The contractor proposes a parallel study to confirm two new methods of detecting human prions: (1) in-vitro measurement of the disease-causing isoform of the prion protein (PrPSc) by conformation-dependent immunoassay (CDI) (Safar et al., 1998), and (2) titration of prions in-vivo by bioassay in highly susceptible transgenic mice (Scott et al., 1999; Telling et al., 1996b; telling et al., 1995). The proposed study will be designed to determine the concentration of prions in body fluids and tissues of patients with sporadic(s) and new variant (nv) Creutzfeldt-Jakob disease (CJD). The contractor plans to collect blood, CSF, urine, and saliva from 100 patients with sporadic and 50 with new variant CJD at multiple times during the clinical phase of their disease, and to collect brain, lymph nodes, thymus, spleen, tonsils, liver, kidney, heart, cornea, skin, and lung autopsy. Each of these tissues will be tested by CDI to measure quantitatively the concentration of PrPSc, and by endpoint titrations in Tg(MHu2IM)Prnp o/o or Tg(BoPrP)Prnp o/o mice to measure prion titer. The PrP gene will be sequenced in all patients to exclude a genetic origin of CJD and to characterize phenotypic variability determined by polymorphisms. The accumulated data will established the distribution of human prions in the brain and peripheral tissues. Moreover, the study will demonstrate sensitivity and specificity for both CDI and bioassays in diagnosis of human prion diseases, and determine which body fluids, as well as tissues, may be used for measuring prions reliably.
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