Abstract
Alzheimer’s disease (AD) is a progressive disease with early degeneration of the central cholinergic neurons. Currently, three of four AD drugs act by inhibiting the acetylcholine (ACh) degrading enzyme, acetylcholinesterase (AChE). Efficacy of these drugs depends on available amount of ACh, which is biosynthesized by choline acetyltransferase (ChAT). We investigated whether treatment with a cholinesterase-inhibitor, galantamine, alters the relative levels of AChE to ChAT in cerebrospinal fluid (CSF) and whether levels of these CSF biomarkers correlate with in vivo AChE activity and nicotinic binding sites in the brain assessed by positron emission tomography (PET). Protein concentrations and activities of ChAT and AChE were measured in CSF of 18 patients with mild AD prior to and after 3 months of treatment with galantamine (n = 12) or placebo (n = 6), followed by nine additional months of galantamine treatment in all patients. A Cholinergic index was defined as the ratio of ChAT to AChE in CSF and was evaluated in relation to the in vivo AChE activity, the nicotinic binding sites and different measures of cognition. Besides an expected inhibition of AChE activity, galantamine treatment was accompanied by a mild increase in CSF ChAT activity. Thereby, the Cholinergic index was significantly increased in the Galantamine group (60% ± 14) after 3 months compared to baseline (p < 0.0023) or (p < 0.0004). This index remained high in the Galantamine group compared to baseline (54% ± 11) at 12 months follow-up, while it showed an increase in the Placebo group when they switched to active galantamine treatment (44% ± 14 vs. baseline, 61% ± 14 vs. 3 months, all p-values < 0.05). Furthermore, the in vivo brain AChE activity (assessed by PET) correlated with the CSF Cholinergic index at 12 months (r = 0.98, p < 0.001). The CSF Cholinergic index also correlated with ADAS-Cog and some other neuropsychological tests at 12 months. This is the first study assessing a CSF Cholinergic index in relation to treatment with a cholinesterase inhibitor. The treatment-specific increase in CSF ChAT activity suggests that cholinesterase-inhibitors may also increase the ACh-biosynthesis capacity in the patients. Additional studies are warranted to evaluate the utility of the CSF Cholinergic index as a biomeasure of therapeutic effect in AD.
Highlights
The central cholinergic pathways have prominent roles in learning and memory
We described for the first time the effect of galantamine treatment on cerebrospinal fluid (CSF) levels of two important enzymes that maintain the steady state of ACh in the brain, in particular, the core-cholinergic enzyme responsible for biosynthesis of ACh, i.e., choline acetyltransferase (ChAT)
We showed that specific inhibition of the CSF AChE activity by galantamine treatment was accompanied by a mild increase of the activity of ChATF in CSF at 3 months follow-up, with no changes seen in the Placebo group regarding the activities of these two enzymes
Summary
The severity of cholinergic deficits in patients with Alzheimer’s disease (AD) correlates with cognitive impairment, which have led to the development of cholinesterase inhibitors (ChEIs). There are three registered ChEIs for symptomatic treatment of dementia, namely donepezil (Winblad et al, 2001; Whitehead et al, 2004), rivastigmine (Rösler et al, 1999) and galantamine (Raskind et al, 2000, 2004; Tariot et al, 2000; Wilcock et al, 2003; Aronson et al, 2009), which have shown both shortand long-term benefits with regard to behavioral and cognitive measurements. Donepezil and galantamine are selective and rapidly reversible inhibitors of AChE, while rivastigmine is a pseudo-irreversible inhibitor of both AChE and its closely related enzyme, butyrylcholinesterase (BChE; Darreh-Shori and Soininen, 2010)
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