Neurofilaments in blood and CSF for diagnosis and prediction of onset in Creutzfeldt-Jakob disease

Abstract

While cerebrospinal fluid (CSF) biomarkers for Creutzfeldt-Jakob disease (CJD) are established and partly included in the diagnostic criteria, no blood biomarkers are available. Here, we assessed the utility of serum neurofilament light chain (NF-L) and tau protein in comparison to CSF markers (NF-L and phosphorylated NF heavy chain (pNF-H), tau, S100B, 14-3-3) and prion conversion assay (real-time quaking induced conversion (RT-QuIC)) for sporadic and genetic CJD. Importantly, a Gerstmann-Sträussler-Scheinker mutation carrier in the asymptomatic phase and at disease onset was included as well. Both NF-L and tau were markedly increased in CJD serum, reaching similar or even better performance as in CSF (sensitivity and specificity for serum NF-L 100% and 85.5%, and for serum tau 84.6% and 96.2%, respectively). Serum S100B showed high sensitivity as well (84.2%), but lower specificity (63%). CSF neurofilaments were increased before symptom onset, while prion seeding assay was negative. Just before a clinical diagnosis could be made, all CSF markers and NF-L in the serum were increased and CSF prion conversion assay was positive. The data suggest that neurofilaments are sensitive and specific blood markers for the diagnosis of genetic and sporadic CJD and might represent promising tools to predict disease onset.

Figure 1. Marker concentrations, ROC diagrams, and RT-QuIC results for CJD and controls.

Boxplots show the serum levels of NF-L (A), tau (B), and S100B (C), as well as the CSF levels of NF-L (D), tau (E), and pNF-H (F). Displayed are the results for CJD patients (indicated separately for sCJD and gCJD) and from demented (DCo) and non-demented controls (Co). The concentrations of analytes determined in serum and CSF from a gCJD patient at presymptomatic and early symptomatic disease stage are indicated by green and red circles, respectively. Boxes give median values with interquartile ranges, whiskers indicate the concentration range. Three and two asterisks indicate statistically significant differences of p < 0.0001 and p < 0.01, respectively. The diagnostic performance of markers is illustrated by ROC curves for serum (G) and CSF (H). Except for S100B, of which levels were determined in DCo only, ROC analyses were conducted considering all CJD measures (i.e. sCJD and gCJD) versus all controls (i.e. DCo and Co). The results of RT-QuIC are shown in (I). Displayed are the mean fluorescence signals with SD detected in the CSF of sCJD patients (n = 6), gCJD patients (n = 4), and controls (n = 6). Separately shown are the results for 3 replicate measurements of the gCJD mutation carrier in the asymptomatic disease stage (orange) and at disease onset (red).