Alzheimers-disease-20160322

[e-mail]2016.03.22Tableofcontents•Introduction•Epidemiology•Anatomy•Pathology•EtiologyandRiskFactors•ClinicalManifestations•DiagnosticEvaluation•TreatmentIntroduction•In1907,AloisAlzheimerpublishedthelandmarkcase.•A51-year-oldwomanwithdeteriorationofhermentalstate.•Herautopsydisclosedneurofibrillarytangles(NFTs)andsenileplaquesinthecerebralneocortexandhippocampus.•Alzheimer’sdiseaseisanervoussystemdegenerativediseases•Themostcommonreasonofdementia.•Itslowlydestroysmemoryandthinkingskillsand,eventually,abilitytocarryoutthesimplesttasks.•Itbeginsslowlyandgetsworseovertime.Epidemiology•5.3millionAmericanshaveAD.•SomeoneinthecountrydevelopsADevery67seconds.By2050,onenewcaseofADisexpectedtodevelopevery33seconds,resultinginnearly1millionnewcasesperyear.•Totalpaymentsin2015forhealthcare,long-termcareandhospiceservicesforpeopleolderthan65yearswithdementiaareexpectedtobe$226billion.Annually,approximately100,000peopledieofADTherewere5.7millionpeopleofADinChinain2010.ChanKY,WangW,WuJJ,etal;GlobalHealthEpidemiologyReferenceGroup(GHERG).EpidemiologyofAlzheimer’sdiseaseandotherformsofdementiainChina,1990–2010:asystematicreviewandanalysis.Lancet.2013;381(9882):2016–2023.Anatomy•Weight:3pounds•Size:amediumcauliflower•Numblerofneurons:100billion•Numblerofsynapses:100trillion1.CerebralHemispheresThethreemainParts2.cerebellumThethreemainParts3.BrainStemThethreemainPartsOtherCrucialParts·Hippocampus:·Thalamus:·Hypothalamus:·Limbicsystem:Differentmentalactivitiestakeplaceindifferentpartsofthebrain.·Thebrainhasbillionsofneurons,eachwithanaxonandmanydendrites.·Tostayhealthy,neuronsmustcommunicatewitheachother,carryoutmetabolism,andrepairthemselves.·ADdisruptsallthreeoftheseessentialjobs.PathologyBrianatrophyPlaquesandTangles:TheHallmarksofAD·Beta-amyloidplaques,whicharedensedepositsofproteinandcellularmaterialthataccumulateoutsideandaroundnervecells·Neurofibrillarytangles,whicharetwistedfibersthatbuildupinsidethenervecellPlaquesandTangles:TheHallmarksofADThree-dimensionalreconstructedimagebyconfocalmicroscopyofaneuritic(senile)plaqueinthecortexofapatientdyingwithAlzheimerdisease.Notethatthisplaquecoreisnotasolidmassofamyloidbutisfragmentedandporousandcontainsabnormalcellprocessesintercalatedwithinit.(ImagecourtesyofDr.EliezerMasliah,UniversityofCalifornia,SanDiego,CA.)EtiologyandRiskFactors•RiskFactors•age,•femalesex,•historyofsevereheadtrauma•Downsyndrome•Aslowactingvirus•Homocysteine，Aboutgene•ApoE4(onchromosome19)•Mutationsinamyloidprecursorprotein(APP)onchromosome21•Mutationsinpresenilin1(PS1)andpresenilin2(PS2)onchromosomes14and1•Mutationonchromosome12encodesa2–macroglobulin•ThegeneforApoE4(onchromosomeisassociatedwithbothearly-andlate-onsetADofbothsporadicandfamilialvarieties.Chia-ChenLiu,TakahisaKanekiyo,HuaxiXu，ApolipoproteinEandAlzheimerdisease:risk,mechanisms,andtherapy，NatRevNeurol.2013Feb;9(2):106–118.Aboutgene•ApoE4(onchromosome19)•Mutationsinamyloidprecursorprotein(APP)onchromosome21•Mutationsinpresenilin1(PS1)andpresenilin2(PS2)onchromosomes14and1•Mutationonchromosome12encodesa2–macroglobulin•Amyloid-betaprecursorprotein(AβPP)mutationsmaycauseincreasedamyloid-beta(Aβ)productionwithsubsequentaggregationinneurons.Thismutationchangesthenormalstructureoftheprotein,alteringitsrecognitionbymetabolizingenzymeslikealpha-secretaseandusingalternativepathwaysfordegradation,leadingtoaprogressiveaccumulationofthepeptide.Aboutgene•ApoE4(onchromosome19)•Mutationsinamyloidprecursorprotein(APP)onchromosome21•Mutationsinpresenilin1(PS1)andpresenilin2(PS2)onchromosomes14and1•Mutationonchromosome12encodesa2–macroglobulinEtiology•Aßaggregation•Tauphosphorylation•inflammatory,•oxidative,•metabolic,•nutritional,•immuneprocesses.1.APPsticksthroughtheneuronmembrane.2.EnzymescuttheAPPintofragmentsofprotein,includingbeta-amyloid.3.Beta-amyloidfragmentscometogetherinclumpstoformplaques.Etiology•Aßaggregation•Tauphosphorylation•inflammatory,•oxidative,•metabolic,•nutritional,•immuneprocesses.•Neuronshaveaninternalsupportstructurepartlymadeupofmicrotubules.Aproteincalledtauhelpsstabilizemicrotubules.InAD,tauchanges,causingmicrotubulestocollapse,andtauproteinsclumptogethertoformneurofibrillarytangles.Etiology•Aßaggregation•Tauphosphorylation•inflammatory,•oxidative,•metabolic,•nutritional,•immuneprocesses.ClinicalManifestations•Doctor,mymotheris75yearsold,andoverthelast3yearsIhavenotedthatsheishavingmoredifficultywithhermemory.Sheremembershermarriage50yearsago,butshedoesnotrememberthatwewerehereyesterday.Sheasksthesamequestionsconstantlyandforgetsmyanswers.Sheisunabletobalancehercheckbook,andyesterdayshecouldnotfindthewayhomefromthedrugstore.whatareriskfactorsinthecase？ClinicalManifestations•Memoryloss•Diffcultyperformingfamiliartasks•Problemswithlanguage•Disorientationtotimeandplace•PooranddecreasedjudgmentMemoryloss•Forgettingrecentlylearnedinformationisoneofthemostcommonearlysignsofdementia.Apersonbeginstoforgetmoreoftenandisunabletorecalltheinformationlater.ClinicalManifestations•Memoryloss•Diffcultype