脑淀粉样血管病-赵元立（英文）

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:AβACysATTRAGelPrPScABriADan病理特点受累血管壁常规染色在光镜下呈不成形的，强嗜伊红的玻璃样即淀粉样改变刚果红染色呈粉红阳性物质在血管及其周围沉积，即嗜刚果红血管病脑膜及皮质中、小血管受累淀粉样物质多沉积于血管中膜及外膜血管壁增厚，管腔狭窄脑淀粉样血管病脑膜表面大血管硬化，管腔狭窄附近小动脉亦明显变性x50脑实质内可见大量淀粉样小体形成脑实质小血管管壁增厚、变性中等量淀粉样小体形成x100HEVSCongoRedPathology由皮层向皮层下过度的区域中受累血管的分布情况高倍镜下典型的嗜刚果红染色的血管壁，呈现“双环”状标本中可见不同程度受累的血管由低倍到高倍示Aβ(+)的脑血管，集中分布在皮层及皮层下区域gradingMortality