Abstract
Rationale
Cholinergic enhancement is among the best established treatments of Alzheimer’s disease (AD). The cognitive effects of treatment are thought to be mediated by improvement of neuronal transmission. Positron emission tomography using (18)F-fluorodeoxyglucose (FDG-PET) by measuring cortical metabolic response to activation assesses integrity of neuronal transmission in vivo.
Objective
To determine the effects of treatment with donepezil, a centrally selective acetylcholinesterase inhibitor, on cortical metabolism in AD using (18)FDG-PET.
Methods
We enrolled 23 patients, 18 of which completed the study, with mild to moderate probable AD (mini-mental status exam scores of 15–28, inclusive) in a double-blind cross over trial of 8 weeks donepezil compared to 8 weeks placebo with repeated double (18)FDG-PET examinations during passive audio-visual stimulation. Effects of treatment on cortical metabolic response to stimulation were determined with a linear model on a voxel level using Statistical Parametric Mapping (SPM 99, Wellcome Department of Imaging Neuroscience, London).
Results
Effects of treatment on cognitive measures were not different between donepezil and placebo. During passive audio-visual stimulation, patients showed activation in posterior visual and auditory areas and decreased activation in frontal cortex and basal ganglia. Resting state metabolism was increased with donepezil in left prefrontal cortex and decreased in right hippocampus. Cortical response to activation was increased in right hippocampus with donepezil compared to placebo.
Conclusion
Donepezil treatment shows a spatially limited functional effect on right hippocampus and left prefrontal cortical metabolism, independently of clinical response to treatment.
Similar content being viewed by others
References
Atri A, Sherman S, Norman KA, Kirchhoff BA, Nicolas MM, Greicius MD, Cramer SC, Breiter HC, Hasselmo ME, Stern CE (2004) Blockade of central cholinergic receptors impairs new learning and increases proactive interference in a word paired-associate memory task. Behav Neurosci 118(1):223–236
Backman L, Andersson JL, Nyberg L, Winblad B, Nordberg A, Almkvist O (1999) Brain regions associated with episodic retrieval in normal aging and Alzheimer’s disease. Neurology 52(9):1861–1870
Birks JS, Melzer D (2000) Donepezil for mild and moderate Alzheimer’s disease. Cochrane Database Syst Rev (2):CD001190
Birks J, Iakovidou V, Tsolaki M (2000) Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev (2):CD001191
Bohnen NI, Kaufer DI, Hendrickson R, Ivanco LS, Lopresti BJ, Koeppe RA, Meltzer CC, Constantine G, Davis JG, Mathis CA, Dekosky ST, Moore RY (2005) Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 76(3):315–319
Brett M, Johnsrude IS, Owen AM (2002) The problem of functional localization in the human brain. Nat Rev Neurosci 3:243–249
Cullen KM, Halliday GM (1998) Neurofibrillary degeneration and cell loss in the nucleus basalis in comparison to cortical Alzheimer pathology. Neurobiol Aging 19(4):297–306
Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental-state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198
Friston K, Ashburner J, Frith CD, Poline J-B, Heather JD, Frackowiak RSJ (1995a) Spatial registration and normalization of image. Hum Brain Mapp 2:165–189
Friston K, Holmes AP, Worsley K, Poline J-B, CD F, Frackowiak RSJ (1995b) Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 2:189–210
Goekoop R, Scheltens P, Barkhof F, Rombouts SA (2006) Cholinergic challenge in Alzheimer patients and mild cognitive impairment differentially affects hippocampal activation—a pharmacological fMRI study. Brain 129(Pt 1):141–157
