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

Karl Hansson; Rahil Dahlén; Oskar Hansson; Elin Pernevik; Ross Paterson; Jonathan M Schott; Nadia Magdalinou; Henrik Zetterberg; Kaj Blennow; Johan Gobom

doi:10.1016/j.clinms.2019.07.002

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

Clin Mass Spectrom. 2019 Jul 15:14 Pt B:74-82. doi: 10.1016/j.clinms.2019.07.002. eCollection 2019 Nov.

Authors

Karl Hansson¹, Rahil Dahlén¹, Oskar Hansson^{2

3}, Elin Pernevik¹, Ross Paterson⁴, Jonathan M Schott⁴, Nadia Magdalinou⁵, Henrik Zetterberg^{1

6}, Kaj Blennow^{1

6}, Johan Gobom^{1

6}

Affiliations

¹ Institute of Neuroscience and Physiology, Department of Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
² Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
³ Memory Clinic, Skåne University Hospital, Malmö, Sweden.
⁴ Dementia Research Centre, UCL Institute of Neurology, London, UK.
⁵ Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, Queen Square, London, UK.
⁶ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

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.

Keywords: AD; AD, Alzheimer’s disease; AUC, Area under the ROC curve; Biomarker; CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; Endogenous peptides; GdnHCl, Guanidinium hydrochloride; Mass spectrometry; Microtubule-associated protein tau; P-tau, phospho-tau protein; PD, Parkinson’s disease; PSP, Progressive Supranuclear Palsy; Peptidomics; SIL, peptide Synthetic isotope-labelled peptide; T-tau, total tau protein.