Tuesday, June 1, 2021

Alzheimer’s disease neuropathological change three decades after iatrogenic amyloid-β transmission

Published: 28 May 2021 

Alzheimer’s disease neuropathological change three decades after iatrogenic amyloid-β transmission 

Zane Jaunmuktane, Gargi Banerjee, Simon Paine, Adrian Parry-Jones, Peter Rudge, Joan Grieve, Ahmed K. Toma, Simon F. Farmer, Simon Mead, Henry Houlden, David J. Werring & Sebastian Brandner Acta Neuropathologica (2021)Cite this article

Human (iatrogenic) transmission of amyloid-β (Aβ) pathology has been shown in brain biopsy or autopsy tissues in patients with and without iatrogenic Creutzfeldt–Jakob disease (iCJD) [1, 5,6,7,8,9,10,11,12,13,14,15,16,17,18, 20,21,22] and these Aβ seeds have been detected in the archival vials containing human cadaver-derived growth hormone (hcGH) [7, 19]. Whilst tau seeds were also found in these hcGH vials [7, 19], to date, no substantial tau pathology has been observed in patients with iCJD, iatrogenically transmitted Aβ pathology or both.

Here we show that a significant tau pathology, similar to that seen in patients with Alzheimer’s disease, can develop in patients with iatrogenic Aβ pathology after incubation periods exceeding 3 decades.

Case 1: a 46-year-old male presented with a 12-month history of cognitive decline, progressive ataxia and myoclonus. He had a medulloblastoma resected at the age of 4 years, but it is not known if a dura patch was used. The patient had learning difficulties since the radio-chemotherapy of his tumour but several months after a caudate nucleus haemorrhage at age 44, he developed gradual cognitive decline. A right frontal brain biopsy showed leptomeningeal and cortical Aβ angiopathy (CAA), parenchymal amyloid-β with diffuse deposits and plaques with central amyloid cores (Fig. 1a), and a tauopathy forming a meshwork of neuropil threads, pre-tangles, tangles and neuritic plaques (Fig. 1b–e). The patient died at the age of 47. APOE testing was not performed, but genetic testing did not identify any pathogenic mutations in 17 genes associated with neurodegenerative diseases [2], notably including the amyloid precursor protein gene (APP) (including duplication of APP), Presenilin 1 (PSEN1), Presenilin 2 (PSEN2) and microtubule-associated protein tau (MAPT). Case 2: a 39-year-old male presented with intracerebral haematoma and underwent emergency blood-clot evacuation. As a child, he had multiple haemangiomas, embolised at the age of 3 years (retro-auricular, embolisation agent unknown), 4 years [facial, embolised with lyophilised cadaveric dura (hcDM)], 8 years (re-embolisation of the facial lesion, with Ivalon (polyvinyl alcohol particles) and at the age of 9 (re-embolisation of the retro-auricular lesion with Ivalon). A parietal lobe biopsy from the perihaematoma region (Fig. 1f–j) showed leptomeningeal and cortical Aβ angiopathy, parenchymal Aβ with diffuse deposits and plaques with central amyloid cores, and tau pathology with a loose meshwork of neuropil threads, occasional pre-tangles and rare tangles and neuritic plaques. At follow-up, the patient had no cognitive impairment. APOE genotype was ε2/ε3, and no genetic risks or pathogenic mutations associated with early Aβ pathology were identified [2].

Case 3: a 45-year-old female presented with a convexity subarachnoid haemorrhage. As a child, she underwent multiple embolisations of facial haemangiomas including lyophilised cadaveric dura at age of 6 years. A right frontal brain biopsy (Fig. 1k–o) showed leptomeningeal and cortical Aβ angiopathy, parenchymal Aβ with diffuse deposits and plaques with central amyloid cores, and a widespread cortical tauopathy with neuropil treads, pre-tangles, tangles, and neuritic plaques. At the time of the biopsy, the patient had no cognitive impairment. Genetic testing showed an APOE ε3/ε3 genotype, and a NOTCH3 c.2183G>A (p.(Arg728His)) variant of unknown significance but no genetic risks associated with early Aβ pathology [2].

All three cases reported here have in common particularly long incubation times, exceeding 35 years for iatrogenically transmitted Aβ. No patient had a history of brain trauma, and neocortical tau pathology is extremely rare in young adults [3]. The few cases with long incubation periods reported to date (Fig. 2) do not show an obvious correlation between the extent of parenchymal Aβ pathology or the type of Aβ plaques (diffuse or plaques with central cores). Notably, plaques with central cores but without associated tau positive neurites are not uncommon in patients with iatrogenically transmitted Aβ [15].

Whilst this study cannot answer if the tauopathy was transmitted or is a consequence of Aβ pathology, the observations described here are important as they show that tau pathology can develop in patients with iatrogenically transmitted Aβ.

