The advances in the early and accurate diagnosis of Creutzfeldt–Jakob disease and other prion diseases: where are we today?

ABSTRACT

Introduction

Before the introduction of MRI diffusion-weighted images (DWI), the diagnosis of Creutzfeldt–Jakob disease (CJD) relied upon nonspecific findings including clinical symptoms, EEG abnormalities, and elevated levels of cerebrospinal fluid 14-3-3 protein. Subsequently, the use of DWI has improved diagnostic accuracy, but it sometimes remains difficult to differentiate CJD from encephalitis, epilepsy, and other dementing disorders. The revised diagnostic criteria include real-time quaking-induced conversion (RT-QuIC), detecting small amounts of CJD-specific prion protein, and clinically sensitive DWI. Combining these techniques has further improved diagnostic accuracy, enabling earlier diagnosis.

Areas covered

Herein, the authors review the recent advances in diagnostic methods and revised diagnostic criteria for sporadic CJD. They also discuss other prion diseases, such as variant CJD and chronic wasting disease, where the emergence of new types is a concern.

Expert opinion

Despite improvements in diagnostic methods and criteria, some subtypes of prion disease are still difficult to diagnose, and even the diagnosis using the most innovative RT-QuIC test remains a challenge in terms of accuracy and standardization. However, these revised criteria can be adapted to the emergence of new types of prion diseases. It is essential to continue careful surveillance and update information on the latest prion disease phenotypes.

KEYWORDS:

• Creutzfeldt–Jakob disease
• chronic wasting disease
• diagnostic criteria
• MRI-diffusion-weighted image
• protein misfolding cyclic amplification
• prion
• real-time quaking-induced conversion

Article highlights

• Creutzfeldt–Jakob disease (CJD) is a human prion disease, caused by the accumulation of disease-associated prion protein (PrPSc) in the central nervous system; it is a fatal neurodegenerative disease for which there is no cure. Prion diseases were diagnosed with nonspecific tests such as clinical symptoms, electroencephalogram (EEG) abnormalities, and cerebrospinal fluid (CSF)14-3-3 protein assays, which sometimes made it difficult to differentiate prion diseases from encephalitis, epilepsy, and other dementias.

• In sporadic CJD, brain MRI-diffusion-weighted imaging (DWI) from early onset shows hyperintensity signals in two or more regions of the cerebral cortex (temporal, parietal, and occipital lobes) or in the caudate nucleus and putamen or both, with excellent sensitivity and specificity. The same regions are reduced in the apparent diffusion coefficient map.

• Real-time quaking-induced conversion (RT-QuIC) assays have been developed to detect small amounts of PrPSc in CSF and nasal mucosa samples by in vitro amplification, and both sensitivity and specificity are superior to conventional CSF surrogate marker assays.

• The diagnostic criteria have been revised to add brain MRI-DWI and the RT-QuIC assay, improving the sensitivity and specificity for the diagnosis of sporadic CJD and enabling early diagnosis.

• There are diverse subtypes of prion diseases, some of which are difficult to diagnose even with the revised criteria and may require a comprehensive decision including clinical presentation, brain MRI-DWI, CSF (14-3-3 protein, total tau protein, and RT-QuIC) assays, EEG, and PRNP genetic analysis.

• Prion diseases are zoonotic, and there is a risk of newly acquired prion diseases, just as bovine spongiform encephalopathy (BSE) transmitted to humans and caused variant CJD. Further advances are expected to standardize new diagnostic techniques and enable the detection of the emergence of new subtypes.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by a grant-in-aid from the Research Committee of Surveillance and Infection Control of Prion Disease, the Ministry of Health, Labor and Welfare of Japan.