北大神经生物学课件6-1神经系统退行性疾病基础

NeurodegenerativeDiseases崔德华DHChui,MD,PhD,）博士生导师Neuroscience,ResearchInstituteandDep.OfNeurobiologyPekingUniversity,ChinaEmail:dchui@bjmu.edu.cnWhatIsNeurodegenerativediseasesHereditaryandsporadicconditionswhicharecharacterizedbyprogressivenervoussystemdysfunction.Thesedisordersareoftenassociatedwithatrophy(Apoptosis)oftheaffectedcentralorperipheralnervoussystemstructures.崔德华DHChuiNeurodegenerativeDiseasesAlzheimer‘sDisease(AD)APP(chr21）PS1(chr14）PS2(chr1）ApoE(chr19）Parkinson'sDisease(PD)parkingenealphsynuclein(autosoma)Huntington'sDisease(HD)CAGrepead(chr4）AmyotrophicLateralSclerosis,ALSCreutzfeldtJakobDisease(CJD)Corticobasaldegeneration(CBD)MultiinfarctDementia(MID)LewyBodyDiseases(LBD)Multiplesystematrophy(MSA)Progressivesupranuclearpalsy(PSP)Pick'sDiseaseHeredodegenerativeDisorders,ParaneoplasticSyndromes,OlivopontocerebellarAtrophiesPostpoliomyelitisSyndrome崔德华DHChui1.大脑皮层变性：包括Alzheimer病、Pick病、Creutzfeldt−Jakob病(海绵状变性)等。2.锥体外系统变性：包括Huntington病、Hallervorden−Spatz病、Wilson病(肝豆状核变性)、Seitelberger病(神经轴索型营养不良)、进行性肌阵挛型癫痫。病损在中脑与纹状体者有Parkinson(帕金森)病、纹状体黑质变性、进行性核上型麻痹(PSP)等。3.脑干小脑变性：包括各种小脑型共济失调、脊髓小脑变性、橄榄−桥脑−小脑变性(OPCA)、Machado−Joseph病等。4.脊髓变性：包括进行性痉挛性截瘫、进行性后索变性、后侧索联合变性、Friedreich共济失调等。5.运动系统变性：包括各型运动神经元病，如肌萎缩侧索硬化(ALS)、进行性脊髓性肌萎缩(SMA)、进行性球麻痹等。6.自主神经系统变性：包括Riley−Day症候群(全自主神经功能不全)、Shy−Drager症候群等。7.多系统变性(MSA)：包括上述1、2、3、6等的混合类型。NeurodegenerativeDiseasesClassification崔德华DHChuiParkinsondisease崔德华DHChui崔德华DHChuiWhatIsAlzheimerDisease?TheMolecularMechanismsofAlzheimerDiseaseTherapeuticApproachforAlzheimerDisease崔德华DHChuiAlzheimerDiseaseThefirstnoticeablesymptomsoftheillnessofthis51yearoldwomanwassuspiciousnessofherhusband.Soon,arapidlyincreasingmemoryimpairmentbecameevident.Shecouldnolongerorientherselfinherowndwelling,draggedobjectshereandthereandhidthem,and,attimesbelievingthatpeoplewereouttomurderher,startedtoscreamloudly.AloisAlzheimer(1907)奥古斯特(51)崔德华DHChuiGrowthinU.S.PopulationAged65+,75+,and85+65+75+85+1900192019401960198019902000202020402050020406080100Source:U.S.CensusBureau崔德华DHChuiGenesAssociatedwithAlzheimerDiseaseDiseaseGeneOnsetProductChromosomeEarlyAmyloidprecursorprotein(APP)21Presenilin1(PS1)14Presenilin2(PS2)1LateApolipoproteinE19LDLreceptorrelatedprotein(LRP)12�2Macroglobulin(�2M)12FE6511Chromosome12geneproduct12distinctfromLRPand�2MChromosomalloci10崔德华DHChuiClassificationofSenileDementiaDSMIV分类1.阿尔茨海默病(AD)2.血管性痴呆(CVD)3.脑外伤所致痴呆4.Parkinson病所致痴呆5.Huntington病所致痴呆6.HIV病所致痴呆7.Pick病所致痴呆8.CreutzfeldtJacob病所致痴呆9.物质和躯体病所致痴呆10.其它痴呆(Lewybodydementia)崔德华DHChuiTheADdiagnosisAD临床诊断的权威标准主要有3个：世界卫生组织的疾病国际分类第10版(internationalclassificationofdiseases,10threvision,ICD10)中的标准；②美国国立神经、语言疾病和卒中研究所(TheNationalInstituteofNeurologicalandCommunicativeDisorders,NINCDS)与AD及相关疾病协会(TheAlzheimer�sDiseaseandRelatedDisordersAssociation,ADRDA)制定的标准；③美国精神病诊断和统计手册修订第4版(theDiagnosticandStatisticalManualofMentalDisorders,4thedition,Revised,DSMIV)的标准。