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.
Highlights
The first aim of this study was to investigate the diagnostic accuracy of CSF t-tau in the differentiation of Sporadic Creutzfeldt-Jakob disease (sCJD) from Alzheimer’s disease (AD) and rapidly-progressive AD, an AD subgroup that is defined by rapid cognitive decline [16], altered biomarker profiles [17], and potentially represents a disease entity with distinct beta-amyloid strains [18]
Tau biomarker dataset, clinical diagnosis of probable AD [11], and sufficient follow-up information to differentiate between non-rapidly-progressive AD (rpAD) and rpAD
Very high t-tau values may occur in other diseases, especially in rpAD and in the non-neurodegenerative etiologies of rapidly-progressive dementia
Summary
Sporadic Creutzfeldt-Jakob disease (sCJD) is the most frequent form of human prion diseases, and accounts for around 90% of all cases, with an incidence of 1.5–2 per million person-years. It is clinically characterized by a rapidlyprogressive encephalopathy, inevitably leading to death after a mean disease duration of. Protein 14-3-3 and RT-QuIC analyses are usually only performed in specialized centers In this context, CSF total Tau (t-tau), a microtubule-associated neuronal and glial protein [7], is considered as a valuable alternative biomarker with a good diagnostic accuracy [8] that might be improved by calculating a ratio with phosphorylated tau181 protein (t-tau/p-tau ratio) [9,10]. Results: CSF t-tau showed an AUC of 0.942 in the discrimination of sCJD from
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