Abstract
This study investigates the diagnostic and prognostic potential of different forms of tau in biofluids from patients with Creutzfeldt-Jakob disease (CJD). Extracellular tau, which is molecularly heterogeneous, was measured using ultra-sensitive custom-made Simoa assays for N-terminal (NT1), mid-region, and full-length tau. We assessed cross-sectional CSF and plasma from healthy controls, patients with Alzheimer’s disease (AD) and CJD patients. Then, we evaluated the correlation of the best-performing tau assay (NT1-tau) with clinical severity and functional decline (using the MRC Prion Disease Rating Scale) in a longitudinal CJD cohort (n = 145). In a cross-sectional study, tau measured in CSF with the NT1 and mid-region Simoa assays, separated CJD (n = 15) from AD (n = 18) and controls (n = 21) with a diagnostic accuracy (AUCs: 0.98–1.00) comparable to or better than neurofilament light chain (NfL; AUCs: 0.96–0.99). In plasma, NT1-measured tau was elevated in CJD (n = 5) versus AD (n = 15) and controls (n = 15). Moreover, in CJD plasma (n = 145) NT1-tau levels correlated with stage and rate of disease progression, and the effect on clinical progression was modified by the PRNP codon 129. Our findings suggest that plasma NT1-tau shows promise as a minimally invasive diagnostic and prognostic biomarker of CJD, and should be further investigated for its potential to monitor disease progression and response to therapies.
Highlights
Creutzfeldt-Jakob disease (CJD) is the most common prion disorder afflicting humans and is characterized by rapid and widespread neurodegeneration [1,2,3,4]
In accordance with our prior findings [20], mid-region and NT1 assays measured the highest levels of tau in cerebrospinal fluid (CSF), and we discovered that the NT1-tau assay perfectly discriminated CJD from both Alzheimer’s disease (AD) and controls
Our MR Simoa assay had low tolerance for guanidine hydrochloride (GuHCl) (Figure 1E), the increased sensitivity made it possible to dilute samples to abrogate the effects of GuHCl and still detect accurate values (Figure 1E, Supplemental Figure S1)
Summary
Creutzfeldt-Jakob disease (CJD) is the most common prion disorder afflicting humans and is characterized by rapid and widespread neurodegeneration [1,2,3,4]. An assessment of CSF tau using mid-region (MR) assays differentiates CJD from other neurodegenerative conditions (including rapidly progressing AD) and controls [8,9,12,13,15,19]. The use of a single immunoassay provides little information about which forms of tau are elevated in CJD. This is important since increasing evidence suggests that extracellular tau is molecularly complex and includes an array of differentially truncated forms of tau, some of which may have greater diagnostic potential than others [20,21,22,23,24,25,26,27]. Measuring different forms of tau in human fluids affords an opportunity to identify and evaluate new biomarkers, but should provide insights into the forms of tau involved in disease and their molecular mechanisms
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