Drugs & Aging

, Volume 28, Issue 3, pp 205–217 | Cite as

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

  • Marco LorenziEmail author
  • Alberto Beltramello
  • Nicola B. Mercuri
  • Elisa Canu
  • Giada Zoccatelli
  • Francesca B. Pizzini
  • Franco Alessandrini
  • Maria Cotelli
  • Sandra Rosini
  • Daniela Costardi
  • Carlo Caltagirone
  • Giovanni B. Frisoni
Original Research Article



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.


Independent Component Analysis Memantine Default Mode Network Independent Component Analysis Algorithm Rest State Network 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



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.

Supplementary material

40266_2012_28030205_MOESM1_ESM.pdf (104 kb)
Supplementary material, approximately 107 KB.


  1. 1.
    Areosa SA, Sherriff F. Memantine for dementia. Cochrane Database Syst Rev 2005; (3): CD003154Google Scholar
  2. 2.
    Lopez OL, Becker JT, Wahed AS, et al. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry 2009; 80(6): 600–7PubMedCrossRefGoogle Scholar
  3. 3.
    Peskind ER, Potkin SG, Pomara N, et al. Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. Am J Geriatr Psychiatry 2006; 14(8): 704–5PubMedCrossRefGoogle Scholar
  4. 4.
    Tariot PN, Farlow MR, Grossberg GT. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004; 291(3): 317–24PubMedCrossRefGoogle Scholar
  5. 5.
    Bakchine S, Loft H. Memantine treatment in patients with mild to moderate Alzheimer’s disease: results of a randomised, double-blind, placebo-controlled 6-month study. J Alzheimers Dis 2008; 13(1): 97–107PubMedGoogle Scholar
  6. 6.
    Schmidt R, Ropele S, Pendl B, et al. Longitudinal multimodal imaging in mild to moderate Alzheimer disease: a pilot study with memantine. J Neurol Neurosurg Psychiatry 2008; 79(12): 1312–17PubMedCrossRefGoogle Scholar
  7. 7.
    Parsons CG, Stöffler A, Danysz W. Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system — too little activation is bad, too much is even worse. Neuropharmacology 2007; 53(6): 699–723PubMedCrossRefGoogle Scholar
  8. 8.
    Seeman P, Caruso C, Lasaga M. Memantine agonist action at dopamine D2High receptors. Synapse 2008; 62(2): 149–53PubMedCrossRefGoogle Scholar
  9. 9.
    Giustizieri M, Cucchiaroni ML, Guatteo E, et al. Memantine inhibits ATP-dependent K+ conductances in dopamine neurons of the rat substantia nigra pars compacta. J Pharmacol Exp Ther 2007; 322(2): 721–9PubMedCrossRefGoogle Scholar
  10. 10.
    Hesse S, Ballaschke O, Barthel H, et al. Dopamine transporter imaging in adult patients with attention-deficit/hyperactivity disorder. Psychiatry Res 2009; 171(2): 120–8PubMedCrossRefGoogle Scholar
  11. 11.
    Gilden DL, Marusich LR. Contraction of time in attention-deficit hyperactivity disorder. Neuropsychology 2009; 23(2): 265–9PubMedCrossRefGoogle Scholar
  12. 12.
    Monastero R, Camarda C, Pipia C, et al. Visual hallucinations and agitation in Alzheimer’s disease due to memantine: report of three cases. J Neurol Neurosurg Psychiatry 2007; 78(5): 546PubMedCrossRefGoogle Scholar
  13. 13.
    Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci 2007; 8(9): 700–11PubMedCrossRefGoogle Scholar
  14. 14.
    Fransson P. How default is the default mode of brain function? Further evidence from intrinsic BOLD signal fluctuations. Neuropsychologia 2006; 44(14): 2836–45PubMedCrossRefGoogle Scholar
  15. 15.
    Gusnard DA, Akbudak E, Shulman GL, et al. Medial prefrontal cortex and self-referential mental activity: relation to a default mode of brain function. Proc Natl Acad Sci U S A 2001; 98: 4259–64PubMedCrossRefGoogle Scholar
  16. 16.
    Broyd SJ, Demanuele C, Debener S, et al. Default-mode brain dysfunction in mental disorders: a systematic review. Neurosci Biobehav Rev 2009; 33(3): 279–96PubMedCrossRefGoogle Scholar
  17. 17.
    Rombouts S, Barkhof F, Goekoop R, et al. Altered resting state networks in mild cognitive impairment and mild Alzheimer’s. Hum Brain Mapp 2005; 26: 231–9PubMedCrossRefGoogle Scholar
  18. 18.
    Liu Y, Wang K, Yu C, et al. Regional homogeneity, functional connectivity and imaging markers of Alzheimer’s disease: a review of resting-state fMRI studies. Neuropsychologia 2008; 46(6): 1648–56PubMedCrossRefGoogle Scholar
