PAPER

Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer’s disease

N I Bohnen^1,2,3, 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 and R Y Moore¹

¹ Department of Neurology, University of Pittsburgh Medical School, Pittsburgh, PA, USA
² Department of Radiology, University of Pittsburgh Medical School, Pittsburgh, PA, USA
³ VA Pittsburgh Healthcare system, Pittsburgh, PA, USA
⁴ Department of Radiology, The University of Michigan, Ann Arbor, MI, USA
⁵ Department of Mathematics and Statistics, University of Pittsburgh, Pittsburgh, PA, USA

Correspondence to:
Correspondence to:
Dr Bohnen
University of Pittsburgh, Liliane S Kaufmann Building, Suite 811, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA; nbohnen{at}pitt.edu

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.

Abbreviations: 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

Keywords: acetylcholinesterase; Alzheimer’s disease; donepezil; positron emission tomography

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Relevant Article

Action of cholinesterase inhibitors in patients’ brains

K Herholz
J. Neurol. Neurosurg. Psychiatry 2005 76: 305. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

• Yesavage, J. A., Friedman, L., Ashford, J. W., Kraemer, H. C., Mumenthaler, M. S., Noda, A., Hoblyn, J. (2008). Acetylcholinesterase Inhibitor in Combination With Cognitive Training in Older Adults. Journals of Gerontology Series B: Psychological Sciences and Social Science 63: P288-P294 [Abstract] [Full Text]  
• HERHOLZ, K, CARTER, S F, JONES, M (2007). Positron emission tomography imaging in dementia. Br. J. Radiol. 80: S160-S167 [Abstract] [Full Text]  
• Lippa, C. F., Duda, J. E., Grossman, M., Hurtig, H. I., Aarsland, D., Boeve, B. F., Brooks, D. J., Dickson, D. W., Dubois, B., Emre, M., Fahn, S., Farmer, J. M., Galasko, D., Galvin, J. E., Goetz, C. G., Growdon, J. H., Gwinn-Hardy, K. A., Hardy, J., Heutink, P., Iwatsubo, T., Kosaka, K., Lee, V. M.-Y., Leverenz, J. B., Masliah, E., McKeith, I. G., Nussbaum, R. L., Olanow, C. W., Ravina, B. M., Singleton, A. B., Tanner, C. M., Trojanowski, J. Q., Wszolek, Z. K., for the DLB/PDD Working Group, (2007). DLB and PDD boundary issues: Diagnosis, treatment, molecular pathology, and biomarkers. Neurology 68: 812-819 [Abstract] [Full Text]  
• Herholz, K (2005). Action of cholinesterase inhibitors in patients' brains. J. Neurol. Neurosurg. Psychiatry 76: 305-305 [Full Text]