''The clinical syndrome developed by these individuals can, therefore, be termed iatrogenic Alzheimer’s disease, and Alzheimer’s disease should now be recognized as a potentially transmissible disorder.''
Published: 29 January 2024
Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone
Gargi Banerjee, Simon F. Farmer, Harpreet Hyare, Zane Jaunmuktane, Simon Mead, Natalie S. Ryan, Jonathan M. Schott, David J. Werring, Peter Rudge & John Collinge Nature Medicine (2024)Cite this article
Abstract
Alzheimer’s disease (AD) is characterized pathologically by amyloid-beta (Aβ) deposition in brain parenchyma and blood vessels (as cerebral amyloid angiopathy (CAA)) and by neurofibrillary tangles of hyperphosphorylated tau. Compelling genetic and biomarker evidence supports Aβ as the root cause of AD. We previously reported human transmission of Aβ pathology and CAA in relatively young adults who had died of iatrogenic Creutzfeldt–Jakob disease (iCJD) after childhood treatment with cadaver-derived pituitary growth hormone (c-hGH) contaminated with both CJD prions and Aβ seeds. This raised the possibility that c-hGH recipients who did not die from iCJD may eventually develop AD. Here we describe recipients who developed dementia and biomarker changes within the phenotypic spectrum of AD, suggesting that AD, like CJD, has environmentally acquired (iatrogenic) forms as well as late-onset sporadic and early-onset inherited forms. Although iatrogenic AD may be rare, and there is no suggestion that Aβ can be transmitted between individuals in activities of daily life, its recognition emphasizes the need to review measures to prevent accidental transmissions via other medical and surgical procedures. As propagating Aβ assemblies may exhibit structural diversity akin to conventional prions, it is possible that therapeutic strategies targeting disease-related assemblies may lead to selection of minor components and development of resistance.
Main
Mammalian prions are protein-only infectious agents that cause fatal neurodegenerative diseases1. They comprise assemblies of misfolded host-encoded cellular prion protein (PrPC)-forming amyloid fibrils that propagate by elongation and fission1,2. Prions exist as diverse strains enciphered by variation in fibril structure that cause distinct clinicopathological disease phenotypes2. Although prion diseases are transmissible conditions, the large majority of human prion disease actually occurs as a late-onset sporadic condition, sporadic Creutzfeldt–Jakob disease (CJD), and almost all other cases result from autosomal dominant coding mutations in the prion protein gene (PRNP), causing the inherited prion diseases. Acquired or iatrogenic CJD is rare, currently accounting for approximately 1% of recognized cases. Iatrogenic CJD arises from accidental inoculation with prions during medical or surgical procedures. These include former use of human cadaveric pituitary-derived growth hormone or gonadotrophin, dura mater and corneal grafting and via contaminated neurosurgical instruments. An epidemic human prion disease, kuru, occurred in Papua New Guinea and was transmitted by ingestion of human tissue at mortuary feasts as a mark of mourning and respect. Since the cessation of this practice in the late 1950s, kuru gradually disappeared but enabled documentation of the range of incubation periods of human prion infection; the mean incubation period is approximately 12 years but can exceed 50 years3. There is also worldwide genetic evidence for prehistoric human prion disease epidemics4. A novel human acquired prion disease, variant CJD, arose in the 1990s, following dietary exposure to the zoonotic prion disease of cattle, bovine spongiform encephalopathy (BSE)5,6.
The far wider relevance of prion mechanisms was first exemplified with the discovery of yeast prions7 but has also widened considerably with the recognition that the more common human neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases8, involve accumulation and spread of assemblies of misfolded host proteins in what is often described as a ‘prion-like’ fashion with experimental transmission of relevant pathology in primates9 or mouse models10. However, the importance for human disease was unclear until the recognition of human transmission of amyloid-beta (Aβ) pathology via iatrogenic routes after prolonged incubation periods, causing iatrogenic cerebral amyloid angiopathy (CAA) and raising the possibility that iatrogenic Alzheimer’s disease may occur at even longer latency11,12.
