Analytical performance and clinical utility of the INNOTEST® PHOSPHO-TAU(181P) assay for discrimination between Alzheimer's disease and dementia with Lewy bodies

Abstract

Background: Total tau (T-tau) and b-amyloid (Ab 1-42 ) levels in cerebrospinal fluid (CSF) can differentiate Alzheimer's disease (AD) from normal aging or depressive pseudo-dementia. Differential diagnosis from dementia with Lewy bodies (DLB) in clinical settings is difficult. Methods: The analytical performance of the INNO-TEST ᮋ PHOSPHO-TAU (181P) assay was validated in terms of selectivity, sensitivity, specificity, precision, robustness, and stability. Clinical utility of the assay alone, or combined with T-tau and Ab 1-42 , for discrimination of AD (ns94) from patients suffering from DLB (ns60) or from age-matched control subjects (CS) (ns60) was assessed in a multicenter study. Results: CSF concentrations of tau phosphorylated at threonine 181 (P-tau 181P ) in AD was significantly higher than in DLB and CS. Discriminant analysis, a classification tree, and logistic regression showed that P-tau 181P was the most statistically significant single variable of the three biomarkers for discrimination between AD and DLB. Conclusions: P-tau 181P quantification is a robust and reliable assay that may be useful in discriminating AD from DLB.

Importance and Impact of Preanalytical Variables on Alzheimer Disease Biomarker Concentrations in Cerebrospinal Fluid

“…T-tau is considered to be very stable, as several authors failed to find significant differences in T-tau concentrations between samples frozen and thawed once (11,13 ) and in up to 6 freeze-thaw cycles (11,12,16 ), although Schoonenboom et al (11 ) also observed an increase in T-tau followed by a decrease. P-tau 181P , on the other hand, proved to be very stable in the present study, and the small CIs point to a low variability in evolution of P-tau 181P among the different individuals, in accord with the results of earlier studies (10,16,29 ). Zimmermann et al (18 ) found no significant systematic changes of the biomarker concentrations, but did observe increasing unsystematic variation after 3 freeze-thaw cycles, especially for A␤ and T-tau.…”

“…No effects of storage at room temperature on P-tau 181P were found in previous studies (10,14,16 ). One study that examined possible differences between storage at 4°C for 4, 24, and 72 h and immediate freezing at Ϫ80°C could not demonstrate an effect (10 ). In conclusion, we found significant differences in A␤ (and P-tau 181P ) concentrations after delayed storage before freezing.…”

“…Although A␤ can also be found in plasma, originating from different pools such as platelets, muscle, and liver, its concentration is much lower than in CSF (23 ) and is therefore unlikely to significantly alter the concentrations measured in blood-contaminated CSF. Maximal differences of 9% and 7% for fractionated sampling and centrifugation, respectively, were smaller than the reported interassay CV for the assays used (10,17 ). In addition, centrifugation of the non-bloodcontaminated samples did not lead to a significantly different intraassay CV for A␤ 1-42 (4.6% vs 3.8%), T-tau (4.1% vs 4.8%), or P-tau 181P (2.2% vs 1.4%).…”

“…T-tau was found to be stable at room temperature (14,16,28 ), for up to 22 days in 1 particular study, but tended to decrease in that same study after 12 days when stored at 37°C degrees (11 ), which would indicate that stability of T-tau is also dependent on temperature. No effects of storage at room temperature on P-tau 181P were found in previous studies (10,14,16 ). One study that examined possible differences between storage at 4°C for 4, 24, and 72 h and immediate freezing at Ϫ80°C could not demonstrate an effect (10 ).…”

Early-onset and late-onset Alzheimer's disease are associated with distinct patterns of memory impairment

“…Clinical inclusion criteria were probable amnestic AD with high level of evidence of AD pathophysiological process, such as determined by Innotest Amyloid Tau Index (IATI) < 0.8 and P-Tau > 60 (an optimal combination of CSF biomarkers that predicts AD with a specificity of 95% and a sensitivity of 85%) (Vanderstichele et al, 2006); presence of a reliable informant; mild dementia severity (Clinical Dementia Rating -CDR of 1) (Morris, 1993); onset of symptoms ranging from 1 to 5 years prior to inclusion; no personal history of neurological or psychiatric disorder; no family history of AD that could suggest autosomal dominant inheritance; no abnormal feature on brain MRI including stroke, more than one ischemic lacuna, and white matter changes on FLAIR, above grade 2 at the Fazecas scale (Fazekas et al, 1987;Gour et al, 2013).…”