Variant Creutzfeldt-Jakob Disease Research Articles

A man who changed six spectacles: а case of Heidenhain variant of the Creutzfeldt–Jakob disease

Creutzfeldt–Jakob Disease (CJD) is a rare and rapidly progressive condition. A 54-year-old professor initially presented with insidious, progressive visual symptoms. Imaging suggested post-infectious encephalitis, but symptoms progressed to ataxia, coordination difficulties, and cognitive decline. Repeat MRI revealed findings consistent with CJD, supported by clinical and electrophysiological evidence. Though 14-3-3 protein in CSF was inconclusive, Heidenhain variant CJD was strongly suspected. Isolated visual symptoms progressing rapidly alongside ataxia and dementia prompt suspicion of this variant. Clinical examination, neuroimaging, and EEG play crucial roles in the diagnosis.

A man who changed six spectacles: а case of Heidenhain variant of the Creutzfeldt–Jakob disease

Creutzfeldt–Jakob Disease (CJD) is a rare and rapidly progressive condition. A 54-year-old professor initially presented with insidious, progressive visual symptoms. Imaging suggested post-infectious encephalitis, but symptoms progressed to ataxia, coordination difficulties, and cognitive decline. Repeat MRI revealed findings consistent with CJD, supported by clinical and electrophysiological evidence. Though 14-3-3 protein in CSF was inconclusive, Heidenhain variant CJD was strongly suspected. Isolated visual symptoms progressing rapidly alongside ataxia and dementia prompt suspicion of this variant. Clinical examination, neuroimaging, and EEG play crucial roles in the diagnosis.

Assessing the risk of transfusion-transmitted variant Creutzfeldt-Jakob disease: a European perspective.

Several countries have recently reassessed the international risk of variant Creutzfeldt-Jakob disease (vCJD) transmission through transfusion of blood and blood components (red blood cells, platelets and plasma) and relaxed donor deferrals based on geographic and transfusion exposure in countries formerly considered to be high risk, such as the UK. In this regard, the European Blood Alliance organised a consensus meeting of experts and involved professionals to discuss current knowledge, epidemiological data, prevention and various methods for assessing the risk of transfusion-transmitted vCJD, as well as to develop an appropriate position on possible approaches to address these challenges in Europe. Participants reached a consensus that the current risk of transfusion-transmitted vCJD associated with blood donors who either travelled to or received transfusions in the UK during the vCJD outbreak is minimal. In addressing such risks, it would be pragmatic that assessments and guidelines are developed by European expert bodies, rather than individual assessments by Member States. Regardless of the approach used, European or national, a qualitative risk assessment based on a review and analysis of available data, considering all the uncertainties and experiences of other countries, would provide crucial information to reassess blood donation strategies regarding the transfusion-associated vCJD risk.

Interactions between Cytokines and the Pathogenesis of Prion Diseases: Insights and Implications.

Transmissible Spongiform Encephalopathies (TSEs), including prion diseases such as Bovine Spongiform Encephalopathy (Mad Cow Disease) and variant Creutzfeldt-Jakob Disease, pose unique challenges to the scientific and medical communities due to their infectious nature, neurodegenerative effects, and the absence of a cure. Central to the progression of TSEs is the conversion of the normal cellular prion protein (PrPC) into its infectious scrapie form (PrPSc), leading to neurodegeneration through a complex interplay involving the immune system. This review elucidates the current understanding of the immune response in prion diseases, emphasizing the dual role of the immune system in both propagating and mitigating the disease through mechanisms such as glial activation, cytokine release, and blood-brain barrier dynamics. We highlight the differential cytokine profiles associated with various prion strains and stages of disease, pointing towards the potential for cytokines as biomarkers and therapeutic targets. Immunomodulatory strategies are discussed as promising avenues for mitigating neuroinflammation and delaying disease progression. This comprehensive examination of the immune response in TSEs not only advances our understanding of these enigmatic diseases but also sheds light on broader neuroinflammatory processes, offering hope for future therapeutic interventions.

Absence of evidence of transfusion transmission risk of Creutzfeldt-Jakob disease in the United States: Results froma 28-year lookback study.

