THURSDAY 12 JANUARY 2023
UCLan dentistry research directly links infected teeth and Alzheimer's Disease
This is the first study to link both root canal infections and gum disease directly to Alzheimer’s
A new study by researchers at the University of Central Lancashire (UCLan)’s School of Dentistry has revealed that Alzheimer’s disease may potentially be spread from infected teeth via dental procedures.
The new findings, by UCLan’s Dr Shalini Kanagasingam, have been recently published in the Journal of Alzheimer’s Disease Reports. They show that fragments of the ‘amyloid-beta’ – a protein which collects in the brains of those suffering from Alzheimer’s disease and subsequently kills nerve cells in the brain – has also been detected in infected teeth.
Alzheimer’s disease is the most common form of dementia, characterised by failing memory, behavioural changes and eventually a loss of ability to perform daily tasks. Understanding the onset of the commonest form of Alzheimer’s disease is very complex, as there are multiple factors involved, making it very difficult to prevent and treat.
However, it is recognised that one of the two main lesions of brain damage in those suffering from Alzheimer’s disease is an extensive build-up of amyloid-beta protein in the brain, and new therapies being approved for early Alzheimer’s treatment have focussed on reducing the deposits of these proteins. Recently, the drug Lecanemab has been shown to slow the progression of the disease, by signalling to the immune system to target and remove amyloid-beta clumps in the brain.
"Successful treatment and management of these oral health issues are a key part of protecting your long-term brain and general health."
— Dr Shalini Kanagasingam, Senior Clinical Lecturer at UCLan's School of Dentistry It has largely been believed that the amyloid-beta protein in those suffering from Alzheimer’s disease is produced by local cells in the brain. However, scientists now understand that these specific proteins are released by the body as a response to infection and can therefore be produced by all cells in the body.
Because oral diseases are driven by infections, there is an abundance of amyloid-beta protein within and around the external surfaces of infected teeth. The protein may then filter into the blood circulation, where it can potentially be transported to the brain.
UCLan’s laboratory-based investigation, led by Dr Shalini Kanagasingam and her Supervisory team - including Dr Sim Singhrao - examined extracted teeth which also had root canal infection and additional links to gum disease. The results revealed the novel possibility that amyloid-beta protein can be produced in the mouth in response to oral bacteria involved in gum disease as well as root canal disease. This may act as a potential early risk for Alzheimer’s disease, as the sticky protein can be seeded from one site to another – for example, between patients via contaminated dental instruments.
This method of spread via dental procedures has been observed previously with different proteins known as prions, which can potentially result in the fatal neurodegenerative disorder known as the variant Creutzfeldt-Jakob disease (vCJD). As a result, in 2006, special guidance was issued as a precautionary measure, to say that root canal dental instruments should only be used once, since prions are not susceptible to the sterilisation procedures used in dentistry. Could the same potentially be said for amyloid-beta protein?
"People should be reassured that here in the UK, we have very strict and effective dental protocols in place to prevent cross-infection between patients."
— Dr Shalini Kanagasingam Such a scenario prompts consideration of whether it’s possible that Alzheimer’s disease can be spread via contaminated dental instruments. Dr Shalini Kanagasingam adds that although it is plausible, the risk of this occurring is very low:
“People should be reassured that here in the UK, we have very strict and effective dental protocols in place to prevent cross-infection between patients. For example, root canal instruments such as files and reamers are only ever used once. The findings of this study do not suggest dental procedures pose a risk of spreading Alzheimer’s disease; but they do really highlight that amyloid-beta, which is found in the brain of Alzheimer’s sufferers, is very much present in infected teeth, with root canal infection and gum disease.
So rather than deter people from visiting the dentist, Dr Kanagasingam says the research instead underlines the importance of everyone visiting the dentist regularly:
“Anybody suffering from a root canal infection or gum disease should absolutely not leave these untreated.
“This study is the first to link both of these oral diseases with Alzheimer’s disease via amyloid-beta protein, and if anyone notices that they’re suffering from symptoms such as bleeding gums, bad breath, loose teeth, gum swellings or toothache, they should seek help from their dental team as soon as possible. Early diagnosis is vital, as successful treatment and management of these oral health issues are a key part of protecting your long-term brain and general health.”
Ex vivo Detection of Amyloid-β in Naturally Formed Oral Biofilm
Article type: Research Article
Authors: Kanagasingam, Shalinia | von Ruhland, Christopherb | Welbury, Richarda | Singhrao, Sim K.a; *
Affiliations: [a] Brain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK | [b] Electron and Light Microscopy Facility, College of Biomedical and Life Sciences, Cardiff University, Wales, UK
Correspondence: [*] Correspondence to: Sim K. Singhrao, University of Central Lancashire, Preston, PR1 2HE, UK. E-mail: SKSinghrao@uclan.ac.uk.
Keywords: Amyloid-β fibrils, biofilm, extracellular polymeric substance, periodontal bacteria, root canal
DOI: 10.3233/ADR-220076
Journal: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 757-773, 2022
Received 21 September 2022 | Accepted 18 November 2022 | Published: 16 December 2022
Abstract
Background:
Oral infection has been implicated in the possible etiology of Alzheimer’s disease.
Objective:
To detect amyloid-β (Aβ) within microbial biofilms.
Methods:
Freshly extracted teeth (N = 87) with periodontal disease were separated into Group A (N = 11), with primary root canal infection and Group B (N = 21) with failed endodontic treatment identified by the presence of, gutta percha root filling. Biofilm characteristics were observed by scanning electron microscopy (SEM). Demineralized paraffin wax embedded tooth sections and mineralized calculus biofilm were immunostained with the anti-Aβ antibody. The gutta perchas were processed either for on-section acrylic resin tissue immunocolloidal gold silver staining (IGSS) using the anti-Aβ antibody or in Araldite resin for ultrastructure.
Results:
SEM demonstrated calculus and gutta percha in situ harboring a polymicrobial biofilm featuring extracellular polymeric substance (EPS) and water channels. Immunohistochemistry on rehydrated paraffin wax tooth sections from Group A, demonstrated Aβ staining on external (calculus and plaque) and all intracanal infected regions. In Group B, the gutta percha biofilm IGSS gave an inconclusive result for Aβ. Transmission electron microscopy of selected teeth with infected intra-canals (Group A) and 20% of gutta percha biofilm (Group B) EPS contained electron dense fibrils of variable sizes, some of which were typical of human Aβ fibrils.
Conclusion:
This study detected both soluble and insoluble Aβ fibrils within the EPS of periodontal and endodontic natural biofilm, strongly suggesting its role as an antimicrobial peptide in combatting local infection, with potential risk for cross-seeding into the brain for AD development.
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Conclusions
The present study has been valuable as a pilot study to understand the microbial biofilm Aβ from naturally formed oral heterogenous consortium of bacterial communities. The major strength being that they were naturally formed in the human host, which include the host-related parameters including age, local environmental factors, similar immune status, and lifestyle, such as diet and oral health condition.
The host appears to have responded to the infection by releasing Aβ as an innate response in group A tooth biofilms and to the gutta percha associated biofilm. Overall, this study detected insoluble Aβ within the periodontal and endodontic natural biofilm formation parameters. Clinical significance of the present study is that endodontic teeth can harbor multi-Kingdom species of microbes including viruses, and bacteria. These microbes can give rise to insoluble Aβ experimentally, not dissimilar to the mechanism with which prions deposit insoluble fibrils in Aβ plaques. Like prions, insoluble Aβ will remain a risk for being cross seeded to the brain and for the plausible development of AD later in life. Further research is required to clarify the extent of such a risk and the mechanism by which Aβ could translocate from the mouth to the brain.
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Wide distribution of prion infectivity in the peripheral tissues of vCJD and sCJD patients
Jean-Yves Douet, Alvina Huor, Hervé Cassard, Séverine Lugan, Naima Aron, Mark Arnold, Didier Vilette, Juan-Maria Torres, James W. Ironside & Olivier Andreoletti
Abstract
Sporadic Creutzfeldt-Jakob disease (sCJD) is the commonest human prion disease, occurring most likely as the consequence of spontaneous formation of abnormal prion protein in the central nervous system (CNS). Variant Creutzfeldt–Jakob disease (vCJD) is an acquired prion disease that was first identified in 1996. In marked contrast to vCJD, previous investigations in sCJD revealed either inconsistent levels or an absence of PrPSc in peripheral tissues. These findings contributed to the consensus that risks of transmitting sCJD as a consequence of non-CNS invasive clinical procedures were low. In this study, we systematically measured prion infectivity levels in CNS and peripheral tissues collected from vCJD and sCJD patients. Unexpectedly, prion infectivity was detected in a wide variety of peripheral tissues in sCJD cases. Although the sCJD infectivity levels varied unpredictably in the tissues sampled and between patients, these findings could impact on our perception of the possible transmission risks associated with sCJD.
