Wojdała Anna L, Bellomo Giovanni, Gaetani Lorenzo, Teunissen Charlotte E, Parnetti Lucilla, Chiasserini Davide
Laboratory of Clinical Neurochemistry, Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
Neurochemistry Laboratory, Department of Laboratory Medicine, Amsterdam UMC, Amsterdam, the Netherlands.
Nat Commun. 2025 Jan 2;16(1):214. doi: 10.1038/s41467-024-54878-8.
Different forms of phosphorylated tau (p-tau) have shown strong potential as Alzheimer's disease (AD) biomarkers in both cerebrospinal fluid (CSF) and plasma. We hypothesized that p-tau proteoforms simultaneously phosphorylated at two different sites may have an increased diagnostic value compared with tau phosphorylated at a single site. Here, we developed two immunoassays detecting CSF and plasma tau simultaneously phosphorylated at both T181 and T231 (p-tau181&231) and at T217 and T231 (p-tau217&231). Subsequently, we measured CSF and plasma p-tau181&231, p-tau217&231, p-tau181, p-tau217, and p-tau231 levels in two cohorts across the AD continuum and in frontotemporal dementia (FTD) patients (discovery n = 55, validation n = 118). CSF and plasma p-tau217&231, p-tau181, p-tau217, and p-tau231 and CSF, but not plasma, p-tau181&231 were significantly elevated in all AD continuum groups vs. Neurological Disease Control group. Notably, plasma p-tau217&231 consistently showed an improved diagnostic performance compared with single-site phosphorylation assays - p-tau217 or p-tau231. The differences observed between CSF and plasma measurements suggest matrix-specific protein processing, underscoring the need for further research on the dynamics of tau phosphorylation pattern along the AD continuum.
不同形式的磷酸化tau蛋白（p-tau）在脑脊液（CSF）和血浆中均显示出作为阿尔茨海默病（AD）生物标志物的强大潜力。我们假设，与单一位点磷酸化的tau蛋白相比，在两个不同位点同时磷酸化的p-tau蛋白亚型可能具有更高的诊断价值。在此，我们开发了两种免疫测定法，分别用于检测在T181和T231位点同时磷酸化的脑脊液和血浆tau蛋白（p-tau181&231）以及在T217和T231位点同时磷酸化的tau蛋白（p-tau217&231）。随后，我们在AD连续体的两个队列以及额颞叶痴呆（FTD）患者中测量了脑脊液和血浆中p-tau181&231、p-tau217&231、p-tau181、p-tau217和p-tau231的水平（发现队列n = 55，验证队列n = 118）。与神经疾病对照组相比，所有AD连续体组的脑脊液和血浆p-tau217&231、p-tau181、p-tau217和p-tau231以及脑脊液（而非血浆）p-tau181&231均显著升高。值得注意的是，与单一位点磷酸化检测（p-tau217或p-tau231）相比，血浆p-tau217&231始终表现出更好的诊断性能。脑脊液和血浆测量结果之间的差异表明存在基质特异性蛋白质加工，这突出了对AD连续体中tau磷酸化模式动态变化进行进一步研究的必要性。
