The Tracy Family SILQ Center, Washington University School of Medicine, St Louis, MO, USA.
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Nat Med. 2023 Aug;29(8):1954-1963. doi: 10.1038/s41591-023-02443-z. Epub 2023 Jul 13.
Aggregated insoluble tau is one of two defining features of Alzheimer's disease. Because clinical symptoms are strongly correlated with tau aggregates, drug development and clinical diagnosis need cost-effective and accessible specific fluid biomarkers of tau aggregates; however, recent studies suggest that the fluid biomarkers currently available cannot specifically track tau aggregates. We show that the microtubule-binding region (MTBR) of tau containing the residue 243 (MTBR-tau243) is a new cerebrospinal fluid (CSF) biomarker specific for insoluble tau aggregates and compared it to multiple other phosphorylated tau measures (p-tau181, p-tau205, p-tau217 and p-tau231) in two independent cohorts (BioFINDER-2, n = 448; and Knight Alzheimer Disease Research Center, n = 219). MTBR-tau243 was most strongly associated with tau-positron emission tomography (PET) and cognition, whereas showing the lowest association with amyloid-PET. In combination with p-tau205, MTBR-tau243 explained most of the total variance in tau-PET burden (0.58 ≤ R ≤ 0.75) and the performance in predicting cognitive measures (0.34 ≤ R ≤ 0.48) approached that of tau-PET (0.44 ≤ R ≤ 0.52). MTBR-tau243 levels longitudinally increased with insoluble tau aggregates, unlike CSF p-tau species. CSF MTBR-tau243 is a specific biomarker of tau aggregate pathology, which may be utilized in interventional trials and in the diagnosis of patients. Based on these findings, we propose to revise the A/T/(N) criteria to include MTBR-tau243 as representing insoluble tau aggregates ('T').
聚集的不溶性 tau 蛋白是阿尔茨海默病的两个定义特征之一。由于临床症状与 tau 聚集物密切相关，因此药物开发和临床诊断需要具有成本效益且易于获得的 tau 聚集物的特异性液体生物标志物；然而，最近的研究表明，目前可用的液体生物标志物不能特异性地追踪 tau 聚集物。我们表明，含有残基 243 的微管结合区（MTBR）的 tau（MTBR-tau243）是一种新的脑脊液（CSF）生物标志物，特异性针对不溶性 tau 聚集物，并将其与其他多个磷酸化 tau 测量值（p-tau181、p-tau205、p-tau217 和 p-tau231）进行了比较在两个独立的队列中（BioFINDER-2，n = 448；和 Knight Alzheimer 疾病研究中心，n = 219）。MTBR-tau243 与 tau 正电子发射断层扫描（PET）和认知能力的相关性最强，而与淀粉样蛋白-PET 的相关性最低。与 p-tau205 相结合，MTBR-tau243 解释了 tau-PET 负担的大部分总方差（0.58 ≤ R ≤ 0.75）和预测认知测量值的性能（0.34 ≤ R ≤ 0.48）接近 tau-PET（0.44 ≤ R ≤ 0.52）。与 CSF p-tau 物种不同，MTBR-tau243 水平随不溶性 tau 聚集物而纵向增加。CSF MTBR-tau243 是 tau 聚集物病理学的特异性生物标志物，可用于干预试验和患者诊断。基于这些发现，我们建议修订 A/T/(N) 标准，将 MTBR-tau243 纳入代表不溶性 tau 聚集物的“T”。
