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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.

SUBMITTER: Habak C

PROVIDER: S-EPMC4208466 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Dopamine transporter SLC6A3 genotype affects cortico-striatal activity of set-shifts in Parkinson's disease.

Habak Claudine C Noreau Anne A Nagano-Saito Atsuko A Mejía-Constaín Beatriz B Degroot Clotilde C Strafella Antonio P AP Chouinard Sylvain S Lafontaine Anne-Louise AL Rouleau Guy A GA Monchi Oury O

Brain : a journal of neurology 20140910 Pt 11

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 pat ...[more]

PMID: 25212851

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Project description:BackgroundAsymmetric hemispheric loss of dopaminergic neurons is one of the characteristic features of Parkinson's disease (PD). However, it is still debated if right or left asymmetry differently affects cognitive and motor progression.ObjectivesThe objective of this study was to investigate, for the first time, the relevance of dopamine transporter (DAT) asymmetry on cognitive and motor manifestations at onset and at 4-year progression in drug-naïve PD.MethodsFrom the Parkinson's Progression Markers Initiative multicenter cohort, we identified 249 right-handed patients with PD with baseline asymmetry greater than 20% in putamen DAT binding at single-photon emission computed tomography. A predominant putamen asymmetry was found on the left in 143 patients (PD-left), and on the right side in 106 patients (PD-right); we compared them with 196 healthy controls. Patients were followed longitudinally (2-year and 4-year visits), examining their clinical, cognitive, and imaging data.ResultsAt baseline, the PD-left group showed worse performance on the Symbol Digit Modality Test, an attention and processing-speed test, and lower cerebrospinal fluid β-amyloid levels than the PD-right group. These differences were maintained at follow-up, declining over time in both groups. By contrast, the PD-right group showed greater motor impairment at baseline, which increased over 4 years. Striatal DAT binding decreased over time in both groups, but the PD-right group showed a steeper decline, particularly during the first 2-year follow-up. Putaminal asymmetry assessed at baseline was maintained over time.ConclusionsThese findings suggest that hemispheric asymmetric dopaminergic denervation influences PD cognitive and motor performance as well as progression. Predominant right hemisphere nigrostriatal dopaminergic loss is associated with greater motor severity, whereas more pronounced left hemisphere denervation affects cognitive manifestations at onset and their progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dataset Information

Dopamine transporter SLC6A3 genotype affects cortico-striatal activity of set-shifts in Parkinson's disease.

Publications

Dopamine transporter SLC6A3 genotype affects cortico-striatal activity of set-shifts in Parkinson's disease.

Similar Datasets

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