Snellman, Anniina; Lantero-Rodriguez, Juan; Emeršič, Andreja; Vrillon, Agathe; Karikari, Thomas K; Ashton, Nicholas J; Gregorič Kramberger, Milica; ... Blennow, Kaj; + view all Snellman, Anniina; Lantero-Rodriguez, Juan; Emeršič, Andreja; Vrillon, Agathe; Karikari, Thomas K; Ashton, Nicholas J; Gregorič Kramberger, Milica; Čučnik, Saša; Paquet, Claire; Rot, Uroš; Zetterberg, Henrik; Blennow, Kaj; - view fewer (2022) N-terminal and mid-region tau fragments as fluid biomarkers in neurological diseases. Brain 10.1093/brain/awab481. (In press).

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Abstract

Brain-derived tau secreted into CSF and blood consists of different N-terminal and mid-domain fragments, which may have a differential temporal course and thus, biomarker potential across the Alzheimer's disease continuum or in other neurological diseases. While current clinically validated total-tau (t-tau) assays target mid-domain epitopes, comparison of these assays with new biomarkers targeting N-terminal epitopes using the same analytical platform may be important to increase the understanding of tau pathophysiology. We developed three t-tau immunoassays targeting specific N-terminal (NTA and NTB t-tau) or mid-region (MR t-tau) epitopes, using single molecule array technology. After analytical validation, the diagnostic performance of these biomarkers was evaluated in CSF and compared with the Innotest t-tau (and as proof of concept, with N-p-tau181 and N-p-tau217) in three clinical cohorts (n = 342 total). The cohorts included participants across the Alzheimer's disease continuum (n = 276), other dementia (n = 22), Creutzfeldt-Jakob disease (n = 24), acute neurological disorders (n = 18) and progressive supranuclear palsy (n = 22). Furthermore, we evaluated all three new t-tau biomarkers in plasma (n = 44) and replicated promising findings with NTA t-tau in another clinical cohort (n = 50). In CSF, all t-tau biomarkers were increased in Alzheimer's disease compared with controls (P < 0.0001) and correlated with each other (rs = 0.53-0.95). NTA and NTB t-tau, but not other t-tau assays, distinguished amyloid-positive and amyloid-negative mild cognitive impairment with high accuracies (AUCs 84% and 82%, P < 0.001) matching N-p-tau217 (AUC 83%; DeLong test P = 0.93 and 0.88). All t-tau assays were excellent in differentiating Alzheimer's disease from other dementias (P < 0.001, AUCs 89-100%). In Creutzfeldt-Jakob disease and acute neurological disorders, N-terminal t-tau biomarkers had significantly higher fold changes versus controls in CSF (45-133-fold increase) than Innotest or MR t-tau (11-42-fold increase, P < 0.0001 for all). In progressive supranuclear palsy, CSF concentrations of all t-tau biomarkers were similar to those in controls. Plasma NTA t-tau concentrations were increased in Alzheimer's disease compared with controls in two independent cohorts (P = 0.0056 and 0.0033) while Quanterix t-tau performed poorly (P = 0.55 and 0.44). Taken together, N-terminal-directed CSF t-tau biomarkers increase ahead of standard t-tau alternatives in the Alzheimer's disease continuum, increase to higher degrees in Creutzfeldt-Jakob disease and acute neurological diseases and show better potential than Quanterix t-tau as Alzheimer's disease blood biomarkers. For progressive supranuclear palsy, other tau biomarkers should still be investigated.

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