Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer’s disease
- N I Bohnen1,2,3,
- D I Kaufer1,
- R Hendrickson1,
- L S Ivanco1,
- B J Lopresti2,
- R A Koeppe4,
- C C Meltzer2,
- G Constantine5,
- J G Davis2,
- C A Mathis2,
- S T DeKosky1,
- R Y Moore1
- 1Department of Neurology, University of Pittsburgh Medical School, Pittsburgh, PA, USA
- 2Department of Radiology, University of Pittsburgh Medical School, Pittsburgh, PA, USA
- 3VA Pittsburgh Healthcare system, Pittsburgh, PA, USA
- 4Department of Radiology, The University of Michigan, Ann Arbor, MI, USA
- 5Department of Mathematics and Statistics, University of Pittsburgh, Pittsburgh, PA, USA
- Correspondence to: Dr Bohnen University of Pittsburgh, Liliane S Kaufmann Building, Suite 811, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA;
- Received 9 February 2004
- Accepted 31 May 2004
- Revised 15 April 2004
Objectives: To determine in vivo cortical acetylcholinesterase (AChE) activity and cognitive effects in subjects with mild Alzheimer’s disease (AD, n = 14) prior to and after 12 weeks of donepezil therapy.
Methods: Cognitive and N-[11C]methyl-piperidin-4-yl propionate ([11C]PMP) AChE positron emission tomography (PET) assessments before and after donepezil therapy.
Results: Analysis of the PET data revealed mean (temporal, parietal, and frontal) cortical donepezil induced AChE inhibition of 19.1% (SD 9.4%) (t = −7.9; p<0.0001). Enzyme inhibition was most robust in the anterior cingulate cortex (24.2% (6.9%), t = −14.1; p<0.0001). Donepezil induced cortical inhibition of AChE activity correlated with changes in the Stroop Color Word interference scores (R2 = 0.59, p<0.01), but not with primary memory test scores. Analysis of the Stroop test data indicated that subjects with AChE inhibition greater than the median value (>22.2%) had improved scores on the Stroop Color Word Test compared with subjects with less inhibition who had stable to worsening scores (t = −2.7; p<0.05).
Conclusions: Donepezil induced inhibition of cortical AChE enzyme activity is modest in patients with mild AD. The degree of cortical enzyme inhibition correlates with changes in executive and attentional functions.
- AChE, acetylcholinesterase
- AD, Alzheimer’s disease
- AIR, automated image registration
- ChE-I, cholinesterase inhibitor
- [11C]PMP, N-[11C]methyl-piperidin-4-yl propionate
- COWA, Controlled Oral Word Association
- CVLT, California Verbal Learning Test
- LTM, long term memory
- MR, magnetic resonance
- PET, positron emission tomography, ROI, region of interest
- SPGR, spoiled gradient recall
- STM, short term memory
- TMT, Trail Making Test
Supported by a grant from National Institute of Aging, Bethesda, MD, USA (Alzheimer Disease Research Center, AG05133).
Competing interests: Drs D I Kaufer and R Y Moore have received either speaking honoraria, consulting fees, educational fees, or research support from Eisai-Pfizer, Janssen, Cephalon, Takeda, and Novartis