Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease

Abstract

Highly sensitive and specific plasma biomarkers for Alzheimer’s disease (AD) have the potential to improve diagnostic accuracy in the clinic and facilitate research studies including enrollment in prevention and treatment trials. We recently reported CSF tau hyperphosphorylation, especially on T217, is an accurate predictor of β-amyloidosis at asymptomatic and symptomatic stages. In the current study, we determine by mass spectrometry the potential utility of plasma p-tau isoforms to detect AD pathology and investigate CSF and plasma tau isoforms’ profile relationships. Plasma tau was truncated as previously described in CSF. CSF and plasma measures of p-tau-217 and p-tau-181 were correlated. No correlation was found between CSF and plasma on total-tau levels and pS202 measures. We found p-tau-217 and p-tau-181 were highly specific for amyloid plaque pathology in the discovery cohort (n = 36, AUROC = 0.99 and 0.98 respectively). In the validation cohort (n = 92), p-tau-217 measures were still specific to amyloid status (AUROC = 0.92), and p-tau-181 measures were less specific (AUROC = 0.75).

Prediction of future Alzheimer’s disease dementia using plasma phospho-tau combined with other accessible measures

“…Plasma P-tau217 had higher predictive accuracy in BioFINDER than P-tau181 in ADNI. Although this might be caused by population-specific differences or preanalytical differences, the somewhat higher accuracy of P-tau217 is in agreement with previous comparisons between P-tau217 and P-tau181 both in plasma 16,23 and in CSF 3,34 .…”

Peripheral Blood and Salivary Biomarkers of Blood–Brain Barrier Permeability and Neuronal Damage: Clinical and Applied Concepts

“…Accumulating evidence points to blood phosphorylated tau as a promising biomarker to improve the diagnosis and staging of and to enable trials in Alzheimer's disease (AD) subjects. In a cross-sectional study performed in AD patients, phosphorylated tau isoforms were used as diagnostic biomarkers to track disease progression ( 91 ). A method measuring attomolar concentrations of tau isoforms in plasma was implemented using stable isotope labeling kinetics and mass spectroscopy.…”

Significance of Blood and Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease: Sensitivity, Specificity and Potential for Clinical Use

“…While writing this review, two groups published strong data in support of the use of a blood-based assay detecting p-T217 tau. First, Barthelemy et al [ 256 ] developed a protocol of purification and enrichment of tau from plasma, followed by liquid chromatography (LC-MS); this system (1) allows reliable detection of p-T217 showing high correlation with the CSF measurements, and (2) confirms the ability of this biomarker in clustering amyloid positive and negative patients. The limitation of this strategy is the high volume of blood needed to purify and extract tau and the elaborate methodology, not compatible with the idea of developing a fast and easy-to- use assay.…”

“…The limitation of this strategy is the high volume of blood needed to purify and extract tau and the elaborate methodology, not compatible with the idea of developing a fast and easy-to- use assay. In the second study, Palmqvist et al [ 256 ] employed the Meso Scale Discovery (MSD)/Lilly platform (described below) and validated the value of p-T217 in plasma to discriminate Aβ+ MCI and AD patients from other neurodegenerative disorders and controls, including sensitive discrimination of autosomal-dominant pre-symptomatic Aβ+ patients. In all, given the high potential of measuring CSF p-T217 previously described, it will be of great interest to follow the development and validation of novel ultrasensitive platforms aimed at detecting p-T217 in blood, employing fully automated platforms to integrate this biomarker in clinical practice.…”

“…To further quantify tau at high sensitivity, Barthelemy et al has developed a protocol to detect tau and p-tau in CSF and plasma employing targeted high-resolution mass spectrometry (MS) [ 225 , 226 , 256 , 260 , 261 ]. Additionally, superconducting-quantum-interference-device Immunomagnetic reduction (SQUID-IMR) has proven efficient at quantifying t-tau and p-T181 in plasma in early stages of AD [ 172 , 252 ].…”