Cholinesterase inhibition modulates visual and attentional brain responses in Alzheimer's disease and health

Abstract

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.

Figure 1

In the scanner, subjects performed one of two tasks in block-fashion: Color task: subjects were prompted as to whether the image was red or green; Age task: subjects were prompted as to whether the depicted object was old or young /modern. Face and building-stimuli occurred with equal frequency in each task. Subjects were reminded of the key-press meanings prior to each stimulus.

Figure 2

RT and accuracy responses separated by stimulus-type and task for each combination of group and treatment. * denotes significant task × treatment interactions for the AD group (p < 0.05).

Figure 3

A, B – Main-effect of face > building in controls (A) and AD (B) on placebo at the level of mid-fusiform cortex and precuneus (y = −50). C, D – Interaction of face-selectivity × treatment in controls (C) and AD (D) demonstrating reduced selectivity in right fusiform cortex with physostigmine in both groups (y = −50 and −54, respectively). There was no between-group difference in face-selectivity or in the interaction of selectivity × treatment in the right fusiform cortex (p>0.1). E, F – E: interaction of face-selectivity × group (on placebo) demonstrating reduction of selectivity in AD relative to controls in precuneus. F: interaction of face-selectivity × treatment in AD demonstrating increased selectivity in precuneus with physostigmine relative to placebo. G, H, I – Main-effect of building > face in controls (G), AD (H) and the difference between them (I), on placebo, at the level of parahippocampal cortices (z = −16), demonstrating reduction of selectivity in AD relative to controls in posterior parahippocampal cortex. J, K, L – Interaction of building-selectivity × treatment in controls (J) and AD (K) demonstrating that physostigmine induces a reduction of selectivity in controls (J) but an increase in selectivity in AD (K) in right posterior parahippocampal cortex. L depicts the interaction of building-selectivity × treatment × group. M – Plots of %-signal change for face > building contrast in right fusiform cortex, and precuneus, and for building > face contrast in right posterior parahippocampal cortex, under each combination of treatment and group. Coordinates plotted are those at the maxima of selectivity × treatment interaction in controls (first graph); and selectivity × treatment in AD (second and third graphs). Activations are thresholded at p<0.001, uncorrected, and are superimposed on the mean normalised EPI of controls or patients as appropriate (group interactions are overlaid on patients' mean).

Figure 4

A, B, C – Main-effect of task (Age > Color) in controls (A), AD (B), and the difference between them (C), on placebo. There were no interactions with stimulus-type in regions shown (p>0.1). D, E, F – Interaction of task × treatment in controls (D), AD (E) and the difference between them (F): regions shown are those in which the task-effect is decreased by physostigmine relative to placebo in controls (D) but increased by physostigmine relative to placebo in AD (E). G – Plots of %-signal change for Color and Age tasks, for each treatment and group at the maxima for the 3-way interaction (from F). Activations are thresholded at p<0.001, uncorrected, and are superimposed on the mean normalised EPI of controls or patients as appropriate (group interactions are overlaid on patients’ mean).

Figure 5

A, B – Main-effect of face > building (first slice) and building > face (second slice) stimuli in control (A) and AD (B) subjects on placebo. The slices chosen include regions which additionally show interactions with task, treatment and group as illustrated below. Regions shown for face-selectivity are bilateral posterior STS (z = +12); and for building-selectivity are lateral occipital and retrosplenial cortices (z = +2). C, D, E – Interaction of stimulus-selectivity × task in controls (C), AD (D) and the difference between them (E) on placebo: regions shown are those in which Age relative to Color task results in greater face-versus-building (first slice) and building-versus-face (second slice) responses. F, G, H – Interaction of stimulus-selectivity × task × treatment in controls (F), AD (G) and the difference between them (H): circled regions are those in which task-enhancements of face- and building- selectivity are decreased by physostigmine relative to placebo in controls (F) but increased by physostigmine relative to placebo in AD (G). I – Interaction of stimulus-selectivity (face > building) × task in controls (first slice) and AD (second slice); region circled shows greater task task-modulation of stimulus-selectivity in AD relative to controls, that itself is cholinergic dependent (z = +8; see text). J – Plots of %-signal change for face > building (first and third graphs) and building > face (second graph) contrasts, under each task, treatment and group at the maxima for the 4-way interaction (from H; first two graphs) and at the maximum task × stimulus interaction in AD (from I; third graph). Activations are thresholded at p<0.001, uncorrected, except for F and G that are thresholded at p<0.01, uncorrected, and are superimposed on the mean normalised EPI of controls or patients as appropriate (group interactions are overlaid on patients' mean).