{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T22:44:04Z","timestamp":1784241844968,"version":"3.55.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T00:00:00Z","timestamp":1654128000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T00:00:00Z","timestamp":1654128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["npj Parkinsons Dis."],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Prognosis of patients with parkinsonism varies greatly between the various parkinsonian syndromes. However, it is often difficult to distinguish the different forms, particularly in early stages. We examined predictors of mortality and functional outcome in patients with recent-onset parkinsonism with an initially uncertain diagnosis (<jats:italic>n<\/jats:italic>\u2009=\u2009156). Patients were recruited between 2003 and 2006, comprehensively investigated, and followed prospectively (up to 15 years, mean 7 years). A final clinical diagnosis was established after follow-up. Independent predictors of mortality were investigated with multivariable Cox regression and combined into a simple prediction model. Model performance to predict 5- and 10-year mortality and functional outcome after 3 years was evaluated and externally validated in a second cohort of 62 patients with parkinsonism with an initially uncertain diagnosis. Ninety-one patients died (58%). Orthostatic hypotension, impaired cognition, abnormal tandem gait, and elevated neurofilament light chain concentration in serum or CSF were associated with mortality. A simple model that combined these factors showed excellent performance for prediction of functional outcome after 3 years and mortality after 5 and 10 years (<jats:italic>c<\/jats:italic>-statistic ~0.90 for all models). Model performance was confirmed after external validation: prediction of functional outcome after 3 years (<jats:italic>c<\/jats:italic>-statistic 0.89, 95% CI 0.80\u20130.98) and mortality after 5 years (<jats:italic>c<\/jats:italic>-statistic 0.91, 95% CI 0.84\u20130.99) were comparable to the results in the discovery cohort. These findings help clinicians to estimate a patient\u2019s prognosis, irrespective of the specific diagnosis.<\/jats:p>","DOI":"10.1038\/s41531-022-00329-4","type":"journal-article","created":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T10:06:52Z","timestamp":1654164412000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Factors associated with mortality in early stages of parkinsonism"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9093-041X","authenticated-orcid":false,"given":"Anouke","family":"van Rumund","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rianne A. J.","family":"Esselink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjolein B.","family":"Berrevoets-Aerts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4273-4267","authenticated-orcid":false,"given":"Markus","family":"Otto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6371-3337","authenticated-orcid":false,"given":"Bastiaan R.","family":"Bloem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4635-7876","authenticated-orcid":false,"given":"Marcel M.","family":"Verbeek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,6,2]]},"reference":[{"key":"329_CR1","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1212\/01.WNL.0000052991.70149.68","volume":"60","author":"U Nath","year":"2003","unstructured":"Nath, U., Ben-Shlomo, Y., Thomson, R. G., Lees, A. J. & Burn, D. J. Clinical features and natural history of progressive supranuclear palsy: a clinical cohort study. Neurology 60, 910\u2013916 (2003).","journal-title":"Neurology"},{"key":"329_CR2","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/S1474-4422(12)70327-7","volume":"12","author":"GK Wenning","year":"2013","unstructured":"Wenning, G. K. et al. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol. 12, 264\u2013274 (2013).","journal-title":"Lancet Neurol."