An Open-Label Exploratory Study with Memantine: Correlation between Proton Magnetic Resonance Spectroscopy and Cognition in Patients with Mild to Moderate Alzheimer's Disease (P04.198)

Abstract

Objective: To characterize Alzheimer9s disease (AD) progression using proton magnetic resonance spectroscopy ( 1 H MRS) and cognitive measures in mild-moderate AD patients treated with open-label memantine in addition to cholinesterase inhibitor (ChEI). Background While cross-sectional studies have shown reduced N-acetylaspartate (NAA) and elevated myo-inositol (mI) in AD patients, the feasibility of 1 H MRS as a longitudinal biomarker for clinical trials remains to be elucidated. Design/Methods: 11 subjects with mild-moderate AD (baseline MMSE 21.9 ± 3.0) were on stable dose ChEI for at least 3 months prior to study entry. Neuropsychometric testing and single-voxel 1 H MRS from the precuneus and posterior cingulate region were performed at baseline, after 24 weeks of ongoing ChEI monotherapy, and after another 24 weeks of open-label memantine in addition to ChEI. Baseline 1 H MRS metabolite [NAA, mI, choline (Cho), and creatine (Cr)] ratios in AD subjects were compared to 29 age-matched, cognitively normal controls (MMSE 28.3 ± 1.6). Results: Compared to controls, AD subjects had significantly higher mI/Cr (p=0.0155) and lower NAA/Cr (p=0.0487), NAA/Cho (p=0.0222) and NAA/mI (p=0.0105). In AD subjects, baseline Alzheimer9s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores significantly correlated with NAA/Cr (Spearman r = 0.80, p=0.0032), mI/Cr (Spearman r = -0.73, p=0.0115), and NAA/mI (Spearman r = 0.83, p=0.0014). Baseline cognitive measures did not correlate with metabolite ratios. There was no significant change in neuropsychometric test performance on combination therapy as compared with ChEI monotherapy. There was a decrease in NAA/mI on combination therapy as compared with ChEI monotherapy, but this was not significant after correction for multiple comparisons. Conclusions: We found significant differences in 1 H MRS metabolite ratios between mild-moderate AD and control subjects. Baseline 1 H MRS metabolite ratios correlated with function (ADCS-ADL). There was no significant change in neuropsychometric performance or 1 H MRS metabolite ratios when open-label memantine was added to stable dose ChEI. Supported by: Forest Research Institute. Disclosure: Dr. Gordon has received personal compensation for activities with Accera Inc. and Eli Lilly & Company as a consultant. Dr. Gordon has received research support from Forest Laboratories and Eli Lilly & Company. Dr. Kingsley has nothing to disclose. Dr. Goldberg has received personal compensation for activities with Merck & Co., Inc. as a consultant. Dr. Koppel holds stock and/or stock options in Eli Lilly & Company. Dr. Christen has nothing to disclose. Dr. Keehlisen has nothing to disclose. Dr. Kohn has nothing to disclose. Dr. Davies has has received (royalty or license fee or contractual rights) payments from Eli Lilly.Dr. Davies has received research support from Eli Lilly.