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。     

干预Aβ代谢及其毒性治疗阿尔茨海默病的研究现状及展望

β淀粉样蛋白(Aβ)是阿尔茨海默病(AD)特征性病理改变之一。淀粉样前体蛋白(APP)经分泌酶水解后产生有毒性的Aβ,转运至大脑异常聚集产生Aβ寡聚体,从而引起线粒体功能障碍、氧化应激、突触传递功能障碍等,最终引起乙酰胆碱酯酶神经元坏死,导致痴呆。因此减少Aβ在脑内的产生、促进Aβ清除、抑制Aβ聚集以及降低其神经毒性已成为治疗AD的主要措施之一,本文针对干预Aβ代谢及其神经毒性治疗AD的研究作一综述。     

自噬在阿尔茨海默病中的作用机制及治疗前景

自噬作为细胞内一种清除非必需或异常物质的基本代谢途径,在阿尔茨海默病的发病过程中扮演重要角色。自噬过程中可产生β-淀粉样蛋白,同时自噬溶酶体系统也直接参与Aβ和tau蛋白清除机制。溶酶体功能障碍和自噬囊泡大量聚集导致Aβ和tau蛋白聚集,可能是阿尔茨海默病的病因之一。基于此,恢复受损的自噬溶酶体功能在阿尔茨海默病治疗中具有重要潜在价值。本文就自噬途径如何介导阿尔茨海默病的发病及其药物治疗前景作一概述。     

阿尔茨海默病中β淀粉样多肽与线粒体异常及靶向治疗

β淀粉样多肽沉积与线粒体异常改变均为阿尔茨海默病的主要特征,也是其发病机制中的关键环节。β淀粉样多肽通过在线粒体内沉积导致线粒体功能障碍;通过与分裂/融合蛋白相互作用引起线粒体形态分布异常及突触功能损害;通过引起线粒体内钙稳态失调诱导细胞凋亡。同时,线粒体异常也加重β淀粉样多肽的毒性。在以上作用环节中,对电子传递链、分裂/融合蛋白、亲环蛋白D等新旧靶点及相关治疗药物的深入研究为阿尔茨海默病的线粒体靶向治疗带来希望。     

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.     

低密度脂蛋白受体相关蛋白1在阿尔茨海默病中的研究进展

阿尔茨海默病的主要病理学特征之一是β-淀粉样蛋白(Aβ)过度沉积,基于β-淀粉样蛋白级联学说,降低Aβ水平是对抗阿尔茨海默病的有效策略。本文对低密度脂蛋白受体相关蛋白1(LRP1)介导的细胞对Aβ的摄取及降解以及LRP1介导的外周与中枢神经系统中Aβ转运及清除的具体机制的研究进展作一综述。     

阿尔茨海默病的免疫治疗

β淀粉样蛋白(Aβ)的沉积是阿尔茨海默病发病的始发因素,所形成的老年斑是该病的主要病理改变之一。针对Aβ的免疫治疗包括主动免疫和被动免疫,许多动物实验证明Aβ的免疫治疗可以预防或清除脑中淀粉样蛋白沉积,并使动物认知功能改善。虽然Aβ疫苗的临床试验中部分患者脑内特定区域淀粉样蛋白的沉积得到有效遏制,但由于严重的副作用而终止。免疫治疗真正运用于人类阿尔茨海默病的预防和治疗仍有很多问题需要解决。     

Alzheimer病β淀粉样前体蛋白跨膜区未发现核苷酸序列变化

Alzheimcr病的病理生化基础是β淀粉样蛋白(βA4),βA4由其前体APP水解产生。正常情况下该糖基化的膜蛋白前体经蛋白酶解后并不产生淀粉样产物,在AD中,APP由于异常剪接而产生βA4,进而在脑和血管壁产生淀粉样沉积。在早发性家族性AD中,APP基因跨膜区已发现有三     

β淀粉样蛋白及其前体在脑缺血性损伤中的机制研究进展

传统观念认为β淀粉样蛋白是阿尔茨海默病的主要致病物质，具有神经毒性，启动了阿尔茨海默病的病理过程。而近年来研究发现，它同时参与了脑缺血性损伤的过程。本文综述了β淀粉样蛋白在脑缺血性损伤中的机制。     