},{"key":"329_CR3","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1212\/WNL.0000000000006576","volume":"91","author":"D Backstrom","year":"2018","unstructured":"Backstrom, D. et al. Early predictors of mortality in parkinsonism and Parkinson disease: a population-based study. Neurology 91, 2045\u20132056 (2018).","journal-title":"Neurology"},{"key":"329_CR4","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.parkreldis.2016.08.010","volume":"32","author":"S Fielding","year":"2016","unstructured":"Fielding, S., Macleod, A. D. & Counsell, C. E. Medium-term prognosis of an incident cohort of parkinsonian patients compared to controls. Parkinsonism Relat. Disord. 32, 36\u201341 (2016).","journal-title":"Parkinsonism Relat. Disord."},{"key":"329_CR5","doi-asserted-by":"publisher","first-page":"1615","DOI":"10.1002\/mds.25898","volume":"29","author":"AD Macleod","year":"2014","unstructured":"Macleod, A. D., Taylor, K. S. & Counsell, C. E. Mortality in Parkinson\u2019s disease: a systematic review and meta-analysis. Mov. Disord. 29, 1615\u20131622 (2014).","journal-title":"Mov. Disord."},{"key":"329_CR6","doi-asserted-by":"publisher","first-page":"e0230611","DOI":"10.1371\/journal.pone.0230611","volume":"15","author":"H Lennaerts-Kats","year":"2020","unstructured":"Lennaerts-Kats, H. et al. RADPAC-PD: A tool to support healthcare professionals in timely identifying palliative care needs of people with Parkinson\u2019s disease. PLoS ONE 15, e0230611 (2020).","journal-title":"PLoS ONE"},{"key":"329_CR7","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1002\/mds.27485","volume":"33","author":"TG Beach","year":"2018","unstructured":"Beach, T. G. & Adler, C. H. Importance of low diagnostic Accuracy for early Parkinson\u2019s disease. Mov. Disord. 33, 1551\u20131554 (2018).","journal-title":"Mov. Disord."},{"key":"329_CR8","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1093\/brain\/awf080","volume":"125","author":"AJ Hughes","year":"2002","unstructured":"Hughes, A. J., Daniel, S. E., Ben-Shlomo, Y. & Lees, A. J. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 125, 861\u2013870 (2002).","journal-title":"Brain"},{"key":"329_CR9","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1161\/CIRCULATIONAHA.105.598722","volume":"114","author":"KM Rose","year":"2006","unstructured":"Rose, K. M. et al. Orthostatic hypotension predicts mortality in middle-aged adults: the Atherosclerosis Risk In Communities (ARIC) Study. Circulation 114, 630\u2013636 (2006).","journal-title":"Circulation"},{"key":"329_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000255459","volume":"34","author":"KM Rose","year":"2010","unstructured":"Rose, K. M. et al. Orthostatic hypotension and cognitive function: the Atherosclerosis Risk in Communities Study. Neuroepidemiology 34, 1\u20137 (2010).","journal-title":"Neuroepidemiology"},{"key":"329_CR11","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1136\/jnnp.2006.091322","volume":"77","author":"WF Abdo","year":"2006","unstructured":"Abdo, W. F. et al. Ten steps to identify atypical parkinsonism. J. Neurol. Neurosurg. Psychiatry 77, 1367\u20131369 (2006).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"329_CR12","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1016\/j.parkreldis.2014.02.030","volume":"20","author":"LM de Lau","year":"2014","unstructured":"de Lau, L. M., Verbaan, D., Marinus, J. & van Hilten, J. J. Survival in Parkinson\u2019s disease. Relation with motor and non-motor features. Parkinsonism Relat. Disord. 20, 613\u2013616 (2014).","journal-title":"Parkinsonism Relat. Disord."},{"key":"329_CR13","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1002\/mds.20115","volume":"19","author":"BR Bloem","year":"2004","unstructured":"Bloem, B. R., Hausdorff, J. M., Visser, J. E. & Giladi, N. Falls and freezing of gait in Parkinson\u2019s disease: a review of two interconnected, episodic phenomena. Mov. Disord. 19, 871\u2013884 (2004).","journal-title":"Mov. Disord."},{"key":"329_CR14","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.jns.2005.03.015","volume":"233","author":"A Petzold","year":"2005","unstructured":"Petzold, A. Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss. J. Neurol. Sci. 233, 183\u2013198 (2005).","journal-title":"J. Neurol. Sci."