An early diagnosis is required for intervention in prion disease cases. To elucidate the specificity of early electroencephalography discharges in cases of sporadic Creutzfeldt-Jakob disease, we analysed epileptiform discharges through electroencephalography. Nine patients with methionine/methionine type 1/classic sporadic Creutzfeldt-Jakob disease and 20 patients with status epilepticus were included. Generalized periodic discharges, lateralized periodic discharges, and central sagittal sporadic epileptiform discharges were evaluated. Central sagittal sporadic epileptiform discharges were defined as nonrhythmic and nonperiodic waveforms showing generalized spike-and-wave complexes and/or sharp waves predominantly in the central sagittal region. In the sporadic Creutzfeldt-Jakob disease group, central sagittal sporadic epileptiform discharges, lateralized periodic discharges, and generalized periodic discharges were observed in five (55.6%), one (11.1%), and eight (88.9%) patients, respectively, with an average duration from onset to the appearance of the discharges of 1.6, 1.0, and 2.44 months, respectively. In the status epilepticus group, these discharges were detected in one (5.0%), six (30.0%), and six (30.0%) patients, respectively. The incorporation of central sagittal sporadic epileptiform discharges and lateralized periodic discharges into the World Health Organization diagnostic criteria, alongside generalized periodic discharges, significantly shortened the average lapse from symptom onset to sporadic Creutzfeldt-Jakob disease diagnosis (2.06 months vs. 2.44 months;  = 0.02). Central sagittal sporadic epileptiform discharges emerge as promising biomarkers for distinguishing sporadic Creutzfeldt-Jakob disease from status epilepticus, and together with lateralized periodic discharges provide an opportunity for early diagnosis of sporadic Creutzfeldt-Jakob disease.

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative disorders that result from abnormally folded prion proteins. These disorders can be sporadic, acquired, or genetic. Acquired TSEs can be found in a number of animal species including sheep (scrapie), cows (bovine spongiform encephalopathy), and cervids (chronic wasting disease). Chronic wasting disease (CWD) is unusual in that it is found in free ranging animals in their natural environment. There has been heretofore no reported cases of CWD being transmitted to humans; however, the possibility of future adaption for human transmission exists. Several novel approaches for the prevention and treatment of prion disease in humans are under development, including knockdown of endogenous prion expression or overexpression of dominant negative prion forms. Here, I propose that CWD, as a naturally occurring prion disease, should be considered an important testing target for such therapies, which can demonstrate efficacy outside of controlled laboratory environments. Further, from the ethical standpoint of reducing animal suffering, decreasing the CWD burden in cervid populations is highly desirable. Finally, lowering CWD incidence can reduce future possibilities of transmission to humans or to other animal species.

The FXR1 protein regulates the stability and translation of a number of RNA molecules and plays an important role in the regulation of cellular processes under normal conditions and stress. In particular, this protein is known to be a negative regulator of the key proinflammatory cytokine TNF alpha. We had previously shown that FXR1 functioned in the amyloid form in neurons of the brain of jawed vertebrates. Under stress conditions, FXR1 is incorporated into stress granules in some cell lines, but such studies have not been conducted for neuronal cells. Here, we showed the ability of the FXR1 protein to form cytoplasmic granules in a neuroblastoma cell line under various types of stress. This protein colocalizes with core proteins of neuronal stress granules upon heat shock and sodium arsenite treatment. We also showed that FXR1 colocalizes with anti-amyloid antibodies OC under both normal and stress conditions. Given that stress granules are dynamic structures, we propose that amyloid FXR1-containing RNP particles interact with other stress granule proteins through weak intermolecular hydrogen bonds. Using a yeast model system, we found that FXR1 colocalizes and physically interacts with stress granule proteins such as TIA-1, FMRP, FXR2, and SFPQ. Overall, our results provide new insights into the role of the RNA-binding protein FXR1 in neuronal stress response. We believe that FXR1 inactivation in neuronal stress granules can contribute to an increase in the level of the proinflammatory cytokine TNF alpha in neurodegenerative diseases.

