脑淀粉样血管病赵元立（英文）

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 areas M 189:720-725 Guideline for diagnosis Boston Group - Four levels Definite CAA: lobar, cortical, or subcortical hemorrhage evidence of severe CAA Probable CAA with supporting pathological evidence: clinical data + some degree of vascular amyloid deposition Probable CAA: clinical data + MR, no pathological specimen multiple hematomas in patient 60 Possible CAA: patient 60 clinical + MR: single lobar, cortical, or corticosubcortical hemorrhage, no other cause multiple hemorrhages with a possible but not a definite cause or 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 protein, 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 basal 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 as tiny blood vessels carrying amyloid deposits become heavier and more brittle more likely to burst with minor trauma or with fluctuating blood pressure Aneurysms may develop, and may also rupture Amyloid deposits may destroy smooth muscle cells or cause inflammation in the blood vessel wall, cause blood 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 known In hereditary CAA, genetic defects, typically on chromosome 21, allow accumulation of amyloid, a protein made up of units called 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 theory amyloid beta protein in blood deposited in blood vessels in the brain breakdown blood-brain barrier amyloid beta protein deposited in brain substance forms neuritic plaque Second theory amyloid fibrils produced by perivascular microglia Third theory both nerve cells and glia produce amyloid precursor protein, increases with aging 病理机制 Amyloid damages the media and adventitia leading to thickening of the basal membrane stenosis of the vessel lumen fragmentation of the internal elastic lamina result in fibrinoid necrosis and microaneurysm formation Some evidence suggests that the amyloid is produced in the smooth 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 elimination 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 CAA Many types of amyloid protein are present in the body, but some are unique to the brain. -amyloid is a unique cerebrovascular amyloid protein Amyloid Family: A ACys ATTR AGel PrPSc ABri ADan 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 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 outcome 25-40% have a recurrence, with the highest risk in 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