Henry-Feugeas M C
Department of Radiology, Bichat-Claude Bernard University Hospital, AP-HP, Paris Cedex 18, France.
Med Hypotheses. 2008;70(4):866-75. doi: 10.1016/j.mehy.2007.07.027. Epub 2007 Sep 6.
Alzheimer's disease (AD) is thought to be the most common cause of late-life dementia. But pure AD is infrequent whereas AD pathology is often insufficient to explain dementia in the elderly. Conversely, cerebrovascular disease is omnipresent and the crucial role of microvascular alterations increasingly recognized in late dementia or "Alzheimer syndrome". Pathomechanisms of vascular cognitive impairment are still debated but recent data indicate that the initial concept of chronic low grade cerebral hypoxia should not have been abandoned. Thus, it is proposed that windkessel dysfunction is the missing link between vascular and craniospinal senescence on the one hand, and chronic low grade cerebral hypoxia, "senile brain degeneration" and "Alzheimer syndrome" on the other hand. An age-related decrease in the buffering capacity of both the vessels and the craniospinal cavity favours cerebral hypoxia; due to increased capillary pulsatility with disturbances in capillary exchanges or due to a marked reduction in craniospinal compliance with a mechanical reduction in cerebral arterial inflow. "Invisible" windkessel dysfunction, most often related to "hardening of the arteries" may be the most frequent pathomechanism of late-onset dementia whereas associated mild or moderate AD may be merely a toxic manifestation of a primarily hypoxic disease. Structural patterns of arteriosclerotic dementia fit well with an underlying arterial windkessel dysfunction: with secondary mechanical damage to the cerebral small vessels and the brain and predominantly deep hypoxia. The clinical significance of leukoaraïosis, small foci of necrosis, ventricular dilatation, hippocampal and cortical atrophy is in good agreement with their value as indirect markers of windkessel dysfunction. An age-related "invisible" reduction in craniospinal compliance may also contribute to the associations between heart failure, arterial hypotension and cognitive impairment in the elderly and to the high percentage of dementia of unknown origin in the very old. Both neuropathological and clinical overlap between AD and windkessel dysfunction can explain that cerebrovascular dysfunction remains misdiagnosed for AD in the elderly. Evidence of the key role of cerebrovascular dysfunction should markedly facilitate and widen therapeutic research in late-life dementia. Routine MRI including direct assessment of intracranial dynamics should be increasingly used to define etiological subtypes of the "Alzheimer syndrome" and develop a well-targeted therapeutic strategy.
阿尔茨海默病（AD）被认为是晚年痴呆最常见的病因。但单纯的AD并不常见，而AD病理改变往往不足以解释老年人的痴呆症状。相反，脑血管疾病普遍存在，微血管改变在晚期痴呆或“阿尔茨海默综合征”中的关键作用日益受到认可。血管性认知障碍的发病机制仍存在争议，但最近的数据表明，不应摒弃慢性轻度脑缺氧的最初概念。因此，有人提出，弹性贮器功能障碍一方面是血管和颅脊髓衰老之间缺失的环节，另一方面是慢性轻度脑缺氧、“老年脑变性”和“阿尔茨海默综合征”之间缺失的环节。血管和颅脊髓腔缓冲能力的年龄相关性下降有利于脑缺氧的发生，这是由于毛细血管搏动增加伴毛细血管交换紊乱，或由于颅脊髓顺应性显著降低伴脑动脉流入机械性减少所致。“隐匿性”弹性贮器功能障碍，最常与“动脉硬化”相关，可能是晚发性痴呆最常见的发病机制，而相关的轻度或中度AD可能仅仅是一种主要缺氧性疾病的毒性表现。动脉硬化性痴呆的结构模式与潜在的动脉弹性贮器功能障碍非常吻合：伴有脑小血管和脑的继发性机械损伤以及主要是深部缺氧。白质疏松、小坏死灶、脑室扩大、海马和皮质萎缩的临床意义与其作为弹性贮器功能障碍间接标志物的价值高度一致。与年龄相关的颅脊髓顺应性“隐匿性”降低也可能导致老年人心力衰竭、动脉低血压与认知障碍之间的关联，以及极高龄老年人中不明原因痴呆的高比例。AD与弹性贮器功能障碍之间的神经病理学和临床重叠可以解释为什么老年人脑血管功能障碍仍被误诊为AD。脑血管功能障碍关键作用的证据应显著促进和拓宽对晚年痴呆的治疗研究。应越来越多地使用包括直接评估颅内动力学的常规MRI来定义“阿尔茨海默综合征”的病因亚型，并制定有针对性的治疗策略。
