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The Journal of Neuroscience, May 2, 2007, 27(18):4832-4838; doi:10.1523/JNEUROSCI.0774-07.2007

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Neurobiology of Disease
Catechol O-Methyltransferase val¹⁵⁸met Genotype Influences Frontoparietal Activity during Planning in Patients with Parkinson's Disease

Caroline H. Williams-Gray,¹ Adam Hampshire,² Trevor W. Robbins,³ Adrian M. Owen,^2 * and Roger A. Barker^1 *

¹Cambridge Centre for Brain Repair and Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 2PY, United Kingdom, ²Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, Cambridge CB2 7EF, United Kingdom, and ³Department of Experimental Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom

Correspondence should be addressed to Caroline Williams-Gray, Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 2PY, UK. Email: chm27{at}cam.ac.uk

Cognitive dysfunction commonly occurs even in the early stages of Parkinson's disease (PD). Impairment on frontostriatally based executive tasks is particularly well described but affects only a proportion of early PD patients. Our previous work suggests that a common functional polymorphism (val¹⁵⁸met) within the catechol O-methyltransferase (COMT) gene underlies some of this executive heterogeneity. In particular, an increasing number of methionine alleles, resulting in lower enzyme activity, is associated with impaired performance on the "Tower of London" planning task. The main objective of this study was to investigate the underlying neural basis of this genotype–phenotype effect in PD using functional magnetic resonance imaging. We scanned 31 patients with early PD who were homozygous for either valine (val) (n = 16) or methionine (met) (n = 15) at the COMT val¹⁵⁸met polymorphism during performance of an executive task comprising both Tower of London (planning) and simple subtracting ("control") problems. A cross-group comparison between genetic subgroups revealed that response times for planning problems were significantly longer in met compared with val homozygotes, whereas response times for control problems did not differ. Furthermore, imaging data revealed a significant reduction in blood oxygen level-dependent signal across the frontoparietal network involved in planning in met/met compared with val/val patients. Hence, we have demonstrated that COMT genotype impacts on executive function in PD through directly influencing frontoparietal activation. Furthermore, the directionality of the genotype–phenotype effect observed in this study, when interpreted in the context of the existing literature, adds weight to the hypothesis that the relationship between prefrontal function and dopamine levels follows as an inverted U-shaped curve.

Key words: Parkinson's disease; cognition; planning; COMT; functional MRI; prefrontal cortex

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Received Nov. 19, 2006; accepted March 21, 2007.

Correspondence should be addressed to Caroline Williams-Gray, Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 2PY, UK. Email: chm27{at}cam.ac.uk

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