Between 1959 and 1985, at least 1,848 patients in the United Kingdom were treated with human cadaveric pituitary-derived growth hormone (c-hGH)13. Worldwide, over 200 cases of iatrogenic CJD have occurred as a consequence of childhood treatment with c-hGH14, with 80 cases recorded in the United Kingdom15. We first reported human-to-human transmission of Aβ pathology in people who had received c-hGH in childhood and died of iatrogenic CJD11; we later demonstrated that some of the archived batches of c-hGH used to treat these people contained measurable quantities of Aβ (and tau) and that this historical material still contained Aβ seeding activity able to transmit pathology to mice12. These experiments provided clear evidence that iatrogenic Aβ transmission had occurred in people treated with c-hGH. Multiple postmortem reports of iatrogenic Aβ transmission caused by c-hGH16,17,18 (and also via other routes16,19,20,21,22,23,24) were subsequently made by others.
The Aβ peptide is implicated in Alzheimer’s disease and is found in the form of parenchymal deposits, including neuritic plaques, and parenchymal and leptomeningeal vascular aggregation, corresponding to CAA. CAA is seen as a co-pathology in the large majority of people with Alzheimer’s disease and can also independently present with intracerebral hemorrhage25. There are now a number of clinical descriptions of iatrogenic CAA in people who developed symptoms during life26, typically due to brain hemorrhage. All affected individuals had prior exposure to cadaveric dura mater or had childhood neurosurgical procedures, both of which are recognized routes for prion transmission causing iatrogenic CJD27. However, until now, there have been, to our knowledge, no clinical (that is, premortem) descriptions of iatrogenic disease caused by Aβ transmission in c-hGH recipients, despite the substantial experimental evidence for transmission via this route.
Further new clinical presentations in c-hGH recipients The National Prion Clinic (NPC) forms part of the United Kingdom national referral system for suspected prion diseases and coordinates the National Prion Monitoring Cohort (NPMC), a longitudinal study of individuals with confirmed prion diseases (sporadic, inherited, iatrogenic or variant forms) and those at risk of inherited, iatrogenic or variant CJD28, including people previously treated with c-hGH29.
Since our earlier report of iatrogenic CAA in this cohort, eight further individuals with a history of treatment with c-hGH were referred to, or reviewed by, the NPC between 2017 and 2022. All individuals had received c-hGH prepared using the Wilhelmi or Hartree-modified Wilhelmi preparation (abbreviated here as HWP) method (Table 1), the preparation that has been implicated in all cases of iatrogenic CJD in the United Kingdom13,29. We previously reported12 values of Aβ-40, Aβ-42 and tau in HWP batches received by four of the individuals we report here (HWP 40, HWP 42, HWP 43, HWP 47 and HWP 51, received by cases 1, 5, 6 and 7) and demonstrated Aβ transmission in mice from two batches (HWP 42 and HWP 51) received by three of these individuals (cases 1, 5 and 7); these batches also resulted in Aβ transmission in certain patients in our previous description of patients who died of iatrogenic CJD11,12. The diagnosis of iatrogenic CJD was excluded in all eight individuals on the basis of clinical presentation, neuroimaging and biomarkers and, in two cases, by postmortem examination. Clinical descriptions of all cases are provided in the Supplementary Information. https://www.nature.com/articles/s41591-023-02729-2#MOESM1
Five of these eight c-hGH recipients (Table 2; cases 2, 3, 4, 5 and 8) were referred with symptoms consistent with early-onset dementia, with progressive cognitive impairment in two or more domains severe enough to affect the performance of usual activities of daily living; in some cases, progression was rapid (Supplementary Information). Symptom onset was between the ages of 38 years and 49 years in four patients (cases 3, 4, 5 and 8) and at age 55 years in the remaining patient (case 2). In three of these five patients (cases 3, 4 and 8), a diagnosis of Alzheimer’s disease had been made before referral to the NPC; two individuals presented with typical amnestic symptoms (cases 4 and 8) and met National Institute on Aging and Alzheimer’s Association (NIA-AA) diagnostic criteria30 for probable Alzheimer’s disease, and the other individual (case 3) presented with with non-amnestic (language) symptoms. The remaining two patients met NIA-AA diagnostic criteria30 for probable Alzheimer’s disease with non-amnestic presentations (dysexecutive (case 2) and language (case 5)). All five cases would meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V) criteria for major neurocognitive disorder due to Alzheimer’s disease31. Of the remaining three individuals, one had symptoms (onset aged 42 years; case 1) meeting NIA-AA criteria for mild cognitive impairment32 (predominantly affecting behavior and personality); one had subjective cognitive symptoms only (case 7); the other was asymptomatic (case 6). For those with symptoms, the latency from c-hGH exposure was three to four decades (Table 2).
snip…
We hypothesize that iatrogenic Aβ amyloidosis caused by c-hGH can result in a different clinical phenotype (possibly mediated by Aβ strain type), in which clinical CAA is less prominent (although CAA may be present pathologically, as in sporadic Alzheimer’s disease). Additionally, it is entirely possible that some iatrogenic cases of Alzheimer’s disease may differ markedly from sporadic and inherited forms in both clinical and neuropathological features; the full spectrum of dementias caused by Aβ transmission remains to be elucidated.
