. 2021;11(2):395-404.

doi: 10.3233/JPD-202472.

Parkinson's Disease Subtypes: Critical Appraisal and Recommendations

Tiago A Mestre^{1

2}, Seyed-Mohammad Fereshtehnejad², Daniela Berg³, Nicolaas I Bohnen⁴, Kathy Dujardin⁵, Roberto Erro⁶, Alberto J Espay⁷, Glenda Halliday⁸, Jacobus J van Hilten⁹, Michele T Hu¹⁰, Beomseok Jeon¹¹, Christine Klein¹², Albert F G Leentjens¹³, Johan Marinus⁹, Brit Mollenhauer¹⁴, Ronald Postuma¹⁵, Rajasumi Rajalingam¹⁶, Mayela Rodríguez-Violante¹⁷, Tanya Simuni¹⁸, D James Surmeier¹⁹, Daniel Weintraub²⁰, Michael P McDermott²¹, Michael Lawton²², Connie Marras¹⁶

Affiliations

¹ Parkinson's disease and Movement Disorders Center, Division of Neurology, Department of Medicine, The Ottawa Hospital Research Institute, The University of Ottawa Brain and Research Institute, Ottawa, ON, Canada.
² Division of Neurology, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada.
³ Department of Neurology, Christian-Albrechts-University, Kiel, Germany.
⁴ Departments of Radiology & Neurology, University of Michigan, University of Michigan Udall Center, Ann Arbor VAMC, Ann Arbor, MI, USA.
⁵ Movement Disorders Department, Center of Excellence for Neurodegenerative Diseases LiCEND, Lille, France.
⁶ Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", Neuroscience Section, University of Salerno, Baronissi (SA), Italy.
⁷ James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
⁸ Brain and Mind Centre and Central Clinical School, Faculty of Medicine and Health, University of Sydney, Australia.
⁹ Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
¹⁰ Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Neurology Department, Oxford, United Kingdom.
¹¹ Department of Neurology, Seoul National University Hospital, Seoul, Korea.
¹² Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
¹³ Department of Psychiatry, Maastricht University Medical Center, Maastricht, The Netherlands.
¹⁴ Paracelsus-Elena-Klinik, Kassel and University Medical Center Goettingen, Department of Neurology, Kassel, Germany.
¹⁵ Department of Neurology, McGill University, Montreal, Quebec, Canada.
¹⁶ Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Toronto, Canada.
¹⁷ National Institute of Neurology and Neurosurgery, Mexico City, Mexico.
¹⁸ Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹⁹ Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
²⁰ Departments of Psychiatry and Neurology, Perelman School of Medicine at the University of Pennsylvania; Parkinson's Disease Research, Education and Clinical Center (PADRECC), Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA.
²¹ Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, USA.
²² Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

PMID: 33682731
PMCID: PMC8150501
DOI: 10.3233/JPD-202472

Parkinson's Disease Subtypes: Critical Appraisal and Recommendations

Tiago A Mestre et al. J Parkinsons Dis. 2021.

. 2021;11(2):395-404.

doi: 10.3233/JPD-202472.

Authors

Affiliations

¹ Parkinson's disease and Movement Disorders Center, Division of Neurology, Department of Medicine, The Ottawa Hospital Research Institute, The University of Ottawa Brain and Research Institute, Ottawa, ON, Canada.
² Division of Neurology, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada.
³ Department of Neurology, Christian-Albrechts-University, Kiel, Germany.
⁴ Departments of Radiology & Neurology, University of Michigan, University of Michigan Udall Center, Ann Arbor VAMC, Ann Arbor, MI, USA.
⁵ Movement Disorders Department, Center of Excellence for Neurodegenerative Diseases LiCEND, Lille, France.
⁶ Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", Neuroscience Section, University of Salerno, Baronissi (SA), Italy.
⁷ James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
⁸ Brain and Mind Centre and Central Clinical School, Faculty of Medicine and Health, University of Sydney, Australia.
⁹ Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
¹⁰ Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Neurology Department, Oxford, United Kingdom.
¹¹ Department of Neurology, Seoul National University Hospital, Seoul, Korea.
¹² Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
¹³ Department of Psychiatry, Maastricht University Medical Center, Maastricht, The Netherlands.
¹⁴ Paracelsus-Elena-Klinik, Kassel and University Medical Center Goettingen, Department of Neurology, Kassel, Germany.
¹⁵ Department of Neurology, McGill University, Montreal, Quebec, Canada.
¹⁶ Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Toronto, Canada.
¹⁷ National Institute of Neurology and Neurosurgery, Mexico City, Mexico.
¹⁸ Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹⁹ Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
²⁰ Departments of Psychiatry and Neurology, Perelman School of Medicine at the University of Pennsylvania; Parkinson's Disease Research, Education and Clinical Center (PADRECC), Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA.
²¹ Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, USA.
²² Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

PMID: 33682731
PMCID: PMC8150501
DOI: 10.3233/JPD-202472

Abstract

Background: In Parkinson's disease (PD), there is heterogeneity in the clinical presentation and underlying biology. Research on PD subtypes aims to understand this heterogeneity with potential contribution for the knowledge of disease pathophysiology, natural history and therapeutic development. There have been many studies of PD subtypes but their impact remains unclear with limited application in research or clinical practice.

Objective: To critically evaluate PD subtyping systems.

Methods: We conducted a systematic review of PD subtypes, assessing the characteristics of the studies reporting a subtyping system for the first time. We completed a critical appraisal of their methodologic quality and clinical applicability using standardized checklists.

Results: We included 38 studies. The majority were cross-sectional (n = 26, 68.4%), used a data-driven approach (n = 25, 65.8%), and non-clinical biomarkers were rarely used (n = 5, 13.1%). Motor characteristics were the domain most commonly reported to differentiate PD subtypes. Most of the studies did not achieve the top rating across items of a Methodologic Quality checklist. In a Clinical Applicability Checklist, the clinical importance of differences between subtypes, potential treatment implications and applicability to the general population were rated poorly, and subtype stability over time and prognostic value were largely unknown.

Conclusion: Subtyping studies undertaken to date have significant methodologic shortcomings and most have questionable clinical applicability and unknown biological relevance. The clinical and biological signature of PD may be unique to the individual, rendering PD resistant to meaningful cluster solutions. New approaches that acknowledge the individual-level heterogeneity and that are more aligned with personalized medicine are needed.

Keywords: Parkinson’s disease; heterogeneity; subtypes.

PubMed Disclaimer

Conflict of interest statement

Michele Hu reports that ODPC Discovery COhort was funded by the Monument Trust Discovery Award from Parkinson’s UK and supported by the Na-tional Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford and the Dementias and Neurodegenerative Diseases Research Network (DeNDRoN).

Nicholas Bohnen received research funding from the NIH, Department of Veterans Affairs and the Michael J. Fox Foundation.

Glenda Halliday is a National Health and Medical Research Council of Australia Leadership Fellow (#1176607).

The remaining authors report there are no disclosures or conflicts of interest.

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Parkinson's Disease Subtypes: Critical Appraisal and Recommendations

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Parkinson's Disease Subtypes: Critical Appraisal and Recommendations

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