Love Seth, Miners J Scott
Institute of Clinical Neurosciences, School of Clinical Sciences, Learning and Research Level 2, Southmead Hospital, University of Bristol, Bristol, BS10 5NB, UK.
Acta Neuropathol. 2016 May;131(5):645-58. doi: 10.1007/s00401-015-1522-0. Epub 2015 Dec 28.
Cerebrovascular disease (CVD) and Alzheimer's disease (AD) have more in common than their association with ageing. They share risk factors and overlap neuropathologically. Most patients with AD have Aβ amyloid angiopathy and degenerative changes affecting capillaries, and many have ischaemic parenchymal abnormalities. Structural vascular disease contributes to the ischaemic abnormalities in some patients with AD. However, the stereotyped progression of hypoperfusion in this disease, affecting first the precuneus and cingulate gyrus, then the frontal and temporal cortex and lastly the occipital cortex, suggests that other factors are more important, particularly in early disease. Whilst demand for oxygen and glucose falls in late disease, functional MRI, near infrared spectroscopy to measure the saturation of haemoglobin by oxygen, and biochemical analysis of myelin proteins with differential susceptibility to reduced oxygenation have all shown that the reduction in blood flow in AD is primarily a problem of inadequate blood supply, not reduced metabolic demand. Increasing evidence points to non-structural vascular dysfunction rather than structural abnormalities of vessel walls as the main cause of cerebral hypoperfusion in AD. Several mediators are probably responsible. One that is emerging as a major contributor is the vasoconstrictor endothelin-1 (EDN1). Whilst there is clearly an additive component to the clinical and pathological effects of hypoperfusion and AD, experimental and clinical observations suggest that the disease processes also interact mechanistically at a cellular level in a manner that exacerbates both. The elucidation of some of the mechanisms responsible for hypoperfusion in AD and for the interactions between CVD and AD has led to the identification of several novel therapeutic approaches that have the potential to ameliorate ischaemic damage and slow the progression of neurodegenerative disease.
脑血管疾病（CVD）和阿尔茨海默病（AD）的共同之处不止于与衰老的关联。它们有共同的风险因素，且在神经病理学上存在重叠。大多数AD患者存在Aβ淀粉样血管病以及影响毛细血管的退行性改变，许多患者还存在缺血性实质异常。结构性血管疾病在一些AD患者中导致了缺血性异常。然而，该疾病中灌注不足的刻板进展模式，首先影响楔前叶和扣带回，然后是额叶和颞叶皮质，最后是枕叶皮质，这表明其他因素更为重要，尤其是在疾病早期。虽然在疾病晚期对氧气和葡萄糖的需求下降，但功能磁共振成像、用于测量血红蛋白氧饱和度的近红外光谱以及对氧合减少敏感性不同的髓磷脂蛋白的生化分析均表明，AD中血流减少主要是血液供应不足的问题，而非代谢需求降低。越来越多的证据表明，非结构性血管功能障碍而非血管壁的结构异常是AD中脑灌注不足的主要原因。可能有几种介质起作用。一种正在成为主要促成因素的是血管收缩剂内皮素-1（EDN1）。虽然灌注不足和AD的临床及病理效应显然有累加成分，但实验和临床观察表明，疾病过程在细胞水平上也以一种相互加剧的方式发生机制性相互作用。对AD中灌注不足的一些机制以及CVD与AD之间相互作用的阐明，已导致确定了几种新的治疗方法，这些方法有可能改善缺血性损伤并减缓神经退行性疾病的进展。
