Diagnostic and prognostic value of human prion detection in cerebrospinal fluid

Abstract

Objective Several prion amplification systems have been proposed for detection of prions in cerebrospinal fluid (CSF), most recently, the measurements of prion seeding activity with second-generation real-time quaking-induced conversion (RT-QuIC). The objective of this study was to investigate the diagnostic performance of the RT-QuIC prion test in the broad phenotypic spectrum of prion diseases. Methods We performed CSF RT-QuIC testing in 2,141 patients who had rapidly progressive neurological disorders, determined diagnostic sensitivity and specificity in 272 cases which were autopsied, and evaluated the impact of mutations and polymorphisms in the PRNP gene, and Type 1 or Type 2 of human prions on diagnostic performance. Results The 98.5% diagnostic specificity and 92% sensitivity of CSF RT-QuIC in a blinded retrospective analysis matched the 100% specificity and 95% sensitivity of a blind prospective study. The CSF RT-QuIC differentiated 94% of cases of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 from the sCJD MM2 phenotype, and 80% of sCJD VV2 from sCJD VV1. The mixed prion type 1–2 and cases heterozygous for codon 129 generated intermediate CSF RT-QuIC patterns, while genetic prion diseases revealed distinct profiles for each PRNP gene mutation. Interpretation The diagnostic performance of the improved CSF RT-QuIC is superior to surrogate marker tests for prion diseases such as 14-3-3 and Tau proteins and together with PRNP gene sequencing, the test allows the major prion subtypes to be differentiated in vivo. This differentiation facilitates prediction of the clinicopathological phenotype and duration of the disease—two important considerations for envisioned therapeutic interventions.

Subtype Specific CSF Biomarkers in Sporadic Creutzfeldt-Jakob Disease

“…More precisely authors have shown that t-tau resulted in a lesser number of false positive results, particularly in cases having inflammatory related disorders and sub-acute dementias; and it has higher sensitivity than 14-3-3 for the sCJD MV2K type [24]. Altogether, data suggest that the t-tau assay has technical advantages as compared to the standard western blot 14-3-3 assay, providing an evidence for a change in the current approvals to prioritise t-tau analysis over 14-3-3 although in case of differential diagnosis with Alzheimer disease, t-tau is less accurate than 14-3-3 [24,37,46]. For differential diagnosis with AD, combination of Aβ42, p-tau and total-PrP levels with the calculation of t-tau/p-tau and other ratios based on different combinations of these four biomarkers has considerably improved diagnostic accuracy [25,27,42].…”

“…Altogether, these studies indicate that the level of PrP in CSF are on average lower level in individuals with prion disease and could be a specific marker in symptomatic prion disease patients than in controls [25][26][27][28]37] but not at the subtype levels.…”

Current Infection Control Recommendations for Prion Disease; A Difficult Problem for the Deployed Personnel of the Armed Forces

“…The definitive diagnosis of CJD comes from histological pathology from infected tissue (10), usually postmortem. Invasive biopsies are the only way to diagnose prion disease through detection of PrPsc definitively (11).…”

“…It was found to have 100% specificity and 83% sensitivity. In a recent publication by Foutz et al (2017) the work from Atarashi progressed to test the assay on over 2000 patients with degenerative neurological conditions in Australia. The measurement of prion seeding activity with RT-QuIC found that it was a superior method to current diagnostic techniques with 95% sensitivity and 100% specificity (11).…”

“…Current practice utilizing surrogate markers for 14 -3 -3 and tau proteins from biopsy samples are invasive, slow diagnostic times and high rates of false-positives (12). RT-QuIC is now available at the national prion disease surveillance center in Cleveland, OH (11). This method is being identified as a potential opportunity to test blood to ensure blood and tissue products are clear of prions before transfusions and transplants.…”