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

Petra Steinacker,Patrick Oeckl,Song Shi,Jens Kuhle,Armin Giese,Kaj Blennow,Henrik Zetterberg,Dana Slivarichova,Markus Otto,Viktoria Ruf,Steffen Halbgebauer

doi:10.1038/srep38737

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.

Highlights

Prion diseases are transmissible and fatal neurodegenerative diseases neuropathologically characterized by the presence of misfolded prion proteins, which are exceptionally resistant to routine decontamination procedures
neurofilament light chain (NF-L) serum concentrations were higher in both sporadic CJD (sCJD) and genetic CJD (gCJD) compared to DCo or Co
Improvement of Creutzfeldt-Jakob disease (CJD) diagnosis is attempted in two ways: (1) There is a search for surrogate markers in the serum of CJD patients, and (2) Methods are developed to amplify the minute amounts of abnormal PrP present in body fluids for a specific diagnosis

Summary

Introduction

Prion diseases are transmissible and fatal neurodegenerative diseases neuropathologically characterized by the presence of misfolded prion proteins, which are exceptionally resistant to routine decontamination procedures. While for a long time the detection of misfolded prion protein in body fluids failed, some approaches have eventually been successful[9] and high diagnostic accuracy was reported for the recently developed real-time quaking induced conversion (RT-QuIC) prion conversion assay which uses minute amounts of the β-structure-rich insoluble conformer of the prion protein (PrPSc) in CSF as seeds[10,11] while other studies report lower diagnostic performance[12]. It is unclear when the misfolded prion protein appears or reaches the detectable limit in CSF of CJD patients. In the present study we addressed the questions whether we can measure these biomarkers with newly established assays in blood, of which diagnostic value they are, and how early in the disease process these markers appear

Methods

Results

Conclusion