Transmission of Cerebral ß-Amyloidosis Among Individuals.

Deposition of amyloid ß protein (Aß) in the brain (cerebral ß-amyloidosis) is a hallmark of Alzheimer's disease (AD). So far, there have been increasing number of experimental studies using AD mouse model that cerebral ß-amyloidosis could be transmitted among individuals as prion-like mechanism. Furthermore, several pathological studies using autopsied patients with iatrogenic Creutzfeldt-Jakob disease (CJD) showed that cerebral ß-amyloidosis in addition to the CJD pathology could be transmitted among humans via medical procedures, such as human growth hormone derived from cadaver injection and cadaveric dura mater graft. In addition, although cerebral amyloid angiopathy (CAA), which is Aß deposition in the cerebral vessels, related cerebral hemorrhage rarely develops in young people, several patients with CAA-related cerebral hemorrhage under the age of 55 with histories of neurosurgeries with and without dura mater graft in early childhood have been reported. These patients might show that Aß pathology is often recognized as Aß-CAA rather than parenchymal Aß deposition in the transmission of cerebral ß-amyloidosis in humans, and we proposed an emerging concept, "acquired CAA". Considering that there have been several patients with acquired CAA with an incubation period from neurosurgery and the onset of CAA related cerebral hemorrhage of longer than 40 years, the number of cases is likely to increase in the future, and detailed epidemiological investigation is required. It is necessary to continue to elucidate the pathomechanisms of acquired CAA and urgently establish a method for preventing the transmission of cerebral ß-amyloidosis among individuals.

Prion strains associated with iatrogenic CJD in French and UK human growth hormone recipients.

Treatment with human pituitary-derived growth hormone (hGH) was responsible for a significant proportion of iatrogenic Creutzfeldt-Jakob disease (iCJD) cases. France and the UK experienced the largest case numbers of hGH-iCJD, with 122 and 81 cases respectively. Differences in the frequency of the three PRNP codon 129 polymorphisms (MM, MV and VV) and the estimated incubation periods associated with each of these genotypes in the French and the UK hGH-iCJD cohorts led to the suggestion that the prion strains responsible for these two hGH-iCJD cohorts were different. In this study, we characterized the prion strains responsible for hGH-iCJD cases originating from UK (n = 11) and France (n = 11) using human PrP expressing mouse models. The cases included PRNP MM, MV and VV genotypes from both countries. UK and French sporadic CJD (sCJD) cases were included as controls. The prion strains identified following inoculation with hGH-iCJD homogenates corresponded to the two most frequently observed sCJD prion strains (M1CJD and V2CJD). However, in clear contradiction to the initial hypothesis, the prion strains that were identified in the UK and the French hGH-iCJD cases were not radically different. In the vast majority of the cases originating from both countries, the V2CJD strain or a mixture of M1CJD + V2CJD strains were identified. These data strongly support the contention that the differences in the epidemiological and genetic profiles observed in the UK and France hGH-iCJD cohorts cannot be attributed only to the transmission of different prion strains.

Potential for transmission of sporadic Creutzfeldt-Jakob disease through peripheral routes.

Five sporadic Creutzfeldt-Jakob disease (CJD) strains have been identified to date, based on differences in clinicopathological features of the patients, the biochemical properties of abnormal prion proteins, and transmission properties. Recent advances in our knowledge about iatrogenic transmission of sporadic CJD have raised the possibility that the infectivity of sporadic CJD strains through peripheral routes is different from that of intracranial infection. To test this possibility, here we assessed systematically the infectivity of sporadic CJD strains through the peripheral route for the first time using a mouse model expressing human prion protein. Although the infectivity of the V2 and M1 sporadic CJD strains is almost the same in intracerebral transmission studies, the V2 strain infected more efficiently than the M1 strain through the peripheral route. The other sporadic CJD strains examined lacked infectivity. Of note, both the V2 and M1 strains showed preference for mice with the valine homozygosity at the PRNP polymorphic codon. These results indicate that the V2 strain is the most infectious sporadic CJD strain for infection through peripheral routes. In addition, these findings raise the possibility that individuals with the valine homozygosity at the PRNP polymorphic codon might have higher risks of infection through peripheral routes compared with the methionine homozygotes. Thus, preventive measures against the transmission of the V2 sporadic CJD strain will be important for the eradication of iatrogenic CJD transmission through peripheral routes.

