Attentional control in Parkinson's disease is dependent on COMT val158met genotype

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 (val(158)met) 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 val(158)met 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.