1927年,脑淀粉样血管病(CAA)首次被描述为与阿尔茨海默病患者脑内淀粉样斑块相关的充血性血管病变,1与颅内大出血和颅内小出血均相关。因此,颅内出血(ICH),尤其是在老年患者或没有高血压的患者中,其鉴别诊断包括CAA。广泛使用的波士顿CAA诊断标准依赖于该病的出血特征2。CAA患者ICH的病理生理学机制仍不确定。因此,它的预后、风险分层和临床管理面临挑战。CAA的其他影像学特征为病理生理学提供了新的视角。对于大多数习惯于认为CAA为出血性疾病的临床医生来说,CAA缺血性病变的报道是一个新的概念。观察表明,患有严重淀粉样血管病的阿尔茨海默病痴呆患者的梗死更为普遍3-5,随后的研究发现,淀粉样物质在中小型皮质血管中沉积,血管壁的病理性增厚导致血管腔狭窄或闭塞,从而在缺血中发挥积极作用6,7。皮质浅表性含铁血黄素沉着(CSS)是 CAA显著的和共同的特征,应用现代的MRI技术很容易探测到。这些成像特征如何适应更大的CAA模型尚不清楚。他们是不是偶发现象?他们能不能教我们关于这种疾病的知识?在本期《Neurology®》杂志中,有两篇文章提示CAA本身可能是一个多层面的血管实体,并且阐明这些新特征可以增加我们对其病理生理学的理解,从而有更好的预后和管理。
van Veluw等8对79例可能的CAA患者纵向MRI的DWI序列高信号病灶的发生和进展进行分析。他们假设,如果DWI病变在广谱的CAA缺血表现中可以代表一个独立的阶段,那么就可以找到他与皮层微梗死(CMIs) 和之后MRI随访发展为慢性梗死而不是微出血之间的横断面相关性。百分之十八的患者有DWI病灶,与CMIs确实相关。DWI病变也与cSS相关,但与其他小血管疾病的影像学标记、微出血或ICH无关。作者未发现DWI损伤存在的具体诱发因素。在随访的T2加权MRI中,总共有24个(62%)可见的急性DWI病灶,其中有5例患者有腔隙形成的表现,根据《神经影像学标准血管变化的标准》将其描述成慢性腔隙性梗死。9只有1例患者显示含铁血黄素沉积的特征与微出血一致。这些研究结果表明,虽然根据成像标准CAA 的急性DWI病灶不一定演变成慢性梗死,但是不太可能演变成微出血,这支持作者的主要假设。纵向研究CAA的缺血性表现是一个主要证据。可能的非随机小样本是不允许统计得出与脑血管危险因素或认知性能之间关系的稳健性结论,这是一个主要的限制,并留下了临床相关性的问题未得到解决。
Charidimou等10人对313例原发性脑出血患者单中心纵向前瞻性队列研究中更详细地探讨了CAA中的CSS。作者使用一种新的0~4阶序量表对CSS进行分级,分数越高表明CSS多灶性的程度越高。他们提出了2个主要问题:(1)CSS是否代表了淀粉样化蛛网膜下腔血管的原位微出血,或是否提示脑叶出血的产物再分布?(2)CSS在未来脑出血风险中的作用是什么?21%的患者发生多灶性CSS,很可能的/明确的CAA中出现多灶性CSS的频率比可能的CAA要高。在很可能的/明确的CAA组中,CSS多灶性与CAA严重程度的其他标志相关联,支持原位微出血假说。相反,在可能的CAA组中,只有ICH严重程度的标志物(ICH体积和脑室扩大)预测cSS事件更高,这表明在该亚组中cSS可能与血肿扩展进入蛛网膜下腔有关。作者还报告了cSS事件与复发性脑叶出血风险之间有强烈关联。在多变量Logistic和有序回归模型中,CSS级别最高的患者未来发生脑叶出血的风险比无cSS的患者高5倍。值得注意的是,传统上与脑出血复发相关的其他因素,如年龄和先前的脑叶出血,与复发无关,最令人印象深刻的是脑微出血与脑出血复发之间无明显关联。这些发现为我们理解cSS的发病机制提供了线索,也揭示了我们对cSS发病机制的认识,并突出了其作为-继发出血的危险因素的重要性。虽然新的cSS分级系统具有直观的意义,并提供了更大的间隔尺度,一个完整的病理生理解释仍然是难以找到。此外,小样本和低概率事件(58)降低了统计学强度,并且宽的置信区间需要独立的重复和外部验证。
综上所述,这些文章提出了关于CAA的重要问题:这些病变是血管淀粉样沉积的直接结果,还是仅仅在老年脑血管病患者中共存?淀粉样沉积的过程可以同时解释缺血性病变和CSS吗?CAA的每一个特征——缺血性病变、CSS、CMIS、微出血、ICH——融入一个更大的概念模型?它们是共同的起源单一病理生理过程还是并行过程?最后,他们中的任何一个,单独或联合起来,认知障碍的临床表现有关吗?van Veluw等和Charidimou等的研究表达了复杂疾病的个体因素,但这些发现能否转化为更深层次的理解——将这些因素联系在一起?这是我们前进的挑战。
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Cerebral amyloid angiopathy (CAA), first described in 1927 as a congophilic angiopathy associated with amyloid plaque in brains of patients with Alzheimer dementia,1 has an association with large and small intracranial hemorrhages (ICH). The differential diagnosis of ICH therefore includes CAA, especially in older patients or those without hypertension. The widely used Boston Criteria for diagnosis of CAA in vivo rely on the hemorrhagic characteristics of the disease.2 The pathophysiology of ICH in CAA remains uncertain. Thus, its prognosis, risk stratification, and clinical management present a challenge. Additional imaging features of CAA have contributed potential new perspectives on pathophysiology. The report of ischemic lesions in CAA may represent a novel concept for most clinicians accustomed to thinking about CAA as a hemorrhagic