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Specific protein aggregates associated with neurodegenerative diseases are present in the retina and could be visualised in a non-invasive way. This study aims to assess the specificity and sensitivity of retinal \u03b1-synuclein aggregates in neuropathologically characterised \u03b1-synucleinopathies, other neurodegenerative diseases and non-neurological controls. Post-mortem eyes (<jats:italic>N<\/jats:italic>\u2009=\u200999) were collected prospectively through the Netherlands Brain Bank from donors with Parkinson\u2019s disease (and dementia), dementia with Lewy bodies, multiple system atrophy, Alzheimer\u2019s disease, other neurodegenerative diseases and non-neurological controls. Multiple retinal and optic nerve cross-sections were immunostained with anti-\u03b1-synuclein antibodies (LB509, KM51, and anti-pSer129) and assessed for aggregates and inclusions. \u03b1-Synuclein was observed as Lewy neurites in the retina and oligodendroglial cytoplasmic inclusions in the optic nerve and was highly associated with Lewy body disease (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001) and multiple system atrophy (<jats:italic>P<\/jats:italic>\u2009=\u20090.001). In all multiple system atrophy cases, the optic nerve showed oligodendroglial cytoplasmic inclusions, while retinal Lewy neurites were absent, despite coincidental brain Lewy pathology. With high specificity (97%) and sensitivity (82%), retinal\/optic nerve \u03b1-synuclein differentiates primary \u03b1-synucleinopathies from other cases and controls. \u03b1-Synuclein pathology occurs specifically in the retina and optic nerve of primary \u03b1-synucleinopathies as opposed to other neurodegenerative diseases\u2014with and without \u03b1-synuclein co-pathology\u2014and controls. The absence of retinal Lewy neurites in multiple system atrophy could contribute to the development of an in vivo retinal biomarker that discriminates between Lewy body disease and multiple system atrophy.<\/jats:p>","DOI":"10.1038\/s41531-023-00570-5","type":"journal-article","created":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T15:06:38Z","timestamp":1693235198000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["\u03b1-Synuclein pathology in post-mortem retina and optic nerve is specific for \u03b1-synucleinopathies"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5023-4882","authenticated-orcid":false,"given":"Frederique J.","family":"Hart de Ruyter","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tjado H. 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He has received royalties related to IP on OCT technologies and semiconductor metrology. He has acted as an expert witness for a UK-based law firm; P.S. has received consultancy fees (paid to the university) from Alzheon, Brainstorm Cell and Green Valley. Within his university affiliation, he is the global PI of the phase 1b study of AC Immune, Phase 2b study with FUJI-film\/Toyama and phase 2 study of UCB and phase 1 study with ImmunoBrain Checkpoint. He is chair of the EU steering committee of the phase 2b programme of Vivoryon, the phase 2b study of Novartis Cardiology and co-chair of the phase 3 study with NOVO-Nordisk. He is also an employee of EQT Life Sciences (formerly LSP); F.B. performs contract research for Optina Dx and Optos; she has been an invited speaker at Roche and has been invited for expert testimony at Biogen. All funding is paid to her institution; J.J.M.H. received grants from the Dutch Research Council (ZonMW), and, Alzheimer Netherlands, performed contract research or received grants from Merck, ONO Pharmaceuticals, Janssen Prevention Center, DiscovericBio, AxonNeurosciences, Roche, Genentech, Promis, Denali, FirstBiotherapeutics, and Ensol Biosciences. All payments were made to the institution. J.J.M.H. participates in the scientific advisory board of Alzheimer Netherlands and is Editor-in-Chief for <i>Acta Neuropathologica Communications<\/i>. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"124"}}