Pathogenesis of cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) is the result of the deposition of an amyloidogenic protein in cortical and leptomeningeal vessels. The most common type of CAA is caused by amyloid β-protein (Aβ), which is particularly associated with Alzheimer's disease (AD). Excessive Aβ-CAA formation can be caused by several mutations in the Aβ precursor protein and presenilin genes. The origin of Aβ in CAA is likely to be neuronal, although cerebrovascular cells or the circulation cannot be excluded as a source. Despite the apparent similarity, the pathogenesis of CAA appears to differ from that of senile plaques in several aspects, including the mechanism of Aβ-induced cellular toxicity, the extent of inflammatory reaction and the role of oxidative stress. Therefore, therapeutic strategies for AD should, at least in part, also target CAA. Moreover, CAA and cerebrovascular disease (CVD) may set a lower threshold for AD-like changes to cause dementia and may even cause dementia on its own, since patients with AD and CAA and/or CVD appear to be more cognitively impaired than patients with only AD. In conclusion, the precise impact of CAA on AD or dementia remains unclear, however, its role may have been underestimated in the past, and more extensive studies of in vitro and in vivo models for CAA will be needed to elucidate the importance of CAA-specific approaches in designing intervention strategies for AD.     

Creutzfeldt-Jakob disease and cerebral amyloid angiopathy

An 83-year-old female with no personal or familial neurological history developed progressive gait and speech disturbance and left motor deficit. She suffered intractable seizures and died 3 months after the onset of neurological signs. Neuropathology showed severe spongiosis and gliosis in the cortex and basal ganglia, and diffuse cerebral amyloid angiopathy. Immunostaining for prion protein (PrP) showed intense PrP positivity in areas of confluent spongiosis and some granular staining in astrocytes. The cortical vessel walls stained positively for /A4 amyloid but not for PrP amyloid. Both types of amyloid were only observed in pericapillary parenchyma, in areas with severe spongiosis. There were only a few tangles and neuritic plaques in the temporal cortex; amyloid plaques were not present either by silver stains or immunostains. There was neither arteriopathic leukoencephalopathy nor cerebral hemorrhage. Immunoblot analysis of brain extracts revealed an abnormal proteinase K-resistant isoform of PrP. Association of Creutzfeldt-Jakob disease and Cerebral amyloid angiopathy in the absence of Alzheimer changes is unusual. The association of PrP and /A4 amyloid deposits could have been fortuitous in an 83-year-old patient. An etiopathogenic relationship between /A4 amyloid deposition and PrP accumulation may also be considered.Supported by a Concerted Action of the European community This case was the subject of a preliminary presentation at the eighty-seventh meeting of the British Neuropathological Society [17]     

Recurrent cerebral hemorrhage and amyloid angiopathy

A patient with no previous relevant history presented with recurrent cerebral hemorrhages of which he died 4 years 5 months after the onset. On autopsy, an amyloid angiopathy was present and localised to the cerebrovascular system. Hemorrhages were associated with some small infarcts in the subcortical regions. The leptomeninges and the cortical arteries were mostly involved by an infiltration mainly in the adventitia and media. There were no senile plaques in the cortex. The amyloid deposit present in the senile plaques and in the vessel walls of the amyloid angiopathy could be the result of two distinct pathological processes.     

Review: sporadic cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) may result from focal to widespread amyloid-β protein (Aβ) deposition within leptomeningeal and intracortical cerebral blood vessels. In addition, pericapillary Aβ refers to Aβ depositions in the glia limitans and adjacent neuropil, whereas in capillary CAA Aβ depositions are present in the capillary wall. CAA may cause lobar intracerebral haemorrhages and microbleeds. Hypoperfusion and reduced vascular autoregulation due to CAA might cause infarcts and white matter lesions. CAA thus causes vascular lesions that potentially lead to (vascular) dementia and may further contribute to dementia by impeding the clearance of solutes out of the brain and transport of nutrients across the blood brain barrier. Severe CAA is an independent risk factor for cognitive decline. The clinical diagnosis of CAA is based on the assessment of associated cerebrovascular lesions. In addition, perivascular spaces in the white matter and reduced concentrations of both Aβ(40) and Aβ(42) in cerebrospinal fluid may prove to be suggestive for CAA. Transgenic mouse models that overexpress human Aβ precursor protein show parenchymal Aβ and CAA, thus corroborating the current concept of CAA pathogenesis: neuronal Aβ enters the perivascular drainage pathway and may accumulate in vessel walls due to increased amounts and/or decreased clearance of Aβ, respectively. We suggest that pericapillary Aβ represents early impairment of the perivascular drainage pathway while capillary CAA is associated with decreased transendothelial clearance of Aβ. CAA plays an important role in the multimorbid condition of the ageing brain but its contribution to neurodegeneration remains to be elucidated.     