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Peripheral tissue infectivity in sCJD Seminal transmission experiments of peripheral tissues from sCJD cases in primate models failed to detect infectivity in a large selection of peripheral tissues, body fluids and excretions (except in one liver sample) [10]. Abnormal PrP immunodetection techniques (Western blot and immunohistochemistry) also failed to reveal the presence of prion in the peripheral tissues of sCJD patients [27, 28].These findings led to the generally accepted view that prion infectivity in the sCJD remains mostly confined to the CNS.
In 2003, improved Western Blot protocols for PrPres immunodetection revealed the presence of prion in the spleen (10 positive out of 28 cases) and/or the skeletal muscle (8 positive out of 32 cases) [24]. More recently, transmission studies of sCJD tissues in human PrP expressing transgenic mice (using plasma and bone marrow samples) and in vitro amplification of prions in a small number of sCJD peripheral tissues (skin, kidney, lung, adrenal gland) provided further evidence to the view that prions can accumulate in the peripheral tissues of sCJD affected patients [17, 32, 43, 52].
The results that we here report provide unequivocal and definitive evidence of the widespread distribution of the prion infectivity in the peripheral tissues in MM1 sCJD patients.
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In conclusion, the systematic surveillance of CJD and related epidemiological studies in many countries confirm the decline of cases of iatrogenic CJD due to recognised medical or surgical procedures, such as human dura mater graft surgery or treatment with human pituitary-derived growth hormone. However, they do not exclude the possibility that iatrogenic transmission could at least partly account for some sCJD cases observed in the population, particularly in localized geographic regions with evidence of CJD case clusters [50].
Many uncertainties remain on the early stages of the prion accumulation and infectivity in the peripheral tissues in patients infected with sCJD. However, the results of this study suggest that the iatrogenic transmission risks associated with sCJD peripheral tissues should not be disregarded.
WHO Tables on Tissue Infectivity Distribution in Transmissible Spongiform Encephalopathies
Table IC: Tissues with no detected infectivity or PrPTSE
Dental pulp NT - NT - NT NT NT NT NT NT
Transmission of the 263K scrapie strain by the dental route
Loredana lngrosso1, Flavio Pisani1, Maurizio Pocchiari1 View Affiliations Published: 01 November 1999 https://doi.org/10.1099/0022-1317-80-11-3043
ABSTRACT
Apart from a few cases of iatrogenic and familial human transmissible spongiform encephalopathies (TSEs) or prion diseases, the cause of Creutzfeldt–Jakob disease (CJD) remains unknown. In this paper we investigated the possibility that dental procedures may represent a potential route of infection. This was assessed by using the experimental model of scrapie in hamster. In the first part of this study we found that after intraperitoneal inoculation, oral tissues commonly involved in dental procedures (gingival and pulp tissues) bore a substantial level of infectivity. We also found high scrapie infectivity in the trigeminal ganglia, suggesting that the scrapie agent had reached the oral tissues through the sensitive terminal endings of the trigeminal nerves. In the second part of the study we inoculated a group of hamsters in the tooth pulp and showed that all of them developed scrapie disease. In these animals, we detected both infectivity and the pathological prion protein (PrPsc) in the trigeminal ganglion homolateral to the site of injection but not in the controlateral one. This finding suggests that the scrapie agent, and likely other TSE agents as well, spreads from the buccal tissues to the central nervous system through trigeminal nerves. Although these findings may not apply to humans affected by TSEs, they do raise concerns about the possible risk of transmitting these disorders through dental procedures. Particular consideration should be taken in regard to new variant CJD patients because they may harbour more infectivity in peripheral tissues than sporadic CJD patients.
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Although these results cannot be directly applied to humans affected by TSEs, they raise the possibility that surgical instruments used during major dental procedures in CJD patients and inadequately decontaminated may represent a means of man-to-man transmission of TSEs. People incubating nvCJD are of particular concern, because they carry higher level of PrPsc, and likely infectivity, in peripheral tissues than sporadic CJD cases (Hill et al., 1999R21 ). Concern will further increase if upcoming studies show that trigeminal ganglia of nvCJD patients are more affected than those of sporadic CJD cases.
Levels of abnormal prion protein in dental tissue
Donald J Jeffries British Dental Journal
volume 195, page 331 (2003)
Previous studies have indicated that dental surgery is not a risk factor for sporadic CJD, but in variant CJDthe tissue distribution of infectivity is much wider, raising concerns over transmission via dental surgical instruments. A range of dental tissues were studied for the presence of the abnormal form of the prion protein, using a combination of immunohistochemistry and a sensitive Western blot assay. Abnormal prion protein was detected in the trigeminal ganglia, tonsil and lymph nodes in variant CJD but not in sporadic CJD cases. Alveolar nerves, gingiva, dental pulp, tongue and salivary gland tissue were negative in all cases. Lymphoid tissues (including tonsil) were negative in sporadic CJD. Since the presence of the abnormal form of the prion protein is associated with infectivity, these findings indicate that the highest levels of infectivity in dental tissues are likely to be found in the tonsil and associated lymphoid tissues. This does not exclude the presence of lower levels of infectivity in the negative tissues in our study. These new findings will be of use to inform the risk assessment on dental tissues and variant CJD. Abstract
Objective To study the distribution of disease-associated prion protein (PrP) in oral and dental tissues in variant CJD.
Design Prospective single centre autopsy based study.
Setting Within the National CJD Surveillance Unit, UK, 2000–2002.
Materials and methods Patients with suspected variant CJD undergoing autopsy where permission to remove tissues for research purposes had been obtained from the relatives. Fixed and frozen autopsy tissues from the brain, trigeminal ganglion, alveolar nerve, dental pulp, gingiva, salivary gland, tongue and tonsils were studied by Western blot, PET blot and immunocytochemistry to detect disease-associated PrP.
Results Disease-associated PrP was only detected in the brain, trigeminal ganglia and tonsils.
Conclusions The failure to detect disease-associated PrP in most dental and oral tissues will help inform ongoing risk assessments for dental surgery in relation to the possible iatrogenic transmission of variant CJD via dental instruments.
Main
Investigation of PrPres in dental tissues in variant CJD M. W. Head, D. Ritchie, V. McLoughlin and J. W. Ironside Br Dent J 2003; 195: 339–343
Comment
The discovery of thermostable strains of the transmissible spongiform encephalopathy (TSE) agents, BSE and scrapie, together with convincing evidence that BSE and variant CJD are caused by the same agent, has led to concern that the diseases may be transmitted by surgical and dental instruments. This concern was justified by a risk assessment conducted by the Department of Health which concluded that 'Surgical transmission of vCJD cannot be ruled out as a risk to public health' (www.doh.gov.uk/cjd/riskassessmentsi.htm).
Further concerns come from the knowledge that infectivity is present in rodent models of TSE and infection can be transmitted to other rodents by inoculation into the tongue or dental pulp. Studies of reamers and files used in endodontic work have demonstrated that these instruments are extremely difficult, if not impossible, to clean, and residual protein is easily visible to the naked eye.
Of some consolation is the fact that dental procedures have not been associated epidemiologically with transmission of the sporadic form of CJD. In a small study, the abnormal (potentially infectious) form of the prion protein (PrPres) was not detected in the dental pulp from patients with sporadic CJD.
Variant CJD agent is more widely distributed outside of the CNS, than agents of other forms of CJD. As most of the population of the UK have been exposed by diet to this agent and the number of individuals who are carriers of this infection is unknown, it is important to ascertain whether PrPres (and infectious prion) is present in dental tissues.
This paper is an important step forward, as no PrPres was detected in the gingiva of three patients who had died of variant CJD, nor in the dental pulp and alveolar nerve of two of the patients. The authors emphasise however, that although this is encouraging, the limits of sensitivity of this technology mean that infectious agent could still be residing in the tissues and present a risk through instrument contamination. Thus, they stress the need to ensure that decontamination procedures, particularly washing and autoclaving, are maintained at a high level throughout the country.
Professor of Virology Head of Department of Medical Microbiology, St Bartholomew's and the Royal London Hospitals, Donald J Jeffries Rights and permissions
Jeffries, D. Levels of abnormal prion protein in dental tissue. Br Dent J 195, 331 (2003). https://doi.org/10.1038/sj.bdj.4810534
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Short paper
Disease-Associated Prion Protein in the Dental Tissue of Mice Infected with Scrapie
Author links open overlay panel
H. Okada, M. Sakurai, T. Yokoyama, S. Mohri
Summary
Transmissible spongiform encephalopathies (TSEs) induce fatal neurodegenerative diseases in man and animals. The present study demonstrates immunohistochemically the presence of disease-associated prion protein (PrPSc) in the epithelial cell rests of Malassez (ERM) of mice experimentally infected with ME7 scrapie by the intracerebral route. Mouse bioassay of scrapie-infected dental tissue revealed prolonged incubation periods, suggesting that there are relatively low amounts of infectious agent in dental tissue compared with the brain. These findings indicate that PrPSc may spread from the brain to the ERM along the cranial nerves via the trigeminal ganglion that innervates the dental tissues. Dental tissue might therefore be a potential source of PrPSc for horizontal transmission of TSEs.
