Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) might reduce the penetrance of LRRK2 mutations associated with Parkinson disease (PD), according to new research. The findings raise the possibility of a simple disease-modifying treatment for people with LRRK2 variants.
Inflammation is thought to be involved in the pathogenesis of PD, and use of NSAIDs, such as aspirin and ibuprofen, has previously been associated with a lower risk of PD. In the new study, the researchers investigated this association specifically among people with LRRK2 mutations.
Autosomal dominant mutations in LRRK2 are the most common cause of Mendelian PD, though the penetrance of these mutations is low at ~30% at age 80 years. Other variants in LRRK2 are also associated with an increased risk of PD. LRRK2 encodes leucine-rich repeat kinase 2, which is expressed in immune cells and influences inflammatory pathways. This role in inflammation provided the basis for investigating the effects of NSAIDs in people with LRRK2 mutations.
The study involved members of two international cohorts: the Parkinson’s Disease Genetic and Environmental Modifiers cohort, and the Michael J. Fox Foundation LRRK2 Cohort Consortium. In total, 577 individuals with pathogenic or risk variants in LRRK2 were included — 259 had PD and 318 were asymptomatic. Participants were asked whether they had ever taken ibuprofen-based medication, aspirin or other anti-inflammatory medications regularly, defined as two or more pills weekly for >6 months.
Regular use of NSAIDs was more common among asymptomatic carriers of LRRK2 variants than among symptomatic carriers. Regression analysis indicated that regular NSAID use is associated with a lower risk of PD among people with LRRK2 mutations. The association was true for risk variants as well as pathogenic variants.
“Anti-inflammatory drugs may be useful as disease-modifying treatments in LRRK2-PD”
“Our results support the hypothesis that aspirin and ibuprofen can reduce the risk of PD manifestation among LRRK2 carriers,” says lead author Marta San Luciano. “Anti-inflammatory drugs may be useful as disease-modifying treatments in LRRK2-PD, and the ability to identify an at-risk population makes interventions in this subgroup particularly feasible. However, these findings need to be replicated in other cohorts and in longitudinal studies, which is our planned next step.”
San Luciano, M. et al. Nonsteroidal anti-inflammatory use and LRRK2 Parkinson’s disease penetrance. Mov. Disord. https://doi.org/10.1002/mds.28189 (2020)
Tolosa, E. et al. LRRK2 in Parkinson disease: challenges of clinical trials. Nat. Rev. Neurol. 16, 97–107 (2020)
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Fyfe, I. Aspirin and ibuprofen could lower risk of LRRK2 Parkinson disease. Nat Rev Neurol 16, 460 (2020). https://doi.org/10.1038/s41582-020-0394-7