散发性脑淀粉样血管病的危险因素及治疗方法的研究进展

散发性脑淀粉样血管病（cerebral amyloid angiopathy,CAA）是一种老年人中常见的颅内微 血管病。CAA相关病变（如脑出血、认知功能下降等）的发生主要包括淀粉样蛋白沉积于脑血管壁、 继发血管损伤两个重要过程,其危险因素包括ApoE 基因多态性等遗传因素和高血压病等非遗传因素。 免疫治疗和一些天然多酚类物质可防止脑血管内的淀粉样蛋白沉积,而控制高血压等非遗传危险因 素或使用依达拉奉能减轻CAA继发血管损伤。这些方法有望成为今后散发性CAA治疗的发展方向。     

Intracisternal injection of beta-amyloid seeds promotes cerebral amyloid angiopathy

Beta amyloid (Aβ) is a key component of parenchymal Aβ plaques and vascular Aβ fibrils, which lead to cerebral amyloid angiopathy (CAA) in Alzheimer’s disease (AD). Recent studies have revealed that Aβ contained in the cerebrospinal fluid (CSF) can re-enter into brain through paravascular spaces. However, whether Aβ in CSF may act as a constant source of pathogenic Aβ in AD is still unclear. This study aimed to examine whether Aβ pathology could be worsened when CSF Aβ level was enhanced by intra-cisternal infusion of aged brain extract containing abundant Aβ in TgCRND8 host mice. TgCRND8 mouse is an AD animal model which develops predominant parenchymal Aβ plaques in the brain at as early as 3 months of age. Here, we showed that single intracisternal injection of Aβ seeds into TgCRND8 mice before the presence of Aβ pathology induced robust prion-like propagation of CAA within 90 days. The induced CAA is mainly distributed in the cerebral cortex, hippocampus and thalamus of TgCRND8 mice. Surprisingly, despite the robust increase in CAA levels, the TgCRND8 mice had a marked decrease in parenchymal Aβ plaques and the plaques related neuroinflammation in the brains compared with the control mice. These results amply indicate that Aβ in CSF may act as a source of Aβ contributing to the growth of vascular Aβ deposits in CAA. Our findings provide experimental evidence to unravel the mechanisms of CAA formation and the potential of targeting CSF Aβ for CAA.     

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.     

Hereditary cerebral hemorrhage with amyloidosis‐Dutch type

The amyloid β‐protein (Aβ) E22Q mutation of the rare disorder hereditary cerebral hemorrhage with amyloidosis‐Dutch type (HCHWA‐D) causes severe cerebral amyloid angiopathy (CAA) with hemorrhagic strokes of mid‐life onset and dementia. The mutation does not affect total Aβ production but may alter the Aβ1–42:Aβ1–40 ratio, and affect the proteolytic degradation of Aβ and its transport across the blood–brain barrier. Aβ E22Q aggregates faster into more stable amyloid‐like fibrils than wild‐type Aβ. Non‐fibrillar Aβ(x‐42) deposits precede the appearance of fibrils and the deposition of Aβ(x‐40) in the vascular basement membrane. CAA severity tends to increase with age but may vary greatly among patients of comparable ages. Lumenal narrowing of affected blood vessels, leukoencephalopathy, CAA‐associated vasculopathies, and perivascular astrocytosis, microgliosis, and neuritic degeneration complicate the development of HCHWA‐D CAA. Parenchymal Aβ deposition is also enhanced in the HCHWA‐D brain with non‐fibrillar membrane‐bound Aβ(x‐42) deposits evolving into relatively fibrillar diffuse plaques variously associated with reactive astrocytes, activated microglia, and degenerating neurites. Plaque density tends to decrease with age. Neurofibrillary degeneration is absent or limited. HCHWA‐D dementia is associated with CAA severity independently of Braak stage, age, and plaque density. Particularly, microaneurysms may contribute to the development of (small) hemorrhages/infarcts and the latter to cognitive decline in affected subjects. However, the relative importance of cerebral hemorrhages/infarcts, white matter damage and/or other CAA‐ or Aβ‐related factors for cognitive deterioration in HCHWA‐D remains to be determined.     

