Hirotaka Iwaki1,2, Cornelis Blauwendraat1, Hampton L Leonard1,2, Mary B Makarious1, Jonggeol J Kim1, Ganqiang Liu3,4,5, Jodi Maple-Grødem6,7, Jean-Christophe Corvol8, Lasse Pihlstrøm9, Marlies van Nimwegen10, Luba Smolensky11, Ninad Amondikar11, Samantha J Hutten11, Mark Frasier11, Khanh-Dung H Nguyen12, Jacqueline Rick13, Shirley Eberly14, Faraz Faghri1, Peggy Auinger15, Kirsten M Scott16, Ruwani Wijeyekoon16, Vivianna M Van Deerlin17, Dena G Hernandez1, Raphael J Gibbs1, Aaron G Day-Williams18,19, Alexis Brice20,21,22, Guido Alves6,7,23, Alastair J Noyce24,25, Ole-Bjørn Tysnes26,27, Jonathan R Evans28, David P Breen29,30,31, Karol Estrada12, Claire E Wegel32, Fabrice Danjou20, David K Simon33,34, Ole A Andreassen35,36, Bernard Ravina37,38, Mathias Toft9,39, Peter Heutink40,41, Bastiaan R Bloem10, Daniel Weintraub42,43, Roger A Barker44, Caroline H Williams-Gray45, Bart P van de Warrenburg10, Jacobus J Van Hilten46, Clemens R Scherzer4,5, Andrew B Singleton1, Mike A Nalls1,2. 1. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. 2. Data Tecnica International, Glen Echo, Maryland, USA. 3. School of Medicine, Sun Yat-sen University, Guangzhou, China. 4. Advanced Center for Parkinson's Disease Research, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. 5. Precision Neurology Program, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA. 6. The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway. 7. Department of Chemistry, Bioscience and Environmental Engineering, University in Stavanger, Stavanger, Norway. 8. Assistance-Publique Hôpitaux de Paris, ICM, INSERM UMRS 1127, CNRS 7225, ICM, Department of Neurology and CIC Neurosciences, Pitié-Salpêtrière Hospital, Paris, France. 9. Department of Neurology, Oslo University Hospital, Oslo, Norway. 10. Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands. 11. The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA. 12. Translational Genome Sciences, Biogen, Cambridge, Massachusetts, USA. 13. Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 14. Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, USA. 15. Department of Neurology, Center for Health + Technology, University of Rochester, Rochester, New York, USA. 16. Department of Clinical Neurosciences, University of Cambridge, John van Geest Centre for Brain Repair, Cambridge, UK. 17. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. 18. Flagship Labs 60 Inc, Cambridge, Massachusetts, USA. 19. Statistical Genetics, Biogen, Cambridge, Massachusetts, USA. 20. Institut du cerveau et de la moelle épinière ICM, Paris, France. 21. Sorbonne Université SU, Paris, France. 22. INSERM UMR1127, Paris, France. 23. Department of Neurology, Stavanger University Hospital, Stavanger, Norway. 24. Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK. 25. Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, London, UK. 26. Department of Neurology, Haukeland University Hospital, Bergen, Norway. 27. Department of Clinical Medicine, University of Bergen, Bergen, Norway. 28. Department of Neurology, Nottingham University NHS Trust, Nottingham, UK. 29. Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland, UK. 30. Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, UK. 31. Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK. 32. Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, USA. 33. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 34. Harvard Medical School, Boston, Massachusetts, USA. 35. NORMENT; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 36. Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. 37. Voyager Therapeutics, Cambridge, Massachusetts, USA. 38. Department of Neurology, University of Rochester School of Medicine, Rochester, New York, USA. 39. Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 40. German Center for Neurodegenerative Diseases-Tubingen, Tuebingen, Germany. 41. HIH Tuebingen, Tuebingen, Germany. 42. Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 43. Department of Veterans Affairs, Philadelphia, Pennsylvania, USA. 44. Department of Clinical Neurosciences and WT-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. 45. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. 46. Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.
Abstract
BACKGROUND: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. OBJECTIVES: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. METHODS: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. RESULTS: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. CONCLUSIONS: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management.
BACKGROUND: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. OBJECTIVES: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. METHODS: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. RESULTS: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. CONCLUSIONS: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management.
