Effect of memantine on resting state default mode network activity in Alzheimer's disease.
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.
Laboratory of Epidemiology, Neuroimaging and Telemedicine, Istituto di Ricerca e Cura a Carattere Scientifico San Giovanni di Dio Fatebenefratelli, Brescia, Italy. mlorenzi@fatebenefratelli.it
Marco
M
Lorenzi
Alberto
A
Beltramello
Nicola B
NB
Mercuri
Elisa
E
Canu
Giada
G
Zoccatelli
Francesca B
FB
Pizzini
Franco
F
Alessandrini
Maria
M
Cotelli
Sandra
S
Rosini
Daniela
D
Costardi
Carlo
C
Caltagirone
Giovanni B
GB
Frisoni
D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy / Q000503:physiopathology*; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008559:Memantine / Q000494:pharmacology* / Q000627:therapeutic use; D009483:Neuropsychological Tests; D012146:Rest
D008559:Memantine
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4259-64
11259662
J Pharmacol Exp Ther. 2007 Aug;322(2):721-9
17496164
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4188-93
17360498
Neurosci Biobehav Rev. 2009 Mar;33(3):279-96
18824195
Neuropsychologia. 2008;46(6):1648-56
18346763
Neurology. 1994 Dec;44(12):2308-14
7991117
PLoS Comput Biol. 2007 Feb 2;3(2):e17
17274684
Neuroscience. 1999;92(4):1465-74
10426500
Philos Trans R Soc Lond B Biol Sci. 1999 Jul 29;354(1387):1155-63
10466143
Magn Reson Imaging. 2007 Jun;25(5):684-94
17540281
Dev Neurosci. 1998;20(2-3):216-28
9691195
J Psychiatr Res. 1975 Nov;12(3):189-98
1202204
Dev Neurosci. 1998;20(4-5):380-8
9778575
Neuropsychopharmacology. 2009 Jan;34(2):436-45
18536704
Neuropsychologia. 2006;44(14):2836-45
16879844
J Neurosci. 2005 Aug 24;25(34):7709-17
16120771
MAGMA. 2003 Feb;16(1):29-42
12695884
Lancet. 2001 Apr 14;357(9263):1191-4
11323066
Nat Rev Neurol. 2010 Feb;6(2):67-77
20139996
Nat Neurosci. 2007 Dec;10(12):1515-7
17982452
Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003154
15846650
JAMA. 2004 Jan 21;291(3):317-24
14734594
News Physiol Sci. 1999 Oct;14:177-182
11390847
J Neurosci. 1996 Jul 1;16(13):4231-9
8753884
Synapse. 2008 Feb;62(2):149-53
18000814
Hum Brain Mapp. 2005 Dec;26(4):231-9
15954139
Eur J Neurosci. 2008 Nov;28(10):1989-2002
19046381
Neuroimage. 2003 Jul;19(3):1233-9
12880848
J Neurol Neurosurg Psychiatry. 2008 Dec;79(12):1312-7
18586865
Ann N Y Acad Sci. 1994 May 31;719:248-56
8010597
Neuropharmacology. 2007 Nov;53(6):699-723
17904591
Ann Intern Med. 2001 Apr 17;134(8):663-94
11304107
Eur J Neurosci. 2004 Apr;19(8):2212-20
15090047
Psychiatry Res. 2009 Feb 28;171(2):120-8
19176281
Am J Geriatr Psychiatry. 2006 Aug;14(8):704-15
16861375
Neurology. 1984 Jul;34(7):939-44
6610841
Neuroreport. 1995 Nov 27;6(17):2409-13
8747164
J Neurochem. 1997 Jan;68(1):305-12
8978739
Ann Neurol. 1997 Jul;42(1):85-94
9225689
J Magn Reson Imaging. 2007 Aug;26(2):401-4
17610281
Neuropsychology. 2009 Mar;23(2):265-9
19254099
J Neurol Neurosurg Psychiatry. 2007 May;78(5):546
17030587
Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8235-40
10393978
Neuropsychopharmacology. 2008 Aug;33(9):2228-36
17971830
Brain Res. 1997 Apr 18;754(1-2):65-71
9134960
Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):316-21
9419373
J Neurol Neurosurg Psychiatry. 2009 Jun;80(6):600-7
19204022
Ann Neurol. 1980 May;7(5):486-8
7396427
Nat Rev Neurosci. 2007 Sep;8(9):700-11
17704812
Hum Brain Mapp. 2001 Nov;14(3):140-51
11559959
Curr Opin Pharmacol. 2006 Feb;6(1):61-7
16368266
J Alzheimers Dis. 2008 Feb;13(1):97-107
18334761
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4637-42
15070770
Brain Res. 2009 Apr 10;1265:75-9
19236854
Neurology. 1993 Nov;43(11):2412-4
8232972