eprintid: 10089781
rev_number: 30
eprint_status: archive
userid: 608
dir: disk0/10/08/97/81
datestamp: 2020-01-17 15:10:20
lastmod: 2021-10-01 23:59:36
status_changed: 2020-01-17 15:10:20
type: article
metadata_visibility: show
creators_name: Blennow, K
creators_name: Chen, C
creators_name: Cicognola, C
creators_name: Wildsmith, KR
creators_name: Manser, PT
creators_name: Bohorquez, SMS
creators_name: Zhang, Z
creators_name: Xie, B
creators_name: Peng, J
creators_name: Hansson, O
creators_name: Kvartsberg, H
creators_name: Portelius, E
creators_name: Zetterberg, H
creators_name: Lashley, T
creators_name: Brinkmalm, G
creators_name: Kerchner, GA
creators_name: Weimer, RM
creators_name: Ye, K
creators_name: Höglund, K
title: Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology
ispublished: pub
divisions: UCL
divisions: B02
divisions: C07
divisions: D07
divisions: F86
keywords: Alzheimer’s disease, CSF, biomarkers, pathology, tau
note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
abstract: 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.
date: 2020-02
date_type: published
official_url: https://doi.org/10.1093/brain/awz346
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1732105
doi: 10.1093/brain/awz346
pii: 5675540
lyricists_name: Lashley, Tammaryn
lyricists_name: Zetterberg, Henrik
lyricists_id: TJOHN05
lyricists_id: HZETT94
actors_name: Zahnhausen-Stuber, Petra
actors_id: PMZAH20
actors_role: owner
full_text_status: public
publication: Brain
volume: 143
number: 2
article_number: 79
pagerange: 650-660
event_location: England
citation:        Blennow, K;    Chen, C;    Cicognola, C;    Wildsmith, KR;    Manser, PT;    Bohorquez, SMS;    Zhang, Z;                                                 ... Höglund, K; + view all <#>        Blennow, K;  Chen, C;  Cicognola, C;  Wildsmith, KR;  Manser, PT;  Bohorquez, SMS;  Zhang, Z;  Xie, B;  Peng, J;  Hansson, O;  Kvartsberg, H;  Portelius, E;  Zetterberg, H;  Lashley, T;  Brinkmalm, G;  Kerchner, GA;  Weimer, RM;  Ye, K;  Höglund, K;   - view fewer <#>    (2020)    Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology.                   Brain , 143  (2)    , Article 79.  10.1093/brain/awz346 <https://doi.org/10.1093/brain%2Fawz346>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10089781/3/Zetterberg_Blennow.pdf