Tuesday, April 15, 2025

Cases of Creutzfeldt-Jakob disease in young individuals: open questions regarding aetiology

Cases of Creutzfeldt-Jakob disease in young individuals: open questions regarding aetiology

***> Recently, two young individuals, aged 15 and 21, were diagnosed with sporadic Creutzfeldt-Jakob disease (sCJD) in Canada and the United States, respectively (D'Arcy et al., 2019; Ahn et al., 2024).

OPINION article

Front. Cell. Neurosci., 13 April 2025

Sec. Cellular Neuropathology


Cases of Creutzfeldt-Jakob disease in young individuals: open questions regarding aetiology

Ilia V. Baskakov, .jpegIlia V. Baskakov1,2*

1Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD, United States 2Department of Neurobiology, University of Maryland School of Medicine, Baltimore, MD, United States

Recently, two young individuals, aged 15 and 21, were diagnosed with sporadic Creutzfeldt-Jakob disease (sCJD) in Canada and the United States, respectively (D'Arcy et al., 2019; Ahn et al., 2024). Considering that the mean age of onset for sCJD is 67 years, these early onset cases are exceedingly rare. Both patients were methionine/valine heterozygous at codon 129 of the prion protein gene (PRNP) and were classified as the MV1 subtype of sCJD. Both individuals exhibited an atypical clinical presentation and unusual profile of PrPSc, notably lacking the diglycosylated glycoform. Following clinical onset, disease progression was remarkably slow in both cases, with disease durations of 119 and 39 months in the 15- and 21-year-old individuals, respectively.

Although sCJD in adolescents is very rare, such cases are not unprecedented. Two adolescent cases, in which patients succumbed to the disease at ages 16 and 20, were previously reported in the United Kingdom (Murray et al., 2008). In one of these cases, the diagnosis of sCJD was confirmed based on neuropathological findings, PrPScsubtype analysis, and transmission in mice. Additionally, a 19-year-old patient was identified in Germany among a cohort of 52 sCJD patients aged 50 or younger at symptom onset during 1993–2003 (Boesenberg et al., 2005). The clinical manifestations in younger sCJD patients differ from those in older individuals in terms of clinical signs, disease duration, and neuropathological lesion profiles (Pocchiari et al., 2004; Boesenberg et al., 2005), with a younger age at onset correlating with prolonged survival (Pocchiari et al., 2004). In a cohort of 2,304 sCJD cases identified in Western Europe between 1993 and 2000, two cases with onset between 11 and 20 years exhibited disease durations of 54 and 58 months, respectively (Pocchiari et al., 2004). Valine homozygosity at codon 129 was more frequent in the “young” cohort (patients younger than 50 at symptom onset) compared to the “old” cohort (patients older than 50; Boesenberg et al., 2005). The ratio of type 1 to type 2 PrPSc subtypes, determined based on glycoform ratios and the electrophoretic mobility of proteinase K-resistant core, did not differ between the two groups (Boesenberg et al., 2005).

In the case of the 21-year-old patient identified in the United States (Ahn et al., 2024), the absence of the diglycosylated isoform and the higher molecular weight of the mono- and unglycosylated isoforms, relative to those typically observed in type 1 or type 2 PrPSc subtypes, raise questions about whether the disease phenotype aligns with any known sCJD subtype. The possibility of CJD transmission was ruled out, as the patient had never undergone any medical procedures associated with a risk of prion transmission nor traveled to countries affected by bovine spongiform encephalopathy (BSE; Ahn et al., 2024). Nevertheless, although such an early age of onset is rare for sCJD, it is characteristic of variant CJD (vCJD), which has a median onset age of 28 years.

Unlike sCJD, vCJD is acquired through the consumption of beef or beef products contaminated with BSE, also known as mad cow disease—a fatal prion disorder in cattle (Prusiner, 1997). While prion diseases primarily affect the brain, the lymphoreticular system playing a crucial role in transmission of BSE to humans (Hilton et al., 2004b; Aguzzi et al., 2013). Shortly after exposure, lymphotropic prion strains, including BSE, colonize secondary lymphoid organs (SLOs), where they exploit follicular dendritic cells to replicate and accumulate before spreading to the central nervous system (CNS; Hilton et al., 1998; Brown et al., 1999; McCulloch et al., 2011; Mabbott, 2012; Aguzzi et al., 2013). Similar to BSE, chronic wasting disease (CWD), a prion disease affecting cervids, also exhibits strong lymphotropism (Sigurdson et al., 1999).

CWD, which affects deer, elk, and moose, has been rapidly expanding across Canada and the U.S. As of early 2025, CWD has been detected in 36 U.S. states (USGS, 2025). The disease is highly contagious and primarily transmitted horizontally among cervids. CWD prions are shed in bodily fluids such as urine, saliva, and feces, contributing to persistent environmental contamination, particularly in soil (Tamgüney et al., 2009; Bartelt-Hunt and Bartz, 2013; Henderson et al., 2015, 2017; Davenport et al., 2018; Denkers et al., 2020; Tennant et al., 2020; Hwang et al., 2021; Denkers et al., 2024; Kuznetsova et al., 2024). Prions can be taken up by plants from contaminated soil and accumulate at levels sufficient for transmission to animals (Pritzkow et al., 2015; Carlson et al., 2023). Additionally, ticks have been shown to carry lethal doses of CWD infectivity (Inzalaco et al., 2023). While a substantial portion of the U.S. and Canadian populations is exposed to CWD through environmental contamination, the risk of transmission to humans is considered very low due to a significant species barrier.