For many years, there has been concern about the risk of transmission of classic forms of Creutzfeldt-Jakob disease (CJD) by blood transfusion, particularly after the recognition of such transmission of variant CJD (vCJD). We report on a 28-year lookback study of recipients of blood from donors who subsequently developed CJD. Patients with diagnosed CJD and a history of blood donation were identified. Blood centers were asked to provide information about the distribution of the donations and consignees were requested to provide information about the recipients of the donations. Vital status of each available recipient was determined and, if deceased, the reported cause(s) of death were obtained primarily from the National Death Index. All recipients included in the study database contributed person-time up to the last recorded review of vital status. There were 84 eligible donors who gave 3284 transfusable components, and it was possible to evaluate 1245 recipients, totaling 6495 person-years of observation. The mean observation period per recipient was 5.5 years with a maximum of 51 years. No case of CJD or prion disease was reported among the recipient population. The study suggests that CJD may not be transfusion-transmissible, a position in agreement with similar findings from two similar European reports amounting to an overall observation period of 15,500 person-years. These studies have supported the conclusion that the risk, if any, of transmission of CJD by blood products is extremely small and remains theoretical.

Clinical characteristics and diagnostics of human spongiform encephalopathies: an update

Human spongiform encephalopathies are rare transmissible neurodegenerative diseases of the brain and the nervous system that are caused by misfolding of the physiological prion protein into apathological form and its deposition in the central nervous system (CNS). Prion diseases include Creutzfeldt-Jakob disease (CJD, sporadic or familial), Gerstmann-Straussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI). Prion diseases can be differentiated into three etiological categories: spontaneous (sporadic CJD), inherited (familial CJD, FFI, and GSS) and acquired (variant CJD and iatrogenic CJD). Most cases occur sporadically. Prion diseases can lead to avariety of neurological symptoms and always have an inevitably fatal course. Cerebrospinal fluid analysis and magnetic resonance imaging (MRI) play acrucial role in the diagnostics of prion diseases and may facilitate an early and reliable clinical diagnosis. Acausal treatment or specific therapeutic agents are not yet available. In general, apalliative therapeutic concept is indicated.

Has the frequency of ABO RhD blood groups in Australian blood donors changed as a result of the removal of the variant Creutzfeldt-Jakob disease-based deferral?

Until 25 July 2022, Australians who had spent more than 6 months in the United Kingdom or territories between 1980 and 1996 were deferred from blood donation due to the risk of variant Creutzfeldt-Jakob disease. Removal of this geography-based donor deferral on RhD-negative blood availability has not been reported. All donors who donated at least once from 25 July 2022 to 25 July 2023 were included. UK donor status, first-time donor and ABO RhD data were extracted from the National Blood Management System. Data from 566,447 blood donors with a valid ABO RhD result were analysed. Of these, 34,560 were new or returning lapsed donors following removal of the UK donor deferral. The median age [range] in years for all donors was 43 [75] with UK donors being older 53 [70]. There was a higher prevalence of RhD-negative status in UK donors (20.2%) compared with first-time blood donors (15.7%). UK donors were generally older, female and more likely to be RhD-negative. Although UK donors provided a boost to RhD-negative blood collections, the overall prevalence of ABO RhD blood groups in the total Australian blood donor panel remained similar to previous estimates.

Prospective 25-year surveillance of prion diseases in France, 1992 to 2016: a slow waning of epidemics and an increase in observed sporadic forms.

BackgroundPrion diseases are rare, fatal disorders that have repeatedly raised public health concerns since the early 1990s. An active prion disease surveillance network providing national level data was implemented in France in 1992.AimWe aimed to describe the epidemiology of sporadic, genetic and infectious forms of prion diseases in France since surveillance implementation.MethodsWe included all suspected cases notified from January 1992 to December 2016, and cases who died during the period with a definite or probable prion disease diagnosis according to EuroCJD criteria. Demographic, clinical, genetic, neuropathological and biochemical data were collected.ResultsIn total, 25,676 suspected cases were notified and 2,907 were diagnosed as prion diseases, including 2,510 (86%) with sporadic Creutzfeldt-Jakob disease (sCJD), 240 (8%) genetic and 157 (6%) with infectious prion disease. Suspected cases and sCJD cases increased over time. Younger sCJD patients (≤ 50 years) showed phenotypes related to a distinct molecular subtype distribution vs those above 50 years. Compared to other European countries, France has had a higher number of cases with iatrogenic CJD after growth hormone treatment and variant CJD (vCJD) linked to bovine spongiform encephalopathy (second after the United Kingdom), but numbers slowly decreased over time.ConclusionWe observed a decrease of CJD infectious forms, demonstrating the effectiveness of measures to limit human exposure to exogenous prions. However, active surveillance is needed regarding uncertainties about future occurrences of vCJD, possible zoonotic potential of chronic wasting diseases in cervids and increasing trends of sCJD observed in France and other countries.