Wide distribution of prion infectivity in the peripheral tissues of vCJD and sCJD patients.

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.

Application of telehealth for comprehensive Creutzfeldt-Jakob disease surveillance in the United Kingdom.

Creutzfeldt-Jakob disease (CJD) is a fatal human prion disease. Surveillance systems operate globally with the goals of accurate in-life case ascertainment, appropriate public health interventions to minimise secondary transmission, and monitoring trends in disease epidemiology. The UK experienced the highest incidence of variant CJD (vCJD) in the world following widespread population exposure to bovine spongiform encephalopathy (BSE). 178 cases of vCJD have been identified in the UK by the National CJD Research & Surveillance Unit (NCJDRSU), including three cases of secondary transmission via blood transfusion. The NCJDRSU performs high-fidelity surveillance, assessing all cases of suspected CJD referred to the unit. COVID-19 has caused widespread disruption to healthcare and poses a threat to services. The NCJDRSU converted to telehealth-based surveillance in March 2020. We report the results of the application of telehealth for comprehensive CJD surveillance during the first four months of the pandemic. 59 cases were assessed for suspected CJD. In 52 cases the relatives were interviewed for an informant history, by video conference or telephone call. 34 patients underwent video examination; 1 case was examined in-person. MRI images were assessed in all cases and 46 underwent CSF testing. Feedback was obtained from interviewees and the NCJDRSU team on their experiences. 50 cases were diagnosed with sporadic CJD; 5 received an alternative diagnosis, and the remaining 4 remained unresolved, with further investigations underway. Telehealth significantly reduced time taken to assessment compared to in-person assessments in 2019. Telehealth is an effective way to provide comprehensive CJD surveillance at a national level.

Potential human transmission of amyloid ß pathology: surveillance and risks.

Studies in experimental animals show transmissibility of amyloidogenic proteins associated with prion diseases, Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Although these data raise potential concerns for public health, convincing evidence for human iatrogenic transmission only exists for prions and amyloid ß after systemic injections of contaminated growth hormone extracts or dura mater grafts derived from cadavers. Even though these procedures are now obsolete, some reports raise the possibility of iatrogenic transmission of amyloid ß through putatively contaminated neurosurgical equipment. Iatrogenic transmission of amyloid ß might lead to amyloid deposition in the brain parenchyma and blood vessel walls, potentially resulting in cerebral amyloid angiopathy after several decades. Cerebral amyloid angiopathy can cause life-threatening brain haemorrhages; yet, there is no proof that the transmission of amyloid ß can also lead to Alzheimer's dementia. Large, long-term epidemiological studies and sensitive, cost-efficient tools to detect amyloid are needed to better understand any potential routes of amyloid ß transmission and to clarify whether other similar proteopathic seeds, such as tau or α-synuclein, can also be transferred iatrogenically.

Prions from Sporadic Creutzfeldt-Jakob Disease Patients Propagate as Strain Mixtures.

Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently classified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K-digested abnormal prion protein (PrPres) isoform identified by Western blotting (type 1 or type 2). Converging evidence led to the view that MM/MV1, VV/MV2, and VV1 and MM2 sCJD cases are caused by distinct prion strains. However, in a significant proportion of sCJD patients, both type 1 and type 2 PrPres were reported to accumulate in the brain, which raised questions about the diversity of sCJD prion strains and the coexistence of two prion strains in the same patient. In this study, a panel of sCJD brain isolates (n = 29) that displayed either a single or mixed type 1/type 2 PrPres were transmitted into human-PrP-expressing mice (tgHu). These bioassays demonstrated that two distinct prion strains (M1CJD and V2CJD) were associated with the development of sCJD in MM1/MV1 and VV2/MV2 patients. However, in about 35% of the investigated VV and MV cases, transmission results were consistent with the presence of both M1CJD and V2CJD strains, including in patients who displayed a "pure" type 1 or type 2 PrPres The use of a highly sensitive prion in vitro amplification technique that specifically probes the V2CJD strain revealed the presence of the V2CJD prion in more than 80% of the investigated isolates, including isolates that propagated as a pure M1CJD strain in tgHu. These results demonstrate that at least two sCJD prion strains can be present in a single patient.IMPORTANCE sCJD occurrence is currently assumed to result from spontaneous and stochastic formation of a misfolded PrP nucleus in the brains of affected patients. This original nucleus then recruits and converts nascent PrPC into PrPSc, leading to the propagation of prions in the patient's brain. Our study demonstrates the coexistence of two prion strains in the brains of a majority of the 23 sCJD patients investigated. The relative proportion of these sCJD strains varied both between patients and between brain areas in a single patient. These findings strongly support the view that the replication of an sCJD prion strain in the brain of a patient can result in the propagation of different prion strain subpopulations. Beyond its conceptual importance for our understanding of prion strain properties and evolution, the sCJD strain mixture phenomenon and its frequency among patients have important implications for the development of therapeutic strategies for prion diseases.

Transmission characteristics of heterozygous cases of Creutzfeldt-Jakob disease with variable abnormal prion protein allotypes.

In the human prion disease Creutzfeldt-Jakob disease (CJD), different CJD neuropathological subtypes are defined by the presence in normal prion protein (PrPC) of a methionine or valine at residue 129, by the molecular mass of the infectious prion protein PrPSc, by the pattern of PrPSc deposition, and by the distribution of spongiform change in the brain. Heterozygous cases of CJD potentially add another layer of complexity to defining CJD subtypes since PrPSc can have either a methionine (PrPSc-M129) or valine (PrPSc-V129) at residue 129. We have recently demonstrated that the relative amount of PrPSc-M129 versus PrPSc-V129, i.e. the PrPSc allotype ratio, varies between heterozygous CJD cases. In order to determine if differences in PrPSc allotype correlated with different disease phenotypes, we have inoculated 10 cases of heterozygous CJD (7 sporadic and 3 iatrogenic) into two transgenic mouse lines overexpressing PrPC with a methionine at codon 129. In one case, brain-region specific differences in PrPSc allotype appeared to correlate with differences in prion disease transmission and phenotype. In the other 9 cases inoculated, the presence of PrPSc-V129 was associated with plaque formation but differences in PrPSc allotype did not consistently correlate with disease incubation time or neuropathology. Thus, while the PrPSc allotype ratio may contribute to diverse prion phenotypes within a single brain, it does not appear to be a primary determinative factor of disease phenotype.

Transmission of CJD from nasal brushings but not spinal fluid or RT-QuIC product.

