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Hallmark protein aggregates in the retinal neuronal tissue could be imaged through light non-invasively. Post-mortem studies have already shown the presence of specific hallmark proteins in Alzheimer\u2019s disease, primary tauopathies, synucleinopathies and frontotemporal lobar degeneration. This study aims to assess proteinopathy in a post-mortem cohort with different neurodegenerative diseases and assess the presence of the primary pathology in the retina. Post-mortem eyes were collected in collaboration with the Netherlands Brain Bank from donors with Alzheimer\u2019s disease (<jats:italic>n<\/jats:italic>\u2009=\u200917), primary tauopathies (<jats:italic>n<\/jats:italic>\u2009=\u20098), synucleinopathies (<jats:italic>n<\/jats:italic>\u2009=\u200927), frontotemporal lobar degeneration (<jats:italic>n<\/jats:italic>\u2009=\u20098), mixed pathology (<jats:italic>n<\/jats:italic>\u2009=\u200911), other neurodegenerative diseases (<jats:italic>n<\/jats:italic>\u2009=\u20096), and cognitively normal controls (<jats:italic>n<\/jats:italic>\u2009=\u200925). Multiple cross sections of the retina and optic nerve tissue were immunostained using antibodies against pTau Ser202\/Thr205 (AT8), amyloid-beta (4G8), alpha-synuclein (LB509), pTDP-43 Ser409\/410 and p62-lck ligand (p62) and were assessed for the presence of aggregates and inclusions. pTau pathology was observed as a diffuse signal in Alzheimer\u2019s disease, primary tauopathies and controls with Alzheimer\u2019s disease neuropathological changes. Amyloid-beta was observed in the vessel wall and as cytoplasmic granular deposits in all groups. Alpha-synuclein pathology was observed as Lewy neurites in the retina in synucleinopathies associated with Lewy pathology and as oligodendroglial cytoplasmic inclusions in the optic nerve in multiple system atrophy. Anti-pTDP-43 generally showed typical neuronal cytoplasmic inclusion bodies in cases with frontotemporal lobar degeneration with TDP-43 and also in cases with later stages of limbic-associated TDP-43 encephalopathy. P62 showed inclusion bodies similar to those seen with anti-pTDP-43. Furthermore, pTau and alpha-synuclein pathology were significantly associated with increasing Braak stages for neurofibrillary tangles and Lewy bodies, respectively. Mixed pathology cases in this cohort consisted of cases (<jats:italic>n<\/jats:italic>\u2009=\u20096) with high Braak LB stages (&gt;\u20094) and low or moderate AD pathology, high AD pathology (<jats:italic>n<\/jats:italic>\u2009=\u20091, Braak NFT 6, Thal phase 5) with moderate LB pathology, or a combination of low\/moderate scores for different pathology scores in the brain (<jats:italic>n<\/jats:italic>\u2009=\u20094). There were no cases with advanced co-pathologies. In seven cases with Braak LB\u2009\u2265\u20094, LB pathology was observed in the retina, while tau pathology in the retina in the mixed pathology group (<jats:italic>n<\/jats:italic>\u2009=\u200911) could not be observed. From this study, we conclude that the retina reflects the presence of the major hallmark proteins associated with neurodegenerative diseases. Although low or moderate levels of copathology were found in the brains of most cases, the retina primarily manifested protein aggregates associated with the main neurodegenerative disease. These findings indicate that with appropriate retinal imaging techniques, retinal biomarkers have the potential to become highly accurate indicators for diagnosing the major neurodegenerative diseases of the brain.<\/jats:p>","DOI":"10.1007\/s00401-024-02769-z","type":"journal-article","created":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T19:02:02Z","timestamp":1724094122000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Neuropathological hallmarks in the post-mortem retina of neurodegenerative diseases"],"prefix":"10.1007","volume":"148","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":"Manon J. A. 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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; A.J.M.R. received grants from Alzheimer Netherlands. 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 acts as Editor-in-Chief for Acta Neuropathologica Communications. The other authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"24"}}