The species barrier of CWD transmission to humans has been extensively studied using mouse models expressing human prion protein (PrPC; Kong et al., 2005; Sandberg et al., 2010; Wilson et al., 2012; Race et al., 2019; Hannaoui et al., 2022; Race et al., 2022; Wadsworth et al., 2022). In nearly all studies, humanized mice inoculated with CWD prions showed no clinical or subclinical disease and no detectable prion infectivity, with one notable exception (Hannaoui et al., 2022). In that study, infected humanized mice exhibited atypical clinical signs, prion seeding activity, and transmissible prion infectivity (Hannaoui et al., 2022).

In all previous studies assessing this risk, the intracranial (ic) route was used to administer CWD prions to humanized mice (Kong et al., 2005; Sandberg et al., 2010; Wilson et al., 2012; Race et al., 2019; Hannaoui et al., 2022; Race et al., 2022; Wadsworth et al., 2022). Ic inoculation is the most effective method for transmitting prions both within and across species (Race et al., 2009). However, successful cross-species transmission of lymphotropic prion strains appears to depend on SLOs for adaptation to a new host. Among the aforementioned studies, only one examined PrPSc accumulation in the spleen following CWD transmission to humanized mice (Wilson et al., 2012). When prions, such as BSE and CWD, cross species barriers, SLOs consistently exhibit greater permissiveness to prion replication than the brain (Béringue et al., 2012). Moreover, even after ic inoculation, lymphoreticular tissues exhibit a higher capacity than the brain to sustain and replicate lymphotropic prion strains, particularly at low-dose exposure (Halliez et al., 2014). This may be attributed to differences in glycosylation and sialylation between prions residing in the lymphoreticular system and those in the brain (Srivastava et al., 2015; Wagner et al., 2022). In spleens and lymph nodes, prions exhibit increased sialylation, potentially enhancing their resistance to clearance by innate immune system (Srivastava et al., 2015, 2017). Consequently, SLOs may provide a more favorable environment than the brain for prion adaptation to a new species. Furthermore, prion isolates, including CWD, have been shown to produce divergent disease phenotypes when introduced via ic versus peripheral routes, suggesting that brain and lymphoreticular tissues preferentially support different variants of PrPSc present in natural prion isolates (Béringue et al., 2012; DeFranco et al., 2024). Whether peripheral exposure facilitates more efficient cross-species adaptation of CWD prions remains unclear. Nonetheless, assessing PrPSc accumulation in SLOs following ic inoculation of humanized mice could provide a more sensitive approach for evaluating the potential risk of CWD transmission across species.

Additionally, with one exception (Wilson et al., 2012), all previous studies assessing the zoonotic potential of CWD have employed humanized mice homozygous for either 129MM or 129VV PrP (Kong et al., 2005; Sandberg et al., 2010; Race et al., 2019; Hannaoui et al., 2022; Race et al., 2022; Wadsworth et al., 2022). In the study that employed heterozygous 129MV humanized mice, the risk of transmission was assessed using only one CWD isolate (Wilson et al., 2012). In 129MV hosts, PrPSc structures must accommodate both 129M and 129V PrP molecules, likely resulting in an alternating incorporation of these isoforms. The presence of both 129M and 129V PrPC substrates is expected to boost the conformational diversity of PrPSc variants. Whether the structure of 129MV PrPSc is more compatible with CWD strains than that of 129MM or 129VV PrPSc, and whether the 129MV genotype is more susceptible to CWD prions, remains to be investigated.

With the continuous geographical expansion of CWD into highly populated areas and its increasing prevalence, human exposure—including that of children—to high doses of CWD prions via the environment may become unavoidable. The decomposition of carcasses from free-ranging deer infected with CWD could create environmental hotspots containing high concentrations of prions, posing long-term risks to ecosystems.

The uptake of prions by plants raises the possibility of contamination in the food chain, including dairy products. Evidence from prion research suggests that prions can be present in the mammary glands and milk of sheep incubating scrapie, the prion disease of sheep (Ligios et al., 2005; Lacroux et al., 2008; Maddison et al., 2009). If CWD prions can be adsorbed by the digestive system of cattle without causing clinical disease, they may still be excreted into milk, thereby introducing an unrecognized route of human exposure. The potential for milk contamination in dairy cattle that are not infected but are persistently exposed to CWD prions in contaminated environments warrants investigation.

A number of species, including goats, sheep, swine, rodents, mink, ferrets, raccoons, and possibly wild pigs and cattle are susceptible to CWD (Hamir et al., 2005, 2006; Raymond Gregory et al., 2007; Sigurdson et al., 2008; Heisey et al., 2010; Greenlee et al., 2012; Kurt and Sigurdson, 2016; Moore et al., 2017, 2019, 2022; Soto et al., 2025). Prions are subject to evolution and adaptation (Li et al., 2010; Baskakov, 2014). Upon transmission to new hosts, prion replication in a novel molecular environment enhances the conformational diversity of PrPSc variants, accelerating evolution and generating new strains with altered transmission characteristics (Gonzalez-Montalban et al., 2013; Makarava and Baskakov, 2013; Katorcha et al., 2018). As such, interspecies passage of CWD through different hosts may serve as a breeding ground for novel prion strains to emerge.

To date, more than 10 distinct CWD strains have been identified in deer, elk, moose, and reindeer (Otero et al., 2023; Sun et al., 2023). Assessing the transmissibility of diverse CWD strains is crucial for evaluating the potential risk of transmission to humans. Due to prion protein gene polymorphisms, cross-species transmission of CWD strains among different cervid species can alter strain properties, potentially leading to the emergence of novel variants with modified transmission characteristics (Bian et al., 2019, 2021; Otero et al., 2023). Such adaptations could expand the range of hosts susceptible to CWD.

