转化为双重的临实体转化为双重的临床床(ln chun(ln chun)和病理和病理实体的结合实体的结合n n新：新：ADAD的诊断是临床的诊断是临床(ln chun(ln chun)伴活体病理肯定的诊断，伴活体病理肯定的诊断，不再是可能不再是可能或很可能的单一的临床或很可能的单一的临床(ln chun(ln chun)诊断，尸诊断，尸检只用于验证诊断检只用于验证诊断theInternationalWorkingGroupClinicallyClinicallysymptomaticsymptomaticTypicalADAtypicalADADdementiaMixedADProdromalADClinicallyClinicallyasymptomaticasymptomaticPreclinicalstatesofADPreclinicalstatesofAD“asymptomaticat-riskstateforAD”“presymptomaticAD”MildcognitiveimpairmentMildcognitiveimpairment第20页/共98页第二十页，共98页。21A new lexicon for Alzheimers diseasen nADAD涉及两个临床阶段涉及两个临床阶段:前驱期前驱期AD and AD dementiaAD and AD dementian n前驱期前驱期AD=memo+,bio+AD=memo+,bio+，无痴呆，一定，无痴呆，一定(ydng)(ydng)进展为进展为ADDADDn n临床前期临床前期ADAD：n n无症状无症状ADAD的危险状态的危险状态:不诊断不诊断ADAD，(memo-,bio+)(memo-,bio+)，无，无ADAD症状，条件转化为症状，条件转化为ADADn n症状前期不诊断症状前期不诊断ADAD，(memo-,bio-)(memo-,bio-)，无，无ADAD症状，有症状，有ADAD单基因突变单基因突变n nMCI MCI 不诊断不诊断ADAD，(memo-,bio-)(memo-,bio-)，无，无ADAD症状，不一定症状，不一定(ydng)(ydng)转化为转化为ADAD第21页/共98页第二十一页，共98页。22New Research Criteria framework for the Diagnosis of ADAD dementia phase:AD dementia phase:n nTypical ADTypical ADn nearly&progressive episodic memory,remains dominant in later stages,early&progressive episodic memory,remains dominant in later stages,followed by other CI and NPIfollowed by other CI and NPIn nsupported by supported by 1 1 in-vivo biomarkers of Alzheimers pathology in-vivo biomarkers of Alzheimers pathologyn nMixed ADMixed ADn nfully fulfil the diagnostic criteria for typical ADfully fulfil the diagnostic criteria for typical ADn npresent with clinical and brain imaging/biological evidence of other comorbid disorderspresent with clinical and brain imaging/biological evidence of other comorbid disordersn nAtypical ADAtypical ADn nconfirmed neuropathologically as being AD confirmed neuropathologically as being AD n nwith atypical features with atypical features n ninclude non-amnestic focal cortical syndromes,such as progressive non-fluent aphasia,include non-amnestic focal cortical syndromes,such as progressive non-fluent aphasia,logopenic aphasia,and posterior cortical atrophylogopenic aphasia,and posterior cortical atrophytheInternationalWorkingGroup第22页/共98页第二十二页，共98页。23Recommendations for diagnosisn nClinical history Clinical history 应有应有(yn(yn y y u)u)知情者补充知情者补充(Level A).(Level A).n nA neurological and physical examination,ADL assessed(Level A).A neurological and physical examination,ADL assessed(Level A).n nCognitive assessment(Level A).Cognitive assessment(Level A).n nFor questionable or very early AD(Level B)For questionable or very early AD(Level B)n nAssessment of BPSD(Level A).Assessment of BPSD(Level A).n nAssessment of co-morbidity should always be considered as a possible cause of Assessment of co-morbidity should always be considered as a possible cause of BPSD(Level C).BPSD(Level C).n nBlood levels of folate,vitamin B12,thyroid stimulating hormone,calcium,Blood levels of folate,vitamin B12,thyroid stimulating hormone,calcium,glucose,complete blood cell count,renal and liver function tests should be glucose,complete blood cell count,renal and liver function tests should be evaluated at the time of diagnosis evaluated at the time of diagnosis n nserological tests for syphilis,borelia and HIV might also be needed in cases with serological tests for syphilis,borelia and HIV might also be needed in cases with atypical presentation or clinical features suggestive of these disorders(good atypical presentation or clinical features suggestive of these disorders(good practice point).practice point).