title: Dopamine transporter SLC6A3 genotype affects cortico-striatal activity of set-shifts in Parkinson's disease.
abstract: Parkinson's disease is a neurodegenerative condition that affects motor function along with a wide range of cognitive domains, including executive function. The hallmark of the pathology is its significant loss of nigrostriatal dopamine, which is necessary for the cortico-striatal interactions that underlie executive control. Striatal dopamine reuptake is mediated by the SLC6A3 gene (formerly named DAT1) and its polymorphisms, which have been largely overlooked in Parkinson's disease. Thirty patients (ages 53-68 years; 19 males, 11 females) at early stages of Parkinson's disease, were genotyped according to a 9-repeat (9R) or 10-repeat (10R) allele on the SLC6A3/DAT1 gene. They underwent neuropsychological assessment and functional magnetic resonance imaging while performing a set-shifting task (a computerized Wisconsin Card Sorting Task) that relies on fronto-striatal interactions. Patients homozygous on the 10R allele performed significantly better on working memory tasks than 9R-carrier patients. Most importantly, patients carrying a 9R allele exhibited less activation than their 10R homozygous counterparts in the prefrontal cortex, premotor cortex and caudate nucleus, when planning and executing a set-shift. This pattern was exacerbated for conditions that usually recruit the striatum compared to those that do not. This is the first study indicating that the SLC6A3/DAT1 genotype has a significant effect on fronto-striatal activation and performance in Parkinson's disease. This effect is stronger for conditions that engage the striatum. Longitudinal studies are warranted to assess this polymorphism's effect on the clinical evolution of patients with Parkinson's disease, especially with cognitive decline.
authors.affiliation: 1 Research Centre, Institut universitaire de Gériatrie de Montréal, University of Montréal, Montréal, Québec, H3W 1W5, Canada.
authors.forename: Claudine
authors.initials: C
authors.lastname: Habak
authors.affiliation: 2 Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Québec, Canada 3 Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Noreau
authors.affiliation: 1 Research Centre, Institut universitaire de Gériatrie de Montréal, University of Montréal, Montréal, Québec, H3W 1W5, Canada.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nagano-Saito
authors.affiliation: 1 Research Centre, Institut universitaire de Gériatrie de Montréal, University of Montréal, Montréal, Québec, H3W 1W5, Canada.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Mejía-Constaín
authors.affiliation: 1 Research Centre, Institut universitaire de Gériatrie de Montréal, University of Montréal, Montréal, Québec, H3W 1W5, Canada.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Degroot
authors.affiliation: 4 Movement Disorder Unit and E.J. Safra Parkinson Disease Program, Toronto Western Hospital, UHN, University of Toronto, Ontario, Canada.
authors.forename: Antonio P
authors.initials: AP
authors.lastname: Strafella
authors.affiliation: 2 Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Québec, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chouinard
authors.affiliation: 3 Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Anne-Louise
authors.initials: AL
authors.lastname: Lafontaine
authors.affiliation: 2 Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Québec, Canada 3 Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: 1 Research Centre, Institut universitaire de Gériatrie de Montréal, University of Montréal, Montréal, Québec, H3W 1W5, Canada 5 Département de Radiologie, Université de Montréal, Montréal, Québec, Canada oury.monchi@umontreal.ca.
authors.forename: Oury
authors.initials: O
authors.lastname: Monchi
mesh_terms: D000368:Aged; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D056344:Executive Function / Q000502:physiology*; D005260:Female; D005625:Frontal Lobe / Q000503:physiopathology*; D059907:Functional Neuroimaging; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017072:Neostriatum / Q000503:physiopathology*; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology*; D011110:Polymorphism, Genetic
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human
keywords: SLC6A3/DAT1; dopamine; executive function; functional MRI; polymorphism