Risk of Multiple System Atrophy and the Use of Anti-Inflammatory Drugs: A Danish Register-Based Case-Control Study

Abstract

<b><i>Introduction:</i></b> Multiple system atrophy (MSA) is a rare rapidly progressive atypical Parkinson disorder presenting clinically with parkinsonism and/or a cerebellar syndrome in combination with dysautonomia. Severe neuroinflammation develops along with hallmark neuropathological changes, and as in Parkinson’s disease, intake of anti-inflammatory medication has been hypothesized to be protective for development of disease. We aimed to investigate if use of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, or statins were associated with a reduced risk of MSA. <b><i>Methods:</i></b> We performed a register-based case-control study in MSA (<i>n</i> = 155) cases and population controls (<i>n</i>= 7,750) matched on age, gender, and place of residency by risk-set sampling. Pharmacological exposure prior to diagnosis was assessed in 2 categories (user vs. nonuser, cumulated dose in tertiles [T1-T3]). In an unconditional logistic regression model, adjusted for age, gender, residency, and chronic obstructive pulmonary disease (COPD), we estimated ORs and 95% CIs. <b><i>Results:</i></b> Data suggested a trend towards non-aspirin NSAID use to be associated with a decreased risk of MSA (OR 0.72 [95% CI 0.49–1.06]) compared to nonusers, decreasing dose-dependently (T2 OR 0.77 [95% CI 0.43–1.38]; T3 OR 0.55 [95% CI 0.29–1.06]). However, data were based on small numbers. Use of statins and low-dose aspirin was not associated with a decreased risk of MSA. Results were lagged 5 years from index date to address reverse causation. <b><i>Conclusion:</i></b> A trend toward use of non-aspirin NSAID and an associated reduced risk of MSA was observed in this study. However, our analyses had limited statistical precision, and further studies including larger sample sizes and longer exposure periods are needed.

Association between 23 drugs and Parkinson's disease: A two‐sample Mendelian randomization study

“…According to a retrospective investigation, the utilization of aspirin has been purportedly linked with a considerably heightened vulnerability to PD (Chen et al., 2021). Also, there was no statistically significant correlation between low‐dose aspirin and the risk of multiple system atrophy (MSA, a rare atypical form of PD) (Starhof et al., 2020). A case‐control study also found no statistically significant association between the long‐term use of aspirin and the incidence of PD (Becker et al., 2011).…”

α-Synuclein strains influence multiple system atrophy via central and peripheral mechanisms

“…This study therefore suggests that inflammation in MSA can be a contributor of pathology in response to ɑSyn strains. Chronic administration of non-steroidal anti-inflammatory drugs (NSAIDs) can reduce MSA risk 48 and cytokine profiling from cerebrospinal fluid and brain tissue from patients showed that pro-inflammatory pathways are upregulated [49][50][51] . Given that ɑSyn strains exist in the brain of people with MSA and that strains can specifically cause a detrimental immune response, targeting MSA strains or reducing inflammation in MSA could be a valuable therapeutic strategy.…”