增龄相关性脑小血管病谱系的病理基础及其影像学特点

增龄相关性脑小血管病谱系（spectrum o f a ge-related cerebral small vessel diseases， ArCSVDS）是指随着年龄的增长，脑小动脉、微动脉、毛细血管、微静脉、小静脉出现老化的一组脑 小血管病（cerebral small vessel disease，CSVD），包括深穿支动脉病（deep perforating arteriopathy，DPA） 和β淀粉样蛋白（β-amyloid，Aβ）有关的脑淀粉样血管病（cerebral amyloid angiopathy，CAA）。以往的 研究往往将这两种疾病视为独立的实体，然而最近的研究发现，无论从年龄、高血压等相似的脑血 管病危险因素，还是从潜在的相互作用角度出发，DPA与CAA是一组ArCSVDS疾病，血脑屏障（blood brain barrier，BBB）破坏、内皮细胞损伤、血管周围Aβ是连接DPA与CAA的共同发病机制，而且有 30%～68%的患者两者可以重叠发病。     

脑淀粉样血管病的病理学机制及影像学研究进展

脑淀粉样血管病（cerebral amyloid angiopathy，CAA）是淀粉样物质沉积于大脑皮质和软脑膜中、小动脉壁而引起的血管病变，以痴呆、精神症状、进行性反复多病灶出血为主要临床表现。脑淀粉样血管病的发病率国内外报道相仿，在无症状老年人群中的发生率〉30％，并随着年龄的增加而逐渐升高，与性别无明显相关性。脑淀粉样血管病为非高血压老年脑出血的重要原因之一，其所引起的脑出血占原发性脑出血的5％～10％，且可能参与不同类型老年痴呆的发病机制。笔就近年来散发性脑淀粉样血管病的发病机制和影像学研究进展进行综述。[第一段]     

脑淀粉样血管病发病机制的研究进展

脑淀粉样血管病（cerebral amyloid angiopathy，CAA）的主要致病物质是β淀粉样蛋白，其 产生异常、清除障碍导致异常沉积，引起管壁破坏、管腔狭窄等病理变化，最终导致CAA。目前CAA的 具体发病机制尚不清楚，涉及的成分复杂。本文介绍了β淀粉样蛋白产生及清除的三种过程及其平 衡破坏的后续效应和主要影响因素，同时从病因分类的角度阐明CAA的类型。     

增龄相关性脑小血管病治疗新进展

随着全球预期寿命的延长，增龄相关性脑小血管病（cerebral small vessel disease，CSVD）患 病率不断增加。最近研究显示，深穿支动脉病（deep perforating arteriopathy，DPA）和脑淀粉样血管病 （cerebral amyloid angiopathy，CAA）均属于增龄相关性脑小血管病谱系（spectrum of age-related cerebral small vessel diseases）疾病，两者存在重叠性，且相互作用。增龄相关性CSVD治疗包括特异性及非特 异性治疗。非特异性治疗包括控制血管危险因素、抗血小板治疗及静脉溶栓等。特异性治疗方面，最 近研究提示抗炎治疗对增龄相关性CSVD或许有效；而针对CAA相关性炎症，已显示其对类固醇和（或） 环磷酰胺有良好的反应。随着对增龄相关性CSVD发病机制的进一步了解，未来可能会出现更多特异 性的治疗方法。     

脑淀粉样血管病5例分析

本文对5例脑淀粉样血管病患者临床资料进行分析时认为:脑淀粉样血管病均以脑血管病的临床形式表现,多伴有CAA—AV改变,高血压、Alzheimer病及脑淀粉样血管病并存可增加脑梗塞的危险性,CAA患者存在潜在反复性出血的危险。同时作者提出CAA患者在外科手术时应考虑到术中止血的难度及术后病人继发出血的可能性。     

