Friday, February 15, 2013

Scottish TSE Network November Symposium Announcement Event: 12 November 2012 Title: Is Alzheimer’s Disease a transmissible disease? SUMMARY

Scottish TSE Network November Symposium Announcement Event: 12 November 2012 Title: Is Alzheimer’s Disease a transmissible disease? SUMMARY

Cell to cell spread of misfolded protein

A meeting was held on the 12th November hosted by the Scottish Transmissible Spongiform Encephalopathy Network (STN) at the Roslin Institute, University of Edinburgh with the aim of examining whether Alzheimer's disease should be classed as a “transmissible disease”? Speakers included international experts in prion and Alzheimer's diseases examining the evidence from studies in the human population and in animal models. The presentations reviewed the current position and the final discussion drew some important conclusions.

It is well known that in prion diseases an abnormal misfolded protein (PrPSc) derived from a normal host protein (PrPC) accumulates and spreads through the brain along defined neuroanatomical pathways. Prion diseases affect both animals (scrapie in sheep, BSE in cattle, chronic wasting disease in deer) and humans (Creutzfeldt - Jakob Disease (CJD)). Transmission between individuals in the natural state has been observed for some prion diseases, for example in sheep and deer. Many, although not all, prion diseases in animals can be experimentally transmitted from animal to animal, and one has transmitted from animal to human,BSE. CJD can also be transmitted to experimental animals. However, transmission of CJD between humans only occurs very rarely and in exceptional circumstances such as the transfer of tissue from an individual with CJD to another by a surgical procedure or via certain medical treatments. Transmission between individuals and spread from cell to cell within an individual, have both been termed “prion transmission”.

It has been shown in neuropathological studies of brains from patients with Alzheimer’s disease that the pathology also spreads in a predictable way through the brain. This spread of pathology in the grey matter of the brain involves the formation of amyloid plaques, comprised of A, outside nerve cells, and neurofibrillary tangles inside nerve cells. Mice carrying human genes that lead to the deposition of the A peptide in the brain have been used to study aspects of Alzheimer’s disease pathology. Experimental studies show that injection of A plaque material, isolated from a human Alzheimer’s disease brain, or another mouse with A plaques can accelerate the deposition of A in the brain and its deposition along neuronal pathways. This predictable spread from cell to cell has been referred to as “prion-like transmission” and has now been demonstrated not only in mouse models with the A protein, but also in other models of neurodegenerative disease that involve the misfolding of proteins. It was suggested by several of the speakers that the injected misfolded peptide or protein acts as a “seed” for further deposition of misfolded protein akin to the growth of a crystal. It is likely that there are considerable parallels between prion diseases and Alzheimer’s disease in the molecular and cellular events leading to cell to cell transmission.

There is no evidence to date from analysis of patient populations that transmission of Alzheimer’s disease between individuals has occurred. It was concluded that human to human transmission of any protein misfolding disease requires a set of very unusual circumstances to occur, as has been documented in the prion diseases. The evidence from human and animal studies does not support the idea that Alzheimer's disease is transmissible between individuals. The term “prion-like transmission” has been unhelpful in the context of Alzheimer’s disease and other protein misfolding diseases as it does not distinguish between spread between cells and transmission between individuals. The meeting concluded that the term “prion-like cell to cell spread” should be used to convey a clear message. The robust experimental models in prion disease provide an opportunity to understand the cellular and molecular mechanisms of cell to cell spread and identify therapeutic targets to delay disease progression for both prion and Alzheimer’s disease.

Professor Jean Manson, The Roslin Institute, University of Edinburgh and R(D)SVS Easter Bush Professor Hugh Perry, University of Southampton


UPDATE JUNE 28, 2012

Scottish TSE Network November Symposium Announcement Event: 12 November 2012

Chair: Prof Hugh Perry, University of Southampton, Southampton UK

Location: The Roslin Institute Building Auditorium

If you would like to book a place at this event, please let Gila Holliman know.

Cost: £125.

Title: Is Alzheimer’s Disease a transmissible disease?


