Early-start vs delayed-start donepezil against cognitive decline in Parkinson disease: a randomized clinical trial

ABSTRACT

Background

Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD).

Research design and methods

The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120.

Results

A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048).

Conclusions

Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.

KEYWORDS:

• Cholinergic inflammatory reflex
• dementia
• apolipoprotein ε4

Acknowledgments

We thank Yuko Mori, BA for technical assistance in apolipoprotein genotyping, and Kyoko Waki, BSc for help in the study. We thank Barry Patel, PhD, from Edanz Group for editing a draft of this manuscript.

Author contribution

Conception and design: HS

Analysis and interpretation of the data: HS, TO, KY

The drafting the paper or revising it critically for intellectual content: HS, TO

The final approval of the version to be published: HS, TO, MK, ST, AU, KP, KY, KK

All authors agree to be accountable for all aspects of the work

Declaration of interest

Eisai Pharmaceutical Company supplied donepezil tablets (3 mg and 5 mg) and placebo tablets (3 mg and 5 mg) for the study. The trial drugs were donated by Eisai Pharmaceutical Company in phase 1 and were purchased by the primary investigator in phase 2. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Study sponsorship and funding

The study was supported by a Grant for the Designated Clinical Research from the National Hospital Organization, Tokyo, Japan. Eisai Pharmaceutical Company supplied donepezil tablets (3 mg and 5 mg) and placebo tablets (3 mg and 5 mg) in the study. No salaries or stipends were paid. The trial drugs were donated by Eisai Pharmaceutical Company in phase 1 and were purchased by the primary investigator in phase 2

Statistical Analysis

Conducted by Hideyuki Sawada.

Additional information

Funding

The study was supported by a National Hospital Organization Research Grant from the National Hospital Organization, Tokyo, Japan.