Given the scale of potential CWD exposure, rare instances of transmission to humans might be expected beyond those directly linked to hunting. Since the clinical presentation of CWD in humans has not been defined, it is challenging to determine whether individuals diagnosed with sporadic sCJD at young ages, such as 15 and 21 years old, may have been infected with CWD. Autopsy of SLOs, including the spleen, lymph nodes, and tonsils, could help differentiate between sporadic and acquired forms of CJD. In sCJD patients, prions are detected in SLOs at a low prevalence (Glatzel et al., 2003), whereas in vCJD cases, linked to consumption of BSE-contaminated products, prions have been found in lymphoreticular tissues at a 100% rate (Hill et al., 1999; Ironside et al., 2002). Similarly, if CWD were transmissible to humans, it is expected that prions would accumulate in SLOs. Therefore, histopathological examination and biochemical analysis of PrPSc in SLOs should be conducted for all young individuals succumbed to CJD, as well as older individuals presenting with atypical clinical or neuropathological features. Additionally, transmission studies in animal models could provide further insights into distinguishing between sCJD and zoonotic forms of CJD.

Lymphotropic prion strains, such as BSE, acquired through cross-species transmission, can persist stably and silently in SLOs for extended periods without neuroinvasion (Peden et al., 2010; Bishop et al., 2013). In fact, SLOs serve as silent reservoirs of prion infection, where prions may remain undetected while posing a potential risk of transmission (Hilton et al., 2004a; Peden et al., 2004; Wroe et al., 2006; Peden et al., 2010; Bishop et al., 2013; Gill et al., 2013). Screening human lymphoreticular tissues in regions with a long history of CWD could provide valuable insights into whether CWD prions are silently harbored within the human population.

In conclusion, the expanding scale of human exposure to the growing CWD epidemic necessitates urgent discussions on safeguarding public health. The implementation of lymphoid tissue autopsies could aid in differentiating between sCJD from CJD acquired via transmission. Furthermore, improved risk assessment for CWD transmission to humans could be achieved by analyzing PrPSc accumulation in both the spleen and brain following ic inoculation of humanized mice along with the use of humanized mouse models with the 129MV genotype.

Author contributions IB: Writing – original draft, Writing – review & editing.

Funding The author(s) declare that financial support was received for the research and/or publication of this article. Financial support for this study was provided by National Institute of Health Grants R01 NS045585 and R01 NS129502 to IB.

Conflict of interest The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Generative AI statement The author(s) declare that no Gen AI was used in the creation of this manuscript.

Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References…snip…end


CDC CWD TSE Prion Update 2025

KEY POINTS

Chronic wasting disease affects deer, elk and similar animals in the United States and a few other countries.

The disease hasn't been shown to infect people.

However, it might be a risk to people if they have contact with or eat meat from animals infected with CWD.


Prions in Muscles of Cervids with Chronic Wasting Disease, Norway

Volume 31, Number 2—February 2025



Volume 31, Number 2—February 2025

Detection of Chronic Wasting Disease Prions in Raw, Processed, and Cooked Elk Meat, Texas, USA

Overall, our study results confirm previous reports describing the presence of CWD prions in elk muscles (13). The data also demonstrated CWD prion persistence in food products even after processing through different procedures, including the addition of salts, spices, and other edible elements. Of note, our data show that exposure to high temperatures used to cook the meat increased the availability of prions for in vitro amplification. Considering the potential implications in food safety and public health, we believe that the findings described in this study warrant further research. Our results suggest that although the elk meat used in this study resisted different manipulations involved in subsequent consumption by humans, their zoonotic potential was limited. Nevertheless, even though no cases of CWD transmission to human have been reported, the potential for human infection is still unclear and continued monitoring for zoonotic potential is warranted.


Volume 31, Number 1—January 2025

Detection of Prions in Wild Pigs (Sus scrofa) from Areas with Reported Chronic Wasting Disease Cases, United States


Detection of chronic wasting disease prions in processed meats

Aims: identify the presence of CWD prions in processed meats derived from elk.

Conclusions: These results suggest CWD prions are accessible to humans through meats, even after processing and cooking. Considering the fact that these samples were collected from already processed specimens, the availability of CWD prions to humans is probably underestimated.

"Our results show positive prion detection in all the samples analyzed using deer and elk substrates. Surprisingly, cooked meats displayed increased seeding activities."

PRION 2023 CONTINUED;


The detection and decontamination of chronic wasting disease prions during venison processing

Conclusions: These preliminary results suggest that Dawn dish soap and Briotech do not reliably decontaminate CWD prions from these surfaces. Our data suggest that Virkon-S and various bleach concentrations are more effective in reducing prion contamination of meat processing surfaces; however, surface type may also influence the ability of prions to adsorb to surfaces, preventing complete decontamination. Our results will directly inform best practices to prevent the introduction of CWD prions into the human food chain during venison processing.

Prion 2023 Abstracts


DETECTION OF CHRONIC WASTING DISEASE PRIONS IN PROCESSED MEATS.

The zoonotic potential of chronic wasting disease (CWD) remains unknown. Currently, there are no known natural cases of CWD transmission to humans but increasing evidence suggests that the host range of CWD is not confined only to cervid species. Alarmingly, recent experimental evidence suggests that certain CWD isolates can induce disease in non-human primates. While the CDC strongly recommends determining CWD status in animals prior to consumption, this practice is voluntary. Consequently, it is plausible that a proportion of the cervid meat entering the human food chain may be contaminated with CWD. Of additional concern is that traditional diagnostic techniques used to detect CWD have relatively low sensitivity and are only approved for use in tissues other than those typically ingested by humans. In this study, we analyzed different processed meats derived from a pre-clinical, CWD-positive free-ranging elk. Products tested included filets, sausages, boneless steaks, burgers, ham steaks, seasoned chili meats, and spiced meats. CWD-prion presence in these products were assessed by PMCA using deer and elk substrates. Our results show positive prion detection in all products. To confirm the resilience of CWD-prions to traditional cooking methods, we grilled and boiled the meat products and evaluated them for any remnant PMCA seeding activity. Results confirmed the presence of CWD-prions in these meat products suggesting that infectious particles may still be available to people even after cooking. Our results strongly suggest ongoing human exposure to CWD-prions and raise significant concerns of zoonotic transmission through ingestion of CWD contaminated meat products.

