[en] Parkinson's disease is the second most common neurodegenerative disease. Despite this, there are no robust biomarkers to predict progression, and understanding of disease mechanisms is limited. We used the Subtype and Stage Inference algorithm to characterize Parkinson's disease heterogeneity in terms of spatiotemporal subtypes of macroscopic atrophy detectable on T1-weighted MRI-a successful approach used in other neurodegenerative diseases. We trained the model on covariate-adjusted cortical thicknesses and subcortical volumes from the largest known T1-weighted MRI dataset in Parkinson's disease, Enhancing Neuroimaging through Meta-Analysis consortium Parkinson's Disease dataset (n = 1100 cases). We tested the model by analyzing clinical progression over up to 9 years in openly-available data from people with Parkinson's disease from the Parkinson's Progression Markers Initiative (n = 584 cases). Under cross-validation, our analysis supported three spatiotemporal atrophy subtypes, named for the location of the earliest affected regions as: 'Subcortical' (n = 359, 33%), 'Limbic' (n = 237, 22%) and 'Cortical' (n = 187, 17%). A fourth subgroup having sub-threshold/no atrophy was named 'Sub-threshold atrophy' (n = 317, 29%). Statistical differences in clinical scores existed between the no-atrophy subgroup and the atrophy subtypes, but not among the atrophy subtypes. This suggests that the prime T1-weighted MRI delineator of clinical differences in Parkinson's disease is atrophy severity, rather than atrophy location. Future work on unravelling the biological and clinical heterogeneity of Parkinson's disease should leverage more sensitive neuroimaging modalities and multimodal data.
Disciplines :
Neurology Radiology, nuclear medicine & imaging
Author, co-author :
Shawa, Zeena ; UCL Hawkes Institute and Department of Medical Physics and Biomedical Engineering, University College London, London WC1E 6BT, United Kingdom
Shand, Cameron; UCL Hawkes Institute and Department of Computer Science, University College London, London WC1E 6BT, United Kingdom
Taylor, Beatrice ; UCL Hawkes Institute and Department of Computer Science, University College London, London WC1E 6BT, United Kingdom
Berendse, Henk W; Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Neurodegeneration, 1081 Amsterdam, The Netherlands
Vriend, Chris; Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands ; Department of Anatomy & Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Compulsivity Impulsivity & Attention, 1081 Amsterdam, The Netherlands
van Balkom, Tim D; Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands ; Department of Anatomy & Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Compulsivity Impulsivity & Attention, 1081 Amsterdam, The Netherlands
van den Heuvel, Odile A; Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands ; Department of Anatomy & Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Compulsivity Impulsivity & Attention, 1081 Amsterdam, The Netherlands
van der Werf, Ysbrand D; Department of Anatomy & Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Compulsivity Impulsivity & Attention, 1081 Amsterdam, The Netherlands
Wang, Jiun-Jie ; Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan 33302, Taiwan ; Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Keelung 204, Taiwan
Tsai, Chih-Chien; Healthy Aging Research Center, Chang Gung University, Taoyuan 33302, Taiwan
Druzgal, Jason; Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22903, USA
Newman, Benjamin T ; Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22903, USA
Melzer, Tracy R; Department of Medicine, University of Otago, Christchurch 8011, New Zealand ; New Zealand Brain Research Institute, Christchurch 8011, New Zealand ; Te Kura Mahi ā-Hirikapo, School of Psychology, Speech and Hearing, University of Canterbury, Christchurch 8041, New Zealand
Pitcher, Toni L; Department of Medicine, University of Otago, Christchurch 8011, New Zealand ; New Zealand Brain Research Institute, Christchurch 8011, New Zealand
Dalrymple-Alford, John C; Department of Medicine, University of Otago, Christchurch 8011, New Zealand ; New Zealand Brain Research Institute, Christchurch 8011, New Zealand ; Te Kura Mahi ā-Hirikapo, School of Psychology, Speech and Hearing, University of Canterbury, Christchurch 8041, New Zealand
