Nonsteroidal Anti-inflammatory Use and LRRK2 Parkinson's Disease Penetrance

Marta San Luciano; Caroline M Tanner; Cheryl Meng; Connie Marras; Samuel M Goldman; Anthony E Lang; Eduardo Tolosa; Birgitt Schüle; J William Langston; Alexis Brice; Jean-Christophe Corvol; Stefano Goldwurm; Christine Klein; Simone Brockman; Daniela Berg; Kathrin Brockmann; Joachim J Ferreira; Meriem Tazir; George D Mellick; Carolyn M Sue; Kazuko Hasegawa; Eng King Tan; Susan Bressman; Rachel Saunders-Pullman; Michael J. Fox Foundation LRRK2 Cohort Consortium

doi:10.1002/mds.28189

Nonsteroidal Anti-inflammatory Use and LRRK2 Parkinson's Disease Penetrance

Mov Disord. 2020 Oct;35(10):1755-1764. doi: 10.1002/mds.28189. Epub 2020 Jul 14.

Authors

Marta San Luciano¹, Caroline M Tanner^{1

2}, Cheryl Meng¹, Connie Marras^{3

4}, Samuel M Goldman^{1

5}, Anthony E Lang^{3

4}, Eduardo Tolosa⁶, Birgitt Schüle⁷, J William Langston^{7

8}, Alexis Brice⁹, Jean-Christophe Corvol⁹, Stefano Goldwurm¹⁰, Christine Klein¹¹, Simone Brockman¹², Daniela Berg^{13

14}, Kathrin Brockmann^{13

14}, Joachim J Ferreira¹⁵, Meriem Tazir¹⁶, George D Mellick¹⁷, Carolyn M Sue¹⁸, Kazuko Hasegawa¹⁹, Eng King Tan²⁰, Susan Bressman²¹, Rachel Saunders-Pullman²¹; Michael J. Fox Foundation LRRK2 Cohort Consortium

Collaborators

Michael J. Fox Foundation LRRK2 Cohort Consortium:
Rachel Saunders-Pullman, Deborah Raymond, Andres Deik, Matthew James Barrett, Jose Cabassa, Mark Groves, Ann L Hunt, Naomi Lubarr, Joan Miravite, Christina Palmese, Rivka Sachdev, Harini Sarva, Lawrence Severt, Vicki Shanker, Matthew Carrington Swan, Jeannie Soto-Valencia, Brooke Johannes, Robert Ortega, Laurie Ozelius, Susan Bressman, Roy N Alcalay, Ming-X Tang, Helen Mejia Santana, Ernest Roos, Martha Orbe-Reilly, Stanley Fahn, Lucien Cote, Cheryl Waters, Pietro Mazzoni, Blair Ford, Elan Louis, Oren Levy, Llency Rosado, Diana Ruiz, Tsvyatko Dorovski, Lorraine Clark, Karen S Marder, Jean-Christophe Corvol, Florence Cormier, Anne-Marie Bonnet, Marie-Laure Welter, Valerie Mesnage, Marie Vidailhet, Emmanuel Roze, Lucette Lacomblez, David Grabli, Jose Felix Mart I Masso, Javier Ruiz Martinez, Elisabet Mondragon Rezola, Ainara Estanga Alustiza, Ana Gorostidi Pagola, Claustre Pont-Sunyer, Dolores Vilas Rolan, Ruben Fernandez-Santiago, Maria Quintana, Manel Fernandez, Laura Maragall, Faycal Hentati, Matthew Farrer, John Duda, Matt Read, Lefkos Middleton, Rachel Gibson, Joanne Trinh, Samia Ben Sassi, Mourad Zouari, Rimamouri, Emna Farhat, Fatma Nabli, Jan Aasly, Bjørg Johanne Warø, Sigrid Andersen, John Bertoni, Julie Carter, Lawrence Elmer, Nestor Galvez Jimenez, Wayne Martin, Rajesh Pahwa, Kelly Lyons, Stephen Reich, Robert Rodnitzky, Carmen Serrano Ramos, Joanne Wojcieszek, Anat Mirelman, Tanya Gurevich, Anat Bar Shira, Mali Gana Weisz, Kira Yasinovsky, Maayan Zalis, Avner Thaler, Avi Orr-Urtreger, Nir Giladi, Joanna Mountain, Tiago Mestre, Naomi Visanji, Taneera Ghate, Jennifer Singerman, Amaal Al Dakheel, Barbara S Connolly, Thomas Gasser, Kathrin Brockmann, Emily Drabant Conley, Meghan E Mullins, Carrie Northover, Maurizio Facheris, Brian Fiske, Alison Urkowiz

Affiliations

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 (OR_Pathogenic , 0.38; 95% CI, 0.21-0.67 and OR_RiskVariant , 0.19; 95% CI, 0.04-0.99). Similar associations were observed for ibuprofen and aspirin separately (OR_Ibuprofen , 0.19; 95% CI, 0.07-0.50 and OR_Aspirin , 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. © 2020 International Parkinson and Movement Disorder Society.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
Genetic Predisposition to Disease
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
Mutation / genetics
Parkinson Disease* / drug therapy
Parkinson Disease* / genetics
Penetrance

Substances

Anti-Inflammatory Agents, Non-Steroidal
LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2

Grants and funding

K23 NS099441/NS/NINDS NIH HHS/United States