Snip…
Discussion Although Alzheimer’s disease arises predominantly as a sporadic condition of late adult life, there are rarer early-onset Mendelian forms caused by mutations in the APP gene or in genes (PSEN1 and PSEN2) known to alter its enzymatic cleavage. We now provide evidence that Alzheimer’s disease is also transmissible in certain circumstances and, therefore, that Alzheimer’s disease (like Aβ-CAA) has the full triad of etiologies (sporadic, inherited and rare acquired forms) characteristic of conventional prion diseases. This should further emphasize that the principles of prion biology have relevance for other neurodegenerative diseases involving the accumulation of diverse assemblies of misfolded host proteins, which may have propagating and neurotoxic forms1,68. Our cases suggest that, similarly to what is observed in human prion diseases, iatrogenic forms of Alzheimer’s disease differ phenotypically from sporadic and inherited forms, with some individuals remaining asymptomatic despite exposure to Aβ seeds due to protective factors that, at present, are unknown.
Our previous report of transmission of Aβ pathology, causing the disease iatrogenic CAA, led to international meetings to consider public health risk assessment and risk management69,70. It is important to emphasize that the cases described here developed symptoms after repeated exposure to contaminated c-hGH, over a period of years, and that treatment with c-hGH was discontinued many years ago (in the United Kingdom, in 1985); there is no evidence that Aβ can be transmitted in other contexts—for example, during activities of daily life or provision of routine care. The individuals whom we previously reported with iatrogenic CAA had died from iatrogenic CJD after exposure to c-hGH contaminated with both CJD prions and Aβ seeds (and also tau). Given the far higher population prevalence of Alzheimer’s pathology than CJD, it is expected that c-hGH batches, prepared from very large pools of cadaveric pituitary glands, will be much more frequently contaminated by Aβ seeds than CJD prions. Consequently, we considered the possibility that some c-hGH-exposed individuals who did not develop CJD might progress to develop the full pathological features of Alzheimer’s disease at even longer incubation periods than those we described for iatrogenic CAA. The symptomatic cases that we report here are consistent with that conclusion and should prompt both further consideration of public health implications and the primary prevention of iatrogenic Alzheimer’s disease—for example, by ensuring effective decontamination of surgical instruments. Additionally, the extent to which prion-like mechanisms are involved in Alzheimer’s pathogenesis may have important bearings on therapeutic strategies targeting disease-related Aβ assemblies if these exist as quasispecies and show strain diversity and propagation kinetics akin to conventional prions with a diversity of propagating and/or neurotoxic conformers1,65,68,71,72,73. Structurally diverse conformers, present as minor components, may be selected for propagation by a drug that binds to the dominant species, potentially leading to the development of resistance.
Snip…
The clinical syndrome developed by these individuals can, therefore, be termed iatrogenic Alzheimer’s disease, and Alzheimer’s disease should now be recognized as a potentially transmissible disorder.
Snip…see full text;
Singeltary Reply
Published: 09 September 2015
Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Singeltary Comment at very bottom of this Nature publishing;
re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
I would kindly like to comment on the Nature Paper, the Lancet reply, and the newspaper articles.
First, I applaud Nature, the Scientist and Authors of the Nature paper, for bringing this important finding to the attention of the public domain, and the media for printing said findings.
Secondly, it seems once again, politics is getting in the way possibly of more important Transmissible Spongiform Encephalopathy TSE Prion scientific findings. findings that could have great implications for human health, and great implications for the medical surgical arena. but apparently, the government peer review process, of the peer review science, tries to intervene again to water down said disturbing findings.
where have we all heard this before? it's been well documented via the BSE Inquiry. have they not learned a lesson from the last time?
we have seen this time and time again in England (and other Country's) with the BSE mad cow TSE Prion debacle.
That 'anonymous' Lancet editorial was disgraceful. The editor, Dick Horton is not a scientist.
The pituitary cadavers were very likely elderly and among them some were on their way to CJD or Alzheimer's. Not a bit unusual. Then the recipients ?
who got pooled extracts injected from thousands of cadavers ? were 100% certain to have been injected with both seeds. No surprise that they got both diseases going after thirty year incubations.