Surgical experience with cerebral amyloid angiopathy

Cerebral amyloid angiopathy can present as lobar intracerebral hemorrhage in an elderly person, presumably due to increased fragility of the vessels affected by amyloid deposition. For this reason, patients presenting with intracerebral hemorrhage and suspected of having cerebral amyloid angiopathy have often been treated nonsurgically. Since 1983 we have evaluated 11 patients with cerebral amyloid angiopathy (nine women and two men, mean age 73 years) who have undergone either intracerebral hematoma evacuation or brain biopsy. Nine of the 11 patients presented with intracerebral hemorrhage, which was unilobar in three patients and multilobar in six and involved the parietal lobes seven times, the frontal lobes four times, the temporal lobes four times, and the occipital lobes twice. These nine patients underwent hematoma removal, with no cases of abnormal intraoperative bleeding or recurrent hemorrhage. Six patients improved neurologically, and two were unchanged after hematoma evacuation; the remaining patient had a fatal cardiopulmonary arrest during the immediate postoperative period. During follow-up in seven patients (median 11 months, range 1 week to 74 months) none experienced a recurrent intracerebral hemorrhage and four continued to improve. Two of the 11 patients had cerebral amyloid angiopathy diagnosed by brain biopsy as part of an evaluation for dementia, also without surgical complications. This series suggests that patients with cerebral amyloid angiopathy may safely undergo operative procedures, and patients presenting with intracerebral hemorrhage may show neurologic improvement following evacuation of the hematoma.     

Aβ-related cerebral amyloid angiopathy

Neurological Sciences - Cerebral amyloid angiopathy is due to β-protein accumulation in the vessel walls and occurs in normal aging, Alzheimer’s disease and hereditary cerebral...     

Ubiquitin in cerebral amyloid angiopathy.

Immunohistological findings in cerebral blood vessels of 4 cases with cerebral amyloid angiopathy (CAA) were compared with those of 4 Alzheimer's (AD) cases. A panel of antibodies against 2 neurofilament subunits (BF10 and RT97), a microtubule-associated protein (TAU) and ubiquitin were used. CAA cases showed a strong immunoreactivity for ubiquitin in blood vessel wall. Senile plaques (SPs) in CAA cases showed strong ubiquitin positivity but the central amyloid core was negative. AD brains showed immunoreactivity with all antibodies in SPs and neurofibrillary tangles (NFTs); blood vessels were consistently negative for ubiquitin. Control brains showed few SPs and NFTs; these were positive for ubiquitin, but blood vessels were negative. These results indicate that vascular amyloid deposition in CAA and AD may have different pathophysiological mechanisms.     

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.     

Leukoencephalopathy in diffuse hemorrhagic cerebral amyloid angiopathy

We have studied 12 patients with diffuse hemorrhagic cerebral amyloid angiopathy clinically and at postmortem examination. The brains in 8 patients had diffuse bilateral loss of myelin in the hemispheric white matter sparing the U fibers, corpus callosum, and internal capsules. The periventricular areas were predominantly affected. Microscopic examination of the white matter showed an association with subacute or chronic edematous lesions: spongiosis, swollen oligodendroglia, widening of the perivascular spaces with edema fluid or siderophages, hyalinization of the blood vessel walls, incomplete myelin loss, and astrocytic gliosis. Three of 8 autopsied patients had undergone computed tomographic examination, which showed bilateral hypodensity of the hemispheric white matter. The brains of 4 patients with illnesses of shorter duration showed only discrete but similar lesions in the centrum semiovale. These white matter changes are similar to those observed in Binswanger's subcortical encephalopathy. We suggest that a common mechanism of hypoperfusion of the distal white matter causes the leukoencephalopathy.     

