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Research paper
Developing and validating Parkinson’s disease subtypes and their motor and cognitive progression
  1. Michael Lawton1,
  2. Yoav Ben-Shlomo1,
  3. Margaret T May1,
  4. Fahd Baig2,3,
  5. Thomas R Barber2,3,
  6. Johannes C Klein2,3,
  7. Diane M A Swallow4,
  8. Naveed Malek5,
  9. Katherine A Grosset5,
  10. Nin Bajaj6,
  11. Roger A Barker7,
  12. Nigel Williams8,
  13. David J Burn9,
  14. Thomas Foltynie10,
  15. Huw R Morris11,
  16. Nicholas W Wood12,
  17. Donald G Grosset5,
  18. Michele T M Hu2,3
  1. 1 Department of Population Health Sciences, University of Bristol, Bristol, UK
  2. 2 Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, University of Oxford, Oxford, UK
  3. 3 Oxford Parkinson’s Disease Centre, University of Oxford, Oxford, UK
  4. 4 Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK
  5. 5 Department of Neurology, Institute of Neurological Sciences, Glasgow, UK
  6. 6 Department of Neurology, Queen’s Medical Centre, Nottingham, UK
  7. 7 Clinical Neurosciences, John van Geest Centre for Brain Repair, Cambridge, UK
  8. 8 Cardiff University, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff, UK
  9. 9 Faculty of Medical Sciences, Newcastle University, Newcastle, UK
  10. 10 Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London, UK
  11. 11 Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK
  12. 12 Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
  1. Correspondence to Michael Lawton, Department of Population Health Sciences, Canynge Hall, 39 Whatley Road, University of Bristol, Bristol BS8 2PS, UK; Michael.Lawton{at}bristol.ac.uk

Abstract

Objectives To use a data-driven approach to determine the existence and natural history of subtypes of Parkinson’s disease (PD) using two large independent cohorts of patients newly diagnosed with this condition.

Methods 1601 and 944 patients with idiopathic PD, from Tracking Parkinson’s and Discovery cohorts, respectively, were evaluated in motor, cognitive and non-motor domains at the baseline assessment. Patients were recently diagnosed at entry (within 3.5 years of diagnosis) and were followed up every 18 months. We used a factor analysis followed by a k-means cluster analysis, while prognosis was measured using random slope and intercept models.

Results We identified four clusters: (1)  fast motor progression with symmetrical motor disease, poor olfaction, cognition and postural hypotension; (2) mild motor and non-motor disease with intermediate motor progression; (3) severe motor disease, poor psychological well-being and  poor sleep with an intermediate motor progression; (4) slow motor progression with tremor-dominant, unilateral disease. Clusters were moderately to substantially stable across the two cohorts (kappa 0.58). Cluster 1 had the fastest motor progression in Tracking Parkinson’s at 3.2 (95% CI 2.8 to 3.6) UPDRS III points per year while cluster 4 had the slowest at 0.6 (0.1–1.1). In Tracking Parkinson’s, cluster 2 had the largest response to levodopa 36.3% and cluster 4 the lowest 28.8%.

Conclusions We have found four novel clusters that replicated well across two independent early PD cohorts and were associated with levodopa response and motor progression rates. This has potential implications for better understanding disease pathophysiology and the relevance of patient stratification in future clinical trials.

This is an Open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

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Footnotes

  • DGG and MTMH are joint senior authors.

  • DGG and MTMH contributed equally.

  • Contributors ML: analysis and interpretation of the data, writing of the manuscript. YB-S: study concept and design, analysis and interpretation of the data, revision of the manuscript. MTY: analysis and interpretation of the data, revision of the manuscript. FB: acquisition of data, revision of the manuscript. TRB: acquisition of data, revision of the manuscript. JCK: acquisition of data, revision of the manuscript. DMAS: acquisition of data, revision of the manuscript. NM: acquisition of data, revision of the manuscript. KAG: study concept and design, acquisition of data, revision of the manuscript. NB: study concept and design, acquisition of data, revision of the manuscript. RAB: study concept and design, acquisition of data, revision of the manuscript. NW: study concept and design, revision of the manuscript. DJB: study concept and design, acquisition of data, revision of the manuscript. TF: study concept and design, acquisition of data, revision of the manuscript. HRM: study concept and design, acquisition of data, revision of the manuscript. NWW: study concept and design, revision of the manuscript. DGG: study concept and design, acquisition of data, revision of the manuscript. MT-MH: study concept and design, acquisition of data, revision of the manuscript.

  • Funding The Oxford Discovery study was funded by the Monument Trust Discovery Award from Parkinson’s UK and supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford, and the NIHR Clinical Research Network: Thames Valley and South Midlands. The Tracking Parkinson’s study was funded by Parkinson’s UK and supported by the National Institute for Health Research (NIHR) DeNDRoN network, the NIHR Newcastle Biomedical Research Unit based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, and the NIHR-funded Biomedical Research Centre in Cambridge.

  • Disclaimer The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

  • Competing interests NB has received payment for advisory board attendance from UCB, Teva Lundbeck, Britannia, GSK, Boehringer and honoraria from UCB Pharma, GE Healthcare, Lily Pharma and Medtronic. He has received research grant support from GE Healthcare, Wellcome Trust, MRC and Parkinson’s UK and royalties from Wiley. RAB received grants from Parkinson’s UK, NIHR, Cure Parkinson’s Trust, Evelyn Trust, Rosetrees Trust, MRC and EU along with payment for advisory board attendance from Oxford Biomedica and LCT, and honoraria from Wiley and Springer. DJB received grants from NIHR, Wellcome Trust, GlaxoSmithKline Ltd, Parkinson’s UK and Michael J Fox Foundation. TF received payment for advisory board meetings for Abbvie and Oxford Biomedica, and honoraria for presentations at meetings sponsored by Medtronic, St Jude Medical, Britannia and Teva pharmaceuticals. HRM has received grants from Parkinson’s UK, grants from Medical Research Council UK, during the conduct of the study; grants from Welsh Assembly Government, personal fees from Teva, personal fees from Abbvie, personal fees from Teva, personal fees from UCB, personal fees from Boerhinger-Ingelheim, personal fees from GSK, non-financial support from Teva, grants from Ipsen Fund, non-financial support from Medtronic, grants from MNDA, grants from PSP Association, grants from CBD Solutions, grants from Drake Foundation and personal fees from Acorda, outside the submitted work. In addition, HRM has a patent and is a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140) pending. DGG received payment for advisory board attendance from AbbVie and honoraria from UCB Pharma, GE Healthcare and Acorda.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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