Effect of Memantine on Resting State Default Mode Network Activity in Alzheimer’s Disease
- 235 Downloads
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.
To assess the effect of memantine on the activity of the DMN in moderate to severe Alzheimer’s disease.
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.
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.
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.
KeywordsIndependent Component Analysis Memantine Default Mode Network Independent Component Analysis Algorithm Rest State Network
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.
- 1.Areosa SA, Sherriff F. Memantine for dementia. Cochrane Database Syst Rev 2005; (3): CD003154Google Scholar
- 26.Protocollo MEM_T V0 [in Italian]. Brescia: Laboratorio di Epidemiologia e Neuroimaging, IRCCS [online]. Available from URL: http://www.centroalzheimer.it/Public/Protocollo_MEM_T0.doc [Accessed 2010 Nov 26]
- 27.Lezak MD, Howieson DB, Loring DW, et al. Neuropsychological assessment. 4th ed. New York (NY): Oxford University Press, 2004Google Scholar
- 48.Damoiseaux JS, Keller KE, Menon V, et al. Default mode network connectivity tracks clinical progression in Alzheimer’s disease. San Francisco (CA): Organization for the Human Brain Mapping, 2009Google Scholar
- 56.Molinaro G, Battaglia G, Riozzi B, et al. Memantine treatment reduces the expression of the K(+)/CL(−)cotrans-porter KCC2 in the hippocampus and cerebral cortex, and attenuates behavioural responses mediated by GABA(A) receptor activation in mice. Brain Res 2009; 1265: 75–9PubMedCrossRefGoogle Scholar