Keywords
dental tissue epithelial cell rests of Malassez mice scrapie
Bioassay Studies Support the Potential for Iatrogenic Transmission of Variant Creutzfeldt Jakob Disease through Dental Procedures
Published: November 30, 2012
Elizabeth Kirby , Joanne Dickinson , Matthew Vassey, Mike Dennis, Mark Cornwall, Neil McLeod, Andrew Smith, Philip D. Marsh, James T. Walker, J. Mark Sutton , Neil D. H. Raven
Abstract
Background
Evidence is required to quantify the potential risks of transmission of variant Creutzfeldt Jakob (vCJD) through dental procedures. Studies, using animal models relevant to vCJD, were performed to address two questions. Firstly, whether oral tissues could become infectious following dietary exposure to BSE? Secondly, would a vCJD-contaminated dental instrument be able to transmit disease to another patient?
Methods
BSE-301V was used as a clinically relevant model for vCJD. VM-mice were challenged by injection of infected brain homogenate into the small intestine (Q1) or by five minute contact between a deliberately-contaminated dental file and the gingival margin (Q2). Ten tissues were collected from groups of challenged mice at three or four weekly intervals, respectively. Each tissue was pooled, homogenised and bioassayed in indicator mice.
Findings
Challenge via the small intestine gave a transmission rate of 100% (mean incubation 157±17 days). Infectivity was found in both dental pulp and the gingival margin within 3 weeks of challenge and was observed in all tissues tested within the oral cavity before the appearance of clinical symptoms. Following exposure to deliberately contaminated dental files, 97% of mice developed clinical disease (mean incubation 234±33 days).
Interpretation
Infectivity was higher than expected, in a wider range of oral tissues, than was allowed for in previous risk assessments. Disease was transmitted following transient exposure of the gingiva to a contaminated dental file. These observations provide evidence that dental procedures could be a route of cross-infection for vCJD and support the enforcement of single-use for certain dental instruments.
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Implications for public health
Currently there is no evidence for vCJD transmission through either surgery or dentistry. Transmission of vCJD by blood transfusion [5], [9] highlights that any procedure contacting nervous or lymphoid tissue must also be considered a risk given the wider tissue distribution of vCJD infectivity compared to sporadic CJD [19]–[21]. The highly efficient transmission of BSE strain 301 V infection through direct inoculation into the murine small intestine in this study raises similar concerns for vCJD transmission through endoscopic procedures in man.
The observations in the current study also provide theoretical grounds for concern in respect to dental procedures. The levels of infectivity observed in all oral tissues tested (most notably gingival margin with up to ∼1000 ID per mg) were higher than previously considered.
A further element of the study assessed residual protein contamination on a range of dental instruments after routine cleaning and disinfection in general dental practice in England [22]). The study showed a number of instrument types and cleaning procedures where the upper interquartile range for residual protein was in excess of 100 µg. This could equate to up to 100 ID per instrument in the case of gingival tissue. Autoclaving has been shown to achieve only a 3-log inactivation of various TSE agents [23] and an autoclave designed for the dental market has been tested recently and shown to provide only a 100-fold reduction in infectivity in the BSE301V/VM model used here (134°C, 18 minutes; Sutton et al unpublished). A dental instrument soiled with infectious gingival tissue and disinfected under this regimen would have an inadequate safety margin.
The gingival challenge was designed as a worse-case scenario in respect to the infectious load on a dental instrument, but to be of limited invasiveness. The procedure resulted in very high levels of transmission with short incubation periods indicating that a much lower titre challenge material would also have caused some transmission. Even if a relatively rare event, the large number of dental interventions taking place in a younger age profile population (c.f. surgical procedures) and a carrier population of unknown size means these risks are not negligible. This would seem to be at odds with the absence of any reported cases of clinical vCJD transmission linked to dental procedures. This might be explained by a number of factors, including difficulties in linking dental records to known vCJD patients [24], asymptomatic cases [5] and extended incubation periods for patients exposed by blood transfusion (up to 7.8 years; [25]). As a worse case study, the incubation periods described here would be expected to be the most rapid giving rise to prion-disease symptoms in this model, and as a novel low-dose, peripheral model of infection, the incubation periods might be expected to be considerably longer than those observed for blood transfusion cases. Given the difficulties in linking dental procedure case histories to vCJD, such cases may not yet be evident.
Preliminary data from this study have already been provided to the UK Department of Health as part of the revision of the dental risk assessment ( http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/dh/en/documents/digitalasset/dh_081217.pdf
accessed 12th November 2011).
Additional control measures have been incorporated into guidance on decontamination in dental settings in England ( http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_109363 ; accessed 12th November 2011). The emphasis on standardised decontamination methods and single use instruments for difficult to clean devices appear sensible and proportionate given the experimental observations described and discussed here.
Supporting Information
Supporting Information S1 - Bioassay Studies Support the Potential for Iatrogenic Transmission of Variant Creutzfeldt Jakob Disease through Dental Procedures
Further discussion on relative levels of infectivity in vivo and PrPSc-signal detectable in vitro.
Supporting Information S1.
Further discussion on relative levels of infectivity in vivo and PrPSc-signal detectable in vitro.
https://doi.org/10.1371/journal.pone.0049850.s001
(DOCX)
With the recent occasional iatrogenic deaths in France, seems great concern should be readdressed with TSE prion disease and iatrogenic risk factors, including dental...terry
MONDAY, DECEMBER 31, 2007
Risk Assessment of Transmission of Sporadic Creutzfeldt-Jakob Disease in Endodontic Practice in Absence of Adequate Prion Inactivation
Thursday, November 14, 2013
Prion diseases in humans: Oral and dental implications
Detection of Creutzfeldt-Jakob disease prions in skin: implications for healthcare
Akin Nihat & Simon Mead
Genome Medicine volume 10, Article number: 22 (2018) Cite this article
Editorial summary
Evidence has recently been reported of prion seeding activity in skin tissue from patients with sporadic Creutzfeldt-Jakob disease (sCJD). This is relevant information for infection control measures during surgery. The work uses very sensitive prion assays now available for medical research, and may soon be adapted to related neurodegenerative disorders.
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Conclusions and perspectives Abnormal PrP amplification technologies are incredibly sensitive assays that provide evidence for a wider tissue distribution for prions in sCJD and rapid detection in individual patients. Whether these developments will translate into improved infection control measures is a much more complicated question, as it is very hard to find evidence for ongoing person–person transmission with surgical instruments or blood–blood product transfusion. This may be because transmissions are not currently occurring in healthcare settings, or a consequence of the challenges of epidemiological investigation of a rare disorder with potentially very long incubation periods. In this context, any new infection control measures will need to be practical and proportionate.
An increasing body of experimental and observational evidence suggests that more common neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, share fundamental mechanistic similarities with prion disease [10]. Whilst these similarities were proposed following animal transmission experiments and the apparent spreading of protein pathologies in the brain, recent findings raise the possibility of iatrogenic amyloid-beta cerebral amyloid angiopathy in specific circumstances that parallel the experience of acquired prion diseases [11]. This should neither be surprising nor alarming news. In this respect, recent results illustrate the potential of tools developed for prion research for the wider field of neurodegeneration and encourage their adaptation to other misfolded proteins.
Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease
Prions in unexpected places
Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, can be transmitted via neurosurgical instruments or corneal or dura mater transplants contaminated by infectious prions. Some epidemiological studies have associated sCJD risk with surgeries that involve the skin, but whether the skin of sCJD patients contains prion infectivity is not known. Orrú et al. now report detectable prion seeding activity and infectivity in skin from sCJD patients, although at much lower levels compared to brain tissues from sCJD patients. These data suggest that there may be a potential for iatrogenic sCJD transmission through skin.