That the UK has a "system in place to assist science journalists" to squash embargoed science reports they find 'alarming' is pathetic.
Sounds like the journalists had it right in the first place: 'Alzheimer's may be a transmissible infection' in The Independent to 'You can catch Alzheimer's' in The Daily Mirror or 'Alzheimer's bombshell' in The Daily Express
if not for the journalist, the layperson would not know about these important findings.
where would we be today with sound science, from where we were 30 years ago, if not for the cloak of secrecy and save the industry at all cost mentality?
when you have a peer review system for science, from which a government constantly circumvents, then you have a problem with science, and humans die.
to date, as far as documented body bag count, with all TSE prion named to date, that count is still relatively low (one was too many in my case, Mom hvCJD), however that changes drastically once the TSE Prion link is made with Alzheimer's, the price of poker goes up drastically.
so, who makes that final decision, and how many more decades do we have to wait?
the iatrogenic mode of transmission of TSE prion, the many routes there from, load factor, threshold from said load factor to sub-clinical disease, to clinical disease, to death, much time is there to spread a TSE Prion to anywhere, but whom, by whom, and when, do we make that final decision to do something about it globally? how many documented body bags does it take? how many more decades do we wait? how many names can we make up for one disease, TSE prion?
Professor Collinge et al, and others, have had troubles in the past with the Government meddling in scientific findings, that might in some way involve industry, never mind human and or animal health.
FOR any government to continue to circumvent science for monetary gain, fear factor, or any reason, shame, shame on you.
in my opinion, it's one of the reasons we are at where we are at to date, with regards to the TSE Prion disease science i.e. money, industry, politics, then comes science, in that order.
greed, corporate, lobbyist there from, and government, must be removed from the peer review process of sound science, it's bad enough having them in the pharmaceutical aspect of healthcare policy making, in my opinion.
my mother died from confirmed hvCJD, and her brother (my uncle) Alzheimer's of some type (no autopsy?). just made a promise, never forget, and never let them forget, before I do.
I kindly wish to remind the public of the past, and a possible future we all hopes never happens again. ...
[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.]
Singeltary Comment at very bottom of this Nature publishing, takes a while to load...terry
Re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
>>> The only tenable public line will be that "more research is required’’ <<<
>>> possibility on a transmissible prion remains open<<<
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
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
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 ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
Ann N Y Acad Sci. 1982;396:131-43.
Alzheimer's disease and transmissible virus dementia (Creutzfeldt-Jakob disease).
Brown P, Salazar AM, Gibbs CJ Jr, Gajdusek DC.
Abstract
Ample justification exists on clinical, pathologic, and biologic grounds for considering a similar pathogenesis for AD and the spongiform virus encephalopathies. However, the crux of the comparison rests squarely on results of attempts to transmit AD to experimental animals, and these results have not as yet validated a common etiology. Investigations of the biologic similarities between AD and the spongiform virus encephalopathies proceed in several laboratories, and our own observation of inoculated animals will be continued in the hope that incubation periods for AD may be even longer than those of CJD.
CJD1/9 0185 Ref: 1M51A
IN STRICT CONFIDENCE
Dr McGovern From: Dr A Wight Date: 5 January 1993 Copies: Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC. 2. Briefly, the meeting agreed that:
i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegenerative disorders;
ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and
iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion. 93/01.05/4.1
BSE101/1 0136
IN CONFIDENCE
5 NOV 1992 CMO From: Dr J S Metters DCMO 4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognized the public sensitivity of these findings and intend to report them in their proper context. This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.
2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed'. As the report emphasizes the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible. What are the implications for public health?
3. The route of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.
92/11.4/1-1 BSE101/1 0137
4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required" before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.
JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832 121/YdeS 92/11.4/1.2
CJD1/9 0185
Ref: 1M51A
IN STRICT CONFIDENCE
From: Dr. A Wight Date: 5 January 1993
Copies:
Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
http://collections.europa...
''on the possible transmissibility of Alzheimer's''
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.
Posted by flounder on 05 Nov 2014 at 21:27 GMT
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.]
THURSDAY, FEBRUARY 7, 2019
In Alzheimer's Mice, Decades-Old Human Cadaveric Pituitary Growth Hormone Samples Can Transmit and Seed Amyloid-Beta Pathology
WEDNESDAY, JANUARY 31,
Creutzfeldt Jakob Disease, CJD Support Group for short statured children of the 1970's and 1980's And 2024 Alzheimer’s iatrogenic Transmission
https://creutzfeldt-jakob-disease.blogspot.com/2024/01/creutzfeldt-jakob-disease-cjd-support.html
Subject: CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?
