In Alzheimer's Mice, Decades-Old Human Cadaveric Pituitary Growth Hormone Samples Can Transmit and Seed Amyloid-Beta Pathology
Neurology Today: February 7, 2019 - Volume 19 - Issue 3 - p 1,28–32
doi: 10.1097/01.NT.0000553604.42291.66
At the Bench
ARTICLE IN BRIEF:
Investigators injected transgenic Alzheimer's disease mice with tissue from human cadaveric pituitary growth hormone and found that the amyloid-beta deposits were able to infect, “seed,” and lay down clumps of amyloid-beta. The finding suggest that these decades-old samples can transmit one of the pathological hallmarks of Alzheimer's disease.
Some human cadaveric pituitary growth hormone (c-hGH) samples used from the 1950s through the mid-1980s to treat children with short stature were contaminated with prion protein, which decades later resulted in Creutzfeldt–Jakob disease (CJD).
On autopsy, scientists also found amyloid-beta protein (Abeta) deposits in the blood vessels and in between neurons, hints of a pathology that could have ultimately led to Alzheimer's disease (AD).
Now, three years after their first report of the Abeta deposits, scientists at the MRC Prion Unit of University College London in collaboration with scientists at Brigham & Women's Hospital and Harvard Medical School, collected c-hGH samples stored since 1985 (when companies substituted synthetic pituitary growth hormone) and found that the Abeta deposits were able to infect, “seed,” and lay down clumps of Abeta in transgenic AD animal models.
The findings, published December 13 in Nature, suggest that these decades-old samples can transmit one of the pathological hallmarks of AD.
While human-derived pituitary growth hormone is no longer used, the finding raises concern that Abeta material can still set in motion an active toxic state, and the possibility that microscopic Abeta deposits may be resistant to normal cleansing of surgical tools in the neurosurgery suite and could ultimately pose a risk for people undergoing brain surgery.
Rare cases of prion infectivity have been linked to medical or surgical procedures. More than 200 individuals treated with c-hGH worldwide have died of iatrogenic CJD, according to John Collinge, MD, professor of neurology and head of the MRC Prion Unit and senior author of the new study.
Dr. Collinge and his team have been involved with a long-term prospective study of prion disease.
Study Methods, Findings
The findings from the groups' initial 2015 paper in Nature led them to the idea that the stored batches of c-hGH may provide insights into why Abeta was found in the blood vessels and in parts of the brain tissue in people who underwent hormone treatment in childhood and died of prion disease decades later.
“This was unexpected and out of proportion for what you would expect to see in patients in their 30s and 40s,” Dr. Collinge explained. “They had no other risk factors. We thought that the human growth hormone batches may have been seeded with amyloid-beta.”
Public Health England had archived vials of c-hGH, and the scientists were able to obtain samples of some of the material linked back to the eight patients in their earlier study who had died of prion disease. The small amounts of dried powder had been sitting in vials on shelves for more than 30 years.
The 2015 Nature paper reported that the scientists had identified Abeta pathology in the brain tissue and cerebral blood vessels of seven of eight CJD patients tested.
There were several manufacturing procedures used at the time, and only one of them, Hartree-modified Wilhelmi procedure (HWP), has been linked to contaminated material that led to prion disease. Dr. Collinge said that every CJD patient received at least one injection of this hormone preparation as a child.
Now, as reported in the current study, the scientists were able to identify the vials used during the treatments and to distinguish those that were manufactured with other procedures. The material was sent to Dominic M. Walsh, PhD, associate professor at Brigham & Women's Hospital and Harvard Medical School. Dr. Walsh and his team were blinded to the preparations in the vials.
Study Methodology, Findings
To conduct the seeding studies, the research team injected small amounts of the material into the brains of transgenic mice expressing a mutant humanized amyloid precursor protein (APP). As a control, they also injected synthetic pituitary hormone into other transgenic animals
They analyzed the vials for the presence of Abeta peptides (Abeta1–40 and Abeta1–42) and tau proteins. All of the HWP vials tested were positive for Abeta1–40 and tau, and all but one was also positive for Abeta1–42, said Dr. Collinge. They could not detect Abeta peptides or tau in hormone vials manufactured with other preparation methods.
They found that the stored c-hGH material (processed with the HWP technique) seeded and spread Abeta pathology. Abeta seeding did not take place in animals who received the hormone prepared with other non-HWP techniques.
They also injected the decades-old material into wild-type mice that express only murine APP and saw no amyloid deposition, just as they had expected.
“I was amazed that we could seed the material,” said Dr. Collinge.
“Indeed, it is remarkable that detectable seeding activity has persisted at all after decades of storage,” he and his colleagues wrote in the paper. “Our proposal that human transmission of Aβ pathology had occurred as a result of intramuscular injection of c-hGH is now firmly supported by experimental evidence.”
The scientists said they are now conducting studies to see whether the tau identified in the c-hGH vials can seed aggregation in transgenic mice expressing human tau protein.
Others have conducted studies showing it is possible to transmit AD pathology, Dr. Collinge said. “Although we are generating evidence that AD pathology is transmissible, there is no suggestion that AD itself or cerebral amyloid angiopathy or CJD is contagious,” he added. “You can't catch these diseases by contact.”
There has also been no evidence of iatrogenic spread of AD, although the evidence from this study suggests that those patients with evidence of Abeta pathology might have ultimately developed clinical signs of Alzheimer's had they lived longer.
Some of the patients with amyloid aggregation in their cerebral blood vessels had enough pathology to meet a diagnosis of CAA. The Abeta pathology did not meet the full pathological criteria of Alzheimer's disease, according to Dr. Collinge.
“This material may have been contaminated with Abeta seeds and prions,” he added.
