de la Torre Jack C
Institute of Pathology, Case Western Reserve School of Medicine, Cleveland, Ohio, USA.
Neurodegener Dis. 2008;5(3-4):126-32. doi: 10.1159/000113681. Epub 2008 Mar 6.
A large body of evidence indicates that sporadic Alzheimer's disease (AD) is a vascular disorder with neurodegenerative consequences and needs to be treated and managed as such. Epidemiologic studies of vascular risk factors, together with preclinical detection tools for AD are proof of concept that cerebral hypoperfusion is one of the earliest pathological signs in the development of cognitive failure. Vascular risk factors involving heart disease and stroke in the elderly individual who already possesses a dwindling cerebrovascular reserve due to advancing age contribute to further decline in cerebral blood flow (CBF) resulting in unrelenting brain hypoperfusion. Brain hypoperfusion, in turn, can reach a critically attained threshold of cerebral hypoperfusion (CATCH) giving rise to a neuronal energy crisis via reduced ATP synthesis. The ensuing metabolic energy crisis initially carves up ischemic-sensitive neurons in the hippocampus and posterior parietal cortex setting up cognitive meltdown and progressive neurodegenerative and atrophic changes in the brain. Neuronal energy compromise accelerates oxidative stress, excess production of reactive oxygen species, aberrant protein synthesis, ionic membrane pump dysfunction, signal transduction impairment, neurotransmitter failure, abnormal processing of amyloid precursor protein resulting in beta-amyloid deposition and axonal microtubule disruption from tau hyperphosphorylation. The high energy metabolic changes leading to oxidative stress and cellular hypometabolism precede clinical expression of AD. Regional CBF measurements using neuroimaging techniques can predict AD preclinically at the mild cognitive impairment stage or even before any clinical manifestation of dementia is expressed. Clinical diagnostic assessment of elderly persons who could develop or already present with memory complaints can prevent, reverse or slow down AD development. Although pathologic aging is the subject of thousands of studies, the question of why the elderly (and not younger people) succumb to AD has not been adequately addressed. The explanation(s) as to why vascular risk factors, for example, can trigger AD or vascular dementia usually in the elderly and not the young should provide vital clues in the search for a strategically effective dementia treatment. This review offers inductive hypothetical darts relative to that critical question.
大量证据表明，散发性阿尔茨海默病（AD）是一种具有神经退行性后果的血管性疾病，需要据此进行治疗和管理。血管危险因素的流行病学研究以及AD的临床前检测工具证明了脑灌注不足是认知功能衰退发展过程中最早出现的病理体征之一。对于因年龄增长而脑血管储备逐渐减少的老年人，涉及心脏病和中风的血管危险因素会导致脑血流量（CBF）进一步下降，从而导致持续性脑灌注不足。反过来，脑灌注不足会达到临界的脑灌注不足阈值（CATCH），通过减少ATP合成引发神经元能量危机。随之而来的代谢能量危机最初会损害海马体和顶叶后皮质中对缺血敏感的神经元，引发认知崩溃以及大脑中渐进性的神经退行性和萎缩性变化。神经元能量受损会加速氧化应激、活性氧的过量产生、异常蛋白质合成、离子膜泵功能障碍、信号转导受损、神经递质功能衰竭、淀粉样前体蛋白的异常加工导致β-淀粉样蛋白沉积以及tau蛋白过度磷酸化导致轴突微管破坏。导致氧化应激和细胞代谢减退的高能量代谢变化先于AD的临床症状出现。使用神经影像技术进行区域脑血流量测量可以在临床前轻度认知障碍阶段甚至在痴呆的任何临床表现出现之前预测AD。对可能发生或已经出现记忆问题的老年人进行临床诊断评估可以预防、逆转或减缓AD的发展。尽管病理性衰老已成为数千项研究的主题，但为何老年人（而非年轻人）易患AD这一问题尚未得到充分解答。例如，关于为何血管危险因素通常在老年人而非年轻人中引发AD或血管性痴呆的解释，应该为寻找具有战略有效性的痴呆治疗方法提供重要线索。本综述针对这一关键问题提出了归纳性的假设观点。
