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The prion\u2010like behavior of \u03b1\u2010synuclein has been convincingly demonstrated in vitro and in animal models of PD. Lewy\u2010type pathology have been detected in peripheral organs many years prior to PD diagnosis, and 2 independent studies have now suggested that truncal vagotomy may be protective against the disorder. Other lines of evidence are difficult to reconcile with a peripheral onset of PD, most importantly the relative scarcity of post mortem cases with isolated gastrointestinal \u03b1\u2010synuclein pathology without concomitant CNS pathology. This Scientific Perspectives article revisits some important topics with implications for the dual\u2010hit hypothesis. An account of the neuroanatomical pathways necessary for stereotypical \u03b1\u2010synuclein spreading is presented. Parallels to the existing knowledge on true prion disorders, including Creutzfeld\u2010Jakob disease, are examined. Finally, the vagotomy studies and the somewhat inconsistent findings in the growing literature on peripheral \u03b1\u2010synuclein pathology are discussed. It is concluded that the dual\u2010hit hypothesis remains a potential explanation for PD pathogenesis, but several issues need to be resolved before more firm conclusions can be drawn. \u00a9 2017 International Parkinson and Movement Disorder Society<\/jats:p>","DOI":"10.1002\/mds.27138","type":"journal-article","created":{"date-parts":[[2017,8,26]],"date-time":"2017-08-26T06:34:40Z","timestamp":1503729280000},"page":"48-57","source":"Crossref","is-referenced-by-count":133,"title":["How does parkinson's disease begin? Perspectives on neuroanatomical pathways, prions, and histology"],"prefix":"10.1002","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6391-8052","authenticated-orcid":false,"given":"Per","family":"Borghammer","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine &amp; PET Centre Aarhus University Hospital Aarhus C 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