Exploring the ability of plasma pTau217, pTau181 and beta-amyloid in mirroring cerebrospinal fluid biomarker profile of Mild Cognitive Impairment by the fully automated Lumipulse® platform

Abstract

Background: The approval of new disease-modifying therapies by the U.S. Food and Drug Administration and the European Medicine Agency makes it necessary to optimize non-invasive and cost-effective tools for the identification of subjects at-risk of developing Alzheimer's Disease (AD). Plasma biomarkers are excellent candidates. However, their ability to reflect the cerebrospinal fluid (CSF) profile - that remains to date the gold standard for the biochemical diagnosis of AD - needs to be confirmed and validated before their implementation in clinical practice. The aims of this study are to analyse the correlation between CSF and plasma Aβ40, Aβ42, Aβ42/Aβ40 and pTau181, and to assess the diagnostic performance of plasma biomarkers in a cohort of subjects affected by Mild Cognitive Impairment (MCI).

Methods: The study was performed on 306 subjects affected by MCI, enrolled in the context of the Italian Interceptor Project. Aβ40, Aβ42 and pTau181 were analysed in plasma and CSF, and pTau217 was measured in plasma. The fully automated chemiluminescence enzyme immunoassay and the Lumipulse^® G600II (Fujirebio) instrument were used for all measurements. We analysed the correlations between CSF and plasma biomarkers and the differences of plasma biomarker concentrations after grouping MCI cases according to AT classification of CSF AD biomarker profiles.

Results: We found statistically significant positive correlations between CSF and plasma Aβ42, Aβ42/Aβ40 ratio and pTau181. All the biomarkers, except Aβ40, showed differences in A+ vs. A-, A+T+ vs. A-T- and A+T- vs. A-T- patients. Moreover, Aβ42 and Aβ42/Aβ40 plasma levels were lower in A+T- compared to A-T- and A-T+ groups, and pTau181 and pTau217 plasma levels were higher in A+T+ compared to A+T-. Aβ42/Aβ40 and pTau217 showed a robust performance in distinguishing A+ from A- (AUC = 0.857 and 0.862, respectively) and A+T+ from A-T- (AUC = 0.866 and 0.911) subjects.

Conclusions: Our results suggest that plasma biomarkers, and especially Aβ42/Aβ40 ratio and pTau217, are promising candidates for the early detection of AD pathology.

Keywords: Alzheimer’s disease; Aβ; Biomarkers; CSF; Diagnosis; Lumipulse®; Mild Cognitive Impairment; Plasma; pTau.

Fig. 1

Biomarker correlation between plasma and CSF. The graphs represent (a) Aβ42 concentrations, (b) Aβ40 concentrations, (c) Aβ42/Aβ40 ratios, (d) pTau181 concentrations in CSF and plasma. The values are expressed as pg/ml, except for Aβ42/Aβ40 ratio. The symbols represent the CSF and plasma concentration of a single sample, with the colours corresponding to CSF AT status (green A+T-, blue A+T+, red A-T-, yellow A-T+). Abbreviations: Aβ, amyloid beta; pTau181, tau protein phosphorylated at residue 181; CSF, cerebrospinal fluid

Fig. 2

Comparison of plasma biomarkers in A+ and A- groups. The graphs represent the box and whiskers plots of (a) Aβ42 concentrations, (b) Aβ40 concentrations, (c) Aβ42/Aβ40 ratios, (d) pTau181 concentrations and (e) pTau217 concentrations. The values are expressed as pg/ml, except for Aβ42/Aβ40 ratio. Each point corresponds to an individual value. Significant differences were assessed using the Student t test or the Mann Whitney test and are indicated by asterisks: ****p < 0.0001. A+, n = 174; A-, n = 132. Abbreviations: Aβ, amyloid beta; pTau181, tau protein phosphorylated at residue 181; pTau217, tau protein phosphorylated at residue 217; A-, amyloid negative; A+, amyloid positive

Fig. 3

Comparison of plasma biomarkers according to CSF status. The graphs represent the box and whiskers plots of (a) Aβ42 concentrations, (b) Aβ40 concentrations, (c) Aβ42/Aβ40 ratios, (d) pTau181 concentrations and (e) pTau217 concentrations. The values are expressed as pg/ml, except for Aβ42/Aβ40 ratio. Each point corresponds to an individual value. Significant differences were assessed using the Kruskal-Wallis test followed by Steel-Dwass-Critchlow-Fligner test and are indicated by asterisks: *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. A+T-, n = 30; A+T+, n = 144; A-T-, n = 110; A-T+, n = 22. Abbreviations: Aβ, amyloid beta; pTau181, tau protein phosphorylated at residue 181; pTau217, tau protein phosphorylated at residue 217; A-, amyloid negative; A+, amyloid positive; T-, tau negative, T+, tau positive

Fig. 4

Comparison of plasma biomarkers according to CSF status. The graphs represent the box and whiskers plots of (a) pTau181/Aβ42 and (b) pTau217/Aβ42 concentrations in A+ and A- subjects, and (c) pTau181/Aβ42 and (d) pTau217/Aβ42 concentrations in A+T-, A+T+, A-T- and A-T+ subjects. Each point corresponds to an individual value, expressed as pg/ml. Significant differences were assessed using the Student t test or the Mann Whitney test for the comparison between two groups, and the Kruskal-Wallis test followed by Steel-Dwass-Critchlow-Fligner test for the comparisons among four groups, and are indicated by asterisks: *p < 0.05, ***p < 0.001, ****p < 0.0001. A+, n = 174; A-, n = 132; A+T-, n = 30; A+T+, n = 144; A-T-, n = 110; A-T+, n = 22. Abbreviations: Aβ, amyloid beta; pTau181, tau protein phosphorylated at residue 181; pTau217, tau protein phosphorylated at residue 217; A-, amyloid negative; A+, amyloid positive; T-, tau negative, T+, tau positive

Fig. 5

Plasma biomarker diagnostic performance. ROC curves describing the ability of plasma biomarkers in distinguishing (a, c) A+ from A-, and (b, d) A+T+ from A-T- subjects. The ROC curves are described by the AUC, indicated in parenthesis for each biomarker. Abbreviations: Aβ, amyloid beta; pTau181, tau protein phosphorylated at residue 181; pTau217, tau protein phosphorylated at residue 217; ROC, Receiver Operating Characteristic, AUC, Area Under the Curve