Cholinergic system function and cognition in mild cognitive impairment

Abstract

Evidence for cholinergic dysfunction in very early stages of neurodegeneration like mild cognitive impairment (MCI) is inconclusive. Previous positron emission tomography (PET) studies based on small samples investigated if it is related to memory impairment. We examined whether cortical acetylcholine esterase (AChE) activity is reduced at this stage and correlated with cognitive function. N-[¹¹C]-methyl-4-piperidyl acetate ([11C]MP4A), a positron emission tomography tracer for measuring cerebral AChE activity in vivo, was applied in 21 controls and 17 MCI patients. Parametric images of AChE activity were analyzed using standard atlas regions. Principal components analysis (PCA) of regional values of AChE activity and correlation analysis with neuropsychological test results was performed. Cortical AChE activity showed a significant decline in MCI patients compared with controls which was most pronounced in temporal regions. They formed the main part of a principal component that was related significantly to verbal and nonverbal memory, language comprehension and executive function. Cholinergic dysfunction is an early hallmark even before onset of dementia at the clinical stage of MCI. Its impact especially on temporal neocortex is associated with impaired neuropsychological function.

Introduction

The degeneration of cholinergic basal forebrain neurons, especially in the nucleus basalis of Meynert (nbM), and the associated loss of cholinergic neurotransmission into cortical areas are regarded as significant contributors to the deterioration in cognitive function like memory or attention in patients with Alzheimer's disease (AD) — a theory known as the “cholinergic hypothesis” (Bartus, 2000, Geula and Mesulam, 1999, Perry et al., 1999). This view is supported by neuropathological studies revealing a reduction and degeneration of cholinergic neurons of the nbM in late AD patients (Arendt et al., 1985, Whitehouse et al., 1982) and by neurochemical analyses demonstrating reduced cholinergic key enzymes choline acetyltransferase (ChAT) and acetylcholine esterase (AChE) postmortem in the basal forebrain, hippocampus, temporal cortex, parietal cortex, and amygdala (Coyle et al., 1983, Davies and Maloney, 1976, Etienne et al., 1986, Perry et al., 1977). Furthermore, the therapeutic application of AChE inhibitors which increases the concentration of acetylcholine (ACh) in the synaptic cleft resulted in an improvement of memory in healthy controls (Davis et al., 1978) and enhanced cognitive function in AD patients (Birks, 2006).

However, findings regarding early stages of the disease and prestages such as mild cognitive impairment (MCI) are less conclusive and strongly depend on the methodology applied. Neuropathological postmortem studies showed no decrease of cholinergic neurons in the nbM in MCI patients and only a slight nonsignificant reduction in early AD patients (Gilmor et al., 1999). Also, intact levels of ChAT and AChE activity in mild AD in frontal, temporal, parietal, and entorhinal regions were reported (Davis et al., 1999). DeKosky and colleagues even found elevated levels in the frontal cortex and hippocampus in MCI patients, suggesting a possible upregulation of enzyme synthesis in the remaining cholinergic neurons to compensate for lost neurons (DeKosky et al., 2002).

Most in vivo imaging studies using positron emission tomography (PET) tracers like [11C]MP4A and [¹¹C]MP4P revealed a significant reduction of cortical AChE activity, especially in the temporal cortex, already in mild to moderate AD patients and in some patients with MCI (Herholz, 2008) (for an overview on AChE PET studies in MCI and AD patients see supplemental material Table S1). Reductions of the α4β2 nicotinic acetylcholine receptor (nAChR) in MCI patients have also been reported with PET (Sabri et al., 2008) and single-photon emission computed tomography (SPECT) (Terriere et al., 2010) while another SPECT study did not show significant differences between AD, MCI, and age-matched controls (Mitsis et al., 2009b). A decline with age was observed for α4β2 nicotinic ACh receptors (Mitsis et al., 2009a) but not for AChE activity (Kuhl et al., 1999, Namba et al., 1999, Ota et al., 2004).

Experimental and clinical studies have shown the involvement of the cholinergic system in cognitive functioning in animals and humans. Structural lesions to cholinergic basal forebrain neurons or application of muscarinic and nicotinic ACh receptor antagonists leads to impaired memory performances and changed behavior (Damasio et al., 1985, Decker and McGaugh, 1991, Newhouse et al., 1994, Vitiello et al., 1997). Also, the application of a cholinergic replacement therapy in AD patients using ACh receptor agonists or AChE inhibitors improved cognitive efficiency (Buccafusco and Terry, 2000). However, there is only limited information about the relation between in vivo AChE activity and neuropsychological function in AD patients. Shinotoh et al. reported a correlation between a decline in Mini Mental State Examination (MMSE) scores and reduced AChE activity in amygdala and cortex measured with [11C]MP4A PET in AD patients but not with hippocampal enzyme activity (Shinotoh et al., 2000, Shinotoh et al., 2003). Bohnen et al. published results about significant associations between cortical AChE activity and performance on a test of attention and working memory, but not with long term memory function (Bohnen et al., 2005a) and Eggers et al. showed significant correlations between the word fluency task as a measure of executive function and word retrieval and global cortical AChE activities in ApoE4 noncarrier AD patients (Eggers et al., 2006). Also, a link between reduced cortical nicotinic acetylcholine receptor (nAChR) availability and impaired performance on tests for general cognition, attention, and executive function was reported (Kadir et al., 2006, Sabri et al., 2008). However, the significance of cholinergic dysfunction for neuropsychological performance in MCI patients is rather vague and not yet comprehensively studied, and the efficiency of the application of AChE inhibitors in these patients is being widely discussed due to inconsistent therapeutic outcomes (Feldman et al., 2007, Loy and Schneider, 2006, Raschetti et al., 2007).

To enhance the understanding of cholinergic function and its possible impairment in MCI patients in vivo we conducted a study of detailed regional cortical AChE activity in a larger sample of MCI patients than studied previously and compared the findings to healthy age-matched controls. Furthermore, we also examined the regional variation patterns of cortical AChE activity by principal components analysis (PCA) and their relation to general cognitive performance, verbal and nonverbal memory, executive functions, and visuospatial functions.