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To dissect these subtypes, we assessed the association between pupillary dysfunction, mesencephalic raphe and substantia nigra changes, vagus nerve atrophy and vagal electrocardiographic parameters in PD patients and controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this single-center cross-sectional study, we included 54 people with PD and 60 matched healthy controls. Participants underwent clinical assessments, electrocardiography, and sonographic measurements of substantia nigra echoic area, midbrain raphe echo-score and vagus nerve caliber. Dynamic ultrasound pupillometry was performed in drug-na\u00efve de\u00a0novo PD patients and matched controls. The brain-first and body-first subtypes were classified based on the REM-sleep Behavior Disorder Screening Questionnaire and gastrointestinal symptoms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Vagal atrophy increased with disease duration and severity. During the first decade of motor disease, vagal atrophy and dysfunction occurred in body-first but not brain-first PD. Sympathetic pupillary innervation was reduced in de novo body-first but not brain-first PD patients. However, parasympathetic pupillary innervation was reduced in both subtypes at the de novo stage. Substantia nigra hyperechoic area was asymmetrical in brain-first but more symmetrical in body-first PD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings support the concept of two subtypes of PD in which the mesencephalic and vagal parasympathetic systems are affected in opposite sequences. Ultrasonic and electrocardiographic examination could facilitate early subtyping.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-026-13973-0","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T11:32:49Z","timestamp":1782991969000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Brain-first versus body-first Parkinson\u2019s disease: Differential findings on pupillary, brainstem and vagus sonography"],"prefix":"10.1007","volume":"273","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6280-785X","authenticated-orcid":false,"given":"Uwe","family":"Walter","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Batchakaschvili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna Rebekka","family":"Kleinlein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6046-7057","authenticated-orcid":false,"given":"Jakub","family":"Radziwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9266-9673","authenticated-orcid":false,"given":"Wiebke","family":"Hermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmut","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1133-9216","authenticated-orcid":false,"given":"Alexander","family":"Storch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0645-0825","authenticated-orcid":false,"given":"Matthias","family":"L\u00f6hle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"13973_CR1","doi-asserted-by":"publisher","first-page":"S281","DOI":"10.3233\/JPD-191721","volume":"9","author":"P Borghammer","year":"2019","unstructured":"Borghammer P, Van Den Berge N (2019) Brain-first versus gut-first Parkinson\u2019s disease: a hypothesis. 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He has received speaker honoraria and travel grants from Canon Medical Systems Europe B.V., Ipsen Pharma and Merz Therapeutics, and an unrestricted research grant from Merz Therapeutics outside the present study. He serves as Joint Editor-in-Chief of the European Journal of Ultrasound (Thieme, Stuttgart, Germany). M.B. has stated explicitly that there are no conflicts of interest in connection with this article. H.R.K. has stated explicitly that there are no conflicts of interest in connection with this article. J.R. has stated explicitly that there are no conflicts of interest in connection with this article. W.H. has stated explicitly that there are no conflicts of interest in connection with this article. A.S. has received funding from the Deutsche Forschungsgemeinschaft (German Research Association) and the Helmholtz-Association outside the present study. He has received honoraria for presentations\/advisory boards\/consultations from Esteve, Desitin, Lobsor Pharmaceuticals, STADA, Bial, RG Gesellschaft, Zambon, NovoNordisk and AbbVie outside the present study. He has received royalties from Kohlhammer Verlag and Elsevier Press. He serves as an editorial board member of Stem Cells International. M.L. has received honoraria for presentations from AbbVie,\u00a0BIAL, RG Gesellschaft, and STADA.","order":1,"name":"Ethics","label":"Conflicts of interest","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"444"}}