Anderson, Tim J; Department of Medicine, University of Otago, Christchurch 8011, New Zealand ; New Zealand Brain Research Institute, Christchurch 8011, New Zealand ; Department of Neurology, Christchurch Hospital, Te Whatu Ora Health NZ, Waitaha Canterbury 8140, New Zealand
Garraux, Gaëtan ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biochimie et physiologie du système nerveux
Rango, Mario; Neurology Unit, Excellence Interdepartmental Center for Advanced Magnetic Resonance Techniques, Fondazione Ca' Granda, IRCCS, Policlinico, University of Studies of Milano, Milano 20122, Italy
Schwingenschuh, Petra; Department of Neurology, Medical University of Graz, 8036 Graz, Austria
Suette, Melanie; Department of Neurology, Medical University of Graz, 8036 Graz, Austria
Parkes, Laura M ; Division of Psychology, Communication and Human Neuroscience, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK ; Geoffrey Jefferson Brain Research Centre, Faculty of Biology, Medicine and Health, University of Manchester, Salford M6 8HD, UK
Al-Bachari, Sarah; Department of Clinical and Movement Neurosciences, UCL, London WC1E 6BT, UK
Klein, Johannes ; Nuffield Department of Clinical Neurosciences (NDCN), University of Oxford, Oxford OX3 9DU, UK
Hu, Michele T M ; Nuffield Department of Clinical Neurosciences (NDCN), University of Oxford, Oxford OX3 9DU, UK
McMillan, Corey T; Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, United States
Piras, Fabrizio; Laboratory of Neuropsychiatry, Department of Clinical Neuroscience and Neurorehabilitation, Santa Lucia Foundation IRCCS, 00179 Rome, Italy
Vecchio, Daniela; Laboratory of Neuropsychiatry, Department of Clinical Neuroscience and Neurorehabilitation, Santa Lucia Foundation IRCCS, 00179 Rome, Italy
Pellicano, Clelia; Laboratory of Neuropsychiatry, Department of Clinical Neuroscience and Neurorehabilitation, Santa Lucia Foundation IRCCS, 00179 Rome, Italy
Zhang, Chengcheng ; Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Clinical Neuroscience Center, Shanghai 200031, China
Poston, Kathleen L; Department of Neurology & Neurological Sciences, Stanford University, Stanford, Palo Alto, CA 94304, USA
Ghasemi, Elnaz; Department of Neurology & Neurological Sciences, Stanford University, Stanford, Palo Alto, CA 94304, USA
Cendes, Fernando; Department of Neurology, University of Campinas-UNICAMP, Campinas 13083-872, Brazil ; Brazilian Institute of Neuroscience and Neurotechnology, University of Campinas-UNICAMP, Campinas 13083-888, Brazil
Yasuda, Clarissa L; Department of Neurology, University of Campinas-UNICAMP, Campinas 13083-872, Brazil ; Brazilian Institute of Neuroscience and Neurotechnology, University of Campinas-UNICAMP, Campinas 13083-888, Brazil
Tosun, Duygu ; Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA
Mosley, Philip; QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
Thompson, Paul M; Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging & Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Jahanshad, Neda; Laboratory of Brain eScience, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90292, USA
Owens-Walton, Conor; Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging & Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
d'Angremont, Emile; Department of Anatomy & Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Neurodegeneration, 1081 Amsterdam, The Netherlands
van Heese, Eva M; Department of Anatomy & Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Neurodegeneration, 1081 Amsterdam, The Netherlands
Laansma, Max A ; Department of Anatomy & Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Neurodegeneration, 1081 Amsterdam, The Netherlands
Altmann, Andre ; UCL Hawkes Institute and Department of Medical Physics and Biomedical Engineering, University College London, London WC1E 6BT, United Kingdom
ENIGMA Parkinson’s Disease Working Group
Weil, Rimona S ; Dementia Research Centre, Department of Neurodegeneration, UCL Queen Square Institute of Neurology, University College London, London W1T 7NF, United Kingdom
Oxtoby, Neil P ; UCL Hawkes Institute and Department of Computer Science, University College London, London WC1E 6BT, United Kingdom