  19. 19.
    Greicius MD, Srivastava G, Reiss AL, et al. Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A 2004; 101: 4637–42PubMedCrossRefGoogle Scholar
  20. 20.
    Buckner RL, Snyder AZ, Shannon BJ, et al. Molecular, structural, and functional characterization of Alzheimer’s disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 2005; 25: 7709–17PubMedCrossRefGoogle Scholar
  21. 21.
    Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 2001; 357(9263): 1191–4PubMedCrossRefGoogle Scholar
  22. 22.
    Altman DG, Schulz KF, Moher D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001; 134(8): 663–94PubMedGoogle Scholar
  23. 23.
    McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34(7): 939–44PubMedCrossRefGoogle Scholar
  24. 24.
    Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993; 43: 2412–4PubMedCrossRefGoogle Scholar
  25. 25.
    Rosen WG, Terry RD, Fuld PA, et al. Pathological verification of ischemic score in differentiation of dementias. Ann Neurol 1980; 7(5): 486–8PubMedCrossRefGoogle Scholar
  26. 26.
    Protocollo MEM_T V0 [in Italian]. Brescia: Laboratorio di Epidemiologia e Neuroimaging, IRCCS [online]. Available from URL: [Accessed 2010 Nov 26]
  27. 27.
    Lezak MD, Howieson DB, Loring DW, et al. Neuropsychological assessment. 4th ed. New York (NY): Oxford University Press, 2004Google Scholar
  28. 28.
    Folstein MF, Folstein SE, McHugh PR. ‘Mini-mental state’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12(3): 189–98PubMedCrossRefGoogle Scholar
  29. 29.
    Cummings JL, Mega M, Gray K, et al. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44(12): 2308–14PubMedCrossRefGoogle Scholar
  30. 30.
    Eshed I, Althoff CE, Hamm B, et al. Claustrophobia and premature termination of magnetic resonance imaging examinations. J Magn Reson Imaging 2007; 26(2): 401–4PubMedCrossRefGoogle Scholar
  31. 31.
    Calhoun VD, Adali T, Pearlson GD, et al. A method for making group inferences from functional MRI data using independent component analysis. Hum Brain Mapp 2001; 14(3): 140–51PubMedCrossRefGoogle Scholar
  32. 32.
    Correa N, Adali T, Calhoun VD. Performance of blind source separation algorithms for fMRI analysis using a group ICA method. Magn Reson Imaging 2007; 25(5): 684–94PubMedCrossRefGoogle Scholar
  33. 33.
    Maldjian JA, Laurienti PJ, Kraft RA, et al. An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 2003; 19(3): 1233–9PubMedCrossRefGoogle Scholar
  34. 34.
    Hoyer S. Age as risk factor for sporadic dementia of the Alzheimer type? Ann N Y Acad Sci 1994 May 31; 719: 248–56PubMedCrossRefGoogle Scholar
  35. 35.
    Noda M, Nakanishi H, Akaike N. Glutamate release from microglia via glutamate transporter is enhanced by amyloid-beta peptide. Neuroscience 1999; 92(4): 1465–74PubMedCrossRefGoogle Scholar
  36. 36.
    Harris NG, Plant HD, Inglis BA, et al. Neurochemical changes in the cerebral cortex of treated and untreated hydrocephalic rat pups quantified with in vitro 1H-NMR spectroscopy. J Neurochem 1997; 68(1): 305–12PubMedCrossRefGoogle Scholar
  37. 37.
    Magistretti PJ, Pellerin L. Astrocytes couple synaptic activity to glucose utilization in the brain. News Physiol Sci 1999 Oct; 14: 177–82PubMedGoogle Scholar
  38. 38.
    Wu J, Anwyl R, Rowan MJ. beta-Amyloid selectively augments NMDA receptor-mediated synaptic transmission in rat hippocampus. Neuroreport 1995; 6(17): 2409–13PubMedCrossRefGoogle Scholar
  39. 39.
    Johnson JW, Kotermanski SE. Mechanism of action of memantine. Curr Opin Pharmacol 2006; 6(1): 61–7PubMedCrossRefGoogle Scholar
  40. 40.
    Gruetter R, Seaquist ER, Kim S, et al. Localized in vivo 13C-NMR of glutamate metabolism in the human brain: initial results at 4 tesla. Dev Neurosci 1998; 20(4–5): 380–8PubMedCrossRefGoogle Scholar
  41. 41.
    Shen J, Petersen KF, Behar KL, et al. Determination of the rate of the glutamate/glutamine cycle in the human brain by in vivo 13C NMR. Proc Natl Acad Sci U S A 1999; 96(14): 8235–40PubMedCrossRefGoogle Scholar
  42. 42.
    Sibson NR, Dhankhar A, Mason GF, et al. Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. Proc Natl Acad Sci U S A 1998; 95(1): 316–21PubMedCrossRefGoogle Scholar
  43. 43.
