{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T16:52:25Z","timestamp":1754153545928,"version":"3.41.2"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T00:00:00Z","timestamp":1753228800000},"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><jats:title>Objective<\/jats:title><jats:p>The study aimed to compare the progressive gray matter (GM) atrophy between brain-first and body-first Parkinson\u2019s disease (PD) under assumption.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Based on the hypothesis that the timing of rapid eye movement (REM) sleep behavior disorder (RBD) onset relative to motor symptoms may differentiate brain-first from body-first PD subtypes, we stratified PD patients from the Parkinson\u2019s Progression Markers Initiative (PPMI) database into 28 RBD-positive PD patients (PDRBD+), 26 RBD-negative PD patients (PDRBD-), 33 isolated RBD (iRBD) patients, and 35 healthy controls. PDRBD+ and PDRBD\u2212 groups underwent 4 visits within 48\u202fmonths including clinical assessments and structure MRI. We measured GM atrophy cross-sectionally and longitudinally and analyzed their associations with other proposed markers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>At baseline, all groups were comparable and showed no significant difference in GM volume (GMV). The longitudinal GMV analysis (group-by-time interaction) showed that, compared with PDRBD\u2212 group, PDRBD+ demonstrated significant GM loss in the medial surface of the frontal lobes and the left temporal lobe. In the comparison at the 48th month, besides the bilateral frontotemporal lobes, the PDRBD+ group showed significant GM atrophy in the bilateral cerebellum. The two groups had no significant differences in the 12th and 24th months. Over time, each PD group showed extensive cortical GM loss and bilateral caudate and putamen atrophy. The altered GMV (interaction effect) was positively associated with the MoCA scores and negatively with SCOPA-AUT. Furthermore, the group-level F-statistic map highlighted spatially distinct differences in the protein metabolism, signal transduction, and autophagy pathways between PDRBD+ and PDRBD\u2212 groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Body-first PD patients show a relatively rapid GMV loss in specific frontotemporal regions (e.g., left middle temporal gyrus) within 6\u202fyears following motor symptoms. Our findings add further evidence to the <jats:italic>\u03b1<\/jats:italic>-synuclein spreading hypothesis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2025.1579561","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T06:53:46Z","timestamp":1753253626000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Rapid frontotemporal gray matter loss in proposed body-first Parkinson\u2019s disease: a longitudinal voxel-based morphometry study"],"prefix":"10.3389","volume":"16","author":[{"given":"Jin","family":"Yan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ge","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,23]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/s00401-015-1485-1","article-title":"Propagation of alpha-synuclein pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies","volume":"131","author":"Uchihara","year":"2016","journal-title":"Acta Neuropathol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1093\/brain\/awt037","article-title":"Prion-like spreading of pathological \u03b1-synuclein in brain","volume":"136","author":"Masuda-Suzukake","year":"2013","journal-title":"Brain"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/s0197-4580(02)00065-9","article-title":"Staging of brain pathology related to sporadic Parkinson's disease","volume":"24","author":"Braak","year":"2003","journal-title":"Neurobiol Aging"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1007\/s00401-019-02071-3","article-title":"Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85","volume":"138","author":"Raunio","year":"2019","journal-title":"Acta Neuropathol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"105557","DOI":"10.1016\/j.nbd.2021.105557","article-title":"Neuropathological evidence of body-first vs. brain-first Lewy body disease","volume":"161","author":"Borghammer","year":"2021","journal-title":"Neurobiol Dis"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"S281","DOI":"10.3233\/JPD-191721","article-title":"Brain-first versus gut-first Parkinson's disease: a hypothesis","volume":"9","author":"Borghammer","year":"2019","journal-title":"J Parkinsons Dis"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"3077","DOI":"10.1093\/brain\/awaa238","article-title":"Brain-first versus body-first Parkinson's disease: a multimodal imaging case-control study","volume":"143","author":"Horsager","year":"2020","journal-title":"Brain"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1002\/mds.27003","article-title":"Degeneration of rapid eye movement sleep circuitry underlies rapid eye movement sleep behavior disorder","volume":"32","author":"McKenna","year":"2017","journal-title":"Mov Disord"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"105626","DOI":"10.1016\/j.nbd.2022.105626","article-title":"Clinical