Abstract
Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is transmissible through iatrogenic routes due to abundant infectious prions [misfolded forms of the prion protein (PrPSc)] in the central nervous system (CNS). Some epidemiological studies have associated sCJD risk with non-CNS surgeries. We explored the potential prion seeding activity and infectivity of skin from sCJD patients. Autopsy or biopsy skin samples from 38 patients [21 sCJD, 2 variant CJD (vCJD), and 15 non-CJD] were analyzed by Western blotting and real-time quaking-induced conversion (RT-QuIC) for PrPSc. Skin samples from two patients were further examined for prion infectivity by bioassay using two lines of humanized transgenic mice. Western blotting revealed dermal PrPSc in one of five deceased sCJD patients and one of two vCJD patients. However, the more sensitive RT-QuIC assay detected prion seeding activity in skin from all 23 CJD decedents but not in skin from any non-CJD control individuals (with other neurological conditions or other diseases) during blinded testing. Although sCJD patient skin contained ~103- to 105-fold lower prion seeding activity than did sCJD patient brain tissue, all 12 mice from two transgenic mouse lines inoculated with sCJD skin homogenates from two sCJD patients succumbed to prion disease within 564 days after inoculation. Our study demonstrates that the skin of sCJD patients contains both prion seeding activity and infectivity, which raises concerns about the potential for iatrogenic sCJD transmission via skin.
Published: 08 December 2017
Prion disease
Skin is a source of infectious prions in sCJD
Shimona Starling
Nature Reviews Neurology volume 14, pages2–3 (2018)
Second death in France in a laboratory working on prions
Second death in France in a laboratory working on prions
Creutzfeldt-Jakob disease has killed a person who handled this infectious agent at Inrae in Toulouse. After a first death in 2019, a moratorium on work on this pathogen has been extended.
By Hervé Morin
Creutzfeldt-Jakob disease killed a few days ago a retired research technician from the National Research Institute for Agriculture, Food and the Environment (Inrae), who had worked in Toulouse in contact of biological tissue infected with prions. This death sows consternation and concern in the scientific community working with these infectious agents. It follows the death, on June 17, 2019, of Emilie Jaumain, a 33-year-old laboratory technician, suffering from the same incurable neurodegenerative disease. The young woman is said to have contracted it in 2010, cutting herself while handling fragments of the brains of mice infected with prions, in another unit of INRAE, in Jouy-en-Josas.
Computer representation of part of a prion protein on a light micrograph of pyramidal nerve cells (neurons, in black) in the cerebellum of the brain. ALFRED PASIEKA / SCIENCE PHOTO LIBRARY
Regarding the retiree from Toulouse, it will be necessary to determine whether she was the victim of a genetic or sporadic form of Creutzfeldt-Jakob disease, if the disease may have been caused by the ingestion of meat contaminated by the agent of encephalopathy. bovine spongiform (BSE, also called mad cow disease) or, as in the case of Emilie Jaumain, if accidental occupational exposure can be claimed. Prion diseases are caused by proteins taking an aberrant conformation, which gives them the property of replicating to form aggregates that are deleterious for neurons. There are around 150 cases per year in France, resulting in fatal degeneration of the central nervous system.
Temporary suspension of work on prions in French public research laboratories
PRESS RELEASE - The general directorates of ANSES, CEA, CNRS, INRAE and Inserm, have decided jointly and in agreement with the Ministry of Higher Education, Research and Innovation to suspend as a precaution all their research and experimentation work relating to prion diseases, for a period of three months.
This precautionary measure is motivated by the knowledge of a possible new case of a person suffering from Creutzfeldt-Jakob disease and who worked in a laboratory for research on prions.
Posted on July 27, 2021
The suspension period put in place as of this day will make it possible to study the possibility of a link between the observed case and the person's former professional activity and to adapt, if necessary, the preventive measures in force in the research laboratories.
The person with Creutzfeldt-Jakob disease (CJD)1, whose form is not yet known, is a retired INRAE agent. This could be the second case of infectious CJD affecting a scientist who worked on prions, after that of an assistant engineer who died of the disease in 2019, and who was injured in 2010 during of an experiment.
Following this death, a general inspection mission was launched in July 2019 by the ministries of research and agriculture with French laboratories handling prions. Submitted in October 2020, the report concluded on the regulatory compliance of the laboratories visited as well as the presence of a risk control culture within the research teams.
Research around prion proteins, with high public health issues, allows major advances in the understanding of the functioning of these infectious pathogens, and contributes to results that are transferable to other related degenerative diseases such as Alzheimer's and Alzheimer's diseases. Parkinson's.
At the level of each establishment, regular and transparent information will be provided to all the working communities concerned by this measure.
1 The disease Creutzfeldt-Jakob disease (CJD) is one of prion diseases - still called encephalopathies subacute spongiform transmitted(TSE) - of diseases rare, characterized by a degeneration rapid and fatal the system nervous central. They are caused by the accumulation in the brain of a normally expressed protein but poorly conformed - the prion protein - which leads to the formation of deleterious aggregates for neurons. For now , no treatment will allow to change the course of these diseases. It can be of origin sporadic , form the most frequent , original genetic or finally to form infectious following a contamination.
France issues moratorium on prion research after fatal brain disease strikes two lab workers
By Barbara CasassusJul. 28, 2021 , 4:35 AM
PARIS—Five public research institutions in France have imposed a 3-month moratorium on the study of prions—a class of misfolding, infectious proteins that cause fatal brain diseases—after a retired lab worker who handled prions in the past was diagnosed with Creutzfeldt-Jakob disease (CJD), the most common prion disease in humans. An investigation is underway to find out whether the patient, who worked at a lab run by the National Research Institute for Agriculture, Food and Environment (INRAE), contracted the disease on the job.
If so, it would be the second such case in France in the past few years. In June 2019, an INRAE lab worker named Émilie Jaumain died at age 33, 10 years after pricking her thumb during an experiment with prion-infected mice. Her family is now suing INRAE for manslaughter and endangering life; her illness had already led to tightened safety measures at French prion labs.
The aim of the moratorium, which affects nine labs, is to “study the possibility of a link with the [new patient’s] former professional activity and if necessary to adapt the preventative measures in force in research laboratories,” according to a joint press release issued by the five institutions yesterday.
“This is the right way to go in the circumstances,” says Ronald Melki, a structural biologist at a prion lab jointly operated by the French national research agency CNRS and the French Alternative Energies and Atomic Energy Commission (CEA). “It is always wise to ask questions about the whole working process when something goes wrong.” "The occurrence of these harsh diseases in two of our scientific colleagues clearly affects the whole prion community, which is a small 'familial' community of less than 1000 people worldwide," Emmanuel Comoy, deputy director of CEA's Unit of Prion Disorders and Related Infectious Agents, writes in an email to Science. Although prion research already has strict safety protocols, "it necessarily reinforces the awareness of the risk linked to these infectious agents," he says.
In Jaumain’s case, there is little doubt she was infected on the job, according to a paper published in The New England Journal of Medicine (NEJM) in 2020. She had variant CJD (vCJD), a form typically caused by eating beef contaminated with bovine spongiform encephalopathy (BSE), or mad cow disease. But Europe’s BSE outbreak ended after 2000 and vCJD virtually disappeared; the chance that someone of Jaumain’s age in France would contract food-borne vCJD is “negligible or non-existent,” according to the paper.
A scientist with inside knowledge says the new patient, a woman who worked at INRAE’s Host-Pathogen Interactions and Immunity group in Toulouse, is still alive. French authorities were apparently alerted to her diagnosis late last week. The press release suggests it’s not yet clear whether the new case is vCJD or “classic” CJD, which is not known to be caused by prions from animals. Classic CJD strikes an estimated one person per million. Some 80% of cases are sporadic, meaning they have no known cause, but others are genetic or contracted from infected human tissues during transplantations. The two types of CJD can only be distinguished through a postmortem examination of brain tissue.
Lab infections are known to occur with many pathogens, but exposure to CJD-causing prions is unusually risky because there are no vaccines or treatments and the condition is universally fatal. And whereas most infections reveal themselves within days or weeks, CJD’s average incubation period is about 10 years.
For Jaumain, who worked at INRAE’s Molecular Virology and Immunology Unit in Jouy-en-Josas, outside Paris, that long period of uncertainty began on 31 May 2010, when she stabbed her left thumb with a curved forceps while cleaning a cryostat—a machine that can cut tissues at very low temperatures—that she used to slice brain sections from transgenic mice infected with a sheep-adapted form of BSE. She pierced two layers of latex gloves and drew blood. “Émilie started worrying about the accident as soon as it had happened, and mentioned it to every doctor she saw,” says her widower, Armel Houel.
In November 2017, Jaumain developed a burning pain in her right shoulder and neck that worsened and spread to the right half of her body over the following 6 months, according to the NEJM paper. In January 2019, she became depressed and anxious, suffering memory impairment and hallucinations. “It was a descent into hell,” Houel says. She was diagnosed with “probable vCJD” in mid-March of that year and died 3 months later. A postmortem confirmed the diagnosis.