Our observations give some insight into the temporal development of tau pathology. Given that substantial tau pathology in non-iCJD patients has not been seen previously (Fig. 2), at least 35 years appears to be necessary for the development of neocortical neurofibrillary tangle and widespread thread tau pathology. However, tau pathology of similar severity is not present in all patients with iatrogenic Aβ pathology with an incubation period exceeding 35 years. The three cases reported by us previously [1, 16], with equally long incubation, and similarly widespread parenchymal Aβ pathology did not show such severe tau pathology in the neocortical biopsies, although one of these cases for which whole brain tissue was available for analysis, did show tau pathology in the medial temporal lobe corresponding to Braak & Braak stage II [16].

This study highlights the importance of enquiring about previous potential iatrogenic exposure and searching medical records for treatments with hcGH or interventions using hcDM in patients with early-onset intracranial (intracerebral or non-aneurysmal subarachnoid) haemorrhages as hcDM was used not only for neurosurgical repairs but also for interventional embolisation and other surgeries [4]. The severe, often fatal, haemorrhagic consequences of iatrogenic vascular Aβ pathology have been documented [1, 6, 8, 10, 11, 13, 14, 16, 18, 21] (Fig. 2). The cases reported here indicate that in addition to CAA and parenchymal Aβ pathology, tau pathology, indistinguishable from Alzheimer’s type changes, can develop after particularly long incubation periods.

References 



From: "Terry S. Singeltary Sr." <flounder9@verizon.net> 
Date: September 19, 2019 at 2:15:17 PM CDT 
To:
Subject: Arguments for Alzheimer’s and Parkinson’s diseases caused by prions Stanley B. Prusiner

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)

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.


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


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.

http://onlinelibrary.wile...

http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.1982.tb26849.x/abstract

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

http://collections.europa...

http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf

http://web.archive.org/web/20090506012455/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf

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

http://collections.europa...

http://web.archive.org/web/20090506032549/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf

BSE101/1 0136

IN CONFIDENCE

CMO

From: Dr J S Metters DCMO

4 November 1992

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

http://collections.europa...

http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf

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...

http://web.archive.org/web/20090506032549/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf

Tuesday, November 26, 2013

Transmission of multiple system atrophy prions to transgenic mice

‘’Our results provide compelling evidence that α-synuclein aggregates formed in the brains of MSA patients are transmissible and, as such, are prions.’’

http://www.pnas.org/conte...

Transmission of a neurodegenerative disorder from humans to mice

The findings suggest that the α-synuclein deposits that form in the brains of patients with MSA behave like prions and are transmissible under certain circumstances, according to the authors. — N.Z.

α-Synuclein deposits in the brainstems of inoculated mice.

http://www.pnas.org/conte...


kind regards, terry

No competing interests declared.





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.]




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)


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;


THURSDAY, FEBRUARY 7, 2019 

In Alzheimer's Mice, Decades-Old Human Cadaveric Pituitary Growth Hormone Samples Can Transmit and Seed Amyloid-Beta Pathology


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 ???


MONDAY, APRIL 8, 2019 

Studies Further Support Transmissibility of Alzheimer Disease–Associated Proteins


P1-187 AGED CATTLE BRAIN DISPLAYSALZHEIMER’S-LIKE PATHOLOGY THATCAN BE PROPAGATED IN A PRION-LIKE MANNER

Ines Moreno-Gonzalez1, George A. Edwards, III,1, Nazaret Gamez Ruiz1,Priyadarshini Peter1, Rodrigo Morales1, Mercedes Marquez2, Marti Pumarola2,Claudio Soto1,1The University of Texas Health Science Center at Houston, Houston, TX, USA;2Animal Tissue Bank of Catalunya (BT A C), Universidad Autonoma de Barcelona, Barcelona, Spain . Contact e-mail: Ines.M.Gonzalez@uth.tmc.edu

Background: Amyloid beta (Ab) and hyperphosphorylated tau(ptau) are the proteins undergoing misfolding in Alzheimer’s dis-ease (AD). Recent studies have shown that brain homogenates rich in amyloid aggregates are able to seed the misfolding and ag-gregation of amyloidogenic proteins inducing an earlier onset of the disease in mouse models of AD. This seeding behavior is analogous to the disease transmission by propagation of prion protein misfold-ing observed in prion diseases. Prion diseases can be transmitted across species by inoculation of the misfolded prion protein from one specie into an appropriate host. For example, material from cattle affected by bovine spongiform encephalopathy can be propagate in humans inducing variant Creutzfeldt-Jakob disease.

Methods: In this study, we analyzed the presence of AD-related protein aggre-gates in the brain of old cows and investigated whether these aggregates are capable to induce pathology in animal models of AD.

Results: We observed that many of the typical hallmarks detected in human AD brains, including Ab aggregates and tangles, were present in cow brains. When cattle tissue containing Ab aggregates or ptau were intracerebrally inoculated into APP/PS1 or P301Smice, we observed an acceleration of brain misfolded protein deposition and faster cognitive impairment compared to controls. How-ever, when the material was orally inoculated, no effect was observed.

