Treatment Effects of Therapeutic Cholinesterase Inhibitors on Visuospatial Processing in Alzheimer’s Disease: A Longitudinal Functional MRI Study

Abstract

Background/Aims: Visuospatial impairments are known to occur in Alzheimer’s disease (AD). We hypothesised that functional magnetic resonance imaging (fMRI) response in task-related brain regions would be impaired in patients with AD during the task and that treatment with acetyl cholinesterase inhibitors would enhance activations in brain regions concerned with this visual perceptual processing. Method: Ten AD subjects were neuropsychologically assessed and underwent fMRI imaging whilst performing a series of visuospatial perception tasks, before and after treatment with acetyl cholinesterase inhibitors. Eleven healthy elderly comparison subjects were also scanned twice. Results: Regions of increased brain activation in AD included the left precuneus, left cuneus, left supramarginal gyrus, right parieto-temporal cortex and right inferior parietal lobule. Further, increased activation in the left precuneus was found to correlate significantly with improved functioning of activities of daily living. Conclusions: We believe this to be the first fMRI study that, after controlling for the confound of repeat scanning, demonstrates altered patterns of brain activation associated with visuospatial processing following treatment in patients with AD. The treatment-related improvement of visual perception in AD may rely on enhanced attentional mechanisms, thereby possibly supporting independent living through improvement on activities of daily living.

Evidence of Altered Corticomotor System Connectivity in Early-Stage Alzheimer's Disease

“…The use of PPI allowed us to globally assess regions functionally associated with M1, addressing the limitation of model-based connectivity analysis 11 . However, unlike Agosta et al 53 we cannot infer direct connectivity between regions. Further, 6 participants with AD were on an established regimen of an acetylcholinesterase inhibitor, a known modifier of cortical activation.…”

Cholinergic Enhancement of Brain Activation in Mild Cognitive Impairment during Episodic Memory Encoding

“…However, previous studies evaluating activation changes in response to treatment with ChEIs have shown drug effects in both the left and right medial temporal lobes during episodic encoding and recognition (16, 19). Studies of fMRI activation during other cognitive tasks, such as a visual attention task and a location-matching task, have also shown activation changed in both left and right medial temporal lobes in response to ChEI treatment in AD and MCI patients (20, 22, 23, 27). Furthermore, improved cognitive performance has been associated with increased activation in both the left and right medial temporal lobes after treatment with donepezil (31).…”

“…In AD patients, acute dosing with ChEIs resulted in primarily increased activation post-drug treatment during episodic face encoding and recognition, working memory, and visual and attention tasks in task-related regions (15, 19, 22, 29). Chronic dosing of AD patients with ChEIs for varying periods (10–24 weeks) also showed a post-drug effect on brain activation, with patients showing increased activation during episodic encoding and recognition, semantic association, working memory, and visuospatial perceptual tasks in task-related areas (18, 21, 27, 29). Increased activation in task-related regions during episodic encoding after ChEI treatment in AD patients was also associated with improved clinical memory performance (31).…”

Clinical Applications of fMRI

“…For example, Woodruff's research group sought to test the rationale for use of cholinesterase inhibitors to reduce visuospatial impairments with AD (Thiyagesh et al 2010). They did this using a small patient population studied with an fMRI visuospatial processing task before and after cholinesterase inhibition.…”