BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disorder originating from exposure to bovine-spongiform-encephalopathy-like prions. Prion infections are associated with long and clinically silent incubations. The number of asymptomatic individuals with vCJD prion infection is unknown, posing risk to others via blood transfusion, blood products, organ or tissue grafts, and contaminated medical instruments. We aimed to establish the sensitivity and specificity of a blood-based assay for detection of vCJD prion infection. METHODS: We developed a solid-state binding matrix to capture and concentrate disease-associated prion proteins and coupled this method to direct immunodetection of surface-bound material. Quantitative assay sensitivity was assessed with a serial dilution series of 10⁻⁷ to 10⁻¹⁰ of vCJD prion-infected brain homogenate into whole human blood, with a baseline control of normal human brain homogenate in whole blood (10⁻⁶). To establish the sensitivity and specificity of the assay for detection of endogenous vCJD, we analysed a masked panel of 190 whole blood samples from 21 patients with vCJD, 27 with sporadic CJD, 42 with other neurological diseases, and 100 normal controls. Samples were masked and numbered by individuals independent of the assay and analysis. Each sample was tested twice in independent assay runs; only samples that were reactive in both runs were scored as positive overall. FINDINGS: We were able to distinguish a 10⁻¹⁰ dilution of exogenous vCJD prion-infected brain from a 10⁻⁶ dilution of normal brain (mean chemiluminescent signal, 1·3×10⁵ [SD 1·1×10⁴] for vCJD vs 9·9×10⁴ [4·5×10³] for normal brain; p<0·0001)—an assay sensitivity that was orders of magnitude higher than any previously reported. 15 samples in the masked panel were scored as positive. All 15 samples were from patients with vCJD, showing an assay sensitivity for vCJD of 71·4% (95% CI 47·8–88·7) and a specificity of 100% (95% CIs between 97·8% and 100%). INTERPRETATION: These initial studies provide a prototype blood test for diagnosis of vCJD in symptomatic individuals, which could allow development of large-scale screening tests for asymptomatic vCJD prion infection. FUNDING: UK Medical Research Council.
BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disorder originating from exposure to bovine-spongiform-encephalopathy-like prions. Prion infections are associated with long and clinically silent incubations. The number of asymptomatic individuals with vCJD prion infection is unknown, posing risk to others via blood transfusion, blood products, organ or tissue grafts, and contaminated medical instruments. We aimed to establish the sensitivity and specificity of a blood-based assay for detection of vCJD prion infection. METHODS: We developed a solid-state binding matrix to capture and concentrate disease-associated prion proteins and coupled this method to direct immunodetection of surface-bound material. Quantitative assay sensitivity was assessed with a serial dilution series of 10⁻⁷ to 10⁻¹⁰ of vCJD prion-infected brain homogenate into whole human blood, with a baseline control of normal human brain homogenate in whole blood (10⁻⁶). To establish the sensitivity and specificity of the assay for detection of endogenous vCJD, we analysed a masked panel of 190 whole blood samples from 21 patients with vCJD, 27 with sporadic CJD, 42 with other neurological diseases, and 100 normal controls. Samples were masked and numbered by individuals independent of the assay and analysis. Each sample was tested twice in independent assay runs; only samples that were reactive in both runs were scored as positive overall. FINDINGS: We were able to distinguish a 10⁻¹⁰ dilution of exogenous vCJD prion-infected brain from a 10⁻⁶ dilution of normal brain (mean chemiluminescent signal, 1·3×10⁵ [SD 1·1×10⁴] for vCJD vs 9·9×10⁴ [4·5×10³] for normal brain; p<0·0001)—an assay sensitivity that was orders of magnitude higher than any previously reported. 15 samples in the masked panel were scored as positive. All 15 samples were from patients with vCJD, showing an assay sensitivity for vCJD of 71·4% (95% CI 47·8–88·7) and a specificity of 100% (95% CIs between 97·8% and 100%). INTERPRETATION: These initial studies provide a prototype blood test for diagnosis of vCJD in symptomatic individuals, which could allow development of large-scale screening tests for asymptomatic vCJD prion infection. FUNDING: UK Medical Research Council.
Authors: Gültekin Tamgüney; Jürgen A Richt; Amir N Hamir; Justin J Greenlee; Michael W Miller; Lisa L Wolfe; Tracey M Sirochman; Alan J Young; David V Glidden; Natrina L Johnson; Kurt Giles; Stephen J DeArmond; Stanley B Prusiner Journal: Prion Date: 2012 Jan-Mar Impact factor: 3.931
Authors: Alan M Elder; Davin M Henderson; Amy V Nalls; Edward A Hoover; Anthony E Kincaid; Jason C Bartz; Candace K Mathiason Journal: J Virol Date: 2015-07 Impact factor: 5.103
Authors: Daryl Rhys Jones; Marion Delenclos; AnnMarie T Baine; Michael DeTure; Melissa E Murray; Dennis W Dickson; Pamela J McLean Journal: J Neuropathol Exp Neurol Date: 2015-12 Impact factor: 3.685