Intracerebral hemorrhage related with cerebral amyloid angiopathy

The clinical and neuropathologic findings in 11 cases with intracerebral hemorrhages related to CAA were reported. Their age ranged from 45 to 79 years, the average being 61.8 years. The hematomas were all in cerebral lobes, except two patients whose hematomas were in the basal ganglia and thalamus. These hematomas were in irregular shapes, ruptured into ventricles and/or subarachnoid space in all cases. The vessel's wall of arteries in the leptomeninges, superficial cortex and those adjacent to hemorrhagic foci showed considerable thickness. Hemorrhagic foci showed considerable thickness. Homogeneously eosinophilic structures deposited in these vessel's wall of several small arteries. Some of these vessels showed luminal stenosis. Congo red staining confirmed characteristic amyloid apple-green birefringence under polarizing microscope.     

淀粉样变脑出血的临床特点及诊断方法

目的 分析淀粉样变脑出血的临床特点及诊断方法.方法 对55例自发性脑出血患者的临床表现及预后进行总结,对病理标本进行刚果红特殊染色和β淀粉样蛋白免疫组化染色,以明确病理诊断.结果 55例中6例首诊为可疑性淀粉样变脑出血,1例通过病理染色予以排除;2例术前诊断为可疑高血压性脑出血的患者经病理染色确诊为淀粉样变脑出血.结论 淀粉样变脑出血术前可以根据临床特点做出初步诊断;但是对于临床表现不典型者,诊断上还有一定的困难,病理分析仍然是诊断的金标准.目前对于此病的临床诊断方法需进一步研究改进.     

淀粉样脑血管病相关性脑出血的病理研究

目的 研究新疆少数民族地区自发性脑出血患者中淀粉样脑血管病相关性脑出血(CAAH)的比例及其病理特点.方法 经头颅CT证实为自发性脑出血的124例患者来自于有代表性的南北疆6家三级甲等医院,入组患者接受开颅手术,标本取白血肿腔周围,通过HE染色、刚果红染色偏振光显微镜观察、β淀粉样蛋白(Aβ)免疫组化检测明确是否存在脑血管淀粉样变性.结果124例患者中11例为CAAH,占8.9％,其中4例为嗜刚果红血管病,1例表现为斑样血管病,6例为混合型.结论 新疆少数民族地区手术治疗的自发性脑出血患者中8.9％与淀粉样脑血管病(CAA)相关,其比例随年龄增加;CAA表现为受累的血管壁增厚,血管壁正常结构消失,淀粉样物质在血管被膜中层和外膜中沉积;部分患者脑实质内可见β淀粉样蛋白沉积.     

APOE and cerebral amyloid angiopathy in the elderly

Over 30% of normal elderly people have cerebral amyloid angiopathy (CAA). Possession of APOE epsilon4 is associated with increased prevalence and severity of CAA in Alzheimer's disease (AD) and in cerebral haemorrhage. We examined CAA in relation to APOE genotype in brains from 152 people aged 60-102 years, without AD or cerebral haemorrhage. Prevalence of CAA increased with age (p = 0.003). CAA was not associated with APOE genotype. The frequency of epsilon4 showed a significant negative association with age (p = 0.016). Age at death was significantly lower in those with than without epsilon4 (p = 0.028). Possession of epsilon4 does not by itself confer an increased risk of CAA but may be associated with reduced longevity even in the absence of AD or cerebral haemorrhage.     

Characteristics of dyshoric capillary cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) affects brain parenchymal and leptomeningeal arteries and arterioles but sometimes involves capillaries (capCAA) with spread of the amyloid into the surrounding neuropil, that is, dyshoric changes. We determined the relationship between capCAA and larger vessel CAA, β amyloid (Aβ) plaques, neurofibrillary changes, inflammation, and apolipoprotein E (APOE) in 22 cases of dyshoric capCAA using immunohistochemistry. The dyshoric changes contained predominantly Aβ1-40, whereas dense bulblike deposits adjacent to the capillary wall contained mostly Aβ1-42. There was an inverse local correlation between Aβ plaque load and capCAA severity (p = 0.01), suggesting that Aβ transport between the neuropil and the circulation may be mechanistically involved. Deposits of hyperphosphorylated tau and ubiquitin and clusters of activated microglia, resembling the changes around Aβ plaques, were found around capCAA but were absent around larger vessel CAA. In 14 cases for which APOE genotype was available, there was a high APOE-ε4 allele frequency (54%; 43% homozygous). The severity of CapCAA increased with the number of ε4-alleles; and APOE4 seemed to colocalize with capCAA by immunohistochemistry. These results suggest that capCAA is pathologically and possibly pathogenetically distinct from larger vessel CAA, and that it is associated with a high APOE-ε4 allele frequency.     

