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Differential response to donepezil in MRI subtypes of mild cognitive impairment
Patricia Diaz-Galvan1, Giulia Lorenzon2, Rosaleena Mohanty2
1Department of Radiology, Mayo Clinic, Rochester, MN, USA.
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.
Insights
Donepezil may benefit mild cognitive impairment patients with minimal atrophy or hippocampal-sparing subtypes. A new continuous subtyping method better identified these responders compared to traditional approaches.
Area of Science:
- Neurology
- Neuroimaging
- Pharmacology
Background:
- Donepezil is an Alzheimer's disease (AD) treatment with inconsistent clinical trial results.
- Inconsistent results may stem from methodological issues, AD heterogeneity, and participant diversity.
- This study explores donepezil response variability in mild cognitive impairment (MCI) based on magnetic resonance imaging (MRI) subtypes.
Purpose of the Study:
- To investigate if donepezil response differs among MCI individuals with distinct MRI-defined subtypes.
- To compare a novel continuous subtyping approach with conventional categorical methods for identifying treatment response.
Main Methods:
- Utilized data from the Hippocampus Study, a randomized trial involving 173 MCI participants (83 donepezil, 90 placebo).
- Assessed annualized percentage change (APC) in brain volumes (hippocampal, ventricular, total grey matter) and AD cortical thickness signature.
- Classified participants into MRI subtypes: typical AD, limbic-predominant, hippocampal-sparing, or minimal atrophy using both continuous and categorical approaches.
Main Results:
- Donepezil-treated MCI individuals showed slower atrophy rates than placebo, specifically in minimal atrophy and hippocampal-sparing subtypes.
- The continuous subtyping approach effectively identified this differential response.
- The conventional categorical subtyping approach did not capture the differential treatment effect.
Conclusions:
- MCI individuals with hippocampal-sparing or minimal atrophy subtypes may derive greater benefit from donepezil.
- The continuous subtyping method shows promise for stratifying patients and predicting treatment response.
- Further research is needed to validate subtype stratification for prognosis and treatment selection in AD.
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