Friday, January 29, 2016

Synucleinopathies: Past, Present and Future, iatrogenic, what if?

Synucleinopathies: Past, Present and Future
Article Type: Editorial
Synucleinopathies: Past, Present and Future
Maria Grazia Spillantini1 and Michel Goedert2
1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
2 MRC Laboratory of Molecular Biology, Cambridge, UK Please send correspondence to MGS ( or MG (
Parkinson’s disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are the most common synucleinopathies. The ordered assembly of α-synuclein leading from a soluble, lipid-bound, to an insoluble, filamentous protein underlies these disorders. Fibrils formed from α-synuclein (Lewy pathology) are seen in brain neurons of more than 95% of patients with PD, and their formation is associated with neurodegeneration. Missense mutations in SNCA, the α-synuclein gene, and multiplications thereof, cause rare cases of PD. Two missense mutations (G51D and A53E) can give rise to neuropathological features reminiscent of both PD and MSA. Sequence variants in the regulatory region of SNCA are associated with increased disease risk. Overexpression of human mutant α-synuclein in animal models causes its ordered assembly and neurodegeneration.
α-Synuclein is a 140 amino acid protein that is concentrated in nerve terminals. It binds to lipids through its amino-terminal half, which comprises seven imperfect repeats, and takes on a partly α-helical structure. Under pathological conditions, α-synuclein self assembles into β-sheet-rich oligomers and fibrils. They assemble from the full-length protein, but only approximately amino acids 30-100 make up the structured part. The related lipid-binding proteins β-synuclein and γ- synuclein are not found in the pathological inclusions of synucleinopathies. Moreover, mouse lines knockout for α-synuclein do not develop neurodegeneration. It follows that synucleinopathies are gain of toxic function, not loss of function, diseases, with the ordered assembly of α- synuclein constituting the gain of toxic function.
Close to 200 years ago, James Parkinson published his 1817 monograph entitled “An Essay on the Shaking Palsy”, in which he reported the first detailed clinical description of the disease that Jean- Martin Charcot named after him in 1872. In 1912, Fritz Heinrich Lewy described the inclusions that characterise PD, PDD and DLB in the dorsal motor nucleus of the vagus nerve, the basal nucleus of Meynert, the globus pallidus and the thalamus. In 1919, Konstantin Tretiakoff reported the presence of what he called “corps de Lewy” (Lewy bodies) in the substantia nigra. He also showed degeneration of the substantia nigra in PD and postulated a connection between nerve cell loss, rigidity and tremor. This discovery followed work by Paul Blocq and Georges Marinesco, who reported a case of parkinsonian tremor caused by a tumour of the substantia nigra. α-Synuclein came to the fore in 1997, when the first genetic cause of PD was identified and the presence of α- synuclein in Lewy bodies and neurites was established in sporadic PD and DLB. The following year, α-synuclein was also shown to be the major component of the filamentous inclusions of MSA (Papp-Lantos bodies).
In this special issue of Neuropathology and Applied Neurobiology on synucleinopathies, leading investigators provide an overview of this vibrating field. A basic understanding is at hand and it appears increasingly likely that safe and effective mechanism-based therapies for synucleinopathies will be developed. They will probably be aimed at prevention rather than at treating already existing disease. PD stands out among neurodegenerative diseases, in that an effective symptomatic therapy in the form of dopamine replacement already exists. In the first contribution, Roger Barker and Caroline Williams-Gray provide a comprehensive overview of the clinical features of PD and compare them with those of other synucleinopathies (1). In the second article, Nadia Stefanova and Gregor Wenning focus on the rarer, but more aggressive, MSA, which is divided into parkinsonian (MSA-P) and cerebellar (MSA-C) forms, with many cases having features of both (mixed-type MSA) (2). Autonomic dysfunction is a major feature of MSA. Atypical MSA defines cases of MSA-P and MSA-C that also have frontotemporal dementia, in the apparent absence of autonomic dysfunction. Pathologically, glial cytoplasmic inclusions, besides neuronal inclusions, distinguish MSA from PD, PDD and DLB, where the α-synuclein-positive Lewy pathology is mostly neuronal. It remains to be seen if distinct strains of aggregated α- synuclein give rise to these pathologies. Two silver staining methods, Gallyas-Braak and Campbell-Switzer, distinguish between the α-synuclein inclusions of MSA and PD. The inclusions of MSA are positive with both stains, whereas those of PD are negative with Gallyas-Braak. Clinically, PD and MSA are primarily movement disorders. Nerve cell loss in the pars compacta of the substantia nigra associated with Lewy pathology is the major hallmark of sporadic PD, which is often preceded by non-motor prodromal signs, such as hyposmia, constipation, depression and sleep disorders. Significant cognitive dysfunction is associated more often with PD than with MSA.
