脑淀粉样血管病-赵元立

CerebralAmyloidAngiopathy

脑淀粉样血管病赵元立北京天坛医院WhatisCAA?amyloiddepositionaged(>=50-60y)arteriesofthecortical,subcorticalareasM&FinincidenceRecurrent,MultipleHemorrhagePradaetal.,J.Neurosci.,2007BackgroundCerebralamyloidangiopathy(CAA)-depositionofβ-amyloidinthemediaandadventitiaofsmall-andmid-sizedarteriesICH-mostrecognizedresultof

CAARelationwithAlzheimerdiseaseCerebralAmyloidangiopathy

Two-photonprojectionofaz-seriesabout150umdeepintothebrainofaliving20-mo-oldtransgenicmouseexpressingamutanthumanamyloidprecursorprotein.Thisanimalhadamyloiddepositssurroundingsomecerebralvessels.

BrianJ.Bacskai,MassachusettsGeneralHospital,USA

EpidemiologyUnitedStates~upto15%ofallICH>60upto50%ofnontraumaticlobarICH>70~15-20per100,000population/yearaseriesof400autopsies:CAAin18.3%ofmen28%ofwomen(age40-90)aseriesof117confirmedAD:83%CAAGreenbergSM,Stroke

28(7):1418–22July1997SexandAgeSexmaybemorecommonlyinwomenincidenceofICHissameAgeagerelatedSporadicICHoccurs>60FamilialCAAatyoungeragesIcelandicform30-40,Dutch50-60DiagnosisCCheadache,vomiting,hemiplegia…PHwithouthypertension,asymptomaticPEICHrelatedfindingsCT/MRIlobar/cortical/subcorticalSAH,ventricularhemorrhage

梯度回声MR:sensitivetomicrohemorrhagePathologyCongoRed(+),Aβ(+)TransaxialT2-weightedgradient-echoMRimagesshowinnumerablemicrohemorrhagespredominantlyatcerebralgray–whitematterjunction.Microhemorrhagesarenotpresentinbasalganglia,pons,orcerebellum.LargefocalhemorrhagesarepresentinbilateralparietallobeMarisaKastoffBlitsteinAJR2007;189:720-725

GuidelinefordiagnosisBostonGroup-FourlevelsDefiniteCAA:lobar,cortical,orsubcorticalhemorrhageevidenceofsevereCAAProbableCAAwithsupportingpathologicalevidence:clinicaldata+somedegreeofvascularamyloiddepositionProbableCAA:clinicaldata+MR,nopathologicalspecimenmultiplehematomasinpatient>60PossibleCAA:patient>60clinical+MR:singlelobar,cortical,orcorticosubcorticalhemorrhage,noothercausemultiplehemorrhageswithapossiblebutnotadefinitecauseorsomehemorrhageinanatypicallocationKnudsenKA,Neurology2001;56:537–9.BhomrajThanviAgeandAgeing200635(6):565-571SpecialtypeofCAADutchtypeofhereditarycerebralhemorrhage:autosomaldominant,withmutationofamyloidprecursorprotein,atage40–60,mayproduceanabnormalanti-coagulant,whichmakeshemorrhagemorelikely.FamilialAlzheimer'sdisease:autosomaldominant,5–10%ofallADIcelandictype:autosomaldominant,withmutationinthegenecodingforcystatinC,beginat30–40withmultiplebrainhemorrhages,mostinvolvethebasalgangliaDownSyndrome:trisomy21Britishtypeoffamilialamyloidosis:autosomaldominant,associatedwithprogressivedementia,spasticity,andataxia.Brainstem,spinalcord,andcerebellumallexhibitamyloiddeposits,buthemorrhagetypicallydoesnotoccur.WhybleedingBleedingintobrainoccurastinybloodvesselscarryingamyloiddepositsbecomeheavierandmorebrittlemorelikelytoburstwithminortraumaorwithfluctuatingbloodpressureAneurysmsmaydevelop,andmayalsoruptureAmyloiddepositsmaydestroysmoothmusclecellsorcauseinflammationinthebloodvesselwall,causebloodvesseltobreakmoreeasilySethLove,FrontiersinBioscience14,4778-4792,January,2009ThecauseofamyloiddepositsinbloodvesselsinthebraininsporadicCAAisnotknownInhereditaryCAA,geneticdefects,typicallyonchromosome21,allowaccumulationofamyloid,aproteinmadeupofunitscalledbeta-pleatedsheetfibrils.Thefibrilstendtoclumptogether,sothattheamyloidcannotbedissolvedandbuildsupinthebrainbloodvesselwalls.Oneformofamyloidfibrilsubunitproteinsistheamyloidbetaprotein.StevenGreenbergGeriatricsandaging,200811(5):15-17Systemictheoryamyloidbetaproteininblooddepositedinbloodvesselsinthebrainbreakdownblood-brainbarrieramyloidbetaproteindepositedinbrainsubstanceformsneuriticplaqueSecondtheoryamyloidfibrilsproducedbyperivascularmicrogliaThirdtheorybothnervecellsandgliaproduceamyloidprecursorprotein,increaseswithaging病理机制AmyloiddamagesthemediaandadventitialeadingtothickeningofthebasalmembranestenosisofthevessellumenfragmentationoftheinternalelasticlaminaresultinfibrinoidnecrosisandmicroaneurysmformationSomeevidencesuggeststhattheamyloidisproducedinthesmoothmusclecellsofthetunicamediaasaresponsetodamageofthevesselwall(perhapsbyarteriosclerosisorhypertension)病理机制severalkeyprocessesareinvolved:productionofamyloidprecursorproteins(APP),processingofprecursorproteins,aggregationofprotein,andfibrilformation.

Impairedeliminationandaccumulationofsolubleandinsolubleβ-amyloidpeptidemayunderliethepathogenesisofCAAandexplainthelinkbetweenCAAandAD.ElectronmicroscopydemonstratesfibrilsofamyloidintheouterbasementmembraneintheinitialstageofCAAManytypesofamyloidproteinarepresentinthebody,butsomeareuniquetothebrain.β-amyloidisauniquecerebrovascularamyloidproteinAmyloidFamily:AβACysAT