Elsevier

The Lancet Neurology

Volume 20, Issue 3, March 2021, Pages 235-246
The Lancet Neurology

Review
Biomarkers and diagnostic guidelines for sporadic Creutzfeldt-Jakob disease

https://doi.org/10.1016/S1474-4422(20)30477-4Get rights and content

Summary

Sporadic Creutzfeldt-Jakob disease is a fatal neurodegenerative disease caused by misfolded prion proteins (PrPSc). 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 PrPSc seeding activity in different tissues, and trial monitoring. Moreover, emerging blood-based, prognostic, and potentially pre-symptomatic biomarker candidates are under investigation.

Introduction

Sporadic Creutzfeldt-Jakob disease is a rapidly progressive neuropsychiatric syndrome that is fatal and characterised by aggregations of misfolded prion protein Scrapie (PrPSc) in the brain. Sporadic Creutzfeldt-Jakob disease is the most common form of human prion disease (∼90% of cases) with an incidence of approximately 1·5–2·0 cases per million person-years.1 Different phenotypes of sporadic Creutzfeldt-Jakob disease can vary in symptom evolution, biomarker profile, and neuropathological characteristics. They are defined by the polymorphism (Met and Val) at codon 129 of the prion protein gene (PRNP) and by the molecular mass of PrPSc (glycotype 1 and 2).2 Definite diagnosis requires neuropathological confirmation.

The spectrum of possible symptoms is highly heterogeneous and includes rapidly progressive dementia, cerebellar ataxia, and myoclonus, which means that high-performing (ie, high sensitivity and specificity) biomarkers are important for making a confident clinical diagnosis. In 1998, WHO included a combination of particular symptoms, EEG, and detection of CSF 14-3-3 proteins in the standard diagnostic criteria.3 Patterns of signal alteration on fluid attenuated inversion recovery (FLAIR) or diffusion weighted imaging (DWI) sequences, or both, of brain MRI were suggested in 2009.4 Another CSF protein, total-tau (T-tau), is considered a valuable supportive biomarker.5 Although comparative data on imaging markers for sporadic Creutzfeldt-Jakob disease are scarce, several studies have evaluated the diagnostic performance of CSF biomarkers, with occasional discrepancies leading to controversy about their clinical utility.6, 7

Since 2011, development and clinical application of PrPSc amplification assays, such as protein misfolding cyclic amplification (PMCA) and real-time quaking induced conversion (RT-QuIC),8 have constituted major breakthroughs as aids for an improved pre-mortem diagnosis of prion diseases. RT-QuIC has shown excellent diagnostic accuracy for sporadic Creutzfeldt-Jakob disease in retrospective studies, ring trials (consistency between laboratories),9, 10 and prospective studies,11, 12 which shows its high value for an early and accurate diagnosis. Consequently, RT-QuIC (using CSF or other tissue, such as olfactory mucosa) was included in diagnostic criteria for sporadic Creutzfeldt-Jakob disease of some surveillance centers.12, 13 However, an important discussion on its clinical utility is needed. Another unmet need is the identification of blood-based biomarkers for early diagnosis and disease progression,14, 15, 16 particularly regarding potential new therapeutic strategies.

The aim of this Review is to provide an overview of the biomarker-based diagnosis of sporadic Creutzfeldt-Jakob disease and to suggest guidelines for clinicians to use in the differential diagnosis of rapidly progressive dementias. Advances of the past 5 years are discussed and put in the context of clinical relevance, established biomarkers, and epidemiology.

Section snippets

Investigating diagnostic tests

When estimates of diagnostic accuracy are being translated into clinical practice, potential selection biases of case and control groups should be considered. The selection of control groups can be particularly challenging. Healthy age-matched controls usually do not reflect the population in which a diagnostic biomarker is used. However, referral centres often use Creutzfeldt-Jakob disease mimics (eg, autoimmune encephalitis) that represent the diagnostic challenges but might not reflect the

Advances in biomarker research

Neuropathological investigation and immunostaining of PrPSc allow a definite diagnosis of prion diseases.19 For definite ante-mortem diagnosis, brain biopsy is required but is complicated by infection control concerns, the possibility of a false negative result due to sampling error in which typical pathology and PrPSc might not be present in all cortical regions (eg, sporadic or familial fatal insomnia), and issues with tissue quality. Given these considerations and the highly invasive nature

PMCA

In 2001, PMCA was developed to reproduce and amplify PrPSc in microtubes. Brain homogenate provided normal prion protein (PrPC) substrate for the reaction and sonication fragmented growing PrPSc particles to increase their concentration.22 Subsequently, a modified protocol introduced the use of recombinant hamster PrPC as substrate to accelerate the reaction and increase its sensitivity to detect PrPSc in the CSF of scrapie-infected hamsters.23 PMCA protocols showed excellent sensitivity for