    Aubert A, Pellerin L, Magistretti PJ, et al. A coherent neurobiological framework for functional neuroimaging provided by a model integrating compartmentalized energy metabolism. Proc Natl Acad Sci USA 2007; 104(10): 4188–93PubMedCrossRefGoogle Scholar
  44. 44.
    Magistretti PJ, Pellerin L. Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Philos Trans R Soc Lond B Biol Sci 1999; 354(1387): 1155–63PubMedCrossRefGoogle Scholar
  45. 45.
    Lin AP, Shic F, Enriquez C, et al. Reduced glutamate neurotransmission in patients with Alzheimer’s disease: an in vivo (13) C magnetic resonance spectroscopy study. MAGMA 2003; 16(1): 29–42PubMedCrossRefGoogle Scholar
  46. 46.
    Parpura-Gill A, Beitz D, Uemura E. The inhibitory effects of beta amyloid on glutamate and glucose uptakes by cultured astrocytes. Brain Res 1997; 754: 65–71PubMedCrossRefGoogle Scholar
  47. 47.
    Minoshima S, Giordani B, Berent S, et al. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 1997; 42: 85–94PubMedCrossRefGoogle Scholar
  48. 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
  49. 49.
    Peters M, Romieu P, Maurice T, et al. Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine. Eur J Neurosci 2004; 19(8): 2212–20CrossRefGoogle Scholar
  50. 50.
    Meisner F, Scheller C, Kneitz S, et al. Memantine upregulates BDNF and prevents dopamine deficits in SIV-infected macaques: a novel pharmacological action of memantine. Neuropsychopharmacology 2008; 33(9): 2228–36PubMedCrossRefGoogle Scholar
  51. 51.
    Achard S, Bullmore E. Efficiency and cost of economical brain functional networks. PLoS Comput Biol 2007; 3(2): e17PubMedCrossRefGoogle Scholar
  52. 52.
    Thomas TC, Grandy DK, Gerhardt GA, et al. Decreased dopamine D4 receptor expression increases extracellular glutamate and alters its regulation in mouse striatum. Neuropsychopharmacology 2009; 34(2): 436–45PubMedCrossRefGoogle Scholar
  53. 53.
    Konradi C, Leveque JC, Hyman SE. Amphetamine and dopamine-induced immediate early gene expression in striatal neurons depends on postsynaptic NMDA receptors and calcium. J Neurosci 1996; 16(13): 4231–9PubMedGoogle Scholar
  54. 54.
    Keefe KA, Ganguly A. Effects of NMDA receptor antagonists on D1 dopamine receptor-mediated changes in striatal immediate early gene expression: evidence for involvement of pharmacologically distinct NMDA receptors? Dev Neurosci 1998; 20(2–3): 216–8PubMedCrossRefGoogle Scholar
  55. 55.
    Northoff G, Walter M, Schulte RF, et al. GABA concentrations in the human anterior cingulate cortex predict negative BOLD responses in fMRI. Nat Neurosci 2007; 10(12): 1515–7PubMedCrossRefGoogle Scholar
  56. 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
  57. 57.
    Song MS, Rauw G, Baker GB, et al. Memantine protects rat cortical cultured neurons against beta-amyloid-induced toxicity by attenuating tau phosphorylation. Eur J Neurosci 2008; 28(10): 1989–2002PubMedCrossRefGoogle Scholar
  58. 58.
    Frisoni GB, Fox NC, Jack CR, et al. The clinical use of structural MRI in Alzheimer disease. Nat Rev Neurol 2010 Feb; 6(2): 67–77PubMedCrossRefGoogle Scholar
  59. 59.
    Lin Q, Zheng Y, Yin F, et al. A fast algorithm for one-unit ICA-R. Information Sci 2007; 177: 1265–75CrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  • Marco Lorenzi
    • 1
    • 2
    Email author
  • Alberto Beltramello
    • 3
  • Nicola B. Mercuri
    • 4
  • Elisa Canu
    • 1
  • Giada Zoccatelli
    • 3
  • Francesca B. Pizzini
    • 3
  • Franco Alessandrini
    • 3
  • Maria Cotelli
    • 5
  • Sandra Rosini
    • 5
  • Daniela Costardi
    • 1
  • Carlo Caltagirone
    • 4
  • Giovanni B. Frisoni
    • 1
  1. 1.Laboratory of Epidemiology, Neuroimaging and Telemedicine -LENITEM-Istituto di Ricerca e Cura a Carattere Scientifico San Giovanni di Dio FatebenefratelliBresciaItaly
  2. 2.Project Team AsclepiosInstitut national de recherche en informatique et automatique (INRIA)Sophia AntipolisFrance
  3. 3.Ospedale MaggioreService of NeuroradiologyBorgo Trento, VeronaItaly
  4. 4.Fondazione Istituto di Ricerca e Cura a Carattere Scientifico, Santa LuciaUniversità Tor VergataRomeItaly
  5. 5.Cognitive Neuroscience SectionIstituto di Ricerca e Cura a Carattere Scientifico San Giovanni di Dio FatebenefratelliBresciaItaly

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