Chronic wasting disease (CWD) is a contagious prion disorder affecting cervids such as deer, elk, caribou, and moose, causing progressive and severe neurological degeneration followed by eventual death. As CWD prions (PrP) accumulate in the body, they are shed through excreta and secreta, as well as through decomposing carcasses. Prions can persist in the environment for years, posing significant concerns for ongoing transmission to susceptible cervids and pose an unknown risk to sympatric species. We used a validated protocol for real-time quaking-induced conversion (RT-QuIC) prion amplification assay to detect prions in soil collected within and around an illegal white-tailed deer (, WTD) carcass disposal site and associated captive WTD farm in Beltrami County, Minnesota. We detected PrP in 26 of 201 soil samples across 15 locations within the illegal disposal site and one on the farm that housed the cervids. Importantly, a subset of RT-QuIC positive soil samples was collected from soils where carcasses were recovered, providing direct evidence that environmental contamination resulted from this illegal activity. These findings reveal that improper cervid carcass disposal practices may have important implications for ongoing CWD transmission through the environment.

The Prion 2024 annual conference, held in Nanchang, China, from 23 to 27 October, drew nearly 300 leading scientists, clinicians, researchers, and students from 17 countries to examine the latest advancements in prion research and related diseases. This landmark event marked the inaugural international prion conference hosted in a developing nation for the first time and celebrated the 20th anniversary of the NeuroPrion Association, the organizing body of this prestigious annual gathering - '.' The conference spotlighted key themes such as epidemiology, pathogenesis, the connections between ageing and neurodegenerative diseases. It showcased innovative diagnostic and therapeutic strategies for both human and animal prion diseases, as well as related conditions including Alzheimer's and Parkinson's diseases, prion protein-associated cancers, and renal injury. The programme featured 70 invited talks and 21 selected oral presentations, culminating in 7 plenary sessions led by esteemed speakers, including Nobel Laureate Stanley B. Prusiner. This overview summarizes key presentations and highlights significant aspects of the conference, emphasizing the impactful discussions and collaborations that emerged from this historic event.

Chronic wasting disease (CWD) is a highly contagious prion disease occurring in free-ranging and farmed cervids. In the Republic of Korea, cases of CWD continue to be detected almost annually, on both new and occasionally previously infected farms. CWD-infected animals contaminate soil and other environmental components by shedding prions through their excreta. Since shed prions remain infectious for years in the environment, they can act as infectivity reservoirs facilitating horizontal transmission of CWD. To prevent the further spread of CWD and allow farms to resume operations, control measures on infected farms, including topsoil removal and thorough environmental treatment with 2N NaOH, have been implemented in the Republic of Korea. Restocking remediated farms with cervids was permitted after confirming the absence of prion seeding activity in soil samples using protein misfolding cyclic amplification (PMCA). A total of 215 samples from 18 remediated farms were collected and analysed using PMCA, with only 3 samples from 3 farms displaying prion seeding activity. While the disease control measures effectively eliminated prion seeding activity in CWD-affected farms, CWD recurred at two of the 18 remediated farms 4 to 5 years after restocking animals. It remains unclear whether the recurrence of CWD at the two farms was due to residual prions in the environment after the control measures, or the introduction of the infected animals from other farms. This uncertainty is heightened by the annual occurrence of CWD at multiple farms and the absence of a traceability system for farmed cervids.

Chronic wasting disease (CWD) is a fatal, neurodegenerative disease of cervids, and its management heavily relies on diagnostic testing. Test results are commonly used to calculate 'apparent prevalence' (AP) - the percent of animals tested for CWD (CWD tests) with CWD-positive test results (CWD cases) - but this obscures how tests and cases individually contribute to this statistic. This is most relevant when CWD testing is limited because when few animals are tested, detection of even a single infected deer can result in a high AP that poorly reflects reality. We hypothesized that when CWD testing is limited, AP is negatively driven by testing - rather than cases - with more tests corresponding to lower APs. Graphed CWD surveillance data from townships in Illinois and Wisconsin, USA, indicate that CWD AP values ≥50% were only observed when <23 deer were tested. We used Bayesian multilevel zero-inflated Beta regression to model AP as a function of CWD tests, CWD cases and nonlinear transformations of these two terms separately for each state. The best-fit models of both identified a statistically significant negative relationship between AP and testing numbers that was modified by a positive nonlinear test covariate. This means adding tests when testing is low can have a big impact on decreasing the AP, but this relationship weakens as testing increases. We urge treating apparent prevalences ≥50% with caution and emphasize the importance of increasing the test results when initial surveillance has yielded <23 tests.

