Association of SNCA Parkinson's Disease Risk Polymorphisms With Disease Progression in Newly Diagnosed Patients.

Aleksandra A Szwedo,Guido Alves,Angus D Macleod,Johannes Lange,Lars Forsgren,Anastasia Ushakova,Carl E Counsell,Jodi Maple-Grødem,Camilla Christina Pedersen,Ole-Bjørn Tysnes

doi:10.3389/fneur.2020.620585

Abstract

Objectives: To evaluate the impact of SNCA polymorphisms originally identified as risk factors for Parkinson's disease (PD) on the clinical presentation and progression of the disease in a large cohort of population-based patients with incident PD.Methods: Four hundred thirty-three patients and 417 controls from three longitudinal cohorts were included in the study. Disease progression was recorded annually for up to 9 years using the Unified Parkinson's Disease Rating Scale (UPDRS) or Mini-Mental State Examination. Genotypes for five variants within the SNCA locus (rs2870004, rs356182, rs5019538, rs356219, and rs763443) were determined. We studied the association between each variant and disease progression using linear mixed-effects regression models.Results: The clinical profile of the patients with PD at the point of diagnosis was highly uniform between genotype groups. The rs356219-GG genotype was associated with a higher UPDRS II score than A-allele carriers (β = 1.52; 95% confidence interval 0.10–2.95; p = 0.036), but no differences were observed in the rate of progression of the UPDRS II scores. rs356219-GG was also associated with a faster annual change in Mini-Mental State Examination score compared with A-carriers (β = 0.03; 95% confidence interval 0.00–0.06; p = 0.043).Conclusions: We show that the known PD-risk variant rs356219 has a minor effect on modifying disease progression, whereas no differences were associated with rs2870004, rs356182, rs5019538, and rs763443. These findings suggest that SNCA variants associated with PD risk may not be major driving factors to the clinical heterogeneity observed for PD.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the core motor symptoms, bradykinesia, resting tremor, rigidity, and postural instability, though often accompanied by a wide spectrum of additional motor and non-motor signs [1]
We explored the effect of five SNCA polymorphisms linked to PD risk on the progression of the disease
Based on the prospective assessment of three population-based incident cohorts of patients with PD, we show an association between rs356219 and the rate of cognitive decline measured from the time of PD diagnosis

Summary

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the core motor symptoms, bradykinesia, resting tremor, rigidity, and postural instability, though often accompanied by a wide spectrum of additional motor and non-motor signs [1]. The severity and rate of progression of clinical symptoms in PD are highly variable between patients. Some patients experience mild motor decline and non-motor symptoms, whereas some experience fast deterioration in motor symptoms and prominent non-motor symptoms. These differences are in part predicted by sex, age at diagnosis, motor phenotype, and disease severity [2]. The timing and rate of cognitive decline vary widely among individuals with PD [3], and certain measures, including older age or differences in motor phenotype at diagnosis, predict a more rapid rate of cognitive decline in subgroups of patients [4]. The observed heterogeneity can pose prognostic difficulties in a clinical setting, compromising both the planning of appropriate patient management and clinical trial design

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