},{"key":"329_CR15","doi-asserted-by":"publisher","first-page":"e1479","DOI":"10.1212\/WNL.0000000000007179","volume":"92","author":"TM Marques","year":"2019","unstructured":"Marques, T. M. et al. Serum NFL discriminates Parkinson disease from atypical parkinsonisms. Neurology 92, e1479\u2013e86 (2019).","journal-title":"Neurology"},{"key":"329_CR16","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1016\/j.neurobiolaging.2006.03.010","volume":"28","author":"WF Abdo","year":"2007","unstructured":"Abdo, W. F., Bloem, B. R., Van Geel, W. J., Esselink, R. A. & Verbeek, M. M. CSF neurofilament light chain and tau differentiate multiple system atrophy from Parkinson\u2019s disease. Neurobiol. Aging 28, 742\u2013747 (2007).","journal-title":"Neurobiol. Aging"},{"key":"329_CR17","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1212\/WNL.0000000000003699","volume":"88","author":"G Alves","year":"2017","unstructured":"Alves, G. & Bonanni, L. Neurofilament light: a heavyweight diagnostic biomarker in neurodegenerative parkinsonism? Neurology 88, 922\u2013923 (2017).","journal-title":"Neurology"},{"key":"329_CR18","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.jns.2015.03.041","volume":"352","author":"W Sako","year":"2015","unstructured":"Sako, W., Murakami, N., Izumi, Y. & Kaji, R. Neurofilament light chain level in cerebrospinal fluid can differentiate Parkinson\u2019s disease from atypical parkinsonism: evidence from a meta-analysis. J. Neurol. Sci. 352, 84\u201387 (2015).","journal-title":"J. Neurol. Sci."},{"key":"329_CR19","doi-asserted-by":"publisher","first-page":"e1104","DOI":"10.1212\/WNL.0000000000008088","volume":"93","author":"CH Lin","year":"2019","unstructured":"Lin, C. H. et al. Blood NfL: a biomarker for disease severity and progression in Parkinson disease. Neurology 93, e1104\u2013e11 (2019).","journal-title":"Neurology"},{"key":"329_CR20","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1007\/s00415-014-7568-4","volume":"262","author":"MB Aerts","year":"2015","unstructured":"Aerts, M. B. et al. Ancillary investigations to diagnose parkinsonism: a prospective clinical study. J. Neurol. 262, 346\u2013356 (2015).","journal-title":"J. Neurol."},{"key":"329_CR21","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1002\/sim.7992","volume":"38","author":"RD Riley","year":"2019","unstructured":"Riley, R. D. et al. Minimum sample size for developing a multivariable prediction model: PART II\u2014binary and time-to-event outcomes. Stat. Med. 38, 1276\u20131296 (2019).","journal-title":"Stat. Med"},{"key":"329_CR22","doi-asserted-by":"publisher","first-page":"m441","DOI":"10.1136\/bmj.m441","volume":"368","author":"RD Riley","year":"2020","unstructured":"Riley, R. D. et al. Calculating the sample size required for developing a clinical prediction model. BMJ 368, m441 (2020).","journal-title":"BMJ"},{"key":"329_CR23","doi-asserted-by":"publisher","DOI":"10.1186\/s12883-018-1072-x","volume":"18","author":"A van Rumund","year":"2018","unstructured":"van Rumund, A. et al. Parkinson\u2019s Disease Diagnostic Observations (PADDO): study rationale and design of a prospective cohort study for early differentiation of parkinsonism. BMC Neurol. 18, 69 (2018).","journal-title":"BMC Neurol."},{"key":"329_CR24","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1212\/WNL.17.5.427","volume":"17","author":"MM Hoehn","year":"1967","unstructured":"Hoehn, M. M. & Yahr, M. D. Parkinsonism: onset, progression and mortality. Neurology 17, 427\u2013442 (1967).","journal-title":"Neurology"},{"key":"329_CR25","unstructured":"Fahn, S. & Elton, R. Unified Parkinson\u2019s Disease Rating Scale. Macmillan Healthc. Inf. 153\u2013163, 293\u2013304 (1987)."},{"key":"329_CR26","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/S0022-510X(96)00231-6","volume":"145","author":"P Trouillas","year":"1997","unstructured":"Trouillas, P. et al. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J. Neurol. Sci. 145, 205\u2013211 (1997).","journal-title":"J. Neurol. Sci."},{"key":"329_CR27","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/0022-3956(75)90026-6","volume":"12","author":"MF Folstein","year":"1975","unstructured":"Folstein, M. F., Folstein, S. E. & McHugh, P. R. Mini-mental state\u201d. A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12, 189\u201398 (1975).","journal-title":"J. Psychiatr. Res"},{"key":"329_CR28","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1002\/ana.25447","volume":"85","author":"A van Rumund","year":"2019","unstructured":"van Rumund, A. et al. alpha-Synuclein real-time quaking-induced conversion in the cerebrospinal fluid of uncertain cases of parkinsonism. Ann. Neurol. 