Conclusions: These results may contribute to uncover a previously unsuspected etiology surrounding some cases of spo-radic AD. However, the early and controversial stage of the field of prion-like transmission in non-prion diseases added to the artificial nature of the animal models utilized for these studies, indicate that extrapolation of the results to humans should not be done without further experiments.


P75 Determining transmissibility and proteome changes associated with abnormal bovine prionopathy 

Dudas S (1,2), Seuberlich T (3), Czub S (1,2) 

In prion diseases, it is believed that altered protein conformation encodes for different pathogenic strains. Currently 3 different strains of bovine spongiform encephalopathy (BSE) are confirmed. Diagnostic tests for BSE are able to identify animals infected with all 3 strains, however, several diagnostic laboratories have reported samples with inconclusive results which are challenging to classify. It was suggested that these may be novel strains of BSE; to determine transmissibility, brain material from index cases were inoculated into cattle. 

In the first passage, cattle were intra-cranially challenged with brain homogenate from 2 Swiss animals with abnormal prionopathy. The challenged cattle incubated for 3 years and were euthanized with no clinical signs of neurologic disease. Animals were negative when tested on validated diagnostic tests but several research methods demonstrated changes in the prion conformation in these cattle, including density gradient centrifugation and immunohistochemistry. Currently, samples from the P1 animals are being tested for changes in protein levels using 2-D Fluorescence Difference Gel Electrophoresis (2D DIGE) and mass spectrometry. It is anticipated that, if a prionopathy is present, this approach should identify pathways and targets to decipher the source of altered protein conformation. In addition, a second set of cattle have been challenged with brain material from the first passage. Ideally, these cattle will be given a sufficient incubation period to provide a definitive answer to the question of transmissibility. 

=====prion 2018=== 

Prion Conference 2018

Sunday, February 25, 2018 

PRION ROUND TABLE CONFERENCE 2018 MAY, 22-25 A REVIEW


uesday, December 15, 2020

Risk of Transmissibility From Neurodegenerative Disease-Associated Proteins: Experimental Knowns and Unknowns


Wednesday, December 16, 2020 

Expanding spectrum of prion diseases Prusiner et al


Expanding spectrum of prion diseases

Jacob I. Ayers; Nick A. Paras; Stanley B. Prusiner 

Emerg Top Life Sci (2020) 4 (2): 155–167.


Prions were initially discovered in studies of scrapie, a transmissible neurodegenerative disease (ND) of sheep and goats thought to be caused by slow viruses. Once scrapie was transmitted to rodents, it was discovered that the scrapie pathogen resisted inactivation by procedures that modify nucleic acids. Eventually, this novel pathogen proved to be a protein of 209 amino acids, which is encoded by a chromosomal gene. After the absence of a nucleic acid within the scrapie agent was established, the mechanism of infectivity posed a conundrum and eliminated a hypothetical virus. Subsequently, the infectious scrapie prion protein (PrPSc) enriched for β-sheet was found to be generated from the cellular prion protein (PrPC) that is predominantly α-helical. The post-translational process that features in nascent prion formation involves a templated conformational change in PrPC that results in an infectious copy of PrPSc. Thus, prions are proteins that adopt alternative conformations, which are self-propagating and found in organisms ranging from yeast to humans. Prions have been found in both Alzheimer's (AD) and Parkinson's (PD) diseases. Mutations in APP and α-synuclein genes have been shown to cause familial AD and PD. Recently, AD was found to be a double prion disorder: both Aβ and tau prions feature in this ND. Increasing evidence argues for α-synuclein prions as the cause of PD, multiple system atrophy, and Lewy body dementia.

Keywords:α-synuclein, amyloid beta, neurodegeneration, prion, tau proteins 

Subjects:Aging, Molecular Bases of Health & Disease, Neuroscience


11. Arguments for Alzheimer’s and Parkinson’s diseases caused by prions

Stanley B. Prusiner

Institute of Neurodegenerative Diseases, and Professor of Neurology and Biochemistry, University of California San Francisco

ABSTRACT

Arguments for Alzheimer’s (AD) and Parkinson’s diseases (PD) being caused by prions continue to advance with new evidence. Findings in the brains of deceased AD patients argue that both Aβ and tau prions can be demonstrated by bioassays in cultured cells as well as in transgenic (Tg) mice. Likewise, studies of the brains of deceased MSA patients have been found to contain α-synuclein prions by bioassays in cultured cells and Tg mice. Conversely, the brains of AD patients do not contain α-synuclein prions, and the brains of MSA patients do not contain Aβ or tau prions. Additionally, while the brains of patients who died of either progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) contained tau prions, neither Aβ nor α-synuclein prions were detectable. Merely measuring the levels of Aβ, tau, and α-synuclein appears to give misleading information about the etiology and pathogenesis of neurodegenerative diseases (NDs). From a large array of bioassays, we conclude that AD, PD, MSA, and the frontotemporal dementias, including PSP and CBD, are all prion diseases. Our findings argue that changes in the conformations of Aβ, tau, and α-synuclein underlie the acquisition of prion infectivity in all of these NDs.




Terry S. Singeltary Sr.

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