Monitoring the Sign & Symptoms of Variant Creutzfeldt-Jakob Disease Among Patients with Multiple Myeloma Treated with Ixazomib Capsules in China: A Real-World Pharmacovigilance Survey

Introduction: Variant Creutzfeldt-Jakob disease (vCJD) is a fatal and transmittable neurodegenerative disorder in humans, associated with ingestion of products from Bovine spongiform encephalopathy (BSE) affected cattle. 1 Since April 2018, Ixazomib is approved by National Medical Products Administration (NMPA) for the treatment of multiple myeloma (MM), in China. Before March 2019, the gelatin used for encapsulating ixazomibcapsules was sourced from countries with BSE outbreaks, although all the sources were fully complaint with regulations MM patients were still at risk for BSE, particularly vCJD. Definitive diagnosis of vCJD requires brain biopsy, which is a complex procedure with many complications. World Health Organization (WHO) has indicated a combination of signs and symptoms to assist in defining possible, probable, and definite vCJD cases. 2,3 Here we present phase-2 results from a retrospective analysis, conducted to describe physician-observed signs and symptoms, which may be related to vCJD in MM patients, treated with ixazomibbefore December 2019 in China. Methods: This multi-centre, cross-sectional, web-based survey was conducted in China. Licensed physicians who have prescribed ixazomibcapsules for MM patients before December 2019 and participated in the Phase 1 survey, titled attending or above, specialized in haematology or other related departments and practised in outpatient clinics once a week in the past six months were included. The primary objective was to describe physicians' observed signs and symptoms and the secondary objective was to describe physicians' concerns and awareness of signs and symptoms, which may be related to vCJD in MM patients treated with ixazomib. Eligible physicians completed an online questionnaire with closed-ended multiple-choice questions related to patients' clinical characteristics, responder characteristics, awareness on vCJD-related signs and symptoms, concern on vCJD risk, willingness to prescribe ixazomib in future. Physicians' concern about MM patients who have consumed contaminated ixazomibto get vCJD was measured on a 10-point scale, in which 0 stands for no concern while 10 stands for extremely concerned. Statistical analysis was performed using R, version 3.2 Results: A total of 311 valid questionnaires were received from 318 physicians. The baseline characteristics of respondents are depicted in Table 1. The mean (standard deviation) time of awareness on potential contamination was 19.1 (4.69) months. The average degree of concern decreased from 4.6 in phase 1 to 4.2 in phase 2, as measured on a 10-point scale and willingness to prescribe ixazomibhad increased from 70.1% to 87.8% , after knowing NINLARO ® capsule was sourced (produced before December 2019) from regions with BSE outbreak. A total of 288 respondents reported 1,485 deceased MM patients, who also received ixazomib before 2020. During phase 1, 7 respondents reported 17 patients, who were presented with at least 4 out of 5 prespecified symptoms for potential vCJD. Of which, 2 respondents reported that presented symptoms of 2 patients were caused by vCJD. However, in phase 2, all the 7 respondents have changed their opinion and reported no patient with at least 4 out of 5 prespecified symptoms for potential vCJD, this indicates the possibility of respondents developing better understanding of cVJD after phase 1. Further during phase 2, one respondent reported 2 new living patients presented with at least four of five pre-specified symptoms for potential vCJD and/or ixazomib. On further investigation, the respondent reported the symptoms were not related to vCJD and no tests were performed further to confirm a vCJD diagnosis, possibility of occurrence of these symptoms after phase 1 cannot be ruled out. Additionally, another respondent reported death of a patient that died due to severe diarrhea before reaching hospital. As per respondent, the death may be associated with NINLARO ® and not related to vCJD as the patient was prescribed with ixazomib before December 2019. Conclusion: This study indicates that the risk of vCJD was no longer a concerning factor for physicians and would no longer influence their willingness to prescribe ixazomib.

Development of a sensitive real-time quaking-induced conversion (RT-QuIC) assay for application in prion-infected blood.

