New Tools for the Diagnosis of CJD
By Joseph E. Safdieh, MD
Vice Chair and Associate Professor, Weill Cornell Medical College
Dr. Safdieh reports no financial relationships relevant to this field of study.
SYNOPSIS: Cerebrospinal fluid analysis using second-generation, real-time, quaking-induced conversion has a high sensitivity and specificity for the diagnosis of Creutzfeldt-Jakob disease.
SOURCE: Foutz A, Appleby BS, Hamlin C, et al. Diagnostic and prognostic value of human prion detection in cerebrospinal fluid. Ann Neurol 2017;81:79-92.
Prion diseases are uncommon and invariably fatal neurologic disorders caused by propagation of misfolded proteins from the normal alpha-helix form to the pathogenic beta-pleated sheet form. Prion diseases in humans include Creutzfeldt-Jakob disease (CJD), variant CJD, fatal familial insomnia, and Gerstmann–Sträussler–Scheinker syndrome. Patients are suspected to have CJD when they present with a rapidly progressive dementia often associated with myoclonus and ataxia. Supportive diagnostic testing includes characteristic MRI changes (cortical ribbon and thalamic/basal ganglia hyperintensities on DWI) and associated lumbar puncture characteristics (elevation of the 14-3-3 protein). However, none of these tests provide enough sensitivity and specificity to firmly establish the diagnosis, often necessitating a brain biopsy.
Over the past few years, a novel testing method that can amplify tiny amounts of prion protein in the laboratory, called real-time quaking-induced conversion (RT-QuIC), has been proposed as a more sensitive and specific diagnostic test for CJD. RT-QuIC is performed by mixing recombinant prion protein with small amounts of pathogenic prion protein, which induces the formation of amyloid fibrils that can be detected by thioflavin T staining. In this study, the authors evaluated the sensitivity and specificity of RT-QuIC testing of cerebrospinal fluid (CSF) in patients with suspected CJD. The study had both a retrospective and prospective arm. The study was performed by the National Prion Disease Pathology Surveillance Center, which maintains a detailed database of all referred cases.
In the study, 2,141 CSF samples were tested with RT-QuIC. In the retrospective cohort of CJD cases (126 patients), 92% of the samples had positive RT-QuIC testing, as compared to 81.7% with elevated 14-3-3 protein. In the prospective cohort of CJD cases (65 patients), 95.4% of the samples had positive RT-QuIC testing, as compared to 81.5% with elevated 14-3-3 protein. Overall sensitivity of the RT-QuIC test (92-95%) was higher than assaying CSF 14-3-3 protein (81.2-81.5%). Of note, in both groups, approximately 76% of patients had characteristic MRI changes for CJD. Only 29% of patients in the retrospective cohort manifested characteristic EEG changes (periodic sharp waves).
To assess the specificity of the RT-QuIC assay, other rapidly progressive neurologic disorders were used as controls. Of note, the most common neuropathological diagnosis in the non-CJD cohort was Alzheimer’s disease. In the prospective cohort, none of the non-CJD cases demonstrated abnormal RT-QuIC assays (100% specificity), and in the retrospective cohort, there was one non-CJD case with abnormal RT-QuIC (98.5% specificity). The specificity of the 14-3-3 protein assay was much lower (62% in the retrospective cohort and 48% in the prospective cohort). In the prospective cohort the positive predictive value of RT-QuIC was 100% and of 14-3-3 was 86.9%. The negative predictive value was 82.4% for RT-QuIC and 50% for 14-3-3.
COMMENTARY
This study contributes valuable additional experience with RT-QuIC testing in the diagnostic workup of suspected CJD. Other studies have assessed RT-QuIC in CSF and even in nasal brushings, demonstrating a high degree of sensitivity and specificity. This study is extremely important because it confirms the diagnostic value of CSF RT-QuIC testing in both a retrospective and a prospective cohort. The test is demonstrated to have higher sensitivity and specificity than 14-3-3 protein and total tau. In the prospective cohort, specificity was 100%, suggesting that this test is highly unlikely to be positive in a non-CJD case. This is a significant advance over 14-3-3, which is sensitive but not very specific. In the setting of an appropriate clinical picture, a positive RT-QuIC test in CSF has a strongly positive predictive value, although it is not 100% sensitive, so a negative test may not exclude the disease. The hope for the near future is that by using a combination of imaging modalities with CSF analysis, we will be able to confidently diagnose CJD without resorting to a brain biopsy.
Cerebrospinal fluid analysis using second-generation, real-time, quaking-induced conversion has a high sensitivity and specificity for the diagnosis of Creutzfeldt-Jakob disease.
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