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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 areas M & F in incidence Recurrent, Multiple Hemorrhage,Prada et al., J. Neurosci., 2007,Background,Cerebral amyloid angiopathy (CAA) -deposition of -amyloid in the med
2、ia and adventitia of small- and mid-sized arteries ICH - most recognized result of CAA Relation with Alzheimer disease,Cerebral Amyloid angiopathy Two-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 p
3、rotein. This animal had amyloid deposits surrounding some cerebral vessels. Brian J. Bacskai, Massachusetts General Hospital, USA,Epidemiology,United States up to 15% of all ICH 60 up to 50% of nontraumatic lobar ICH 70 15-20 per 100,000 population / year a series of 400 autopsies: CAA in 18.3% of m
4、en 28% of women (age 40-90) a series of 117 confirmed AD: 83% CAA,Greenberg SM, Stroke 28 (7): 141822 July 1997,Sex and Age,Sex maybe more commonly in women incidence of ICH is same Age age related Sporadic ICH occurs 60 Familial CAA at younger ages Icelandic form 30-40, Dutch 50-60,Diagnosis,CC hea
5、dache, vomiting, hemiplegia PH without hypertension, asymptomatic PE ICH related findings CT/MRI lobar/cortical/subcorticalSAH, ventricular hemorrhage梯度回声MR: sensitive to microhemorrhagePathology Congo Red(+), A(+),Transaxial T2-weighted gradient-echo MR images show innumerable microhemorrhages pred
6、ominantly at cerebral graywhite matter junction. Microhemorrhages are not present in basal ganglia, pons, or cerebellum. Large focal hemorrhages are present in bilateral parietal lobe Marisa Kastoff Blitstein AJR 2007; 189:720-725,Guideline for diagnosis,Boston Group - Four levelsDefinite CAA: lobar
7、, cortical, or subcortical hemorrhageevidence of severe CAAProbable CAA with supporting pathological evidence: clinical data + some degree of vascular amyloid depositionProbable CAA: clinical data + MR, no pathological specimen multiple hematomas in patient 60 Possible CAA: patient 60 clinical + MR:
8、 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
9、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 i
10、n 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 al
11、l 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 ru
12、pture 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 h
13、ereditary 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 fibr
14、il 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
15、 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 intern
16、al elastic lamina result in fibrinoid necrosis and microaneurysm formationSome 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 involve
17、d: 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 CAAMany types of amyloid protein are present in the body, but some are unique to the brain. -amyloid is a unique cerebrovascular amyloid protein,
