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Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer’s disease
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  1. N I Bohnen1,2,3,
  2. D I Kaufer1,
  3. R Hendrickson1,
  4. L S Ivanco1,
  5. B J Lopresti2,
  6. R A Koeppe4,
  7. C C Meltzer2,
  8. G Constantine5,
  9. J G Davis2,
  10. C A Mathis2,
  11. S T DeKosky1,
  12. R Y Moore1
  1. 1Department of Neurology, University of Pittsburgh Medical School, Pittsburgh, PA, USA
  2. 2Department of Radiology, University of Pittsburgh Medical School, Pittsburgh, PA, USA
  3. 3VA Pittsburgh Healthcare system, Pittsburgh, PA, USA
  4. 4Department of Radiology, The University of Michigan, Ann Arbor, MI, USA
  5. 5Department of Mathematics and Statistics, University of Pittsburgh, Pittsburgh, PA, USA
  1. Correspondence to:
 Dr Bohnen
 University of Pittsburgh, Liliane S Kaufmann Building, Suite 811, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA; nbohnenpitt.edu

Abstract

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
  • acetylcholinesterase
  • Alzheimer’s disease
  • donepezil
  • positron emission tomography

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Footnotes

  • 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

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