Dopamine Agonists

Summary statistics for baseline demographics and PD characteristics were reported for all PD patients. Repeated‐measures linear mixed models were used to examine the changes in MDS‐UPDRS total and part III scores, separately for the whole cohort, and for the following subsets of participants: (1) untreated, (2) treated with DT (defined as levodopa and/or dopamine agonists), (3) treated only with levodopa, and (4) treated with other PD medications. Repeated‐measures linear mixed models were also used to examine the changes in clinical characteristics and DAT binding over time for the whole cohort.
Spearman correlations were calculated between MDS‐UPDRS and DAT binding ratios at each time point for the whole cohort and for the subset treated only with levodopa (using OFF scores in treated patients) and also between the change in MDS‐UPDRS and percent change in DAT binding ratios for the whole cohort. The t‐tests were used in pairwise comparisons of the 1‐year change in MDS‐UPDRS total score for patients who were untreated, treated with DT, and treated with other PD medications at year 1.

Chi-square for categorical variables and Mann–Whitney U test for continuous variables due to non-normality were used to compare the baseline characteristics between patients with RLS and RLS-free controls. Cox proportional hazards regression models were applied to explore the association between RLS and the risk of dementia after adjusting for age, sex, income, residence, CCI, and history of other comorbidities. Among the Cox regression models, we used the Fine–Gray subdistribution hazard model with mortality as a competing risk given the old age of the study population. The proportional hazard assumption was satisfied in our Cox model (Schoenfeld individual test p-value > 0.05).
Sensitivity analyses were performed using four different models. In model 1, dementia was defined as the prescription of anti-dementia medications (donepezil, rivastigmine, galantamine, and memantine) at least twice and a diagnosis of the ICD-code of dementia. Although these medications were approved for only AD (rivastigmine additionally for Parkinson’s disease dementia), they can be used for cognitive symptoms in other types of dementia based on recommendations from multiple guidelines [31 (link)–33 (link)]. The previous study revealed that the definition of all-cause dementia by ICD-10 code plus anti-dementia medications had a positive predictive value of 94.7% when reviewing the medical records of 972 patients in two hospitals [34 (link)]. In model 2, medication history was added to the ICD code to define RLS. Patients with RLS ICD-code (G25.8) who had taken dopamine agonists (ropinirole or pramipexole) twice or more were regarded as patients with RLS (n = 1458). In this sensitivity model, we excluded patients with Parkinson’s disease because they could also take dopamine agonists. In model 3, patients taking antipsychotic agents were excluded because the antidopaminergic property of antipsychotic agents could lead to a misdiagnosis of RLS (n = 2482). The following antipsychotic agents approved in South Korea were used in this study: haloperidol, sulpiride, chlorpromazine, perphenazine, pimozide, risperidone, olanzapine, quetiapine, paliperidone, amisulpride, aripiprazole, ziprasidone, clozapine, blonanserin, and zotepine. In model 4, patients with RLS only diagnosed by psychiatrists or neurologists were included (n = 1154) to preclude the possible misdiagnosis by non-expert physicians.
To evaluate the effect of dopamine agonists (pramipexole and ropinirole) on the development of dementia, the risk of dementia was compared after dividing RLS patients by dopamine agonist use. Patients with RLS who were prescribed pramipexole or ropinirole at least once were considered dopamine agonist users. All missing data were addressed using listwise deletion. Data processing and statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). Statistical significance was set at a two-tailed p-value of < 0.05.

HAL (Sigma-Aldrich, St. Louis, MO) was diluted with 0.05% dimethyl sulfoxide (DMSO; Dojindo Laboratories, Japan) in sterile saline (vehicle). The drug is a traditional antipsychotic agent used primarily to treat schizophrenia and other psychoses (Gomes et al. 2013 (link); Vaz et al. 2018 (link); Magno et al. 2015 (link); Bruni et al. 2016 (link)) by relieving the symptoms of delusions and hallucinations commonly associated with schizophrenia. Haloperidol competitively blocks post-synaptic dopamine D2 receptors, eliminating dopamine neurotransmission while partially inhibiting 5-hydroxy-tryptamine (5-HT₂) and α1-receptors. However, there is negligible activation of dopamine D1-receptors (Seibt et al. 2010 (link)).
CBD (Cayman Chemical, Ann Arbor, MI) was diluted with 0.05% methanol and sterile saline. CBD, one of the major compounds present in the marijuana (C. sativa) plant, has some medicinal properties; however, its mechanism is not well known (Andreza et al. 2016 (link); Jeong et al. 2019 (link)).
Ropinirole hydrochloride (ROP; KYOWA Pharmaceutical Industry Co., Ltd, Osaka, Japan) was diluted with 0.05% dimethyl sulfoxide (DMSO; Dojindo Laboratories, Kumamoto, Japan) and sterile saline. The drug is a novel non-ergoline dopamine agonist, has selective affinity for dopamine D2 receptors, and is indicated for the treatment of early and advanced Parkinson’s disease (Pahwa et al. 2004 (link)).