OBJECTIVE: The detection of prion seeding activity in CSF and olfactory mucosal brushings using real-time quaking-induced conversion assays allows highly accurate clinical diagnosis of sporadic Creutzfeldt-Jakob disease. To gauge transmission risks associated with these biospecimens and their testing, we have bioassayed prion infectivity levels in patients' brain tissue, nasal brushings, and CSF, and assessed the pathogenicity of amplified products of real-time quaking-induced conversion assays seeded with Creutzfeldt-Jakob disease prions. METHODS: We obtained olfactory mucosal brushings and CSF from patients with a final diagnosis of sporadic Creutzfeldt-Jakob disease subtype MM1 (n = 3). Samples were inoculated intracerebrally into Tg66 transgenic mice that overexpress the homologous human 129M prion protein. The mice were evaluated for clinical, neuropathological, and biochemical evidence of prion infection. RESULTS: Patients' brain tissue at 102 to 105 fold dilutions affected 47/48 Tg66 mice. In contrast, maximum acutely tolerable doses of insoluble pellets from their olfactory mucosa brushings caused evidence of prion disease in only 4/28 inoculated mice, and no effects were seen with 10-fold dilutions. No clinical prion disease was observed in mice inoculated with antemortem CSF samples or prion-seeded real-time quaking-induced conversion assay products. INTERPRETATION: Pellets from patients' olfactory mucosa brushings had ≥10,000-fold lower infectivity per unit volume than brain tissue, while CSF lacked detectable infectivity. Nonetheless, the results suggest that appropriate precautions may be warranted in surgical interventions involving the olfactory areas. The lack of pathogenic infectivity in the real-time quaking-induced conversion assay products provides evidence that the assay does not replicate biohazardous prions in vitro.

No evidence of transfusion transmitted sporadic Creutzfeldt-Jakob disease: results from a bi-national cohort study.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is an uncommon, invariably fatal, neurodegenerative disorder that presents as progressive dementia with concurrent motor symptoms and myoclonia. The pathophysiology involves prion protein misfolding and spreading in a self-catalyzed manner. It has been shown to be transmissible through tissue transplants. Variant CJD (vCJD), a subtype of the disease is also transmissible through transfusion of blood products. This study aims to corroborate the scarce data that suggest that sporadic CJD (sCJD) is not transmitted via blood transfusion. METHODS AND STUDY DESIGN: A retrospective cohort study was performed, using data from the bi-national Scandinavian Donations and Transfusions (SCANDAT2) database containing data on blood donors, donations, transfusions, and transfused patients in Sweden and Denmark since 1968 and 1982, respectively. Mortality and medical data were collected from nationwide health care and population registries. Donors with subsequent CJD were identified, as well as recipients of blood products from these donors. A second analysis was performed, screening for clustering of CJD cases from donors without a CJD diagnosis. RESULTS: We identified 39 donors with a subsequent diagnosis of sCJD. No cases of CJD occurred among the 883 recipients of blood products from these donors. A total of 89 CJD cases were identified among recipients of transfusions. No clustering of cases from the same donor occurred. DISCUSSION: Using data from a large, bi-national database of transfused patients, we find no evidence of sCJD transmission. Our data adds to the growing body of evidence indicating that sCJD is not transfusion transmitted.

Interventions to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease: a cost-effective modelling review.

