Application of protein misfolding cyclic amplification for the rapid diagnosis of acquired Creutzfeldt-Jakob disease

The susceptibility, clinical phenotype, and pathology of Creutzfeldt-Jakob disease (CJD) depends on both a methionine (M) /valine (V) polymorphism at codon 129 of the PRNP gene and the type of abnormal isoform of prion protein (PrP^Sc), either type 1 or type 2. The majority of CJD is sporadic CJD (sCJD) or genetic CJD, while CJD can be transmitted resulting in acquired CJD. It has been reported that dura mater graft-associated CJD (dCJD) with methionine homozygosity at codon 129 could be divided into distinct two phenotypes, namely the non-plaque-type of dCJD (np-dCJD) or the plaque-type of dCJD (p-dCJD). The cause of these two distinct phenotypes of dCJD was clarified by animal transmission studies using PrP-humanized mice based on the susceptibility and neurological or biochemical features in the mice inoculated with PrP^Sc from each dCJD subgroup. It is now likely that np-dCJD is associated with sCJD-MM1 or -MV1, the most common forms of sCJD (denoted as M1 strain in transmission studies), while p-dCJD is associated with sCJD-VV2 or -MV2, the second most common forms of sCJD (denoted as V2 strain). Although animal transmission studies are the most useful tool for identifying such atypical CJDs, relying exclusively on animal transmission studies may not be feasible due to the enormous cost and time. Therefore, we reported a method that can more easily and rapidly distinguish between M1-derived and V2-derived acquired CJDs using the protein misfolding cyclic amplification (PMCA) technique. Here, we describe the advantages of PMCA as a diagnostic tool for acquired CJD based on a comparison with those of conventional animal transmission studies.