Radboud University Nijmegen Medical Centre, Department of Geriatric Medicine and Alzheimer Centre Nijmegen, The Netherlands.
Behav Brain Res. 2011 Aug 10;221(2):537-42. doi: 10.1016/j.bbr.2009.12.047. Epub 2010 Jan 7.
The intrinsic cholinergic innervation of the cortical microvessels contains both subcortical pathways and local cortical interneurons mediated by muscarinic and nicotinic acetylcholine receptors. Stimulation of this system leads to vasodilatation. In the extrinsic innervation, choline acts as a selective agonist for the α7-nicoticinic acetylcholine receptor on the sympathetic nerves to cause vasodilatation, and through this mechanism, cholinergic modulation may affect this sympathetic vasodilatation. Alzheimer's disease is characterized by a cerebral cholinergic deficit and cerebral blood flow is diminished. Cholinesterase inhibitors, important drugs in the treatment of Alzheimer's disease, could influence the cerebral blood flow through stimulation of the intrinsic cholinergic cerebrovascular innervation. Indeed, cholinesterase inhibitors improve cerebral blood flow in Alzheimer patients who respond to treatment. Further, cerebrovascular reactivity and neurovascular coupling are impaired in Alzheimer's disease and both can be improved by cholinesterase inhibitors. Conversely, cholinesterase inhibitors inhibit the α7-nicoticinic acetylcholine receptor on extrinsic sympathetic nerves and thus may impair vasodilatation. The net outcome of these opposing effects in clinical practice remains unknown. Moreover, it is uncertain whether the regulation of cerebral blood flow during blood pressure changes (cerebral autoregulation) is impaired in patients with Alzheimer's disease. Technological developments now allow us to dynamically measure blood pressure, cerebral blood flow, and cerebral cortical oxygenation. Using simple maneuvers like single sit-stand and repeated sit-stand maneuvers, the regulation of cerebral perfusion in patients with Alzheimer's disease can easily be measured. Sit-stand maneuvers can be considered as a provocation test for cerebral autoregulation, and provide excellent opportunities to study the cerebrovascular effects of cholinesterase inhibitors.
皮质微血管的固有胆碱能神经支配包含皮质下通路和局部皮质中间神经元，由毒蕈碱和烟碱型乙酰胆碱受体介导。刺激该系统可导致血管舒张。在外来神经支配中，胆碱作为交感神经上α7-烟碱型乙酰胆碱受体的选择性激动剂引起血管舒张，通过这种机制，胆碱能调节可能会影响这种交感神经血管舒张。阿尔茨海默病的特征是大脑胆碱能缺乏，脑血流减少。胆碱酯酶抑制剂是治疗阿尔茨海默病的重要药物，通过刺激固有胆碱能脑血管支配，可能会影响脑血流。事实上，胆碱酯酶抑制剂可改善对治疗有反应的阿尔茨海默病患者的脑血流。此外，阿尔茨海默病患者的脑血管反应性和神经血管耦联受损，胆碱酯酶抑制剂均可改善这两种情况。相反，胆碱酯酶抑制剂抑制外在交感神经上的α7-烟碱型乙酰胆碱受体，从而可能损害血管舒张。这些相反作用在临床实践中的净结果尚不清楚。此外，阿尔茨海默病患者的血压变化期间（脑自动调节）的脑血流调节是否受损尚不确定。技术发展现在使我们能够动态测量血压、脑血流和大脑皮质氧合。使用简单的动作，如单次坐站和重复坐站动作，可以轻松测量阿尔茨海默病患者的脑灌注调节。坐站动作可视为脑自动调节的激发试验，为研究胆碱酯酶抑制剂的脑血管效应提供了极好的机会。