Session 1:

Prof Bob Will, National CJD Surveillance Unit, Edinburgh UK

Prof James Ironside, National CJD Surveillance Unit, Edinburgh UK

Prof Lary Walker, Emory School of Medicine, Atlanta USA

Session 2:

Prof Mathias Jucker, Hertie Institute for Clinical Brain Research, Stuttgart Germany

Prof William Van Nostrand, Stony Brook University, Stony Brook USA

Dr Claudio Soto, University of Texas Medical School, Houston USA

Session 3:

Dr Fabrizio Tagliavini, Instituto Neurologico Carlo Besta, Milan Italy

Prof Pedro Piccardo, Food and Drug Administration, Washington DC USA

Dr Bruce Chesebro, National Institutes of Health, Missoula USA

Transmission of Prions and Alzheimer’s disease Abeta Amyloid

Claudio Soto, PhD

Mitchell Center for Alzheimer’s disease and Related Brain Disorders, Dept of Neurology

University of Texas Medical School at Houston

Tuesday, October 4, 2011

Molecular Psychiatry

advance online publication 4 October 2011; doi: 10.1038/mp.2011.120

De novo induction of amyloid-ß deposition in vivo

Our results suggest that some of the typical brain abnormalities associated with AD can be induced by a prion-like mechanism of disease transmission through propagation of protein misfolding. These findings may have broad implications for understanding the molecular mechanisms responsible for the initiation of AD, and may contribute to the development of new strategies for disease prevention and intervention. Keywords: amyloid; prion; protein misfolding; disease transmission

see more here ;

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?


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.


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.


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.


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.



Wednesday, May 16, 2012

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

Proposal ID: 29403

Wednesday, September 21, 2011

PrioNet Canada researchers in Vancouver confirm prion-like properties in Amyotrophic Lateral Sclerosis (ALS)

Wednesday, February 6, 2013

Penn study confirms no transmission of Alzheimer's proteins between humans ?



Evaluation of Potential Infectivity of Alzheimer and Parkinson Disease Proteins in Recipients of Cadaver-Derived Human Growth Hormone

David J. Irwin, MD; Joseph Y. Abrams, MPH; Lawrence B. Schonberger, MD, MPH; Ellen Werber Leschek, MD; James L. Mills, MD, MS; Virginia M.-Y. Lee, PhD, MBA; John Q. Trojanowski, MD, PhD

Importance: Growing evidence of cell-to-cell transmission of neurodegenerative disease (ND)–associated proteins (NDAPs) (ie, tau, A , and -synuclein) suggests possible similarities to the infectious prion protein (PrPsc) in spongiform encephalopathies. There are limited data on the potential human-to-human transmission of NDAPs associated with Alzheimer disease (AD) and other non- PrPsc ND.

Objective: To examine evidence for human-to-human transmission of AD, Parkinson disease (PD), and related NDAPs in cadaveric human growth hormone (chGH) recipients.

Design: We conducted a detailed immunohistochemical analysis of pathological NDAPs other than PrPsc in human pituitary glands. We also searched for ND in recipients of pituitary-derived c-hGH by reviewing the National Hormone and Pituitary Program (NHPP) cohort database and medical literature.

Setting: University-based academic center and agencies of the US Department of Health and Human Services. Participants: Thirty-four routine autopsy subjects (10 non-ND controls and 24 patients with ND) and a US cohort of c-hGH recipients in the NHPP. Main Outcome Measures: Detectable NDAPs in human pituitary sections and death certificate reports of non- PrPsc ND in the NHPP database.

Results: Wefound mild amounts of pathological tau, A , and -synuclein deposits in the adeno/neurohypophysis of patients with ND and control patients. No cases of AD or PD were identified, and 3 deaths attributed to amyotrophic lateral sclerosis (ALS) were found among USNHPP c-hGH recipients, including 2 of the 796 decedents in the originally confirmed NHPP c-hGH cohort database.

Conclusions and Relevance: Despite the likely frequent exposure of c-hGH recipients to NDAPs, and their markedly elevated risk of PrPsc-related disease, this population of NHPP c-hGH recipients does not appear to be at increased risk of AD or PD. We discovered 3 ALS cases of unclear significance among US c-hGH recipients despite the absence of pathological deposits of ALS-associated proteins (TDP-43, FUS, and ubiquilin) in human pituitary glands. In this unique in vivo model of human-to-human transmission, we found no evidence to support concerns that NDAPs underlyingADand PD transmit disease in humans despite evidence of their cell-to-cell transmission in model systems of these disorders. Further monitoring is required to confirm these conclusions.

JAMA Neurol. Published online February 4, 2013. doi:10.1001/jamaneurol.2013.1933



Our findings herein indicate that pathological species of tau, A , and -synuclein are found in the adeno/ neurohypophysis of normal individuals and those with ND, but, this notwithstanding, these NDAPs are unlikely to propagate between individuals as a diseasecausing infectious agent based on our review of the NHPP database for the following reasons.

