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Hallmark蛋白聚集体可以通过光进行非侵入性成像。验尸研究已经表明在阿尔茨海默病中存在特定的标志蛋白,原发性tau蛋白病,突触核蛋白病和额颞叶变性。这项研究旨在评估具有不同神经退行性疾病的死后队列中的蛋白质病,并评估视网膜中主要病理的存在。验尸后的眼睛是与荷兰脑库合作从阿尔茨海默病供体(n=17)收集的,原发性tau蛋白病(n=8),突触核蛋白病(n=27),额颞叶变性(n=8),混合病理学(n=11),其他神经退行性疾病(n=6),和认知正常对照(n=25)。使用抗pTauSer202/Thr205(AT8)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,β淀粉样蛋白(4G8),α-突触核蛋白(LB509),评估pTDP-43Ser409/410和p62-lck配体(p62)和聚集体和内含物的存在。pTau病理学被观察为阿尔茨海默病的弥漫性信号,原发性tau蛋白病变和阿尔茨海默病神经病理学改变的对照。在所有组中,在血管壁中均观察到淀粉样β蛋白,并作为细胞质颗粒沉积物。在与Lewy病理学相关的突触核蛋白病中观察到α-突触核蛋白病理学是视网膜中的路易神经突,在多系统萎缩中观察到视神经中的少突胶质细胞质内含物。在TDP-43的额颞叶变性以及边缘相关的TDP-43脑病的晚期病例中,抗pTDP-43通常显示典型的神经元细胞质包涵体。P62显示出与抗pTDP-43相似的包涵体。此外,pTau和α-突触核蛋白病理学与神经原纤维缠结和路易体的Braak分期增加显着相关,分别。该队列中的混合病理学病例包括具有高BraakLB分期(>4)和低或中度AD病理学的病例(n=6)。高度AD病理(n=1,BraakNFT6,Thal5期),中度LB病理,或大脑中不同病理评分的低/中等评分的组合(n=4)。没有晚期共病病例。在7例BraakLB≥4的患者中,在视网膜中观察到LB病理,而在混合病理组(n=11)的视网膜中没有观察到tau病理。从这项研究中,我们得出的结论是,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了低或中等水平的共病,视网膜主要表现为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。
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.