Authors: Ronald B Postuma; Isabelle Arnulf; Birgit Hogl; Alex Iranzo; Tomoyuki Miyamoto; Yves Dauvilliers; Wolfgang Oertel; Yo-El Ju; Monica Puligheddu; Poul Jennum; Amelie Pelletier; Christina Wolfson; Smaranda Leu-Semenescu; Birgit Frauscher; Masayuki Miyamoto; Valerie Cochen De Cock; Marcus M Unger; Karin Stiasny-Kolster; Maria Livia Fantini; Jacques Y Montplaisir Journal: Mov Disord Date: 2012-05-30 Impact factor: 10.338
Authors: Kallol Ray Chaudhuri; Pablo Martinez-Martin; Anthony H V Schapira; Fabrizio Stocchi; Kapil Sethi; Per Odin; Richard G Brown; William Koller; Paolo Barone; Graeme MacPhee; Linda Kelly; Martin Rabey; Doug MacMahon; Sue Thomas; William Ondo; David Rye; Alison Forbes; Susanne Tluk; Vandana Dhawan; Annette Bowron; Adrian J Williams; Charles W Olanow Journal: Mov Disord Date: 2006-07 Impact factor: 10.338
Authors: Julius B M Anang; Jean-Francois Gagnon; Josie-Anne Bertrand; Silvia Rios Romenets; Veronique Latreille; Michel Panisset; Jacques Montplaisir; Ronald B Postuma Journal: Neurology Date: 2014-08-29 Impact factor: 9.910
Authors: Kara Pigott; Jacqueline Rick; Sharon X Xie; Howard Hurtig; Alice Chen-Plotkin; John E Duda; James F Morley; Lama M Chahine; Nabila Dahodwala; Rizwan S Akhtar; Andrew Siderowf; John Q Trojanowski; Daniel Weintraub Journal: Neurology Date: 2015-09-11 Impact factor: 9.910
Authors: Pablo Martinez-Martin; Cristian Falup Pecurariu; Per Odin; Jacobus J van Hilten; Angelo Antonini; Jose M Rojo-Abuin; Vanderci Borges; Claudia Trenkwalder; Dag Aarsland; David J Brooks; Kallol Ray Chaudhuri Journal: J Neurol Date: 2012-01-12 Impact factor: 4.849
Authors: Emma Borland; Katarina Nägga; Peter M Nilsson; Lennart Minthon; Erik D Nilsson; Sebastian Palmqvist Journal: J Alzheimers Dis Date: 2017 Impact factor: 4.472
Authors: Cornelis Blauwendraat; Hirotaka Iwaki; Mary B Makarious; Sara Bandres-Ciga; Hampton L Leonard; Francis P Grenn; Julie Lake; Lynne Krohn; Manuela Tan; Jonggeol J Kim; Jesse R Gibbs; Dena G Hernandez; Jennifer A Ruskey; Lasse Pihlstrøm; Mathias Toft; Jacobus J van Hilten; Johan Marinus; Claudia Schulte; Kathrin Brockmann; Manu Sharma; Ari Siitonen; Kari Majamaa; Johanna Eerola-Rautio; Pentti J Tienari; Donald G Grosset; Suzanne Lesage; Jean-Christophe Corvol; Alexis Brice; Nick Wood; John Hardy; Ziv Gan-Or; Peter Heutink; Thomas Gasser; Huw R Morris; Alastair J Noyce; Mike A Nalls; Andrew B Singleton Journal: Ann Neurol Date: 2021-05-24 Impact factor: 11.274
Authors: Megan C Bakeberg; Anastazja M Gorecki; Abigail L Pfaff; Madison E Hoes; Sulev Kõks; P Anthony Akkari; Frank L Mastaglia; Ryan S Anderton Journal: NPJ Parkinsons Dis Date: 2021-07-07
Authors: Megan C Bakeberg; Anastazja M Gorecki; Jade E Kenna; Alexa Jefferson; Michelle Byrnes; Soumya Ghosh; Malcolm K Horne; Sarah McGregor; Rick Stell; Sue Walters; Paola Chivers; Samantha J Winter; Frank L Mastaglia; Ryan S Anderton Journal: J Neurol Date: 2021-01-05 Impact factor: 4.849
Authors: Javier Oltra; Carme Uribe; Anna Campabadal; Anna Inguanzo; Gemma C Monté-Rubio; Maria J Martí; Yaroslau Compta; Francesc Valldeoriola; Carme Junque; Barbara Segura Journal: Front Aging Neurosci Date: 2022-01-06 Impact factor: 5.750
Authors: Javier Oltra; Barbara Segura; Carme Uribe; Gemma C Monté-Rubio; Anna Campabadal; Anna Inguanzo; Jèssica Pardo; Maria J Marti; Yaroslau Compta; Francesc Valldeoriola; Alex Iranzo; Carme Junque Journal: J Neurol Date: 2021-08-03 Impact factor: 4.849