The prodromal stages of PD may reflect the presence of Lewy pathology outside the substantia nigra. Based on cross-sectional neuroanatomical studies of the presence of Lewy pathology, Braak, Del Tredici and colleagues have suggested that the disease process may start in the gastrointestinal tract, sympathetic ganglia and olfactory bulb, and then spread to the spinal cord, brainstem, substantia nigra and cerebral cortex. In the third article of this special issue, Kelly Del Tredici and Heiko Braak review their and others’ findings (3), which are consistent with the spreading of pathology over time. During the past eight years, much experimental evidence has been adduced to support the prion-like spreading of α-synuclein aggregates. The first strong indication came from PD patients who had received striatal grafts of embryonic neural tissue to replace the function of lost nigral dopaminergic neurons. When these patients died a decade or more after transplantation, some of the grafted neurons had developed Lewy pathology. In the fourth contribution, Nolwen Rey, Sonia George and Patrik Brundin summarise what is known about the prion-like spreading of aggregated α-synuclein and discuss the methods used to detect seeding and spreading of pathology (4).
In PD, the neuronal Lewy pathology appears to form first in nerve terminals, where soluble α-synuclein is located. This may lead to synaptic dysfunction and retrograde degeneration, with nerve cell loss being a later event. In the fifth article, Arianna Bellucci, Nicola Mercuri, Annalena Venneri, Gaia Faustini, Francesca Longhena, Marina Pizzi, Cristina Missale and PierFranco Spano discuss what is known about the physiological function of α-synuclein and its ordered assembly in relation to synaptic loss and connectome dysfunction (5). A major objective behind the identification of novel disease mechanisms is to discover new therapeutic targets. The final contribution by Elvira Valera, Giacomo Compagnoni and Eliezer Masliah discusses novel strategies to treat synucleinopathies, with an emphasis on MSA (6). Aggregation of α-synuclein and chaperones that influence its aggregation are important targets, since the ordered assembly of α-synuclein constitutes the gain of toxic function that underlies synucleinopathies. The ordered assembly of proteins associated with neurodegenerative diseases, be they Aβ, tau or α-synuclein, is concentration-dependent. Reduced production and increased clearance of α-synuclein are therefore valid targets for therapy. Besides its cell autonomous effects, a reduction in cytosolic α-synuclein is also likely to reduce intercellular propagation, which has emerged as an important contributor to disease pathogenesis. Immunotherapy and degradation by extracellular proteases may target the intercellular transfer of α-synuclein aggregates directly.
The process underlying sporadic synucleinopathies may originate in localised portions of the nervous system. What predisposes certain brain regions and cell types to the assembly of α-synuclein into oligomers and filaments is unknown. Could somatic SNCA mutations play a role? Unlike dominantly inherited forms of synucleinopathies, where half of the expressed α-synuclein molecules are either mutant or over-expressed, most cells express normal levels of wild-type protein in sporadic cases of disease. In these cases, the early events may be followed by the more deterministic spreading of pathology, which will eventually give rise to disease symptoms. The long preclinical phase of synucleinopathies augurs well for the development of therapies.
Accepted Article This article is protected by copyright. All rights reserved.
1 Barker R, Williams-Gray C. The spectrum of clinical features with alpha-synuclein pathology. Neuropathol Appl Neurobiol 2016; 42: xx-xx.
2 Stefanova N, Wenning GK. Multiple system atrophy: emerging targets for interventional therapies. Neuropathol Appl Neurobiol 2016; 42: xx-xx.
3 Del Tredici K, Braak H. Sporadic Parkinson’s disease: development and distribution of α-synuclein pathology. Neuropathol Appl Neurobiol 2016: 42: xx-xx.
