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Cerebrospinal fluid tau fragment correlates with tau PET : a candidate biomarker for tangle pathology

Blennow, Kaj LU ; Chen, Chun ; Cicognola, Claudia LU orcid ; Wildsmith, Kristin R. ; Manser, Paul T. ; Bohorquez, Sandra M.Sanabria ; Zhang, Zhentao ; Xie, Boer ; Peng, Junmin and Hansson, Oskar LU orcid , et al. (2020) In Brain : a journal of neurology 143(2). p.650-660
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer’s disease, biomarkers, CSF, pathology, tau
in
Brain : a journal of neurology
volume
143
issue
2
pages
11 pages
publisher
Oxford University Press
external identifiers
  • pmid:31834365
  • scopus:85079250334
ISSN
1460-2156
DOI
10.1093/brain/awz346
language
English
LU publication?
yes
id
7508c1f3-35a9-4b3a-9036-49f9aadfa5d1
date added to LUP
2020-02-20 15:16:24
date last changed
2024-03-20 05:01:08
@article{7508c1f3-35a9-4b3a-9036-49f9aadfa5d1,
  abstract     = {{<p>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 &lt; 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.</p>}},
  author       = {{Blennow, Kaj and Chen, Chun and Cicognola, Claudia and Wildsmith, Kristin R. and Manser, Paul T. and Bohorquez, Sandra M.Sanabria and Zhang, Zhentao and Xie, Boer and Peng, Junmin and Hansson, Oskar and Kvartsberg, Hlin and Portelius, Erik and Zetterberg, Henrik and Lashley, Tammaryn and Brinkmalm, Gunnar and Kerchner, Geoffrey A. and Weimer, Robby M. and Ye, Keqiang and Höglund, Kina}},
  issn         = {{1460-2156}},
  keywords     = {{Alzheimer’s disease; biomarkers; CSF; pathology; tau}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{650--660}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain : a journal of neurology}},
  title        = {{Cerebrospinal fluid tau fragment correlates with tau PET : a candidate biomarker for tangle pathology}},
  url          = {{http://dx.doi.org/10.1093/brain/awz346}},
  doi          = {{10.1093/brain/awz346}},
  volume       = {{143}},
  year         = {{2020}},
}