脑淀粉样血管病

脑淀粉样血管病（CAA）是血压正常的老年人发生自发性皮层-皮层下出血的重要原因。CAA特征表现为在皮层、皮层下和软脑膜的中小型血管的外膜和中膜中广泛分布β淀粉蛋白。可表现为单发，也可有家族遗传性。遗传综合症少见，且为常染色体遗传。遗传的CAA有着明显的临床表现且好发于年轻人，较早可于30岁患病。     

脑淀粉样血管病的诊断:皮层活检的敏感性和特异性

脑淀粉样血管病(CAA)是淀粉样物质沉积在大脑皮层和软脑膜血管壁的一种疾病,CAA相关出血在临床上很难与其他原因(如外伤、出血性梗塞、高血压、出血性肿瘤、血管畸形、脑血管炎等)引起的脑叶出血相鉴别。     

脑淀粉样血管病的影像学标志物及临床相关性研究进展

脑淀粉样血管病（cerebral amyloid angiopathy,CAA）是一种多见于老年人群中的脑小血管病, 不同于高血压导致的脑小血管病易累及脑深部区域,CAA多累及皮层及软脑膜小血管。多发脑叶微出 血是CAA患者常见的影像学表现,研究认为其与症状性脑叶出血及进行性认知功能下降相关。随着 近年来对脑小血管病影像学表现的深入研究,发现皮层蛛网膜下腔出血与皮层表面含铁血黄素沉 积是CAA相对特异的影像学表现,并且与短暂性局灶性神经系统症状发作相关。此外,脑白质高信号、 小梗死灶等脑小血管病影像学标志均在CAA患者中出现,提示除外临床较关注的出血性改变,CAA患 者的缺血性损伤也是导致临床症状的重要因素。     

脑淀粉样血管病的分子影像研究进展

脑淀粉样血管病(CAA)是以β-淀粉样蛋白(Aβ)沉积于脑血管壁中层及外膜为主要病理特征的一类年龄相关脑小血管病。多种分子影像技术如淀粉样蛋白正电子发射体层摄影(PET)、18F-氟脱氧葡萄糖-PET等已逐渐应用于CAA患者。其中, 淀粉样蛋白PET显像通过正电子核素标记的显像剂特异性结合病理标志物, 反映Aβ沉积的分布和负荷, 可为诊断CAA提供定性与定量信息, 然其在鉴别CAA与其他Aβ相关疾病如阿尔茨海默病方面价值有限。其他分子影像如tau-PET、单光子发射计算机体层摄影等及新型高选择性示踪剂也在被广泛研究中。文中主要就CAA分子影像进展进行综述。     

脑淀粉样血管病研究现状

<正>脑淀粉样血管病(cerebral amyloid angiopathy,CAA)是由淀粉样蛋白沉积在脑皮质、皮质下及软脑膜动脉的一种常见于老年人的脑小血管病,主要累及中小动脉,很少累及静脉,临床上以反复性多发性脑叶出血、认知功能减退等为主要表现~([1])。β淀粉样蛋白(Aβ)在脑血管壁上过量沉积是其主要发病机制。CAA已成为老年人自发性脑出血的常见病因之一,CAA相关性脑出血至少约占自发性脑出血的20%~([2])。     

Differential deposition of amyloid β peptides in cerebral amyloid angiopathy associated with Alzheimer’s disease and vascular dementia

Cerebral amyloid angiopathy (CAA) caused by deposition of amyloid β (Aβ) peptides in the cerebrovasculature, involves degeneration of normal vascular components and increases the risk of infarction and cerebral hemorrhage. Accumulating evidence suggests that sporadic CAA is also a significant contributor to cognitive decline and dementia in the elderly. However, the mechanisms by which CAA arises are poorly understood. While neuronal sources of Aβ peptides are sufficient to cause CAA in transgenic mice overexpressing the amyloid precursor protein, there is reason to believe that in aging man, vascular disease modulates the disease process. To better understand CAA mechanisms in dementia, we assessed the frontal cortex of 62 consecutive cases of Alzheimer’s disease (AD), vascular dementia (VaD), and mixed dementia (MD) using immunohistochemistry with antibodies to Aβ, smooth muscle actin and the carboxyl-terminal peptides to detect Aβ(40) and Aβ(42). While vascular Aβ deposition was invariably associated with smooth muscle degeneration as indicated by absence of smooth muscle cell actin reactivity, VaD/MD cases exhibited markedly more vascular Aβ(42) deposits and smooth muscle actin loss compared to AD cases with similar degrees of CAA and Aβ(40) deposition. This suggests that distinct mechanisms are responsible for the differential deposition of Aβ in CAA associated with AD and that associated with ischemic/cerebrovascular disease. It is plausible that experimental studies on the effects of cerebrovascular disease on Aβ production and elimination will yield important clues on the pathogenesis of CAA.     

Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy

Advanced cerebrovascular β‐amyloid deposition (cerebral amyloid angiopathy, CAA) is associated with cerebral microbleeds, but the precise relationship between CAA burden and microbleeds is undefined. We used T2*‐weighted magnetic resonance imaging (MRI) and noninvasive amyloid imaging with Pittsburgh Compound B (PiB) to analyze the spatial relationship between CAA and microbleeds. On coregistered positron emission tomography (PET) and MRI images, PiB retention was increased at microbleed sites compared to simulated control lesions (p = 0.002) and declined with increasing distance from the microbleed (p < 0.0001). These findings indicate that microbleeds occur preferentially in local regions of concentrated amyloid and support therapeutic strategies aimed at reducing vascular amyloid deposition. Ann Neurol 2010     

Animal models of cerebral β-amyloid angiopathy

Cerebral amyloid angiopathy (CAA) is a significant risk factor for hemorrhagic stroke in the elderly, and occurs as a sporadic disorder, as a frequent component of Alzheimer's disease, and in several rare, hereditary conditions. The most common type of amyloid found in the vasculature of the brain is β-amyloid (Aβ), the same peptide that occurs in senile plaques. A paucity of animal models has hindered the experimental analysis of CAA. Several transgenic mouse models of cerebral β-amyloidosis have now been reported, but only one appears to develop significant cerebrovascular amyloid. However, well-characterized models of naturally occurring CAA, particularly aged dogs and non-human primates, have contributed unique insights into the biology of vascular amyloid in recent years. Some non-human primate species have a predilection for developing CAA; the squirrel monkey (Saimiri sciureus), for example, is particularly likely to manifest β-amyloid deposition in the cerebral blood vessels with age, whereas the rhesus monkey (Macaca mulatta) develops more abundant parenchymal amyloid. These animals have been used to test in vivo β-amyloid labeling strategies with monoclonal antibodies and radiolabeled Aβ. Species-differences in the predominant site of Aβ deposition also can be exploited to evaluate factors that direct amyloid selectively to a particular tissue compartment of the brain. For example, the cysteine protease inhibitor, cystatin C, in squirrel monkeys has an amino acid substitution that is similar to the mutant substitution found in some humans with a hereditary form of cystatin C amyloid angiopathy, possibly explaining the predisposition of squirrel monkeys to CAA. The existing animal models have shown considerable utility in deciphering the pathobiology of CAA, and in testing strategies that could be used to diagnose and treat this disorder in humans.     

Cerebral amyloid angiopathy: An overview

Cerebral amyloid angiopathy (CAA) is characterized by amyloid deposition in cortical and leptomeningeal vessels. Several cerebrovascular amyloid proteins (amyloid β‐protein (Aβ), cystatin C (ACys), prion protein (AScr), transthyretin (ATTR), gelsolin (AGel), and ABri (or A‐WD)) have been identified, leading to the classification of several types of CAA. Sporadic CAA of Aβ type is commonly found in elderly individuals and patients with Alzheimer’s disease. Cerebral amyloid angiopathy is an important cause of cerebrovascular disorders including lobar cerebral hemorrhage, leukoencephalopathy, and small cortical hemorrhage and infarction. We review the clinicopathological and molecular aspects of CAA and discuss the pathogenesis of CAA with future perspectives.     