Grady CL, Haxby JV, Horwitz B, Gillette J, Salerno JA, Gonzalez-Aviles A, Carson RE, Herscovitch P, Schapiro MB, Rapoport SI (1993) Activation of cerebral blood flow during a visuoperceptual task in patients with Alzheimer-type dementia. Neurobiol Aging 14(1):35–44
Harder JA, Baker HF, Ridley RM (1998) The role of the central cholinergic projections in cognition: implications of the effects of scopolamine on discrimination learning by monkeys. Brain Res Bull 45(3):319–326
Herholz K, Weisenbach S, Zundorf G, Lenz O, Schroder H, Bauer B, Kalbe E, Heiss WD (2004) In vivo study of acetylcholine esterase in basal forebrain, amygdala, and cortex in mild to moderate Alzheimer disease. Neuroimage 21(1):136–143
Holmes C, Wilkinson D, Dean C, Vethanayagam S, Olivieri S, Langley A, Pandita-Gunawardena ND, Hogg F, Clare C, Damms J (2004) The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology 63(2):214–219
Lehericy S, Hirsch EC, Cervera-Pierot P, Hersh LB, Bakchine S, Piette F, Duyckaerts C, Hauw JJ, Javoy-Agid F, Agid Y (1993) Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer’s disease. J Comp Neurol 330(1):15–31
Lezak MD (1995) Neuropsychological Assessment. Oxford University Press, New York, NY, pp 381–384
Liotti M, Mayberg HS, Brannan SK, McGinnis S, Jerabek P, Fox PT (2000) Differential limbic–cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders. Biol Psychiatry 48(1):30–42
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 34:939–944
Mega MS, Cummings JL, O’Connor SM, Dinov ID, Reback E, Felix J, Masterman DL, Phelps ME, Small GW, Toga AW (2001) Cognitive and metabolic responses to metrifonate therapy in Alzheimer disease. Neuropsychiatry Neuropsychol Behav Neurol 14(1):63–68
Mega MS, Dinov ID, Porter V, Chow G, Reback E, Davoodi P, O’Connor SM, Carter MF, Amezcua H, Cummings JL (2005) Metabolic patterns associated with the clinical response to galantamine therapy: a fludeoxyglucose f 18 positron emission tomographic study. Arch Neurol 62(5):721–728
Minett TS, Thomas A, Wilkinson LM, Daniel SL, Sanders J, Richardson J, Littlewood E, Myint P, Newby J, McKeith IG (2003) What happens when donepezil is suddenly withdrawn? An open label trial in dementia with Lewy bodies and Parkinson’s disease with dementia. Int J Geriatr Psychiatry 18(11):988–993
Minoshima S (2003) Imaging Alzheimer’s disease: clinical applications. Neuroimaging Clin N Am 13(4):769–780
Morris JC, Heyman A, Mohs RC, Hughes JP, van Belle G, Fillenbaum G, Mellits ED, Clark C (1989) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology 39(9):1159–1165
Muir JL, Page KJ, Sirinathsinghji DJ, Robbins TW, Everitt BJ (1993) Excitotoxic lesions of basal forebrain cholinergic neurons: effects on learning, memory and attention. Behav Brain Res 57(2):123–131
Nordberg A (1993) In vivo detection of neurotransmitter changes in Alzheimer’s disease. Ann NY Acad Sci 695:27–33
Olin J, Schneider L (2002) Galantamine for Alzheimer’s disease. Cochrane Database Syst Rev (3):CD001747
Ongur D, Zalesak M, Weiss AP, Ditman T, Titone D, Heckers S (2005) Hippocampal activation during processing of previously seen visual stimulus pairs. Psychiatry Res 139(3):191–198
Oswald WD, Fleischmann UM (1985) Psychometrics in aging and dementia: advances in geropsychological assessments. Arch Gerontol Geriatr 4(4):299–309
Pietrini P, Alexander GE, Furey ML, Dani A, Mentis MJ, Horwitz B, Guazzelli M, Shapiro MB, Rapoport SI (2000) Cerebral metabolic response to passive audiovisual stimulation in patients with Alzheimer’s disease and healthy volunteers assessed by PET. J Nucl Med 41(4):575–583
Potkin SG, Anand R, Fleming K, Alva G, Keator D, Carreon D, Messina J, Wu JC, Hartman R, Fallon JH (2001) Brain metabolic and clinical effects of rivastigmine in Alzheimer’s disease. Int J Neuropsychopharmacol 4(3):223–230