4 Rey NL, George S, Brundin P. Spreading the word: precise animal models and validated methods are vital when evaluating prion-like behaviour of alpha-synuclein. Neuropathol Appl Neurobiol 2016: 42: xx-xx.
5 Bellucci A, Mercuri NB, Venneri A, Faustini G, Longhena F, Pizzi M, Missale C, Spano P. Parkinson’s disease: from synaptic loss to connectome dysfunction. Neuropathol Appl Neurobiol 2016; 42: xxxx.
6 Valera E, Compagnoni GM, Masliah E. Novel treatment strategies targeting alpha-synuclein in multiple system atrophy as a model of synucleinopathy. Neuropathol Appl Neurobiol 2016; 42: xx-xx.
Review: An update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations
Tammaryn Lashley1, Jonathan D. Rohrer2, Simon Mead3 andTamas Revesz1,* Article first published online: 6 JUL 2015
DOI: 10.1111/nan.12250
© 2015 British Neuropathological Society
Keywords:classification;frontotemporal dementia;frontotemporal lobar degeneration;FUS;pathology;tau;TDP-43
The development of our understanding of frontotemporal dementia (FTD) has gathered pace over the last 10 years. After taking a back seat to Alzheimer's disease for many years FTD has emerged as a significant group of heterogeneous diseases often affecting people under the age of 65. FTD has also been brought into the spotlight as the major disease entities of the group have clinical, genetic and pathological links to motor neuron disease/amyotrophic lateral sclerosis, indicating that they form a disease spectrum. In this review, we overview how the pathological concept of frontotemporal lobar degeneration (FTLD) and the clinical concept of FTD evolved and show that FTLD, once thought of as a single disorder, represents a heterogeneous group of diseases with overlapping clinical symptoms, multiple causative genes and varying underlying pathology. We also provide a brief summary of the clinical manifestations, summarize the major genetic aspects and describe the main pathological features seen in the different subtypes of FTLD. We also summarize the correlations that exist between clinical presentations and pathological variants. An overview of the main pathogenic mechanisms is also provided.
Recent experimental data indicate that tau can show prion-like propagation and spread, which is consistent with pathological disease progression in human disease [74].
TDP-43 also has an N-terminal domain, two RNA-recognition motifs (RRMs) involved in RNA and DNA binding and its glycine-rich C-terminal region contains most of the mutations causing familial MND/ALS and rarely familial FTD [108,109]. The C-terminal region of TDP-43 contains a prion-like protease resistant domain [110].
There is now evidence to suggest that TDP-43 in inclusions, the majority of which have been shown to show amyloid features [114], has cellular prion-like properties, which could have relevance for the pathomechanism of FTLD-TDP [115]. The disease-associated TDP-43 making up the inclusions, is thought to exercise its deleterious effect via toxic gain of function due to overexpression or mutant forms, but given the number of its functions it is also likely that a loss of function effect also has a role in the pathogenesis of FTLD-TDP. FTLD-TDP has recently been reported to be associated with chronic traumatic encephalopathy [116]. TDP43-positive inclusions are also found in around 90% of patients with hippocampal sclerosis, which is also a feature in the majority of FTLD-TDP suggesting a special relationship between these two pathologies [117,118].
***>>>In the third article of this special issue, Kelly Del Tredici and Heiko Braak review their and others’ findings (3), which are consistent with the spreading of pathology over time.
***During the past eight years, much experimental evidence has been adduced to support the prion-like spreading of α-synuclein aggregates.
