Sustained cholinesterase inhibition in AD patients receiving rivastigmine for 12 months
Darreh-Shori T, Almkvist O, Guan ZZ, Garlind A, Strandberg B, Svensson AL, et al.;
Commented by , 22 Oct 2002
Aim of the study
Establish if inhibition of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) is sustained over one year using rivastigmine in patients with Alzheimer’s disease (AD).
Method
Measurement of AChE and BuChe activities in plasma and cerebro-spinal fluid (CSF) of eleven patients with mild stage ‘probable AD’ (MMSE 21 to 29) on therapeutic doses of rivastigmine using Ellman’s colorimetric assay, and measurement of AChE isoforms using an immunoblot analysis.
Results
At twelve months the specific activities of cholinesterase were lower than at baseline (by 36% for AChE and 45% for BuChE), correlating with parallel reduction in plasma (27% for AChE and 33% for BuChE). Immunoblot analysis found higher levels of the stress-associated ‘read-through’AChE isoform (AChE-R) whereas levels of the synaptic isoform were unchanged.
Discussion
This study established that rivastigmine does inhibits both AChE and BuChE for period of up to twelve months. Previous studies with tacrine, donepezil and galantamine have suggested that the AChE inhibition in CSF was limited in time, suggesting an ‘upregulation’ of AChE, potentially leading to reduction in clinical benefit.
Nevertheless, there appears to be ‘upregulation’ of the ‘read-through’ AChE isoform under rivastigmine therapy, which the authors interpret as a positive finding since data on transgenic mice overexpressing AChE suggest that selective up-regulation of AChE-R attenuates neurodegeneration and may exert a neuroprotective effect, whereas excess of the synaptic variant (AChE-S) intensifies neurodeterioration.
The clinical relevance of the dual inhibition of AChE and of BuChE is still debated, and a randomized head-to-head comparison study of donepezil (selective inhibitor of AChE) versus rivastigmine (dual inhibitor) in moderate to severe stage patients with AD is under way, and will help resolve this issue.
Not surprisingly AChE and BuChE inhibition was higher in CSF than plasma, but the plasma levels did correlate with the dose of rivastigmine and the performance on some of the neuropsychological tests performed during the study correlated with plasma enzymatic activity using the higher doses of rivastigmine at one time point (3 months).
Unfortunately these findings seem to suggest that plasma AChE activity is not a useful marker of the therapeutic activity of a cholinesterase inhibitor (CI), an issue that has relevance for the clinical usability of these drugs as a class.
In clinical practice most patients end up on the maximally tolerated dose of one of the CI for six to twelve months, with stabilization of cognitive, functional and possibly neuropsychiatric symptoms, followed by a slow decline, at which point the temptation is to switch to another CI in the hope that AChE inhibition will be achieved again with the second drug.
Fortunately addition of a drug with a different mode of action, such as memantine, is now a realistic option rather than switching between CI.