Tissue transglutaminase: a novel therapeutic target in cerebral amyloid angiopathy

Accumulation of amyloid-β (Aβ) in brain vessel walls, known as cerebral amyloid angiopathy (CAA), plays a key role in Alzheimer's disease pathogenesis. CAA might result from impaired transport of Aβ out of the brain. Although the mechanisms underlying reduced Aβ transport are largely unknown, thickening of basement membrane extracellular matrix (ECM) is likely involved. Tissue transglutaminase (tTG) is an enzyme capable of modulating the ECM by covalently cross-linking ECM proteins. Recently, our group found that tTG and its cross-linking activity are associated with CAA pathology, suggesting a role for tTG in ECM modulation in CAA. Therefore, inhibition of tTG activity might be a promising novel therapeutic target to counteract CAA.     

Amyloid-β plaques may be reduced in advanced stages of cerebral amyloid angiopathy in the elderly

We examined 29 cases in which cerebral amyloid angiopathy (CAA) was detected among routine aged autopsies. Most cases with severe CAA had many amyloid-β (Aβ) plaques in the occipital cortex. Nonetheless, two cases had few Aβ plaques with many small vessels and capillaries with CAA. In the two cases, severe CAA was widely distributed, except in the frontal lobes. Aβ deposits in capillaries often showed the characteristic pattern of dysphoric amyloid angiopathy. A few naked plaques were present. Although Aβ plaques were sparse near small vessels with CAA, there were many Aβ plaques distant from small vessels with CAA. Some of the remaining plaques had a moth-eaten appearance. Based on Aβ-positive star-like appearance and results of double immunohistochemistry for glial fibrillary acidic protein and Aβ_1–42, some astrocytes appeared to contain Aβ. Ionized calcium-binding adapter molecule 1 (Iba1)-positive microglia were scattered within the neuropil, with some present around small vessels with CAA. Iba1-positive microglia also seemed to phagocytose Aβ in several senile plaques by double immunostaining. Neurons and neurites identified with a monoclonal antibody against phosphorylated tau (clone AT8) were occasionally detected in sparse plaque areas, with AT8-identified dot-like structures present around capillaries with CAA. Accumulation of T lymphocytes was detected around vessels in the subarachnoid space in one case. The morphological changes detected in our two cases were similar to those of morphological markers of plaque clearance after Aβ immunotherapy. Nonetheless, our cases did not receive Aβ immunotherapy, but similar pathologies were observed. Overall, advanced CAA cases, including our two cases, may be examples of plaque clearance without Aβ immunotherapy. Further studies are needed to resolve the mechanism of Aβ plaque clearance using these cases.     

Amyloid β-proteins 1—40 and 1—42(43) in the soluble fraction of extra- and intracranial blood vessels

To investigate the process of amyloid β-protein (Aβ) accumulation in cerebral amyloid angiopathy (CAA), the levels of Aβ were determined in the soluble fraction of extra- and intracranial blood vessels and leptomeninges obtained at autopsy. Two enzyme immunoassays were employed that are known to sensitively and specifically quantify two Aβ species, Aβ1–40 and 1–42(43). Aβ was detectable in the intracranial blood vessels and leptomeninges with the latter containing the highest levels, while it was undetectable in the extracranial blood vessels. Thus the levels of soluble Aβ correlated well with the prediiection sites for CAA. Among individuals aged 20 to 90, the Aβ levels in the leptomeninges increased sharply in those aged 50 to 70 and thereafter tended to decline. However, only slight degrees of CAA were detected by immunocytochemistry, even when those leptomeninges contained high levels of Aβ comparable with those in Alzheimer's disease. The level of Aβ1–42 was almost always severalfold that of Aβ1–40 in the soluble fraction of leptomeninges. This is in good agreement with the immunocytochemical result showing the presence of Aβ40-negative, Aβ42(43)-positive meningeal vessels. These results indicate that Aβ1–42 is the initially deposited species in CAA and that the disruption of Aβ homeostasis precedes Aβ deposition in the meningeal vessels.     

