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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 with Braak LB ≥ 4, LB pathology was observed in the retina, while tau pathology in the retina in the mixed pathology group (n = 11) 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., (© 2024. The Author(s).)

Background: Phosphorylated tau (p-tau) accumulation, a hallmark of Alzheimer's disease (AD), can also be found in the retina. However, it is uncertain whether it is linked to AD or another tauopathy., Methods: Retinas from 164 individuals, with and without AD, were analyzed for p-tau accumulation and its relationship with age, dementia, and vision impairment., Results: Retinal p-tau pathology showed a consistent pattern with four stages and a molecular composition distinct from that of cerebral tauopathies. The stage of retinal p-tau pathology correlated with age (r = 0.176, P = 0.024) and was associated with AD (odds ratio [OR] 3.193; P = 0.001), and inflammation (OR = 2.605; P = 0.001). Vision impairment was associated with underlying eye diseases (β = 0.292; P = 0.001) and the stage of retinal p-tau pathology (β = 0.192; P = 0.030) in a linear regression model., Conclusions: The results show the presence of a primary retinal tauopathy that is distinct from cerebral tauopathies., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

There is increasing interest in studying retinal biomarkers for various neurodegenerative diseases. 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 α-synuclein aggregates in neuropathologically characterised α-synucleinopathies, other neurodegenerative diseases and non-neurological controls. Post-mortem eyes (N = 99) were collected prospectively through the Netherlands Brain Bank from donors with Parkinson's disease (and dementia), dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, other neurodegenerative diseases and non-neurological controls. Multiple retinal and optic nerve cross-sections were immunostained with anti-α-synuclein antibodies (LB509, KM51, and anti-pSer129) and assessed for aggregates and inclusions. α-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 (P < 0.001) and multiple system atrophy (P = 0.001). 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 α-synuclein differentiates primary α-synucleinopathies from other cases and controls. α-Synuclein pathology occurs specifically in the retina and optic nerve of primary α-synucleinopathies as opposed to other neurodegenerative diseases-with and without α-synuclein co-pathology-and 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., (© 2023. Springer Nature Limited.)

The retina is a potential source of biomarkers for the detection of neurodegenerative diseases. Accumulation of phosphorylated tau (p-tau) in the brain is a pathological feature characteristic for Alzheimer's disease (AD) and primary tauopathies. In this study the presence of p-tau in the retina in relation to tau pathology in the brain was assessed. Post-mortem eyes and brains were collected through the Netherlands Brain Bank from donors with AD (n = 17), primary tauopathies (n = 8), α-synucleinopathies (n = 13), other neurodegenerative diseases including non-tau frontotemporal lobar degeneration (FTLD) (n = 9), and controls (n = 15). Retina cross-sections were assessed by immunohistochemistry using antibodies directed against total tau (HT7), 3R and 4R tau isoforms (RD3, RD4), and phospho-epitopes Ser202/Thr205 (AT8), Thr217 (anti-T217), Thr212/Ser214 (AT100), Thr181 (AT270), Ser396 (anti-pS396) and Ser422 (anti-pS422). Retinal tau load was compared to p-tau Ser202/Thr205 and p-tau Thr217 load in various brain regions. Total tau, 3R and 4R tau isoforms were most prominently present in the inner plexiform layer (IPL) and outer plexiform layer (OPL) of the retina and were detected in all cases and controls as a diffuse and somatodendritic signal. Total tau, p-tau Ser202/Thr205 and p-tau Thr217 was observed in amacrine and horizontal cells of the inner nuclear layer (INL). Various antibodies directed against phospho-epitopes of tau showed immunoreactivity in the IPL, OPL, and INL. P-tau Ser202/Thr205 and Thr217 showed significant discrimination between AD and other tauopathies, and non-tauopathy cases including controls. Whilst immunopositivity was observed for p-tau Thr212/Ser214, Thr181 and Ser396, there were no group differences. P-tau Ser422 did not show any immunoreactivity in the retina. The presence of retinal p-tau Ser202/Thr205 and Thr217 correlated with Braak stage for NFTs and with the presence of p-tau Ser202/Thr205 in hippocampus and cortical brain regions. Depending on the phospho-epitope, p-tau in the retina is a potential biomarker for AD and primary tauopathies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Previous work has showed the in vivo presence of retinal amyloid in Alzheimer's disease (AD) patients using curcumin. We aimed to replicate these findings in an amyloid biomarker-confirmed cohort., Methods: Twenty-six patients with AD (age 66 [+9], Mini-Mental Status Examination [MMSE] ≥17) and 14 controls (age 71 [+12]) used one of three curcumin formulations: Longvida, Theracurmin, and Novasol. Plasma levels were determined and pre- and post-curcumin retinal fluorescence scans were assessed visually in all cases and quantitatively assessed in a subset., Results: Visual assessment showed no difference between AD patients and controls for pre- and post-curcumin images. This was confirmed by quantitative analyses on a subset. Mean conjugated plasma curcumin levels were 198.7 nM (Longvida), 576.6 nM (Theracurmin), and 1605.8 nM (Novasol)., Discussion: We found no difference in retinal fluorescence between amyloid-confirmed AD cases and control participants, using Longvida and two additional curcumin formulations. Additional replication studies in amyloid-confirmed cohorts are needed to assess the diagnostic value of retinal fluorescence as an AD biomarker., Competing Interests: The research of C.T. is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 [MIRIADE], and JPND), Health Holland, the Dutch Research Council (ZonMW), Alzheimer's Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, Alzheimer's Association. C.T. is recipients of ABOARD, which is a public‐private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). More than 30 partners participate in ABOARD. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes‐Strijbisfonds. C.T. has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly; and has performed contract research or received grants from AC‐Immune, Axon Neurosciences, Biogen, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, PeopleBio, Roche, Toyama, and Vivoryon. F.B. has a collaboration contract with Biogen, Optina Dx, and Roche. Payments are made to the institution of VUMC. F.B. is committee member of EAN and chairs the atypical AD PIA and the Eye as biomarker for AD PIA of ISTAART. P.S. is chair of the steering committee in NOVARTIS, member of DSMB GENENTECH, global PI phase s! study AC IMMUNE, member advisory board AXON NEUROSCIENCE, global PI phase 2B study EIP PHARMA, PI phase 2B study COGRX, member advisory board GEMVAX, COGNOPTIX, and CORTEXZYME, member strategic innovation committee GREEN VALLEY, PI global phase 2B study Vivoryon, PI global phase 2A study TOYAMA/FUJI FILM, PI global phase 1A study IONIS, personal fees from Life Science Partners Amsterdam, outside the submitted work. J.B. is supported for the current study by NWO (Foundation for scientific research in the Netherlands, similar to NIH and NSF) and Co‐financing by Heidelberg engineering as part of the competitive research proposal, administered by the funding agency. Both these fundings are paid to institution. Besides this study J.B. received in the past 36 months research grants from Heidelberg, topconsortia voor kennis en innovatie (TKI), nederlandse organisatie voor toegepast‐natuurwetenschappelijk onderzoek (TNO), and LSHM paid to institution. Personal fees from royalties through former employer, Massachusetts general Hospital, for IP that has been licensed to Terumo, Heidelberg engineering and Spectrawave as well as fees for expert witness for a UK based law firm. He is program committee member for a number of conferences, unpaid. J.dH., B.L., F.H., M.K., M.K., B.B., J.H., A.K., and F.V. report no conflict of interest and have nothing to disclose. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)