血浆脑源性tau蛋白：首个商业化免疫测定法的分析与临床验证

Plasma brain-derived tau: analytical and clinical validation of the first commercial immunoassay.

作者信息

Nafash Michel N, Svirsky Sarah E, Zeng Xuemei, Chen Yijun, Kofler Julia, Cohen Ann D, Okonkwo David O, Lopez Oscar L, Puccio Ava M, Karikari Thomas K

机构信息

Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Biofluid Biomarker Laboratory, Western Psychiatric Hospital, University of Pittsburgh Medical Center, Pittsburgh PA, USA.

出版信息

medRxiv. 2025 Jul 21:2025.07.21.25331193. doi: 10.1101/2025.07.21.25331193.

BACKGROUND

Brain-derived tau (BD-tau) is a promising blood-based biomarker for neurodegeneration/brain injury in neurodegenerative and acute neurological disorders. However, widespread use is hampered by lack of commercial assays. We evaluated the analytical and clinical validity of the first commercial research use only BD-tau assay - the Quanterix BD-tau Advantage PLUS.

METHODS

Using the Simoa HD-X analyzer, we evaluated the assay's robustness, precision, dilution linearity, spike recovery, specificity, and limits of detection. Matrix effect was examined by comparing BD-tau levels in n=48 plasma/serum and n=20 plasma/CSF sample pairs. Clinical performance was examined in a traumatic brain injury (TBI) cohort.

RESULTS

Twenty repeated measurements of three plasma samples gave intra- and inter-plate CVs ≤7.24%. A median drift of 8.00% (decrease) was observed from the start to the end of a full plate run. Analytically, BD-tau concentrations decreased linearly up to 16-fold dilution, spike recovery was 86-96%, and signals were highly specific to the CNS-abundant 2N4R but not the peripherally-enriched "big-tau" isoform. Moreover, signals were stable for up to four freeze/thaw cycles. Furthermore, significant correlations were observed in the plasma/serum (r=0.8392; p<0.0001) and plasma/CSF (r=0.6150; p=0.0039) pairs. Finally, CSF and plasma BD-tau was elevated in severe-acute TBI vs. chronic-mixed TBI and unaffected controls (p<0.0001; AUC=0.9986, and p<0.0001; AUC=1.000, respectively). In severe-acute TBI patients, plasma BD-tau was correlated with plasma p-tau217 (r=0.5761, p=0.0005), NfL (r=0.8910, p=0.0001), and GFAP (r=0.5424, p=0.0011). CSF BD-tau and CSF p-tau217 were strongly correlated (r=0.9667, p=0.0002).

CONCLUSION

BD-tau Advantage PLUS produces robust brain-derived tau-specific readings that demonstrate utility in detecting severe-acute TBI.

背景

脑源性tau蛋白（BD-tau）是一种很有前景的基于血液的生物标志物，可用于神经退行性疾病和急性神经系统疾病中的神经退行性变/脑损伤。然而，由于缺乏商业检测方法，其广泛应用受到阻碍。我们评估了首个仅用于商业研究的BD-tau检测方法——Quanterix BD-tau Advantage PLUS的分析和临床有效性。

方法

使用Simoa HD-X分析仪，我们评估了该检测方法的稳健性、精密度、稀释线性、加标回收率、特异性和检测限。通过比较48对血浆/血清和20对血浆/脑脊液样本中的BD-tau水平来检查基质效应。在创伤性脑损伤（TBI）队列中检查临床性能。

结果

对三个血浆样本进行20次重复测量，板内和板间变异系数（CV）≤7.24%。在一次完整的板运行开始到结束时，观察到中位数漂移为8.00%（下降）。在分析方面，BD-tau浓度在高达16倍稀释时呈线性下降，加标回收率为86-96%，信号对中枢神经系统丰富的2N4R具有高度特异性，而对外周富集的“大tau”异构体则无特异性。此外，信号在多达四个冻融循环中保持稳定。此外，在血浆/血清对（r=0.8392；p<0.0001）和血浆/脑脊液对（r=0.6150；p=0.0039）中观察到显著相关性。最后，与慢性混合性TBI和未受影响的对照组相比，严重急性TBI患者的脑脊液和血浆BD-tau升高（分别为p<0.0001；AUC=0.9986，以及p<0.0001；AUC=1.000）。在严重急性TBI患者中，血浆BD-tau与血浆p-tau217（r=0.5761，p=0.0005）、神经丝轻链（NfL，r=0.8910，p=0.0001）和胶质纤维酸性蛋白（GFAP，r=0.5424，p=0.0011）相关。脑脊液BD-tau和脑脊液p-tau217高度相关（r=0.9667, p=0.0002）。