Elsevier

NeuroImage

Volume 23, Issue 4, December 2004, Pages 1450-1459
NeuroImage

Challenging the cholinergic system in mild cognitive impairment: a pharmacological fMRI study

https://doi.org/10.1016/j.neuroimage.2004.08.006Get rights and content

Mild cognitive impairment (MCI) often represents an early form of Alzheimer disease (AD). In both MCI and AD, characteristic cholinergic changes may occur. Functional magnetic resonance imaging (fMRI) may help to examine neurochemical changes in early disease by studying signal reactivity to pharmacological challenge. In this study, MCI patients [n = 28; mean age 73.6 ± 7.5; mini mental state examination (MMSE) 27.0 ± 1.2] were scanned during task performance in a randomized trial under three different medication regimes: at baseline [BL; no galantamine (GAL)], after a single oral dose of GAL (SD), and after prolonged exposure (steady state: SS). Memory tasks included an episodic face-encoding task and a parametric n-letter back working memory (WM) task. Alterations in brain activation patterns before and after treatment were analyzed for both tasks using multilevel statistical analysis. Significant increases in brain activation from BL were observed after prolonged exposure only. For face encoding (n = 28), these involved left prefrontal areas, the anterior cingulate gyrus, left occipital areas, and left posterior hippocampus. For working memory (n = 28), increased activation was found in right precuneus and right middle frontal gyrus, coinciding with increased accuracy scores after GAL treatment. In conclusion, cholinergic challenge produces alterations in brain activation patterns in elderly MCI patients that can be detected with fMRI. This should encourage further functional imaging studies to examine the status of neurotransmitter systems in disease.

Introduction

Alzheimer disease (AD) is characterized by progressive atrophy of medial temporal, frontal, and parietal brain structures. These structural changes give rise to clinical symptoms such as amnesia, agnosia, and aphasia (Braak et al., 1999, Geula, 1998). Atrophy of basal forebrain nuclei is another major feature in AD, resulting in pathological neurochemical changes throughout the brain. Of these, low acetylcholine levels in particular are thought to contribute significantly to symptoms in AD. Current therapies against AD largely aim at restoring low acetylcholine levels with pharmacological agents (Lanctot et al., 2003, Trinh et al., 2003). Functional imaging techniques are currently being investigated for their ability to detect neurochemical changes and monitor effects of treatment in dementia (Burn and O'Brien, 2003, Freo et al., 2002).

Mild cognitive impairment (MCI) represents a functional continuum between normality and the earliest signs of dementia (most commonly AD). Patients with MCI are at increased risk of developing AD, but clinical outcome may vary considerably (Petersen et al., 2001). Recent evidence shows that alterations in cholinergic system activity also occur in MCI patients. Markers of cholinergic function are upregulated in MCI, possibly to compensate for incipient neurofunctional defects (DeKosky et al., 2002). Functional imaging studies of cholinergic system (re)activity in MCI patients may therefore reveal important clinical information. First, such studies may link the functional status of the cholinergic system to the occurrence of symptoms in very early AD, indicating the necessity of starting cholinomimetic therapy (Volkow et al., 2001). Second, reactivity to cholinergic challenge may predict clinical responsiveness to cholinomimetic treatment, indicating the sensibility of starting a particular therapy (Doraiswamy et al., 2000, Nobili et al., 2002, Volkow et al., 2001). Third, the ability of the cholinergic system to compensate for small decreases in neural function (by altering cerebral plasticity and changing signal-to-noise levels in neural networks) is now increasingly recognized (Burggren et al., 2002, Mesulam, 2004, Parry et al., 2003). If this is true, cholinergic system ‘viability’ (Volkow et al., 2001) or residual function may be a measure of ‘compensatory reserve’ (Mesulam, 2004) and may influence a patient's prognosis.

In view of the above, we set out to study the feasibility of using functional magnetic resonance imaging (fMRI) to detect cholinergic system reactivity to selective pharmacological challenge in elderly patients with MCI. As a cholinomimetic agent, we used galantamine (GAL), which is a cholinesterase inhibitor with known therapeutic potential and has an additional modulatory effect on nicotinergic receptors (Raskind, 2003). To study the distribution of GAL effects across memory systems, memory tasks were used that examine both episodic and working memory (WM) performance. To study the onset time of the effect, fMRI was performed after both a single-dose challenge with GAL and after prolonged exposure.

Section snippets

Study design

Subjects were screened for participation in a randomized study design in which patients themselves served as controls. fMRI was performed at baseline (BL, no medication) after oral intake of a single dose of 8 mg GAL with water (single dose; SD) and after prolonged exposure to GAL [steady state (SS); i.e., a 120-h period (5 days) spread over 6 weekdays: 4 mg GAL (first gift, evening of day 1); 4 mg GAL b.i.d. (mornings and evenings; 4 consecutive days); 4 mg GAL (final gift, morning of day 6)].

Demographics

Mean age of MCI patients was 73.8 (±7.7). Education level was low in 3 patients, middle in 15 patients, and high in 10 patients. Three patients were left-handed, and three were smokers. Mean MMSE score was 27.0 (±1.2), and mean NYU paragraph recall score was 3.2 (±2.9) on delayed recall. CDR was 0.5 by definition.

Patient compliance and discontinuation

Data acquisition was complete in 21 of 30 patients after a single run. Four patients required an extra scan to obtain a complete data set (three patients had poor compliance (i.e.,

Discussion

The functional status of the cholinergic system is thought to contribute significantly to symptoms in AD (Bartus, 2000, Mesulam, 2004). In advanced Alzheimer disease, low levels of cholinergic markers have been found postmortem (DeKosky et al., 2002). The anticholinergic agent scopolamine may induce acute symptoms of moderately severe amnesia in healthy controls, making pharmacologically induced memory loss a successful model to study the cholinergic contribution to AD symptomatology (Assal and

Acknowledgments

Serge Rombouts is supported by a grant from the Netherlands Organization for Scientific Research (NWO; Grant No. 916.36.117). We would like to thank Stephen Smith for advice on data analysis using FSL, Stichting Alzheimer, for financial support and Dr. H. Geerts for supplying references of the pharmacokinetics of GAL. This trial was partly supported by Johnson & Johnson Pharmaceutical Research and Development.

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