title: Differential optimal dopamine levels for set-shifting and working memory in Parkinson's disease.
abstract: Parkinson's disease (PD) is an important model for the role of dopamine in supporting human cognition. However, despite the uniformity of midbrain dopamine depletion only some patients experience cognitive impairment. The neurocognitive mechanisms of this heterogeneity remain unclear. A genetic polymorphism in the catechol O-methyltransferase (COMT) enzyme, predominantly thought to exert its cognitive effect through acting on prefrontal cortex (PFC) dopamine transmission, provides us with an experimental window onto dopamine's role in cognitive performance in PD. In a large cohort of PD patients (n=372), we examined the association between COMT genotype and two tasks known to implicate prefrontal dopamine (spatial working memory and attentional set-shifting) and on a task less sensitive to prefrontal dopamine (paired associates learning). Consistent with the known neuroanatomical locus of its effects, differences between the COMT genotype groups were observed on dopamine-dependant tasks, but not the paired associates learning task. However, COMT genotype had differential effects on the two prefrontal dopamine tasks. Putative prefrontal dopamine levels influenced spatial working memory in an 'Inverted-U'-shaped fashion, whereas a linear, dose-dependant pattern was observed for attentional set-shifting. Cumulatively, these results revise our understanding of when COMT genotype modulates cognitive functioning in PD patients by showing that the behavioural consequences of genetic variation vary according to task demands, presumably because set-shifting and working memory have different optimal dopamine levels.
authors.affiliation: Radboud University, Donders Institute of Brain, Cognition and Behaviour, Netherlands; Department of Experimental Psychology, University of Oxford, Oxford, UK. Electronic address: sean.fallon@psy.ox.ac.uk.
authors.forename: Sean James
authors.initials: SJ
authors.lastname: Fallon
authors.affiliation: Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Nijmegen, Netherlands.
authors.forename: Katrijn
authors.initials: K
authors.lastname: Smulders
authors.affiliation: Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Nijmegen, Netherlands.
authors.forename: Rianne A
authors.initials: RA
authors.lastname: Esselink
authors.affiliation: Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Nijmegen, Netherlands.
authors.forename: Bart P
authors.initials: BP
authors.lastname: van de Warrenburg
authors.affiliation: Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Nijmegen, Netherlands.
authors.forename: Bastiaan R
authors.initials: BR
authors.lastname: Bloem
authors.affiliation: Radboud University, Donders Institute of Brain, Cognition and Behaviour, Netherlands; Radboud University Medical Centre, Department of Psychiatry, Nijmegen, Netherlands.
authors.forename: Roshan
authors.initials: R
authors.lastname: Cools
mesh_terms: D000328:Adult; D000368:Aged; D001245:Association Learning / Q000502:physiology; D001288:Attention / Q000502:physiology; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D004298:Dopamine / Q000378:metabolism*; D056344:Executive Function / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008875:Middle Aged; D009483:Neuropsychological Tests; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D011110:Polymorphism, Genetic; D017397:Prefrontal Cortex / Q000503:physiopathology*; D065852:Spatial Memory / Q000502:physiology
chemical_list: C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; D004298:Dopamine
keywords: COMT; Dopamine; Parkinson's disease; Set-shifting; Working memory