Bovine Spongiform Encephalopathy (BSE) is a fatal neurodegenerative disease in cattle which can be either classical BSE (C-BSE) or atypical BSE (including H-BSE and L-BSE). Here, we report the results of our analyses of an H-BSE case found in Canada in 2021, indicating restriction of the pathological agent (PrP) mainly to the central nervous system with no or occasional weak involvement of peripheral tissues. Importantly, a non-synonymous mutation at codon 211 of the gene was detected and confirmed to be present as a germline mutation. This is the first case of BSE in Canada with a predisposing E211K mutation.

Gerstmann - Sträussler - Scheinker disease (GSS) is a hereditary prion disease characterized by clinicopathological heterogeneity. In Japan, the most common mutation is P102L, typically associated with prion protein (PrP) plaques, spongiform changes, and synaptic PrP deposits. Two major protease-resistant PrP (PrP) types occur: type-1 PrP (21 kDa) and 8-kDa PrP. The codon 129 polymorphism (methionine or valine) influences disease phenotype, but factors underlying exclusive 8-kDa PrP expression remain unclear. We analysed two sibling P102L GSS cases exclusively exhibiting 8-kDa PrP (Case 1: 129 MM, haplotype: P102L-129 M, treated with pentosan polysulfate; Case 2: 129 MV, haplotype: P102L-129 M, treated with quinacrine hydrochloride and quinine hydrochloride) and four P102L-129 MM GSS cases exhibiting type-1 and 8-kDa PrP (Cases 3-6) to elucidate the clinicopathological effect of 8-kDa PrP and codon 129 polymorphisms. Case 1 predominantly exhibited amyloidogenic PrP plaques; Case 2 exhibited non-amyloidogenic cotton-wool PrP plaques, with minimal synaptic PrP deposits. Despite prolonged survival ( > 20 years), spongiform degeneration and neuronal loss were mild. Cases 3-6 showed numerous amyloidogenic PrP plaques, moderate-to-severe synaptic PrP deposits, and significant tissue damage. Homoeostatic microglial markers were preserved in Cases 1 and 2 but absent in Cases 3-6. Cotton-wool PrP plaques lacked amyloid cores and were associated with 8-kDa PrP and codon 129 V from the normal allele. Tissue damage was mild in P102L GSS cases exhibiting 8-kDa PrP, suggesting lower pathogenicity. Cotton-wool PrP plaque formation likely involves 8-kDa PrP and codon 129 V. Further large-scale studies are warranted to elucidate these mechanisms.

Chronic Wasting Disease (CWD) research has experienced significant growth, spanning diverse disciplines such as genetics, immunology, modelling, and behaviour. To gain a broad understanding of the changes in CWD research focusing cervids, we analysed temporal trends in study location, species, genus investigated, infection types, and population type since the discovery of CWD in 1980s. Our findings indicate that Colorado, USA, published the highest number of articles, followed by Wisconsin, and publication numbers correlated with reported CWD cases in states/provinces. emerged as the most studied genus. Wild populations are studied more commonly than captive populations. Keyword analysis of transmission types shows the discovery of novel transmission modes in the recent past. We also used a novel approach to categorize studies into five themes: field-based, lab-based, math/analytics/modelling-based, management-based, and human dimensions. Overall, most studies captured had a lab-based component. The interdisciplinary or transdisciplinary nature of major disciplines and evolving trends in keywords, particularly the increased reliance on genetics/genomics, accentuate the beginning of using genomics to under and tackle CWD at a fundamental scale. Encapsulated in our analysis, these dynamic changes offer valuable insights for navigating CWD through scientifically informed proactive management decisions in conjunction with existing surveillance efforts not only for the commonly studied species but also for potentially susceptible species.

