{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T18:28:59Z","timestamp":1793816939256,"version":"4.6.1"},"reference-count":47,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"unspecified","delay-in-days":29,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2023M730742"],"award-info":[{"award-number":["2023M730742"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key Research and Development Program of Guangzhou","award":["202206010086"],"award-info":[{"award-number":["202206010086"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82071419"],"award-info":[{"award-number":["82071419"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82301663"],"award-info":[{"award-number":["82301663"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2025,7,11]]},"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Parkinson\u2019s disease (PD) is a progressive neurodegenerative disorder characterised by heterogeneous motor and non-motor symptoms. The classification of PD into distinct subtypes remains a major challenge, limiting the development of precision medicine approaches. Existing subtyping methods have relied on clinical features, genetic markers or isolated biomarkers, but an integrated classification system incorporating neuroimaging and fluid biomarkers is lacking. The Prospective Assessments with Neuroimaging and fluid Data Analysis in PD (PANDA) study is a single-centre, longitudinal cohort study designed to explore PD heterogeneity by integrating multimodal neuroimaging, fluid biomarkers and comprehensive clinical assessments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>The PANDA study aims to recruit 500 PD patients and 100 healthy controls (HC) at Guangdong Provincial People\u2019s Hospital from March 2021 to July 2026. Participants undergo three study visits: baseline, 2-year and 4-year follow-ups. Data collection includes brain MRI scans, blood and cerebrospinal fluid sampling, clinical scales, gait assessment, ambulatory blood pressure monitoring and eye-tracking evaluations. A standardised electronic data capture system ensures data accuracy and completeness. The primary objective is to identify biologically and neuroimaging-defined PD subtypes, track disease progression and explore potential biomarkers for stratification. Statistical analyses will include data-driven clustering techniques and longitudinal modelling to assess subtype stability over time.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The PANDA study has been approved by the Institutional Review Board of Guangdong Provincial People\u2019s Hospital (No KY2024-719-01) and is conducted in accordance with the Declaration of Helsinki. Written informed consent is obtained from all participants or their legal guardians prior to study enrolment. The findings from this study will be disseminated through peer-reviewed journals and conference presentations, ensuring accessibility to researchers, clinicians and stakeholders involved in PD research and treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>ChiCTR2400091709.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2025-102417","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T11:20:44Z","timestamp":1753874444000},"page":"e102417","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["PANDA study: subtyping of Parkinson\u2019s disease \u2013 cohort study protocol"],"prefix":"10.1136","volume":"15","author":[{"given":"Rui","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"},{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chentao","family":"He","sequence":"additional","affiliation":[{"name":"Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siming","family":"Rong","sequence":"additional","affiliation":[{"name":"Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"},{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqi","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8919-2217","authenticated-orcid":false,"given":"Zihao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qibing","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xilie","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengfei","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3492-4669","authenticated-orcid":false,"given":"Yuhu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"},{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"2025121605021804000_15.7.e102417.1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(21)00218-x"},{"key":"2025121605021804000_15.7.e102417.2","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2019-322338"},{"key":"2025121605021804000_15.7.e102417.3","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41531-022-00307-w","article-title":"Redefining the hypotheses driving Parkinson\u2019s diseases research","volume":"8","author":"Farrow","year":"2022","journal-title":"npj Parkinsons Dis"},{"key":"2025121605021804000_15.7.e102417.4","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1080\/10408363.2024.2331471","article-title":"Unveiling Parkinson\u2019s disease through biomarker research: current insights and future prospects","volume":"61","author":"Durmaz