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

Research output: Contribution to journalArticle

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 (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.

Details

Authors
  • Karl Hansson
  • Rahil Dahlén
  • Oskar Hansson
  • Elin Pernevik
  • Ross Paterson
  • Jonathan M. Schott
  • Nadia Magdalinou
  • Henrik Zetterberg
  • Kaj Blennow
  • Johan Gobom
Organisations
External organisations
  • Skåne University Hospital
  • University College London
  • Sahlgrenska University Hospital
  • University of Gothenburg
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences

Keywords

  • AD, Biomarker, Endogenous peptides, Mass spectrometry, Microtubule-associated protein tau, Peptidomics
Original languageEnglish
Pages (from-to)74-82
Number of pages9
JournalClinical Mass Spectrometry
Volume14
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes