Quantitative Relationship Between Lumipulse G Measures of pTau217 in Plasma and the Temporal Cortex.

Abstract (English)

BACKGROUND AND OBJECTIVES: Phosphorylated tau217 (pTau217) plasma assays have shown high diagnostic accuracy for Alzheimer disease (AD). However, validation of plasma pTau217 as a direct marker of brain-based pTau pathology requires understanding of its quantitative relationship with cortical pTau217. The primary objective of this postmortem validation study was to determine the quantitative relationship of plasma pTau217 levels and the pTau217/&#x3b2;-amyloid (A&#x3b2;)_1-42 ratio with cortical pTau217 levels measured using Lumipulse G immunoassays. METHODS: In this retrospective study, patients with dementia were recruited from an academic memory clinic (University Hospitals Leuven) based on the joint availability of an antemortem plasma sample and postmortem brain tissue. An N-terminal pTau217 (pTau217_NT) immunoassay was used to measure pTau217 in plasma and inferior temporal neocortex homogenates. In plasma, midregion pTau217 (pTau217_Mid) and the pTau217_Mid/A&#x3b2;_1-42 ratio were also measured. Generalized additive models and partial Spearman correlations were used to evaluate the relationship between blood and cortical pTau217. CIs were estimated using bootstrapping (5,000 iterations). RESULTS: Thirty-two patients with dementia (mean age 66 [SD 10] years, 38% female) were included, of which 19 had an AD diagnosis and 13 had a diagnosis of frontotemporal lobar degeneration with either TDP-43 or tau inclusions, as determined at autopsy. Plasma pTau217_NT, pTau217_Mid, and the pTau217_Mid/A&#x3b2;_1-42 ratios were strongly correlated with pTau217_NT in the temporal cortex (partial Spearman &#x3c1; = 0.73-78, all <i>p</i> < 0.0001). However, models using plasma pTau217_NT or the pTau217_Mid/A&#x3b2;_1-42 ratio as independent variable provided a better fit to cortical pTau217_NT than models using plasma pTau217_Mid (ΔAkaike information criterion = 2.5 and 1.1, ΔBayesian Information criterion = 3.6 and 2.1, respectively). All markers showed excellent diagnostic performance in distinguishing AD patients from non-AD disease control patients (area under the curve = 0.88-0.94). Plasma pTau217_NT, pTau217_Mid, and the pTau217_Mid/A&#x3b2;_1-42 ratios were correlated with neocortical A&#x3b2; plaque (4G8) of pTau (AT8) aggregate densities with comparable strength (partial Spearman &#x3c1; = 0.57-0.69, <i>p</i> < 0.0012). For all plasma markers studied, only the correlation with pTau aggregate density (partial Spearman &#x3c1; = 0.39-0.45, <i>p</i> < 0.05) and not with A&#x3b2; plaque density (partial partial Spearman &#x3c1; = 0.17-0.25, <i>p</i> > 0.19) remained significant after correction for the other pathology. DISCUSSION: Plasma pTau217_NT levels as well as the pTau217_Mid/A&#x3b2;_1-42 ratio strongly relate to postmortem pTau217_NT levels in the temporal cortex.