REVIEW
***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***
***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<***
***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***
***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<***
***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***
Saturday, February 2, 2019
CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?
Friday, January 29, 2016
Synucleinopathies: Past, Present and Future, iatrogenic, what if?
FRIDAY, JANUARY 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
Greetings Friends, Neighbors, and Colleagues,
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
Confucius is confused again.
I was just sitting and thinking about why there is no genetic link to some of these TSE prion sGSS, sFFi, and it’s really been working on my brain, and then it hit me today.
what if, vpspr, sgss, sffi, TSE prion disease, was a by-product from iatrogenic gss, ffi, familial type prion disease ???
it could explain the cases of no genetic link to the gss, ffi, familial type prion disease, to the family.
sporadic and familial is a red herring, in my opinion, and underestimation is spot on, due to the crude prehistoric diagnostic procedures and criteria and definition of a prion disease.
I say again, what if, iatrogenic, what if, with all these neurological disorders, with a common denominator that is increasingly showing up in the picture, called the prion.
I urge all scientist to come together here, with this as the utmost of importance about all these neurological disease that are increasingly showing up as a prion mechanism, to put on the front burners, the IATROGENIC aspect and the potential of transmission there from, with diseases/disease??? in question.
by definition, could they be a Transmissible Spongiform Encephalopathy TSE prion type disease, and if so, what are the iatrogenic chances of transmission?
this is very important, and should be at the forefront of research, and if proven, could be a monumental breakthrough in science and battle against the spreading of these disease/diseases.
the US National Library of Medicine National Institutes of Health pub-med site, a quick search of the word SPORADIC will give you a hit of 40,747. of those, there are a plethora of disease listed under sporadic. sporadic simply means (UNKNOWN).
the US National Library of Medicine National Institutes of Health pub-med site, a quick search of the word FAMILIAL will give you a hit of 921,815. of those, there are a plethora of disease listed under familial.
again, sporadic and familial is a red herring, in my opinion.
also, in my opinion, when you start have disease such as sporadic Fatal Familial Insomnia, (and or sporadic GSS, or the VPSPr type prion disease), and there is NO familial genetic linkage to the family of the diseased, I have serious questions there as to a familial type disease, and thus, being defined as such.
snip...see full text;
Friday, January 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
22 years ago;
2001 Singeltary on CJD
February 14, 2001
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Terry S. Singeltary, Sr
Author Affiliations
JAMA. 2001;285(6):733-734. doi:10-1001/pubs.JAMA-ISSN-0098-7484-285-6-jlt0214
To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
26 MARCH 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
Terry S. Singeltary, retired (medically)
I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?
Singeltary 2001
Subject: CJD or Alzheimer's or the same ???
Date: Sun, 29 Apr 2001 12:45:28 -0700
From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
Bovine Spongiform Encephalopathy
Greetings List,
thought some might be interested in this. I have always wondered if CJD and or all TSEs and Alzheimer's could be linked. i have been of the opinion that Alzheimer's is a TSE for a long time, just at the low end of the titre of infectivity scale. i also believe in the accumulation theory. by dose, you could be killed by one sitting, or one injection, or one whatever, depending on the titre of infectivity of that whatever. on the other hand, if the dose is not a lethal dose, over a period of time, the accumulation will become lethal (if consumption continued), and i believe the route/source/titre of infectivity, will be a key roll to the incubation period, and symptoms.
just my opinion...
Prusiner has spent the last 18 years trying to distance himself from a joint paper with GG Glenner in which prion diseases were recognized as just another amyloid. The recent keynote speech was especially amusing/annoying in that now he is completely turning the tables, trying to adsorb some strains of Alzheimer etc into "prions." The fact is, cross-recruitment has been a standard topic in amyloidoses since the late 70's.
Who would want plasma from someone with the ApoA2 mutation below, given that it can recruit the normal protein?
-=-=-
The context of the paper below is systemic hereditary amyloidosis, by which they mean an inherited condition with amyloid spread far and wide by the circulatory system. Damage from cross-beta fibril deposition occurs in kidneys, heart, periferal neurons, liver, or cornea. in contrast to CNS amyloid like CJD or AD.
