ABSTRACT
may reflect a combination of reactive gliosis following severe neuronal damage (glial cells having preponderantly BuChE) and of an accumulation of BuChE in neuritic plaques, which contain both enzymes.10 As the disease progresses and concentration of synaptic AChE (in particular the membrane-anchored G4 form) decreases,11 ChEIs increase acetylcholine (ACh) concentrations to levels which may be inhibitory for AChE activity. This increase in substrate concentration may trigger glial BuChE to hydrolyze ACh and could thus function as a mechanism to compensate for the loss of neuronal AChE activity. Given the close spatial relationship between glial cell protoplasm and the synaptic gap, it is likely that extracellularly diffusing ACh may come into contact with glial BuChE and be effectively hydrolyzed, as demonstrated in our experiments in rat cortex with intracerebral microdialysis (Figure 18.1)12 and by the administration of rivastigmine (an AChE-BuChE mixed inhibitor) in AD patients.13 In these patients, cerebrospinal fluid (CSF) BuChE inhibition significantly correlated with cognitive benefit measured with a comprehensive computerized neuropsychological test battery (CNTB) (Figure 18.2).13 As discussed in a subsequent section of this chapter, in subjects with mild cognitive impairment (MCI), these decreases in ChE activity are not seen. In the case of dementia with Lewy bodies and in