第23页/共98页第二十三页，共98页。24第24页/共98页第二十四页，共98页。25Probable AD dementia with increased level of Probable AD dementia with increased level of certaintycertaintyn nAll patients who All patients who met criteria for“probable AD”met criteria for“probable AD”by the 1984 by the 1984 NINCDSADRDA criteriaNINCDSADRDA criterian nProbable AD dementia with Probable AD dementia with documented declinedocumented declinen nProgressive cognitive declineProgressive cognitive declinen nNot for increase AD pathophysiology.Not for increase AD pathophysiology.n nProbable AD dementia in Probable AD dementia in a carrier of a causative AD genetic a carrier of a causative AD genetic mutationmutationn nEvidence of a causative genetic mutation(in APP,PSEN1,or PSEN2)Evidence of a causative genetic mutation(in APP,PSEN1,or PSEN2)n nNot for carriage of the 34 alleleNot for carriage of the 34 allelen nIncrease AD pathophysiology Increase AD pathophysiology 第25页/共98页第二十五页，共98页。26Probable AD dementia with evidence of the AD Probable AD dementia with evidence of the AD pathophysiological processpathophysiological processn nIncrease the certaintyIncrease the certainty:clinical dementia syndrome is AD:clinical dementia syndrome is AD pathophysiological processpathophysiological process.n nBiomarkers of brain amyloid-beta(Ab)protein depositionBiomarkers of brain amyloid-beta(Ab)protein depositionn nBiomarkers of downstream neuronal degeneration or injuryBiomarkers of downstream neuronal degeneration or injuryn nNot advocateNot advocate:use of AD biomarker tests for routine diagnostic purposes:use of AD biomarker tests for routine diagnostic purposes at the present timeat the present timen nBiomarkers:Biomarkers:appropriately designed,appropriately designed,n nstandardization of biomarkers from one locale to another,standardization of biomarkers from one locale to another,n nvarying degrees in community settingsvarying degrees in community settingsn nuseful in three circumstancesuseful in three circumstances:n ninvestigational studies,clinical trials,and investigational studies,clinical trials,and n nas optional clinical tools for use where available and when deemed appropriate as optional clinical tools for use where available and when deemed appropriate by the clinicianby the clinician第26页/共98页第二十六页，共98页。27第27页/共98页第二十七页，共98页。28第28页/共98页第二十八页，共98页。29Medial temporal lobe atrophyMedial temporal lobe atrophy第29页/共98页第二十九页，共98页。30Multidetector CT in dementia64slices,0.6mmslicecollimation,5secacquisitiontimeWattjesM,etalRadiology,2009第30页/共98页第三十页，共98页。31HippocampusGyrus parahippocampalisEntorhinal cortexVolumetry of MTA第31页/共98页第三十一页，共98页。32磷酸化Tau-蛋白ng/I（正常值0.149）5375972230.041第32页/共98页第三十二页，共98页。33第33页/共98页第三十三页，共98页。34SilvermanDH,SmallGW,ChangCY,etal.Positronemissiontomographyinevaluationofdementia:Regionalbrainmetabolismandlong-termoutcome.JournaloftheAmericanMedicalAssociation2001;286:2120-2127.FDG PET-sensitivity of 93%(191/206)and specificity of 76%(59/78)-in pathologically verified cases sensitivity was 94%and specificities of 73%(AD)and 78%(other dementias);-a negative PET scan indicates no progression in a 3 year follow-up第34页/共98页第三十四页，共98页。35第35页/共98页第三十五页，共98页。