85, 777\u201381 (2019).","journal-title":"Ann. Neurol."},{"key":"329_CR29","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1136\/jnnp.55.3.181","volume":"55","author":"AJ Hughes","year":"1992","unstructured":"Hughes, A. J., Daniel, S. E., Kilford, L. & Lees, A. J. Accuracy of clinical diagnosis of idiopathic Parkinson\u2019s disease: a clinico-pathological study of 100 cases. J. Neurol. Neurosurg. Psychiatry 55, 181\u2013184 (1992).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"329_CR30","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1212\/01.wnl.0000324625.00404.15","volume":"71","author":"S Gilman","year":"2008","unstructured":"Gilman, S. et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71, 670\u2013676 (2008).","journal-title":"Neurology"},{"key":"329_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1212\/WNL.47.1.1","volume":"47","author":"I Litvan","year":"1996","unstructured":"Litvan, I. et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 47, 1\u20139 (1996).","journal-title":"Neurology"},{"key":"329_CR32","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1002\/mds.20083","volume":"19","author":"JC Zijlmans","year":"2004","unstructured":"Zijlmans, J. C., Daniel, S. E., Hughes, A. J., Revesz, T. & Lees, A. J. Clinicopathological investigation of vascular parkinsonism, including clinical criteria for diagnosis. Mov. Disord. 19, 630\u2013640 (2004).","journal-title":"Mov. Disord."},{"key":"329_CR33","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1002\/mds.26424","volume":"30","author":"RB Postuma","year":"2015","unstructured":"Postuma, R. B. et al. MDS clinical diagnostic criteria for Parkinson\u2019s disease. Mov. Disord. 30, 1591\u20131601 (2015).","journal-title":"Mov. Disord."},{"key":"329_CR34","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1002\/mds.26987","volume":"32","author":"GU Hoglinger","year":"2017","unstructured":"Hoglinger, G. U. et al. Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Mov. Disord. 32, 853\u2013864 (2017).","journal-title":"Mov. Disord."},{"key":"329_CR35","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.parkreldis.2017.12.030","volume":"49","author":"I Rektor","year":"2017","unstructured":"Rektor, I. et al. An updated diagnostic approach to subtype definition of vascular parkinsonism-recommendations from an expert working group. Parkinsonism Relat. Disord. 49, 9\u201316 (2017).","journal-title":"Parkinsonism Relat. Disord"},{"key":"329_CR36","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1093\/biomet\/69.1.239","volume":"69","author":"D Schoenfeld","year":"1982","unstructured":"Schoenfeld, D. Partial residuals for the proportional hazards regression model. Biometrika 69, 239\u201341 (1982).","journal-title":"Biometrika"},{"key":"329_CR37","doi-asserted-by":"publisher","first-page":"55","DOI":"10.7326\/M14-0697","volume":"162","author":"GS Collins","year":"2015","unstructured":"Collins, G. S., Reitsma, J. B., Altman, D. G. & Moons, K. G. Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): the TRIPOD statement. Ann. Intern. Med. 162, 55\u201363 (2015).","journal-title":"Ann. Intern. Med."}],"container-title":["npj Parkinson's Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41531-022-00329-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41531-022-00329-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41531-022-00329-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T19:11:41Z","timestamp":1669317101000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41531-022-00329-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,2]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["329"],"URL":"https:\/\/doi.org\/10.1038\/s41531-022-00329-4","relation":{},"ISSN":["2373-8057"],"issn-type":[{"value":"2373-8057","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,2]]},"assertion":[{"value":"13 July 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 April 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 June 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"67"}}