First, it is highly likely that c-hGH recipients were exposed to the pathogenic proteins (ie, tau, A , and -synuclein) of AD, PD, and FTLD-tau during the frequent administration of c-hGH that patients received over periods of several years. This assumption is based on the fact that low levels of pathological deposits of these NDAPs were present in both affected and unaffected subjects in our immunohistochemical analysis. Indeed, a similar burden of PrPsc inclusions has been demonstrated in the neurohypophysis of sporadic CJD cases, thereby establishing pituitary gland extracts as the likely source of PrPsc for c-hGH recipients.28 Compared with CJD with an incidence of about 1 case per million, the incidence of AD is at least 3 orders of magnitude higher and the inci-dence of PD at least 2 orders of magnitude higher.29 Thus, provided the pathogenic species of the NDAPs linked to AD, FTLD-tau, and PD as well as PrPsc were similarly affected by the c-hGH purification process, c-hGH recipients would most likely have had a much higher probability of exposure to pathological tau, A , and -synuclein than to PrPsc. In addition, our observations of abnormal deposits of NDAPs in aged control pituitary tissue further increase the likelihood of potential exposure to these proteins.

Second, although more than 200 cases of iatrogenic CJD have been identified to date among the estimated 30 000 c-hGH recipients treated between 1959 and 1985 worldwide30 (7700 in the United States, 1880 in France, and 1800 in the United Kingdom alone23), we found no reports of AD, FTLD, or PD, suggesting that these diseases may not be transmissible between humans.

Several caveats should be noted regarding the interpretation of these findings. First, it is currently unclear which species ofNDAPs(monomers, oligomers, or fibrillar forms) is responsible for transmission seen in published models of disease, although the reports by Luk et al2,3 used preformed -synuclein fibrils to transmit lethal Lewy body disease in an animal model. We demonstrate varying degrees of both amyloid-like and diffuse deposits for A , tau, and -synuclein in the neurohypophysis (Figure 1 and Figure 2). Despite the relative stability of PrPsc, it is still probable that most forms of these non-PrPscNDAPsobserved herein could also survive the relatively crude sequential extraction process used to purify c-hGH prior to 1977 in the United States,31 because the pathological species of NDAPs in AD and related proteinopathies are known to remain insoluble in harsher detergents used in experimental sequential extraction techniques.32,33

Our retrospective analysis is limited to reports in the literature and interrogation of a death certificate database that may not be comprehensive enough to detect all clinically manifest NDs. Indeed, neurologic diseases (ie, neoplasms, head trauma, and radiation necrosis) that occur in some c-hGH recipients may be difficult to distinguish from an emerging ND. However, the NHPP database did enable recognition of an increase in CJD in the US cohort of NHPP c-hGH recipients.

Another uncertainty is the potential incubation period for transmitted NDAPs. The reported mean incubation time for prion disease from midpoint of treatment in c-hGH recipients worldwide was 17 years but ranged from 5 to as long as 42 years.23 Endocrine failure or the underlying etiology of hormone deficiency contributed substantially to the young mean age at death of the patients in our cohort (27.2 years) (eTable 2).34 Despite this, more than half the deceased patients survived 15 years or more after the midpoint of c-hGH treatment, and 19% survived 25 years or more (eTable 2). Additionally, the large number of living patients (about 4600 of the cohort) also have not died of an ND after a long follow-up period of 25 years or more from the initial treatment (eTable 2).

The time required for the underlying neuropathology to cause clinical disease in non-PrPsc ND is not clear, but most likely it varies widely among different individuals and commonly spans several decades. There is evidence of neuropathological changes long before the onset of clinical disease. Early preneurofibrillary tangle pathology has been found in asymptomatic patients as young as the first decade of life.35 Furthermore, biomarker studies of AD suggest amyloidosis may be evident decades before clinical symptoms in AD.36,37 Indeed, new criteria to identify asymptomatic “preclinical” AD highlight the importance of AD neuropathological change as an abnormal prodrome to clinical AD.38 As such, it is possible that susceptible c-hGH patients could be in an early asymptomatic phase of transmitted ND that may not have become clinically manifested yet and thus not detected by our study. The lack of autopsy data for the NHPP cohort limits our ability to examine for evidence of a potential subclinical NDAP transmission and thus provide a more definitive conclusion on the subclinical human-to-human transmission of NDAPs; however, we found no evidence to support clinical transmission of AD or PD in this unique cohort after a relatively long incubation period (as compared with our experience with CJD). Continued follow-up of recipients of c-hGH, with reviews of the clinical and autopsy records of those who may die in the future with anNDlisted as a cause of death, will be important to confirm these findings.