36CSF biomarkers:CSF biomarkers:Over 50 studies covering more than 3000 cases Over 50 studies covering more than 3000 cases n nEelevation of CSF tauEelevation of CSF tau：n na relatively accurate marker to identify AD 53.a relatively accurate marker to identify AD 53.n nReduced CSFAb42Reduced CSFAb42：n nindicative of AD dementia with a se of 85%and a sp of 87%,indicative of AD dementia with a se of 85%and a sp of 87%,n nbut Ab42 may not be able to discriminate between AD and other forms of dementia,but Ab42 may not be able to discriminate between AD and other forms of dementia,n nsuch as vascular dementia and frontotemporal dementia on an individual such as vascular dementia and frontotemporal dementia on an individual basis 52,54.basis 52,54.n nEelevation of CSF phosphorylated tau Eelevation of CSF phosphorylated tau n nalso demonstrate diagnostic potential,also demonstrate diagnostic potential,n nbut some overlap between AD dementia and other dementias reduces the diagnostic but some overlap between AD dementia and other dementias reduces the diagnostic value.value.n nSimultaneously measure:Importantly for early diagnosisSimultaneously measure:Importantly for early diagnosisn na combination of high CSF tau&low CSF Ab42 can identify about 95%of a combination of high CSF tau&low CSF Ab42 can identify about 95%of individuals with MCI who will eventually develop AD 52.individuals with MCI who will eventually develop AD 52.第36页/共98页第三十六页，共98页。37D1182D1182王效茹王效茹王效茹王效茹 女女女女 61 61岁（岁（岁（岁（19491949年）年）年）年）初中初中初中初中(chzhng)(chzhng)工人工人工人工人北京市北京市北京市北京市n n脑脊液：脑脊液：2010-9-302010-9-30序号 检验项目检验结果提示单位参考值1磷酸化Tau-蛋白 131ng/I10000ng/I-淀粉体 1-42/1-400.149第37页/共98页第三十七页，共98页。38Neurochemical Dementia Diagnostics in Neurochemical Dementia Diagnostics in Alzheimers DiseaseAlzheimers Diseasen nWhere Are We Now and Where Are We Going?Posted:09/30/2011;ExpertRevProteomics.2011;8(4):447-458.OurrecentlypublishedpreliminarystudydemonstratedthatNDDcharacterizeswithhighersensitivityandshowsalterationsearlierthansingle-photonemissioncomputedtomographyneuroimaging,whereasthelattercharacterizeswithbetterspecificityandcorrelationwiththediseaseseverity.第38页/共98页第三十八页，共98页。39Where are we now?Where are we now?n nThe sensitivity and specificity of A142 alone to distinguish AD from elderly controls were 78 and 81%,The sensitivity and specificity of A142 alone to distinguish AD from elderly controls were 78 and 81%,respectively,in the study by Hulstaert respectively,in the study by Hulstaert et alet al.n nThe meta-analysis of Sunderland The meta-analysis of Sunderland et al.et al.was based on data from 17 reports on A42 and 34 reports on was based on data from 17 reports on A42 and 34 reports on CSF Tau in AD,and all of these studies reported increased CSF total Tau in AD.CSF Tau in AD,and all of these studies reported increased CSF total Tau in AD.n nrecently shown that the phosphorylated Tau(pTau)396/404 to total Tau ratio in CSF could discriminate AD recently shown that the phosphorylated Tau(pTau)396/404 to total Tau ratio in CSF could discriminate AD from other dementias and neurological disorders with a sensitivity of 96%and specificity of 94%from other dementias and neurological disorders with a sensitivity of 96%and specificity of 94%.n nTau protein phosphorylated at both threonine 231 and serine 235 was increased in patients with mild cognitive Tau protein phosphorylated at both threonine 231 and serine 235 was increased in patients with mild cognitive impairment(MCI)who developed AD during follow-up.impairment(MCI)who developed AD during follow-up.第39页/共98页第三十九页，共98页。40Where are we now?Where are we now?第40页/共98页第四十页，共98页。41Where are we going?Where are we going?n nFinding of novel biomarkers(characterizing with better diagnostic-related Finding of novel biomarkers(characterizing with better diagnostic-related performance,such as improved sensitivity and