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Use of the tau protein-to-peptide ratio in CSF to improve diagnostic classification of Alzheimer's disease

Hansson, Karl ; Dahlén, Rahil ; Hansson, Oskar LU orcid ; Pernevik, Elin ; Paterson, Ross ; Schott, Jonathan M. ; Magdalinou, Nadia ; Zetterberg, Henrik LU ; Blennow, Kaj LU and Gobom, Johan (2019) In Clinical Mass Spectrometry 14. p.74-82
Abstract

Cerebrospinal fluid (CSF) tau and phospho-tau are well established biomarkers of Alzheimer's disease. While these measures are conventionally referred to as ‘total tau’ (T-tau) and ‘phospho-tau’ (P-tau), several truncated and modified tau forms exist that may relay additional diagnostic information. We evaluated the diagnostic performance of an endogenous tau peptide in CSF, tau 175–190, in the phosphorylated and non-phosphorylated state. A liquid chromatography-mass spectrometry (LC-MS) method was established to measure these peptides in CSF and was used to analyze two independent clinical cohorts; the first cohort included patients with Alzheimer's disease (AD, n = 15), Parkinson's disease (PD, n = 15), progressive supranuclear palsy... (More)

Cerebrospinal fluid (CSF) tau and phospho-tau are well established biomarkers of Alzheimer's disease. While these measures are conventionally referred to as ‘total tau’ (T-tau) and ‘phospho-tau’ (P-tau), several truncated and modified tau forms exist that may relay additional diagnostic information. We evaluated the diagnostic performance of an endogenous tau peptide in CSF, tau 175–190, in the phosphorylated and non-phosphorylated state. A liquid chromatography-mass spectrometry (LC-MS) method was established to measure these peptides in CSF and was used to analyze two independent clinical cohorts; the first cohort included patients with Alzheimer's disease (AD, n = 15), Parkinson's disease (PD, n = 15), progressive supranuclear palsy (PSP, n = 15), and healthy controls (n = 15), the second cohort included AD patients (n = 16), and healthy controls (n = 24). In both cohorts T-tau and P-tau concentrations were determined by immunoassay. While tau 175–190 and P-tau 175–190 did not differentiate the study groups, the separation of AD and controls by T-tau (area under the ROC Curve (AUC) = 95%) and P-tau (AUC = 92%) was improved when normalizing the ELISA measurements to the concentrations of the endogenous peptides: T-tau/tau 175–190 (AUC = 100%), P-tau/P-tau 175–190 (AUC = 95%). The separation between patients and controls by T-tau (AUC = 88%) and P-tau (AUC = 82%) was similarly improved in the second cohort by taking the ratios of T-tau/tau 175–190 (AUC = 97%) and P-tau/P-tau 175–190 (AUC = 98%). In conclusion, our results suggest that the performance of the AD biomarkers T-tau and P-tau could be improved by normalizing their measurements to the endogenous peptides tau 175–190 and P-tau 175–190, possibly because these endogenous tau peptides serve to normalize for physiological, and disease-independent, secretion of tau from neurons to the extracellular space and the CSF. Finally, the observations made here add to the general applicability of mass spectrometry as a tool for rapid identification and accurate quantification of biomarker candidates.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AD, Biomarker, Endogenous peptides, Mass spectrometry, Microtubule-associated protein tau, Peptidomics
in
Clinical Mass Spectrometry
volume
14
pages
9 pages
publisher
Elsevier
external identifiers
  • scopus:85074551807
ISSN
2376-9998
DOI
10.1016/j.clinms.2019.07.002
language
English
LU publication?
yes
id
9bfa740f-deb2-4674-a983-8114e42e5803
date added to LUP
2019-11-19 12:46:54
date last changed
2022-05-04 02:41:37
@article{9bfa740f-deb2-4674-a983-8114e42e5803,
  abstract     = {{<p>Cerebrospinal fluid (CSF) tau and phospho-tau are well established biomarkers of Alzheimer's disease. While these measures are conventionally referred to as ‘total tau’ (T-tau) and ‘phospho-tau’ (P-tau), several truncated and modified tau forms exist that may relay additional diagnostic information. We evaluated the diagnostic performance of an endogenous tau peptide in CSF, tau 175–190, in the phosphorylated and non-phosphorylated state. A liquid chromatography-mass spectrometry (LC-MS) method was established to measure these peptides in CSF and was used to analyze two independent clinical cohorts; the first cohort included patients with Alzheimer's disease (AD, n = 15), Parkinson's disease (PD, n = 15), progressive supranuclear palsy (PSP, n = 15), and healthy controls (n = 15), the second cohort included AD patients (n = 16), and healthy controls (n = 24). In both cohorts T-tau and P-tau concentrations were determined by immunoassay. While tau 175–190 and P-tau 175–190 did not differentiate the study groups, the separation of AD and controls by T-tau (area under the ROC Curve (AUC) = 95%) and P-tau (AUC = 92%) was improved when normalizing the ELISA measurements to the concentrations of the endogenous peptides: T-tau/tau 175–190 (AUC = 100%), P-tau/P-tau 175–190 (AUC = 95%). The separation between patients and controls by T-tau (AUC = 88%) and P-tau (AUC = 82%) was similarly improved in the second cohort by taking the ratios of T-tau/tau 175–190 (AUC = 97%) and P-tau/P-tau 175–190 (AUC = 98%). In conclusion, our results suggest that the performance of the AD biomarkers T-tau and P-tau could be improved by normalizing their measurements to the endogenous peptides tau 175–190 and P-tau 175–190, possibly because these endogenous tau peptides serve to normalize for physiological, and disease-independent, secretion of tau from neurons to the extracellular space and the CSF. Finally, the observations made here add to the general applicability of mass spectrometry as a tool for rapid identification and accurate quantification of biomarker candidates.</p>}},
  author       = {{Hansson, Karl and Dahlén, Rahil and Hansson, Oskar and Pernevik, Elin and Paterson, Ross and Schott, Jonathan M. and Magdalinou, Nadia and Zetterberg, Henrik and Blennow, Kaj and Gobom, Johan}},
  issn         = {{2376-9998}},
  keywords     = {{AD; Biomarker; Endogenous peptides; Mass spectrometry; Microtubule-associated protein tau; Peptidomics}},
  language     = {{eng}},
  pages        = {{74--82}},
  publisher    = {{Elsevier}},
  series       = {{Clinical Mass Spectrometry}},
  title        = {{Use of the tau protein-to-peptide ratio in CSF to improve diagnostic classification of Alzheimer's disease}},
  url          = {{http://dx.doi.org/10.1016/j.clinms.2019.07.002}},
  doi          = {{10.1016/j.clinms.2019.07.002}},
  volume       = {{14}},
  year         = {{2019}},
}