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By Joseph E. Safdieh, MD
Assistant Professor of Neurology, Weill Cornell Medical College
Dr. Safdieh reports no financial relationships relevant to this field of study.
Synopsis: Novel noninvasive diagnostic tests for Creutzfeldt-Jakob disease (CJD; nasal brushings) and variant CJD (urinary prion proteins) are reported to be highly sensitive and specific in two recent studies.
Sources: Orru’ CD, et al. A test for Creutzfeldt-Jakob disease using nasal brushings. N Engl J Med 2014;371:519-529.
Moda F, et al. Prions in the urine of patients with variant Creutzfeldt-Jakob disease. N Engl J Med 2014;371:530-539.
Masters CL. Shaken, not sonicated? Editorial. N Engl J Med 2014;371:571-572.
Prion diseases are rare and uniformly fatal neurologic conditions. They are caused by propagation of misfolded proteins from the normal form to the pathogenic form. Prion diseases in humans include Creutzfeld-Jakob disease (CJD), variant CJD, fatal familial insomnia, and Gerstmann–Sträussler–Scheinker syndrome. Prion diseases are unique among all medical disorders in that they can be inherited or transmitted. Variant CJD is caused by exposure to the bovine spongiform encephalopathy prion and is acquired by eating infected meat. Patients are suspected to have CJD when they present with a rapidly progressive dementia, associated lumbar puncture characteristics (14-3-3 protein), and associated MRI changes (cortical ribbon and thalamic/basal ganglia hyperintensities on diffusion weighted imaging). However, none of these tests provide enough sensitivity and specificity to firmly establish the diagnosis, often necessitating a brain biopsy. In this set of studies, the authors propose novel, non-invasive methods to diagnose CJD and variant CJD.
Orru et al looked at a novel method of detecting abnormal prion protein via a method called real-time quaking-induced conversion (RT-QUIC) in nasal brushings of patients with and without CJD. RT-QUIC is performed by mixing recombinant prion protein with small amounts of human pathogenic prion protein resulting in the formation of amyloid fibrils that can be detected by Thioflavin T staining. In a prior study, CSF RT-QUIC was found to be 80-90% sensitive in the diagnosis of CJD. In this study, the authors evaluated the sensitivity and specificity of RT-QUIC testing of nasal brushings. The results demonstrated that the RT-QUIC was positive in 30 of 31 cases of confirmed CJD and was negative in all 43 non-CJD patients. Calculated sensitivity was 97% and specificity was 100%. The authors also performed CSF RT-QUIC on the same group of samples and determined a much lower sensitivity of 77%, with the same 100% specificity. Nasal brushings had much higher levels of the abnormal prion protein than CSF.
Moda et al looked at a novel method of detecting abnormal prion protein called PMCA (protein misfolding cyclic amplification) in the urine of patients with and without variant CJD. PMCA is performed by mixing the pellet from centrifuged urine with a suspension of brain specimen from transgenic mice expressing human prior protein. The authors tested urine from patients with variant CJD, sporadic CJD and other non-prion neurologic illnesses as well as healthy controls. The results demonstrated that via PMCA, 13 of 14 patients with variant CJD had detectable abnormal prion in the urine and none of the 224 patients (including those with sporadic and genetic prion diseases) were positive. Calculated sensitivity was 92.9% and specificity 100%.
Both of these studies are extremely important additions to the medical diagnostic literature and move us a step closer to making the diagnosis of CJD and variant CJD without the need to perform brain biopsy, and potentially without the need to perform lumbar puncture. In fact, for sporadic CJD the sensitivity of RT-QUIC is much higher in the nasal brushings than CSF, suggesting that testing nasal brushings may actually be preferred over CSF. In the setting of an appropriate clinical picture and a compatible MRI, a positive RT-QUIC test in nasal brushings will likely have a very positive predictive value, although it is not fully sensitive so a negative test may not exclude the disease. It also seems that a positive test for urine PMCA in variant CJD is likely to have a high positive predictive value, but again a negative test does not fully exclude the disease. More work needs to be done to confirm these findings, and more samples tested will likely tighten up the confidence intervals for specificity, but these studies are very promising and raise the likelihood that there will be a simple non-invasive test for diagnosing CJD or variant CJD in the near future.