Cholinergic pathology in Alzheimer's disease -: discrepancies between clinical experience and pathophysiological findings
Cholinergic pathology in Alzheimer's disease -: discrepancies between clinical experience and pathophysiological findings
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DOI：
10.1007/s007020200083
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发表时间：
2002-01-01
影响因子：
3.3
通讯作者：
Frölich, L
中科院分区：
文献类型：
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作者：
Frölich, L
阿尔茨海默病(AD)的胆碱能假说表明：1.基底前脑中的胆碱能神经元在疾病过程中受到严重影响，在组织病理学和神经化学上都可以检测到乙酰胆碱合成和降解的标志酶的丢失，以及2.由此导致的大脑胆碱能缺陷导致记忆丧失和其他认知和非认知症状，这是该病的特征。这一假设主要是基于对晚期痴呆症患者的大脑进行的研究。然而，它已经成为药物开发的基础，即乙酰胆碱-酯酶抑制剂(AChE-1)，在有限的一段时间内，这些药物对痴呆症的认知能力下降和行为症状显示出一致但温和的临床疗效。这些药物目前被认为是治疗阿尔茨海默病痴呆症的标准药物。现在，由于临床诊断更加敏感和可靠，可以在疾病的早期进行神经生物学检查，那时检测到的变化可能与发病机制更相关。对阿尔茨海默病胆碱能系统病理生理学的新研究表明：1.胆碱能缺陷仅发生在疾病的晚期；2.在疾病的早期，甚至有脑内胆碱能活动的上调；3.在AChE-I的治疗下，AChE的活性可能增加。这些数据表明，AD的中枢胆碱能系统具有可塑性，AChE-I的积极临床作用应与可能的病理生理水平上的有害影响进行权衡。这些数据挑战了目前形式的胆碱能假说，例如应该刺激对潜在过程的研究，这会导致AD患者早期胆碱能系统的活性增加，并可能对胆碱能药物治疗产生临床影响。
The cholinergic hypothesis of Alzheimer's disease (AD) states 1. that cholinergic neurons in the basal forebrain are severely affected in the course of disease, detectable both histopathologically by a loss of neurons and neurochemically, by a loss of marker enzymes for acetylcholine synthesis and degradation, and 2. that the resulting cerebral cholinergic deficit leads to memory loss and other cognitive and non-cognitive symptoms, which are characteristic for the illness. This hypothesis was mainly based on studies, which had been conducted on brains of patients with advanced dementia. Nevertheless, it has served as the rationale for the development of drugs, i.e. acetylcholine-esterase inhibitors (AChE-1), which have shown consistent, but modest clinical efficacy against cognitive decline and behavioural symptoms of dementia for a limited period of time. These drugs are presently regarded the standard treatment of dementia in Alzheimer's disease. Now, due to a more sensitive and reliable clinical diagnosis, neurobiological investigations can be performed on early stages of disease, when the changes detected presumably are more relevant for the pathogenesis. New studies on the pathophysiology of the cholinergic system in AD suggest 1. that the cholinergic deficit occurs only late in the disease, 2. that at the earliest stages there even is an upregulation of cholinergic activity in the brain, and 3. that an increased activity of AChE may develop under therapy with AChE-I's. These data show that there is a plasticity of the central cholinergic system in AD and that the positive clinical effects of AChE-I are to be weighted against possible detrimental effects on a pathophysiological level. These data challenge the cholinergic hypothesis in its present form, e.g. should stimulate studies on the underlying process, which leads the cholinergic system to increase its activity in patients in the early stage of AD and may have clinical consequences regarding cholinergic drug therapy.