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Human prion diseases, including Creutzfeldt‐Jakob disease (CJD), occur in sporadic, genetic, and acquired forms. Variant Creutzfeldt‐Jakob disease (vCJD) first reported in 1996 in the United Kingdom (UK), resulted from contamination of food with bovine spongiform encephalopathy. There is a concern that UK national surveillance mechanisms might miss some CJD cases (including vCJD), particularly in the older population where other neurodegenerative disorders are more prevalent. We developed a highly sensitive protocol for analysing autopsy brain tissue for the misfolded prion protein (PrPSc) associated with prion disease, which could be used to screen for prion disease in the elderly. Brain tissue samples from 331 donors to the Edinburgh Brain and Tissue Bank (EBTB), from 2005 to 2022, were analysed, using immunohistochemical analysis on fixed tissue, and five biochemical tests on frozen specimens from six brain regions, based on different principles for detecting PrPSc. An algorithm was established for classifying the biochemical results. To test the effectiveness of the protocol, several neuropathologically confirmed prion disease controls, including vCJD, were included and blinded in the study cohort. On unblinding, all the positive control cases had been correctly identified. No other cases tested positive; our analysis uncovered no overlooked prion disease cases. Our algorithm for classifying cases was effective for handling anomalous biochemical results. An overall analysis suggested that a reduced biochemical protocol employing only three of the five tests on only two brain tissue regions gave sufficient sensitivity and specificity. We conclude that this protocol may be useful as a UK‐wide screening programme for human prion disease in selected brains from autopsies in the elderly. Further improvements to the protocol were suggested by enhancements of the in vitro conversion assays made during the course of this study. [ABSTRACT FROM AUTHOR]

Human prion diseases, also called transmissible spongi-form encephalopathies, are a group of rare and inevitably fatal neurodegenerative diseases. Prion diseases are unique in that they occur as idiopathic (sporadic), familial, [...]

The challenge of 3T3-F442A fibroblasts with growth hormone led to both a decrease in the mobility on SDS/PAGE and activation of the PDE4A cyclic AMP-specific phosphodiesterase isoform PDE4A5. Activation was mediated by a JAK-2-dependent pathway coupled to the activation of phosphatidylinositol 3-kinase and p70S6 kinase. Activation was not dependent on the ability of growth hormone to stimulate ERK2 or protein kinase C or any effect on transcription. Blockade of activation of murine PDE4A5 ablated the ability of growth hormone to decrease intracellular cAMP levels. Antisense depletion of murine PDE4A5 mimicked the ability of rolipram to enhance the growth hormone-stimulated differentiation of 3T3-F442A cells to adipocytes. It is suggested that activation of PDE4A5 by growth hormone serves as a brake on the differentiation processes.

The phenotypic and strain-related properties of human prion diseases are, according to the prion hypothesis, proposed to reside in the physicochemical properties of the conformationally altered, disease-associated isoform of the prion protein (PrPSc), which accumulates in the brains of patients suffering from Creutzfeldt-Jakob disease and related conditions, such as Gerstmann-Straussler-Scheinker disease. Molecular strain typing of human prion diseases has focused extensively on differences in the fragment size and glycosylation site occupancy of the protease-resistant prion protein (PrPres) in conjunction with the presence of mutations and polymorphisms in the prion protein gene (PRNP). Here we report the results of employing an alternative strategy that specifically addresses the conformational stability of PrPSc and that has been used previously to characterize animal prion strains transmitted to rodents. The results show that there are at least two distinct conformation stability states in human prion diseases, neither of which appears to correlate fully with the PrPres type, as judged by fragment size or glycosylation, the PRNP codon 129 status, or the presence or absence of mutations in PRNP. These results suggest that conformational stability represents a further dimension to a complete description of potentially phenotype-related properties of PrPSc in human prion diseases. [ABSTRACT FROM AUTHOR]

Variant Creutzfeldt-Jakob disease (vCJD) was first identified in 1996 in the UK, and results from human exposure to the bovine spongiform encephalopathy (BSE) agent. vCJD has subsequently been identified in 10 additional countries, and numbers continue to increase in the UK. Unlike other human prion diseases, infectivity and the disease-associated form of the prion protein are readily detected in lymphoid tissues in vCJD. In experimental BSE infection in a sheep model, infectivity has been transmitted by blood transfusion from asymptomatic infected animals to normal recipient animals, indicating that infectivity is present in blood during the incubation period. Recently, two cases of apparent iatrogenic vCJD infection by blood transfusion from asymptomatic donors who subsequently died from vCJD have been reported from the UK. The first case resulted in clinical illness identical to other cases of vCJD, while the second case was an asymptomatic infection detected at autopsy. Sensitive means of detection of disease-associated prion protein in the blood are required in order to be employed for screening purposes, both individually at the time of blood donation, and to help ascertain future numbers of vCJD cases in the UK and beyond. [ABSTRACT FROM AUTHOR]