***The first strong indication came from PD patients who had received striatal grafts of embryonic neural tissue to replace the function of lost nigral dopaminergic neurons. When these patients died a decade or more after transplantation, some of the grafted neurons had developed Lewy pathology. In the fourth contribution, Nolwen Rey, Sonia George and Patrik Brundin summarise what is known about the prion-like spreading of aggregated α-synuclein and discuss the methods used to detect seeding and spreading of pathology (4).<<<***
WHAT IF, friendly fire, pass if forward, iatrogenic, plays a role with the spreading with some of these Synucleinopathies, what if?...tss
Genetics (V Bonifati, Section Editor) Current Neurology and Neuroscience Reports
November 2014, 14:495
First online: 14 September 2014
Prion-like Mechanisms in the Pathogenesis of Tauopathies and Synucleinopathies Michel GoedertAffiliated withMRC Laboratory of Molecular Biology Email author , Ben FalconAffiliated withMRC Laboratory of Molecular Biology , Florence ClavagueraAffiliated withDepartment of Neuropathology, Institute of Pathology , Markus TolnayAffiliated withDepartment of Neuropathology, Institute of Pathology
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Get Access Topical Collection Topical Collection on Genetics Abstract Neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterized by the abnormal aggregation of a small number of intracellular proteins, with tau and α-synuclein being the most commonly affected. Until recently, the events leading to aggregate formation were believed to be entirely cell-autonomous, with protein misfolding occurring independently in many cells. It is now believed that protein aggregates form in a small number of brain cells, from which they propagate intercellularly through templated recruitment, reminiscent of the mechanisms by which prions spread through the nervous system.
Keywords Tau protein Alpha-synuclein Prions Neurodegeneration
Synucleinopathies: Past, Present and Future, iatrogenic, what if?
is Alzheimer’s a Transmissible Spongiform Encephalopathy TSE Prion disease ? that is the question...
I would kindly like to comment further on ;
Alzheimer-type brain pathology may be transmitted by grafts of dura mater
26/01/2016 By Karl Frontzek, et al.:
Original article | Published 26 January 2016, doi:10.4414/smw.2016.14287
Cite this as: Swiss Med Wkly. 2016;146:w14287
Amyloid-β pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting
MY comment as follows ;
Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
07 02:27 AM
Terry S. Singeltary Sr. said:
re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
2015-12-07 02:27 AM
Terry S. Singeltary Sr. said: re-Evidence for human transmission of amyloid- βpathology 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.]
Terry S. Singeltary Sr. Bacliff, Texas USA 77518
snip...see Singeltary comment ;
BSE101/1 0136
From: . Dr J S Metiers DCMO
4 November 1992
1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognised 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 emphasises 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.
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.
J S METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832 llllYc!eS 2 92/11.4/1.2
>>> 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 ?
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
Sunday, November 22, 2015
*** Effect of heating on the stability of amyloid A (AA) fibrils and the intra- and cross-species transmission of AA amyloidosis Abstract
Amyloid A (AA) amyloidosis is a protein misfolding disease characterized by extracellular deposition of AA fibrils. AA fibrils are found in several tissues from food animals with AA amyloidosis. For hygienic purposes, heating is widely used to inactivate microbes in food, but it is uncertain whether heating is sufficient to inactivate AA fibrils and prevent intra- or cross-species transmission. We examined the effect of heating (at 60 °C or 100 °C) and autoclaving (at 121 °C or 135 °C) on murine and bovine AA fibrils using Western blot analysis, transmission electron microscopy (TEM), and mouse model transmission experiments. TEM revealed that a mixture of AA fibrils and amorphous aggregates appeared after heating at 100 °C, whereas autoclaving at 135 °C produced large amorphous aggregates. AA fibrils retained antigen specificity in Western blot analysis when heated at 100 °C or autoclaved at 121 °C, but not when autoclaved at 135 °C. Transmissible pathogenicity of murine and bovine AA fibrils subjected to heating (at 60 °C or 100 °C) was significantly stimulated and resulted in amyloid deposition in mice. Autoclaving of murine AA fibrils at 121 °C or 135 °C significantly decreased amyloid deposition. Moreover, amyloid deposition in mice injected with murine AA fibrils was more severe than that in mice injected with bovine AA fibrils. Bovine AA fibrils autoclaved at 121 °C or 135 °C did not induce amyloid deposition in mice. These results suggest that AA fibrils are relatively heat stable and that similar to prions, autoclaving at 135 °C is required to destroy the pathogenicity of AA fibrils. These findings may contribute to the prevention of AA fibril transmission through food materials to different animals and especially to humans.
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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.
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,
Thursday, January 14, 2016
Preventable Tragedies: Superbugs and How Ineffective Monitoring of Medical Device Safety Fails Patients REPORT
how can it be, HOW CAN IT BE $$$ not a word about CJD GSS FFI VPSPR TSE Prions that I saw...absolutely crazy, WE ARE MISSING THE BIGGER PICTURE!
how many victims that will never be reported ???
