Prion Diseases
A test being developed by National Institutes of Health (NIH) scientists to quickly and accurately diagnose fatal brain diseases performed better than existing tests in a recent study of sporadic Creutzfeldt-Jakob disease (sCJD).
Background
Prion diseases, also known as transmissible spongiform encephalopathies, are difficult to diagnose, untreatable, and ultimately fatal. Normally, prion protein molecules exist harmlessly in every mammal, but for reasons not fully understood, these molecules can develop abnormalities and gather in clusters. Scientists have associated the accumulation of these clusters with tissue damage that leaves microscopic sponge-like holes in the brain.
Prion diseases include sCJD and variant CJD in people; scrapie in sheep; chronic wasting disease in deer, elk, and moose; and bovine spongiform encephalopathy, or mad cow disease, in cattle.
Because animals and people can be infected for years before clinical signs or symptoms appear, NIH scientists are developing a rapid and sensitive screening tool to detect prion diseases. Such a test would help prevent the spread of prion diseases among and between species. Of particular concern is the known transmission of variant CJD via blood transfusions.
Results of Study
The NIH scientists, working with colleagues in the United Kingdom, used real-time quaking induced conversion (RT-QuIC) to test for sCJD in 226 cerebral spinal fluid samples; 122 samples were from confirmed sCJD patients and 104 samples were normal. RT-QuIC was 89-percent sensitive and 99-percent specific in diagnosing sCJD. Sensitivity is a measurement of correct-positive test results; specificity is a measurement of correct-negative test results.
RT-QuIC was developed by the laboratories of Byron Caughey, Ph.D., at NIH’s National Institute of Allergy and Infectious Diseases, and Ryuichiro Atarashi, M.D., Ph.D., a former NIAID post-doctoral fellow trained in Dr. Caughey’s laboratory who is now at Nagasaki University in Japan. The results of the UK/NIH study extend those of a similar study led by Dr. Atarashi.
Significance
Scientists believe that early diagnosis of prion diseases may enable physicians to treat and prolong the life of CJD patients. Presently, by the time physicians diagnose a human prion disease, it has progressed too far for effective treatment.
Next Steps
The research group will focus additional studies on two areas: using blood as a test sample instead of cerebral spinal fluid and using a next-generation testing method known as enhanced quaking-induced protein conversion (e-QuIC), which in preliminary studies has been more sensitive in detecting prion disease than RT-QuIC.
References
McGuire et al. RT-QuIC analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease. Annals of Neurology. DOI: 10.1002/ana.23589 (2012).
C Orru et al. Prion disease blood test using immunoprecipitation and improved quaking-induced conversion. mBio. DOI: 10.1128/mBIo.00078-11 (2011).
R Atarashi, et al. Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nature Medicine. 17(2):175-178 DOI:10.1038/nm.2294 (2011).
J Wilham et al. Rapid end-point quantitation of prion seeding activity with sensitivity comparable to bioassays. PLoS Pathogens 6(12): e1001217. DOI: 10.1371/journal.ppat.1001217 (2010).
R Atarashi, et al. Simplified ultrasensitive prion detection by recombinant PrP conversion with shaking. Nature Methods. 3:2011-2012. DOI:10.1038/nmeth0308-211 (2008)
R Atarashi, et al. Ultrasensitive detection of scrapie prion protein using seeded conversion of recombinant prion protein. Nature Methods. 4:645-50. DOI: 10.1038/nmeth1066 (2007)
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