“The occurrence of these harsh diseases in two of our scientific colleagues clearly affects the whole prion community.” Emmanuel Comoy, French Alternative Energies and Atomic Energy Commission
INRAE only recently admitted the likely link between Jaumain’s illness and the accident. “We recognize, without ambiguity, the hypothesis of a correlation between Emilie Jaumain-Houel’s accident … and her infection with vCJD,” INRAE chair and CEO Philippe Mauguin wrote in a 24 June letter to an association created by friends and colleagues to publicize Jaumain’s case and lobby for improvements in lab safety. (Science has obtained a copy of the letter, which has not been made public.)
Jaumain’s family has filed both criminal charges and an administrative suit against INRAE, alleging a range of problems at Jaumain’s lab. She had not been trained in handling dangerous prions or responding to accidents and did not wear both metal mesh and surgical gloves, as she was supposed to, says Julien Bensimhon, the family’s lawyer. The thumb should have been soaked in a bleach solution immediately, which did not happen, Bensimhon adds.
Independent reports by a company specializing in occupational safety and by government inspectors have found no safety violations at the lab; one of them said there was a “strong culture” of risk management. (Bensimhon calls the reports “biased.”)
The government inspectors’ report concluded that Jaumain’s accident was not unique, however. There had been at least 17 accidents among the 100 or so scientists and technicians in France working with prions in the previous decade, five of whom stabbed or cut themselves with contaminated syringes or blades. Another technician at the same lab had a fingerprick accident with prions in 2005, but has not developed vCJD symptoms so far, Bensimhon says. “It is shocking that no precautionary measures were taken then to ensure such an accident never happened again,” he says.
In Italy, too, the last person to die of vCJD, in 2016, was a lab worker with exposure to prion-infected brain tissue, according to last year’s NEJM paper, although an investigation did not find evidence of a lab accident. That patient and the lab they worked at have not been identified.
After Jaumain’s diagnosis, “We contacted all the research prion labs in France to suggest they check their safety procedures and remind staff about the importance of respecting them,” says Stéphane Haïk, a neuroscientist at the Paris Brain Institute at Pitié-Salpêtrière Hospital who helped diagnose Jaumain and is the corresponding author on the paper. Many labs tightened procedures, according to the government inspectors' report, for instance by introducing plastic scissors and scalpels, which are disposable and less sharp, and bite and cut-resistant gloves. A team of experts from the five research agencies is due to submit proposals for a guide to good practice in prion research to the French government at the end of this year.
The scientific community has long recognized that handling prions is dangerous and an occupational risk for neuropathologists, says neuropathologist Adriano Aguzzi of the University of Zurich. Aguzzi declined to comment on the French CJD cases, but told Science his lab never handles human or bovine prions for research purposes, only for diagnostics. “We conduct research only on mouse-adapted sheep prions, which have never been shown to be infectious to humans,” Aguzzi says. In a 2011 paper, his team reported that prions can spread through aerosols, at least in mice, which “may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories,” they wrote. Aguzzi says he was “totally shocked” by the finding and introduced safety measures to prevent aerosol spread at his own lab, but the paper drew little attention elsewhere.
The moratorium will "obviously" cause delays in research, but given the very long incubation periods in prion diseases, the impact of a 3-month hiatus will be limited, Comoy says. His research team at CEA also works on other neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, and will shift some of its efforts to those.
Although Jaumain’s diagnosis upset many in the field, it hasn't led to an exodus among researchers in France, Haïk says: “I know of only one person who resigned because they were so worried.”
With reporting by Martin Enserink.
Posted in: EuropeHealthScientific Community
doi:10.1126/science.abl6587
Variant Creutzfeldt–Jakob Disease Diagnosed 7.5 Years after Occupational Exposure
Variant Creutzfeldt–Jakob disease was identified in a technician who had cut her thumb while handling brain sections of mice infected with adapted BSE 7.5 years earlier. The long incubation period was similar to that of the transfusion-transmitted form of the disease.
Variant Creutzfeldt–Jakob Disease Diagnosed 7.5 Years after Occupational Exposure
TO THE EDITOR:
We report a case of variant Creutzfeldt–Jakob disease (CJD) that was plausibly related to accidental occupational exposure in a technician who had handled murine samples contaminated with the agent that causes bovine spongiform encephalopathy (BSE) 7.5 years earlier.
In May 2010, when the patient was 24 years of age, she worked in a prion research laboratory, where she handled frozen sections of brain of transgenic mice that overexpressed the human prion protein with methionine at codon 129. The mice had been infected with a sheep-adapted form of BSE. During this process, she stabbed her thumb through a double pair of latex gloves with the sharp ends of a curved forceps used to handle the samples. Bleeding was noted at the puncture site.
In November 2017, she began having burning pain in the right shoulder and neck. The pain worsened and spread to the right half of her body during the following 6 months. In November 2018, an examination of a sample of cerebrospinal fluid (CSF) obtained from the patient was normal. Magnetic resonance imaging (MRI) of the brain showed a slight increase in the fluid-attenuated inversion recovery (FLAIR) signal in the caudates and thalami (Fig. S1A and S1B in the Supplementary Appendix, available with the full text of this letter at NEJM.org). In January 2019, she became depressed and anxious and had memory impairment and visual hallucinations. There was hypertonia on the right side of her body. At that time, an analysis of CSF for 14-3-3 protein was negative. In March 2019, MRI showed an increased FLAIR signal in pulvinar and dorsomedial nuclei of thalami (Fig. S1C through S1E).
Figure 1.
Detection of Abnormal Prion Protein in Biologic Fluid Samples and Postmortem Findings.
The patient was found to be homozygous for methionine at codon 129 of the prion protein gene without mutation. An analysis of a sample of CSF on real-time quaking-induced conversion analysis was negative for a diagnosis of sporadic CJD. However, an analysis of plasma and CSF by means of protein misfolding cyclic amplification was positive for the diagnosis of variant CJD (Figure 1A and 1B). The patient died 19 months after the onset of symptoms. Neuropathological examination confirmed the diagnosis of variant CJD (Figure 1C and 1D). Western blot analysis showed the presence of type 2B protease-resistant prion protein in all sampled brain areas. The clinical characteristics of the patient and the postmortem neuropathological features were similar to those observed in 27 patients with variant CJD who had previously been reported in France.1 (Additional details are provided in the Supplementary Appendix.)
There are two potential explanations for this patient’s condition. Oral transmission from contaminated cattle products cannot be ruled out because the patient was born at the beginning of the French BSE outbreak in cattle. However, the last two patients who had confirmed variant CJD with methionine homozygosity at codon 129 in France and the United Kingdom died in 2014 and 2013, respectively, which makes oral transmission unlikely. In France, the risk of variant CJD in 2019 was negligible or nonexistent in the post-1969 birth cohort.2
Percutaneous exposure to prion-contaminated material is plausible in this patient, since the prion strain that she had handled was consistent with the development of variant CJD.3 The 7.5-year delay between the laboratory accident and her clinical symptoms is congruent with the incubation period in the transfusion-transmitted form of the disease. The ability of this strain to propagate through the peripheral route has been documented, and experimental studies with scrapie strains have shown that scarification and subcutaneous inoculation are effective routes.4,5 The last known Italian patient with variant CJD, who died in 2016, had had occupational contact with BSE-infected brain tissues, although subsequent investigation did not disclose a laboratory accident (Pocchiari M, Italian Registry of CJD: personal communication). Thus, the last two cases of variant CJD outside the United Kingdom have been associated with potential occupational exposure. Such cases highlight the need for improvements in the prevention of transmission of variant CJD and other prions that can affect humans in the laboratory and neurosurgery settings, as outlined in the Supplementary Appendix.
Jean-Philippe Brandel, M.D. Assistance Publique–Hôpitaux de Paris, Paris, France
M. Bustuchina Vlaicu, M.D. Groupe Hospitalier Nord-Essonne, Orsay, France
Audrey Culeux, B.Sc. INSERM Unité 1127, Paris, France
Maxime Belondrade, M.Sc. Daisy Bougard, Ph.D. Etablissement Français du Sang, Montpellier, France
Katarina Grznarova, Ph.D. Angeline Denouel, M.Sc. INSERM Unité 1127, Paris, France
Isabelle Plu, M.D. Elodie Bouaziz-Amar, Pharm.D., Ph.D. Danielle Seilhean, M.D., Ph.D. Assistance Publique–Hôpitaux de Paris, Paris, France
Michèle Levasseur, M.D. Groupe Hospitalier Nord-Essonne, Orsay, France
Stéphane Haïk, M.D., Ph.D. INSERM Unité 1127, Paris, France stephane.haik@upmc.fr
Supported by a grant (ANR-10-IAIHU-06) from Programme d’Investissements d’Avenir and Santé Publique France.
Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
5 References
July 2, 2020
N Engl J Med 2020; 383:83-85
DOI: 10.1056/NEJMc2000687
Metrics
O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ?
Re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)
snip...see full Singeltary Nature comment here;
Alzheimer's disease
let's not forget the elephant in the room. curing Alzheimer's would be a great and wonderful thing, but for starters, why not start with the obvious, lets prove the cause or causes, and then start to stop that. think iatrogenic, friendly fire, or the pass it forward mode of transmission. think medical, surgical, dental, tissue, blood, related transmission. think transmissible spongiform encephalopathy aka tse prion disease aka mad cow type disease...
Commentary: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Subject: CJD: update for dental staff
Date: November 12, 2006 at 3:25 pm PST
1: Dent Update. 2006 Oct;33(8):454-6, 458-60.
CJD: update for dental staff.
Saturday, March 18, 2023
Autoclave treatment fails to completely inactivate DLB alpha-synuclein seeding activity
WHO tse prp tissue table, dental pulp NOT TESTED
https://cdn.who.int/media/docs/default-source/biologicals/blood-products/document-migration/tablestissueinfectivity.pdf
Low risk 18 (33) Endoscopy, gastrointestinal Screening with or without polypectomy 9 (50) Oral and maxillofacial surgery Dental grafting 4 (22)
Bioassay Studies Support the Potential for Iatrogenic Transmission of Variant Creutzfeldt Jakob Disease through Dental Procedures
Elizabeth Kirby ,Joanne Dickinson ,Matthew Vassey,Mike Dennis,Mark Cornwall,Neil McLeod,Andrew Smith,Philip D. Marsh,James T. Walker,J. Mark Sutton ,Neil D. H. Raven
Published: November 30, 2012
Findings
Challenge via the small intestine gave a transmission rate of 100% (mean incubation 157±17 days). Infectivity was found in both dental pulp and the gingival margin within 3 weeks of challenge and was observed in all tissues tested within the oral cavity before the appearance of clinical symptoms. Following exposure to deliberately contaminated dental files, 97% of mice developed clinical disease (mean incubation 234±33 days).
Interpretation
Infectivity was higher than expected, in a wider range of oral tissues, than was allowed for in previous risk assessments. Disease was transmitted following transient exposure of the gingiva to a contaminated dental file. These observations provide evidence that dental procedures could be a route of cross-infection for vCJD and support the enforcement of single-use for certain dental instruments.
snip...
As a worse case study, the incubation periods described here would be expected to be the most rapid giving rise to prion-disease symptoms in this model, and as a novel low-dose, peripheral model of infection, the incubation periods might be expected to be considerably longer than those observed for blood transfusion cases. Given the difficulties in linking dental procedure case histories to vCJD, such cases may not yet be evident.
Published online 2012 Nov 30. doi: 10.1371/journal.pone.0049850
PMCID: PMC3511499
PMID: 23226225
Bioassay Studies Support the Potential for Iatrogenic Transmission of Variant Creutzfeldt Jakob Disease through Dental Procedures
Elizabeth Kirby,# 1 Joanne Dickinson,# 1 Matthew Vassey, 1 Mike Dennis, 1 Mark Cornwall, 1 Neil McLeod, 1 Andrew Smith, 2 Philip D. Marsh, 1 , 3 James T. Walker, 1 J. Mark Sutton, 1 , * and Neil D. H. Raven 1
Noriyuki Nishida, Editor
Abstract
Background
Evidence is required to quantify the potential risks of transmission of variant Creutzfeldt Jakob (vCJD) through dental procedures. Studies, using animal models relevant to vCJD, were performed to address two questions. Firstly, whether oral tissues could become infectious following dietary exposure to BSE? Secondly, would a vCJD-contaminated dental instrument be able to transmit disease to another patient?
Methods
BSE-301V was used as a clinically relevant model for vCJD. VM-mice were challenged by injection of infected brain homogenate into the small intestine (Q1) or by five minute contact between a deliberately-contaminated dental file and the gingival margin (Q2). Ten tissues were collected from groups of challenged mice at three or four weekly intervals, respectively. Each tissue was pooled, homogenised and bioassayed in indicator mice.
Findings
Challenge via the small intestine gave a transmission rate of 100% (mean incubation 157±17 days). Infectivity was found in both dental pulp and the gingival margin within 3 weeks of challenge and was observed in all tissues tested within the oral cavity before the appearance of clinical symptoms. Following exposure to deliberately contaminated dental files, 97% of mice developed clinical disease (mean incubation 234±33 days).
Interpretation
Infectivity was higher than expected, in a wider range of oral tissues, than was allowed for in previous risk assessments. Disease was transmitted following transient exposure of the gingiva to a contaminated dental file. These observations provide evidence that dental procedures could be a route of cross-infection for vCJD and support the enforcement of single-use for certain dental instruments.
Transmission of the 263K scrapie strain by the dental route Free
Loredana lngrosso1, Flavio Pisani1, Maurizio Pocchiari1
Published: 01 November 1999 https://doi.org/10.1099/0022-1317-80-11-3043
Although these findings may not apply to humans affected by TSEs, they do raise concerns about the possible risk of transmitting these disorders through dental procedures. Particular consideration should be taken in regard to new variant CJD patients because they may harbour more infectivity in peripheral tissues than sporadic CJD patients.
Published: 27 September 2003
Investigation of PrPres in dental tissues in variant CJD
M W Head, D Ritchie, V McLoughlin & J W Ironside British Dental Journal volume 195, pages339–343 (2003)Cite this article
Key Points Previous studies have indicated that dental surgery is not a risk factor for sporadic CJD, but in variant CJD the tissue distribution of infectivity is much wider, raising concerns over transmission via dental surgical instruments.
A range of dental tissues were studied for the presence of the abnormal form of the prion protein, using a combination of immunohistochemistry and a sensitive Western blot assay.
Abnormal prion protein was detected in the trigeminal ganglia, tonsil and lymph nodes in variant CJD but not in sporadic CJDcases. Alveolar nerves, gingiva, dental pulp, tongue and salivary gland tissue were negative in all cases. Lymphoid tissues (including tonsil) were negative in sporadic CJD.
Since the presence of the abnormal form of the prion protein is associated with infectivity, these findings indicate that the highest levels of infectivity in dental tissues are likely to be found in the tonsil and associated lymphoid tissues. This does not exclude the presence of lower levels of infectivity in the negative tissues in our study.
These new findings will be of use to inform the risk assessment on dental tissues and variant CJD.
Abstract Objective To study the distribution of disease-associated prion protein (PrP) in oral and dental tissues in variant CJD.
Design Prospective single centre autopsy based study.
Setting Within the National CJD Surveillance Unit, UK, 2000-2002.
Materials and methods Patients with suspected variant CJD undergoing autopsy where permission to remove tissues for research purposes had been obtained from the relatives. Fixed and frozen autopsy tissues from the brain, trigeminal ganglion, alveolar nerve, dental pulp, gingiva, salivary gland, tongue and tonsils were studied by Western blot, PET blot and immunocytochemistry to detect disease-associated PrP.
Results Disease-associated PrP was only detected in the brain, trigeminal ganglia and tonsils.
Conclusions The failure to detect disease-associated PrP in most dental and oral tissues will help inform ongoing risk assessments for dental surgery in relation to the possible iatrogenic transmission of variant CJD via dental instruments.
Introduction
doi: 10.18502/ijps.v16i1.5385 2021 Jan; 16(1): 106–110.
PMCID: PMC8140296
PMID: 34054989
Creutzfeldt-Jakob Disease after Dental Procedure along with the Initial Manifestations of Psychiatric Disorder: A Case Report
Rahim Badrfam,1 Ahmad Ali Noorbala,2 Zahra Vahabi,3 and Atefeh Zandifar4,*
Introduction: Creutzfeldt-Jakob disease (CJD) as a prion disease is an untreatable type of progressive neurodegenerative encephalopathy. Although no definitive case has been reported yet, here we report a case that given the history, course of symptoms, and recent dental practice, it is highly probable that it was caused by dental procedures.
Case Report: The patient was a 52-year-old woman who has had memory problems gradually with forgetting the names of family members since 6 weeks prior to the visit and shortly after the dental procedure. She experienced progressive visual hallucinations accompanied by a sharp decline in cognitive, verbal, and motor abilities in just a few weeks. Finally, the diagnosis of Creutzfeldt-Jakob was made for her based on the clinical history and typical brain MRI.
Discussion: Clinical evidence of this patient, along with positive brain MRI results, indicates the risk of prion transfer through dental procedures. Paying attention to the neurological aspects of psychiatric manifestations and increasing the awareness of dentists about how to deal with and act on the potential dangers of prion transfer is of paramount importance.
