Neuropathological hallmarks in the post-mortem retina of neurodegenerative diseases

• Published in: Acta neuropathologica 2024-08, Vol.148 (1), p.24
• Main Authors: Hart de Ruyter, Frederique J., Evers, Manon J. A. P., Morrema, Tjado H. J., Dijkstra, Anke A., den Haan, Jurre, Twisk, Jos W. R., de Boer, Johannes F., Scheltens, Philip, Bouwman, Femke H., Verbraak, Frank D., Rozemuller, Annemieke J., Hoozemans, Jeroen J. M.
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; alpha-Synuclein - metabolism; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Atrophy; Autopsy; Axons; Biomarkers; Brain; Disease; DNA-Binding Proteins - metabolism; Encephalopathy; Female; Frontotemporal dementia; Humans; Inclusion bodies; Lck protein; Lewy bodies; Male; Medicine; Medicine & Public Health; Middle Aged; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurofibrillary tangles; Neuroimaging; Neuropathology; Neurosciences; Optic nerve; Original Paper; Pathology; Protein sources; Retina; Retina - metabolism; Retina - pathology; Synuclein; Tau protein; tau Proteins - metabolism; Tauopathies - metabolism; Tauopathies - pathology
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-024-02769-z

The retina is increasingly recognised as a potential source of biomarkers for neurodegenerative diseases. 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’s 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’s disease ( n  = 17), primary tauopathies ( n  = 8), synucleinopathies ( n  = 27), frontotemporal lobar degeneration ( n  = 8), mixed pathology ( n  = 11), other neurodegenerative diseases ( n  = 6), and cognitively normal controls ( n  = 25). 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’s disease, primary tauopathies and controls with Alzheimer’s 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 ( n  = 6) with high Braak LB stages (> 4) and low or moderate AD pathology, high AD pathology ( n  = 1, Braak NFT 6, Thal phase 5) with moderate LB pathology, or a combination of low/moderate scores for different pathology scores in the brain ( n  = 4). There were no cases with advanced co-pathologies. In seven cases wi