***> Products tested included filets, sausages, boneless steaks, burgers, ham steaks, seasoned chili meats, and spiced meats.

***> CWD-prion presence in these products were assessed by PMCA using deer and elk substrates.

***> Our results show positive prion detection in all products.

***> Results confirmed the presence of CWD-prions in these meat products suggesting that infectious particles may still be available to people even after cooking.

***> Our results strongly suggest ongoing human exposure to CWD-prions and raise significant concerns of zoonotic transmission through ingestion of CWD contaminated meat products.


Transmission of prion infectivity from CWD-infected macaque tissues to rodent models demonstrates the zoonotic potential of chronic wasting disease.

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***> Further passage to cervidized mice revealed transmission with a 100% attack rate.

***> Our findings demonstrate that macaques, considered the best model for the zoonotic potential of prions, were infected upon CWD challenge, including the oral one.

****> The disease manifested as atypical in macaques and initial transgenic mouse transmissions, but with infectivity present at all times, as unveiled in the bank vole model with an unusual tissue tropism.

***> Epidemiologic surveillance of prion disease among cervid hunters and people likely to have consumed venison contaminated with chronic wasting disease


Transmission of Cervid Prions to Humanized Mice Demonstrates the Zoonotic Potential of CWD

Samia Hannaouia, Irina Zemlyankinaa, Sheng Chun Changa, Maria Immaculata Arifina, Vincent Béringueb, Debbie McKenziec, Hermann M. Schatzla, and Sabine Gilcha

Results: Here, we provide the strongest evidence supporting the zoonotic potential of CWD prions, and their possible phenotype in humans. Inoculation of mice expressing human PrPCwith deer CWD isolates (strains Wisc-1 and 116AG) resulted in atypical clinical manifestations in > 75% of the mice, with myoclonus as leading clinical sign. Most of tg650brain homogenates were positive for seeding activity in RT-QuIC. Clinical disease and presentation was transmissible to tg650 mice and bank voles. Intriguingly, protease-resistant PrP in the brain of tg650 mice resembled that found in a familial human prion disease and was transmissible upon passage. Abnormal PrP aggregates upon infection with Wisc-1 were detectable in thalamus, hypothalamus, and midbrain/pons regions.

Unprecedented in human prion disease, feces of CWD-inoculated tg650 mice harbored prion seeding activity and infectious prions, as shown by inoculation of bank voles and tg650 with fecal homogenates.

Conclusions: This is the first evidence that CWD can infect humans and cause disease with a distinctive clinical presentation, signature, and tropism, which might be transmissible between humans while current diagnostic assays might fail to detect it. These findings have major implications for public health and CWD-management.


The finding that infectious PrPSc was shed in fecal material of CWD-infected humanized mice and induced clinical disease, different tropism, and typical three banding pattern-PrPres in bank voles that is transmissible upon second passage is highly concerning for public health. The fact that this biochemical signature in bank voles resembles that of the Wisc-1 original deer isolate and is different from that of bvWisc-1, in the migration profile and the glyco-form-ratio, is valid evidence that these results are not a product of contamination in our study. If CWD in humans is found to be contagious and transmissible among humans, as it is in cervids [57], the spread of the disease within humans might become endemic.

Transmission of cervid prions to humanized mice demonstrates the zoonotic potential of CWD

Acta Neuropathol 144, 767–784 (2022). https://doi.org/10.1007/s00401-022-02482-9

Published

22 August 2022


Fortuitous generation of a zoonotic cervid prion strain

Aims: Whether CWD prions can infect humans remains unclear despite the very substantial scale and long history of human exposure of CWD in many states or provinces of USA and Canada. Multiple in vitro conversion experiments and in vivo animal studies indicate that the CWD-to-human transmission barrier is not unbreakable. A major long-term public health concern on CWD zoonosis is the emergence of highly zoonotic CWD strains. We aim to address the question of whether highly zoonotic CWD strains are possible.

Materials and Methods: We inoculated several sCJD brain samples into cervidized transgenic mice (Tg12), which were intended as negative controls for bioassays of brain tissues from sCJD cases who had potentially been exposed to CWD. Some of the Tg12 mice became infected and their brain tissues were further examined by Western blot as well as serial passages in humanized or cervidized mice.

Results: Passage of sCJDMM1 in transgenic mice expressing elk PrP (Tg12) resulted in a “cervidized” CJD strain that we termed CJDElkPrP. We observed 100% transmission of the original CJDElkPrP in transgenic mice expressing human PrP. We passaged CJDElkPrP two more times in the Tg12 mice. We found that such second and third passage CJDElkPrP prions retained 100% transmission rate in the humanized mice, despite that the natural elk CWD isolates and CJDElkPrP share the same elk PrP sequence. In contrast, we and others found zero or poor transmission of natural elk CWD isolates in humanized mice.

Conclusions: Our data indicate that highly zoonotic cervid prion strains are not only possible but also can retain zoonotic potential after serial passages in cervids, suggesting a very significant and serious long-term risk of CWD zoonosis given that the broad and continuing spread of CWD prions will provide fertile grounds for the emergence of zoonotic CWD strains over time.


