Background: Selective atrophy of medial temporal lobe (MTL) structures and cholinergic system nuclei (CSN) are 2 major hallmarks of early Alzheimer’s disease (AD). CSN atrophy leads to depletion of the neurotransmitter acetylcholine (ACh), causing at least some symptoms in AD. Galantamine (GAL, a “dual mode” cholinesterase inhibitor) restores ACh levels and has a direct effect on nicotinergic receptors.
Objective: To explore the mechanism of action of GAL in patients with mild cognitive impairment (MCI) using fMRI, by examining the effects of 2 short-term medication regimens on the spatial distribution of brain activation during declarative and working memory (WM) performance.
Methods: 25 MCI patients (mean [SD] age 73.6 [7.5]; MMSE 27.0 [1.2]; CDR 0.5; NYU-paragraph recall 3.2 [2.9]) were scanned using fMRI on 3 medication regimens presented in a randomized order: at baseline (BL: no GAL), after a single oral dose of GAL (SD: 8 mg, 3 hours before scanning), and after steady state was reached (SS: 2x4 mg bid; 5 days). In each scan session, a declarative memory task was performed (face encoding [FE], with face retrieval as behavioral measure), and a parametric N-letter back WM task with 3 conditions: attention, easy WM, and increased WM load. A random-effects analysis was used to calculate average brain activation of BL, SD and SS and differences between regimens.
Results: FE (n = 25): Overall test score (face retrieval) was significantly above chance level with 0.45 ± 0.12, where 0.0 is chance level. Overall average activation was found in primary visual, ventral, and dorsal visual pathways in both hemispheres; frontal and parietal regions bilaterally; plus the anterior cingulate gyrus. There was an exposure-proportional improvement in task performance (BL = 0.36, SD = 0.49, and SS = 0.51; p < 0.01 [SD, SS vs BL]). This coincided with increased activation in left prefrontal areas during SD and SS. WM (n = 21): Overall test scores were 0.94 ± 0.09, 0.95 ± 0.08, and 0.83 ± 0.12 for attention, easy WM, and increased WM load. Overall average activation was present in frontal and parietal structures bilaterally plus the anterior cingulate gyrus. No significant difference was found for WM scores and WM brain activation between any of the regimens.
Conclusion: fMRI using 2 different memory tasks is feasible within an MCI population. Exposure to GAL in MCI patients increases left prefrontal brain activation during declarative memory (FE), which coincides with better task performance. No effect was found on memory scores or brain activation patterns during WM performance. Although preliminary, these data suggest that GAL has a differential influence on both memory systems in this patient group, with an immediate-type action influencing declarative memory.
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