Effects of Donepezil on Cortical Activation in Mild Cognitive Impairment: A Pilot Double-Blind Placebo-Controlled Trial Using Functional MR Imaging

BACKGROUND AND PURPOSE: Cholinesterase-inhibitor therapy is approved for treatment of Alzheimer disease; however, application in patients with mild cognitive impairment (MCI) is still under active investigation. The purpose of this study was to determine the effect of such therapy on the neural substrates underlying memory processing in subjects with MCI by using functional MR imaging (fMRI). MATERIALS AND METHODS: Thirteen subjects with MCI (mean age, 68 +/- 6.9 years) enrolled in a multicenter double-blind placebo-controlled trial testing the clinical efficacy of the cholinesterase-inhibitor, donepezil, were studied with fMRI at baseline and following 12 or 24 weeks of therapy (single-site pilot study). The cognitive paradigm was delayed-response visual memory for novel faces. Within-group 1-sample t tests were performed on the donepezil and placebo groups at baseline and at follow-up. A repeated-measures analysis of variance design was used to look for a Treatment Group X Time interaction showing a significant donepezil- but not placebo-related change in blood oxygen level-dependent response during the course of the study. RESULTS: At baseline, both groups showed multiple areas of activation, including the bilateral dorsolateral prefrontal cortex, fusiform gyrus, and anterior cingulate cortex. On follow-up, the placebo group demonstrated a decreased extent of dorsolateral prefrontal activation, whereas the donepezil group demonstrated an increased extent of activation in the ventrolateral prefrontal cortex. Interaction demonstrated significant donepezil- but not placebo-related change in the left inferior frontal gyrus. CONCLUSIONS: Despite the limitations inherent to a pilot study of a small sample, our results point to specific cortical substrates underlying the actions of donepezil, which can be tested in future studies.