The finding that infectious PrPSc was shed in fecal material of CWD-infected humanized mice and induced clinical disease, different tropism, and typical three banding pattern-PrPres in bank voles that is transmissible upon second passage is highly concerning for public health. The fact that this biochemical signature in bank voles resembles that of the Wisc-1 original deer isolate and is different from that of bvWisc-1, in the migration profile and the glyco-form-ratio, is valid evidence that these results are not a product of contamination in our study. If CWD in humans is found to be contagious and transmissible among humans, as it is in cervids [57], the spread of the disease within humans might become endemic.

Transmission of cervid prions to humanized mice demonstrates the zoonotic potential of CWD

Acta Neuropathol 144, 767–784 (2022). https://doi.org/10.1007/s00401-022-02482-9

Published

22 August 2022


ARS RESEARCH Generation of human chronic wasting disease in transgenic mice

Publication Acceptance Date: 9/8/2021

Research Project: Pathobiology, Genetics, and Detection of Transmissible Spongiform Encephalopathies Location: Virus and Prion Research

Title: Generation of human chronic wasting disease in transgenic mice

Author item WANG, ZERUI - Case Western Reserve University (CWRU) item QIN, KEFENG - University Of Chicago item CAMACHO, MANUEL - Case Western Reserve University (CWRU) item SHEN, PINGPING - Case Western Reserve University (CWRU) item YUAN, JUE - Case Western Reserve University (CWRU) item Greenlee, Justin item CUI, LI - Jilin University item KONG, QINGZHONG - Case Western Reserve University (CWRU) item MASTRIANNI, JAMES - University Of Chicago item ZOU, WEN-QUAN - Case Western Reserve University (CWRU)

Submitted to: Acta Neuropathologica Publication Type: Peer Reviewed Journal Publication Acceptance Date: 9/8/2021 Publication Date: N/A Citation: N/A

Interpretive Summary: Prion diseases are invariably fatal neurologic diseases for which there is no known prevention or cure. Chronic wasting disease (CWD) is the prion disease of deer and elk and is present in farmed and free ranging herds throughout North America. To date there is no clear evidence that the CWD agent could be transmitted to humans. This manuscript describes the use of an in vitro technique, cell-free serial protein misfolding cyclic amplification (sPMCA), to generate a CWD prion that is infectious to transgenic mice expressing the human prion protein. This study provides the first evidence that CWD prions may be able to cause misfolding in the human prion protein. This information will impact medical experts and those involved in making policy for farmed cervids and wildlife.

Technical Abstract: Chronic wasting disease (CWD) is a cervid spongiform encephalopathy or prion disease caused by the infectious prion or PrPSc, a misfolded conformer of cellular prion protein (PrPC). It has rapidly spread in North America and also has been found in Asia and Europe. In contrast to the zoonotic mad cow disease that is the first animal prion disease found transmissible to humans, the transmissibility of CWD to humans remains uncertain although most previous studies have suggested that humans may not be susceptible to CWD. Here we report the generation of an infectious human PrPSc by seeding CWD PrPSc in normal human brain PrPC through the in vitro cell-free serial protein misfolding cyclic amplification (sPMCA). Western blotting confirms that the sPMCA-induced proteinase K-resistant PrPSc is a human form, evidenced by a PrP-specific antibody that recognizes human but not cervid PrP. Remarkably, two lines of humanized transgenic (Tg) mice expressing human PrP-129Val/Val (VV) or -129Met/Met (MM) polymorphism develop prion disease at 233 ± 6 (mean ± SE) days post-inoculation (dpi) and 552 ± 27 dpi, respectively, upon intracerebral inoculation with the sPMCA-generated PrPSc. The brain of diseased Tg mice reveals the electrophoretic profile of PrPSc similar to sporadic Creutzfeldt-Jakob disease (sCJD) MM1 or VV2 subtype but different neuropathological patterns. We believe that our study provides the first evidence that CWD PrPSc is able to convert human PrPC into PrPSc in vitro and the CWD-derived human PrPSc mimics atypical sCJD subtypes in humanized Tg mice.


''The brain of diseased Tg mice reveals the electrophoretic profile of PrPSc similar to sporadic Creutzfeldt-Jakob disease (sCJD) MM1 or VV2 subtype but different neuropathological patterns.''

''We believe that our study provides the first evidence that CWD PrPSc is able to convert human PrPC into PrPSc in vitro and the CWD-derived human PrPSc mimics atypical sCJD subtypes in humanized Tg mice.''

Published: 26 September 2021

Generation of human chronic wasting disease in transgenic mice

Zerui Wang, Kefeng Qin, Manuel V. Camacho, Ignazio Cali, Jue Yuan, Pingping Shen, Justin Greenlee, Qingzhong Kong, James A. Mastrianni & Wen-Quan Zou

Acta Neuropathologica Communications volume 9, Article number: 158 (2021)

Abstract

Chronic wasting disease (CWD) is a cervid prion disease caused by the accumulation of an infectious misfolded conformer (PrPSc) of cellular prion protein (PrPC). It has been spreading rapidly in North America and also found in Asia and Europe. Although bovine spongiform encephalopathy (i.e. mad cow disease) is the only animal prion disease known to be zoonotic, the transmissibility of CWD to humans remains uncertain. Here we report the generation of the first CWD-derived infectious human PrPSc by elk CWD PrPSc-seeded conversion of PrPC in normal human brain homogenates using in vitro protein misfolding cyclic amplification (PMCA). Western blotting with human PrP selective antibody confirmed that the PMCA-generated protease-resistant PrPSc was derived from the human PrPC substrate. Two lines of humanized transgenic mice expressing human PrP with either Val or Met at the polymorphic codon 129 developed clinical prion disease following intracerebral inoculation with the PMCA-generated CWD-derived human PrPSc. Diseased mice exhibited distinct PrPSc patterns and neuropathological changes in the brain. Our study, using PMCA and animal bioassays, provides the first evidence that CWD PrPSc can cross the species barrier to convert human PrPC into infectious PrPSc that can produce bona fide prion disease when inoculated into humanized transgenic mice.