EPSRC - Engineering and Physical Sciences Research Council UCL - University College London NIHR - National Institute for Health and Care Research University College London Hospitals NHS Foundation Trust UKRI - UK Research and Innovation ESRC - Economic and Social Research Council MJFF - Michael J. Fox Foundation for Parkinson's Research NIA - National Institute on Aging NINDS - National Institute of Neurological Disorders and Stroke NIH - National Institutes of Health HRC - Health Research Council of New Zealand CMRF - Canterbury Medical Research Foundation Neurological Foundation of New Zealand University of Otago. Division of Health Sciences Italian Ministry of Health NIHR - National Institute for Health and Care Research
Funding text :
Z.S. is supported by the Engineering and Physical Sciences Research Council (EPSRC) funded University College London (UCL) Centre for Doctoral Training in Intelligent, Integrated Imaging in Healthcare (i4health) (EP/S021930/ 1) and the Department of Health’s National Institute for Health and Care Research (NIHR) funded University College London Hospitals Biomedical Research Centre. N.P.O. and C.S. acknowledge funding from the UK Research and Innovation (UKRI), Medical Research Council via NO’s Future Leaders Fellowship (MRC MR/ S03546X/1). R.S.W. is supported by a Wellcome Career Development Award (#225263/Z/22/Z) and by the University College London Hospitals Biomedical Research Centre. Z.S. is grateful for advice and input from UCL’s Progression of Neurodegenerative Disease (POND) group —especially B.T. and Dr. Peter Wijeratne. A.A. and N.P.O. acknowledge support from the Early Detection of Alzheimer’s Disease Subtypes (E-DADS) project (JPND 2019; MR/T046422/1). B.T. is supported by the Economic and Social Research Council (ESRC) funded UCL, Bloomsbury and East London Doctoral Training Partnership (UBEL-DTP) (ES/P000592/1). C.V. is supported by the Michael J. Fox Foundation for Parkinson’s Research (MJFF-022801). Y.D.v.d.W is supported by National Institute on Aging (NIA) (sub-award No. 1R01AG058854-01A1); National Institute of Neurological Disorders and Stroke (NINDS) (sub-award 1RO1NS107513-01A1); and the Michael J. Fox Foundation for Parkinson’s Research. J.D. is supported by the National Institutes of Health (NIH) (R01NS107513). T.R.M., T.L.P., J.C.D.-A., T.J.A., are all supported by the Health Research Council of New Zealand (14-440; 14-573), Canterbury Medical Research Foundation (12/ 01), Neurological Foundation of New Zealand (1635-PG), University of Otago Research Grant, Brain Research New Zealand. J.C.D.-A. is additionally supported by Health Research Council of New Zealand (20-538), Neurological Foundation of New Zealand (2232-PRG), and Research and Education Trust Pacific Radiology (MRIJDA). C.T.M. is supported by the National Institutes of Health (P01-AG084497). F.P. and D.V. are supported by the Italian Ministry of Health (PNRR-MAD-2022-12375706 and RC 2024, respectively). K.L.P. is supported by the National Institutes of Health (R01 NS115114, P30 AG066515, P50 NS062684) and the Michael J. Fox Foundation for Parkinson’s Research. C.O.-W. is supported by the National Institutes of Health (R01NS107513). J.C.K. is supported by the National Institute for Health and Care
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Research (NIHR) Oxford Health Clinical Research Facility, and the NIHR Oxford Biomedical Research Centre. M.T.M.H. and the Oxford Discovery cohort (within Enhancing Neuroimaging through Meta-Analysis consortium Parkinson’s Disease (ENIGMA-PD)) are supported by Parkinson’s UK, Cure Parkinson’s Trust (CPT), and the NIHR Oxford Biomedical Research Centre. The Parkinson’s Progression Markers Initiative (PPMI)—a public-private partnership—is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson’s, AskBio, Avid Radiopharmaceuticals, BIAL, BioArctic, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Capsida Biotherapeutics, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Jazz Pharmaceuticals, Johnson & Johnson Innovative Medicine, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Neuron23, Neuropore, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager Therapeutics, the Weston Family Foundation and Yumanity Therapeutics.
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