title: Diagnosis of human prion disease.
abstract: With the discovery of the prion protein (PrP), immunodiagnostic procedures were applied to diagnose Creutzfeldt-Jakob disease (CJD). Before development of the conformation-dependent immunoassay (CDI), all immunoassays for the disease-causing PrP isoform (PrPSc) used limited proteolysis to digest the precursor cellular PrP (PrPC). Because the CDI is the only immunoassay that measures both the protease-resistant and protease-sensitive forms of PrPSc, we used the CDI to diagnose human prion disease. The CDI gave a positive signal for PrPSc in all 10-24 brain regions (100%) examined from 28 CJD patients. A subset of 18 brain regions from 8 patients with sporadic CJD (sCJD) was examined by histology, immunohistochemistry (IHC), and the CDI. Three of the 18 regions (17%) were consistently positive by histology and 4 of 18 (22%) by IHC for the 8 sCJD patients. In contrast, the CDI was positive in all 18 regions (100%) for all 8 sCJD patients. In both gray and white matter, approximately 90% of the total PrPSc was protease-sensitive and, thus, would have been degraded by procedures using proteases to eliminate PrPC. Our findings argue that the CDI should be used to establish or rule out the diagnosis of prion disease when a small number of samples is available as is the case with brain biopsy. Moreover, IHC should not be used as the standard against which all other immunodiagnostic techniques are compared because an immunoassay, such as the CDI, is substantially more sensitive.
authors.affiliation: Institute for Neurodegenerative Diseases, Memory and Aging Center, University of California, San Francisco, CA 94143, USA.
authors.forename: Jiri G
authors.initials: JG
authors.lastname: Safar
authors.forename: Michael D
authors.initials: MD
authors.lastname: Geschwind
authors.forename: Camille
authors.initials: C
authors.lastname: Deering
authors.forename: Svetlana
authors.initials: S
authors.lastname: Didorenko
authors.forename: Mamta
authors.initials: M
authors.lastname: Sattavat
authors.forename: Henry
authors.initials: H
authors.lastname: Sanchez
authors.forename: Ana
authors.initials: A
authors.lastname: Serban
authors.forename: Martin
authors.initials: M
authors.lastname: Vey
authors.forename: Henry
authors.initials: H
authors.lastname: Baron
authors.forename: Kurt
authors.initials: K
authors.lastname: Giles
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Dearmond
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
mesh_terms: D001706:Biopsy; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003062:Codon; D007562:Creutzfeldt-Jakob Syndrome / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D018620:PrPSc Proteins / Q000235:genetics / Q000378:metabolism; D012680:Sensitivity and Specificity
chemical_list: D003062:Codon; D018620:PrPSc Proteins
references.citation: J Neuropathol Exp Neurol. 1981 May;40(3):281-8
references.pmid: 7194369
references.citation: N Engl J Med. 2003 Nov 6;349(19):1812-20
references.pmid: 14602879
references.citation: Neurology. 1991 Sep;41(9):1482-90
references.pmid: 1679911
references.citation: J Comp Pathol. 1979 Oct;89(4):551-62
references.pmid: 120379
references.citation: Neurosci Lett. 1989 Jul 17;102(1):1-6
references.pmid: 2550852
references.citation: Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):9126-30
references.pmid: 7916462
references.citation: Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9936-40
references.pmid: 7937921
references.citation: J Pathol. 2004 Jul;203(3):733-9
references.pmid: 15221931
references.citation: Acta Neuropathol. 1989;78(2):194-201
references.pmid: 2546359
references.citation: Nature. 1996 Jan 25;379(6563):339-43
references.pmid: 8552188
references.citation: J Gen Virol. 2001 Jan;82(Pt 1):267-273
references.pmid: 11125179
references.citation: J Virol. 1987 Dec;61(12):3688-93
references.pmid: 2446004
references.citation: Ann Neurol. 1994 May;35(5):513-29
references.pmid: 8179297
references.citation: EMBO J. 2002 Dec 2;21(23):6358-66
references.pmid: 12456643
references.citation: Nat Med. 1997 Jul;3(7):750-5
references.pmid: 9212101
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4784-9
references.pmid: 12684540
references.citation: Genes Dev. 1992 Jul;6(7):1213-28
references.pmid: 1628828
references.citation: Lancet. 2001 Jul 21;358(9277):171-80
references.pmid: 11476832
references.citation: Vet Pathol. 1980 Mar;17(2):187-99
references.pmid: 6767304
references.citation: Nat Biotechnol. 2002 Nov;20(11):1147-50
references.pmid: 12389035
references.citation: J Gen Virol. 2004 Jun;85(Pt 6):1777-1784
references.pmid: 15166463
references.citation: Ann Neurol. 1999 Aug;46(2):224-33
references.pmid: 10443888
references.citation: Clin Radiol. 2001 Sep;56(9):726-39
references.pmid: 11585394
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83
references.pmid: 9811807
references.citation: J Virol. 2004 Feb;78(4):2088-99
references.pmid: 14747574
references.citation: J Infect Dis. 1982 Nov;146(5):657-64
references.pmid: 6813384
references.citation: Ann Neurol. 2004 Jun;55(6):851-9
references.pmid: 15174020
references.citation: Nat Med. 1998 Oct;4(10):1157-65
references.pmid: 9771749
references.citation: Annu Rev Microbiol. 1989;43:345-74
references.pmid: 2572197
references.citation: J Gen Virol. 2003 Jul;84(Pt 7):1921-1925
references.pmid: 12810888
references.citation: Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7620-4
references.pmid: 1354357
references.citation: Cell. 1995 Oct 6;83(1):79-90
references.pmid: 7553876
references.citation: Brain Pathol. 1999 Oct;9(4):707-20
references.pmid: 10517509
references.citation: J Neuropathol Exp Neurol. 2004 Aug;63(8):882-99
references.pmid: 15330342