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Introduction Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive neurodegenerative disease with public health implications. Mean age of onset is 68 years. Age-specific incidence declines after 80 years. This may arise from under-ascertainment or other biological features of the disease. Accurate characterisation of late-onset sCJD is important for early diagnosis, avoiding unnecessary investigations and improving ascertainment for public health purposes. Objective To phenotype the clinical features and investigation profile of sCJD in adults >80 years. Methods We analysed all probable and definite sCJD cases identified by the UK National CJD Research & Surveillance Unit over a 10-year period (2011–2021). Individuals were grouped by age of onset. Clinical features and investigation profiles were compared. Results 10.3% (123/1196) had an age of onset over 80. Median survival was shorter (3.2 vs 4.3 months; P  < 0.001). Pyramidal signs (48.3% vs 34.2%; P  = 0.008) and akinetic mutism (55.1% vs 33.2%; P  < 0.001) were more frequent. Psychiatric symptoms (26.3% vs 39.6%; P  = 0.01) and cerebellar signs (65.4% vs 78.6%, P  = 0.007) were less frequent. Cognitive impairment and myoclonus were highly prevalent regardless of age. Between age groups, the diagnostic sensitivity of cerebrospinal fluid real-time quaking-induced conversion (CSF RT-QuIC) (92.9% vs 91.9%, P  = 0.74) was comparable, electroencephalography was superior (41.5% vs 25.4%; P  = 0.006) and MRI was inferior (67.8% vs 91.4%; P  < 0.001). Conclusions Late-onset sCJD has distinct clinical features, shorter survival and a different profile of investigation sensitivity. CSF RT-QuIC, MRI brain and specialist CJD review is recommended in older adults with a rapidly progressive neurological disorder. Autopsy is valuable when the cause remains elusive. [ABSTRACT FROM AUTHOR]

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]

Three retrospective lymphoreticular tissue studies (Appendix I, II, and III) aimed to estimate the UK prevalence of variant Creutzfeldt-Jakob disease (vCJD), following exposure of the population to the bovine spongiform encephalopathy (BSE) agent, in the late 1980s and 1990s. These studies evaluated the presence of abnormal prion protein aggregates, in archived formalin-fixed paraffin-embedded (FFPE) appendectomy samples, by immunohistochemical detection. Although there was concordance in the estimated prevalence of vCJD from these studies, the identification of positive specimens from pre- and post-BSE-exposure periods in Appendix III study has raised questions regarding the nature and origin of the detected abnormal prion protein. We applied a robust and novel approach in the extraction of disease-associated prion protein (PrPSc) present in frozen and FFPE samples of brain and appendix from a patient with pathologically confirmed vCJD. The extracted material was used to seed the highly sensitive protein misfolding cyclic amplification assay (hsPMCA) to investigate the in vitro and in vivo propagation properties of the extracted abnormal prion protein. We demonstrate that PrPSc can be successfully extracted from FFPE appendix tissue and propagated in vitro. Bioassay in wild-type and gene-targeted mouse models confirmed that the extracted and amplified product is infectious and retains strain properties consistent with vCJD. This provides a highly sensitive and reliable platform for subsequent analysis of the archived FFPE appendix tissue derived from the Appendix II and III surveys, to further evaluate the nature of the abnormal PrP detected in the positive samples. [ABSTRACT FROM AUTHOR]

Chronic wasting disease (CWD) is a fatal contagious prion disease of cervids that is found in the United States, Canada, South Korea, and most recently in Europe (1,2). The species [...]

Prion diseases are rare fatal neurodegenerative conditions that affect humans and animals. The human diseases include Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia. Most cases of human prion [...]

Prion diseases are infectious neurodegenerative disorders that affect humans and animals and that result from the conversion of normal prion protein (PrPC) into the misfolded prion protein (PrPSc). Chronic wasting disease (CWD) is a prion disorder of increasing prevalence within the United States that affects a large population of wild and captive deer and elk. Determining the risk of transmission of CWD to humans is of utmost importance, considering that people can be infected by animal prions, resulting in new fatal diseases. To study the possibility that human PrPC can be converted into the misfolded form by CWD PrPSc, we performed experiments using the protein misfolding cyclic amplification technique, which mimics in vitro the process of prion replication. Our results show that cervid PrPSc can induce the conversion of human PrPC but only after the CWD prion strain has been stabilized by successive passages in vitro or in vivo. Interestingly, the newly generated human PrPSc exhibits a distinct biochemical pattern that differs from that of any of the currently known forms of human PrPSc. Our results also have profound implications for understanding the mechanisms of the prion species barrier and indicate that the transmission barrier is a dynamic process that depends on the strain and moreover the degree of adaptation of the strain. If our findings are corroborated by infectivity assays, they will imply that CWD prions have the potential to infect humans and that this ability progressively increases with CWD spreading. [ABSTRACT FROM AUTHOR]

Protein misfolding cyclic amplification (PMCA) is a technique that takes advantage of the nucleation-dependent prion replication process to accelerate the conversion of PrP(C) into PrP(Sc) in the test tube. PMCA uses ultrasound waves to fragment the PrP(Sc) polymers, increasing the amount of seeds present in the infected sample without affecting their ability to act as conversion nuclei. Over the past 5 years, PMCA has become an invaluable technique to study diverse aspects of prions. The PMCA technology has been used by several groups to understand the molecular mechanism of prion replication, the cellular factors involved in prion propagation, the intriguing phenomena of prion strains and species barriers, to detect PrP(Sc) in tissues and biological fluids, and to screen for inhibitors against prion replication. In this chapter, we describe a detailed protocol of the PMCA technique, highlighting some of the important technical aspects to obtain a successful and reproducible application of the technology.