Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
Turku PET Centre, University of Turku, Turku, Finland.
Brain. 2022 Aug 27;145(8):2834-2848. doi: 10.1093/brain/awab481.
Brain-derived tau secreted into CSF and blood consists of different N-terminal and mid-domain fragments, which may have a differential temporal course and thus, biomarker potential across the Alzheimer's disease continuum or in other neurological diseases. While current clinically validated total tau assays target mid-domain epitopes, comparison of these assays with new biomarkers targeting N-terminal epitopes using the same analytical platform may be important to increase the understanding of tau pathophysiology. We developed three total tau immunoassays targeting specific N-terminal (NTA and NTB total tau) or mid-region (MR total tau) epitopes, using single molecule array technology. After analytical validation, the diagnostic performance of these biomarkers was evaluated in CSF and compared with the Innotest total tau (and as proof of concept, with N-p-tau181 and N-p-tau217) in three clinical cohorts (n = 342 total). The cohorts included participants across the Alzheimer's disease continuum (n = 276), other dementias (n = 22), Creutzfeldt-Jakob disease (n = 24), acute neurological disorders (n = 18) and progressive supranuclear palsy (n = 22). Furthermore, we evaluated all three new total tau biomarkers in plasma (n = 44) and replicated promising findings with NTA total tau in another clinical cohort (n = 50). In CSF, all total tau biomarkers were increased in Alzheimer's disease compared with controls (P < 0.0001) and correlated with each other (rs = 0.53-0.95). NTA and NTB total tau, but not other total tau assays, distinguished amyloid-positive and amyloid-negative mild cognitive impairment with high accuracies (AUCs 84% and 82%, P < 0.001) matching N-p-tau217 (AUC 83%; DeLong test P = 0.93 and 0.88). All total tau assays were excellent in differentiating Alzheimer's disease from other dementias (P < 0.001, AUCs 89-100%). In Creutzfeldt-Jakob disease and acute neurological disorders, N-terminal total tau biomarkers had significantly higher fold changes versus controls in CSF (45-133-fold increase) than Innotest or MR total tau (11-42-fold increase, P < 0.0001 for all). In progressive supranuclear palsy, CSF concentrations of all total tau biomarkers were similar to those in controls. Plasma NTA total tau concentrations were increased in Alzheimer's disease compared with controls in two independent cohorts (P = 0.0056 and 0.0033), while Quanterix total tau performed poorly (P = 0.55 and 0.44). Taken together, N-terminal-directed CSF total tau biomarkers increase ahead of standard total tau alternatives in the Alzheimer's disease continuum, increase to higher degrees in Creutzfeldt-Jakob disease and acute neurological diseases and show better potential than Quanterix total tau as Alzheimer's disease blood biomarkers. For progressive supranuclear palsy, other tau biomarkers should continue to be investigated.
脑源性 tau 分泌到 CSF 和血液中，由不同的 N 端和中间结构域片段组成，这些片段可能具有不同的时间过程，因此在阿尔茨海默病连续体或其他神经疾病中具有潜在的生物标志物。虽然目前临床上验证的总 tau 检测方法针对中间结构域表位，但使用相同的分析平台比较这些检测方法与针对 N 端表位的新生物标志物，可能有助于增加对 tau 病理生理学的理解。我们使用单分子阵列技术开发了三种针对特定 N 端（NTA 和 NTB 总 tau）或中间区域（MR 总 tau）表位的总 tau 免疫测定法。经过分析验证后，在三个临床队列（共 342 名参与者）中评估了这些生物标志物在 CSF 中的诊断性能，并与 Innotest 总 tau（以及作为概念验证，与 N-p-tau181 和 N-p-tau217）进行了比较。队列包括跨越阿尔茨海默病连续体的参与者（n=276）、其他痴呆症（n=22）、克雅氏病（n=24）、急性神经障碍（n=18）和进行性核上性麻痹（n=22）。此外，我们评估了所有三种新的总 tau 生物标志物在血浆中的浓度（n=44），并在另一个临床队列（n=50）中复制了 NTA 总 tau 的有希望的发现。在 CSF 中，与对照组相比，所有总 tau 生物标志物在阿尔茨海默病患者中均升高（P<0.0001），并且彼此相关（rs=0.53-0.95）。NTA 和 NTB 总 tau 可以区分淀粉样蛋白阳性和淀粉样蛋白阴性的轻度认知障碍，准确率高（AUC 分别为 84%和 82%，P<0.001），与 N-p-tau217 相匹配（AUC 为 83%；DeLong 检验 P=0.93 和 0.88）。所有总 tau 检测方法在区分阿尔茨海默病与其他痴呆症方面均表现出色（P<0.001，AUC 为 89-100%）。在克雅氏病和急性神经障碍中，与对照组相比，N 端总 tau 生物标志物在 CSF 中的 fold change 显著更高（45-133 倍增加），而 Innotest 或 MR 总 tau 则为 11-42 倍增加（所有 P<0.0001）。在进行性核上性麻痹中，所有总 tau 生物标志物在 CSF 中的浓度与对照组相似。在两个独立的队列中，与对照组相比，阿尔茨海默病患者的血浆 NTA 总 tau 浓度升高（P=0.0056 和 0.0033），而 Quanterix 总 tau 的表现不佳（P=0.55 和 0.44）。总的来说，在阿尔茨海默病连续体中，针对 N 端的 CSF 总 tau 生物标志物比标准总 tau 替代物更早升高，在克雅氏病和急性神经疾病中升高幅度更高，并且作为阿尔茨海默病的血液生物标志物，其潜力优于 Quanterix 总 tau。对于进行性核上性麻痹，应继续研究其他 tau 生物标志物。