Neuropathologic analysis of hematomas evacuated from patients with spontaneous intracerebral hemorrhage

Spontaneous intracerebral hemorrhage (ICH) is a devastating cause of morbidity and mortality. Intraparenchymal hematomas are often surgically evacuated. This generates fragments of perihematoma brain tissue that may elucidate their etiology. The goal of this study is to analyze the value of these specimens in providing a possible etiology for spontaneous ICH as well as the utility of using immunohistochemical markers to identify amyloid angiopathy. Surgically resected hematomas from 20 individuals with spontaneous ICH were examined with light microscopy. Hemorrhage locations included 11 lobar and nine basal ganglia hemorrhages. Aβ immunohistochemistry and Congo red stains were used to confirm the presence of amyloid angiopathy, when this was suspected. Evidence of cerebral amyloid angiopathy (CAA) was observed in eight of the 20 specimens, each of which came from lobar locations. Immunohistochemistry confirmed CAA in the brain fragments from these eight individuals. Patients with immunohistochemically confirmed CAA were older than patients without CAA, and more likely to have lobar hemorrhages (OR 3.0 and 3.7, respectively). Evidence of CAA was not found in any of the basal ganglia specimens. One specimen showed evidence of CAA‐associated angiitis, with formation of a microaneurysm in an inflamed segment of a CAA‐affected arteriole, surrounded by acute hemorrhage. In another specimen, Aβ immunohistochemistry showed the presence of senile plaques suggesting concomitant Alzheimer's disease (AD) changes. Surgically evacuated hematomas from patients with spontaneous ICH should be carefully examined, paying special attention to any fragments of included brain parenchyma. These fragments can provide evidence of the etiology of the hemorrhage. Markers such as Aβ 1–40 can help to identify underlying CAA, and should be utilized when microangiopathy is suspected. Given the association of (Aβ) CAA with AD, careful examination of entrapped brain fragments may also provide evidence of AD in a given patient.     

Human apolipoprotein E2 promotes parenchymal amyloid deposition and neuronal loss in vasculotropic mutant amyloid-β protein Tg-SwDI mice

Human apolipoprotein (ApoE) genotype influences the development of Alzheimer's disease and cerebral amyloid angiopathy (CAA), where the ε4 allele increases and the ε2 allele decreases the risk for developing disease. Specific mutations within the amyloid-β (Aβ) peptide have been identified that cause familial forms of CAA. However, the influence of APOE genotype on accumulation of CAA mutant Aβ in brain is not well understood. Earlier, we showed that human ApoE4 redistributes fibrillar amyloid deposition from the cerebral microvasculature to parenchymal plaques in Tg-SwDI mice, a model that accumulates human Dutch/Iowa (E22Q/D23N) CAA mutant Aβ in brain (Xu et al., J Neurosci 28, 5312-5320, 2008). Human ApoE2 can reduce Aβ pathology in transgenic models of parenchymal plaques. Here we determined if human ApoE2 can influence the location and severity of amyloid pathology in Tg-SwDI mice. Comparing Tg-SwDI mice bred onto a human APOE2/2 or human APOE4/4 background, we found there was no change in the brain levels of total Aβ(40) and Aβ(42) compared to mice on the endogenous mouse APOE background. In Tg-SwDI mice on either human APOE background, there was a similarly strong reduction in the levels of microvascular CAA and emergence of extensive parenchymal plaque amyloid. In both Tg-SwDI-hAPOE2/2 and Tg-SwDI-hAPOE4/4 mice, the distribution of ApoE proteins and neuronal loss were associated with parenchymal amyloid plaques. These findings suggest that compared with human ApoE4, human ApoE2 does not beneficially influence the quantitative or spatial accumulation of human Dutch/Iowa CAA mutant amyloid or associated pathology in transgenic mice.     

Low avidity and level of serum anti-Aβ antibodies in patients with cerebral amyloid angiopathy-related cerebral hemorrhage

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of the beta-amyloid protein (Aβ) in small cerebral vessels, which is considered a common cause of intracerebral hemorrhage (CAAH) in elderly people. Little is known about the properties of serum naturally occurring anti-Aβ antibodies in patients with CAAH. We investigated the avidity and levels of anti-Aβ antibodies in 20 patients and 20 age-matched healthy controls by an enzyme-linked immunosorbent assay with thiocyanate elution. Our study revealed that both the levels and the avidity of these endogenous anti-Aβ antibodies were lower in patients with CAAH than in controls, which may be a new mechanism for the impaired clearance of cerebral Aβ and have important implications for the development of immune-based therapeutic strategies for CAA.     

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.