Biomarkers and diagnostic guidelines for sporadic Creutzfeldt-Jakob disease

Abstract

Sporadic Creutzfeldt-Jakob disease is a fatal neurodegenerative disease caused by misfolded prion proteins (PrP^Sc). Effective therapeutics are currently not available and accurate diagnosis can be challenging. Clinical diagnostic criteria use a combination of characteristic neuropsychiatric symptoms, CSF proteins 14-3-3, MRI, and EEG. Supportive biomarkers, such as high CSF total tau, could aid the diagnostic process. However, discordant studies have led to controversies about the clinical value of some established surrogate biomarkers. Development and clinical application of disease-specific protein aggregation and amplification assays, such as real-time quaking induced conversion (RT-QuIC), have constituted major breakthroughs for the confident pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Updated criteria for the diagnosis of sporadic Creutzfeldt-Jakob disease, including application of RT-QuIC, should improve early clinical confirmation, surveillance, assessment of PrP^Sc seeding activity in different tissues, and trial monitoring. Moreover, emerging blood-based, prognostic, and potentially pre-symptomatic biomarker candidates are under investigation.

Figure 1.. CJD-typical patterns of restricted diffusion on MRI

A–C: Brain MRI of a patient with sCJD (MM1 subtype); restricted diffusion in occipital and parietal lobes, (left > right hemisphere, yellow arrows); associated hyperintensities on diffusion weighted images (DWI, A) and less impressive on fluid attenuated inversion recovery images (FLAIR, C); hypointensities on apparent diffusion coefficient maps (ADC, B); other MM1 cases may present additional restricted diffusion in caudate nucleus and putamen; a similar pattern (with caudate nucleus and putamen less likely involved) can be seen in MM2 and VV1 subtypes. D–F: Brain MRI of a patient with sCJD (VV2 subtype); restricted diffusion in caudate nucleus, putamen (yellow arrows), and thalamus (less impressive, predominantly in the pulvinar, yellow arrows) in both hemispheres; associated hyperintensities on DWI (D) and FLAIR images (F); hypointensities on ADC maps (E); a similar pattern (with additional cortical involvement) can be seen in the MV2 subtype. MR images were provided by the National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, USA and processed by Peter Herman, University Medical Center Göttingen, Germany.

Figure 2.. Criteria for the clinical diagnosis of sporadic Creutzfeldt-Jakob disease

The figure has been adapted from NCJDRSU criteria that were based on the WHO criteria^, and amended by RT-QuIC as an additional biomarker. Here, imaging criteria were refined and the need for a thorough diagnostic work-up in suspected probable sCJD is emphasized. * Generalised periodic sharp/ wave complexes (PSWCs) ** Restricted diffusion in caudate or caudate/putamen or caudate/putamen/thalamus, or at least two cortical regions (temporal, parietal, occipital) on MRI brain scan, no subcortical white matter involvement, no isolated restricted diffusion in the thalamus. Characteristic hyperintensities may be seen on fluid attenuated inversion recovery (FLAIR) images, but diffusion weighted (DWI) sequences are required to confirm CJD-typical restricted diffusion.^,