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

Date Published: July 14, 2017

Publisher: BioMed Central

Author(s): Joery Goossens, Maria Bjerke, Hanne Struyfs, Ellis Niemantsverdriet, Charisse Somers, Tobi Van den Bossche, Sara Van Mossevelde, Bart De Vil, Anne Sieben, Jean-Jacques Martin, Patrick Cras, Johan Goeman, Peter Paul De Deyn, Christine Van Broeckhoven, Julie van der Zee, Sebastiaan Engelborghs.

http://doi.org/10.1186/s13195-017-0275-5

Abstract

The Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers Aβ1–42, t-tau, and p-tau181 overlap with other diseases. New tau modifications or epitopes, such as the non-phosphorylated tau fraction (p-taurel), may improve differential dementia diagnosis. The goal of this study is to investigate if p-taurel can improve the diagnostic performance of the AD CSF biomarker panel for differential dementia diagnosis.

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 Aβ1–42, t-tau, p-tau181, and p-taurel 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.

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-taurel to the AD biomarker panel decreased its diagnostic performance when discriminating non-AD, FTLD, and DLB from AD. As a single marker, p-taurel increased the diagnostic performance for CJD. No significant difference was found in AUC values with the addition of p-taurel when differentiating between AD or non-AD dementias and controls.

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

The online version of this article (doi:10.1186/s13195-017-0275-5) contains supplementary material, which is available to authorized users.

Partial Text

Cerebrospinal fluid (CSF) biomarkers are being used to improve the clinical diagnostic accuracy of Alzheimer’s disease (AD) [1, 2]. Established markers include levels of amyloid-beta of 42 amino acids (Aβ1–42), total tau protein (t-tau), and phosphorylated tau protein (p-tau) [3]. The most studied isoform of p-tau is that with phosphorylation at threonine 181 (p-tau181), while there are other phosphorylated tau epitopes that have not been thoroughly investigated for their clinical utility such as serine 199 and threonine 231 [4]. Although studies on large neuropathology case series suggest that tau pathology precedes amyloid-β plaque pathology [5], the opposite holds true for the detectable biomarker counterparts in CSF [6]. Thus, there is a discrepancy between neuropathology and detectable clinical biomarker findings [7]. Furthermore, since the current biomarkers are already changed in the mild cognitive impairment (MCI) stage and remain stable during the clinical course, they cannot be used as prognostic markers. As single markers they are not completely specific for AD given that there is a slight overlap with other neurodegenerative diseases, hampering their usefulness as differential diagnostic markers [8, 9]. Indeed, it appears that current assay setups are not sensitive enough to detect, for example, disease-specific changes in tau processing. Together, these limitations have spurred the search for new tau modifications or epitopes that may improve early and differential diagnosis. Recently, a novel assay became available that can detect the non-phosphorylated tau fraction (p-taurel) in CSF [10]. This assay was developed to specifically detect tau protein with no phosphorylation at epitopes threonine T175, T181, and T231 (Fig. 1; [10]). It was found that p-taurel is significantly higher in an AD/MCI cohort in comparison with controls, while differentiation between MCI and AD was not possible [10]. The assay was also proposed to be helpful when differentiating between AD and other dementias, particularly tauopathies. The goal of this study was thus to investigate whether p-taurel can improve the diagnostic performance of the AD CSF biomarker panel for differential dementia diagnosis, comparing AD with a variety of non-AD dementias.Fig. 1Epitopes of different tau assays. Binding sites of antibodies making up total tau (t-tau), tau protein phosphorylated at threonine 181 (p-tau181), and non-phosphorylated tau fraction (p-taurel ) assays. Binding of antibody AT270 requires phosphorylation of threonine (T), while binding of antibody 1G2 requires threonine (T) to be not phosphorylated

