Challenging the cholinergic system in mild cognitive impairment: a pharmacological fMRI study
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.
References (53)
On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis
Exp. Neurol.
(2000)- et al.
A parametric study of prefrontal cortex involvement in human working memory
NeuroImage
(1997) - et al.
Specificity of brain activation patterns in people at genetic risk for Alzheimer disease
Am. J. Geriatr. Psychiatry
(2002) - et al.
A neural network reflecting decisions about human faces
Neuron
(2001) - et al.
“Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician
J. Psychiatr. Res.
(1975) - et al.
Acute and chronic nicotine exposure differentially facilitate the induction of LTP
Brain Res.
(1999) - et al.
A global optimisation method for robust affine registration of brain images
Med. Image Anal.
(2001) - et al.
Improved optimization for the robust and accurate linear registration and motion correction of brain images
NeuroImage
(2002) - et al.
Cognitive effects of nicotine in humans: an fMRI study
NeuroImage
(2003) - et al.
Cognitive mechanisms of nicotine on visual attention
Neuron
(2002)
Cognitive effects of nicotine
Biol. Psychiatry
Imaging brain cholinergic activity with positron emission tomography: its role in the evaluation of cholinergic treatments in Alzheimer's dementia
Biol. Psychiatry
Temporal autocorrelation in univariate linear modeling of fMRI data
NeuroImage
Multilevel linear modelling for fMRI group analysis using Bayesian inference
NeuroImage
Neuropsychiatric symptoms in the dementias
Curr. Opin. Neurol.
Neuropathology of Alzheimer's disease: what is new since A. Alzheimer?
Eur. Arch. Psychiatry Clin. Neurosci.
Use of functional imaging in parkinsonism and dementia
Mov. Disord.
Nicotinic receptors and cholinergic neurotransmission in the central-nervous-system
Diversity Interact. Recept.
Alterations in the bold fMRI signal with ageing and disease: a challenge for neuroimaging
Nat. Rev., Neurosci.
Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment
Ann. Neurol.
Brain magnetic resonance spectroscopy—Role in assessing outcomes in Alzheimer's disease
CNS Drugs
Activation in mesolimbic and visuospatial neural circuits elicited by smoking cues: evidence from functional magnetic resonance imaging
Am. J. Psychiatry
Effect of nicotine on brain activation during performance of a working memory task
Proc. Acad. Natl. Sci. U. S. A.
Improved assessment of significant activation in functional magnetic-resonance-imaging (fMRI)—Use of a cluster-size threshold
Magn. Reson. Med.
A short review of cognitive and functional neuroimaging studies of cholinergic drugs: implications for therapeutic potentials
J. Neural Transm.
Assessing the significance of focal activations using their spatial extent
Hum. Brain Mapp.
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