An association with great implications: vascular pathology and Alzheimer disease.
An association with great implications: vascular pathology and Alzheimer disease.
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具有重大意义的关联：血管病理学和阿尔茨海默病。
DOI：
10.1097/01.wad.0000201855.39246.2d
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发表时间：
2006
影响因子：
2.1
通讯作者：
Beach,ThomasG
中科院分区：
文献类型：
--
作者：
Roher,AlexE;Kokjohn,TylerA;Beach,ThomasG
尽管经过几十年的深入研究，散发性阿尔茨海默病（AD）的发病机制仍然是一个难以捉摸的目标。散发性阿尔茨海默病是一种由多种遗传和环境因素动态相互作用引起的紧急病理，背景是衰老相关的变化。淀粉样蛋白假说的优势倾向于掩盖其他可能的阿尔茨海默病致病机制。淀粉样斑块的准天体形态，它们在阿尔茨海默病中的普遍性，以及生物化学和转基因方法对它们研究的成功，我们可能已经忘记了大脑完全依赖于一个有效的循环系统。血管疾病及其与年龄相关的血液流变学下降可能对散发性AD的发展有显著甚至不成比例的影响。大量证据表明，在许多情况下，AD患者的大脑动脉在形态上发生了改变和功能失调。1-3假设某些AD痴呆病例实际上可能是由慢性脑灌注不足引起的，这并不牵强。计算机文献检索“脑低灌注与AD”主题列出了100多篇出版物，所有这些出版物都表明AD患者存在明显程度的脑缺氧/缺血。最近的报道，使用MRI相衬造影发现，相对于年龄匹配的非痴呆个体（平均：551 mL/min， P< 0.001）， AD患者的总脑血流量（代表颈内动脉和基底动脉的总和）显著减少（平均：443 mL/min）。相比之下，年轻对照组（中位年龄29岁）的平均脑血流量为742 mL/min。目前，心血管疾病是老年人发病和死亡的最常见原因。老年人和AD患者脑灌注不足的病因可能是多因素的，并与个体独特的心血管系统衰退途径有关。高血压、低血压、心肌梗死、瓣膜病、心律失常、心力衰竭、心肌病、心内膜炎和周围血管疾病等相关疾病也可能导致或加重心绞痛，这些疾病可能改变心血管功能和心输出量。在血管疾病中，动脉粥样硬化是老年人普遍存在的疾病。7到85岁时，100%的人都存在不同程度的动脉粥样硬化，主要影响身体的大动脉和冠状动脉，以及威利斯圈动脉和大脑血管。在一些老年人中，严重的脑动脉粥样硬化和/或动脉硬化会阻塞血管腔，损害脑灌注的程度。脂质和结缔组织沉积在动脉壁上的有害影响由于钙化和随之而来的刚性而变得复杂，这将增加周围血管阻力（稳定成分）和血管阻抗（脉动成分），进一步损害脑血流动力学。自阿尔茨海默病以来，研究人员面临的一个关键问题是，脑动脉病理与阿尔茨海默病之间是否存在因果关系。20世纪60年代末，一系列研究发现，脑动脉粥样硬化和痴呆的同时发生缺乏一致性，这一问题显然得到了解决。然而，近年来，这个问题重新浮出水面，因为相当多的证据清楚地表明，动脉粥样硬化性血管疾病的危险因素和标志物，包括高血压、冠状动脉疾病、心肌梗死……
Elucidating the pathogenesis of sporadic Alzheimer disease (AD) remains an elusive goal despite decades of intense research. Sporadic AD is an emergent pathology that arises from a dynamic interplay of multiple genetic and environmental factors, set against a background of senescence-related changes. The dominance of the amyloid hypothesis tends to eclipse other possible AD pathogenic mechanisms. Drawn by the quasi-celestial morphology of amyloid plaques, their universality in AD, and the success of biochemical and transgenic approaches to their study, we have perhaps forgotten that the brain is entirely dependent on an efficient circulatory system. Vascular disease, with its resultant age-related hemorheologic decline, may have significant and perhaps even disproportionate impacts on sporadic AD development. A large body of evidence indicates that in many instances the cerebral arteries are morphologically altered and dysfunctional in AD. 1–3 It is not farfetched to hypothesize that some cases of AD dementia may actually result from a chronic brain hypoperfusion. A computerized literature search of the topic ‘‘Brain Hypoperfusion and AD’’listed over 100 publications, all suggesting a significant degree of brain hypoxia/ischemia in AD. Recent reports, using phase contrast MRI, 4, 5 found that total cerebral blood flow, representing the summation of both internal carotid and basilar arteries combined, was significantly decreased in AD patients (mean: 443 mL/min) relative to that of non-demented age-matched individuals (mean: 551 mL/min; P< 0.001). By contrast, the average cerebral blood flow in a young control group (median age 29 years) was 742 mL/min. At present, cardiovascular disease is the most common cause of morbidity and mortality in the older population. 6 The etiology of brain hypoperfusion in the elderly and AD subjects is probably multifactorial and associated with the individual’s distinctive path of cardiovascular system decline. It can also result or be compounded by associated conditions, including hypertension, hypotension, myocardial infarction, valvulopathies, arrhythmias, heart failure, cardiomyopathies, endocarditis, and peripheral vascular disorders that are likely to alter cardiovascular function and cardiac output. Among the vascular disorders, atherosclerosis, with consequential arterial stenosis, is a widespread disease in the aged. 7 By age 85, atherosclerosis is present in 100% of the population to some degree, mostly affecting the large arteries of the body and the coronary arteries as well as the arteries of the circle of Willis and major cerebral vessels. In some elderly individuals severe cerebral atherosclerosis and/or arteriosclerosis will occlude the vascular lumen to the extent of jeopardizing brain perfusion. The deleterious effect of lipid and connective tissue deposition in the arterial walls is complicated by calcification and ensuing rigidity that will increase both peripheral vascular resistance (the steady component) and vascular impedance (the pulsatile component), further compromising brain hemodynamics.A key issue that has confronted researchers since Alzheimer’s time is whether or not there is a causal relationship between cerebral artery pathology and AD dementia. 8 This issue was apparently resolved in the late 1960s by a series of investigations that found a lack of consistency in the coincidental occurrence of cerebral atherosclerosis and dementia. In recent years, however, the issue has resurfaced, as a considerable body of evidence has clearly shown that risk factors and markers of atherosclerotic vascular disease, including hypertension, coronary artery disease, myocardial infarction …