Key Words: Creutzfeldt-Jakob Disease, Dental Procedures, Psychiatric Manifestation
Thursday, November 14, 2013
Prion diseases in humans: Oral and dental implications
SEAC Position Statement On vCJD Transmission Risks In Dentistry
Issue
1. The Department of Health (DH) asked SEAC to advise on the findings of preliminary research aimed at informing estimates of the risk of variant Creutzfeldt-Jakob Disease (vCJD) transmission via dentistry.
Background
2. Prions are more resistant than other types of infectious agent to the conventional cleaning and sterilisation practices used to decontaminate dental instruments1. Appreciable quantities of residual material may remain adherent to the surface after normal cleaning and sterilisation2. Therefore, if dental tissues are both infectious and susceptible to infection, then dental instruments are a potential mechanism for the secondary transmission of vCJD. Dentistry could be a particularly significant route of transmission for the population as a whole, due to the large number of routine procedures undertaken and also because dental patients have a normal life expectancy. This is in contrast with other transmission routes, such as blood transfusion and neurosurgery, where procedures are often carried out in response to some life-threatening condition. Additionally, the ubiquity of dental procedures and the lack of central records on dental procedures means that should such transmission occur, then it would be difficult to detect and control.
3. No cases of vCJD transmission arising from dental procedures have been reported to date 3 . Previous DH risk assessments4,5 have focused on two possible mechanisms for the transfer of vCJD infectivity via dental instruments; accidental abrasion of the lingual tonsil and endodontic procedures that involve contact with dental pulp. In considering these assessments, SEAC agreed that the risk of transmission via accidental abrasion of the lingual tonsil appears very low. However, the risk of transmission via endodontic procedures may be higher and give rise to a self sustaining vCJD epidemic under circumstances where (i) dental pulp is infective, (ii) transmission via endodontic instruments is efficient and (iii) a large proportion of vCJD infections remain in a subclinical carrier state (SEAC 91, February 2006). In light of this, SEAC advised that restricting endodontic files and reamers to single use be considered 6. SEAC recommended reassessment of these issues as new data emerge.
New Research
4. Preliminary, unpublished results of research from the Health Protection Agency, aimed at addressing some of the uncertainties in the risk assessments, were reviewed by SEAC (SEAC 97, May 2007). The prion agent used in these studies is closely related to the vCJD agent. This research, using a mouse model, shows that following inoculation of mouse-adapted bovine spongiform encephalopathy (BSE) directly into the gut, infectivity subsequently becomes widespread in tissues of the oral cavity, including dental pulp, salivary glands and gingiva, during the preclinical as well as clinical stage of disease.
5. It is not known how closely the level and distribution of infectivity in the oral cavity of infected mice reflects those of humans infected with vCJD, as there are no comparable data from oral tissues, in particular dental pulp and gingiva, from human subclinical or clinical vCJD cases7. Although no abnormal prion protein was found in a study of human dental tissues, including dental pulp, salivary glands and gingiva from vCJD cases , the relationship between levels of infectivity and abnormal prion protein is unclear8. Infectivity studies underway using the mouse model and oral tissues that are presently available from human vCJD cases will provide some comparable data. On the basis of what is currently known, there is no reason to suppose that the mouse is not a good model for humans in respect to the distribution of infectivity in oral tissues. Furthermore, the new data are consistent with published results from experiments using a hamster scrapie model9 .
6. A second set of experiments using the same mouse model showed that non-invasive and transient contact between gingival tissue and fine dental files contaminated with mouse-adapted BSE brain homogenate transmits infection very efficiently. It is not known how efficient gingival transmission would be if dental files were contaminated with infectious oral tissues and then subsequently cleaned and sterilised, a situation which would more closely model human dental practice. Further studies using the mouse model that would be more representative of the human situation, comparing oral tissues with a range of doses of infectivity, cleaned and sterilised files and the kind of tissue contact with instruments that occurs during dentistry, should be considered. 7. SEAC considered that the experiments appear well designed and the conclusions justified and reliable, while recognising that the research is incomplete and confirmatory experiments have yet to be completed. It is recommended that the research be completed, submitted for peer-review and widely disseminated as soon as possible so others can consider the implications. Nevertheless, these preliminary data increase the possibility that some oral tissues of humans infected with vCJD may potentially become infective during the preclinical stage of the disease. In addition, they increase the possibility that infection could potentially be transmitted not only via accidental abrasion of the lingual tonsil or endodontic procedures but a variety of routine dental procedures. Implications for transmission risks
8. The new findings help refine assumptions made about the level of infectivity of dental pulp and the stage of incubation period when it becomes infective in the risk assessment of vCJD transmission from the reuse of endodontic files and reamers10. For example, if one patient in 10 000 were to be carrying infection (equivalent to about 6 000 people across the UK the best current estimate11), the data suggest that in the worst case scenario envisaged in the risk assessment, re-use of endodontic files and reamers might lead to up to 150 new infections per annum. It is not known how many of those infected would go on to develop clinical vCJD. In addition, transmission via the re-use of endodontic files and reamers could be sufficiently efficient to cause a self-sustaining vCJD epidemic arising via this route.
9. These results increase the importance of obtaining reliable estimates of vCJD infection prevalence. Data that will soon be available from the National Anonymous Tonsil Archive may help refine this assessment and provide evidence of the existence and extent of subclinical vCJD infection in tonsillectomy patients. Further data, such as from post mortem tissue or blood donations, will be required to assess prevalence in the general UK population12.
10. Recent guidance issued by DH to dentists to ensure that endodontic files and reamers are treated as single use13 is welcomed and should, as long as it is effectively and quickly implemented, prevent transmission and a self-sustaining epidemic arising via this route. However, the extent and monitoring of compliance with this guidance in private and National Health Service dental practice is unclear.
11. The new research also suggests that dental procedures involving contact with other oral tissues, including gingiva, may also be capable of transmitting vCJD. In the absence of a detailed risk assessment examining the potential for transmission via all dental procedures, it is not possible to come to firm conclusions about the implications of these findings for transmission of vCJD. However, given the potential for transmission by this route serious consideration should be given to assessing the options for reducing transmission risks such as improving decontamination procedures and practice or the implementation of single use instruments.
12. The size of the potential risk from interactions between the dental and other routes of secondary transmission, such as blood transfusion and hospital surgery, to increase the likelihood of a self-sustaining epidemic is unclear.
13. It is likely to be difficult to distinguish clinical vCJD cases arising from dietary exposure to BSE from secondary transmissions via dental procedures, should they arise, as a large proportion of the population is likely both to have consumed contaminated meat and undergone dentistry. However, an analysis of dental procedures by patient age may provide an indication of the age group in which infections, if they occur, would be most likely to be observed. Should the incidence of clinical vCJD cases in this age group increase significantly, this may provide an indication that secondary transmission via dentistry is occurring. Investigation of the dental work for these cases may provide supporting data. There is no clear evidence, to date, based on surveillance or investigations of clinical vCJD cases, that any vCJD cases have been caused by dental procedures but this possibility cannot be excluded.
Conclusions
14. Preliminary research findings suggest that the potential risk of transmission of vCJD via dental procedures may be greater than previously anticipated. Although this research is incomplete, uses an animal model exposed to relatively high doses of infectivity, and there are no data from infectivity studies on human oral tissues, these findings suggest an increased possibility that vCJD may be relatively efficiently transmitted via a range of dental procedures. Ongoing infectivity studies using human oral tissues and the other studies suggested here will enable more precise assessment of the risks of vCJD transmission through dental procedures.
15. Guidance was issued to dentists earlier this year recommending that endodontic files and reamers be treated as single use which, provided it is adhered to, will remove any risk of a self-sustaining epidemic arising from re-use of these instruments. To minimise risk it is critical that appropriate management and audit is in place, both for NHS and private dentistry.
16. It is also critical that a detailed and comprehensive assessment of the risks of all dental procedures be conducted as a matter of urgency. While taking into account the continuing scientific uncertainties, this will allow a more thorough consideration of the possible public health implications of vCJD transmission via dentistry and the identification of possible additional precautionary risk reduction measures. The assessment will require continued updating as more evidence becomes available on the transmissibility of vCJD by dental routes, and on the prevalence of infection within the population. A DH proposal to convene an expert group that includes dental professionals to expedite such an assessment is welcomed. Given the potential for transmission via dentistry, consideration should be given to the urgent assessment of new decontamination technologies which, if proved robust and effective, could significantly reduce transmission risks.
SEAC
June 2007
References
1 Smith et al. (2003) Prions and the oral cavity. J. Dent. Res. 82, 769-775.
2 Smith et al. (2005) Residual protein levels on reprocessed dental instruments. J. Hosp. Infect. 61, 237-241.
3 Everington et al. (2007) Dental treatment and risk of variant CJD a case control study. Brit. Den. J. 202, 1-3.
4 Department of Health. (2003) Risk assessment for vCJD and dentistry.
5 Department of Health (2006) Dentistry and vCJD: the implications of a carrier-state for a self-sustaining epidemic. Unpublished.