Powell HW, Koepp MJ, Symms MR, Boulby PA, Salek-Haddadi A, Thompson PJ, Duncan JS, Richardson MP (2005) Material-specific lateralization of memory encoding in the medial temporal lobe: blocked versus event-related design. Neuroimage 27(1):231–239
Ruberg M, Mayo W, Brice A, Duyckaerts C, Hauw JJ, Simon H, LeMoal M, Agid Y (1990) Choline acetyltransferase activity and [3H]vesamicol binding in the temporal cortex of patients with Alzheimer’s disease, Parkinson’s disease, and rats with basal forebrain lesions. Neuroscience 35(2):327–333
Saito DN, Yoshimura K, Kochiyama T, Okada T, Honda M, Sadato N (2005) Cross-modal binding and activated attentional networks during audio-visual speech integration: a functional MRI study. Cereb Cortex 15(11):1750–1760
Saykin AJ, Flashman LA, Frutiger SA, Johnson SC, Mamourian AC, Moritz CH, O’Jile JR, Riordan HJ, Santulli RB, Smith CA, Weaver JB (1999) Neuroanatomic substrates of semantic memory impairment in Alzheimer’s disease: patterns of functional MRI activation. J Int Neuropsychol Soc 5(5):377–392
Schildein S, Huston JP, Schwarting RK (2002) Open field habituation learning is improved by nicotine and attenuated by mecamylamine administered posttrial into the nucleus accumbens. Neurobiol Learn Mem 77(3):277–290
Shinotoh H, Aotsuka A, Fukushi K, Nagatsuka S, Tanaka N, Ota T, Tanada S, Irie T (2001) Effect of donepezil on brain acetylcholinesterase activity in patients with AD measured by PET. Neurology 56(3):408–410
Shiraishi T, Kikuchi T, Fukushi K, Shinotoh H, Nagatsuka SI, Tanaka N, Ota T, Sato K, Hirano S, Tanada S, Iyo M, Irie T (2005) Estimation of plasma IC(50) of donepezil hydrochloride for brain acetylcholinesterase inhibition in monkey using N-[(11)C]methylpiperidin-4-yl acetate ([(11)C]MP4A) and PET. Neuropsychopharmacology 30(12):2154–2161
Skipper JI, Nusbaum HC, Small SL (2005) Listening to talking faces: motor cortical activation during speech perception. Neuroimage 25(1):76–89
Starr JM, Loeffler B, Abousleiman Y, Simonotto E, Marshall I, Goddard N, Wardlaw JM (2005) Episodic and semantic memory tasks activate different brain regions in Alzheimer disease. Neurology 65(2):266–269
Stefanova E, Wall A, Almkvist O, Nilsson A, Forsberg A, Langstrom B, Nordberg A (2005) Longitudinal PET evaluation of cerebral glucose metabolism in rivastigmine treated patients with mild Alzheimer’s disease. J Neural Transm 113(2):205–218
Talairach J, Tournoux P (1988) Co-planar stereotaxic atlas of the human brain. Thieme, New York
Teipel SJ, Flatz WH, Heinsen H, Bokde ALW, Schoenberg SO, Stöckel S, Dietrich O, Reiser MF, Möller H-J, Hampel H (2005) Measurement of basal forebrain atrophy in AD using MRI. Brain 128(11):2626–2644
Vogels OJ, Broere CA, ter Laak HJ, ten Donkelaar HJ, Nieuwenhuys R, Schulte BP (1990) Cell loss and shrinkage in the nucleus basalis Meynert complex in Alzheimer’s disease. Neurobiol Aging 11(1):3–13
Acknowledgements
We thank Felician Iancu, Christine Sänger, Bea Riemenschneider and Monika Merrath (Department of Psychiatry, LMU Munich) and the staff of the Department of Nuclear Medicine (TU Munich) for technical assistance. We thank Dr. Michael Ewers (Department of Psychiatry, LMU Munich) for critical reading of the manuscript. This study was supported by a grant of Eisai/Pfizer (Frankfurt, Karlsruhe, Germany) to H.H. and S.J.T.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Teipel, S.J., Drzezga, A., Bartenstein, P. et al. Effects of donepezil on cortical metabolic response to activation during 18FDG-PET in Alzheimer’s disease: a double-blind cross-over trial. Psychopharmacology 187, 86–94 (2006). https://doi.org/10.1007/s00213-006-0408-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-006-0408-1