Clinical Use of Improved Diagnostic Testing for Detection of Prion Disease

Abstract

Prion diseases are difficult to recognize as many symptoms are shared among other neurologic pathologies and the full spectra of symptoms usually do not appear until late in the disease course. Additionally, many commonly used laboratory markers are non-specific to prion disease. The recent introduction of second-generation real time quaking induced conversion (RT-QuIC) has revolutionized pre-mortem diagnosis of prion disease due to its extremely high sensitivity and specificity. However, RT-QuIC does not provide prognostic data and has decreased diagnostic accuracy in some rarer, atypical prion diseases. The objective of this review is to provide an overview of the current clinical utility of fluid-based biomarkers, neurodiagnostic testing, and brain imaging in the diagnosis of prion disease and to suggest guidelines for their clinical use, with a focus on rarer prion diseases with atypical features. Recent advancements in laboratory-based testing and imaging criteria have shown improved diagnostic accuracy and prognostic potential in prion disease, but because these diagnostic tests are not sensitive in some prion disease subtypes and diagnostic test sensitivities are unknown in the event that CWD transmits to humans, it is important to continue investigations into the clinical utility of various testing modalities.

Keywords: 14-3-3; Creutzfeldt–Jakob disease (CJD); RT-QuIC; alpha-synuclein; atypical prion disease; chronic wasting disease; diagnostic testing; prion disease; tau.

Figure 1

Brain MRI findings in prion disease. (a) Axial DWI imaging showing a widespread cortical restricted diffusion pattern typically found in sCJD MM1; (b) Axial DWI imaging showing restricted diffusion in the bilateral basal ganglia typically seen in sCJD VV2 (ataxic variant).

Figure 2

Real-time quaking-induced conversion reactions seeded with prion disease brain homogenate, and cerebrospinal fluid from a negative control and a positive result from a patient with the MM1 subtype of sporadic Creutzfeldt–Jakob disease (sCJD MM1). Each sample is run in quadruplicate, organized vertically. Thioflavin T (ThT) fluorescence, indicative of amyloid formation, is measured over time. In the positive sCJD MM1 CSF sample, ThT fluorescence initially increases due to amyloid formation, followed by a characteristic decline thought to be due to self-quenching.