Statin use and the risk of Parkinson's disease in persons with diabetes: A nested case-control study.

AIMS: Persons with diabetes may have an elevated risk of Parkinson's disease (PD). Statin use could also modify the progression of PD. The aim was to study whether there is an association between statin exposure and risk of PD in persons with diabetes. METHODS: A nationwide, nested case-control study restricted to people with diabetes was performed as part of nationwide register-based Finnish study on PD (FINPARK). Study included 2017 PD cases and their 7934 matched controls without PD. Persons with PD were diagnosed between 1999 and 2015, and statin use (1995-2015) was determined from Prescription Register. In the main analysis, exposure at least 3 years before outcome was considered. Cumulative exposure was categorized into tertiles, and associations were analysed with conditional logistic regression (adjusted with comorbidities and number of antidiabetic drugs). RESULTS: Prevalence of statin use was similar in PD cases and controls, with 54.2% of cases and 54.4% controls exposed before the lag time (adjusted odds ratio [aOR] = 1.03; 95% confidence interval [CI]: 0.92-1.15). Those in the highest cumulative statin exposure tertile had higher risk of PD than statin nonusers (aOR = 1.22; 95% CI: 1.04-1.43), or those in the lowest cumulative statin exposure tertile (aOR = 1.29; 95% CI: 1.07-1.57). CONCLUSION: Our nationwide study that controlled for diabetes duration and used 3-year lag between exposure and outcome to account for reverse causality does not provide support for the hypothesis that statin use decreases the risk of PD.

ß2-Adrenoceptor Agonists in Asthma or Chronic Obstructive Pulmonary Disease and Risk of Parkinson's Disease: Nested Case-Control Study.

Introduction: Although ß2-adrenoceptor (ß2AR) agonists have been associated with a lower risk of Parkinson's disease (PD), the findings are inconclusive and may reflect confounding by indication. We studied the association between inhaled ß2AR agonists and risk of PD in persons with asthma or chronic obstructive pulmonary disease (COPD). Methods: The nested case-control study was conducted within a register-based Finnish Parkinson's disease study (FINPARK) and included 1406 clinically verified PD cases diagnosed during 1999-2015, who also had asthma/COPD >3 years before PD. PD cases were matched with up to seven controls by age, sex, duration of asthma/COPD, pulmonary diagnosis, and region (N = 8630). Cumulative and average annual exposure to short- and long-acting ß2AR agonists before a 3-year lag period was assessed with quartiles of defined daily doses (DDDs). Adjusted odds ratios (aORs) were calculated with 95% confidence intervals (CIs) using conditional logistic regression. Results: Cumulative exposure to either short- or long-acting ß2AR agonists was not associated with a risk of PD. With average annual exposure, a decreased risk was observed only for the highest quartile of long-acting ß2AR agonists (aOR 0.75; 95% CI 0.58-0.97). In the stratified analysis the lowest risk estimates were observed among those with both asthma and COPD diagnoses. The suggestion of an inverse association was seen for the highest quartile of long-acting ß2AR agonists in asthma. Discussion: Higher levels of exposure to ß2AR agonists were not consistently associated with a reduced risk of PD. The inverse association in the highest category of average annual exposure to long-acting ß2AR agonists may be explained by unmeasured confounding, such as disease severity or smoking.

Hospitalization and the Risk of Initiation of Antipsychotics in Persons With Parkinson's Disease.

