Differential response to donepezil in MRI subtypes of mild cognitive impairment

Abstract

Background: Donepezil is an approved therapy for the treatment of Alzheimer's disease (AD). Results across clinical trials have been inconsistent, which may be explained by design-methodological issues, the pathophysiological heterogeneity of AD, and diversity of included study participants. We investigated whether response to donepezil differs in mild cognitive impaired (MCI) individuals demonstrating different magnetic resonance imaging (MRI) subtypes.

Methods: From the Hippocampus Study double-blind, randomized clinical trial, we included 173 MCI individuals (donepezil = 83; placebo = 90) with structural MRI data, at baseline and at clinical follow-up assessments (6-12-month). Efficacy outcomes were the annualized percentage change (APC) in hippocampal, ventricular, and total grey matter volumes, as well as in the AD cortical thickness signature. Participants were classified into MRI subtypes as typical AD, limbic-predominant, hippocampal-sparing, or minimal atrophy at baseline. We primarily applied a subtyping approach based on continuous scale of two subtyping dimensions. We also used the conventional categorical subtyping approach for comparison.

Results: Donepezil-treated MCI individuals showed slower atrophy rates compared to the placebo group, but only if they belonged to the minimal atrophy or hippocampal-sparing subtypes. Importantly, only the continuous subtyping approach, but not the conventional categorical approach, captured this differential response.

Conclusions: Our data suggest that individuals with MCI, with hippocampal-sparing or minimal atrophy subtype, may have improved benefit from donepezil, as compared with MCI individuals with typical or limbic-predominant patterns of atrophy. The newly proposed continuous subtyping approach may have advantages compared to the conventional categorical approach. Future research is warranted to demonstrate the potential of subtype stratification for disease prognosis and response to treatment.

Trial registration: ClinicalTrial.gov NCT00403520. Submission Date: November 21, 2006.

Keywords: Alzheimer’s disease; Donepezil; Heterogeneity; Mild cognitive impairment; Precision medicine; Randomized controlled trial; Subtypes.

Fig. 1

Conceptual framework of AD subtyping dimensions. In this study, we selected a global brain atrophy index (BV/CSF index; [29]) as a proxy for the severity dimension, and the ratio between the volume of the hippocampus to the volume of the cortex as a proxy for the typicality dimension [18, 19]. The combination of severity and typicality dimensions indicates four distinct MRI patterns: typical AD, limbic-predominant, hippocampal-sparing, and minimal atrophy. Adapted from Ferreira et al. [17]

Fig. 2

Design and protocol of the Hippocampus Study Clinical Trial (www.clinialTrial.gov; identifier: NCT00403520). The Hippocampus Study Clinical Trial extended for up to 18 months, consisting of a 4-week selection period (visit 0), a 12-month randomized double-blind treatment window (visits 1–4), and an open label extension period of 6 more months (visits 4–5). At the treatment window, individuals were randomly assigned to either the active treatment group or the placebo control group. The treatment group received 1 capsule of 5-mg donepezil daily from week 0 to 6, then 2 capsules of 5-mg donepezil (i.e. 10 mg) until month 12; the placebo group received 1 placebo capsule daily until week 6, and then two placebo capsules until month 12

Fig. 3

Baseline MRI patterns characterized on continuous scales of subtyping dimensions. A Scatterplot of the hippocampus-to-cortex ratio (typicality subtyping dimension) by BV/CSF index (severity subtyping dimension). B Classification of MCI individuals according to the degree of global brain atrophy after applying clinical cut-offs on BV/CSF index (severity subtyping dimension). Note: BV = brain volume; CSF = cerebrospinal fluid

Fig. 4

Interaction plots between severity/typicality subtyping dimensions (X axis) and treatment (Y axis) in APC of AD signature cortical thickness which includes entorhinal, inferior temporal, middle temporal, and fusiform gyri thickness (A, B) and APC of lateral ventricle volume (C)