The prion diseases (PrD) are a group of progressive, fatal, neurodegenerative diseases, for which the Medical Research Council Prion Disease Rating Scale (MRC Scale) can be used to assess patients' functional deterioration. Findings from previous qualitative interviews with caregivers and clinical experts identified potential ambiguities in the scale that could lead to inconsistent scoring within and/or between raters.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are multifunctional proteins with integral roles in RNA metabolism and the regulation of alternative splicing. These proteins typically contain prion-like domains of low complexity (PrLDs or LCDs) that govern their assembly into either functional or pathological amyloid fibrils. To date, over 60 mutations targeting the LCDs of hnRNPs have been identified and associated with a spectrum of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). The cryo-EM structures of pathological and functional fibrils formed by different hnRNPs have been recently elucidated, including those of hnRNPA1, hnRNPA2, hnRNPDL-2, TDP-43, and FUS. In this review, we discuss the structural features of these amyloid assemblies, placing particular emphasis on scrutinizing the impact of prevalent disease-associated mutations mapping within their LCDs. By performing systematic energy calculations, we reveal a prevailing trend of destabilizing effects induced by these mutations in the amyloid structure, challenging the traditionally assumed correlation between pathogenicity and amyloidogenic propensity. Understanding the molecular basis of this discrepancy might provide insights for developing targeted therapeutic strategies to combat hnRNP-associated diseases.

Chronic wasting disease (CWD) is a fatal prion disease of the family that circulates in both wild and captive cervid populations. This disease threatens the health and economic viability of the captive cervid industry, which raises cervids in contained spaces for purposes such as hunting and breeding. Given the high transmissibility and long incubation period of CWD, the introduction and propagation of the infectious prion protein within and between captive cervid farms could be devastating to individual facilities and to the industry as a whole. Despite this risk, there does not yet exist a literature review that summarizes the scientific knowledge, to date, about CWD spread, surveillance, or control measures. Our review, which focused on peer reviewed, primary research conducted in the United States, sought to address this need by searching Google Scholar, Scopus, and Web of Science with a five-term keyword string containing terms related to the (1) location, (2) species affected, (3) disease, (4) captive cervid industry, and (5) topic of focus. Between the three databases, there were 190 articles that were selected for further examination. Those articles were then read to determine if they were about CWD spread, surveillance, and/or control in captive cervid facilities. The 22 articles that met these inclusion criteria were evaluated in detail and discussed, with recommendations for future collaborative work between captive cervid owners, government agencies, and researchers. This work will help to address, inform, and mitigate the rising problem of CWD spread and establishment.

Prion disease is an infectious and fatal neurodegenerative disease. Western blotting (WB)-based identification of proteinase K (PK)-resistant prion protein (PrP) is considered a definitive diagnosis of prion diseases. In this study, we aimed to detect PrP using formalin-fixed paraffin-embedded (FFPE) specimens from cases of sporadic Creutzfeldt-Jakob disease (sCJD), Gerstmann-Sträussler-Scheinker disease (GSS), glycosylphosphatidylinositol-anchorless prion disease (GPIALP), and V180I CJD. FFPE samples were prepared after formic acid treatment to inactivate infectivity. After deparaffinization, PK digestion was performed, and the protein was extracted. In sCJD, a pronounced PrP signal was observed, with antibodies specific for type 1 and type 2 PrP exhibited a strong or weak signals depending on the case. Histological examination of serial sections revealed that the histological changes were compatible with the biochemical characteristics. In GSS and GPIALP, prion protein core-specific antibodies presented as PrP bands at 8-9 kDa and smear bands, respectively. However, an antibody specific for the C-terminus presented as smears in GSS, with no PrP detected in GPIALP. It was difficult to detect PrP in V180I CJD. Collectively, our findings demonstrate the possibility of detecting PrP in FFPE and classifying the prion disease types. This approach facilitates histopathological and biochemical evaluation in the same sample and is safe owing to the inactivation of infectivity. Therefore, it may be valuable for the diagnosis and research of prion diseases.

