In vivo study of acetylcholine esterase in basal forebrain, amygdala, and cortex in mild to moderate Alzheimer disease

Abstract

It is currently unclear whether impairment of the cholinergic system is present in Alzheimer disease (AD) already at an early stage and to what extent it depends on degeneration of the nucleus basalis of Meynert (nbM). We examined acetylcholine esterase activity in vivo in the nbM, the amygdala, and cerebral neocortex. Measurements were performed in normal controls and in patients with mild to moderate AD with positron emission tomography (PET) and C-11-labeled N-methyl-4-piperidyl-acetate (MP4A) which is a specific substrate of AChE. AChE activity was reduced significantly in amygdala and cerebral cortex. In contrast, AChE activity and glucose metabolism appeared preserved or even increased in the nbM. The results support the concept that neocortical and amygdaloid functional changes of the cholinergic system are an early and leading event in AD, rather than the consequence of neurodegeneration of basal nuclei.

Introduction

Evidence for disturbance of cholinergic transmission in Alzheimer disease (AD) was found in many clinical and neuropathological studies (see reviews by Bartus et al., 1982, Coyle et al., 1983). The integrity of the cholinergic system has mostly been studied by histochemistry and immunohistochemistry of its two key enzymes, choline acetyl transferase (ChAT) and acetylcholine esterase (AChE). Cholinergic innervation of cerebral cortex mostly originates from the nucleus basalis of Meynert (nbM) (Mesulam et al., 1983). These neurons and their axons, which stain positive for ChAT and AChE (Mesulam and Geula, 1992), were reduced in autopsy studies of severe AD Davies and Maloney, 1976, Perry et al., 1977, Whitehouse et al., 1982 in correlation with dementia severity (Bierer et al., 1995). There is no in vivo tracer for ChAT but nbM cholinergic neurons express ChAT and AChE in a closely related manner (Mesulam and Geula, 1988b). Therefore imaging of AChE is a suitable in vivo indicator to study the integrity of nbM neurons. There is also a substantial reduction of cortical nicotinic binding sites (see review by Wevers and Schröder, 1999). On the other hand, persistence of shrunken cholinergic neurons in nbM in AD was demonstrated (Pearson et al., 1983) and cortical and nbM ChAT activity was found intact in mild AD Davis et al., 1999, Gilmor et al., 1999, Tiraboschi et al., 2000 or even up-regulated in mild cognitive impairment (Dekosky et al., 2002), challenging the view that loss of cortical cholinergic innervation from nbM is an early and constitutive component of AD.

In recent years, tracers have been developed for in vivo imaging of cerebral AChE with positron emission tomography (PET) Kilbourn et al., 1996, Namba et al., 1994. We used a piperidine analogue of acetylcholine, C-11-labeled N-methyl-4-piperidyl-acetate (MP4A), which enters the brain freely (depending on blood flow) and then accumulates depending on hydrolytic activity of AChE. Reduction of cortical AChE activity in AD has already been described with this technique in previous studies Herholz et al., 2000, Iyo et al., 1997, Kuhl et al., 1999, Shinotoh et al., 2000. Current clinical PET scanners have reached a spatial resolution of 4 mm (Wienhard et al., 1994) and permit imaging even of small brain nuclei, such as basal forebrain nuclei and the amygdala that exhibit high AChE activity and thus high tracer accumulation. We therefore examined whether there is a reduction of AChE activity in nbM that matches the loss of cortical AChE activity in AD. This should clarify whether loss of cortical AChE activity in AD is due to degeneration of nbM, or whether there is a primarily cortical change of AChE activity that is independent from nbM degeneration (Mufson et al., 1987). As an additional check of local neuronal function, local cerebral glucose metabolism was examined by F-18-2-fluoro-2-deoxy-d-glucose (FDG) PET.