Efforts to prevent human-to-human transmission of variant Creutzfeldt-Jakob disease (vCJD) by contaminated blood would be aided by the development of a sensitive diagnostic test that could be routinely used to screen blood donations. As blood samples from vCJD patients are extremely rare, here we describe the optimisation of real-time quaking-induced conversion (RT-QuIC) for detection of PrPSc (misfolded prion protein, a marker of prion infection) in blood samples from an established large animal model of vCJD, sheep experimentally infected with bovine spongiform encephalopathy (BSE). Comparative endpoint titration experiments with RT-QuIC, miniaturized bead protein misfolding cyclic amplification (mb-PMCA) and intracerebral inoculation of a transgenic mouse line expressing sheep PrP (tgOvARQ), demonstrated highly sensitive detection of PrPSc by RT-QuIC in a reference sheep brain homogenate. Upon addition of a capture step with iron oxide beads, the RT-QuIC assay was able to detect PrPSc in whole blood samples from BSE-infected sheep up to two years before disease onset. Both RT-QuIC and mb-PMCA also demonstrated sensitive detection of PrPSc in a reference vCJD-infected human brain homogenate, suggesting that either assay may be suitable for application to human blood samples. Our results support the further development and evaluation of RT-QuIC as a diagnostic or screening test for vCJD.

Diagnostic accuracy of diffusion-weighted imaging in variant Creutzfeldt–Jakob disease

PurposeThis study sought to investigate the diagnostic sensitivity of diffusion-weighted imaging (DWI) in variant Creutzfeldt-Jakob disease (vCJD), a prion disease with significant public health implications on account of its transmissibility. The importance of this research stemmed from the first neuropathologically confirmed vCJD case in a PRNP heterozygous individual in 2016, which displayed DWI features typical of sporadic CJD (sCJD). The case was classified as ‘probable’ sCJD in life, predominantly based on these imaging findings. While DWI has proven valuable in diagnosing sCJD, its utility in vCJD diagnosis remains unclear.MethodsDWI and Fluid-attenuated inversion recovery (FLAIR) images from probable and definite vCJD cases referred to the National CJD Research and Surveillance Unit (NCJDRSU) were independently analysed by an expert neuroradiologist. Scans were reviewed within a mixed cohort of CJD cases including definite sCJD and non-CJD controls.ResultsFLAIR sequences demonstrated greater sensitivity in identifying the pulvinar sign in vCJD compared to DWI (73% vs 41%, p-value <0.001). Basal ganglia hyperintensities were more prevalent in DWI (84%) than FLAIR (64%), and cortical hyperintensities were exclusive to DWI (24%). The pulvinar sign showed a specificity of 98% for vCJD and was rare in sCJD.ConclusionDWI showed reduced sensitivity compared to FLAIR imaging in detecting the pulvinar sign in vCJD. Conversely, DWI can more distinctively identify basal ganglia and cortical hyperintensities, thus leading to imaging patterns more characteristic of sCJD. Therefore, DWI should be cautiously interpreted in vCJD diagnosis, with axial FLAIR potentially providing a more precise evaluation of the pulvinar sign.

Enhanced Creutzfeldt-Jakob disease surveillance in the older population: Assessment of a protocol for screening brain tissue donations for prion disease.

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.

Low risk of variant Creutzfeldt-Jakob disease transmission from blood transfusions in Aotearoa New Zealand suggests donor exclusion policies can be relaxed.

Aotearoa New Zealand currently excludes potential blood donors who lived in the United Kingdom (UK) for 6 months or more between 1980 and 1996. This action is due to the potential for variant Creutzfeldt-Jakob disease (vCJD) following blood transfusions from preclinical vCJD cases, who themselves mostly developed disease from the consumption of cattle with bovine spongiform encephalopathy (BSE) during this period, or from those incubating the misfolded prion proteins that cause disease. This donor exclusion policy led to 10% of New Zealand's active blood donors in 2000 being excluded, and it remains today despite periodic shortages of some blood products. Globally there have been 232 vCJD cases recorded-178 in the UK-with no new cases since 2019 and the peak numbers 23 years ago in 2000. Only three confirmed cases have been linked to blood transfusion. Here, we aimed to estimate the annual risk of vCJD from blood transfusion in New Zealand after restriction removal. We used UK case numbers, population estimates, and donor and recipient transfusion numbers to calculate the risk to the New Zealand public. We calculated the risk, based on approximately 131,000 transfusions a year and accounting for multiple transfusions, might lead to 0.005 cases annually, or approximately one in one billion nationally, and comparable to recent one in 1.45 billion estimates for Australia. Our analyses suggests that relaxing current blood donation restrictions, like Ireland and Australia's recent policy changes, would lead to an extremely low risk of vCJD transfusion-transmission in New Zealand. This policy change would help increase the supply of blood products for multiple medical needs.