BACKGROUND: Creutzfeldt-Jakob disease is a fatal neurological disease caused by abnormal infectious proteins called prions. Prions that are present on surgical instruments cannot be completely deactivated; therefore, patients who are subsequently operated on using these instruments may become infected. This can result in surgically transmitted Creutzfeldt-Jakob disease. OBJECTIVE: To update literature reviews, consultation with experts and economic modelling published in 2006, and to provide the cost-effectiveness of strategies to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease. METHODS: Eight systematic reviews were undertaken for clinical parameters. One review of cost-effectiveness was undertaken. Electronic databases including MEDLINE and EMBASE were searched from 2005 to 2017. Expert elicitation sessions were undertaken. An advisory committee, convened by the National Institute for Health and Care Excellence to produce guidance, provided an additional source of information. A mathematical model was updated focusing on brain and posterior eye surgery and neuroendoscopy. The model simulated both patients and instrument sets. Assuming that there were potentially 15 cases of surgically transmitted Creutzfeldt-Jakob disease between 2005 and 2018, approximate Bayesian computation was used to obtain samples from the posterior distribution of the model parameters to generate results. Heuristics were used to improve computational efficiency. The modelling conformed to the National Institute for Health and Care Excellence reference case. The strategies evaluated included neither keeping instruments moist nor prohibiting set migration; ensuring that instruments were kept moist; prohibiting instrument migration between sets; and employing single-use instruments. Threshold analyses were undertaken to establish prices at which single-use sets or completely effective decontamination solutions would be cost-effective. RESULTS: A total of 169 papers were identified for the clinical review. The evidence from published literature was not deemed sufficiently strong to take precedence over the distributions obtained from expert elicitation. Forty-eight papers were identified in the review of cost-effectiveness. The previous modelling structure was revised to add the possibility of misclassifying surgically transmitted Creutzfeldt-Jakob disease as another neurodegenerative disease, and assuming that all patients were susceptible to infection. Keeping instruments moist was estimated to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease cases and associated costs. Based on probabilistic sensitivity analyses, keeping instruments moist was estimated to on average result in 2.36 (range 0-47) surgically transmitted Creutzfeldt-Jakob disease cases (across England) caused by infection occurring between 2019 and 2023. Prohibiting set migration or employing single-use instruments reduced the estimated risk of surgically transmitted Creutzfeldt-Jakob disease cases further, but at considerable cost. The estimated costs per quality-adjusted life-year gained of these strategies in addition to keeping instruments moist were in excess of £1M. It was estimated that single-use instrument sets (currently £350-500) or completely effective cleaning solutions would need to cost approximately £12 per patient to be cost-effective using a £30,000 per quality-adjusted life-year gained value. LIMITATIONS: As no direct published evidence to implicate surgery as a cause of Creutzfeldt-Jakob disease has been found since 2005, the estimations of potential cases from elicitation are still speculative. A particular source of uncertainty was in the number of potential surgically transmitted Creutzfeldt-Jakob disease cases that may have occurred between 2005 and 2018. CONCLUSIONS: Keeping instruments moist is estimated to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease cases and associated costs. Further surgical management strategies can reduce the risks of surgically transmitted Creutzfeldt-Jakob disease but have considerable associated costs. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017071807. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 11. See the NIHR Journals Library website for further project information.

The aims of this report were to summarise evidence relating to surgically transmitted Creutzfeldt­Jakob disease and to explore the value for money of strategies to reduce the chance of any future surgically transmitted Creutzfeldt­Jakob disease cases. Current recommendations include keeping sets of surgical instruments together for high-risk operations and using separate instruments for people born after 1996. The project involved reviewing published papers, speaking with experts and building a computer model. The literature reviews found that Creutzfeldt­Jakob disease occurs in around 1­2 per million people and that no definite cases of surgically transmitted Creutzfeldt­Jakob disease have been observed since the 1970s. The reviews also looked for information on the possibility of patients being infected with Creutzfeldt­Jakob disease after having surgery on high-risk tissues, such as the brain and the back of the eye. They found that there was a great deal of uncertainty regarding who might have Creutzfeldt­Jakob disease, but not yet have symptoms, as well as the risk of transmission and the ability of strategies to reduce this risk. The computer model aimed to estimate value for money of different strategies to reduce the risks of surgically transmitted Creutzfeldt­Jakob disease. However, the reviews found that some of the numbers needed for the model were not known, so experts were asked to estimate this information instead along with the range of possible values. This information included the effectiveness of different cleaning practices and the chances of infected tissue being transmitted between patients undergoing high-risk surgery. The model found that keeping surgical instruments moist prior to cleaning was likely to save money and reduce the chance of future surgically transmitted Creutzfeldt­Jakob disease cases. However, additional measures, such as using only sets of single-use instruments, ensuring that instruments were kept together in their sets or using separate instruments for those born after 1996, appeared to be poor value for money.

Informing patient contacts about iatrogenic Creutzfeldt-Jakob disease.

The unanticipated diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) in a patient after previous neurosurgery can lead to difficult decisions regarding informing contacts. A patient developed sCJD 3 years after neurosurgery. There were 29 potential contacts and 26 were contacted. Twelve completed a questionnaire. The majority of patients wished to know about the contact and to be seen face-to-face, and their main concern was developing the disease despite verbal and written reassurance that this was unlikely. Informing patients of sCJD contact is difficult and can lead to significant patient anxiety. Face-to-face meetings, a helpline and follow-up can help.

