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 Simoa® 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 18F-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 18F-GTP1 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.

中文翻译：

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脑脊液tau片段与tau PET相关：缠结病理的候选生物标志物。

迄今为止，尚无经过验证的阿尔茨海默氏病tau病理学液体生物标志物，与评估tau PET成像中CSF中磷酸化tau之间相关性的研究结果相矛盾。Tau蛋白在分泌到CSF之前经过蛋白水解加工成片段。最近的一项研究表明，在阿尔茨海默氏病中，天冬酰胺内肽酶（AEP）对368位氨基酸后的tau裂解有上调作用。我们使用了免疫沉淀，随后进行了质谱分析，以评估脑脊液中tau368物种的存在。开发了一种新颖的Simoa®方法测定脑脊液中tau368的含量，同时通过ELISA测定总tau（t-tau），并使用免疫组织化学方法评估缠结中tau368的存在。首先在一项初步研究中评估了tau368的诊断效用（Alzheimer' 疾病= 20，对照组= 20），然后在第二个队列中应用IWG-2生物标志物标准（阿尔茨海默氏病= 37，对照组= 45），最后在第三队列中与18F-GTP1 tau PET相关被评估（阿尔茨海默氏病＝ 38，对照＝ 11）。在所有人群中，阿尔茨海默氏病的tau368 / t-tau比值均显着降低（P <0.001）。免疫组织化学染色显示缠结中存在以368结尾的tau片段。CSF tau368 / t-tau比与18F-GTP1保留之间存在很强的负相关性。我们的数据表明，tau368是缠结丰富的片段，而脑脊液比率tau368 / t-tau反映了缠结病理。这种新型的tau生物标记物可用于改善阿尔茨海默氏病的诊断 疾病并促进针对tau病理学的候选药物的开发。此外，未来的纵向研究将增进我们对阿尔茨海默氏病和其他陶氏病中tau病理生理学的理解。