Removal of UK-donor deferral for variant Creutzfeldt-Jakob disease: A large donation gain in Australia.

Until 25 July 2022, people who spent more than 6 months in the United Kingdom during the variant Creutzfeldt-Jakob disease (vCJD) risk period 1980-1996 (UK donors) were deferred from blood donation in Australia. Regulatory approval to remove the deferral was underpinned by published mathematical modelling predicting negligible vCJD transmission risk increase with a gain of 58,000 donations. The donor questionnaire retained the UK deferral screening question until a version update effective 12 February 2023, which enabled identification of the newly eligible cohort of UK donors. Their donations were tracked for a 6-month period (25 July 2022-24 January 2023) and compared with baseline Lifeblood donation metrics and predicted gains. A total of 38,462 UK donors attended to donate 78,762 times in the 6 months. Of these, 32,358 donors (females = 19,456, males = 12,902) successfully donated 67,914 times representing 8.4% of total collections. Cessation of the UK deferral resulted in donation gains exceeding modelled predictions because of a higher than predicted number of donors who donated at a higher rate. Had these newly eligible donors not donated, overall donation numbers would have been 88% of target rather than the 96% achieved.

Risk of variant Creutzfeldt-Jakob disease in a simulated cohort of Canadian blood donors.

No transfusion-associated cases of variant Creutzfeldt-Jakob disease (vCJD) have occurred in more than 20 years. Yet, many countries have maintained blood donor deferral criteria for vCJD. We developed a risk simulation model to reassess the need for vCJD-related deferral criteria in Canada. The model provides results separately for Héma-Québec (HQ) and Canadian Blood Services (CBS). The model used a Monte Carlo simulation approach to estimate the risk of having a vCJD-contaminated blood donation ('risk of vCJD') in a simulated cohort of 10 million donors followed for up to 85 years. The model assumed current deferral criteria for vCJD were lifted, which would allow new 'at-risk' donors to give blood. The model accounted for disease prevalence, donors' travel/immigration history, PRNP genotype at codon 129, demographics and the type of labile blood product. In the base case, the risk of vCJD was estimated at zero at both blood services. In the most pessimistic scenario, the risk of vCJD was 6.4 × 10-9 (i.e., 1 in 157 million donations) at HQ, or ≤1 in 77 million based on the upper bound of the 95% confidence interval (CI). At CBS, this risk was 4.8 × 10-8 (i.e., 1 in 21 million donations), or ≤1 in 16 million based on the upper bound of the 95% CI. vCJD poses minimal risks to the Canadian blood supply. Current vCJD deferral criteria may, therefore, be lifted with virtually no impact on safety, while significantly expanding the donor base.

Conservation of vCJD Strain Properties After Extraction and In Vitro Propagation of PrPSc from Archived Formalin-Fixed Brain and Appendix Tissues Using Highly Sensitive Protein Misfolding Cyclic Amplification.

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.

Kinetics of Abnormal Prion Protein in Blood of Transgenic Mice Experimentally Infected by Multiple Routes with the Agent of Variant Creutzfeldt-Jakob Disease.

Transmissible spongiform encephalopathies (TSEs) or prion diseases are characterized by the accumulation in affected tissues of the abnormal prion protein PrPTSE. We previously demonstrated PrPTSE in the blood of macaques experimentally infected with variant Creutzfeldt-Jakob disease (vCJD), a human TSE, months to years prior to clinical onset. That work supported the prospect of using PrPTSE as a blood biomarker to detect vCJD and possibly other human TSEs before the onset of overt illness. However, our results also raised questions about the origin of PrPTSE detected in blood early after inoculation and the effects of dose and route on the timing of the appearance of PrPTSE. To investigate these questions, we inoculated vCJD-susceptible transgenic mice and non-infectable prion protein-knockout mice under inoculation conditions resembling those used in macaques, with additional controls. We assayed PrPTSE in mouse blood using the protein misfolding cyclic amplification (PMCA) method. PrPTSE from the inoculum cleared from the blood of all mice before 2 months post-inoculation (mpi). Mouse PrPTSE generated de novo appeared in blood after 2 mpi. These results were consistent regardless of dose or inoculation route. We also demonstrated that a commercial ELISA-like PrPTSE test detected and quantified PMCA products and provided a useful alternative to Western blots.

Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2022.

Nationwide surveillance of Creutzfeldt-Jakob disease (CJD) and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in a heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2022. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2022, a total of 599 domestic CSF specimens were referred for diagnostic testing and 79 persons with suspected human prion disease were formally added to the national register. As of 31 December 2022, just under half of the 79 suspect case notifications (36/79) remain classified as 'incomplete'; 15 cases were classified as 'definite' and 23 as 'probable' prion disease; five cases were excluded through neuropathological examination. For 2022, fifty-five percent of all suspected human-prion-disease-related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. The SARS-CoV-2 pandemic did not affect prion disease surveillance outcomes in Australia during 2022.

Unexpected decrease of full-length prion protein in macaques inoculated with prion-contaminated blood products.

The presence of prion infectivity in the blood of patients affected by variant Creutzfeldt-Jakob disease (v-CJD), the human prion disease linked to the bovine spongiform encephalopathy (BSE), poses the risk of inter-human transmission of this fatal prion disease through transfusion. In the frame of various experiments, we have previously described that several cynomolgus macaques experimentally exposed to prion-contaminated blood products developed c-BSE/v-CJD, but the vast majority of them developed an unexpected, fatal disease phenotype focused on spinal cord involvement, which does not fulfill the classical diagnostic criteria of v-CJD. Here, we show that extensive analyses with current conventional techniques failed to detect any accumulation of abnormal prion protein (PrPv-CJD) in the CNS of these myelopathic animals, i.e., the biomarker considered responsible for neuronal death and subsequent clinical signs in prion diseases. Conversely, in the spinal cord of these myelopathic primates, we observed an alteration of their physiological cellular PrP pattern: PrP was not detectable under its full-length classical expression but mainly under its physiological terminal-truncated C1 fragment. This observed disappearance of the N-terminal fragment of cellular PrP at the level of the lesions may provide the first experimental evidence of a link between loss of function of the cellular prion protein and disease onset. This original prion-induced myelopathic syndrome suggests an unexpected wide extension in the field of prion diseases that is so far limited to pathologies associated with abnormal changes of the cellular PrP to highly structured conformations.

When vision loss is beyond cataract: a case of fatal neurodegenerative disease (P1-9.010)

<h3>Objective:</h3> NA <h3>Background:</h3> Creutzfeldt Jakob disease (CJD) is a rare and fatal neurodegenerative disorder of unclear etiology. Presentation include myoclonic jerks, visual disturbances, pyramidal/extrapyramidal signs and rapidly progressive cognitive decline. Visual symptoms are a common manifestation of CJD. Here we present a case of progressive vision loss initially attributed to cataract with eventual diagnosis of CJD. <h3>Design/Methods:</h3> Patient is a 75-year-old woman with history of osteoporosis, dyslipidemia, and arthritis presented to the emergency (ED) with bilateral vision loss and cognitive decline. Symptoms started 8 weeks prior presentation with progressive vision loss and difficulty recognizing color and shapes. She also had intermittent horizontal diplopia. Patient was initially evaluated by an ophthalmologist where vision loss was attributed to cataract and underwent bilateral cataract extraction with no improvement in vision. Vision loss worsened and she became unable to recognize familiar faces or identify objects, and had recurrent falls. She suffered visual hallucination, progressive abnormal body posturing, memory loss, dysphagia and severe dysarthria. On her exam she was noted to be mute, unable to follow commands, and had stimulus induced myoclonic jerks of limbs. CXR, urine analysis, urine and blood cultures, and urine drug screen were all unrevealing. Serum and CSF paraneoplastic panel were negative. EEG showed absence of the posterior dominant rhythm. Brain MRI demonstrated cortical ribbon sign and hyperintensities of basal ganglia (image 1). CSF Rt-Quic was indeterminate. Given the history, exam and MRI findings, she was diagnosed with Heidenhain variant of CJD and passed away shortly after transfer to inpatient hospice. <h3>Results:</h3> NA <h3>Conclusions:</h3> CJD can present with isolated visual symptoms that precede cognitive decline by weeks. Detailed history and careful exam are essential for early diagnosis as this will allow patients and their families to prepare for the expected disease course, consider goals of care, and possibly have palliative care if desired. <b>Disclosure:</b> Dr. Abusamra has nothing to disclose. Dr. Ali has nothing to disclose. Dr. Sudhakar has nothing to disclose.