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It is worth noting that the annual number of sporadic CJD (sCJD) cases in the USA has increased, with the total number of suspected and confirmed sCJD cases rising from 284 in 2003 to 511 in 2017 (https://www.cdc.gov/prions/cjd/occurrence-transmission.html). The greatly enhanced CJD surveillance and an aging population in the USA certainly contributed to the observed increase in annual sCJD case numbers in recent years, but the possibility cannot be excluded that some of the increased sCJD prevalence is linked to CWD exposure.

In the present study, using serial protein misfolding cyclic amplification (sPMCA) assay we generate PrPSc by seeding CWD prions in normal human brain homogenates. Importantly, we reveal that two lines of humanized Tg mice expressing human PrP-129VV and 129MM develop prion diseases upon intracerebral inoculation of the abnormal PrP generated by sPMCA. We believe that our study provides the first opportunity to dissect the clinical, pathological and biochemical features of the CWD-derived human prion disease in two lines of humanized Tg mice expressing two major human PrP genotypes, respectively.


WA2 Oral transmission of CWD into Cynomolgus macaques: signs of atypical disease, prion conversion and infectivity in macaques and bio-assayed transgenic mice

Schatzl HM (1, 2), Hannaoui S (1, 2), Cheng Y-C (1, 2), Gilch S (1, 2), Beekes M (3), SchulzSchaeffer W (4), Stahl-Hennig C (5) and Czub S (2, 6)

(1) University of Calgary, Calgary Prion Research Unit, Calgary, Canada (2) University of Calgary, Faculty of Veterinary Medicine, Calgary, Canada, (3) Robert Koch Institute, Berlin, Germany, (4) University of Homburg/Saar, Homburg, Germany, (5) German Primate Center, Goettingen, Germany, (6) Canadian Food Inspection Agency (CFIA), Lethbridge, Canada.

To date, BSE is the only example of interspecies transmission of an animal prion disease into humans. The potential zoonotic transmission of CWD is an alarming issue and was addressed by many groups using a variety of in vitro and in vivo experimental systems. Evidence from these studies indicated a substantial, if not absolute, species barrier, aligning with the absence of epidemiological evidence suggesting transmission into humans. Studies in non-human primates were not conclusive so far, with oral transmission into new-world monkeys and no transmission into old-world monkeys. Our consortium has challenged 18 Cynomolgus macaques with characterized CWD material, focusing on oral transmission with muscle tissue. Some macaques have orally received a total of 5 kg of muscle material over a period of 2 years. After 5-7 years of incubation time some animals showed clinical symptoms indicative of prion disease, and prion neuropathology and PrPSc deposition were found in spinal cord and brain of euthanized animals. PrPSc in immunoblot was weakly detected in some spinal cord materials and various tissues tested positive in RT-QuIC, including lymph node and spleen homogenates. To prove prion infectivity in the macaque tissues, we have intracerebrally inoculated 2 lines of transgenic mice, expressing either elk or human PrP. At least 3 TgElk mice, receiving tissues from 2 different macaques, showed clinical signs of a progressive prion disease and brains were positive in immunoblot and RT-QuIC. Tissues (brain, spinal cord and spleen) from these and preclinical mice are currently tested using various read-outs and by second passage in mice. Transgenic mice expressing human PrP were so far negative for clear clinical prion disease (some mice >300 days p.i.). In parallel, the same macaque materials are inoculated into bank voles. Taken together, there is strong evidence of transmissibility of CWD orally into macaques and from macaque tissues into transgenic mouse models, although with an incomplete attack rate. The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology. Our ongoing studies will show whether the transmission of CWD into macaques and passage in transgenic mice represents a form of non-adaptive prion amplification, and whether macaque-adapted prions have the potential to infect mice expressing human PrP. The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD.

See also poster P103

***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD.

Source Prion Conference 2018 Abstracts


However, to date, no CWD infections have been reported in people.

sporadic, spontaneous CJD, 85%+ of all human TSE, did not just happen. never in scientific literature has this been proven. if one looks up the word sporadic or spontaneous at pubmed, you will get a laundry list of disease that are classified in such a way;

sporadic = 54,983 hits


spontaneous = 325,650 hits


key word here is 'reported'. science has shown that CWD in humans will look like sporadic CJD.

SO, how can one assume that CWD has not already transmitted to humans? they can't, and it's as simple as that. from all recorded science to date, CWD has already transmitted to humans, and it's being misdiagnosed as sporadic CJD. ...terry

*** LOOKING FOR CWD IN HUMANS AS nvCJD or as an ATYPICAL CJD, LOOKING IN ALL THE WRONG PLACES $$$ ***

However, to date, no CWD infections have been reported in people. key word here is ‘reported’. science has shown that CWD in humans will look like sporadic CJD. SO, how can one assume that CWD has not already transmitted to humans? they can’t, and it’s as simple as that. from all recorded science to date, CWD has already transmitted to humans, and it’s being misdiagnosed as sporadic CJD. …terry

*** LOOKING FOR CWD IN HUMANS AS nvCJD or as an ATYPICAL CJD, LOOKING IN ALL THE WRONG PLACES $$$ ***

*** These results would seem to suggest that CWD does indeed have zoonotic potential, at least as judged by the compatibility of CWD prions and their human PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests that if zoonotic CWD occurred, it would most likely effect those of the PRNP codon 129-MM genotype and that the PrPres type would be similar to that found in the most common subtype of sCJD (MM1).***




*** now, let’s see what the authors said about this casual link, personal communications years ago, and then the latest on the zoonotic potential from CWD to humans from the TOKYO PRION 2016 CONFERENCE.

see where it is stated NO STRONG evidence. so, does this mean there IS casual evidence ????