Celik","year":"2024","journal-title":"Crit Rev Clin Lab Sci"},{"key":"2025121605021804000_15.7.e102417.5","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2016.196"},{"key":"2025121605021804000_15.7.e102417.6","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00061-2"},{"key":"2025121605021804000_15.7.e102417.7","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1007\/s13311-020-00894-7","article-title":"Therapy of Parkinson\u2019s Disease Subtypes","volume":"17","author":"Marras","year":"2020","journal-title":"Neurotherapeutics"},{"key":"2025121605021804000_15.7.e102417.8","doi-asserted-by":"publisher","DOI":"10.1016\/s1474-4422(23)00109-6"},{"key":"2025121605021804000_15.7.e102417.9","doi-asserted-by":"publisher","DOI":"10.1016\/s1474-4422(19)30024-9"},{"key":"2025121605021804000_15.7.e102417.10","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41531-021-00241-3","article-title":"Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson\u2019s disease enrolled in PPMI","volume":"7","author":"Huh","year":"2021","journal-title":"npj Parkinsons Dis"},{"key":"2025121605021804000_15.7.e102417.11","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s00702-016-1650-2","article-title":"Relationship between the plasma levels of neurodegenerative proteins and motor subtypes of Parkinson\u2019s disease","volume":"124","author":"Ding","year":"2017","journal-title":"J Neural Transm (Vienna)"},{"key":"2025121605021804000_15.7.e102417.12","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26913"},{"key":"2025121605021804000_15.7.e102417.13","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00405-2"},{"key":"2025121605021804000_15.7.e102417.14","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00404-0"},{"key":"2025121605021804000_15.7.e102417.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0221-2"},{"key":"2025121605021804000_15.7.e102417.16","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1007\/s00259-022-06104-0","article-title":"18F-Florzolotau PET imaging captures the distribution patterns and regional vulnerability of tau pathology in progressive supranuclear palsy","volume":"50","author":"Liu","year":"2023","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"2025121605021804000_15.7.e102417.17","doi-asserted-by":"crossref","unstructured":"Cai M , He C , Li H , et al . Advanced brain aging, selective vulnerability in gray matter, and cognition in Parkinson\u2019s disease. J Gerontol A Biol Sci Med Sci 2025.:glaf124. doi:10.1093\/gerona\/glaf124","DOI":"10.1093\/gerona\/glaf124"},{"key":"2025121605021804000_15.7.e102417.18","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.nicl.2018.01.009","article-title":"Regional expression of genes mediating trans-synaptic alpha-synuclein transfer predicts regional atrophy in Parkinson disease","volume":"18","author":"Freeze","year":"2018","journal-title":"Neuroimage Clin"},{"key":"2025121605021804000_15.7.e102417.19","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pbio.3000495","article-title":"Local vulnerability and global connectivity jointly shape neurodegenerative disease propagation","volume":"17","author":"Zheng","year":"2019","journal-title":"PLoS Biol"},{"key":"2025121605021804000_15.7.e102417.20","first-page":"e300","article-title":"Association of Cortical and Subcortical Microstructure With Clinical Progression and Fluid Biomarkers in Patients With Parkinson Disease","volume":"101","author":"Wang","year":"2023","journal-title":"Neurology (ECronicon)"},{"key":"2025121605021804000_15.7.e102417.21","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26424"},{"key":"2025121605021804000_15.7.e102417.22","doi-asserted-by":"publisher","DOI":"10.1002\/mds.22340"},{"key":"2025121605021804000_15.7.e102417.23","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1007\/s00702-010-0424-5","article-title":"The wearing-off phenomenon and the use of questionnaires to facilitate its recognition in Parkinson\u2019s disease","volume":"117","author":"Stacy","year":"2010","journal-title":"J Neural Transm (Vienna)"},{"key":"2025121605021804000_15.7.e102417.24","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(06)70373-8"},{"key":"2025121605021804000_15.7.e102417.25","doi-asserted-by":"publisher","DOI":"10.1002\/mds.24893"},{"key":"2025121605021804000_15.7.e102417.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2023.11.001"},{"key":"2025121605021804000_15.7.e102417.27","doi-asserted-by":"crossref","first-page":"105316","DOI":"10.1016\/j.parkreldis.2023.105316","article-title":"Classification and staging of Parkinson\u2019s disease using video-based eye tracking","volume":"110","author":"Brien","year":"2023","journal-title":"Parkinsonism & Related Disorders"},{"key":"2025121605021804000_15.7.e102417.28","doi-asserted-by":"crossref","DOI":"10.1007\/s40520-025-03089-2","article-title":"Eye movement parameters as biomarkers for diagnosis and levodopa responsiveness in patients with Parkinson\u2019s disease","volume":"37","author":"Luo","year":"2025","journal-title":"Aging Clin Exp Res"},{"key":"2025121605021804000_15.7.e102417.29","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1002\/alz.13517","article-title":"A