Imaging of amyloid burden and distribution in cerebral amyloid angiopathy

OBJECTIVE: Cerebrovascular deposition of beta-amyloid (cerebral amyloid angiopathy [CAA]) is a major cause of hemorrhagic stroke and a likely contributor to vascular cognitive impairment. We evaluated positron emission tomographic imaging with the beta-amyloid-binding compound Pittsburgh Compound B (PiB) as a potential noninvasive method for detection of CAA. We hypothesized that amyloid deposition would be observed with PiB in CAA, and based on the occipital predilection of CAA pathology and associated hemorrhages, that specific PiB retention would be disproportionately greater in occipital lobes. METHODS: We compared specific cortical PiB retention in 6 nondemented subjects diagnosed with probable CAA with 15 healthy control subjects and 9 patients with probable Alzheimer's disease (AD). RESULTS: All CAA and AD subjects were PiB-positive, both by distribution volume ratio measurements and by visual inspection of positron emission tomographic images. Global cortical PiB retention was significantly increased in CAA (distribution volume ratio 1.18 +/- 0.06) relative to healthy control subjects (1.04 +/- 0.10; p = 0.0009), but was lower in CAA than in AD subjects (1.41 +/- 0.17; p = 0.002). The occipital-to-global PiB ratio, however, was significantly greater in CAA than in AD subjects (0.99 +/- 0.07 vs 0.86 +/- 0.05; p = 0.003). INTERPRETATION: We conclude that PiB-positron emission tomography can detect cerebrovascular beta-amyloid and may serve as a method for identifying the extent of CAA in living subjects.     

Genetic-morphologic association study: association between the low density lipoprotein-receptor related protein (LRP) and cerebral amyloid angiopathy

Accumulating evidence suggests that genetic factors such as apolipoprotein E (APOE), can act in different ways in the pathogenesis of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). The role of the low-density lipoprotein-receptor related protein (LRP), the major cerebral APOE receptor, in AD has been discussed controversially depending on data from different populations and methodological approaches. We examined the influence of LRP polymorphisms on CAA in 125 post-mortem cases genotyped for APOE and classified according to the neurofibrillary Braak and Braak staging of AD (indicating neurodegeneration grade). CAA was assessed separately for leptomeningeal (CAAlep.), noncapillary cortical (CAAcort.) and capillary cortical (CAAcap.) vessels in beta-amyloid stained sections. Our results suggest: (i) the 87 bp allele of LRP5' polymorphism (LRP5') is an independent predictive factor for CAAcort. and CAAlep.; (ii) the C/C genotype (C allele) of the LRP exon 3 polymorphism is positively associated with the severity of CAAlep. and CAAcort., implicating a younger age of CAA onset and/or faster CAA progression; (iii) as CAAcort. and CAAlep. showed different genetic associations in contrast to CAAcap., we can underscore the hypothesis that different molecular mechanisms are involved in CAA pathogenesis of noncapillary and capillary cerebral vessels. Our results lead us to postulate that the LRP5'87 bp and the LRP exon 3 C alleles of the LRP gene (or another locus that might be in linkage disequilibrium with these LRP polymorphic sites) could modify cerebrovascular LRP function or expression in noncapillary cerebral vessels, leading to an increased cerebrovascular amyloid deposition.     

Cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) is characterized by deposition of cerebrovascular amyloid protein in the media of leptomeningeal vessels. (amyloid B protein, cystatin C, transthyretin, gelsolin, and prion protein). It is a cause of cerebrovascular disorders including cerebral hemorrhage, cognitive impairment and unusually transient neurological symptoms. It is the main contributing factor to cerebral hemorrhage after hypertension in the elderly. We aimed to review epidemiological, pathophysiological and clinical and MRI imaging data in CAA.