Donepezil Impairs Memory in Healthy Older Subjects: Behavioural, EEG and Simultaneous EEG/fMRI Biomarkers

Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil) on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week followups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify the precise neuroanatomical origins of EEG drug markers using simultaneous EEG/fMRI. The results of this study may be useful for evaluating novel drugs for cognitive enhancement.

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Donepezil for language dysfunction in Alzheimer's disease

Introduction

Progressive language impairment is among the primary components of cognitive decline in Alzheimer's disease (AD). Because expressive and receptive language helps maintain emotional connection to caregivers and supports management of AD functional needs, language plays a critical role in patients' emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we performed a post hoc analysis to determine whether a higher dose of donepezil was associated with greater benefits in language function.

Methods

In the original randomized, double-blind clinical trial, 1467 patients with moderate to severe AD (baseline Mini-Mental State Examination [MMSE] scores 0-20) were randomized 2:1 to receive donepezil 23 mg/d or to continue on donepezil 10 mg/d for 24 weeks. In this post hoc analysis, the Severe Impairment Battery language (SIB-L) scale and a new 21-item SIB-derived language scale (the SIB[lang]) were used to explore differences in language function between the treatment groups. Correlations between SIB-L and SIB[lang] scores and scores on the severe version of the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL-sev), the Clinician's Interview-Based Impression of Severity/Change-plus caregiver input (CIBIS/CIBIC-plus), and the MMSE were also investigated.

Results

At Week 24, treatment with donepezil 23 mg/d was associated with an improvement in language in the full intention-to-treat (ITT) population, whereas language function declined with donepezil 10 mg/d (SIB-L treatment difference 0.8, P = 0.0013; SIB[lang] treatment difference 0.8, P = 0.0009). Similar results were observed in a cohort of patients with more severe baseline disease (MMSE, 0-16). At baseline and Week 24, correlations between the SIB-derived language scales and the ADCS-ADL-sev and CIBIC-plus were moderate, but were stronger between the language scales and MMSE.

Conclusions

Patients with moderate to severe AD receiving donepezil 23 mg/d showed greater language benefits compared with those receiving 10 mg/d, as measured by SIB-derived language assessments. Increasing the dose of donepezil to 23 mg/d may provide language benefits in patients with moderate to severe AD, for whom preservation of language abilities is especially critical. ClinicalTrials.gov identifier: NCT00478205.

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