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.

视网膜越来越被认为是神经退行性疾病生物标志物的潜在来源。视网膜神经元组织中的标志性蛋白质聚集体可以通过光非侵入性地成像。尸检研究已经表明，阿尔茨海默病、原发性tau蛋白病、突触核蛋白病和额颞叶变性中存在特定的标志蛋白。本研究旨在评估不同神经退行性疾病死后队列中的蛋白质病，并评估视网膜中主要病理的存在。与荷兰脑库合作，从患有阿尔茨海默病 ( n = 17)、原发性 tau蛋白病 ( n = 8)、突触核蛋白病 ( n = 27)、额颞叶变性 ( n = 8)、混合病理的捐献者中收集死后眼睛( n = 11)、其他神经退行性疾病 ( n = 6) 和认知正常对照 ( n = 25)。使用针对 pTau Ser202/Thr205 (AT8)、淀粉样蛋白-β (4G8)、α-突触核蛋白 (LB509)、pTDP-43 Ser409/410 和 p62-lck 配体 (p62) 的抗体对视网膜和视神经组织的多个横截面进行免疫染色。 ）并评估是否存在聚集体和夹杂物。 pTau 病理学在阿尔茨海默病、原发性 tau 病和阿尔茨海默病神经病理变化对照中被观察为弥散信号。在所有组中均在血管壁中和细胞质颗粒沉积物中观察到淀粉样蛋白-β。在与路易病理相关的突触核蛋白病中，观察到α-突触核蛋白病理为视网膜中的路易神经突，在多系统萎缩中观察为视神经中的少突胶质细胞质包涵体。 在患有 TDP-43 的额颞叶变性病例以及边缘系统相关 TDP-43 脑病的晚期病例中，抗 pTDP-43 通常显示出典型的神经元细胞质包涵体。 P62 显示出与抗 pTDP-43 所见相似的包涵体。此外，pTau 和 α-突触核蛋白病理学分别与神经原纤维缠结和路易体的 Braak 阶段的增加显着相关。该队列中的混合病理病例包括具有高 Braak LB 分期 (> 4) 和低或中度 AD 病理的病例 ( n = 6)，以及具有中度 LB 病理的高 AD 病理 ( n = 1、Braak NFT 6、Thal 5 期) ，或大脑中不同病理评分的低/中等评分的组合 ( n = 4)。没有出现晚期共病理的病例。 Braak LB ≥ 4 的 7 例患者视网膜中观察到 LB 病理，而混合病理组（ n = 11）视网膜中未观察到 tau 病理。从这项研究中，我们得出结论，视网膜反映了与神经退行性疾病相关的主要标志蛋白的存在。尽管在大多数病例的大脑中发现低或中等水平的共病理，但视网膜主要表现出与主要神经退行性疾病相关的蛋白质聚集体。这些发现表明，通过适当的视网膜成像技术，视网膜生物标志物有可能成为诊断大脑主要神经退行性疾病的高度准确的指标。