PDF(Pubmed)
Abstract：
This study investigates various pathological tau isoforms in the retina of individuals with early and advanced Alzheimer\'s disease (AD), exploring their connection with disease status. Retinal cross-sections from predefined superior-temporal and inferior-temporal subregions and corresponding brains from neuropathologically confirmed AD patients with a clinical diagnosis of either mild cognitive impairment (MCI) or dementia (n = 45) were compared with retinas from age- and sex-matched individuals with normal cognition (n = 30) and non-AD dementia (n = 4). Retinal tau isoforms, including tau tangles, paired helical filament of tau (PHF-tau), oligomeric-tau (Oligo-tau), hyperphosphorylated-tau (p-tau), and citrullinated-tau (Cit-tau), were stereologically analyzed by immunohistochemistry and Nanostring GeoMx digital spatial profiling, and correlated with clinical and neuropathological outcomes. Our data indicated significant increases in various AD-related pretangle tau isoforms, especially p-tau (AT8, 2.9-fold, pS396-tau, 2.6-fold), Cit-tau at arginine residue 209 (CitR209-tau; 4.1-fold), and Oligo-tau (T22+, 9.2-fold), as well as pretangle and mature tau tangle forms like MC-1-positive (1.8-fold) and PHF-tau (2.3-fold), in AD compared to control retinas. MCI retinas also exhibited substantial increases in Oligo-tau (5.2-fold), CitR209-tau (3.5-fold), and pS396-tau (2.2-fold). Nanostring GeoMx analysis confirmed elevated retinal p-tau at epitopes: Ser214 (2.3-fold), Ser396 (2.6-fold), Ser404 (2.4-fold), and Thr231 (1.8-fold), particularly in MCI patients. Strong associations were found between retinal tau isoforms versus brain pathology and cognitive status: a) retinal Oligo-tau vs. Braak stage, neurofibrillary tangles (NFTs), and CDR cognitive scores (ρ = 0.63-0.71), b) retinal PHF-tau vs. neuropil threads (NTs) and ABC scores (ρ = 0.69-0.71), and c) retinal pS396-tau vs. NTs, NFTs, and ABC scores (ρ = 0.67-0.74). Notably, retinal Oligo-tau strongly correlated with retinal Aβ42 and arterial Aβ40 forms (r = 0.76-0.86). Overall, this study identifies and quantifies diverse retinal tau isoforms in MCI and AD patients, underscoring their link to brain pathology and cognition. These findings advocate for further exploration of retinal tauopathy biomarkers to facilitate AD detection and monitoring via noninvasive retinal imaging.
摘要：
这项研究调查了早期和晚期阿尔茨海默病（AD）个体视网膜中的各种病理性tau亚型，探索他们与疾病状态的联系。将预定义的颞上和颞下亚区域的视网膜横截面以及经神经病理证实的临床诊断为轻度认知障碍（MCI）或痴呆（n=45）的AD患者的相应大脑与年龄和性别匹配的视网膜进行比较认知正常（n=30）和非AD痴呆（n=4）的个体。视网膜tau亚型，包括tau缠结，成对螺旋丝的tau（PHF-tau），寡聚tau（Oligo-tau），高磷酸化tau（p-tau），和瓜氨酸tau（Cit-tau），通过免疫组织化学和NanostringGeoMx数字空间谱分析进行了立体分析，并与临床和神经病理学结果相关。我们的数据表明各种AD相关的前角tau亚型显著增加，尤其是p-tau(AT8，2.9倍，pS396-tau,2.6折),精氨酸残基209处的Cit-tau（CitR209-tau；4.1倍），和Oligo-tau(T22+,9.2折)，以及预缠结和成熟的tau缠结形式，如MC-1阳性（1.8倍）和PHF-tau（2.3倍），在AD中与对照视网膜相比。MCI视网膜也表现出Oligo-tau的显着增加（5.2倍），CitR209-tau（3.5倍），和pS396-tau(2.2倍)。NanostringGeoMx分析证实，表位上的视网膜p-tau升高：Ser214（2.3倍），Ser396（2.6倍），Ser404（2.4倍），和Thr231（1.8倍），尤其是MCI患者。在视网膜tau亚型与脑病理学和认知状态之间发现了强烈的关联：a）视网膜Oligo-tau与Braak阶段,神经原纤维缠结（NFT），和CDR认知得分(ρ=0.63-0.71)，b)视网膜PHF-tau与神经纤维线程(NTs)和ABC得分(ρ=0.69-0.71)，和c）视网膜pS396-tau与NTs,NFTs,和ABC得分(ρ=0.67-0.74)。值得注意的是,视网膜Oligo-tau与视网膜Aβ42和动脉Aβ40形式密切相关（r=0.76-0.86）。总的来说,这项研究鉴定并量化了MCI和AD患者中不同的视网膜tau亚型，强调他们与大脑病理学和认知的联系。这些发现主张进一步探索视网膜tau病变生物标志物，以通过非侵入性视网膜成像促进AD检测和监测。