OBJECTIVES: The use of antipsychotics in persons with Parkinson's disease (PD) is common, although their use may aggravate the symptoms of PD. Clozapine and quetiapine are the only antipsychotics recommended in PD treatment guidelines. Information on factors associated with initiation of antipsychotics is needed. We investigated whether recent hospitalization is associated with initiation of antipsychotics in persons with PD, and whether discharge diagnoses differ between those who had antipsychotics initiated and those who did not. DESIGN: Nested case-control study in the nationwide register-based Finnish Study on Parkinson's disease (FINPARK). SETTING AND PARTICIPANTS: The FINPARK study includes 22,189 persons who received an incident, clinically verified PD diagnosed during 1996-2015 and were community-dwelling at the time of diagnosis. The cases were 5088 persons who had antipsychotics initiated after PD diagnosis, identified with 1-year washout. The controls were 5088 age-, sex-, and time from PD diagnosis-matched persons who did not use antipsychotics on the matching date (antipsychotic purchase date). Recent hospitalization was defined as discharge in the 2-week period preceding the matching date. METHODS: Associations were investigated with conditional logistic regression. RESULTS: Quetiapine was the most commonly initiated antipsychotic (72.0% of cases), followed by risperidone (15.0%). Clozapine was initiated rarely (1.1%). Recent hospitalization associated strongly with antipsychotic initiation [61.2% of cases and 14.9% of controls, odds ratio (OR) 9.42, 95% CI 8.33-10.65], and longer hospitalizations were more common among cases. PD was the most common discharge diagnosis category (51.2% of hospitalized cases and 33.0% controls), followed by mental and behavioral disorders (9.3%) and dementia (9.0%) among cases. Antidementia and other psychotropic medication use were more common among cases. CONCLUSIONS AND IMPLICATIONS: These results suggest that antipsychotics were initiated because of neuropsychiatric symptoms or aggravation of those symptoms. Antipsychotics should be prescribed after careful consideration to avoid adverse effects in persons with Parkinson's disease.

Identification of Drugs Associated with Lower Risk of Parkinson's Disease Using a Systematic Screening Approach in a Nationwide Nested Case-Control Study.

Introduction: Drugs for other indications may be repurposable as disease-modifying drugs for Parkinson's disease (PD). A systematic hypothesis-free approach can enable identification of candidates for repurposing. We applied a hypothesis-free systematic approach to identify drugs associated with lower risk of PD to discover candidates with potential for repurposing as disease-modifying drugs for PD and to illustrate challenges in observational studies that simultaneously investigate multiple repurposing candidates. Methods: The Finnish Parkinson's disease study (FINPARK), a nationwide nested case-control study, was randomized to screening (10,183 cases, 67,849 controls) and replication (10,184 cases, 67,754 controls) samples, including cases diagnosed in 1998-2015. After screening all univariable associations of register-derived exposure to individual-drug, group- and subgroup level since 1995 (exposure ≥3 years before outcome, threshold P = 0.1), different exposure periods were used in confounder-adjusted replication analyses. Results: In screening stage, the group-level (antipsoriatics and antigout preparations) and subgroup-level (cicatrizants, topical antipsoriatics, antigout preparations and mydriatics and cycloplegics) associations were mainly due to individual drugs. Seven other drugs (eg methotrexate, drugs for chronic obstructive pulmonary disease, COPD and/or asthma) were associated with lower risk. Associations of antigout preparations and antipsoriatics were replicated. COPD/asthma drugs, methotrexate and diabetes drugs were studied in separate, indication-restricted designs. Discussion: The results reflect the known risk factors and the implied role of the immune system in PD pathogenesis and spurious associations. They underline the importance of controlling for confounding by indication, which is challenging to apply to systematic screening.

Disease-Modifying Antirheumatic Drugs and Risk of Parkinson Disease: Nested Case-Control Study of People With Rheumatoid Arthritis.

