Brain Advance Access originally published online on January 4, 2008
Brain 2008 131(2):397-408; doi:10.1093/brain/awm313
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Attentional control in Parkinson's disease is dependent on COMT val158met genotype
1Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge and 2MRC Cognition and Brain Sciences Unit, Cambridge, UK
Correspondence to: Caroline Williams-Gray, Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK E-mail: chm27{at}cam.ac.uk
Cognitive deficits occur even in the earliest stages of Parkinson's disease. Some such deficits are known to relate to dysfunction in dopaminergic frontostriatal networks, and may be influenced by a common functional polymorphism (val158met) within the catechol O-methyltransferase (COMT) gene. Abnormal attentional shifting behaviour is an important and well-recognized cognitive problem in PD, but nonetheless its precise cognitive and neural basis remains unclear. Here we explored this impairment in an fMRI study employing a recently developed cognitive task designed to fractionate components of attentional control. We investigated the impact of the COMT val158met genotype and dopaminergic medication on both patterns of behaviour and associated brain activation in 29 medicated patients with early PD. Genotype had a critical impact on task strategy: whilst patients with high activity COMT genotypes (val/val) adopted a typical approach of preferentially shifting attention within rather than between dimensions, those with low activity genotypes (met/met) failed to adopt such a strategy, suggesting an inability to form an attentional ‘set’. Moreover, this behaviour was associated with significant underactivation across the frontoparietal attentional network. Furthermore, we demonstrated an interactive effect of COMT genotype and dopaminergic medication on task performance and BOLD response. Hence we have shown for the first time that attentional control in PD is critically determined by genetic and pharmacological influences on dopaminergic activity in frontoparietal networks. This has important implications for understanding the neurobiological basis of attentional control, and highlights the risk of medication-induced cognitive dysfunction in certain genotypic groups of PD patients, which may ultimately impact on clinical practice.
Key Words: Parkinson's disease; attentional set shifting; catechol O-methyl transferase; functional MRI; prefrontal cortex
Abbreviations: COMT, catechol O-methyltransferase; PD, Parkinson's disease; val, valine; met, methionine; ED, extradimensional; ID, intradimensional; PFC, prefrontal cortex; DLPFC, dorsolateral prefrontal cortex; VLPFC, ventrolateral prefrontal cortex; PPC, posterior parietal cortex
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Received September 10, 2007. Revised November 23, 2007. Accepted November 28, 2007.
*These authors contributed equally to this work.
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