Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology
Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology
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DOI：
10.1093/brain/awz346
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发表时间：
2020-02-01
期刊：
影响因子：
14.5
通讯作者：
Hoglund, Kina
中科院分区：
文献类型：
--
作者：
Blennow, Kaj;Chen, Chun;Hoglund, Kina
到目前为止，还没有用于阿尔茨海默病tau病理的有效液体生物标记物，这与评估脑脊液中磷酸化tau与tau PET成像之间的相关性的研究得出的结果相互矛盾。Tau蛋白在被分泌到脑脊液之前会被蛋白质分解成片段。最近的一项研究表明，天冬酰胺内肽酶(AEP)在氨基酸368之后对tau的切割在阿尔茨海默病中上调。我们使用免疫沉淀和质谱分析来评估脑脊液中tau368种物质的存在。建立了一种新的脑脊液中tau368的SIMOE(R)定量方法，同时用ELISA法测定总tau(t-tau)，并用免疫组织化学方法检测脑脊液中tau368的存在。Tau368的诊断效用首先在一项初步研究中进行了评估(阿尔茨海默病=20，对照=20)，然后在应用IWG-2生物标记物标准的第二个队列中(阿尔茨海默病=37，对照=45)，最后在第三个队列中，评估了与F-18-GTP1 tau PET的相关性(阿尔茨海默病=38，对照=11)。在所有队列中，阿尔茨海默病患者的tau368/t-tau比率均显著降低(P<；0.001)。免疫组织化学染色显示，在368结束的tau片段以缠结形式存在。脑脊液tau368/t-tau比值与F-18-GTPI滞留呈显著负相关。我们的数据表明tau368是一个富含缠结的片段，而脑脊液tau368/t-tau的比率反映了缠结的病理。这种新的tau生物标志物可用于提高对阿尔茨海默病的诊断，并促进针对tau病理的候选药物的开发。此外，未来的纵向研究将增加我们对tau在阿尔茨海默病和其他tau病中的病理生理学的理解。
To date, there is no validated fluid biomarker for tau pathology in Alzheimer's disease, with contradictory results from studies evaluating the correlation between phosphorylated tau in CSF with tau PET imaging. Tau protein is subjected to proteolytic processing into fragments before being secreted to the CSF. A recent study suggested that tau cleavage after amino acid 368 by asparagine endopeptidase (AEP) is upregulated in Alzheimer's disease. We used immunoprecipitation followed by mass spectrometric analyses to evaluate the presence of tau368 species in CSF. A novel Simoe (R) assay for quantification of tau368 in CSF was developed, while total tau (t-tau) was measured by ELISA and the presence of tau368 in tangles was evaluated using immunohistochemistry. The diagnostic utility of tau368 was first evaluated in a pilot study (Alzheimer's disease = 20, control = 20), then in a second cohort where the IWG-2 biomarker criteria were applied (Alzheimer's disease = 37, control = 45), and finally in a third cohort where the correlation with F-18-GTP1 tau PET was evaluated (Alzheimer's disease = 38, control = 11). The tau368/t-tau ratio was significantly decreased in Alzheimer's disease (P < 0.001) in all cohorts. Immunohistochemical staining demonstrated that tau fragments ending at 368 are present in tangles. There was a strong negative correlation between the CSF tau368/t-tau ratio and F-18-GTPI retention. Our data suggest that tau368 is a tangle-enriched fragment and that the CSF ratio tau368/t-tau reflects tangle pathology. This novel tau biomarker could be used to improve diagnosis of Alzheimer's disease and to facilitate the development of drug candidates targeting tau pathology. Furthermore, future longitudinal studies will increase our understanding of tau pathophysiology in Alzheimer's disease and other tauopathies.