and imaging evidence of brain-first and body-first Parkinson's disease","volume":"164","author":"Horsager","year":"2022","journal-title":"Neurobiol Dis"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"455","DOI":"10.3233\/JPD-202481","article-title":"The \u03b1-Synuclein origin and connectome model (SOC model) of Parkinson's disease: explaining motor asymmetry, non-motor phenotypes, and cognitive decline","volume":"11","author":"Borghammer","year":"2021","journal-title":"J Parkinsons Dis"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.1002\/mds.29172","article-title":"Gray matter volume loss in proposed brain-first and body-first Parkinson's disease subtypes","volume":"37","author":"Banwinkler","year":"2022","journal-title":"Mov Disord"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1007\/s10072-017-2886-9","article-title":"Diagnostic accuracy of REM sleep behaviour disorder screening questionnaire: a meta-analysis","volume":"38","author":"Li","year":"2017","journal-title":"Neurol Sci"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"2386","DOI":"10.1002\/mds.21740","article-title":"The REM sleep behavior disorder screening questionnaire--a new diagnostic instrument","volume":"22","author":"Stiasny-Kolster","year":"2007","journal-title":"Mov Disord"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.neuroimage.2019.01.011","article-title":"A practical guide to linking brain-wide gene expression and neuroimaging data","volume":"189","author":"Arnatkeviciute","year":"2019","journal-title":"NeuroImage"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s13024-018-0273-5","article-title":"A new hypothesis for Parkinson's disease pathogenesis: GTPase-p38 MAPK signaling and autophagy as convergence points of etiology and genomics","volume":"13","author":"Obergasteiger","year":"2018","journal-title":"Mol Neurodegener"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s40035-017-0105-5","article-title":"Clinical features of Parkinson's disease with and without rapid eye movement sleep behavior disorder","volume":"6","author":"Liu","year":"2017","journal-title":"Transl Neurodegener"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1093\/sleep\/zsx101","article-title":"REM sleep behavior disorder and cognitive impairment in Parkinson's disease","volume":"40","author":"Jozwiak","year":"2017","journal-title":"Sleep"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1001\/jamaneurol.2015.0703","article-title":"New clinical subtypes of Parkinson disease and their longitudinal progression: a prospective cohort comparison with other phenotypes","volume":"72","author":"Fereshtehnejad","year":"2015","journal-title":"JAMA Neurol"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1001\/jamaneurol.2018.4377","article-title":"Prognosis and Neuropathologic correlation of clinical subtypes of Parkinson disease","volume":"76","author":"De Pablo-Fern\u00e1ndez","year":"2019","journal-title":"JAMA Neurol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1007\/s11910-017-0738-x","article-title":"Subtypes of Parkinson's disease: what do they tell us about disease progression?","volume":"17","author":"Fereshtehnejad","year":"2017","journal-title":"Curr Neurol Neurosci Rep"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1002\/mds.25652","article-title":"Relation of clinical subtypes in Parkinson's disease with survival","volume":"29","author":"de Lau","year":"2014","journal-title":"Mov Disord"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"2120","DOI":"10.1093\/brain\/awt152","article-title":"The coeruleus\/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson's disease","volume":"136","author":"Garc\u00eda-Lorenzo","year":"2013","journal-title":"Brain"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1101623","DOI":"10.3389\/fnins.2023.1101623","article-title":"Functional and structural alterations as diagnostic imaging markers for depression in de novo Parkinson's disease","volume":"17","author":"Wang","year":"2023","journal-title":"Front Neurosci"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"29080","DOI":"10.1073\/pnas.2015635117","article-title":"Differential attentional control mechanisms by two distinct noradrenergic coeruleo-frontal cortical pathways","volume":"117","author":"Bari","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1093\/brain\/awx348","article-title":"Evaluation of the noradrenergic system in Parkinson's disease: an 11C-MeNER PET and neuromelanin MRI study","volume":"141","author":"Sommerauer","year":"2018","journal-title":"Brain"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1007\/s00401-022-02477-6","article-title":"Spatiotemporal characterization of cellular tau pathology in the human locus coeruleus-pericoerulear complex by three-dimensional imaging","volume":"144","author":"Gilvesy","year":"2022","journal-title":"Acta Neuropathol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"334","DOI":"10.3389\/fneur.2018.00334","article-title":"Alterations of brain structural network in Parkinson's disease with and without rapid eye movement sleep behavior