In early Alzheimer’s disease, which initially presents with progressive loss of short-term memory, neurodegeneration especially affects cholinergic neurons of the basal forebrain. Pharmacotherapy of Alzheimer’s disease therefore often targets the cholinergic system. In contrast, cholinergic pharmacotherapy of mild cognitive impairment is debated since its efficacy to date remains controversial. We here investigated the relationship between cholinergic treatment effects and the integrity of the cholinergic system in mild cognitive impairment due to Alzheimer’s disease. Fourteen patients with high likelihood of mild cognitive impairment due to Alzheimer’s disease and 16 age-matched cognitively normal adults performed an episodic memory task during functional magnetic resonance imaging under three conditions: (i) without pharmacotherapy; (ii) with placebo; and (iii) with a single dose of rivastigmine (3 mg). Cortical acetylcholinesterase activity was measured using PET with the tracer ¹¹C-N-methyl-4-piperidyl acetate (MP4A). Cortical acetylcholinesterase activity was significantly decreased in patients relative to controls, especially in the lateral temporal lobes. Without pharmacotherapy, mild cognitive impairment was associated with less memory-related neural activation in the fusiform gyrus and impaired deactivation in the posterior cingulate cortex, relative to controls. These differences were attenuated under cholinergic stimulation with rivastigmine: patients showed increased neural activation in the right fusiform gyrus but enhanced deactivation of the posterior cingulate cortex under rivastigmine, compared to placebo. Conversely, controls showed reduced activation of the fusiform gyrus and reduced deactivation of the posterior cingulate under rivastigmine, compared to placebo. In both groups, the change in neural activation in response to rivastigmine was negatively associated with local acetylcholinesterase activity. At the behavioural level, an analysis of covariance revealed a significant group × treatment interaction in episodic memory performance when accounting for hippocampal grey matter atrophy and function. Our results indicate that rivastigmine differentially affects memory-related neural activity in patients with mild cognitive impairment and cognitively normal, age-matched adults, depending on acetylcholinesterase activity as a marker for the integrity of the cortical cholinergic system. Furthermore, hippocampal integrity showed an independent association with the response of memory performance to acetylcholinesterase inhibition.

中文翻译：

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胆碱能治疗的效果取决于早期阿尔茨海默氏病的胆碱能完整性

在早期表现为短期记忆进行性丧失的早期阿尔茨海默氏病中，神经退行性变尤其影响基底前脑的胆碱能神经元。因此，阿尔茨海默氏病的药物治疗通常针对胆碱能系统。相比之下，轻度认知障碍的胆碱能药物治疗一直存在争议，因为迄今为止其疗效尚存争议。我们在这里研究了由于阿尔茨海默氏病引起的轻度认知障碍中胆碱能治疗效果与胆碱能系统完整性之间的关系。14名因阿尔茨海默氏病引起轻度认知障碍的可能性较高的患者和16名年龄相匹配的认知正常的成年人在以下三种情况下进行了功能性磁共振成像中的情景记忆任务：（i）不进行药物治疗；（ii）使用安慰剂；（iii）单剂量的卡巴拉汀（3 mg）。使用示踪剂使用PET测量皮质乙酰胆碱酯酶活性¹¹ C- N-甲基-4-哌啶基乙酸酯（MP4A）。相对于对照，尤其是在颞颞叶，患者的皮质乙酰胆碱酯酶活性显着降低。如果没有药物治疗，相对于对照，轻度认知障碍与梭状回中与记忆有关的神经激活较少，后扣带回皮质的失活受损有关。在利伐斯的明胆碱能刺激下，这些差异减弱了：与安慰剂相比，患者在右梭形回中神经激活增加，但在卡斯汀明的作用下，后扣带回皮层的失活增强。相反，与安慰剂相比，对照组显示在rivastigmine的作用下梭状回的激活减少，后扣带回的激活减少。在两组中 rivastigmine反应中神经激活的变化与局部乙酰胆碱酯酶活性呈负相关。在行为方面，对协方差的分析显示，在考虑海马灰质萎缩和功能时，情景记忆表现中存在显着的组×治疗相互作用。我们的研究结果表明，利伐斯的明有差异地影响轻度认知障碍和认知正常，年龄匹配的成年人的记忆相关神经活动，这取决于乙酰胆碱酯酶活性作为皮质胆碱能系统完整性的标志。此外，海马完整性显示出与记忆能力对乙酰胆碱酯酶抑制反应的独立关联。在行为方面，对协方差的分析显示，在考虑海马灰质萎缩和功能时，情景记忆表现中存在显着的组×治疗相互作用。我们的研究结果表明，利伐斯的明有差异地影响轻度认知障碍和认知正常，年龄匹配的成年人的记忆相关神经活动，这取决于乙酰胆碱酯酶活性作为皮质胆碱能系统完整性的标志。此外，海马完整性显示出与记忆能力对乙酰胆碱酯酶抑制反应的独立关联。在行为方面，对协方差的分析显示，在考虑海马灰质萎缩和功能时，情景记忆表现中存在显着的组×治疗相互作用。我们的研究结果表明，利伐斯的明有差异地影响轻度认知障碍和认知正常，年龄匹配的成年人的记忆相关神经活动，这取决于乙酰胆碱酯酶活性作为皮质胆碱能系统完整性的标志。此外，海马完整性显示出与记忆能力对乙酰胆碱酯酶抑制反应的独立关联。我们的研究结果表明，利伐斯的明有差异地影响轻度认知障碍和认知正常，年龄匹配的成年人的记忆相关神经活动，这取决于乙酰胆碱酯酶活性作为皮质胆碱能系统完整性的标志。此外，海马完整性显示出与记忆能力对乙酰胆碱酯酶抑制反应的独立关联。我们的研究结果表明，利伐斯的明有差异地影响轻度认知障碍和认知正常，年龄匹配的成年人的记忆相关神经活动，这取决于乙酰胆碱酯酶活性作为皮质胆碱能系统完整性的标志。此外，海马完整性显示出与记忆能力对乙酰胆碱酯酶抑制反应的独立关联。