The first was observed in 1950 by Ostertag, though it wasn't until 1978 that a constituent protein was identified (transthyretin, today 77 known mutational forms). Table I of the paper lists cystatin C (1 mutation), gelsolin (2), apolipoprotein A1 (9), lysozyme (2), and fibrinogen Aalpha (4).
None of these proteins are related. There are no sequence similarities or shared motifs. Most have alpha helix; large semi-speculative literature has these destablized by mutation or amphipathic with respect to beta sheet, or kinetically trapped during folding.
About a quarter of the mutations are frameshifts or stop codon read-thrus, ie mutations that generate random, unadapted polypeptide stretches. They are generally autosomal dominant, indicative of toxic gain-of-function, eg fibril formation. This means heterozygous; sometimes the normal product is recruited to amyloid, the mutant product is always there.
In some amyloids, the entire protein is present; in others just a proteolytic fragment. In the case here, the entire normal protein, as well as the extended read-through product, was found in amyloid. The patient studied spent 9 years on hemodialysis during which considerable readsorption of amyloid occurred, ie amyloid formation is balanced against amyloid degradation.
The most interesting observation in this paper is that there are now 4 lipid binding proteins seen in amyloid, serum amyloid A, ApoA1, ApoE, and now ApoA2.
"As a class, these proteins exist in a partly folded state in solution. The helical content is increased and stabilized upon binding to lipid ... any change in lipid metabolism or mutation in the protein that alters lipid binding will favor aggregatin and fibrillogenesis." That suggests that some apoA2 cases will appear sporadic, eg, be attributable to the disruption of lipid metabolism rather than be a mutation in this gene.
A New Human Hereditary Amyloidosis: The Result of a Stop-Codon Mutation in the Apolipoprotein AII Gene Genomics pp. 272-277 (doi:10.1006/geno.2000.6499) published electronically April 02, 2001
Merrill D. Benson1, ... Barbara Kluve-Beckerman Telephone: (317) 278-3428. E-mail: mdbenson@iupui.edu .
Hereditary systemic amyloidosis may be caused by mutations in a number of plasma proteins including transthyretin, apolipoprotein AI, fibrinogen A-chain, lysozyme, and gelsolin. Each type of amyloidosis is inherited as an autosomal dominant disease and is associated with a structurally altered protein that aggregates to form amyloid fibrils. Here we report that the amyloid protein in a family with previously uncharacterized hereditary renal amyloidosis is apolipoprotein AII (apoAII) with a 21-residue peptide extension on the carboxyl terminus. Sequence analysis of the apoAII gene of affected individuals showed heterozygosity for a single base substitution in the apoAII stop codon. The mutation results in extension of translation to the next in-frame stop codon 60 nucleotides downstream and is predicted to give a 21-residue C-terminal extension of the apoAII protein identical to that found in the amyloid. This mutation produces a novel Bst NI restriction site that can be used to identify individuals with this gene by restriction fragment length polymorphism analysis. This is the first report of apoAII amyloid in humans and the first mutation identified in apoAII protein. Amyloid fibril formation from apoAII suggests that this lipoprotein, which is predicted to have an amphipathic helical structure, must undergo a transition to a beta -pleated sheet by a mechanism shared by other lipoproteins that form amyloid.
=-=-=-=-=
This can't be studied in the human genome because it lies in a wholly unsequenced region.
987696512-14444-6374
MKLLAATVLLLTICSLEGALVRRQAKEPCVESLVSQYFQTVTDYGKDLMEKVKSPELQAEAKSYFEKSKEQLTPLIKKAGTELVNFLSYFVELGTQPATQ
1 aggcacagac accaaggaca gagacgctgg ctaggccgcc ctccccactg ttaccaacat
61 gaagctgctc gcagcaactg tgctactcct caccatctgc agccttgaag gagctttggt
121 tcggagacag gcaaaggagc catgtgtgga gagcctggtt tctcagtact tccagaccgt
181 gactgactat ggcaaggacc tgatggagaa ggtcaagagc ccagagcttc aggccgaggc
241 caagtcttac tttgaaaagt caaaggagca gctgacaccc ctgatcaaga aggctggaac
301 ggaactggtt aacttcttga gctatttcgt ggaacttgga acacagcctg ccacccagtg
361 aagtgtccag accattgtct tccaacccca gctggcctct agaacaccca ctggccagtc
421 ctagagctcc tgtccctacc cactctttgc tacaataaat gctgaatgaa tcc
kind regards,
Terry S. Singeltary Sr., Bacliff, Texas USA
http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html
SATURDAY, JULY 22, 2023
Alzheimer's Disease Update
TSE Prion and Endoscopy Equipment
Subject: Re: CJD * Olympus Endoscope
Date: Tue, 12 Oct 1999 15:57:03 –0500
From: "Terry S. Singeltary Sr."
