Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
Alzheimers Res Ther. 2022 May 11;14(1):65. doi: 10.1186/s13195-022-01011-w.
Blood phosphorylated tau (p-tau) forms are promising Alzheimer's disease (AD) biomarkers, but validation in matrices other than ethylenediaminetetraacetic acid (EDTA) plasma is limited. Firstly, we assessed the diagnostic potential of p-tau231 and p-tau181 in paired plasma and serum samples. Secondly, we compared serum and cerebrospinal fluid (CSF) samples from biomarker-positive AD and biomarker-negative control participants.
We studied three independent cohorts (n=115 total): cohorts 1 and 2 included individuals with paired plasma and serum, while cohort 3 included paired serum and CSF. Blood-based p-tau231 and p-tau181 were measured using in-house or commercial single molecule array (Simoa) methods.
Serum and plasma p-tau231 and p-tau181 were two- to three-fold increased in biomarker-positive AD versus biomarker-negative controls (P≤0.0008). Serum p-tau231 separated diagnostic groups with area under the curve (AUC) of 82.2% (cohort 3) to 88.2% (cohort 1) compared with 90.2% (cohort 1) for plasma. Similarly, p-tau181 showed AUC of 89.6% (cohort 1) to 89.8% (cohort 3) in serum versus 85.4% in plasma (cohort 1). P-tau231 and p-tau181 correlated slightly better in serum (rho=0.92 for cohort 1, 0.93 for cohort 3) than in plasma (rho=0.88, cohort 1). Within-individual p-tau181 (Quanterix) and p-tau231 concentrations were twice higher in plasma versus serum, but p-tau181 (in-house, Gothenburg) levels were not statistically different. Bland-Altman plots revealed that the relative difference between serum/plasma was larger in the lower range. P-tau levels in paired plasma and serum correlated strongly with each other (rho=0.75-0.93) as well as with CSF Aβ (rho= -0.56 to -0.59), p-tau and total-tau (rho=0.53-0.73). Based on the results, it seems possible that serum p-tau reflects the same pool of brain-secreted p-tau as in CSF; we estimated that less than 2% of CSF p-tau is found in serum, being same for both controls and AD.
Comparable diagnostic performances and strong correlations between serum versus plasma pairs suggest that p-tau analyses can be expanded to research cohorts and hospital systems that prefer serum to other blood matrices. However, absolute biomarker concentrations may not be interchangeable, indicating that plasma and serum samples should be used independently. These results should be validated in independent cohorts.
血液磷酸化 tau（p-tau）形式是有前途的阿尔茨海默病（AD）生物标志物，但在乙二胺四乙酸（EDTA）以外的其他基质中进行验证的情况有限。首先，我们评估了 p-tau231 和 p-tau181 在配对血浆和血清样本中的诊断潜力。其次，我们比较了生物标志物阳性 AD 和生物标志物阴性对照参与者的血清和脑脊液（CSF）样本。
我们研究了三个独立的队列（共 115 人）：队列 1 和 2 包括配对的血浆和血清样本，而队列 3 包括配对的血清和 CSF 样本。使用内部或商业单分子阵列（Simoa）方法测量血液中的 p-tau231 和 p-tau181。
与生物标志物阴性对照组相比，生物标志物阳性 AD 患者的血清和血浆 p-tau231 和 p-tau181 增加了两到三倍（P≤0.0008）。与血浆相比，p-tau231 以 82.2%（队列 3）至 88.2%（队列 1）的 AUC 将诊断组分开，血清中 p-tau231 的 AUC 为 89.6%（队列 1）至 89.8%（队列 3）。同样，血清中的 p-tau181 显示 AUC 为 89.6%（队列 1）至 89.8%（队列 3），而血浆中的 AUC 为 85.4%（队列 1）。p-tau231 和 p-tau181 在血清中的相关性稍好（队列 1 的 rho=0.92，队列 3 的 rho=0.93），而在血浆中的相关性稍差（rho=0.88，队列 1）。个体内 p-tau181（Quanterix）和 p-tau231 浓度在血浆中是血清中的两倍，但 p-tau181（哥德堡内部）水平无统计学差异。Bland-Altman 图显示，血清/血浆之间的相对差异在较低范围内更大。配对血浆和血清中的 p-tau 水平彼此之间以及与 CSF Aβ（rho=-0.56 至-0.59）、p-tau 和总 tau（rho=0.53-0.73）密切相关。根据这些结果，似乎可以认为血清 p-tau 反映了与 CSF 中相同的脑分泌 p-tau 池；我们估计，CSF 中不到 2%的 p-tau 存在于血清中，在对照组和 AD 患者中均相同。
血清与血浆对之间可比的诊断性能和强烈相关性表明，p-tau 分析可以扩展到更倾向于使用血清而不是其他血液基质的研究队列和医院系统。然而，绝对生物标志物浓度可能无法互换，这表明血浆和血清样本应独立使用。这些结果应在独立队列中得到验证。