disease. The observation that Alzheimer dementia brains with severe amyloid angiopathy had more prevalent infarcts3–5 prompted subsequent investigations suggesting that amyloid deposition in small and medium-sized cortical vessels may play an active role in ischemia through pathologic thickening of the vessel wall, producing reduction or obliteration of the vessel lumen.6,7 Cortical superficial siderosis (cSS), easy to detect with modern MRI, is a striking and common feature of CAA. How these additional imaging features fit into a larger model of CAA remains unclear. Are they an epiphenomenon or can they teach us about the disease? In the current issue of Neurology®, a pair of articles suggest that CAA might be a multifaceted vascular entity in its own right, and elucidation of these newer features may increase our understanding of its pathophysiology, leading to better prognosis and management.
1927年,脑淀粉样血管病(CAA)首次被描述为与阿尔茨海默病患者脑内淀粉样斑块相关的充血性血管病变,1与颅内大出血和颅内小出血均相关。因此,颅内出血(ICH),尤其是在老年患者或没有高血压的患者中,其鉴别诊断包括CAA。广泛使用的波士顿CAA诊断标准依赖于该病的出血特征2。CAA患者ICH的病理生理学机制仍不确定。因此,它的预后、风险分层和临床管理面临挑战。CAA的其他影像学特征为病理生理学提供了新的视角。对于大多数习惯于认为CAA为出血性疾病的临床医生来说,CAA缺血性病变的报道是一个新的概念。观察表明,患有严重淀粉样血管病的阿尔茨海默病痴呆患者的梗死更为普遍3-5,随后的研究发现,淀粉样物质在中小型皮质血管中沉积,血管壁的病理性增厚导致血管腔狭窄或闭塞,从而在缺血中发挥积极作用6,7。皮质浅表性含铁血黄素沉着(CSS)是 CAA显著的和共同的特征,应用现代的MRI技术很容易探测到。这些成像特征如何适应更大的CAA模型尚不清楚。他们是不是偶发现象?他们能不能教我们关于这种疾病的知识?在本期《Neurology®》杂志中,有两篇文章提示CAA本身可能是一个多层面的血管实体,并且阐明这些新特征可以增加我们对其病理生理学的理解,从而有更好的预后和管理。
The article by van Veluw et al.8 investigates the presence and evolution of diffusion-weighted imaging (DWI)–hyperintense lesions in 79 patients with probable CAA using longitudinal MRI. They hypothesized that if DWI lesions represent an independent stage in the broader spectrum of ischemic manifestations of CAA, one would expect to find a cross-sectional correlation with cortical microinfarcts (CMIs) and evolution into chronic infarcts rather than microhemorrhages on followup MRI. Eighteen percent of patients had DWI lesions, which were indeed associated with CMIs. DWI lesions were also associated with cSS but not with any other small vessel disease imaging markers, microbleeds, or ICH. The authors found no specific predisposing factors for DWI lesion presence. A total of 24 (62%) of the acute DWI lesions were visible in follow-upT2-weightedMRI,and5 of those had acavitated appearance that would qualify them as chronic lacunar infarcts by Standards for Reporting Vascular Changes on Neuroimaging criteria.9 Only one manifested features of hemosiderin deposition compatible with a microbleed. These findings suggest that although not necessarily evolving into chronic infarcts by imaging criteria, acute DWI lesions in CAA appear extremely unlikely to evolve into microhemorrhages, supporting the authors’ main hypothesis. The longitudinal approach to studying the ischemic manifestations of CAA represents a major strength. The small and likely nonrandom sample size, which did not allow for statistically robust conclusions of relationships to cerebrovascular risk factors or to cognitive performance, is a major limitation and leaves the issues of clinical relevance unaddressed.