To: GOLDSS@...
References: 1
Dear Mr. Goldstine, Hello again, I hope the CDC has not changed your mind, since our phone call, about sending me the information, in which we spoke of. I am still waiting for the information, re-fax. Someone had told me, you would not send me the information, but I told them you would, due to the importance of it pertaining to public safety, and the fact, you are a Doctor. I hope you don't disappoint me, and the rest of the public, and hide the facts, as the CDC and NIH have for years. Olympus can be part of the Truth, or you can be part of the cover-up. We are going to find out, sooner or later.
I already know, as do many more.
Still waiting,
Kind Regards,
Terry S. Singeltary Sr.
Wednesday, March 02, 2016
Endoscope Maker Olympus Agrees To $646 Million Settlement Over Kickbacks, while still ignoring the elephant in the room, CJD TSE PRIONS Health Inc.
*** Evidence For CJD TSE Transmission Via Endoscopes 1-24-3 re-Singeltary to Bramble et al ***
Evidence For CJD/TSE Transmission Via Endoscopes
From Terry S. Singletary
see full text;
Evidence For CJD/TSE Transmission Via Endoscopes
From Terry S. Singletary, Sr flounder@wt.net 1-24-3
I have researched human/animal TSEs now for over 5 years due to the death of my Mother from the Heidenhain Variant Creutzfeldt Jakob disease, one of six - known - variants of the infamous 'sporadic' CJD.
I did a little survey several years ago about CJD and ENDOSCOPY in 2001, and then went there again when another article was released recently. However, they seemed to only be concerned with the vCJD strain and risk from endoscopy equipment.
My concerns are if vCJD can be transmitted by blood, and there are now 6 variants of the infamous sporadic CJDs that they are documenting to date, how do they know that none of these 6 variants will not transmit the agent (prion) via blood?...especially since the sporadic CJDs are the only ones documented to date to transmit via the surgical arena and now that the CWD is spreading more and more, who knows about the cattle?
I would always read this study and it would bring me back to reality as to how serious/dangerous this agent is in the surgical/medical arena. You might want to read this short abstract from the late, great Dr. Gibbs twice, and let it really sink in. And please remember while reading some of these transmission studies, that most all, if not ALL these agents transmit freely to primates. Humans, of course, are primates.
Regarding claims that:
'Well, it has never been documented to transmit to humans."
There are two critical factors to think about:
A. CJD/TSEs in the USA are NOT reportable in most states and there is NO CJD/TSE questionnaire for most victims and their families, and the one they are now issuing asks absolutely nothing about route and source of the (prion) agent, only how the disease was diagnosed. Furthermore, the elderly are only very rarely autopsied, ie looking for Alzheimer's or 'FAST Alzheimer's' OR prion disease-related factors and phenomena, such as heart failure caused by disease.
B. It is unethical and against the law to do transmission studies of TSEs to humans, they are 100% FATAL.
I suggest you read these case studies about medical arena CJD transmission very carefully:
1: J Neurol Neurosurg Psychiatry 1994 Jun;57(6):757-8
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.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8006664&dopt=Abstract
Thursday, January 25, 2024
TSE Prion Disease, Eyes, Ophthalmology Diagnostic Equipment, Iatrogenic, What If?
September 12, 2023
Intracerebral Hemorrhage Among Blood Donors and Their Transfusion Recipients
Jingcheng Zhao, MD, PhD1; Klaus Rostgaard, MSc2,3; Elsa Lauwers, PhD4; et alTorsten Dahlén, MD, PhD1,5; Sisse Rye Ostrowski, MD, PhD, DMSc6,7; Christian Erikstrup, MD, PhD8,9; Ole Birger Pedersen, MD, PhD7,10; Bart de Strooper, MD, PhD4,11,12; Robin Lemmens, MD, PhD4,11,13; Henrik Hjalgrim, MD, PhD, DMSc2,3,7,14; Gustaf Edgren, MD, PhD1,15
JAMA. 2023;330(10):941-950. doi:10.1001/jama.2023.14445
Key Points Question Is there an association between the occurrence of spontaneous intracerebral hemorrhage among blood donors and the risk of spontaneous intracerebral hemorrhage in patients who receive a transfusion with their blood?
