{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:30:08Z","timestamp":1792099808475,"version":"4.4.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2020,8,24]],"date-time":"2020-08-24T00:00:00Z","timestamp":1598227200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["R190-2014-4183"],"award-info":[{"award-number":["R190-2014-4183"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Parkinson\u2019s disease is characterized by the presence of abnormal, intraneuronal \u03b1-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial \u03b1-synuclein aggregates originate. We have hypothesized that Parkinson\u2019s disease comprises two subtypes. A brain-first (top-down) type, where \u03b1-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. We also hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type. Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups. We included 37 consecutive de novo patients with Parkinson\u2019s disease into this case-control PET study. Patients with Parkinson\u2019s disease were divided into 24 RBD-negative (PDRBD\u2212) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients. We used 11C-donepezil PET\/CT to assess cholinergic (parasympathetic) innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and 18F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity. Colon volume and transit times were assessed with CT scans and radiopaque markers. Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons. The PDRBD\u2212 and PDRBD+ groups showed similar marked reductions in putaminal FDOPA-specific uptake, whereas two-thirds of iRBD patients had normal scans (P\u2009&amp;lt;\u200910\u221213, ANOVA). When compared to the PDRBD\u2212 patients, the PDRBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (P\u2009&amp;lt;\u200910\u22125, ANOVA) and colon 11C-donepezil standard uptake values (P\u2009=\u20090.008, ANOVA). The PDRBD+ group trended towards a reduced mean MRI locus coeruleus: pons ratio compared to PDRBD\u2212 (P\u2009=\u20090.07, t-test). In comparison to the other groups, the PDRBD+ group also had enlarged colon volumes (P\u2009&amp;lt;\u20090.001, ANOVA) and delayed colonic transit times (P\u2009=\u20090.01, Kruskal-Wallis). The combined iRBD and PDRBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA uptake. In contrast, the PDRBD\u2212 data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake followed by a secondary loss of cardiac MIBG signal and 11C-donepezil signal. These findings support the existence of brain-first and body-first subtypes of Parkinson\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awaa238","type":"journal-article","created":{"date-parts":[[2020,7,1]],"date-time":"2020-07-01T15:10:48Z","timestamp":1593616248000},"page":"3077-3088","source":"Crossref","is-referenced-by-count":792,"title":["Brain-first versus body-first Parkinson\u2019s disease: a multimodal\u00a0imaging case-control study"],"prefix":"10.1093","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6098-0045","authenticated-orcid":false,"given":"Jacob","family":"Horsager","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrine B","family":"Andersen","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karoline","family":"Knudsen","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casper","family":"Skj\u00e6rb\u00e6k","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4840-742X","authenticated-orcid":false,"given":"Tatyana D","family":"Fedorova","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels","family":"Okkels","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Schaeffer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Christian-Albrechts-University Kiel, Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3249-1724","authenticated-orcid":false,"given":"Sarah K","family":"Bonkat","sequence":"additional","affiliation":[{"name":"Department of Neurology, Christian-Albrechts-University Kiel, Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Geday","sequence":"additional","affiliation":[{"name":"Neurologen, Horsens, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marit","family":"Otto","sequence":"additional","affiliation":[{"name":"Aarhus University Hospital, Department of Clinical Neurophysiology, Aarhus, Denmark"},{"name":"Aarhus University Hospital, Department of Neurology, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Sommerauer","sequence":"additional","affiliation":[{"name":"University of Cologne, Department of Neurology, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik H","family":"Danielsen","sequence":"additional","affiliation":[{"name":"Aarhus University Hospital, Department of Neurology, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Einar","family":"Bech","sequence":"additional","affiliation":[{"name":"Neuroklinik-Aarhus, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Kraft","sequence":"additional","affiliation":[{"name":"Neurolog Jonas Kraft, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole L","family":"Munk","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra D","family":"Hansen","sequence":"additional","affiliation":[{"name":"Neurolog i Odense, Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6801-6194","authenticated-orcid":false,"given":"Nicola","family":"Pavese","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark"},{"name":"Institute of Translational and Clinical Neuroscience, Newcastle University, Newcastle, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"G\u00f6der","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Christian-Albrechts-University Kiel, Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J","family":"Brooks","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and 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