van Veluw等8对79例可能的CAA患者纵向MRI的DWI序列高信号病灶的发生和进展进行分析。他们假设,如果DWI病变在广谱的CAA缺血表现中可以代表一个独立的阶段,那么就可以找到他与皮层微梗死(CMIs) 和之后MRI随访发展为慢性梗死而不是微出血之间的横断面相关性。百分之十八的患者有DWI病灶,与CMIs确实相关。DWI病变也与cSS相关,但与其他小血管疾病的影像学标记、微出血或ICH无关。作者未发现DWI损伤存在的具体诱发因素。在随访的T2加权MRI中,总共有24个(62%)可见的急性DWI病灶,其中有5例患者有腔隙形成的表现,根据《神经影像学标准血管变化的标准》将其描述成慢性腔隙性梗死。9只有1例患者显示含铁血黄素沉积的特征与微出血一致。这些研究结果表明,虽然根据成像标准CAA 的急性DWI病灶不一定演变成慢性梗死,但是不太可能演变成微出血,这支持作者的主要假设。纵向研究CAA的缺血性表现是一个主要证据。可能的非随机小样本是不允许统计得出与脑血管危险因素或认知性能之间关系的稳健性结论,这是一个主要的限制,并留下了临床相关性的问题未得到解决。
The article by Charidimou et al.10 explores cSS in CAA in more detail in a single-center longitudinal prospective cohort of 313 patients with primary lobar ICH. The authors grade cSS using a novel ordinal scale of 0–4, with higher scores denoting higher degree of cSS multifocality. They pose 2 main questions: (1) Does cSS represent independent in situ microhemorrhages of amyloid-laden subarachnoid vessels, or does it suggest redistribution of hemorrhagic products from lobar ICH? and (2) What is the role of cSS in future lobar ICH risk? Multifocal cSS occurred in 21% of patients, more frequently in probable/definite CAA compared to possible CAA. In the probable/definitive CAA groups, cSS multifocality was associated with other markers of CAA severity, lending support to the in situ microhemorrhage hypothesis. By contrast, in the possible CAA group, only markers of ICH severity(ICH volume and intraventricular extension) predicted higher cSS burden, suggesting that in this subgroup cSS might be related to hematoma extension into the subarachnoid space. The authors also report a robust association between cSS burden and risk of recurrent lobar ICH. In multivariable logistic and ordinal regression models, those with the highest cSS grade had a nearly 5-fold higher risk of future lobar ICH compared to those with no cSS. Notably, other factors traditionally linked with ICH recurrence, such as age and prior lobar hemorrhage, lost their association with recurrence, and most impressively the association between cerebral microbleeds and ICH recurrence was rendered insignificant. The findings shed light on our understanding of the pathogenesis of cSS and highlight its importance as a risk factor for subsequent bleeding. Although the novel cSS grading system makes intuitive sense and provides increased granularity, a complete pathophysiologic explanation remains elusive. Furthermore, the small sample size and lowevent rate (58) reduced statistical power, and the wide confidence intervals necessitate independent replication and external validation.
