Vrillon Agathe, Spina Salvatore, Mejia-Perez Jhony, Lamore Tia, Yballa Claire, Soleimani-Meigooni David N, Blazhenets Ganna, Boxer Adam L, Rojas Julio C, Lago Argentina L, Jagust William J, Miller Bruce L, Rosen Howard J, Seeley William W, Grinberg Lea T, Rabinovici Gil D, Vandevrede Lawren, La Joie Renaud
Weill Institute for Neurosciences, Department of Neurology, Memory and Aging Center University of California San Francisco, San Francisco, California USA.
Global Brain Health Institute, University of California in San Francisco, San Francisco, CA, USA.
medRxiv. 2025 May 16:2025.05.14.25326954. doi: 10.1101/2025.05.14.25326954.
Evaluating tau biomarkers in patients with available autopsy data is critical for validating their sensitivity and specificity to detect Alzheimer's disease neuropathologic changes (ADNC). We examined the association between tau-PET (using [F]Flortaucipir), plasma ptau-217, and measures of AD neuropathology in a group of clinically-impaired participants from a tertiary dementia center, including patients with AD and FTLD.
We analyzed Flortaucipir-PET (80-100 minutes post-injection acquisition, normalized to inferior cerebellar cortex) from 73 patients with a clinical diagnosis of various neurodegenerative diseases who underwent autopsy at the Neurodegenerative Disease Brain Bank (median [IQR] age: 67 [59, 73] years, 60% male, median [IQR] PET-to-autopsy duration: 3.9 years, [2.1, 5.1]). Standardized uptake value ratios (SUVRs) were extracted from the entorhinal cortex (an early tau region) and the temporal meta-ROI (a widely used AD signature region). A semi-quantitative rating of AD NFT burden in cortical areas was available for 56 participants. Plasma p-tau217 was quantified with Simoa (Janssen) in 56 participants (median [IQR] PET-to-plasma duration: 1.7 months [0.5, 4.1]).
Our cohort included patients with a primary pathological diagnosis of AD (n=39), FTLD (tauopathies n=28, non-tauopathies n=4), and Lewy body dementia (n=2). Flortaucipir SUVRs were elevated in patients with a neuropathological diagnosis of AD compared with non-AD patients. Consistently elevated PET signal was detected in both the entorhinal cortex and temporal meta-ROI of patients with neurofibrillary tangle (NFT) at Braak stage VI and with high ADNC levels. No elevation of Flortaucipir SUVRs was observed at intermediate levels of ADNC. The burden of AD NFTs was correlated with local Flortaucipir SUVRs across cortical brain regions. Plasma p-tau217 concentrations were increased in patients at Braak stage V and VI and strongly correlated with Flortaucipir SUVRs across ROIs (r's≥0.75), driven by Braak V-VI cases. Flortaucipir SUVRs and plasma p-tau217 concentrations identified high Braak stages (V-VI) and high/intermediate ADNC levels with similarly high performance (area under the curve≥ 0.90).
Flortaucipir-PET and plasma p-tau217 both displayed strong specificity for primary AD neuropathological diagnosis but lacked sensitivity to detect early AD-related tau co-pathology in patients with a non-AD diagnosis.
在有尸检数据的患者中评估tau生物标志物对于验证其检测阿尔茨海默病神经病理改变（ADNC）的敏感性和特异性至关重要。我们在一家三级痴呆中心的一组临床受损参与者中，研究了tau-PET（使用[F]氟代托品）、血浆ptau-217与AD神经病理学指标之间的关联，这些参与者包括AD和额颞叶痴呆（FTLD）患者。
我们分析了来自神经退行性疾病脑库的73例临床诊断为各种神经退行性疾病且接受尸检的患者的氟代托品-PET（注射后80 - 100分钟采集，以小脑下皮质标准化）（年龄中位数[四分位间距]：67[59, 73]岁，60%为男性，PET至尸检的时间中位数[四分位间距]：3.9年，[2.1, 5.1]）。从内嗅皮质（一个早期tau区域）和颞叶元感兴趣区（一个广泛使用的AD特征区域）提取标准化摄取值比率（SUVRs）。56名参与者可获得皮质区域AD神经纤维缠结（NFT）负担的半定量评分。56名参与者用Simoa（杨森公司）对血浆p-tau217进行了定量（PET至血浆的时间中位数[四分位间距]：1.7个月[0.5, 4.1]）。
我们的队列包括原发性病理诊断为AD的患者（n = 39）、FTLD（tau病n = 28，非tau病n = 4）和路易体痴呆患者（n = 2）。与非AD患者相比，神经病理诊断为AD的患者氟代托品SUVRs升高。在Braak VI期有神经原纤维缠结（NFT）且ADNC水平高的患者的内嗅皮质和颞叶元感兴趣区均检测到PET信号持续升高。在ADNC的中间水平未观察到氟代托品SUVRs升高。AD NFT的负担与整个皮质脑区的局部氟代托品SUVRs相关。在Braak V期和VI期患者中血浆p-tau217浓度升高，并且在Braak V - VI期病例的驱动下，与各感兴趣区的氟代托品SUVRs密切相关（r≥0.75）。氟代托品SUVRs和血浆p-tau217浓度在识别高Braak分期（V - VI）和高/中间ADNC水平方面具有相似的高性能（曲线下面积≥0.90）。
氟代托品-PET和血浆p-tau217对原发性AD神经病理诊断均显示出很强的特异性，但在检测非AD诊断患者中早期AD相关tau共病理方面缺乏敏感性。