“Our conclusion stating that we found no strong evidence of CWD transmission to humans”

From: TSS Subject: CWD aka MAD DEER/ELK TO HUMANS ???

Date: September 30, 2002 at 7:06 am PST

From: "Belay, Ermias"

To:

Cc: "Race, Richard (NIH)" ; ; "Belay, Ermias"

Sent: Monday, September 30, 2002 9:22 AM

Subject: RE: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS

Dear Sir/Madam, In the Archives of Neurology you quoted (the abstract of which was attached to your email), we did not say CWD in humans will present like variant CJD.. That assumption would be wrong. I encourage you to read the whole article and call me if you have questions or need more clarification (phone: 404-639-3091).

Also, we do not claim that "no-one has ever been infected with prion disease from eating venison." Our conclusion stating that we found no strong evidence of CWD transmission to humans in the article you quoted or in any other forum is limited to the patients we investigated.

Ermias Belay, M.D. Centers for Disease Control and Prevention

-----Original Message-----

From:

Sent: Sunday, September 29, 2002 10:15 AM

To: rr26k@nih.gov; rrace@niaid.nih.gov; ebb8@CDC.GOV

Subject: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS

Sunday, November 10, 2002 6:26 PM .......snip........end..............TSS

''The association between venison eating and risk of CJD shows similar pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK OF CJD (p = 0.04).''

CREUTZFELDT JAKOB DISEASE SURVEILLANCE IN THE UNITED KINGDOM THIRD ANNUAL REPORT AUGUST 1994

Consumption of venison and veal was much less widespread among both cases and controls. For both of these meats there was evidence of a trend with increasing frequency of consumption being associated with increasing risk of CJD. (not nvCJD, but sporadic CJD...tss) These associations were largely unchanged when attention was restricted to pairs with data obtained from relatives. ...

Table 9 presents the results of an analysis of these data.

There is STRONG evidence of an association between ‘’regular’’ veal eating and risk of CJD (p = .0.01).

Individuals reported to eat veal on average at least once a year appear to be at 13 TIMES THE RISK of individuals who have never eaten veal.

There is, however, a very wide confidence interval around this estimate. There is no strong evidence that eating veal less than once per year is associated with increased risk of CJD (p = 0.51).

The association between venison eating and risk of CJD shows similar pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK OF CJD (p = 0.04).

There is some evidence that risk of CJD INCREASES WITH INCREASING FREQUENCY OF LAMB EATING (p = 0.02).

The evidence for such an association between beef eating and CJD is weaker (p = 0.14). When only controls for whom a relative was interviewed are included, this evidence becomes a little STRONGER (p = 0.08).

snip...

It was found that when veal was included in the model with another exposure, the association between veal and CJD remained statistically significant (p = < 0.05 for all exposures), while the other exposures ceased to be statistically significant (p = > 0.05).

snip...

In conclusion, an analysis of dietary histories revealed statistical associations between various meats/animal products and INCREASED RISK OF CJD. When some account was taken of possible confounding, the association between VEAL EATING AND RISK OF CJD EMERGED AS THE STRONGEST OF THESE ASSOCIATIONS STATISTICALLY. ...

snip...

In the study in the USA, a range of foodstuffs were associated with an increased risk of CJD, including liver consumption which was associated with an apparent SIX-FOLD INCREASE IN THE RISK OF CJD. By comparing the data from 3 studies in relation to this particular dietary factor, the risk of liver consumption became non-significant with an odds ratio of 1.2 (PERSONAL COMMUNICATION, PROFESSOR A. HOFMAN. ERASMUS UNIVERSITY, ROTTERDAM). (???...TSS)

snip...see full report ;




Stephen Dealler is a consultant medical microbiologist deal@airtime.co.uk

BSE Inquiry Steve Dealler

Management In Confidence

BSE: Private Submission of Bovine Brain Dealler

END

snip...end

########### http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############

BSE INQUIRY

CJD9/10022

October 1994

Mr R.N. Elmhirst Chairman British Deer Farmers Association Holly Lodge Spencers Lane

BerksWell Coventry CV7 7BZ

Dear Mr Elmhirst,

CREUTZFELDT-JAKOB DISEASE (CJD) SURVEILLANCE UNIT REPORT

Thank you for your recent letter concerning the publication of the third annual report from the CJD Surveillance Unit. I am sorry that you are dissatisfied with the way in which this report was published.

The Surveillance Unit is a completely independant outside body and the Department of Health is committed to publishing their reports as soon as they become available. In the circumstances it is not the practice to circulate the report for comment since the findings of the report would not be amended.. In future we can ensure that the British Deer Farmers Association receives a copy of the report in advance of publication.

The Chief Medical Officer has undertaken to keep the public fully informed of the results of any research in respect of CJD. This report was entirely the work of the unit and was produced completely independantly of the the Department.

The statistical results reqarding the consumption of venison was put into perspective in the body of the report and was not mentioned at all in the press release. Media attention regarding this report was low key but gave a realistic presentation of the statistical findings of the Unit. This approach to publication was successful in that consumption of venison was highlighted only once by the media ie. in the News at one television proqramme.

I believe that a further statement about the report, or indeed statistical links between CJD and consumption of venison, would increase, and quite possibly give damaging credence, to the whole issue. From the low key media reports of which I am aware it seems unlikely that venison consumption will suffer adversely, if at all.


