Objective: The Catechol-O-Methyltransferase (COMT) Val158Met polymorphism has been proposed to be associated with increased risk of PD and have a specific impact on dopamine-mediated prefrontal executive function in an inverted-U curve manner. We tested this hypothesis in a well-established Chinese cohort of early PD patients.

Background: It has been proved that a polymorphism in the COMT gene (rs4608) causes a substitution of the amino acid valine 158 for methionine (Val158Met), results in a three to four fold decrease in the COMT enzyme activity and leads to a hyperdopaminergic state. The interindividual variability in COMT enzyme activity affects prefrontal dopamine level and then influences prefrontal executive function. Our hypothesis is that the COMT Val158Met polymorphism specifically affects dopamine-mediated executive function in frontostriatal networks, and PD patients in the early stage with low activity met/met genotype perform worse on executive function compared with the val/val and val/met genotype.

Methods: Cognitive functions were assessed in 250 patients with early PD using Wechsler Adult Intelligence Scale-Chinese Revision (WAIS-RC) and Wechsler Memory Scale-Chinese Revision (WMS-RC). These patients and 300 healthy controls were subsequently genotyped for the COMT gene Val158Met polymorphism. We employed analysis of covariance (ANCOVA) and a stratified analysis to determine the associations between the COMT Val158Met genotype and cognitive functions.

Results: The COMT Val158Met allele frequency and genotype distributions showed no statistically significant differences between PD patients and controls. However, patients with met/met genotype performed significantly worse on WAIS-RC similarities, a measure of executive function, compared to individuals with val/val and val/met genotype. Subsequent ANCOVA analysis revealed that COMT genotype interacted with sex and daily levodopa equivalent dose (LED) to influence executive function. Further stratified analysis showed that the lower-activity COMT met/met genotype has a detrimental effect on executive function among women.

Conclusions: Our results demonstrate that COMT Val158Met polymorphism is not associated with increased risk of PD, but has an effect on prefrontal executive function interacting with gender and dopaminergic medication in an inverted U-shaped curve manner.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/catechol-o-methyltransferase-val158met-polymorphism-influences-prefrontal-executive-function-in-early-parkinsons-disease/