Findings In this exploratory retrospective cohort study, which included 759 858 patients in Sweden and 329 512 patients in Denmark, receiving red blood cell transfusions from donors who later developed multiple spontaneous intracerebral hemorrhages was significantly associated with an increased risk of developing spontaneous intracerebral hemorrhage compared with receiving a transfusion from donors without subsequent intracerebral hemorrhage (hazard ratios, 2.73 and 2.32 in the Swedish and Danish cohorts, respectively).
Meaning The findings suggest a transfusion-transmissible agent associated with some types of spontaneous intracerebral hemorrhage, but findings may be susceptible to selection bias and residual confounding, and further research is required to understand the potential underlying mechanism.
Abstract Importance Recent reports have suggested that cerebral amyloid angiopathy, a common cause of multiple spontaneous intracerebral hemorrhages (ICHs), may be transmissible through parenteral injection of contaminated cadaveric pituitary hormone in humans.
Objective To determine whether spontaneous ICH in blood donors after blood donation is associated with development of spontaneous ICH in transfusion recipients.
Design, Setting, and Participants Exploratory retrospective cohort study using nationwide blood bank and health register data from Sweden (main cohort) and Denmark (validation cohort) and including all 1 089 370 patients aged 5 to 80 years recorded to have received a red blood cell transfusion from January 1, 1970 (Sweden), or January 1, 1980 (Denmark), until December 31, 2017.
Exposures Receipt of red blood cell transfusions from blood donors who subsequently developed (1) a single spontaneous ICH, (2) multiple spontaneous ICHs, or (3) no spontaneous ICH.
Main Outcomes and Measures Spontaneous ICH in transfusion recipients; ischemic stroke was a negative control outcome.
Results A total of 759 858 patients from Sweden (median age, 65 [IQR, 48-73] years; 59% female) and 329 512 from Denmark (median age, 64 [IQR, 50-73] years; 58% female) were included, with a median follow-up of 5.8 (IQR, 1.4-12.5) years and 6.1 (IQR, 1.5-11.6) years, respectively. Patients who underwent transfusion with red blood cell units from donors who developed multiple spontaneous ICHs had a significantly higher risk of a single spontaneous ICH themselves, compared with patients receiving transfusions from donors who did not develop spontaneous ICH, in both the Swedish cohort (unadjusted incidence rate [IR], 3.16 vs 1.12 per 1000 person-years; adjusted hazard ratio [HR], 2.73; 95% CI, 1.72-4.35; P < .001) and the Danish cohort (unadjusted IR, 2.82 vs 1.09 per 1000 person-years; adjusted HR, 2.32; 95% CI, 1.04-5.19; P = .04). No significant difference was found for patients receiving transfusions from donors who developed a single spontaneous ICH in the Swedish cohort (unadjusted IR, 1.35 vs 1.12 per 1000 person-years; adjusted HR, 1.06; 95% CI, 0.84-1.36; P = .62) nor the Danish cohort (unadjusted IR, 1.36 vs 1.09 per 1000 person-years; adjusted HR, 1.06; 95% CI, 0.70-1.60; P = .73), nor for ischemic stroke as a negative control outcome.
Conclusions and Relevance In an exploratory analysis of patients who received red blood cell transfusions, patients who underwent transfusion with red blood cells from donors who later developed multiple spontaneous ICHs were at significantly increased risk of spontaneous ICH themselves. This may suggest a transfusion-transmissible agent associated with some types of spontaneous ICH, although the findings may be susceptible to selection bias and residual confounding, and further research is needed to investigate if transfusion transmission of cerebral amyloid angiopathy might explain this association.
Editorial Blood Transfusion and Brain Amyloidosis JAMA
Professor John Collinge on tackling prion diseases
“The best-known human prion disease is sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia which accounts for around 1 in 5000 deaths worldwide.”
it has been established that similar so-called “prion-like” mechanisms are involved in much commoner conditions including Alzheimer’s and Parkinson’s diseases.
We defined iatrogenic cerebral amyloid angiopathy as a new disease, with relevance to Alzheimer’s disease and public health.
it has been established that similar so-called “prion-like” mechanisms are involved in much commoner conditions including Alzheimer’s and Parkinson’s diseases.
We defined iatrogenic cerebral amyloid angiopathy as a new disease, with relevance to Alzheimer’s disease and public health.
Terry S. Singeltary Sr., Bacliff, Texas, 77518, Galveston Bay, flounder9@verizon.net
