Marta San Luciano1, Caroline M Tanner1,2, Cheryl Meng1, Connie Marras3,4, Samuel M Goldman1,5, Anthony E Lang3,4, Eduardo Tolosa6, Birgitt Schüle7, J William Langston7,8, Alexis Brice9, Jean-Christophe Corvol9, Stefano Goldwurm10, Christine Klein11, Simone Brockman12, Daniela Berg13,14, Kathrin Brockmann13,14, Joachim J Ferreira15, Meriem Tazir16, George D Mellick17, Carolyn M Sue18, Kazuko Hasegawa19, Eng King Tan20, Susan Bressman21, Rachel Saunders-Pullman21. 1. Department of Neurology, University of California San Francisco, San Francisco, California, USA. 2. Department of Neurology, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA. 3. The Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Centre, Toronto, Ontario, Canada. 4. Department of Neurology, Toronto Western Hospital, Toronto, Ontario, Canada. 5. Department of Medicine, University of California San Francisco, San Francisco, California, USA. 6. Movement Disorders Unit, Neurology Service, Hospital Clínic, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (IDIBAPS) Universitat de Barcelona, Catalonia, Spain. 7. Department of Pathology, Stanford University School of Medicine, Stanford, California, USA. 8. Department of Neurology, Stanford University School of Medicine, Stanford, California, USA. 9. Sorbonne Universites, UPMC Universite Paris 6 UMR_S 1127, INSERM U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle epiniere, ICM, Paris, France. 10. Parkinson Institute, ASST G.Pini-CTO, Milano, Italy. 11. Institute of Neurogenetics, University of Luebeck, Luebeck, Germany. 12. School of Psychiatry and Clinical Neurosciences, University of Western Australia and Fremantle Hospital, Western Australia, Australia. 13. Department for Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany. 14. Department of Neurology, Christian-Albrechts-University of Kiel, Kiel, Germany. 15. Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal. 16. Service de Neurologie CHU Mustapha, Alger, Algeria. 17. Griffith Institute for Drug Discovery, Griffith University, Brisbane, Australia. 18. Department of Neurogenetics, Kolling Institute, University of Sydney, Sydney, Australia. 19. Department of Neurology, Sagamihara National Hospital, Kanagawa, Japan. 20. Department of Neurology, Singapore General Hospital, Singapore. 21. Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Abstract
BACKGROUND: The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown. OBJECTIVES: The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD. METHODS: Symptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups. RESULTS: A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21-0.57) and in both pathogenic and risk variant carriers (ORPathogenic , 0.38; 95% CI, 0.21-0.67 and ORRiskVariant , 0.19; 95% CI, 0.04-0.99). Similar associations were observed for ibuprofen and aspirin separately (ORIbuprofen , 0.19; 95% CI, 0.07-0.50 and ORAspirin , 0.51; 95% CI, 0.28-0.91). CONCLUSIONS: Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association.
BACKGROUND: The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown. OBJECTIVES: The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD. METHODS: Symptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups. RESULTS: A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21-0.57) and in both pathogenic and risk variant carriers (ORPathogenic , 0.38; 95% CI, 0.21-0.67 and ORRiskVariant , 0.19; 95% CI, 0.04-0.99). Similar associations were observed for ibuprofen and aspirin separately (ORIbuprofen , 0.19; 95% CI, 0.07-0.50 and ORAspirin , 0.51; 95% CI, 0.28-0.91). CONCLUSIONS: Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association.
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