TSE in wild UK deer? The first case of BSE (as we now realise) was in a nyala in London zoo and the further zoo cases in ungulates were simply thought of as being interesting transmissions of scrapie initially. The big problem started to appear with animals in 1993-5 when it became clear that there was an increase in the CJD cases in people that had eaten deer although the statistics involved must have been questionable. The reason for this was that the CJD Surveillance was well funded to look into the diet of people dying of CJD. This effect is not clear with vCJD...if only because the numbers involved are much smaller and hence it is difficult to gain enough statistics. They found that many other foods did not appear to have much association at all but that deer certainly did and as years went by the association actually became clearer. The appearance of vCJD in 1996 made all this much more difficult in that it was suddenly clearer that the cases of sporadic CJD that they had been checking up until then probably had nothing to do with beef...and the study decreased. During the period there was an increasing worry that deer were involved with CJD..

see references:

DEER BRAIN SURVEY


CONFIDENTIAL AND IN CONFIDENCE TRANSMISSION TO CHIMPANZEES AND PIGS

IN CONFIDENCE

TRANSMISSION TO CHIMPANZEES

Kuru and CJD have been successfully transmitted to chimpanzees but scrapie and TME have not.

We cannot say that scrapie will not transmit to chimpanzees. There are several scrapie strains and I am not aware that all have been tried (that would have to be from mouse passaged material). Nor has a wide enough range of field isolates subsequently strain typed in mice been inoculated by the appropriate routes (i/c, i/p and i/v).

I believe the proposed experiment to determine transmissibility, if conducted, would only show the susceptibility or resistance of the chimpanzee to infection/disease by the routes used and the result could not be interpreted for the predictability of the susceptibility for man. proposals for prolonged oral exposure of chimpanzees to milk from cattle were suggested a long while ago and rejected.

In view of Dr Gibbs' probable use of chimpazees Mr Wells' comments (enclosed) are pertinent. I have yet to receive a direct communication from Dr Schellekers but before any collaboration or provision of material we should identify the Gibbs' proposals and objectives.

A positive result from a chimpanzee challenged severely would likely create alarm in some circles even if the result could not be interpreted for man. I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough. Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.

A negative result would take a lifetime to determine but that would be a shorter period than might be available for human exposure and it would still not answer the question regarding mans ‘susceptibility. In the meantime no doubt the negativity would be used defensively. It would however be counterproductive if the experiment finally became positive. We may learn more about public reactions following next Monday's meeting.

R Bradley

CVO (+ Mr Wells’ commenters 23 September 1990 Dr T W A Little Dr B J Shreeve

90/9.23/1.1


Control of Chronic Wasting Disease OMB Control Number: 0579-0189APHIS-2021-0004 Singeltary Submission



Docket No. APHIS-2018-0011 Chronic Wasting Disease Herd Certification



Docket No. FDA-2003-D-0432 (formerly 03D-0186) Use of Material from Deer and Elk in Animal Feed

PUBLIC SUBMISSION

Comment from Terry Singeltary Sr.

Posted by the Food and Drug Administration on May 17, 2016 Comment

Docket No. FDA-2003-D-0432 (formerly 03D-0186) Use of Material from Deer and Elk in Animal Feed Singeltary Submission



Wednesday, May 24, 2023

***> WAHIS, WOAH, OIE, United States of America Bovine spongiform encephalopathy Immediate notification




SATURDAY, MAY 20, 2023

***> Tennessee State Veterinarian Alerts Cattle Owners to Disease Detection Mad Cow atypical L-Type BSE



MAY 19, 2023


2 weeks before the announcement of this recent mad cow case in the USA, i submitted this to the APHIS et al;

***> APPRX. 2 weeks before the recent mad cow case was confirmed in the USA, in Tennessee, atypical L-Type BSE, I submitted this to the APHIS et al;

Document APHIS-2023-0027-0001 BSE Singeltary Comment Submission May 2, 2023

''said 'burden' cost, will be a heavy burden to bear, if we fail with Bovine Spongiform Encephalopathy BSE TSE Prion disease, that is why this information collection is so critical''...



Expanding Distribution of Chronic Wasting Disease

Active

By National Wildlife Health Center February 10, 2025


Neuropsychiatric symptoms in sporadic Creutzfeldt-Jakob disease

Jennifer Zitser, Sven Forner, Katherine Wong, Jin Chengshi, John Neuhaus, Jennifer Martindale, Ben J Raudabaugh, Kendra Benisano, Kelly Goodman-O’Leary, Stacy Metcalf .

Brain, awaf077, https://doi.org/10.1093/brain/awaf077 Published: 28 March 2025

Although no neuropsychiatric symptom is pathognomonic for sCJD, certain symptoms might help differentiate sCJD from some other neurodegenerative diseases. Our findings support the inclusion of behavioral symptoms in sCJD diagnostic criteria.

https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awaf077/8098176?login=false

***> See further ;

https://creutzfeldt-jakob-disease.blogspot.com/2025/03/neuropsychiatric-symptoms-in-sporadic.html

SUNDAY, MARCH 23, 2025

Creutzfeldt Jakob Disease TSE Prion Increasing 2025 Update



RESTRICTED – POLICY CJD IN ADOLESCENTS (16 year old Vickey Rimmer), FARMERS WITH BSE HERDS, AND FARMERS WIFE with Sporadic CJD

June 2015

https://creutzfeldt-jakob-disease.blogspot.com/2015/06/restricted-policy-cjd-in-adolescents-16.html


Iatrogenic Transmissible Spongiform Encephalopathy 


terry

posted by Terry S. Singeltary Sr. at 3:36 PM