detection model of cognitive impairment via the integrated gait and eye movement analysis from a large Chinese community cohort","volume":"20","author":"Lin","year":"2024","journal-title":"Alzheimer's &amp; Dementia"},{"key":"2025121605021804000_15.7.e102417.30","doi-asserted-by":"publisher","DOI":"10.1067\/mob.2002.125704"},{"key":"2025121605021804000_15.7.e102417.31","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.b2393","article-title":"Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls","volume":"338","author":"Sterne","year":"2009","journal-title":"BMJ"},{"key":"2025121605021804000_15.7.e102417.32","doi-asserted-by":"crossref","first-page":"102603","DOI":"10.1016\/j.pneurobio.2024.102603","article-title":"The STRAT-PARK cohort: A personalized initiative to stratify Parkinson\u2019s disease","volume":"236","author":"Stige","year":"2024","journal-title":"Prog Neurobiol"},{"key":"2025121605021804000_15.7.e102417.33","doi-asserted-by":"crossref","DOI":"10.1186\/s12883-019-1394-3","article-title":"The Personalized Parkinson Project: examining disease progression through broad biomarkers in early Parkinson\u2019s disease","volume":"19","author":"Bloem","year":"2019","journal-title":"BMC Neurol"},{"key":"2025121605021804000_15.7.e102417.34","doi-asserted-by":"crossref","DOI":"10.3389\/fnagi.2018.00326","article-title":"The Luxembourg Parkinson\u2019s Study: A Comprehensive Approach for Stratification and Early Diagnosis","volume":"10","author":"Hipp","year":"2018","journal-title":"Front Aging Neurosci"},{"key":"2025121605021804000_15.7.e102417.35","doi-asserted-by":"publisher","DOI":"10.1002\/mds.29683"},{"key":"2025121605021804000_15.7.e102417.36","doi-asserted-by":"crossref","DOI":"10.1186\/s40478-021-01282-8","article-title":"High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson\u2019s disease","volume":"9","author":"Russo","year":"2021","journal-title":"Acta Neuropathol Commun"},{"key":"2025121605021804000_15.7.e102417.37","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1002\/mds.27646","article-title":"Comparative study of cerebrospinal fluid \u03b1-synuclein seeding aggregation assays for diagnosis of Parkinson\u2019s disease","volume":"34","author":"Kang","year":"2019","journal-title":"Mov Disord"},{"key":"2025121605021804000_15.7.e102417.38","doi-asserted-by":"crossref","DOI":"10.1186\/s40035-019-0155-y","article-title":"Erythrocytic \u03b1-Synuclein as a potential biomarker for Parkinson\u2019s disease","volume":"8","author":"Tian","year":"2019","journal-title":"Transl Neurodegener"},{"key":"2025121605021804000_15.7.e102417.39","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28639"},{"key":"2025121605021804000_15.7.e102417.40","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2019-322588"},{"key":"2025121605021804000_15.7.e102417.41","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1001\/jamaneurol.2023.4398","article-title":"Neuronally Derived Extracellular Vesicle \u03b1-Synuclein as a Serum Biomarker for Individuals at Risk of Developing Parkinson Disease","volume":"81","author":"Yan","year":"2024","journal-title":"JAMA Neurol"},{"key":"2025121605021804000_15.7.e102417.42","doi-asserted-by":"crossref","unstructured":"Kalluri R , LeBleu VS . The biology, function, and biomedical applications of exosomes. Science 2020;367.","DOI":"10.1126\/science.aau6977"},{"key":"2025121605021804000_15.7.e102417.43","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(16)30291-5"},{"key":"2025121605021804000_15.7.e102417.44","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-023-32480-0","article-title":"Evaluation of plasma levels of NFL, GFAP, UCHL1 and tau as Parkinson\u2019s disease biomarkers using multiplexed single molecule counting","volume":"13","author":"Youssef","year":"2023","journal-title":"Sci Rep"},{"key":"2025121605021804000_15.7.e102417.45","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1002\/mds.26578","article-title":"Longitudinal Measurements of Cerebrospinal Fluid Biomarkers in Parkinson\u2019s Disease","volume":"31","author":"Hall","year":"2016","journal-title":"Mov Disord"},{"key":"2025121605021804000_15.7.e102417.46","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1212\/WNL.0000000000004609","article-title":"Longitudinal CSF biomarkers in patients with early Parkinson disease and healthy controls","volume":"89","author":"Mollenhauer","year":"2017","journal-title":"Neurology (ECronicon)"},{"key":"2025121605021804000_15.7.e102417.47","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-024-00806-0"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2025-102417","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T13:02:28Z","timestamp":1765890148000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2025-102417"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7]]},"references-count":47,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7,30]]},"published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1136\/bmjopen-2025-102417"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2025-102417","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7]]}}}