Demographic, clinical, and biomarker data of all groups are summarized in Table 1 and Fig. 2. Patient cohorts were not matched for age and gender but there was no observable effect of these parameters on biomarker levels (data not shown). Two FTLD patients and two CJD patients were excluded from statistical analysis as all their biomarker values were below the respective limits of detection, probably related to preanalytical factors. Concentration of t-tau was above the detection limit in 5/45 AD and 17/19 CJD cases and below the detection limit in 1/43 FTLD cases; Aβ1–42 was below the detection limit in 1/19 CJD cases only; p-tau181 was below the detection limit in 3/43 FTLD cases and 1/19 CJD cases; p-taurel was below the detection limit in 13/20 controls, 4/45 AD, 21/43 FTLD, and 13/45 DLB cases. As dilution of samples is not recommended for the three INNOTEST assays, out-of-range biomarker values were set to the lowest/highest detection point ±20%, and this value was used in statistical analyses. Due to the high number of samples with out-of-range biomarker values (especially the case for p-taurel, see Discussion), non-parametric statistical analyses were performed.Table 1Demographic, clinical, and biomarker dataControlsADFTLDDLBCJDp valueGender (% male/female) (n)55/45 (20)49/51 (45)51/49 (45)71/39 (45)33/67 (21)0.049Age at CSF sampling (years)69.4 (61.5–74.7)71.2 (66.7–79.2)63.6 (55.1–71.7)75.5 (71.2–81.2)67.2 (57.4–76.4)<0.001eMMSE (0–30) (n)NA*20 (15–25) (42)21 (15–25) (29)19 (16–23) (38)NA0.54Aβ1–42 (pg/mL)812 (646–1108)509 (372–594)641 (457–858)547 (423–744)545 (300–686)<0.001a,c,d,et-tau (pg/mL)257 (173–381)627 (429–928)320 (219–420)272 (232–398)>1440$<0.001a,d,e,fp-tau181 (pg/mL)40.3 (32.9–58.6)80.0 (60.5–105.0)36.7 (28.3–49.0)45.0 (39.8–64.7)46.0 (32.2–53.4)<0.001a,e,f,gp-taurel (pg/mL)32.0 (32.0–49.7)82.7 (46.6–135.7)32.0 (32.0–59.0)44.3 (32.0–73.8)1375 (738–1820)<0.001a,d,e,f,gAβ1–42/t-tau3.40 (2.20–4.76)0.75 (0.50–1.02)2.00 (1.36–3.33)2.08 (1.10–3.13)0.39 (0.24–0.60)<0.001a,d,e,fAβ1–42/p-tau18120.2 (14.7–24.7)5.8 (4.1–7.1)18.5 (11.1–25.0)13.7 (6.8–18.3)12.3 (6.8–19.6)<0.001a,c,e,f,gAβ1–42/p-taurel23.1 (16.2–30.3)5.0 (3.5–10.3)15.8 (9.2–21.6)11.6 (8.0–16.0)0.4 (0.2–0.9)<0.001a,c,d,e,f,gp-tau181/t-tau0.176 (0.156–0.197)0.132 (0.104–0.149)0.117 (0.097–0.149)0.158 (0.143–0.177)0.033 (0.024–0.038)<0.001a,b,d,f,gp-tau181/p-taurel1.17 (0.85–1.30)1.00 (0.64–1.43)0.82 (0.61–1.11)0.94 (0.70–1.16)0.03 (0.03–0.06)<0.001d,gAPOEε4 carriers (%) (n)40.0 (5)61.1 (36)32.1 (28)33.3 (33)NA0.059Values are presented as median (interquartile range), percentage (%) or number (n)Gender distribution was compared by Chi-square testSignificant differences in clinical data and biomarker levels were determined by Kruskal-Wallis with post-hoc Dunn’s correction: a controls vs. AD; b controls vs. FTLD; c controls vs. DLB; d controls vs. CJD; e AD vs. FTLD; f AD vs. DLB; g AD vs. CJDAge at CSF sampling was also significantly different for FTLD vs. DLB and CJD vs. DLBStatistically significant p values (<0.05) are marked in bold*MMSE only performed when clinically relevant (n = 3), no score <27$Most CJD patients had t-tau values above the detection limit, which were set to highest point of the standard curve +20%Aβ1–42 amyloid-beta of 42 amino acids, AD Alzheimer’s disease, CJD Creutzfeldt-Jakob disease, CSF cerebrospinal fluid, DLB dementia with Lewy bodies, FTLD frontotemporal lobar degeneration, MMSE Mini-Mental State Examination, NA not available, p-tau181 tau protein phosphorylated at threonine 181, p-taurel non-phosphorylated tau fraction, t-tau total tau proteinFig. 2Dot plots of individual markers and ratios. Dot plots showing individual biomarker levels in each subgroup. a amyloid-beta of 42 amino acids (Aβ1–42); b total tau protein (t-tau); c tau protein phosphorylated at threonine 181(p-tau181); d non-phosphorylated tau fraction (p-taurel); e Aβ1–42/t-tau; f Aβ1–42/p-tau181; g Aβ1–42/p-taurel; h p-tau181/t-tau; i p-tau181/p-taurel. Lines indicate median with interquartile range. AD Alzheimer’s disease, CJD Creutzfeldt-Jakob disease, DLB dementia with Lewy bodies, FTLD frontotemporal lobar degeneration This study aimed to evaluate the diagnostic value of the non-phosphorylated tau fraction in comparison to that of the established AD biomarker panel for the differentiation between AD and non-AD dementias. In conclusion, this study shows that the addition of p-taurel to the AD CSF biomarker panel did not improve the differential diagnosis between AD and non-AD dementias. However, limited sensitivity of the assay might mask the potential diagnostic value of non-phosphorylated tau as a biomarker.   Source: http://doi.org/10.1186/s13195-017-0275-5

 

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