上述3个标准都是当前国际公认的AD诊断标准，临床上可根据需要选择或互相参照使用。其中美国NINCDSADRDA制定的标准中，将AD定义为很可能AD(ProbableAD)、可能AD(PossibleAD)和确定的AD，操作性较好。应用该标准及相关的诊断量，AD临床诊断的准确率可以提高到90%以上。崔德华DHChuiADclinicalsymptom神经症状和体征认知性症状记忆非认知性症状精神和行为症状失用失认失语执行功能崔德华DHChui崔德华DHChuiAgentRecognizesiteCompanysampleDetectmethodINNOTEST®hTauAghumantau,antigeninCSFInnogenetics,Belgium25µLCSFELISAmicroplateassayINNOTEST®PHOSPHOTAU(181P)tau(181p)Innogenetics,Belgium75µLCSFELISAmicroplateassayINNOTEST®ßAMYLOID(142)humanßamyloid142(Aß142)Innogenetics,Belgium25µLCSFELISAmicroplateassayINNOLiPAApoEapolipoproteinEgenotypese2,e3,ande4Innogenetics,BelgiumbloodlineprobeassayINNOBIAAlzBio3Aß142,totaltau,Ptau181PInnogenetics,BelgiumUndiluted(75µL)CSFbeadbasedmultiparameterimmunoassayCommercialBiomarkerKitsforDiagnosisAD崔德华DHChui崔德华DHChui崔德华DHChuiHowDiscriminationBetweenEarlierPeriodADandAgeAssociatedMemoryImpairmentinAging崔德华DHChui1986年美国国立精神保健研究所提出:AAMIAgeAssociatedMemoryImpairment@随年龄增加出现非病理性的记忆力下降@健忘是老年人脑功能衰弱的表现.@痴呆则是病理性的脑器质性智能衰退。崔德华DHChui如何区分老年健忘与早期如何区分老年健忘与早期ADAD健忘是老年人脑功能衰弱的表现，而痴呆则是病理性的脑器质性智能衰退，遗忘区别健忘的老年人对做过事情的遗忘总是部分性的；痴呆的遗忘则是完全恶性的，记不起发生过的事情，似乎此事已完全消失。认知能力健忘老人虽然记忆力下降，但对时间、地点、人物关系和周围环境的认知能力丝毫未减；痴呆老人却丧失了识别周围环境的认知能力，分不清上下午，不知季节变化，不知身在何处，有时甚至找不到家的路。生活能力健忘老人虽会记错日期有时前讲后忘，但他们仍能料理自己的生活，甚至能照顾家人；痴呆老人随着病情加重，会逐渐丧失生活自理能力。情绪变化健忘老人有七情六欲；痴呆老人的情感世界则变得�与世无争�，麻木不仁。思维变化健忘老人对记忆力下降相当苦恼，为了不致误事，常记个备忘录；痴呆老人毫无烦恼，思维越来越迟钝，言语越来越贫乏，缺乏幽默感，反应迟缓。是否语言丰富，幽默多彩，是区别生理健忘和痴呆的重要标志之一。崔德华DHChui90y崔德华DHChuiNostatisticallysignificantdifferencesinthetotalnumberofneuronswereobservedinthenondementedgroupTheJournalofNeuroscience,July15,1996,16(14):4491?4500崔德华DHChuiProfoundLossofEntorhinalCortexNeuronsOccursinVeryMildAlzheimerDiseaseTheJournalofNeuroscience,July15,1996,16(14):4491?4500ThenumberofneuronsintheECintheADgroup(n=10)comparedwithCDR50controls(n=10),correlatedwiththeclinicalseverityofdementia.Thedifferenceincreasedfrom32%intheCDR=0.5subgroup(n=4)to69%intheCDR=3subgroup(n=5).崔德华DHChuiSchematicrepresentationofregionalandlaminarNFTformationandneuronallossinnormalagingandADSCIENCEVOL.278,412419,1997@NFT:densitiestheyellowflameshapedstructuresrepresentasemiquantitative@EC:entorhinalcortex@SP:stratumpyramidaleoftheCA1field@ITC::inferiortemporalcortex@SFC:superiorfrontalcortex崔德华DHChuiWhatisPairedHelicalFilamentsTau？PHFTau崔德华DHChuia)Thecytoskeletonb)componentsofthecytoskeleton崔德华DHChuiSulfoglycosaminoglycancontentaffectsPHFtausolubilityandallowstheidentificationofdifferenttypesofPHFs崔德华DHChui崔德华DHChui崔德华DHChuiAPP:Amyloidprecursorprotein崔德华DHChui 幻灯片编号1 幻灯片编号2 幻灯片编号3 幻灯片编号4 幻灯片编号5 幻灯片编号6 WhatIsAlzheimerDisease? AlzheimerDisease GrowthinU.S.PopulationAged65+,75+,and85+ GenesAssociatedwithAlzheimerDisease ClassificationofSenileDementia 幻灯片编号12 ADclinicalsymptom 幻灯片编号14 幻灯片编号15 幻灯片编号16 幻灯片编号17 幻灯片编号18 幻灯片编号19 幻灯片编号20 幻灯片编号21 幻灯片编号22 幻灯片编号23 幻灯片编号24 幻灯片编号25 幻灯片编号26 SulfoglycosaminoglycancontentaffectsPHFtausolubilityandallowstheidentificationofdifferenttypesofPHFs 幻灯片编号28 幻灯片编号29 幻灯片编号30