Infectious prions are resistant to degradation and remain infectious in the environment for several years. Chronic wasting disease (CWD) has been detected in cervids inhabiting North America, the Nordic countries, and South Korea. CWD-prion spread is partially attributed to carcass transport and disposal. We employed a forensic approach to investigate an illegal carcass dump site connected with a CWD-positive herd. We integrated anatomic, genetic, and prion amplification methods to discover CWD-positive remains from six white-tailed deer () and, using microsatellite markers, confirmed a portion originated from the CWD-infected herd. This approach provides a foundation for future studies of carcass prion transmission risk.

The history of human prion diseases began with the original description, by Hans Gerhard Creutzfeldt and by Alfons Maria Jakob, of patients with a severe brain disease that included speech abnormalities, confusion, and myoclonus, in a disease that was then named Creutzfeldt Jakob disease (CJD). Later, in Papua New Guinea, a disease characterized by trembling was identified, and given the name "Kuru". Neuropathological examination of the brains from CJD and Kuru patients, and of brains of sheep with scrapie disease revealed significant similarities and suggested a possible common mode of infection that, at the time, was thought to derive from an unknown virus that caused slow infections. John Stanley Griffith hypothesized that the agent causing these diseases was "probably a protein without nucleic acid" and, in 1982, Stanley Prusiner reported the identification of a proteinaceous infectious particle (coining the term prion) that was resistant to inactivation methods that were at the time standard for nucleic acids, and identified PrP as the major protein component of the infectious agent in scrapie and in Creutzfeldt-Jakob disease, classifying this also as a prion disease. Interestingly, the prion concept had been previously expanded to yeast proteins capable of replicating their conformation, seeding their own aggregation and transmitting phenotypic information. The prion concept has been more recently expanded to refer to misfolded proteins that are capable of converting a normal form of a protein into an abnormal form. The quest to understand and treat prion diseases has united a specific research community around the topic, and regular meetings (Prion Meetings) have taken place over the years to enable discussions, train junior researchers, and inspire research in the field.

Authors are commenting on the evolving geographical incidence trends observed with the genetic form of Creutzfeldt-Jakob disease and discussing the diverse array of factors contributing to the heightened incidence rates observed in specific geographical regions.

Although the development of aggregation assays has noticeably improved the accuracy of the clinical diagnosis of prion diseases, research on biomarkers remains vital. The major challenges to overcome are non-invasive sampling and the exploration of new biomarkers that may predict the onset or reflect disease progression. This will become extremely important in the near future, when new therapeutics are clinically evaluated and eventually become available for treatment. This article aims to provide an overview of the achievements of biomarker research in human prion diseases, addresses unmet needs in the field, and points out future perspectives.

Chronic wasting disease (CWD) is a transmissible and fatal prion disease that affects cervids. While both oral and nasal routes of exposure to prions cause disease, the spatial and temporal details of how prions enter the central nervous system (CNS) are unknown. Carotid bodies (CBs) are structures that are exposed to blood-borne prions and are densely innervated by nerves that are directly connected to brainstem nuclei, known to be early sites of prion neuroinvasion. All CBs examined contained mast cells expressing the prion protein which is consistent with these cells playing a role in neuroinvasion following prionemia.

Rapidly progressive dementias (RPDs) are a type of fatal dementias that cause rapid progression of neuronal dysfunction. This study aimed to assess the prevalence of APOE genotypes (ε2, ε3, ε4) and PRNP mutations (E200K, M129V) in the general population of Pakistan because of their association with RPDs, including Rapidly Progressive Alzheimer's Disease (rpAD) and Creutzfeldt-Jakob Disease (CJD). Blood samples ( = 100) were collected from healthy Pakistani population and the stated mutations were assessed using polymerase chain reaction. In the analysis of the APOE genotype, ε3/ε3 genotype was the most common (95%), followed by ε3/ε4 (5%) and ε2 allele was completely absent. A low frequency of ε4 allele and the absence of a protective ε2 allele is associated with an increased risk of rpAD. In the case of PRNP mutations, the most common genotype was M129-Ε200 (71%) and V129-Ε200 (29%). E200K mutation was completely absent from the given population. It is noteworthy that the MM homozygous genotype was present in 71 samples, VV genotype was present in 29. Homozygosity on codon 129, as observed in most of our samples, has been associated with more efficient production of PrP and disease pathology. This study provides preliminary data indicating that rpAD and CJD pose a significant threat to the Pakistani population.