14-3-3 proteins

The 14-3-3 proteins are abundantly but not solely expressed in the brain. They are located in the cytoplasm, plasma membranes, and organelles. Involvement in various functions (eg, cell signalling, growth, apoptosis) has been identified but not completely clarified.46 Since 14-3-3 protein detection by western blot became part of commonly used clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease,3 several studies evaluated its diagnostic performance. In 2012, a structured

Blood-based biomarker candidates

Several potential roles might feasibly be fulfilled by blood-based biomarkers. Currently, there is no immediate prospect of a highly specific diagnostic blood test comparable to RT-QuIC in CSF samples. Blood assays, however, might offer an accessible triage test in primary care or first specialist assessment that flags the possibility of rapid neuronal damage, and could be useful in case prioritisation.

One potential candidate is t-Tau concentration in plasma or serum. Studies showed elevated

MRI

MRI is an essential tool in the diagnosis of sporadic Creutzfeldt-Jakob disease. It allows the identification of important differential diagnoses such as ischaemia, encephalitis, and neoplasia. In Creutzfeldt-Jakob disease, typical patterns of restricted diffusion on DWI and hyperintensities in FLAIR images were suggested to be included in the WHO diagnostic criteria in 2009.4 Another widely used protocol recommends the use of DWI and apparent diffusion coefficient (ADC) maps only.84, 85

EEG

Periodic sharp-wave complexes (PSWCs) with a frequency of 1 Hz are considered as an EEG pattern typical of Creutzfeldt-Jakob disease and have shown a sensitivity of 64% and a specificity of 91%.97 The non-convulsive status epilepticus is the most common clinical condition with Creutzfeldt-Jakob disease EEG.98, 99 Over the past 5 years, CSF biomarker studies reported a substantially lower sensitivity (39% to 45%) for EEG.12, 34, 37, 40 Most likely, the decreasing sensitivity of EEG is a result

Genetic markers

PRNP mutations account for 10–15% of all human prion diseases.1 Some cause specific clinical syndromes (eg, Gerstmann–Sträussler–Scheinker syndrome or fatal familial insomnia), whereas others can mimic clinical presentation and biomarker profiles of sporadic Creutzfeldt-Jakob disease (eg, E200K).102 Thus, the sequencing of PRNP is an important biomarker that should be considered in the differential diagnosis of prion diseases and is crucial in atypical cases, and in cases with positive or

Clinical value of RT-QuIC and CSF surrogate biomarkers

Over the past 9 years, the evidence suggesting CSF RT-QuIC as a major improvement in the clinical diagnosis of sporadic Creutzfeldt-Jakob disease has accumulated. The test sensitivity is similar to the best available surrogate biomarkers and the data display superior specificity (table). By contrast with all established biomarkers for sporadic Creutzfeldt-Jakob disease and other neurodegenerative diseases, RT-QuIC is able to detect the protein that was consensually identified to be primarily

Guidelines for biomarker-based diagnosis

Based on WHO criteria,3, 4 the studies presented here, and previous suggestions that include RT-QuIC,12, 13 the majority of the authors recommend amended criteria for the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (figure 2). Because of the outstanding specificity of RT-QuIC, positive cases can be classified as probable sporadic Creutzfeldt-Jakob disease in early clinical stages, even when only one cardinal symptom is present, which will improve the early identification of

Conclusions and future directions

Despite improvements of diagnostic measures for sporadic Creutzfeldt-Jakob disease over the past 25 years, there are still plenty of challenges. The value of established and new biomarkers in the differential diagnosis of sporadic Creutzfeldt-Jakob disease subtypes and other human prion diseases (eg, iatrogenic Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, and genetic Creutzfeldt-Jakob disease) has to be clarified. RT-QuIC has to be widely distributed, protocols have to be

Search strategy and selection criteria

We searched Google Scholar and PubMed using the terms “prion” and “Creutzfeldt-Jakob disease”, each in combination with “diagnosis”, “criteria”, “biomarker”, “imaging”, “MRI”, “EEG”, and “RT-QuIC”. We included articles published between Jan 1, 2015, and Nov 15, 2020, written in English or German, on the basis of the scientific merit and contribution to developments in biomarker research for sporadic Creutzfeldt-Jakob disease (ie, the biomarkers have shown potential for a clinical use and

Acknowledgments

The research of IZ and PH was funded by the German Federal Ministry of Health through grants from the Robert Koch Institute (grant 139-341). BC was funded by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. SJC is funded in part by a NHMRC Practitioner Fellowship (ID# APP1105784). FL was supported by grant from the Institute of Health Carlos III, grant PI19/00144. MG was supported by grants from the US National

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