“Although we reiterate that there is no suggestion that Alzheimer's disease is contagious, and no supportive evidence from epidemiological studies that it is transmissible (notably by blood transfusion), we consider it important to evaluate the risks of iatrogenic transmission of CAA, and potentially of Alzheimer's disease,” the scientists wrote in the paper.
“Given the lack of disease-modifying therapeutics for Alzheimer's disease and other distressing and fatal neurodegenerative conditions, it will be important to consider introducing improved methods for removing proteopathic seeds from surgical instruments on a precautionary basis.”
Expert Commentary
“The finding solidifies that the amyloid-beta pathology found in the patients who died of CJD was transmitted by human material,” said David M. Holtzman, MD, FAAN, the Andrew B. and Gretchen P. Jones professor and chairman of the department of neurology at Washington University School of Medicine. “This practice of using human pituitary growth hormone doesn't occur anymore. While they proved that this material transmits amyloid pathology, none of the CJD patients developed clinical manifestations of Alzheimer's disease. It could be that they didn't live long enough. Whether any of this is currently relevant we just don't know.”
Dr. Holtzman co-authored an editorial on the study in the same issue of Nature. “But some people wonder whether people undergoing brain surgery could be at risk from direct contact with contaminated material left behind on tools,” he told Neurology Today. “The field should explore whether this material is resistant to sterilization and could be left behind on instruments used during brain surgery.”
“Scenarios such as this are all still very rare but we still worry mostly because of issue of transmissibility,” said Samuel E. Gandy, MD, PhD, professor of neurology and psychiatry and the Mount Sinai chair in Alzheimer's disease research at the Icahn School of Medicine at Mount Sinai. “For example, I am a dementia expert but I have seen only two CJD patients in my life, so it's really rare, but if you're the one patient who has CJD, it's 100 percent fatal for you.”
“Another issue is incubation time,” he continued. “At this point, we are nearly 35 years past the peak of pituitary extract use. Between 1963 and 1985, about 7,700 children in the United States and 27,000 children worldwide were given growth hormone extracted from human pituitary glands. This would mean that children treated between 1985 and the current day will have outgrown the need for hormone and hopefully they will have outgrown the window of opportunity for prion disease to appear.”
“The Alzheimer transmissibility risk used to be believed to be zero but there is evidence from our work and others that while AD is far less transmissible than CJD, AD transmission potential may be greater than zero,” Dr. Gandy pointed out. There has also been concern about CJD contamination of the blood supply.
Dr. Gandy cited research by a team of scientists in Germany, France, and Spain that characterized the presence and distribution of CJD agents (sporadic and variant forms) in the blood. They quantified the levels of infectivity associated with different blood fractions from CJD affected patients. The blood cells (white and red blood cells) and the plasma from a variant CJD affected patient contained infectivity, he said. Regarding sporadic CJD, infectivity was detected in the plasma of two out of the four investigated cases.
There are no blood tests to identify misfolded brain proteins associated with Alzheimer's, Parkinson's. and prion disease, Dr. Gandy noted. But he added that federal scientists at the Rocky Mountain Laboratories in Montana, part of the National Institutes of Health, are testing ultrasensitive RT-QuIC seed amplification assays for disease-associated tau, alpha-synuclein, and prion aggregates in cerebrospinal fluid.
“They recently described a tau RT-QuIC prototype to diagnosis and confirmation of Pick's disease (with predominant 3R tau pathology) in postmortem CSF samples,” Dr. Gandy said.
Disclosures
Drs. Collinge and Gandy reported no relevant disclosures. Dr. Holtzman has served on the scientific advisory board or consulted for Genentech, Eli Lilly, and AbbVie.
TUESDAY, JANUARY 1, 2019
CHILDHOOD EXPOSURE TO CADAVERIC DURA
Singeltary comments;
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
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)
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.]
please see more of this history and references there from (these blogs are for educational use, I do not advertise or make money from this. just made a promise to mom dod 12/14/97 hvCJD, never forget, and never let them forget.) human transmission of amyloid-β pathology and cerebral amyloid angiopathy, Singeltary Submission to Nature
P132 Aged cattle brain displays Alzheimer’s-like pathology that can be propagated in a prionlike manner
Ines Moreno-Gonzalez (1), George Edwards III (1), Rodrigo Morales (1), Claudia Duran-Aniotz (1), Mercedes Marquez (2), Marti Pumarola (2), Claudio Soto (1)
snip...
These results may contribute to uncover a previously unsuspected etiology surrounding some cases of sporadic 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)
1. Canadian Food Inspection Agency, NCAD Lethbridge Laboratory, Canada 2. University of Calgary, Canada 3. University of Bern, Switzerland.
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===
***however in 1 C-type challenged animal, Prion 2015 Poster Abstracts
S67 PrPsc was not detected using rapid tests for BSE.
***Subsequent testing resulted in the detection of pathologic lesion in unusual brain location and PrPsc detection by PMCA only.
*** IBNC Tauopathy or TSE Prion disease, it appears, no one is sure ***
Posted by Terry S. Singeltary Sr. on 03 Jul 2015 at 16:53 GMT
Discussion: The C, L and H type BSE cases in Canada exhibit molecular characteristics similar to those described for classical and atypical BSE cases from Europe and Japan.
*** This supports the theory that the importation of BSE contaminated feedstuff is the source of C-type BSE in Canada.
*** It also suggests a similar cause or source for atypical BSE in these countries. ***
see page 176 of 201 pages...tss
*** Singeltary reply ; Molecular, Biochemical and Genetic Characteristics of BSE in Canada Singeltary reply;
Terry S. Singeltary Sr. Bacliff, Texas USA 77518