BACKGROUND AND OBJECTIVES: Epidemiologic studies have suggested a link between rheumatoid arthritis and Parkinson disease (PD). Disease-modifying antirheumatic drugs (DMARDs) might explain this association. The aim of this work was to evaluate the association between DMARDs and risk of PD in persons with rheumatoid arthritis. METHODS: This nested nationwide case-control study was conducted within the Finnish Parkinson's Disease (FINPARK) cohort, which includes 22,189 Finnish persons with clinically verified PD diagnosed in 1996 to 2015. The cases had recorded diagnosis of PD in the Special Reimbursement Register and had no exclusion diagnoses with symptoms that may be confused with PD within 2 years of PD diagnosis. This study included cases with PD diagnosed during 1999 to 2015 and rheumatoid arthritis diagnosed >3 years before PD. Rheumatoid arthritis was identified from the Finnish Care Register for Health Care and Special Reimbursement Register. Cases were matched with up to 7 controls by age, sex, duration of rheumatoid arthritis, and region. DMARDs were categorized into 5 classes, and data on purchased prescriptions were identified from the Prescription Register since 1995. Associations were studied with conditional logistic regression adjusted for confounders. RESULTS: Altogether, 315 cases with PD and 1,571 matched controls were included. The majority (>60%) were women, and the median duration of rheumatoid arthritis on matching date was 11.6 years for controls and 12.6 years for cases. Use of DMARDs was not associated with risk of PD with a 3-year lag period applied between exposure and outcome except chloroquine/hydroxychloroquine, which associated with decreased risk (adjusted odds ratio [OR] 0.74, 95% confidence interval [CI] 0.56-0.97). Other DMARDs, including sulfasalazine, methotrexate, gold preparations, and immunosuppressants, were not associated with PD. DISCUSSION: Our results suggest that the lower risk of PD in people with rheumatoid arthritis is not explained by DMARD use because these drugs in general did not modify the risk of PD among persons with rheumatoid arthritis. Association between chloroquine/hydroxychloroquine and lower risk of PD and the possible underlying mechanisms should be further investigated. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in individuals with rheumatoid arthritis using DMARDs, only chloroquine/hydroxychloroquine was associated with a potentially decreased risk of developing PD (adjusted OR 0.74, 95% CI 0.56-0.97).

Incidence of muscle relaxant use in relation to diagnosis of Parkinson's disease.

Background Parkinson's disease is the second most common neurodegenerative disorder. Motor and non-motor symptoms seem to precede the diagnosis of Parkinson's disease. Objective To evaluate the incidence of muscle relaxant use in community-dwelling persons with and without Parkinson's disease from 4 years before to 4 years after the diagnosis of Parkinson's disease. Method Nationwide register-based cohort included all community-dwelling Finnish persons who received reimbursement of Parkinson's disease drugs between 2000 and 2015 (N = 17,450) and comparison persons without Parkinson's disease who were matched for age, gender and region of residence (N = 122,694). Data on muscle relaxant use during 1995-2016 were collected from the Prescription Register. Results The incidence of muscle relaxant use was higher among persons with Parkinson's disease in comparison to persons without Parkinson's disease from 3 years before the diagnosis until 6 months after the diagnosis. The largest difference in incidence rates was observed at the time of the diagnosis (incidence rate ratio = 2.04, 95% confidence interval = 1.81-2.30). Tizanidine was the most frequently initiated muscle relaxant. Conclusions The incidence of muscle relaxant use starts increasing years before the diagnosis of Parkinson's disease but declines after that. It is important to identify the causes of muscle symptoms to avoid unnecessary muscle relaxant use and consequent adverse effects and events.

Epigenetic upregulation of endogenous VEGF-A reduces myocardial infarct size in mice.

"Epigenetherapy" alters epigenetic status of the targeted chromatin and modifies expression of the endogenous therapeutic gene. In this study we used lentiviral in vivo delivery of small hairpin RNA (shRNA) into hearts in a murine infarction model. shRNA complementary to the promoter of vascular endothelial growth factor (VEGF-A) was able to upregulate endogenous VEGF-A expression. Histological and multiphoton microscope analysis confirmed the therapeutic effect in the transduced hearts. Magnetic resonance imaging (MRI) showed in vivo that the infarct size was significantly reduced in the treatment group 14 days after the epigenetherapy. Importantly, we show that promoter-targeted shRNA upregulates all isoforms of endogenous VEGF-A and that an intact hairpin structure is required for the shRNA activity. In conclusion, regulation of gene expression at the promoter level is a promising new treatment strategy for myocardial infarction and also potentially useful for the upregulation of other endogenous genes.