disorder","volume":"9","author":"Guo","year":"2018","journal-title":"Front Neurol"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"26782","DOI":"10.1038\/srep26782","article-title":"Structural brain alterations associated with rapid eye movement sleep behavior disorder in Parkinson's disease","volume":"6","author":"Boucetta","year":"2016","journal-title":"Sci Rep"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1111\/j.1468-1331.2010.03283.x","article-title":"Regional cerebral blood flow changes in patients with idiopathic REM sleep behavior disorder","volume":"18","author":"Hanyu","year":"2011","journal-title":"Eur J Neurol"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.parkreldis.2011.08.023","article-title":"Voxel-based magnetic resonance imaging study of structural brain changes in patients with idiopathic REM sleep behavior disorder","volume":"18","author":"Hanyu","year":"2012","journal-title":"Parkinsonism Relat Disord"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1002\/ana.24937","article-title":"Involvement of the cerebellum in Parkinson disease and dementia with Lewy bodies","volume":"81","author":"Seidel","year":"2017","journal-title":"Ann Neurol"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.3389\/fneur.2019.01329","article-title":"Brain MRI reveals ascending atrophy in Parkinson's disease across severity","volume":"10","author":"Blair","year":"2019","journal-title":"Front Neurol"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.jns.2019.01.020","article-title":"Cortical thinning across Parkinson's disease stages and clinical correlates","volume":"398","author":"Wilson","year":"2019","journal-title":"J Neurol Sci"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.parkreldis.2018.02.006","article-title":"Cortical atrophy patterns in early Parkinson's disease patients using hierarchical cluster analysis","volume":"50","author":"Uribe","year":"2018","journal-title":"Parkinsonism Relat Disord"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"2583","DOI":"10.1002\/mds.28706","article-title":"International multicenter analysis of brain structure across clinical stages of Parkinson's disease","volume":"36","author":"Laansma","year":"2021","journal-title":"Mov Disord"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"440","DOI":"10.7554\/eLife.08440","article-title":"Network structure of brain atrophy in de novo Parkinson's disease","volume":"4","author":"Zeighami","year":"2015","journal-title":"eLife"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1679","DOI":"10.1002\/mds.29898","article-title":"Understanding REM sleep behavior disorder through functional MRI: a systematic review","volume":"39","author":"Churchill","year":"2024","journal-title":"Mov Disord"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.1111\/ene.13388","article-title":"Rapid eye movement sleep behaviour disorder and striatal dopamine depletion in patients with Parkinson's disease","volume":"24","author":"Chung","year":"2017","journal-title":"Eur J Neurol"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"349","DOI":"10.3389\/fnins.2020.00349","article-title":"Serial dopamine transporter imaging of nigrostriatal function in Parkinson's disease with probable REM sleep behavior disorder","volume":"14","author":"Cao","year":"2020","journal-title":"Front Neurosci"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/s41531-024-00685-3","article-title":"Investigating the aspect of asymmetry in brain-first versus body-first Parkinson's disease","volume":"10","author":"L\u00f6vdal","year":"2024","journal-title":"NPJ Parkinsons Dis"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/nrn.2016.178","article-title":"Selective neuronal vulnerability in Parkinson disease","volume":"18","author":"Surmeier","year":"2017","journal-title":"Nat Rev Neurosci"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1093\/brain\/awr031","article-title":"Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important?","volume":"134","author":"Compta","year":"2011","journal-title":"Brain"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s12916-024-03766-5","article-title":"Longitudinal decline in DAT binding in Parkinson's disease: connections with sleep disturbances","volume":"22","author":"Ren","year":"2024","journal-title":"BMC Med"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1002\/mds.28493","article-title":"The logic and pitfalls of Parkinson's disease as \"brain-first\" versus \"body-first\" subtypes","volume":"36","author":"Fearon","year":"2021","journal-title":"Mov Disord"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1579561\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T06:53:47Z","timestamp":1753253627000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1579561\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,23]]},"references-count":44,"alternative-id":["10.3389\/fneur.2025.1579561"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2025.1579561","relation":{},"ISSN":["1664-2295"],"issn-type":[{"type":"electronic","value":"1664-2295"}],"subject":[],"published":{"date-parts":[[2025,7,23]]},"article-number":"1579561"}}