The combination of acetylcholinesterase inhibitor therapy and high‐frequency repetitive transcranial magnetic stimulation in Alzheimer’s disease: A preliminary fMRI study

Abstract

AbstractBackgroundBasal forebrain (BF) cholinergic dysfunction is one of the characteristics in Alzheimer’s disease (AD). Acetylcholinesterase inhibitors (AChEI) are approved drus currently used for the clinical treatment of AD. However, drug therapy has considerable side effects, and not everyone can benefit from it. Previous studies have shown that repetitive transcranial magnetic stimulation (rTMS) can improve cognitive function in patients with AD. Therefore, we aimed to determine the effect of cholinergic treatment on BF functional brain networks using functional connectivity (FC) analysis, and investigate whether donepezil therapy combined with rTMS is superior to monotherapy of AD.MethodThirty AD patients received ten sessions of 10Hz high frequency rTMS (HF‐rTMS) at 110% of the motor threshold on the left dorsolateral prefrontal cortex (DLPFC) and the left lateral parietal cortex (combination therapy group, n=15) or sham stimulation (drug treatment group, n=15), added to their donepezil treatment (5mg/d), in a randomized double‐blind design. Fifteen untreated and age, gender and years of education matched AD patients served as control group. The resting‐state FC of BF was calculated using a seed‐based approach. Spearman correlation with false discovery rate (FDR) correction was used to investigate the relationship between clinical and cognitive tests scores and FC values.ResultCompared to control group, the combination therapy group showed BF seed‐based FC enhancement in the bilateral posterior cingulate cortex (PCC), superior parietal lobule, left hippocampus, precuneus, and cerebellum. Drug treatment patients showed increased BF‐related FC in the bilateral PCC, and left hippocampus, and cerebellum. In addition, combination therapy group patients had significantly higher BF seed‐based FC in the left PCC and precuneus than drug treatment patients. Moreover, these brain regions are mainly concentrated in the default mode network (DMN).ConclusionOur results indicate that the levels of functional connectivity between the BF and the DMN is significantly higher in the combination therapy group than that in the other groups, and which is positively correlated with improvements in MMSE and ADL. HF‐rTMS over the left DLPFC and the left lateral parietal cortex is an add‐on strategy of clinical significance in combination with donepezil in patients with AD.