Total and Phosphorylated Cerebrospinal Fluid Tau in the Differential Diagnosis of Sporadic Creutzfeldt-Jakob Disease and Rapidly Progressive Alzheimer's Disease

Abstract

Background: CSF total-tau (t-tau) became a standard cerebrospinal fluid biomarker in Alzheimer's disease (AD). In parallel, extremely elevated levels were observed in Creutzfeldt-Jakob disease (CJD). Therefore, tau is also considered as an alternative CJD biomarker, potentially complicating the interpretation of results. We investigated CSF t-tau and the t-tau/phosphorylated tau181 ratio in the differential diagnosis of sCJD and rapidly-progressive AD (rpAD). In addition, high t-tau concentrations and associated tau-ratios were explored in an unselected laboratory cohort.

Methods: Retrospective analyses included n = 310 patients with CJD (n = 205), non-rpAD (n = 65), and rpAD (n = 40). The diagnostic accuracies of biomarkers were calculated and compared. Differential diagnoses were evaluated in patients from a neurochemistry laboratory with CSF t-tau >1250 pg/mL (n = 199 out of 7036).

Results: CSF t-tau showed an AUC of 0.942 in the discrimination of sCJD from AD and 0.918 in the discrimination from rpAD. The tau ratio showed significantly higher AUCs (p < 0.001) of 0.992 versus non-rpAD and 0.990 versus rpAD. In the neurochemistry cohort, prion diseases accounted for only 25% of very high CSF t-tau values. High tau-ratios were observed in CJD, but also in non-neurodegenerative diseases.

Conclusions: CSF t-tau is a reliable biomarker for sCJD, but false positive results may occur, especially in rpAD and acute encephalopathies. The t-tau/p-tau ratio may improve the diagnostic accuracy in centers where specific biomarkers are not available.

Keywords: Alzheimer’s disease; Creutzfeldt-Jakob disease; biomarker; cerebrospinal fluid; rapidly-progressive dementia; tau; tau-ratio.

Figure 1

T-tau and p-tau181 levels in sCJD, classical (non-rp) AD, and rpAD. (A) Box plot of cerebrospinal fluid total-Tau (t-au) levels in non-rapidly-progressive Alzheimer’s disease (non-rpAD) patients, rapidly-progressive AD (rpAD), and sporadic Creutzfeldt-Jakob disease (sCJD) patients. (B) Box plot of cerebrospinal fluid phosphorylated Tau181 protein (p-tau) levels in non-rpAD, rpAD, and sCJD patients. (C) Box plot of t-tau/p-tau ratio values in non-rpAD, rpAD, and sCJD patients. (D) Mean difference, 95% confidence intervals (CI), and according p-values from univariate variance analyzes and post hoc Tukey HSD tests for multiple comparisons between log-transferred biomarker levels and ratio values. Bars above box plots (A–C) indicate significance levels from the comparison model. * p < 0.05; *** p < 0.001. Black dots above and below boxes indicate outliers. To improve readability, logarithmic scaling was chosen for x-axes in (A,C).

Figure 2

2ROC-Analyses of t-tau, p-tau181, and their ratio in the discrimination of AD and rpAD from sCJD. (A) Receiver operating characteristics (ROC) in the discrimination of sporadic Creutzfeldt-Jacob disease (sCJD) from Alzheimer’s disease AD, displaying total cerebrospinal fluid Tau (t-tau, red line), phosphorylated cerebrospinal fluid Tau (p-tau181, blue line), and the t-tau/p-tau ratio (green). (B) Receiver operating characteristics (ROC) in the discrimination of sCJD from non-rapidly-progressive Alzheimer’s disease (non-rpAD), displaying t-tau (red line), p-tau181 (blue line), and the t-tau/p-tau ratio (t-tau/p-tau ratio) (green). (C) Receiver operating characteristics (ROC) in the discrimination of sCJD from rapidly-progressive Alzheimer’s disease (rpAD), displaying t-tau (red line), p-tau181 (blue line), and the t-tau/p-tau ratio (green). (D) Comparison and indication of significant differences with 95% confidence intervals (CI) between Areas Under the Curve (AUC) from ROC analyzes.

Figure 3

Differential diagnoses of high CSF t-Tau concentrations (A) Pie chart: Differential diagnoses of all cases with cerebrospinal fluid total-Tau >1250 pg/mL analyzed in the neurochemistry lab of the Göttingen University Medical Center between 2010 and 2019 (total n = 199). Prion diseases were present in n = 49 (25%), Alzheimer’s disease in n = 46 (23%), acute and chronic vascular encephalopathy in n = 31 (16%), seizures in n = 24 (12%), inflammatory CNS disease in n = 17 (9%), and mixed neurodegenerative dementia in n = 12 (6%) cases. Other conditions (normal pressure hydrocephalus, other neurodegenerative dementia, hypoxic brain damage, toxic-metabolic encephalopathy, MELAS, and CNS Neoplasia) were present in n = 14 (7%) cases, n = 6 (3%) cases remained unclassified. (B) Pie chart: Differential diagnoses of all cases with cerebrospinal fluid total-Tau 2200 pg/mL (n = 98). Prion diseases were present in n = 40 (41%), Alzheimer’s disease in n = 7 (7%), acute and chronic vascular encephalopathy in n = 21 (21%), seizures in n = 10 (10%), and inflammatory CNS disease in n = 9 (9%). Other conditions (normal pressure hydrocephalus, other neurodegenerative dementia, hypoxic brain damage, toxic-metabolic encephalopathy, and MELAS) were present in n = 11 (11%) patients.

Figure 4

T-tau/p-tau ratio in differential diagnoses of CSF t-tau values >1250 pg/mL. Boxplot of t-tau/p-tau ratios (n = 170) in patients with CSF t-tau >1250 pg/mL. PD: Prion disease (n = 34, median: 40.56), AD: Alzheimer’s disease (n = 46, median: 9.80), VD/Stroke: acute and chronic vascular encephalopathy (n = 28, median: 24.69), inflammatory CNS diseases (n = 15, median: 35.06), MD: mixed AD and vascular dementia (n = 12, median: 10.85), seizures and status epilepticus (n = 19, median 23.44), and others (n = 16, median: 29.19). Black dots above boxes indicate outliers.