Sunday, January 17, 2016
Of Grave Concern Heidenhain Variant Creutzfeldt Jakob Disease
Tuesday, January 26, 2016
Amyloid-β pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting
Tuesday, January 26, 2016
Alzheimer-type brain pathology may be transmitted by grafts of dura mater
Suspect symptoms
What if you can catch old-fashioned CJD by eating meat from a sheep infected with scrapie?
28 Mar 01
Most doctors believe that sCJD is caused by a prion protein deforming by chance into a killer. But Singeltary thinks otherwise. He is one of a number of campaigners who say that some sCJD, like the variant CJD related to BSE, is caused by eating meat from infected animals. Their suspicions have focused on sheep carrying scrapie, a BSE-like disease that is widespread in flocks across Europe and North America. Now scientists in France have stumbled across new evidence that adds weight to the campaigners' fears. To their complete surprise, the researchers found that one strain of scrapie causes the same brain damage in mice as sCJD.
"This means we cannot rule out that at least some sCJD may be caused by some strains of scrapie," says team member Jean-Philippe Deslys of the French Atomic Energy Commission's medical research laboratory in Fontenay-aux-Roses, south-west of Paris. Hans Kretschmar of the University of Göttingen, who coordinates CJD surveillance in Germany, is so concerned by the findings that he now wants to trawl back through past sCJD cases to see if any might have been caused by eating infected mutton or lamb...
Title: Transmission of scrapie prions to primate after an extended silent incubation period
item Comoy, Emmanuel - item Mikol, Jacqueline - item Luccantoni-Freire, Sophie - item Correia, Evelyne - item Lescoutra-Etchegaray, Nathalie - item Durand, Valérie - item Dehen, Capucine - item Andreoletti, Olivier - item Casalone, Cristina - item Richt, Juergen item Greenlee, Justin item Baron, Thierry - item Benestad, Sylvie - item Hills, Bob - item Brown, Paul - item Deslys, Jean-Philippe -
Submitted to: Scientific Reports Publication Type: Peer Reviewed Journal Publication Acceptance Date: May 28, 2015 Publication Date: June 30, 2015 Citation: Comoy, E.E., Mikol, J., Luccantoni-Freire, S., Correia, E., Lescoutra-Etchegaray, N., Durand, V., Dehen, C., Andreoletti, O., Casalone, C., Richt, J.A., Greenlee, J.J., Baron, T., Benestad, S., Brown, P., Deslys, J. 2015. Transmission of scrapie prions to primate after an extended silent incubation period. Scientific Reports. 5:11573.
Interpretive Summary: The transmissible spongiform encephalopathies (also called prion diseases) are fatal neurodegenerative diseases that affect animals and humans. The agent of prion diseases is a misfolded form of the prion protein that is resistant to breakdown by the host cells. Since all mammals express prion protein on the surface of various cells such as neurons, all mammals are, in theory, capable of replicating prion diseases. One example of a prion disease, bovine spongiform encephalopathy (BSE; also called mad cow disease), has been shown to infect cattle, sheep, exotic undulates, cats, non-human primates, and humans when the new host is exposed to feeds or foods contaminated with the disease agent. The purpose of this study was to test whether non-human primates (cynomologous macaque) are susceptible to the agent of sheep scrapie. After an incubation period of approximately 10 years a macaque developed progressive clinical signs suggestive of neurologic disease. Upon postmortem examination and microscopic examination of tissues, there was a widespread distribution of lesions consistent with a transmissible spongiform encephalopathy. This information will have a scientific impact since it is the first study that demonstrates the transmission of scrapie to a non-human primate with a close genetic relationship to humans. This information is especially useful to regulatory officials and those involved with risk assessment of the potential transmission of animal prion diseases to humans. Technical Abstract: Classical bovine spongiform encephalopathy (c-BSE) is an animal prion disease that also causes variant Creutzfeldt-Jakob disease in humans. Over the past decades, c-BSE's zoonotic potential has been the driving force in establishing extensive protective measures for animal and human health.
