Cerebrospinal fluid levels of biomarkers and activity of acetylcholinesterase (AChE) and butyrylcholinesterase in AD patients before and after treatment with different AChE inhibitors

Abstract

In order to evaluate the biochemical effects of long-term treatment with inhibitors of acetylcholinesterase (AChE) in patients with Alzheimer's disease (AD), we measured the activities of AChE and butyrylcholinesterase (BuChe) and the concentrations of beta-amyloid (1-42), tau and phosphorylated tau proteins in the cerebrospinal fluid (CSF). A total of 91 patients suffering from probable AD of mild to moderate degree were treated for 6 months with donepezil (n=59), galantamine (n=15), rivastigmine (n=10), or placebo (n=7). AChE activity in CSF was significantly increased after treatment with donepezil and galantamine; the opposite was observed in the rivastigmine-treated group. Untreated patients did not show any AChE activity variation. BuChE did not show any change in any of the groups studied. Mean values of beta-amyloid(1-42), total tau and phosphorylated tau also did not vary significantly. We conclude that AChE inhibitors induce different effects on CSF AChE activity, while other CSF biomarkers are not significantly affected by treatment.

Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:

“…102 These data suggest that rivastigmine, as a dual ChE inhibitor, may possess a greater disease-modifying potential than the AChE-specific inhibitors donepezil and galantamine, although further studies in this area are warranted. As mentioned earlier, long-term rivastigmine treatment results in sustained ChE inhibition, 21 whereas long-term administration of both donepezil and galantamine has been shown to increase AChE activity, [18][19][20] which may exacerbate the rate of disease progression.…”

“…10,11 Although all ChE inhibitors share the same basic mode of action (inhibition of AChE), their pharmacokinetic characteristics differ substantially ( Table I). [12][13][14][15][16][17][18][19][20][21][22][23][24] …”

“…These differences occur as a direct result of the underlying pharmacodynamic and pharmacokinetic properties of ChE inhibitors, as outlined in Table I. [12][13][14][15][16][17][18][19][20][21][22][23][24] Safety Drug-Drug Interactions Donepezil and galantamine are both metabolized via the hepatic cytochrome P450 (CYP450) enzyme system. 12 Therefore, caution should be exercised when coprescribing other drugs metabolized via these pathways.…”

“…21 In comparison, 6 to 12 months of treatment with donepezil or galantamine resulted in increased AChE activity. [18][19][20] The effects of long-term donepezil and rivastigmine administration on ChE activities are depicted in Figure 1. 18,21 Although these findings clearly warrant further investigation, the increase in ACh activity seen with donepezil and galantamine may have negative implications in terms of disease progression and may explain why a sudden worsening of symptoms, or "crash effect," has been observed in some patients following discontinuation of donepezil.…”

“…At present, only limited data 9 are available to examine this hypothesis. For example, delayed-start clinical trials in patients with mild to moderately severe AD (baseline MMSE scores, [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] indicate that any delay in the initiation of treatment with ChE inhibitors may result in irretrievable loss of benefit compared with patients receiving treatment earlier in the disease course. Two 52-week studies 9,93 were conducted, with an initial 26-week placebo-controlled phase followed by a 26-week, openlabel extension study during which all patients received rivastigmine.…”