No added diagnostic value of non-phosphorylated tau fraction (p-taurel) in CSF as a biomarker for differential dementia diagnosis

Abstract

Background: The Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers Aβ_1-42, t-tau, and p-tau₁₈₁ overlap with other diseases. New tau modifications or epitopes, such as the non-phosphorylated tau fraction (p-tau_rel), may improve differential dementia diagnosis. The goal of this study is to investigate if p-tau_rel can improve the diagnostic performance of the AD CSF biomarker panel for differential dementia diagnosis.

Methods: The study population consisted of 45 AD, 45 frontotemporal lobar degeneration (FTLD), 45 dementia with Lewy bodies (DLB), and 21 Creutzfeldt-Jakob disease (CJD) patients, and 20 cognitively healthy controls. A substantial subset of the patients was pathology-confirmed. CSF levels of Aβ_1-42, t-tau, p-tau₁₈₁, and p-tau_rel were determined with commercially available single-analyte enzyme-linked immunosorbent assay (ELISA) kits. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analyses, and area under the curve (AUC) values were compared using DeLong tests.

Results: The diagnostic performance of single markers as well as biomarker ratios was determined for each pairwise comparison of different dementia groups and controls. The addition of p-tau_rel to the AD biomarker panel decreased its diagnostic performance when discriminating non-AD, FTLD, and DLB from AD. As a single marker, p-tau_rel increased the diagnostic performance for CJD. No significant difference was found in AUC values with the addition of p-tau_rel when differentiating between AD or non-AD dementias and controls.

Conclusions: The addition of p-tau_rel to the AD CSF biomarker panel failed to improve differentiation between AD and non-AD dementias.

Keywords: Alzheimer’s disease; Biomarkers; Cerebrospinal fluid; Creutzfeldt-Jakob disease; Dementia with Lewy bodies; Differential diagnosis; Frontotemporal lobar degeneration; Tau.

Fig. 1

Epitopes of different tau assays. Binding sites of antibodies making up total tau (t-tau), tau protein phosphorylated at threonine 181 (p-tau ₁₈₁), and non-phosphorylated tau fraction (p-tau _rel ) assays. Binding of antibody AT270 requires phosphorylation of threonine (T), while binding of antibody 1G2 requires threonine (T) to be not phosphorylated

Fig. 2

Dot plots of individual markers and ratios. Dot plots showing individual biomarker levels in each subgroup. a amyloid-beta of 42 amino acids (Aβ _1–42); b total tau protein (t-tau); c tau protein phosphorylated at threonine 181(p-tau ₁₈₁); d non-phosphorylated tau fraction (p-tau _rel); e Aβ_1–42/t-tau; f Aβ_1–42/p-tau₁₈₁; g Aβ_1–42/p-tau_rel; h p-tau₁₈₁/t-tau; i p-tau₁₈₁/p-tau_rel. Lines indicate median with interquartile range. AD Alzheimer’s disease, CJD Creutzfeldt-Jakob disease, DLB dementia with Lewy bodies, FTLD frontotemporal lobar degeneration