Charidimou等10人对313例原发性脑出血患者单中心纵向前瞻性队列研究中更详细地探讨了CAA中的CSS。作者使用一种新的0~4阶序量表对CSS进行分级,分数越高表明CSS多灶性的程度越高。他们提出了2个主要问题:(1)CSS是否代表了淀粉样化蛛网膜下腔血管的原位微出血,或是否提示脑叶出血的产物再分布?(2)CSS在未来脑出血风险中的作用是什么?21%的患者发生多灶性CSS,很可能的/明确的CAA中出现多灶性CSS的频率比可能的CAA要高。在很可能的/明确的CAA组中,CSS多灶性与CAA严重程度的其他标志相关联,支持原位微出血假说。相反,在可能的CAA组中,只有ICH严重程度的标志物(ICH体积和脑室扩大)预测cSS事件更高,这表明在该亚组中cSS可能与血肿扩展进入蛛网膜下腔有关。作者还报告了cSS事件与复发性脑叶出血风险之间有强烈关联。在多变量Logistic和有序回归模型中,CSS级别最高的患者未来发生脑叶出血的风险比无cSS的患者高5倍。值得注意的是,传统上与脑出血复发相关的其他因素,如年龄和先前的脑叶出血,与复发无关,最令人印象深刻的是脑微出血与脑出血复发之间无明显关联。这些发现为我们理解cSS的发病机制提供了线索,也揭示了我们对cSS发病机制的认识,并突出了其作为-继发出血的危险因素的重要性。虽然新的cSS分级系统具有直观的意义,并提供了更大的间隔尺度,一个完整的病理生理解释仍然是难以找到。此外,小样本和低概率事件(58)降低了统计学强度,并且宽的置信区间需要独立的重复和外部验证。
Taken together, these articles raise important questions about CAA: Do these lesions arise as a direct consequence of vascular amyloid deposition, or do they simply cohabitate in an elderly population with cerebrovascular risk? Does the process of amyloid deposition explain both ischemic lesions and cSS? How would each feature of CAA—ischemic lesions, cSS, CMIs, microbleeds, ICH—fit into a larger conceptual model? Are they serial processes in a single pathophysiologic train or parallel processes with a common origin? Finally, can any of them, individually or in combination, be tied to the clinical manifestation of cognitive impairment? The articles by van Veluw et al. and Charidimou et al. contribute to characterizing individual elements of a complex disease, but can the findings be translated into a deeper understanding that can tie the elements together? This is our challenge moving forward.
综上所述,这些文章提出了关于CAA的重要问题:这些病变是血管淀粉样沉积的直接结果,还是仅仅在老年脑血管病患者中共存?淀粉样沉积的过程可以同时解释缺血性病变和CSS吗?CAA的每一个特征——缺血性病变、CSS、CMIS、微出血、ICH——融入一个更大的概念模型?它们是共同的起源单一病理生理过程还是并行过程?最后,他们中的任何一个,单独或联合起来,认知障碍的临床表现有关吗?van Veluw等和Charidimou等的研究表达了复杂疾病的个体因素,但这些发现能否转化为更深层次的理解——将这些因素联系在一起?这是我们前进的挑战。
(全文终)
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