{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T05:05:48Z","timestamp":1780635948586,"version":"3.54.1"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>While prospective cohort research in Parkinson\u2019s disease (PD) suggests a linear increase in motor disability, there is some clinico-pathological evidence for exponential progression in the final disease stage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Thirty-four patients with PD composed a long-term cohort. Defined\n                      <jats:italic>off<\/jats:italic>\n                      state with levodopa test dose motor scoring on a modified Webster disability scale and Mini-Mental State Examination (MMSE) were conducted every 3 years. Twenty-four patients had 2 or more assessments. For each progression segment, defined as the interval between consecutive assessments, motor progression was calculated as the annual percentage increase of maximum disability score. The entire disease duration is now known for all members of this cohort. Serial motor scores were aligned with time of death, permitting late and earlier observations to be separated for analysis. Progression segments were classified in 3 ways to capture the advanced stage of PD\u2014i) the final segment for each participant; ii) any segment that concluded within 5 years of death; iii) any segment that concluded with a MMSE score &amp;lt; 24. Each advanced category was compared with all other segments from the cohort.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Median age at death was 78.4. Mean disease duration was 14.5 years. Late\n                      <jats:italic>off<\/jats:italic>\n                      scores progressed twice as fast, and\n                      <jats:italic>on<\/jats:italic>\n                      scores three times as fast, as earlier disease segments (\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001 for all comparisons). Classification by presence of cognitive impairment had the strongest effect.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Progression of motor disability accelerates in advanced PD. It is possible that the entire disease course has an exponential character.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1788633","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T04:43:54Z","timestamp":1780634634000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Evidence for exponential progression in advanced Parkinson\u2019s disease: retrospective analysis of a prospective cohort study"],"prefix":"10.3389","volume":"17","author":[{"given":"Sophie Merve","family":"Yener","sequence":"first","affiliation":[{"name":"Neurosciences Department, Monash Medical Centre","place":["Melbourne, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Ding","sequence":"additional","affiliation":[{"name":"Neurosciences Department, Monash Medical Centre","place":["Melbourne, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganga","family":"Ganesvaran","sequence":"additional","affiliation":[{"name":"Neurosciences Department, Monash Medical Centre","place":["Melbourne, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane E.","family":"Alty","sequence":"additional","affiliation":[{"name":"Neurosciences Department, Monash Medical Centre","place":["Melbourne, VIC, Australia"]},{"name":"Tasmanian School of Medicine, University of Tasmania","place":["Hobart, TAS, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin G.","family":"Clissold","sequence":"additional","affiliation":[{"name":"Neurosciences Department, Monash Medical Centre","place":["Melbourne, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig D.","family":"McColl","sequence":"additional","affiliation":[{"name":"Neurosciences Department, Monash Medical Centre","place":["Melbourne, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrina A.","family":"Reardon","sequence":"additional","affiliation":[{"name":"Neurosciences Department, Monash Medical Centre","place":["Melbourne, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Schiff","sequence":"additional","affiliation":[{"name":"Neurosciences Department, Monash Medical Centre","place":["Melbourne, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A.","family":"Kempster","sequence":"additional","affiliation":[{"name":"Neurosciences Department, Monash Medical Centre","place":["Melbourne, VIC, Australia"]},{"name":"Department of Medicine, School of Clinical Sciences, Monash University","place":["Melbourne, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1452741","DOI":"10.3389\/fneur.2024.1452741","article-title":"Rate of motor progression in Parkinson\u2019s disease: a systematic review and meta-analysis","volume":"15","author":"Pauwels","year":"2024","journal-title":"Front Neurol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1093\/brain\/awq059","article-title":"Relationships between age and late progression of Parkinson's disease: a clinico-pathological study","volume":"133","author":"Kempster","year":"2010","journal-title":"Brain"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1002\/mds.26497","article-title":"Study of levodopa response in Parkinson\u2019s disease: observations on rates of motor progression","volume":"31","author":"Ding","year":"2016","journal-title":"Mov 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Relation to on-off phenomenon","volume":"49","author":"Nutt","year":"1992","journal-title":"Arch Neurol"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1212\/WNL.37.9.1539","article-title":"Does long-term aggravation of Parkinson\u2019s disease result from nondopaminergic lesions?","volume":"37","author":"Bonnet","year":"1987","journal-title":"Neurology"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.1002\/mds.26712","article-title":"Unmasking levodopa resistance in Parkinson\u2019s disease","volume":"31","author":"Nonnekes","year":"2016","journal-title":"Mov Disord"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1002\/mds.22340","article-title":"Movement Disorder Society-sponsored revision of the unified Parkinson\u2019s disease rating scale (MDS-UPDRS): scale presentation and clinimetric testing results","volume":"23","author":"Goetz","year":"2008","journal-title":"Mov Disord"},{"key":"ref27","first-page":"153","volume-title":"Recent Developments in Parkinson\u2019s Disease","author":"Fahn","year":"1987"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1212\/01.wnl.0000310812.43352.66","article-title":"Fourteen year final report of the randomized PDRG-UK trial comparing three initial treatments in PD","volume":"71","author":"Katzenschlager","year":"2008","journal-title":"Neurology"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1788633\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T04:44:03Z","timestamp":1780634643000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1788633\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,5]]},"references-count":28,"alternative-id":["10.3389\/fneur.2026.1788633"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2026.1788633","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,5]]},"article-number":"1788633"}}