Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study.
Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study.
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血浆磷酸化tau 217和磷酸化tau 181作为阿尔茨海默病和额颞叶变性的生物标志物：一项回顾性诊断性能研究
DOI：
10.1016/s1474-4422(21)00214-3
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发表时间：
2021-09
期刊：
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通讯作者：
Advancing Research and Treatment for Frontotemporal Lobar Degeneration investigators
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作者：
Thijssen EH;La Joie R;Strom A;Fonseca C;Iaccarino L;Wolf A;Spina S;Allen IE;Cobigo Y;Heuer H;VandeVrede L;Proctor NK;Lago AL;Baker S;Sivasankaran R;Kieloch A;Kinhikar A;Yu L;Valentin MA;Jeromin A;Zetterberg H;Hansson O;Mattsson-Carlgren N;Graham D;Blennow K;Kramer JH;Grinberg LT;Seeley WW;Rosen H;Boeve BF;Miller BL;Teunissen CE;Rabinovici GD;Rojas JC;Dage JL;Boxer AL;Advancing Research and Treatment for Frontotemporal Lobar Degeneration investigators
血浆P-tau 217和P-tau 181与阿尔茨海默病（AD）tau病理学相关。P-tau 217是一种更新颖的血液生物标志物，在诊断上可能上级P-tau 181。我们比较了认知正常参与者和临床诊断为轻度认知障碍、AD或额颞叶变性（FTLD）的患者队列中两种生物标志物的诊断价值。在这项多队列诊断性能研究中，我们从加州大学旧金山弗朗西斯科记忆和衰老中心以及额颞叶变性的先进研究和治疗联盟收集了血浆样本。血浆Ptau-181和Ptau-217使用基于电化学发光的测定法测量，其仅在生物素化抗体表位特异性方面不同。接受者操作特征分析用于确定两种血浆标志物的诊断准确性，使用临床诊断、神经病理学发现和淀粉样蛋白和tau-PET测量作为金标准。采用Delong检验检验两次曲线下面积（AUC）分析之间的差异。数据收集自2020年7月至11月期间的593名参与者（平均年龄64岁[SD 13]，294名[49.6%]女性）。血浆P-tau 217和P-181相关（r=0.90，p<0.0001）。P-tau 217和P-tau 181浓度在临床AD中均升高，（平均年龄65.3岁）相对于认知正常对照（平均年龄60.9岁）（P-tau 217 AUC=0.98，95%CI=[0.95-1.00]，P-tau 181 AUC=0.97，95%CI=[0.94-0.99]，p[差异]=0.31，n=75 vs 118）和病理学证实的AD（平均年龄72.8岁）vs FTLD（平均年龄67.1岁）（P-tau 217 AUC=0.96，95%CI=[0.92-1.00]，P-tau 181 AUC=0.91，95%CI=[0.82-1.00]，p[差异]=0.22，n=15 vs 68）。P-tau 217在区分临床AD与FTLD谱（平均年龄66.8岁）方面优于P-tau 181（P-tau 217 AUC=0.93，95%CI=[0.91-0.96]，P-tau 181 AUC=0.91，95%CI=[0.88-0.94]，p[差异]=0.007，n=75 vs 274）。P-tau 217是淀粉样蛋白-PET阳性的更强指标（P-tau 217：AUC=0.91，95%CI=[0.88-0.94]，P-tau 181：AUC=0.89，95%CI=[0.86-0.93]，p[差异]=0.049，n=146 vs 214）。颞叶皮质中的Tau-PET结合与P-tau 217的相关性比与P-tau 181的相关性更强（r=0.79 vs r=0.72，p[差异] <0.0001，n=230）。在使用匹配的免疫测定的直接比较中，P-tau 217和P-tau 181对于区分AD与其他组具有优异的诊断性能。对于临床AD的鉴别诊断、淀粉样蛋白-PET阳性的指示以及与tau-PET信号的更强相关性，存在有利于P-tau 217的小的但统计学显著的差异。在独立的、多样化的和较老的队列中待复制，血浆P-tau 217和P-tau 181可能是鉴定具有潜在淀粉样蛋白和AD tau病理学的个体的有用的筛选工具。美国国立卫生研究院、加州卫生服务部、雨水慈善基金会、迈克尔·J·福克斯基金会、阿尔茨海默氏症协会。
Plasma P-tau217 and P-tau181 are associated with Alzheimer’s disease (AD) tau pathology. P-tau217 is a more novel blood-based biomarker that may be diagnostically superior to P-tau181. We compared the diagnostic value of both biomarkers in a cohort of cognitively normal participants and patients with a clinical diagnosis of Mild Cognitive Impairment, AD or frontotemporal lobar degeneration (FTLD). In this multi-cohort diagnostic performance study, we gathered plasma samples from the University of California San Francisco Memory and Aging Center and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration consortium. Plasma Ptau-181 and Ptau-217 were measured using electrochemiluminescence-based assays which only differed in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid- and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses was tested with the Delong test. Data were collected from 593 participants (mean age 64 years [SD 13], 294 [49.6%] females) between July and November 2020. Plasma P-tau217 and P-181 were correlated (r=0.90, p<0·0001). Both P-tau217 and P-tau181 concentrations were increased in clinical AD (mean age 65.3 years) relative to cognitively normal controls (mean age 60.9 years) (P-tau217 AUC=0.98, 95%CI=[0.95–1.00], P-tau181 AUC=0.97, 95%CI=[0.94–0.99], p[difference]=0.31, n=75 vs 118) and in pathology-confirmed AD (mean age 72.8 years) vs FTLD (mean age 67.1 years) (P-tau217 AUC=0.96, 95%CI=[0.92–1.00], P-tau181 AUC=0.91, 95%CI=[0.82–1.00], p[difference]=0.22, n=15 vs 68). P-tau217 outperformed P-tau181 in differentiating clinical AD from FTLD spectrum (mean age 66.8 years) (P-tau217 AUC=0.93, 95%CI=[0.91–0.96], P-tau181 AUC=0.91, 95%CI=[0.88–0.94], p[difference]=0.007, n=75 vs 274). P-tau217 was a stronger indicator of amyloid-PET positivity (P-tau217: AUC=0.91, 95%CI=[0.88–0.94], P-tau181: AUC=0.89, 95%CI=[0.86–0.93], p[difference]=0.049, n=146 vs 214). Tau-PET binding in the temporal cortex was more strongly associated with P-tau217 than P-tau181 (r=0.79 vs r=0.72, p[difference] <0·0001, n=230). In a direct comparison using matched immunoassays, both P-tau217 and P-tau181 had excellent diagnostic performance for differentiating AD from other groups. There were small, but statistically significant differences in favor of P-tau217 for differential diagnosis of clinical AD, indication of amyloid-PET-positivity and stronger correlations with tau-PET signal. Pending replication in independent, diverse, and older cohorts, plasma P-tau217 and P-tau181 may be useful screening tools to identify individuals with underlying amyloid and AD tau pathology. US National Institutes of Health, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J Fox foundation, Alzheimer’s Association.