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

Hansson, K; Dahlen, R; Hansson, O; Pernevik, E; Paterson, R; Schott, JM; Magdalinou, N; ... Gobom, J; + view all (2019) Use of the tau protein-to-peptide ratio in CSF to improve diagnostic classification of Alzheimer's disease. Clinical Mass Spectrometry , 14 (Part B) pp. 74-82. 10.1016/j.clinms.2019.07.002. Green open access

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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.

Type: Article
Title: Use of the tau protein-to-peptide ratio in CSF to improve diagnostic classification of Alzheimer's disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.clinms.2019.07.002
Publisher version: https://doi.org/10.1016/j.clinms.2019.07.002
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: AD, Microtubule-associated protein tau, Endogenous peptides, Biomarker, Peptidomics, Mass spectrometry, CEREBROSPINAL-FLUID, PHOSPHORYLATED-TAU, CRITERIA, QUANTIFICATION, THREONINE-181, BIOMARKERS
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10087031
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