Bentley Paul, Driver Jon, Dolan Ray J
Wellcome Centre for Neuroimaging at UCL, London WC1N 3BG, UK.
Brain. 2008 Feb;131(Pt 2):409-24. doi: 10.1093/brain/awm299. Epub 2007 Dec 12.
Visuo-attentional deficits occur early in Alzheimer's disease (AD) and are considered more responsive to pro-cholinergic therapy than characteristic memory disturbances. We hypothesised that neural responses in AD during visuo-attentional processing would be impaired relative to controls, yet partially susceptible to improvement with the cholinesterase inhibitor physostigmine. We studied 16 mild AD patients and 17 age-matched healthy controls, using fMRI-scanning to enable within-subject placebo-controlled comparisons of effects of physostigmine on stimulus- and attention- related brain activations, plus between-group comparisons for these. Subjects viewed face or building stimuli while performing a shallow judgement (colour of image) or a deep judgement (young/old age of depicted face or building). Behaviourally, AD subjects performed slower than controls in both tasks, while physostigmine benefited the patients for the more demanding age-judgement task. Stimulus-selective (face minus building, and vice versa) BOLD signals in precuneus and posterior parahippocampal cortex were attenuated in patients relative to controls, but increased following physostigmine. By contrast, face-selective responses in fusiform cortex were not impaired in AD and showed decreases following physostigmine for both groups. Task-dependent responses in right parietal and prefrontal cortices were diminished in AD but improved following physostigmine. A similar pattern of group and treatment effects was observed in two extrastriate cortical regions that showed physostigmine-induced enhancement of stimulus-selectivity for the deep versus shallow task. Finally, for the healthy group, physostigmine decreased stimulus and task-dependent effects, partly due to an exaggeration of selectivity during the shallow relative to deep task. The differences in brain activations between groups and treatments were not attributable merely to performance (reaction time) differences. Our results demonstrate that physostigmine can improve both stimulus- and attention-dependent responses in functionally affected extrastriate and frontoparietal regions in AD, while perturbing the normal pattern of responses in many of the same regions in healthy controls.
视觉注意缺陷在阿尔茨海默病（AD）早期就会出现，并且被认为比典型的记忆障碍对促胆碱能治疗更敏感。我们假设，与对照组相比，AD患者在视觉注意处理过程中的神经反应会受损，但部分可通过胆碱酯酶抑制剂毒扁豆碱得到改善。我们研究了16名轻度AD患者和17名年龄匹配的健康对照者，使用功能磁共振成像扫描进行受试者内安慰剂对照比较，以观察毒扁豆碱对与刺激和注意力相关的大脑激活的影响，并进行组间比较。受试者在执行浅层判断（图像颜色）或深层判断（所描绘面孔或建筑的年轻/年老）时观看面孔或建筑刺激。行为上，AD患者在两项任务中的表现均比对照组慢，而毒扁豆碱使患者在要求更高的年龄判断任务中受益。与对照组相比，患者楔前叶和海马旁回后部皮质中刺激选择性（面孔减去建筑，反之亦然）的血氧水平依赖（BOLD）信号减弱，但在使用毒扁豆碱后增加。相比之下，梭状回皮质中的面孔选择性反应在AD中未受损，且两组在使用毒扁豆碱后均降低。右侧顶叶和前额叶皮质中与任务相关的反应在AD中减弱，但在使用毒扁豆碱后改善。在两个纹外皮质区域观察到了类似的组间和治疗效果模式，这些区域显示毒扁豆碱可增强深层与浅层任务的刺激选择性。最后，对于健康组，毒扁豆碱降低了刺激和任务相关效应，部分原因是浅层任务相对于深层任务期间选择性的夸大。组间和治疗之间大脑激活差异不仅仅归因于表现（反应时间）差异。我们的结果表明，毒扁豆碱可改善AD患者功能受影响的纹外和额顶区域中与刺激和注意力相关的反应，同时扰乱健康对照者许多相同区域的正常反应模式。
