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1、Cerebral Amyloid Angiopathy脑淀粉样血管病,赵元立北京天坛医院,What is CAA?,amyloid deposition aged(=50-60y)arteries of the cortical,subcortical areasM&F in incidenceRecurrent,Multiple Hemorrhage,Prada et al.,J.Neurosci.,2007,Background,Cerebral amyloid angiopathy(CAA)-deposition of-amyloid in the media and adventiti
2、a of small-and mid-sized arteriesICH-most recognized result ofCAARelation with Alzheimer disease,Cerebral Amyloid angiopathyTwo-photon projection of a z-series about 150 um deep into the brain of a living 20-mo-old transgenic mouse expressing a mutant human amyloid precursor protein.This animal had
3、amyloid deposits surrounding some cerebral vessels.Brian J.Bacskai,Massachusetts General Hospital,USA,Epidemiology,United States up to 15%of all ICH 60up to 50%of nontraumatic lobar ICH 70 15-20 per 100,000 population/yeara series of 400 autopsies:CAA in 18.3%of men 28%of women(age 40-90)a series of
4、 117 confirmed AD:83%CAA,Greenberg SM,Stroke 28(7):141822 July 1997,Sex and Age,Sexmaybe more commonly in womenincidence of ICH is sameAgeage relatedSporadic ICH occurs 60 Familial CAA at younger agesIcelandic form 30-40,Dutch 50-60,Diagnosis,CC headache,vomiting,hemiplegiaPH without hypertension,as
5、ymptomaticPE ICH related findingsCT/MRI lobar/cortical/subcortical SAH,ventricular hemorrhage 梯度回声MR:sensitive to microhemorrhage Pathology Congo Red(+),A(+),Transaxial T2-weighted gradient-echo MR images show innumerable microhemorrhages predominantly at cerebral graywhite matter junction.Microhemo
6、rrhages are not present in basal ganglia,pons,or cerebellum.Large focal hemorrhages are present in bilateral parietal lobe Marisa Kastoff BlitsteinAJR 2007;189:720-725,Guideline for diagnosis,Boston Group-Four levelsDefinite CAA:lobar,cortical,or subcortical hemorrhage evidence of severe CAAProbable
7、 CAA with supporting pathological evidence:clinical data+some degree of vascular amyloid depositionProbable CAA:clinical data+MR,no pathological specimenmultiple hematomas in patient 60 Possible CAA:patient 60 clinical+MR:single lobar,cortical,or corticosubcortical hemorrhage,no other causemultiple
8、hemorrhages with a possible but not a definite causeor some hemorrhage in an atypical location,Knudsen KA,Neurology 2001;56:5379.,Bhomraj Thanvi Age and Ageing 2006 35(6):565-571,Special type of CAA,Dutch type of hereditary cerebral hemorrhage:autosomal dominant,with mutation of amyloid precursor pr
9、otein,at age 4060,may produce an abnormal anti-coagulant,which makes hemorrhage more likely.Familial Alzheimers disease:autosomal dominant,510%of all AD Icelandic type:autosomal dominant,with mutation in the gene coding for cystatin C,begin at 3040 with multiple brain hemorrhages,most involve the ba
10、sal ganglia Down Syndrome:trisomy 21 British type of familial amyloidosis:autosomal dominant,associated with progressive dementia,spasticity,and ataxia.Brain stem,spinal cord,and cerebellum all exhibit amyloid deposits,but hemorrhage typically does not occur.,Why bleeding,Bleeding into brain occur a
11、s tiny blood vessels carrying amyloid deposits become heavier and more brittlemore likely to burst with minor trauma or with fluctuating blood pressureAneurysms may develop,and may also rupture Amyloid deposits may destroy smooth muscle cells or cause inflammation in the blood vessel wall,cause bloo
