Preventing levodopa induced dyskinesia in Parkinsonâs Disease with Statins

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The purpose of this project is to determine whether HMG-CoA reductase inhibitors (statins) will inhibit the progression of levodopa (LD) induced dyskinesia in Parkinson disease (PD) given that rodent and primate models have carefully demonstrated this. LD is the most important medication that Veterans with PD will take to control their symptoms and has remained so since its discovery in the 1960s. Unfortunately, early recognition of the benefits of LD against the stiffness, slowness and tremor of PD was accompanied in many cases by the side effect of dyskinesia, or unwanted purposeless excessive movements. Dyskinesias, which appear choreic, jerky or dystonic become more severe over time and have few treatment options, including reducing dopaminergic medications, which can lead to intolerable worsening of parkinsonian symptoms. Other options include amantadine, or deep brain stimulation. These treatments are not suitable for all patients, illustrating the need for other strategies including preventive, or “disease modifying” approaches. In animal models, statins applied comcomitantly with first ever LD ingestion interrupted the dyskinesia priming process as proven by reduction in not only dyskinesia biomarker levels, but significantly lessened future expression of dyskinesia. In this project, we will perform a retrospective cohort study using VA databases to select 40 Veterans with PD who have been prescribed statins prior to or concomitant to being prescribed LD for PD for several years (giving him/her ample time to potentially develop dyskinesia) and compare with a group of who never used statins. We will measure dyskinesia that has developed in these cohorts precisely using not only current standard methods but our unique methods of data gathering which includes a LD infusion and electronic dyskinesia measurements. We will determine if statin exposure was protective, resulting in less severe dyskinesia expression years later. We will also study a third 40 subject cohort prescribed a statin after LD initiation, to see if the eventual severity of dyskinesia is lessened, implying slowing of rate of dyskinesia progression. (secondary prevention). The power of the VA databases is in identifying subjects with the correct order of administration of statin and levodopa as well as continued administration through the years, along with baseline characteristics so that appropriate cohorts can be generated in sufficient numbers. By the end of this project, we will determine if statin exposure at the beginning of LD use is important to retarding the priming process for dyskinesia development, and whether there is still room for modifying the rate of progression of dyskinesia even if started late. If our study shows that statins do modify the rate of dyskinesia progression, then a multicenter prospective trial of statins would certainly be warranted. A means of preventing a dreaded complication of PD treatment would be welcome.