Diagnostic Accuracy of Prion Disease Biomarkers in Iatrogenic Creutzfeldt-Jakob Disease.

Franc Llorens,Miguel Calero,Christiane Stehmann,Fabio Moda,Francesca Brett,Josephine Heffernan,Anna Ladogana,Shannon Sarros,Olga Calero,Matthias Schmitz,Inga Zerr,Anna Poleggi,Sigrid Klotz,Marcella Catania,Maurizio Pocchiari,C J O’regan ,Isidró Ferrer ,Anna Villar‐Piqué ,Gábor G Kovács ,Steven Collins ,Péter Hermann

doi:10.3390/biom10020290

Abstract

Human prion diseases are classified into sporadic, genetic, and acquired forms. Within this last group, iatrogenic Creutzfeldt–Jakob disease (iCJD) is caused by human-to-human transmission through surgical and medical procedures. After reaching an incidence peak in the 1990s, it is believed that the iCJD historical period is probably coming to an end, thanks to lessons learnt from past infection sources that promoted new prion prevention and decontamination protocols. At this point, we sought to characterise the biomarker profile of iCJD and compare it to that of sporadic CJD (sCJD) for determining the value of available diagnostic tools in promptly recognising iCJD cases. To that end, we collected 23 iCJD samples from seven national CJD surveillance centres and analysed the electroencephalogram and neuroimaging data together with a panel of seven CSF biomarkers: 14-3-3, total tau, phosphorylated/total tau ratio, alpha-synuclein, neurofilament light, YKL-40, and real-time quaking induced conversion of prion protein. Using the cut-off values established for sCJD, we found the sensitivities of these biomarkers for iCJD to be similar to those described for sCJD. Given the limited relevant information on this issue to date, the present study validates the use of current sCJD biomarkers for the diagnosis of future iCJD cases.

Highlights

Prion diseases or transmissible spongiform encephalopathies (TSEs) are a family of rare neurodegenerative disorders that affect both humans and animals, caused by the conversion of the physiological cellular prion protein (PrPc) into a disease-associated isoform (PrPSc)
A longer survival time in iatrogenic Creutzfeldt–Jakob disease (iCJD) was associated with MV heterozygosity at codon 129 and with cases caused by growth hormone treatment [36], we could not validate these findings probably due to the strong imbalance of our cohort regarding these variables
In our biomarker panel study, we found the accuracy of EEG, magnetic resonance image (MRI), and CSF 14-3-3 WB in iCJD to be broadly in line with what has been reported for sporadic Creutzfeldt-Jakob disease (sCJD)

Summary

Introduction

Prion diseases or transmissible spongiform encephalopathies (TSEs) are a family of rare neurodegenerative disorders that affect both humans and animals, caused by the conversion of the physiological cellular prion protein (PrPc) into a disease-associated isoform (PrPSc). The sporadic form of the disease, known as sporadic Creutzfeldt-Jakob disease (sCJD), accounts for about 85–90% of all human cases [3]. Some 10–15% of cases are associated with autosomal dominant pathogenic sequence variations in the prion protein gene (PRNP), while acquired forms are rare and are caused by the transmission of infective material from human to human (Kuru and iatrogenic Creutzfeldt-Jakob disease (iCJD)) or from cattle to human (variant CJD) [4]. The use of contaminated growth hormone and dura mater grafts derived from human cadavers with undiagnosed sCJD are the principal sources of iCJD [5,6]. Iatrogenic transmission of the CJD agent has been reported in over 490 patients worldwide [7]

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