12、d vessel to break more easily,Seth Love,Frontiers in Bioscience 14,4778-4792,January,2009,The cause of amyloid deposits in blood vessels in the brain in sporadic CAA is not knownIn hereditary CAA,genetic defects,typically on chromosome 21,allow accumulation of amyloid,a protein made up of units call
13、ed beta-pleated sheet fibrils.The fibrils tend to clump together,so that the amyloid cannot be dissolved and builds up in the brain blood vessel walls.One form of amyloid fibril subunit proteins is the amyloid beta protein.,Steven Greenberg Geriatrics and aging,2008 11(5):15-17,Systemic theoryamyloi
14、d beta protein in blood deposited in blood vessels in the brainbreakdown blood-brain barrieramyloid beta protein deposited in brain substanceforms neuritic plaqueSecond theoryamyloid fibrils produced by perivascular microgliaThird theoryboth nerve cells and glia produce amyloid precursor protein,inc
15、reases with aging,病理机制,Amyloid damages the media and adventitialeading to thickening of the basal membranestenosis of the vessel lumenfragmentation of the internal elastic laminaresult in fibrinoid necrosis and microaneurysm formationSome evidence suggests that the amyloid is produced in the smooth
16、muscle cells of the tunica media as a response to damage of the vessel wall(perhaps by arteriosclerosis or hypertension),病理机制,several key processes are involved:production of amyloid precursor proteins(APP),processing of precursor proteins,aggregation of protein,and fibril formation.Impaired elimina
17、tion and accumulation of soluble and insoluble-amyloid peptide may underlie the pathogenesis of CAA and explain the link between CAA and AD.Electron microscopy demonstrates fibrils of amyloid in the outer basement membrane in the initial stage of CAAMany types of amyloid protein are present in the b
18、ody,but some are unique to the brain.-amyloid is a unique cerebrovascular amyloid protein,Amyloid Family:AACysATTRAGelPrPScABriADan,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
19、增厚、变性中等量淀粉样小体形成 x100,HE VS Congo Red,Pathology,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A(+)的脑血管，集中分布在皮层及皮层下区域,grading,Mortality and Morbidity,CAA ICH associated with lower mortality rate(11-32%)and better functional outcome25-40%have a recurrence,with the highest risk i
20、n the first year,associated with a high mortality rate(up to 40%)Cognitive impairment is common,建立规范化的微创外科诊断治疗标准（新增样本2000例）,规范试验标准,多中心大样本研究,小骨窗手术,大骨瓣减压手术,其它微创手段,病理学检查,高血压动脉硬化性,淀粉样血管病,疗效分析,自然史研究,新增2000例,既往2764例,筛选疾病相关危险因素,建立预警体系,卫生经济学研究,建立关于成本/效益的数学模型,社区干预,淀粉样变脑血管病研究-技术路线,数据库网络平台,现有病例分析,67例确诊为自发性脑出血开
21、颅手术获取出血灶周围病理标本刚果红染色和A免疫组化染色结果 病理学证实8例为淀粉样血管病占11.9男:女48:19(CAA男:女6:2)40-49岁组15.8%(3/19)50-59岁组13.0%(3/23)60-69岁组占9.1%(1/11)70岁以上组11.1%(1/9),典型病例,典型复发性、多发脑出血女性，73岁主因“突发意识丧失1小时”于2008年4月22日急诊入院3年前曾因“突发头痛、头晕、呕吐1天”急诊收入我院神经内科否认高血压病、糖尿病、高血脂、冠心病等病史无服用抗凝药物史此次入院时深昏迷，去脑强直状态，四肢肌张力增高，病理征（）急诊行额颞顶大骨瓣开颅血肿清除术病理诊断为淀粉样脑血管病,CT Scan(1)1/10/2005 8mL right occipital lobe,CT Scan(2)5/20/2005,CT Scan(3)4/22/2008 100ml,recurrent bilateral multiple hemorrhage,CT Scan(4)4/23/2008 P.O,CT Scan(5)5/19/2008,Thank you!,