Prion disease and recommended procedures for flexible endoscope reprocessing - a review of policies worldwide and proposal for a simplified approach.

Several guidelines recommend specific treatments for endoscopes, procedures of quarantine for endoscopes, or additional treatments for the endoscope washer disinfector (EWD) in suspected or confirmed cases of Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD) but vary in many details. This study therefore reviewed guidelines on reprocessing flexible endoscopes after use in patients with suspected or confirmed prion disease. In addition, a literature search was performed in Medline on prion, CJD, vCJD, chemical inactivation, transmission healthcare, epidemiology healthcare, concentration tissue human and endoscope. Thus far, no case of CJD or vCJD transmitted by flexible endoscope has been reported. In animals it has been shown that oral uptake of 0.1-5 g of bovine spongiform encephalopathy (BSE)-infected brain homogenate is necessary for transmission. The maximum prion concentration in other tissues (e.g., terminal ileum) is at least 100-fold lower. Automated cleaning of endoscopes alone results in very low total residual protein ≤5.6 mg per duodenoscopes. Recommendations vary between countries, sometimes with additional cleaning, use of alkaline cleaners, no use of cleaners with fixative properties, use of disinfectants without fixative properties or single-use disinfectants. Sodium hydroxide (1 M) and sodium hypochlorite (10,000 and 25,000 mg/L) are very effective in preventing transmission via contaminated wires implanted into animal brains, but their relevance for endoscopes is questionable. Based on circumstantial evidence, it is proposed to consider validated reprocessing as appropriate in the case of delayed suspected prion disease when immediate bedside cleaning, routine use of alkaline cleaners, no fixative agents anywhere prior to disinfection and single use brushes and cleaning solutions can be assured.

Creutzfeldt-Jakob disease: a systematic review of global incidence, prevalence, infectivity, and incubation.

Creutzfeldt-Jakob disease (CJD) is a fatal disease presenting with rapidly progressive dementia, and most patients die within a year of clinical onset. CJD poses a potential risk of iatrogenic transmission, as it can incubate asymptomatically in humans for decades before becoming clinically apparent. In this Review, we sought evidence to understand the current iatrogenic risk of CJD to public health by examining global evidence on all forms of CJD, including clinical incidence and prevalence of subclinical disease. We found that although CJD, particularly iatrogenic CJD, is rare, the incidence of sporadic CJD is increasing. Incubation periods as long as 40 years have been observed, and all genotypes have now been shown to be susceptible to CJD. Clinicians and surveillance programmes should maintain awareness of CJD to mitigate future incidences of its transmission. Awareness is particularly relevant for sporadic CJD, which occurs in older people in whom clinical presentation could resemble rapidly developing dementia.

Sporadic Creutzfeldt-Jakob disease prion infection of human cerebral organoids.

For the transmissible, neurogenerative family of prion diseases, few human models of infection exist and none represent structured neuronal tissue. Human cerebral organoids are self-organizing, three-dimensional brain tissues that can be grown from induced pluripotent stem cells. Organoids can model aspects of neurodegeneration in Alzheimer's Disease and Down's Syndrome, reproducing tau hyperphosphorylation and amyloid plaque pathology. To determine whether organoids could be used to reproduce human prion infection and pathogenesis, we inoculated organoids with two sporadic Creutzfeldt-Jakob Disease prion subtypes. Organoids showed uptake, followed by clearance, of the infectious inoculum. Subsequent re-emergence of prion self-seeding activity indicated de novo propagation. Organoid health assays, prion titer, prion protein electrophoretic mobility and immunohistochemistry demonstrated inoculum-specific differences. Our study shows, for the first time, that cerebral organoids can model aspects of human prion disease and thus offer a powerful system for investigating different human prion subtype pathologies and testing putative therapeutics.