*** In complement to the recent demonstration that humanized mice are susceptible to scrapie, we report here the first observation of direct transmission of a natural classical scrapie isolate to a macaque after a 10-year incubation period. Neuropathologic examination revealed all of the features of a prion disease: spongiform change, neuronal loss, and accumulation of PrPres throughout the CNS.
*** This observation strengthens the questioning of the harmlessness of scrapie to humans, at a time when protective measures for human and animal health are being dismantled and reduced as c-BSE is considered controlled and being eradicated.
*** Our results underscore the importance of precautionary and protective measures and the necessity for long-term experimental transmission studies to assess the zoonotic potential of other animal prion strains.
WITH regards to Docket No. APHIS-2007-0127 Scrapie in Sheep and Goats, I kindly submit the following ;
>>>The last major revision of the scrapie regulations occurred on August 21, 2001, when we published in theFederal Register(66 FR 43964, Docket No. 97-093-5) a final rule amending part 79 by imposing additional restrictions on the interstate movement of sheep and goats.<<<
Indeed, much science has changed about the Scrapie TSE prion, including more science linking Scrapie to humans. sadly, politics, industry, and trade, have not changed, and those usually trump sound science, as is the case with all Transmissible Spongiform Encephalopathy TSE Prion disease in livestock producing animals and the OIE. we can look no further at the legal trading of the Scrapie TSE prion both typical and atypical of all strains, and CWD all stains. With as much science of old, and now more new science to back this up, Scrapie of all types i.e. atypical and typical, BSE all strains, and CWD all strains, should be regulated in trade as BSE TSE PRION. In fact, I urge APHIS et al and the OIE, and all trading partners to take heed to the latest science on the TSE prion disease, all of them, and seriously reconsider the blatant disregards for human and animal health, all in the name of trade, with the continued relaxing of TSE Prion trade regulations through the ‘NEGLIGIBLE BSE RISK’ PROGRAM, which was set up to fail in the first place. If the world does not go back to the ‘BSE RISK ASSESSMENTS’, enhance, and or change that assessment process to include all TSE prion disease, i.e. ‘TSE RISK ASSESSMENT’, if we do not do this and if we continue this farce with OIE and the USDA et al, and the ‘NEGLIGIBLE BSE RISK’ PROGRAM, we will never eradicate the TSE prion aka mad cow type disease, they will continue to mutate and spread among species of human and animal origin, and they will continue to kill. ...
please see ;
O.05: Transmission of prions to primates after extended silent incubation periods: Implications for BSE and scrapie risk assessment in human populations
Emmanuel Comoy, Jacqueline Mikol, Valerie Durand, Sophie Luccantoni, Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys Atomic Energy Commission; Fontenay-aux-Roses, France
Prion diseases (PD) are the unique neurodegenerative proteinopathies reputed to be transmissible under field conditions since decades. The transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that an animal PD might be zoonotic under appropriate conditions. Contrarily, in the absence of obvious (epidemiological or experimental) elements supporting a transmission or genetic predispositions, PD, like the other proteinopathies, are reputed to occur spontaneously (atpical animal prion strains, sporadic CJD summing 80% of human prion cases). Non-human primate models provided the first evidences supporting the transmissibiity of human prion strains and the zoonotic potential of BSE. Among them, cynomolgus macaques brought major information for BSE risk assessment for human health (Chen, 2014), according to their phylogenetic proximity to humans and extended lifetime. We used this model to assess the zoonotic potential of other animal PD from bovine, ovine and cervid origins even after very long silent incubation periods.
*** We recently observed the direct transmission of a natural classical scrapie isolate to macaque after a 10-year silent incubation period,
***with features similar to some reported for human cases of sporadic CJD, albeit requiring fourfold long incubation than BSE. Scrapie, as recently evoked in humanized mice (Cassard, 2014),
***is the third potentially zoonotic PD (with BSE and L-type BSE),
***thus questioning the origin of human sporadic cases. We will present an updated panorama of our different transmission studies and discuss the implications of such extended incubation periods on risk assessment of animal PD for human health.
