title: Regional effects of donepezil and rivastigmine on cortical acetylcholinesterase activity in Alzheimer's disease.
abstract: Donepezil and rivastigmine are acetylcholinesterase (AChE) inhibitors used to improve cholinergic neurotransmission and cognitive function in Alzheimer's disease (AD). This study examined direct effects of these drugs on AChE activity in the frontal, temporal, and parietal cortices in AD. Six AD patients were scanned with positron emission tomography before and after 3 months of treatment with donepezil (10 mg/day), and five AD patients were scanned before and after 3 to 5 months of treatment with rivastigmine (9 mg/day). Healthy unmedicated controls were imaged twice to evaluate the reproducibility of the method. A specific AChE tracer, [methyl-11C]N-methyl-piperidyl-4-acetate, and a 3D positron emission tomography system with MRI coregistration were used for imaging. Treatment with donepezil reduced the AChE activity (k3 values) in the AD brain by 39% in the frontal (p < 0.001, Bonferroni corrected), 29% in the temporal (p = 0.02, corrected) and 28% in the parietal cortex (p = 0.05, corrected). The corresponding levels of inhibition for rivastigmine were 37% (p = 0.003, corrected), 28% (p = 0.03, uncorrected) and 28% (p = 0.05, corrected). When the treatment groups were combined, the level of AChE inhibition was significantly greater in the frontal cortex compared to the temporal cortex (p = 0.03, corrected). The test-retest analysis with healthy subjects indicated good reproducibility for the method, with a nonsignificant 0% to 7% intrasubject variability between scans. The present study provides first evidence for the effect of rivastigmine on cortical AChE activity. Our results indicate that the pooled effects of donepezil and rivastigmine on brain AChE are greater in the frontal cortex compared to the temporal cortex in AD. This regional difference is probably related to the prominent temporoparietal reduction of AChE in AD. We hypothesize that the clinical improvement in behavioral and attentional symptoms of AD due to AChE inhibitors is associated with the frontal AChE inhibition.
authors.affiliation: Department of Neurology, University of Turku, Turku, Finland.
authors.forename: Valtteri
authors.initials: V
authors.lastname: Kaasinen
authors.forename: Kjell
authors.initials: K
authors.lastname: Någren
authors.forename: Tarja
authors.initials: T
authors.lastname: Järvenpää
authors.forename: Anne
authors.initials: A
authors.lastname: Roivainen
authors.forename: Meixiang
authors.initials: M
authors.lastname: Yu
authors.forename: Vesa
authors.initials: V
authors.lastname: Oikonen
authors.forename: Timo
authors.initials: T
authors.lastname: Kurki
authors.forename: Juha O
authors.initials: JO
authors.lastname: Rinne
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology*; D002219:Carbamates / Q000494:pharmacology* / Q000627:therapeutic use; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D005260:Female; D005625:Frontal Lobe / Q000000981:diagnostic imaging / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D010296:Parietal Lobe / Q000000981:diagnostic imaging / Q000187:drug effects / Q000201:enzymology; D048448:Phenylcarbamates; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D015203:Reproducibility of Results; D000068836:Rivastigmine; D013702:Temporal Lobe / Q000000981:diagnostic imaging / Q000187:drug effects / Q000201:enzymology; D014055:Tomography, Emission-Computed
chemical_list: D002219:Carbamates; D002800:Cholinesterase Inhibitors; D007189:Indans; D048448:Phenylcarbamates; D010880:Piperidines; D000077265:Donepezil; D000110:Acetylcholinesterase; D000068836:Rivastigmine