Changes in Brain Functional Connectivity Following Donepezil Treatment in Alzheimer's Disease

This study used resting state functional connectivity magnetic resonance imaging (fcMRI) to explore changes in brain connectivity and their behavior correlates in nine regions of interest (ROIs) in eleven patients with mild Alzheimer's disease (AD) following treatment with the cholinesterase inhibitor, donepezil. The ROIs were selected on the basis of their association with cholinergic neurotransmission, AD neuropathology, and neurocognitive deficits in AD. These ROIs included the medial septal nuclei, left and right hippocampi, left Broca's area and its right hemisphere homologue, left and right dorsolateral prefrontal cortices, and left and right primary visual cortices. Changes in connectivity were also related to changes in performance on neurocognitive tests of verbal fluency and episodic memory. Among the ROIs, the effects of the drug were selective. Only the connection between left and right DLPFC increased significantly after treatment. However, ten of the eighteen connections measured showed significant relationships between connectivity and behavior. The significant correlations centered around left hippocampus, left Broca's area, and dorsolateral prefrontal cortex bilaterally. Connections originating in the left hippocampus showed mostly inverse relationships with behavior. Predictions of selective increases in connectivity in networks associated with the neurochemical, the neuropathological, and neurocognitive profiles of AD were generally not supported. A separate, whole-brain, exploratory, analysis measured changes in connectivity throughout the brain with each of the nine regions of interest (ROIs). There were increases in connectivity among bilateral frontal areas in language circuits, including the left IFG, left superior temporal gyrus, and left supramarginal gyrus, and in the sensory-motor integrative network. Further connections were noted between the left inferior frontal gyrus and caudate nucleus. The data suggest that the drug had selective effects on executive networks of attention.