Two types of sporadic cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) is a type of beta-amyloidosis that occurs in leptomeningeal and cortical vessels of the elderly. In a sample of 41 CAA cases including 16 Alzheimer disease (AD) cases and 28 controls, we show that 2 types of sporadic CAA exist: The first type is characterized by immunohistochemically detectable amyloid beta-protein (Abeta) in cortical capillaries, leptomeningeal and cortical arteries, arterioles, veins, and venules. It is referred to here as CAA-Type 1. The second type of CAA also exhibits immunohistochemically detectable Abeta deposits in leptomeningeal and cortical vessels, with the exception of cortical capillaries. This type is termed CAA-Type 2. In cases with CAA-Type 1, the frequency of the apolipoprotein E (ApoE) epsilon4 allele is more than 4 times greater than in CAA-Type 2 cases and in controls. CAA-Type 2 cases have a higher epsilon2 allele frequency than CAA-Type 1 cases and controls. The ratio of CAA-Type 2 to CAA-Type 1 cases does not shift significantly with respect to the severity of AD-related beta-amyloidosis, with respect to degrees of CAA-severity, or with increasing age. Therefore, CAA-Type 1 is unlikely to be the late stage of CAA-Type 2; rather, they represent 2 different entities. Since both the ApoE epsilon2 and the epsilon4 allele are known to be risk factors for CAA, we can assign the risk factor ApoE epsilon4 to a distinct morphological type of CAA. The ApoE epsilon4 allele constitutes a risk factor for CAA-Type 1 and, as such, for neuropil-associated dyshoric vascular Abeta deposition in capillaries, whereas the e2 allele does not. CAA-Type 2 is not associated with the epsilon4 allele as a risk factor but shows a higher epsilon2 allele frequency than CAA-Type 1 cases and controls in our sample.     

Reversible leukoencephalopathy associated with cerebral amyloid angiopathy

The authors describe three patients with reversible leukoencephalopathy associated with cerebral amyloid angiopathy (CAA). Rapid progression of neurologic symptoms was followed by dramatic clinical and radiographic improvement. Pathologically, CAA was associated with varying degrees of inflammation ranging from none to transmural granulomatous infiltration. In the appropriate clinical context, the MRI finding of lobar white matter edema with evidence of prior hemosiderin deposition may indicate the presence of a reversible CAA leukoencephalopathy.     

淀粉样脑血管病的病理

26例淀粉样脑血管病(CAA)中,脑出血20例,蛛网膜下腔出血2例,脑梗塞3例,硬膜下血肿1例。CAA主要累及脑实质的小、中动脉的中膜及外膜以及毛细血管。本组50％病例有淀粉样脑血管病伴随血管病(CAA-AV),包括微小动脉瘤、“双桶”、葱皮样改变、类纤维素性坏死、微小动脉丛及血管周围淋巴细胞浸润。CAA往往同时伴有老年斑和神经原纤维缠结。     

Ischemic brain injury in cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) is a common form of cerebral small vessel disease and an important risk factor for intracerebral hemorrhage and cognitive impairment. While the majority of research has focused on the hemorrhagic manifestation of CAA, its ischemic manifestations appear to have substantial clinical relevance as well. Findings from imaging and pathologic studies indicate that ischemic lesions are common in CAA, including white-matter hyperintensities, microinfarcts, and microstructural tissue abnormalities as detected with diffusion tensor imaging. Furthermore, imaging markers of ischemic disease show a robust association with cognition, independent of age, hemorrhagic lesions, and traditional vascular risk factors. Widespread ischemic tissue injury may affect cognition by disrupting white-matter connectivity, thereby hampering communication between brain regions. Challenges are to identify imaging markers that are able to capture widespread microvascular lesion burden in vivo and to further unravel the etiology of ischemic tissue injury by linking structural magnetic resonance imaging (MRI) abnormalities to their underlying pathophysiology and histopathology. A better understanding of the underlying mechanisms of ischemic brain injury in CAA will be a key step toward new interventions to improve long-term cognitive outcomes for patients with CAA.