title: Changes in the activity and protein levels of CSF acetylcholinesterases in relation to cognitive function of patients with mild Alzheimer's disease following chronic donepezil treatment.
abstract: OBJECTIVE
  To evaluate long-term changes in acetylcholinesterase (AChE) activity in CSF and blood following donepezil treatment in relation to the concentration of donepezil and cognition in AD patients.
  
  
  METHODS
  CSF or blood (or both) samples of a total of 104 patients with mild AD were used [MMSE score 23 +/- 0.4; age 75 +/- 1 years (mean +/- SEM); n=53 for CSF and n=51 for plasma/red blood cell (RBC) samples]. The patients were treated with 5 or 10 mg/day donepezil and clinically followed for 2 years. The CSF and RBC AChE activities were measured by the Ellman's direct colorimetric assay. Protein levels of two variants of AChE ("read-through" AChE-R and synaptic AChE-S) were determined by an ELISA-like method.
  
  
  RESULTS
  The plasma donepezil concentration was dose-dependent (between 30 and 60 ng/mL in the 5-mg and 10-mg group, respectively). The CSF donepezil concentration was 10 times lower than the plasma level and showed dose- and time-dependent kinetics. The RBC AChE inhibition was moderate (19-29%). CSF AChE-S inhibition was estimated to 30-40% in the 5-mg and 45-55% in the 10-mg group. Positive correlations were observed between the CSF AChE inhibition, an increased protein level of the AChE-R variant and MMSE examination. Patients with high AChE inhibition (>or=45%) showed a stabilized MMSE test result after up to two years, while a significant decline was observed in AD patients with lower AChE inhibition (<or=30%).
  
  
  CONCLUSIONS
  An increase in the protein level of the AChE-R variant corresponded to a high AChE inhibition in CSF and favored less cognitive deterioration.
authors.affiliation: Division of Molecular Neuropharmacology, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Darreh-Shori
authors.forename: L
authors.initials: L
authors.lastname: Meurling
authors.forename: T
authors.initials: T
authors.lastname: Pettersson
authors.forename: K
authors.initials: K
authors.lastname: Hugosson
authors.forename: E
authors.initials: E
authors.lastname: Hellström-Lindahl
authors.forename: N
authors.initials: N
authors.lastname: Andreasen
authors.forename: L
authors.initials: L
authors.lastname: Minthon
authors.forename: A
authors.initials: A
authors.lastname: Nordberg
mesh_terms: D000110:Acetylcholinesterase / Q000134:cerebrospinal fluid / Q000187:drug effects*; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000032:analysis / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D003071:Cognition / Q000187:drug effects*; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D005260:Female; D006801:Humans; D007189:Indans / Q000032:analysis / Q000627:therapeutic use*; D008297:Male; D010880:Piperidines / Q000032:analysis / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D000110:Acetylcholinesterase