Cerebrospinal Fluid P-tau181P Research Articles

Cerebrospinal Fluid P-Tau181P: Biomarker for Improved Differential Dementia Diagnosis.

The goal of this study is to investigate the value of tau phosphorylated at threonine 181 (P-tau181P) in the Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarker panel for differential dementia diagnosis in autopsy confirmed AD and non-AD patients. The study population consisted of 140 autopsy confirmed AD and 77 autopsy confirmed non-AD dementia patients. CSF concentrations of amyloid-β peptide of 42 amino acids (Aβ1–42), total tau protein (T-tau), and P-tau181P were determined with single analyte ELISA-kits (INNOTEST®, Fujirebio, Ghent, Belgium). Diagnostic accuracy was assessed through receiver operating characteristic (ROC) curve analyses to obtain area under the curve (AUC) values and to define optimal cutoff values to discriminate AD from pooled and individual non-AD groups. ROC curve analyses were only performed on biomarkers and ratios that differed significantly between the groups. Pairwise comparison of AUC values was performed by means of DeLong tests. The Aβ1–42/P-tau181P ratio (AUC = 0.770) performed significantly better than Aβ1–42 (AUC = 0.677, P = 0.004), T-tau (AUC = 0.592, P < 0.001), and Aβ1–42/T-tau (AUC = 0.678, P = 0.001), while P-tau181P (AUC = 0.720) performed significantly better than T-tau (AUC = 0.592, P < 0.001) to discriminate between AD and the pooled non-AD group. When comparing AD and the individual non-AD diagnoses, Aβ1–42/P-tau181P (AUC = 0.894) discriminated AD from frontotemporal dementia significantly better than Aβ1–42 (AUC = 0.776, P = 0.020) and T-tau (AUC = 0.746, P = 0.004), while P-tau181P/T-tau (AUC = 0.958) significantly improved the differentiation between AD and Creutzfeldt-Jakob disease as compared to Aβ1–42 (AUC = 0.688, P = 0.004), T-tau (AUC = 0.874, P = 0.040), and Aβ1–42/P-tau181P (AUC = 0.760, P = 0.003). In conclusion, this study demonstrates P-tau181P is an essential component of the AD CSF biomarker panel, and combined assessment of Aβ1–42, T-tau, and P-tau181P renders, to present date, the highest diagnostic power to discriminate between AD and non-AD dementias.

The role of clusterin in amyloid-β-associated neurodegeneration.

Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer disease neurodegeneration. However, the precise role of clusterin in Alzheimer disease pathogenesis is still not well understood. To elucidate the relationship between clusterin, amyloid-β (Aβ), phosphorylated tau (p-tau), and the rate of brain atrophy over time among nondemented older individuals. This longitudinal cohort included cognitively normal older participants and individuals with mild cognitive impairment assessed with baseline lumbar puncture and longitudinal structural magnetic resonance imaging. We examined 241 nondemented older individuals from research centers across the United States and Canada (91 participants with a Clinical Dementia Rating score of 0 and 150 individuals with a Clinical Dementia Rating score of 0.5). Using linear mixed-effects models, we investigated interactions between cerebrospinal fluid (CSF) clusterin, CSF Aβ1-42, and CSF p-tau at threonine 181 (p-tau181p) on the atrophy rate of the entorhinal cortex and hippocampus. Across all participants, we found a significant interaction between CSF clusterin and CSF Aβ1-42 on the entorhinal cortex atrophy rate but not on the hippocampal atrophy rate. Cerebrospinal fluid clusterin was associated with the entorhinal cortex atrophy rate among CSF Aβ1-42-positive individuals but not among CSF Aβ1-42-negative individuals. In secondary analyses, we found significant interactions between CSF Aβ1-42 and CSF clusterin, as well as CSF Aβ1-42 and CSF p-tau181p, on the entorhinal cortex atrophy rate. We found similar results in subgroup analyses within the mild cognitive impairment and cognitively normal cohorts. In nondemented older individuals, Aβ-associated volume loss occurs in the presence of elevated clusterin. The effect of clusterin on Aβ-associated brain atrophy is not confounded or explained by p-tau. These findings implicate a potentially important role for clusterin in the earliest stages of the Alzheimer disease neurodegenerative process and suggest independent effects of clusterin and p-tau on Aβ-associated volume loss.

P3-068: Improved discrimination of Alzheimer's disease from other dementias using cerebrospinal fluid P-tau 181P

P3-068: Improved discrimination of Alzheimer's disease from other dementias using cerebrospinal fluid P-tau 181P