Effects of Statins on Dopamine Loss and Prognosis in Parkinson's Disease

Seong Ho Jeong; Hye Sun Lee; Seok Jong Chung; Han Soo Yoo; Jin Ho Jung; Kyoungwon Baik; Yang Hyun Lee; Young H. Sohn; Phil Hyu Lee

Disclosures

Brain. 2021;144(10):3191-3200. 

In This Article

Abstract and Introduction

Abstract

Statins are more widely used not only for the primary and secondary prevention of cardiovascular disease by blocking cholesterol biosynthesis but also for the potential neuroprotective agents during neurological disorders due to their pleiotropic effects. In this study, we investigate whether the previous use of statins affect baseline nigrostriatal dopamine loss at the time of diagnosis and longitudinal motor and cognitive outcomes in patients with Parkinson's disease.

Five hundred drug-naïve patients with Parkinson's disease who underwent dopamine transporter imaging were classified into two groups according to the prior use of statins: patients with and without statin use. Multivariate linear regression was used to determine intergroup differences in dopamine transporter availability. We evaluated the longitudinal changes in levodopa-equivalent dose and dementia conversion between the groups using a linear mixed model and survival analysis, respectively. In addition, mediation analysis was applied to examine the effect of total cholesterol.

Patients with Parkinson's disease treated with statins had a lower baseline dopamine transporter availability in the anterior (2.13 ± 0.55 versus 2.37 ± 0.67; P = 0.002), posterior (1.31 ± 0.43 versus 1.49 ± 0.54; P = 0.003) and ventral putamina (1.40 ± 0.39 versus 1.56 ± 0.47; P = 0.002) than that in matched patients with Parkinson's disease without statins. After adjusting for age at symptom onset, sex, disease duration and vascular risk factors, linear regression models showed that a previous treatment with statins remained significantly and independently associated with more severely decreased dopamine transporter availability in the anterior putamen (Beta = −0.140, P = 0.004), posterior putamen (Beta = −0.162, P = 0.001) and ventral putamen (Beta = −0.140, P = 0.004). A linear mixed model revealed that patients with Parkinson's disease being treated with statins had a faster longitudinal increase in levodopa-equivalent dose than those without. A survival analysis showed that the rate of dementia conversion was significantly higher in patients with Parkinson's disease with statins (hazard ratio, 2.019; 95% confidence interval, 1.108–3.678; P = 0.022) than those without. Mediation analyses revealed that the effect of statin treatment on baseline dopamine transporter availability and longitudinal outcome was not mediated by total cholesterol levels.

Introduction

Statins are more widely used not only for the primary and secondary prevention of cardiovascular disease by blocking cholesterol biosynthesis[1] but also for the potential neuroprotective agents during neurological disorders due to their pleiotropic effects.[2,3] In Parkinson's disease, a number of in vitro and in vivo studies have shown that statins have beneficial effects on α-synuclein aggregation and dopaminergic neuronal death via modulation of oxidative and inflammatory processes.[4–6] Moreover, epidemiological studies demonstrated that statin therapy was significantly associated with the risk reduction of Parkinson's disease,[7,8] supporting the results of previous preclinical studies. Based on preclinical and observational studies, a clinical trial recently reported that lovastatin treatment showed a tendency to reduce the motor symptom progression.[9]

However, the relationship between statins and Parkinson's disease is not simple. Observational studies reported that the lower incidence of Parkinson's disease is primarily ascribed to high cholesterol levels,[10] given that patients with Parkinson's disease have decreased cholesterol biosynthesis.[11] Thus, recent epidemiological studies have raised the issue that statin therapy raises the risk of Parkinson's disease.[12–14] In terms of longitudinal outcomes in patients with Parkinson's disease, few previous studies reported beneficial effects of statins on the progression of motor deficits and cognitive impairment[15,16] However, these studies had small sample sizes and a high rate of censored data to draw consolidated conclusions.

In the present study, to uncover whether previous use of statins directly affects nigral degeneration at the time of Parkinson's disease diagnosis and longitudinal outcomes, we investigated the effects of statins on baseline nigrostriatal dopamine loss and longitudinal motor and cognitive outcomes in drug-naïve patients with Parkinson's disease.

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