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Effect of Memantine on Resting State Default Mode Network Activity in Alzheimer’s Disease

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Abstract

Background

Memantine is an approved symptomatic treatment for moderate to severe Alzheimer’s disease that reduces the excitotoxic effects of hyperactive glutamatergic transmission. However, the exact mechanism of the effect of memantine in Alzheimer’s disease patients is poorly understood. Importantly, the default mode network (DMN), which plays a key role in attention, is hypoactive in Alzheimer’s disease and is under glutamatergic control.

Objective

To assess the effect of memantine on the activity of the DMN in moderate to severe Alzheimer’s disease.

Methods

Functional magnetic resonance imaging (MRI) data from 15 patients with moderate to severe Alzheimer’s disease, seven treated with memantine (mean±SD age 77±8 years, mean±SD Mini-Mental State Examination [MMSE] score 16±5) and eight with placebo (mean±SD age 76±6 years, mean±SD MMSE score 13±1), were acquired at baseline (T0) and after 6 months of treatment (T6). Resting state components were extracted after spatial normalization in individual patients with independent component analysis. The consistency of the components was assessed using ICASSO and the DMN was recognized through spatial correlation with a pre-defined template. Voxel-based statistical analyses were performed to study the change in DMN activity from T0 to T6 in the two groups.

Results

At T0, the two groups showed similar DMN activity except in the precuneus and cuneus, where the patients who started treatment with memantine had slightly greater activity (p <0.05 corrected for familywise error [FWE]). The prospective comparison between T0 and T6 in the treated patients showed increased DMN activation mapping in the precuneus (p <0.05, FWE corrected), while the prospective comparison in the untreated patients did not show significant changes. The treatment×time interaction term was significant at p <0.05, FWE corrected.

Conclusions

The results suggest a positive effect of memantine treatment in patients with moderate to severe Alzheimer’s disease, resulting in an increased resting DMN activity in the precuneus region over 6 months. Future studies confirming the present findings are required to further demonstrate the beneficial effects of memantine on the DMN in Alzheimer’s disease.

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Acknowledgements

This work has been co-funded by research grant N. 125/2004 of the Italian Ministry of Health, Ricerca Finalizzata “Malattie neurodegenerative legate all’invecchiamento: dalla patogenesi alle prospettive terapeutiche per un progetto traslazionale” and by an unrestricted grant by Lundbeck Italia SpA Pharmaceutical.

Marco Lorenzi, Alberto Beltramello, Nicola B. Mercuri, Elisa Canu, Giada Zoccatelli, Francesca B. Pizzini, Franco Alessandrini, Maria Cotelli, Sandra Rosini, Daniela Costardi and Carlo Caltagirone have no conflicts of interest to declare. Giovanni B. Frisoni has received fees for scientific consultations from Lundbeck International.

The authors are very grateful to Dr Melissa Romano, Laboratory of Epidemiology, Neuroimaging and Telemedicine -LENITEM-, Istituto di Ricerca e Cura a Carattere Scientifico San Giovanni di Dio Fatebenefratelli, Brescia, Italy, for her excellent organizational contribution to the realization and progression of the study, and to Dr Chiara Barattieri of the same institution for her contribution to the proof reading of the manuscript. We wish to thank the patients and their families for their continuous and admirable cooperation.

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Authors and Affiliations

  1. Laboratory of Epidemiology, Neuroimaging and Telemedicine -LENITEM-, Istituto di Ricerca e Cura a Carattere Scientifico San Giovanni di Dio Fatebenefratelli, Brescia, Italy

    Marco Lorenzi, Elisa Canu, Daniela Costardi & Giovanni B. Frisoni

  2. Project Team Asclepios, Institut national de recherche en informatique et automatique (INRIA), Sophia Antipolis, France

    Marco Lorenzi

  3. Ospedale Maggiore, Service of Neuroradiology, Borgo Trento, Verona, Italy

    Alberto Beltramello, Giada Zoccatelli, Francesca B. Pizzini & Franco Alessandrini

  4. Fondazione Istituto di Ricerca e Cura a Carattere Scientifico, Santa Lucia, Università Tor Vergata, Rome, Italy

    Nicola B. Mercuri & Carlo Caltagirone

  5. Cognitive Neuroscience Section, Istituto di Ricerca e Cura a Carattere Scientifico San Giovanni di Dio Fatebenefratelli, Brescia, Italy

    Maria Cotelli & Sandra Rosini

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  1. Marco Lorenzi
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Correspondence to Marco Lorenzi.

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Lorenzi, M., Beltramello, A., Mercuri, N.B. et al. Effect of Memantine on Resting State Default Mode Network Activity in Alzheimer’s Disease. Drugs Aging 28, 205–217 (2011). https://doi.org/10.2165/11586440-000000000-00000

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