. 2021 Jan;36(1):106-117.

doi: 10.1002/mds.28312. Epub 2020 Oct 1.

Differences in the Presentation and Progression of Parkinson's Disease by Sex

Hirotaka Iwaki^{1

2}, Cornelis Blauwendraat¹, Hampton L Leonard^{1

2}, Mary B Makarious¹, Jonggeol J Kim¹, Ganqiang Liu^{3

4

5}, Jodi Maple-Grødem^{6

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-Williams^{18

19}, Alexis Brice^{20

21

22}, Guido Alves^{6

7

23}, Alastair J Noyce^{24

25}, Ole-Bjørn Tysnes^{26

27}, Jonathan R Evans²⁸, David P Breen^{29

30

31}, Karol Estrada¹², Claire E Wegel³², Fabrice Danjou²⁰, David K Simon^{33

34}, Ole A Andreassen^{35

36}, Bernard Ravina^{37

38}, Mathias Toft^{9

39}, Peter Heutink^{40

41}, Bastiaan R Bloem¹⁰, Daniel Weintraub^{42

43}, Roger A Barker⁴⁴, Caroline H Williams-Gray⁴⁵, Bart P van de Warrenburg¹⁰, Jacobus J Van Hilten⁴⁶, Clemens R Scherzer^{4

5}, Andrew B Singleton¹, Mike A Nalls^{1

2}

Affiliations

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.

PMID: 33002231
PMCID: PMC7883324
DOI: 10.1002/mds.28312

Differences in the Presentation and Progression of Parkinson's Disease by Sex

Hirotaka Iwaki et al. Mov Disord. 2021 Jan.

. 2021 Jan;36(1):106-117.

doi: 10.1002/mds.28312. Epub 2020 Oct 1.

Authors

Affiliations

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.

PMID: 33002231
PMCID: PMC7883324
DOI: 10.1002/mds.28312

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. © 2020 International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; gender; sex; dyskinesias; cognitive impairment; activities of daily livings.

PubMed Disclaimer

Conflict of interest statement

Relevant conflicts of interests/financial disclosures: Nothing to report.

Figures

**FIG. 1.**
Forest plots depicting sex differences in outcomes in progression analyses. DATATOP, Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism; DIGPD, Drug Interaction with Genes in Parkinson’s Disease; HBS, Harvard Biomarkers Study; NET-PD_LS1, NIH Exploratory Trials in Parkinson’s Disease Large Simple Study 1; PARKFIT, ParkFit study; PARKWEST, The Norwegian ParkWest study; PDBP, Parkinson’s Disease Biomarker Program; PICNICS, Parkinsonism Incidence and Cognitive and Non-motor heterogeneity In Cambridgeshire; PPMI, Parkinson’s Progression Markers Initiative; PreCEPT_PostCEPT, Parkinson Research Examination of CEP-1347 Trial and PostCEPT; PROPARK, Profiling Parkinson’s disease study; and UDALL_PENN, Morris K. Udall Centers for Parkinson’s Research.P, non-adjusted P-values; I_sq, I² statistic; QEp, test of heterogeneity. “_scaled” scores were normalized (mean 0, standard deviation of 1) to the baseline distributions as the original scores.

**FIG. 2.**
Forest plots depicting sex differences in outcomes in baseline analyses. DATATOP, Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism; DIGPD, Drug Interaction with Genes in Parkinson’s Disease; HBS, Harvard Biomarkers Study; NET-PD_LS1, NIH Exploratory Trials in Parkinson’s Disease Large Simple Study 1; PARKFIT, ParkFit study; PARKWEST, The Norwegian ParkWest study; PDBP, Parkinson’s Disease Biomarker Program; PICNICS, Parkinsonism Incidence and Cognitive and Non-motor heterogeneity In Cambridgeshire; PPMI, Parkinson’s Progression Markers Initiative; PreCEPT_PostCEPT, Parkinson Research Examination of CEP-1347 Trial and PostCEPT; PROPARK, Profiling Parkinson’s disease study; and UDALL_PENN, Morris K. Udall Centers for Parkinson’s Research.P, non-adjusted P-values; I_sq, I² statistic; QEp, test of heterogeneity. “_scaled” scores were normalized (mean 0, standard deviation of 1) to the baseline distributions as the original scores

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Comment in

Sex Differences in Parkinson's Disease Phenotype and Caregiving Disparities.
de la Rosa T, Amado Scerni D, Scorza FA. de la Rosa T, et al. Mov Disord. 2021 Feb;36(2):526. doi: 10.1002/mds.28459. Mov Disord. 2021. PMID: 33599002 No abstract available.
Reply to: 'Letter to the Editor on "Sex Differences in Parkinson's Disease Phenotype and Caregiving Disparities"'.
Antar T, Iwaki H, B Singleton A. Antar T, et al. Mov Disord. 2021 Feb;36(2):527-528. doi: 10.1002/mds.28456. Mov Disord. 2021. PMID: 33599005 No abstract available.

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Differences in the Presentation and Progression of Parkinson's Disease by Sex

Affiliations

Differences in the Presentation and Progression of Parkinson's Disease by Sex

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

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Medical