Research & Projects

Background

Current prion diagnostics have limited utility as no effective therapeutics or preventatives exist. Discovering biomarkers that detect prion diseases in pre-clinical stages is essential for monitoring at-risk individuals and guiding potential treatments. However, existing collection and analysis methods like lumbar punctures, biopsies, MRIs, and RT-QuIC are slow, costly, and invasive, highlighting the need for more efficient diagnostic tools.

Position Statement

The development of affordable, rapid, and accessible diagnostic tools is critical for advancing prion disease research and treatment. Cheaper diagnostics would enable broader population screening, including at-risk groups and individuals in pre-clinical stages, facilitating early intervention and more comprehensive epidemiological studies. Prioritizing diagnostics with higher specificity over sensitivity is crucial, as it allows for more accurate exclusion of individuals without prion diseases or genetic predispositions to prion disease. This targeted approach will enhance the efficiency of population-wide studies and improve the overall understanding of prion diseases.

Introduction

With an annual incidence of only 1-2 cases per million,(18) research in prion diseases remains slow due to small study populations. This literature review aims to identify efficient, affordable, and non-invasive methods for screening large populations to better understand prion disease prevalence, especially among high-risk and pre-clinical individuals. Identifying such patients early will expand research potential, allowing for the discovery of progression biomarkers, resistance genes, and broader disease patterns. Given the ongoing threat of prion diseases, like vCJD in UK blood supplies, accessible diagnostics and ante-mortem studies are crucial for public health.

Objectives & Questions

1.  Evaluate Prion Diagnostics: Identify strengths and limitations in current prion diagnostic methods (cost, speed, invasiveness, specificity).

2.  Identify Early-Stage Biomarkers: Explore biomarkers from similar diseases for their potential to track prion progression.

3.  Research Scalable Diagnostics: Investigate low-cost, non-invasive diagnostic tools feasible for large-scale screening.

4.  Address Population Limitations: How can we increase the size of patient sample sizes in prion studies?

5.  Assess Public Health Impact: What policy updates could improve prion screening to enhance public health safety?

Methods

A comprehensive internet research strategy was employed, focusing on the keywords “prion disease” and “prion disease academic papers.” Upon identifying relevant articles, citation tracking was utilized to discover additional pertinent studies. The analysis involved a thorough review of selected papers, where key findings were highlighted and summarized, emphasizing the significance of each research contribution. This synthesis aimed to address the central questions of how to diagnose prion disease more quickly and less invasively, identify reliable biomarkers for prion disease, and assess the specificity of various diagnostic methods and biomarkers for different prion disease types. The goal was to determine effective diagnostic strategies that were highly specific, gave quick results and required minimal invasive sample collection.

Findings of Interest

• Advances in RT-QuIC diagnostics have made testing fast, sensitive and specific.(1) While PCMA can detect prions in femtomolar amounts,(14) the testing procedure is slow and the efficiency varies among prion strains.(13)

• Bank vole rPrP is a universal substrate for testing all prion diseases.(2)

• IOME-RT-QuIC allows for detection of prions in whole blood samples.(3)

• Prions can be detected in less invasive sample types such as blood,(3,6,11) tears,(4) feces,(7) and urine.(8,9,10)

• ELISA-type assays for detecting PrPSc in blood(6) and urine(10) show potential for further research.

Discussion

One bottleneck in prion disease research is small sample sizes, a consequence of the rarity of prion diseases. Large living population samples show overall disease prevalence, and patterns in disease progression, genetics and biomarkers.

Most studies on prion diseases use CSF samples for diagnostics. While this sample type has been clinically validated, the invasiveness and anxiety of the procedure can reduce patient compliance.(12) Furthermore, lumbar punctures are expensive as they require trained staff, a sterile setting, anesthetics and specialized medical equipment.(17)

Non-invasive diagnostic methods are ideal for performing ante-mortem prion disease research because they encourage consistent compliance and they are cost effective collection techniques which allow for large studies on living populations. There have been promising studies on non-invasive prion diagnostic methods, including tears, urine and blood. However, there has been little follow up or validation of these studies for clinical use. 

Conclusion

Studies with large numbers of currently living populations allow for monitoring disease progression. Non-invasive collection techniques should be further developed and validated for clinical use.

Testing pre-clinical populations and healthy carriers allows for identification of prodromal biomarkers, phenoconversion risk factors and possible treatment strategies. One study in the recruitment phase is seeking to address these issues.(5)

As prion diseases are rare, the differential diagnosis includes other neurological conditions such as, Alzheimers, dementia, encephalitis and many others.(15) The standard workup for a neurological condition requires a spinal tap as many biomarkers for other diseases can only be detected in CSF.(16) This has hindered research into non-invasive prion diagnostics as a lumbar puncture would be needed anyways to rule out other diagnoses. 

Recommendations

• Validate Bank vole rPrP for use in clinical practice, as it can detect all prion strains.*

• Perform confirmatory and validation studies on non-invasive prion diagnostics, development of these diagnostics will enable faster, cheaper and broader screening of prion diseases. 

• As prions can be detected in urine and feces, the feasibility of a UK vCJD wastewater study should be explored, as this would give us a more accurate picture of the current state of vCJD prevalence.

• International collaboration in prion disease studies is essential, and researchers should strive to follow up on novel research and keep clinical diagnostic guidelines as up to date as possible.

*This idea has been challenged by Tse How Mok, apparently Bank vole rPrP only works with all prion strains when using brain homogenate.