6 SEAC (2006) Position statement on vCJD and endodontic dentistry. http://www.seac.gov.uk/statements/statement0506.htm
7 Head et al. (2003) Investigation of PrPres in dental tissues in variant CJD. Br. Dent. J. 195, 339-343.
8 SEAC 90 reserved business minutes.
9 Ingrosso et al. (1999) Transmission of the 263K scrapie strain by the dental route. J. Gen. Virol. 80, 3043-3047.
10 Department of Health (2006) Dentistry and vCJD: the implications of a carrier-state for a self-sustaining epidemic. Unpublished.
11 Clarke & Ghani (2005) Projections of future course of the primary vCJD epidemic in the UK: inclusion of subclinical infection and the possibility of wider genetic susceptibility R. J. Soc. Interface. 2, 19-31. 12 SEAC Epidemiology Subgroup (2006) position statement of the vCJD epidemic.
http://www.seac.gov.uk/statements/state260106subgroup.htm 13 DH (2007) Precautionary advice given to dentists on re-use of instruments
http://www.gnn.gov.uk/environment/fullDetail.asp?ReleaseID= 279256&NewsAreaID=2&NavigatedFromDepartment=False
POTENTIAL vCJD TRANSMISSION RISKS VIA DENTISTRY: AN INTERIM REVIEW MAIN TEXT
December 14, 2007
IMPORTANT ADVICE FOR DENTISTS ON RE-USE OF ENDODONTIC INSTRUMENTS AND VARIANT CREUTZFELDT-JAKOB DISEASE (vCJD)
Risk assessment for vCJD and dentistry
Document type: Publication Author: Department of Health. Economics and Operational Research Division Published date: July 2003 Primary audience: Professionals Gateway reference: 2003 Document size: A4 Pages: 27p Electronic only: No Copyright holder: Crown
This report analyses the potential risk of vCJD transmission through re-use of instruments in dental surgery. Based on an existing EOR model for hospital surgery, the analysis considers a wide range of scenarios to allow for multiple uncertainties. It covers procedures carried out in "high street" dental practice, rather than more specialised maxillo-facial surgery.
If patients are recognised as being at heightened risk of infection with any form of CJD, instruments used on them are already subject to special precautions against onward infection, being quarantined and if necessary destroyed. However this analysis concerns potential risks of transmission amongst the generality of patients, where instruments might unknowingly be used on someone incubating vCJD. Two potential transmission routes are considered:
Expert consultation suggested an initial focus on the possibility of transmitting infection through accidental abrasion of an infective patient's lingual tonsils, these being the only relevant oral tissue for which there is direct evidence of vCJD infectivity in humans. Most of this analysis focuses on this topic.
However, vCJD infectivity in other tissues encountered in dentistry - e.g. dental pulp - is implied by some animal models. Though such infectivity has not so far been detected in humans, the possibility cannot be ruled out. Furthermore there is evidence that some instruments used in endodontic surgery - e.g. files and reamers - are particularly difficult to clean, and may carry significant residues of material after washing. We therefore also include some illustrative calculations of the transmission risks that could be posed if this residue were to carry vCJD infectivity. It should be stressed that this part of the analysis is purely hypothetical.
Conclusions Risks to individual patients
On present evidence and advice, the chance of vCJD being transmitted via tonsillar abrasion appears remote. The previous analysis of hospital surgery provides some points of comparison. For example, if similar standards of instrument decontamination are achieved in the two settings:
With assumptions about tissue abrasion as suggested by expert consultation, a single dental procedure on an infective patient would be about 1,000,000,000 times less likely to transmit vCJD than - say - a tonsillectomy. (The latter in turn would be much less likely to do so than a procedure involving the Central Nervous System or the back of the eye.)
Even with very pessimistic assumptions about the chances of tissue abrasion, a differential of about 10,000-fold with tonsillectomy would remain.
If tissues such as dental pulp were to be infective, the risks of transmitting vCJD would obviously increase. However the analysis suggests that even taking a pessimistic scenario, the risks per operation would still be low (at least 10 times lower than for a tonsillectomy).
Risks to public health
Any risk of transmission depends critically on the initial prevalence of the disease and the number of invasive dental procedures. As the former is unknown, a range of scenarios is considered. The number of dental procedures in the UK is very large - estimated at about 75 million annually, including both NHS and private treatment. Of these, around 2 million are endodontic procedures. Even so, any risk to public health posed by dental transmission appears small compared to that for hospital surgery in similar scenarios.
Risk reduction measures
As for hospital surgery, the key consideration in minimising any risk of transmission is assuring the efficacy of instrument decontamination, even though current methods cannot remove such risks completely. In line with existing SEAC advice, potential risks can be further reduced by introduction of more single-use instruments where appropriate, especially of difficult-to-clean items.
Qualification of analysis
Almost all the analysis reported here is subject to two major caveats. The first is that decontamination procedures used in "high street" dentistry are not (in general) significantly less effective than has been assumed here. Though the assumptions used are intended to give fairly conservative estimates for the reductions in infectivity achieved, this continues to be an area of uncertainty. It therefore remains important to monitor actual decontamination practice and encourage its improvement.
Download Risk assessment for vCJD and dentistry July 2003 (PDF, 97K)
Download Risk assessment for vCJD and dentistry July 2003 Annexes (PDF, 204K)
CJD publications
see;
Dentistry and vCJD The implications of a “carrier state” for a self-sustaining epidemic due to endodontic dentistry
Whatever may be the actual case, the risks outlined in this paper could be avoided by making the ‘files and reamers’ used in endodontic dental surgery, single use.
The following professions have been reported in sCJD cases: dentists (n=5), dental surgeon (n=1), neurosurgeons (n=2), pathologist (n=1), internist with training in pathology (n=1) and orthopaedic surgeon who had worked with sheep and human dura mater for industrial purposes (n=1) [12]. The majority of the remaining health professionals were nurses, two of whom had worked in neurosurgery and neurological care. Two other workers had been or were technicians at pathology laboratories.
Subject: CJD: update for dental staff
Date: November 12, 2006 at 3:25 pm PST
1: Dent Update. 2006 Oct;33(8):454-6, 458-60.
CJD: update for dental staff.
least we forget...
*** Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery ***
Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC.
Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them.
2012
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Background
Alzheimer’s disease and Transmissible Spongiform Encephalopathy disease have both been around a long time, and was discovered in or around the same time frame, early 1900’s. Both diseases are incurable and debilitating brain disease, that are in the end, 100% fatal, with the incubation/clinical period of the Alzheimer’s disease being longer (most of the time) than the TSE prion disease. Symptoms are very similar, and pathology is very similar.
Methods
Through years of research, as a layperson, of peer review journals, transmission studies, and observations of loved ones and friends that have died from both Alzheimer’s and the TSE prion disease i.e. Heidenhain Variant Creutzfelt Jakob Disease CJD.
Results
I propose that Alzheimer’s is a TSE disease of low dose, slow, and long incubation disease, and that Alzheimer’s is Transmissible, and is a threat to the public via the many Iatrogenic routes and sources. It was said long ago that the only thing that disputes this, is Alzheimer’s disease transmissibility, or the lack of. The likelihood of many victims of Alzheimer’s disease from the many different Iatrogenic routes and modes of transmission as with the TSE prion disease.
Conclusions
There should be a Global Congressional Science round table event set up immediately to address these concerns from the many potential routes and sources of the TSE prion disease, including Alzheimer’s disease, and a emergency global doctrine put into effect to help combat the spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and blood arena’s. All human and animal TSE prion disease, including Alzheimer’s should be made reportable in every state, and Internationally, WITH NO age restrictions. Until a proven method of decontamination and autoclaving is proven, and put forth in use universally, in all hospitals and medical, surgical arena’s, or the TSE prion agent will continue to spread. IF we wait until science and corporate politicians wait until politics lets science _prove_ this once and for all, and set forth regulations there from, we will all be exposed to the TSE Prion agents, if that has not happened already.
end...tss
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
source references ...end...tss
Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease
*** Singeltary comment PLoS ***
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
IN CONFIDENCE
5 NOVEMBER 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication.
There are also results to be made available shortly
(1) concerning a farmer with CJD who had BSE animals,
(2) on the possible transmissibility of Alzheimer’s and
(3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]
TUESDAY, FEBRUARY 22, 2022
Aged Cattle Brain Displays Alzheimer's Disease-Like Pathology and Promotes Brain Amyloidosis in a Transgenic Animal Model
Terry S. Singeltary Sr.
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