Lim Yen Ying, Maruff Paul, Schindler Rachel, Ott Brian R, Salloway Stephen, Yoo Don C, Noto Richard B, Santos Cláudia Y, Snyder Peter J
Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA.
Cogstate Ltd, Melbourne, Victoria, Australia; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia.
Neurobiol Aging. 2015 Oct;36(10):2709-15. doi: 10.1016/j.neurobiolaging.2015.07.009. Epub 2015 Jul 10.
Disruption in cholinergic neurotransmission is one of the earliest neuropathological changes in preclinical Alzheimer's disease (AD) and may be associated with abnormal beta-amyloid (Aβ) accumulation. Therefore, disruption of cholinergic neurotransmission with scopolamine may unmask otherwise undetectable cognitive deficits in preclinical AD. To compare the effects of low-dose (0.20 mg s.c.) scopolamine on cognition between Aβ+ and Aβ- cognitively normal (CN) older adults using the Groton Maze Learning Test (GMLT). CN older adults completed the GMLT predose and then received scopolamine (0.20 mg) subcutaneously. Participants were reassessed 1-, 3-, 5-, 7-, and 8-hours post dose. All participants underwent positron emission tomography neuroimaging for Aβ using (18)F-florbetapir within 6 weeks of their baseline visit. Rhode Island Hospital Clinical Research Center, Providence, USA. CN older adults (n = 63), with a family history of AD and subjective memory complaints were enrolled (15 were classified as Aβ+ and 48 were classified as Aβ-). Cognition was assessed using the computerized GMLT at all predose and post-dose time points. At 5-hours post dose, the Aβ+ group performed significantly worse than the Aβ- group on all measures of learning efficiency and working memory and/or executive function (Cohen's d = 1.13-1.56). When participants were classified as having an abnormal response to scopolamine (based on change score at 5-hours post dose >0), 100% were correctly classified as Aβ+ and 67% as Aβ-. The results of this study suggest that diminished cholinergic tone likely occurs in preclinical AD, and as such, the use of a cholinergic stress test to perturb an already compromised neurotransmitter system may be an effective way of identifying CN older adults who are in this preclinical stage of AD.
胆碱能神经传递障碍是临床前阿尔茨海默病（AD）最早出现的神经病理学变化之一，可能与β-淀粉样蛋白（Aβ）异常积聚有关。因此，用东莨菪碱破坏胆碱能神经传递可能会揭示临床前AD中原本无法检测到的认知缺陷。使用格罗顿迷宫学习测试（GMLT）比较低剂量（0.20mg皮下注射）东莨菪碱对Aβ阳性和Aβ阴性认知正常（CN）老年人认知的影响。CN老年人在给药前完成GMLT，然后皮下注射东莨菪碱（0.20mg）。在给药后1、3、5、7和8小时对参与者进行重新评估。所有参与者在基线访视后6周内使用（18）F-氟代贝他吡进行Aβ正电子发射断层扫描神经成像。美国普罗维登斯罗德岛医院临床研究中心。纳入有AD家族史和主观记忆主诉的CN老年人（n = 63）（15例分类为Aβ阳性，48例分类为Aβ阴性）。在所有给药前和给药后时间点使用计算机化GMLT评估认知。给药后5小时，Aβ阳性组在学习效率、工作记忆和/或执行功能的所有测量指标上的表现均显著差于Aβ阴性组（科恩d值 = 1.13 - 1.56）。当参与者被分类为对东莨菪碱有异常反应时（基于给药后5小时的变化分数>0），100%被正确分类为Aβ阳性，67%被分类为Aβ阴性。本研究结果表明，临床前AD可能出现胆碱能张力降低，因此，使用胆碱能应激试验干扰已经受损的神经递质系统可能是识别处于AD临床前阶段的CN老年人的有效方法。