***thus questioning the origin of human sporadic cases***
snip...see ;
Monday, November 16, 2015
*** Docket No. APHIS-2007-0127 Scrapie in Sheep and Goats Terry Singeltary Sr. Submission ***
Thursday, January 14, 2016
EMERGING ANIMAL DISEASES Actions Needed to Better Position USDA to Address Future Risks Report to the Chairman, Committee on Energy and Commerce, House of Representatives December 2015 GAO-16-132
Tuesday, January 26, 2016
*** Needless conflict ***
Nature 485, 279–280 (17 May 2012) doi:10.1038/485279b
Published online 16 May 2012
Terry S. Singeltary Sr. said:
I kindly wish to submit the following please ;
Comments on technical aspects of the risk assessment were then submitted to FSIS.
Comments were received from Food and Water Watch, Food Animal Concerns Trust (FACT), Farm Sanctuary, R-CALF USA, Linda A Detwiler, and Terry S. Singeltary.
This document provides itemized replies to the public comments received on the 2005 updated Harvard BSE risk assessment. Please bear the following points in mind:
Owens, Julie
From: Terry S. Singeltary Sr. []
Sent: Monday, July 24, 2006 1:09 PM
To: FSIS RegulationsComments
Subject: [Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine Spongiform Encephalopathy (BSE)
Page 1 of 98
Singeltary to APHIS FDA USDA et al ;
Thursday, October 22, 2015
Former Ag Secretary Ann Veneman talks women in agriculture and we talk mad cow disease USDA and what really happened
Scrapie has been known since 1732...tss
2.2 History
Scrapie is not only the prototype of TSEs but also the prion disease with the longest history of publication. The fi rst authentic report on scrapie was written in Germany and dates back to year 1750 (Leopoldt 1750 ) . However, a later publication (Comber 1772 ) even mentions cases in England that occurred already in 1732. Several authors at later times even referred to much earlier time periods, spanning from Roman times up to the seventeenth century, but without giving corresponding references (for a detailed review see Schneider et al. 2008 ) . Moreover in former times, many sheep diseases were confused with scrapie. Other dif fi culties were the various names that were used to describe this disease throughout Europe: “Goggles”, “Ricketts”, “Rubbing Disease” and “Trotting Disease” in England, “Scratchie” and “Yeukie pine” in Scotland, “Basqvilla Disease” in Spain, “La maladie convulsive”, “La Tremblante” and “Prurigo lumbaire” in France, “Rida” in Iceland, “Gnave-og travesjuke” in Norway and “Gnubberkrankheit”, “Petermännchen”, “Traber” or “Reiberkrankheit” in Germany. Altogether, at least 42 different names were used in Europe and India (Schneider et al. 2008 ) for this disease in small ruminants.
The infectious nature of scrapie was already reckoned in the eighteenth century (Leopoldt 1750 ). In the following decades and centuries, different transmission routes were discussed in which the sexual intercourse was the most suspected modus. However, among other causes like atmospheric disturbances, a few authors proposed a mere coexistence of infected and non-infected animals or a spontaneous origin of the diseases (Schneider et al. 2008 ) . In addition, a broad consent existed already in the nineteenth century concerning the role of hereditary factors for scrapie. Initially, a hereditary predisposition and the transmission by asymptomatic animals were assumed (Thaer 1821 ; von Richthofen 1821 ) and even the existence of hereditary and non-hereditary scrapie forms was postulated (von Richthofen 1826 ) .
>>>Close to 200 years ago, James Parkinson published his 1817 monograph entitled “An Essay on the Shaking Palsy”, in which he reported the first detailed clinical description of the disease that Jean- Martin Charcot named after him in 1872.<<<
*** An Essay on the Shaking Palsy
Alzheimer’s disease is named after Dr. Alois Alzheimer. In 1906, Dr. Alzheimer noticed changes in the brain tissue of a woman who had died of an unusual mental illness. Her symptoms included memory loss, language problems, and unpredictable behavior. After she died, he examined her brain and found many abnormal clumps (now called amyloid plaques) and tangled bundles of fibers (now called neurofibrillary, or tau, tangles).
Creutzfeldt-Jakob disease was first described by Creutzfeldt in 1920 and by Jakob in 1921. It was set apart as a new entity on the basis of its distinctive pathological features. Based on 8 cases, Jakob (1923) gave a lucid outline of the major clinical features.
Terry S. Singeltary Sr. Bacliff, Texas

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