The discovery of 2 deaths attributed to ALS among the initially confirmed cohort of NHPP c-hGH recipients and 1 additional case identified in the literature, especially at such young ages, is disquieting. However, the identification of ALS cases among c-hGH recipients does not definitively indicate transmission of pathogenic TDP- 43, ubiquilin, or FUS since we found no evidence of these proteins in the adeno/neurohypophysis of any of the cases studied herein. Notably, unlike tau, A , and -synuclein pathology, no abnormal TDP-43 deposits occur in the olfactory epithelium as well.26 These data suggest it is very unlikely c-hGH recipients were exposed to ALSassociated pathogenic proteins (ie, TDP-43, FUS, and ubiquilin). Furthermore, autopsy was not performed in 1 case and the others lacked state-of-the-art techniques for modern diagnosis; thus, the molecular etiology of the clinical syndrome in these cases remains uncertain. Indeed, 1 case was described to have degeneration of sensory tracts,27 which is atypical for ALS. Although the earlier- mentioned data suggest infectivity to be an unlikely etiology, surveillance of the c-hGH cohort for ALS and related NDs is necessary to monitor the occurrence of additional cases.

In our follow-up of the unusually young ALS casepatient identified in our literature review,27 we learned that no transmission of ALS per se occurred in a capuchin monkey that in September 1986 had received an intracerebral inoculation of 0.1 mL of a 20% suspension of this patient’s frozen cervical cord tissue. The inoculated monkey died in August 1997 without having developed signs of a neurological disease; an autopsy report, however, was unavailable (P. Brown, MD, and D. M. Asher, MD, oral and written communication, June 18 and 25, 2012). In addition, since the early 1970s, investigators at the National Institutes of Health conducted primate transmission studies with tissues from 58 other cases of ALS, 105 cases of AD, and 24 cases of PD with dementia; in none of these studies did the inoculated pri- mates develop lower motor neuron signs, behavioral changes, or a movement disorder consistent with a non- PrPsc ND, nor did neuropathologists find postmortem evidence for the transmission of these diseases39 (P. Brown, MD, and D. M. Asher, MD, oral and written communication, June 18 and 25, 2012). In contrast, there were at least 300 cases of experimentally transmitted prion diseases during this same period.39 Despite this substantial negative body of evidence for non-PrPsc ND transmission in nonhuman primates, 2 studies in the early 1990s reported that subclinical AD-like plaques were induced in marmosets following central nervous system inoculation with human brain lysates (0.3 mL of 10% saline suspensions).40,41 The majority of human brain lysates shown to induce A pathology in these studies were derived from CJD cases and not AD and there was also no evidence of transmission of clinical disease or tau pathology in any of these inoculated primates.

To our knowledge, only 1 other group of human subjects can provide some additional insights into the transmissibility of NDAPs and that is those patients with PD who received striatal fetal mesencephalic grafts as experimental therapy. Neurons within these grafts showed evidence of PD-like -synuclein Lewy body pathology, but the number of patients whose grafts showed this pathology was small and only rare grafted neurons developed -synuclein Lewy body pathology at or beyond 10 years postgrafting.42-45 However, while this -synuclein pathology could reflect the transmission of pathological -synuclein from the host striatum to the grafted neurons, other explanations are possible, such as the effects of the hosts’ PD neurodegenerative condition on the grafts aside from the -synuclein pathology.12,46

In summary, despite the limitations of this study discussed earlier, to our knowledge, we provide the most compelling human in vivo evidence currently available to suggest that while there are some similarities between the cell-to-cell spread of PrPsc and non-PrPsc NDAPs in experimental models there is currently no documentation that AD, FTLD-tau, or PD-associated proteins (ie, tau, A , or -synuclein) transmit disease in human or nonhuman primates like PrPsc. Prospective monitoring of all c-hGH recipients for CJD and non-PrPsc NDs should be continued.

Accepted for Publication: November 27, 2012. Published Online: February 4, 2013. doi:10.1001 /jamaneurol.2013.1933 Author Affiliations: Center

Wednesday, February 6, 2013

Penn study confirms no transmission of Alzheimer's proteins between humans ?

Sunday, February 10, 2013

Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a Prion-Like Disorder?

Thursday, February 14, 2013

The Many Faces of Mad Cow Disease Bovine Spongiform Encephalopathy BSE and TSE prion disease


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