----- Original Message -----
From: Senator Kay Bailey Hutchison
To: flounder9@verizon.net
Sent: Monday, October 25, 2010 11:32 AM
Subject: Constituent Response From Senator Kay Bailey Hutchison
Dear Friend:
Thank you for contacting me regarding funding for Alzheimer’s disease. I welcome your thoughts and comments.
On July 22, 2009, Senator Barbara Mikulski (D-MD) introduced S. 1492, the Alzheimer’s Breakthrough Act. This bill would increase Alzheimer’s research funding through the National Institutes of Health (NIH) from $400 million to $2 billion in 2010. The legislation would also establish a National Summit on Alzheimer’s disease to coordinate researchers, policymakers and public health professionals. Additionally, it would expand the Alzheimer’s State Matching Grant Program as well as the Alzheimer’s 24/7 call center to provide updated resources and tools for caregivers, family members and those affected in a multilingual capacity.
The Alzheimer’s Breakthrough Act has been referred to the Senate Committee on Health, Education, Labor and Pensions, on which I do not serve. Should this legislation come before the full Senate for a vote, you may be certain I will keep your views in mind.
I am a strong proponent of biomedical research to help discover the causes of and cures for diseases like Alzheimer’s. I recently supported an amendment introduced by Senator Tom Harkin (D-IA) to H.R. 1, America’s Recovery and Reinvestment Act, which appropriated $6.5 billion to the NIH.
As a member of the Senate Appropriations Committee, I worked to include more than $945 million for chronic disease prevention, health promotion and genomics in the FY 2010 Labor, Health and Human Services, Education, and Related Agencies Appropriations Bill (H.R. 3293). This funding is almost a $65 million increase from FY 2009 and includes $2 million specifically for Alzheimer's disease. I also worked with the Committee to include approximately $1.1 billion for the National Institute on Aging (NIA) and strongly urged the NIA to devote more funding to clinical studies and the renewal of the Alzheimer's Disease Neuroimaging Initiative. H.R. 3293 was passed by the Senate Appropriations Committee on July 30, 2009, and is now ready to be considered by the full Senate.
I appreciate hearing from you, and I hope that you will not hesitate to contact me on any issue that is important to you.
Sincerely,
Kay Bailey Hutchison
United States Senator
284 Russell Senate Office Building
Washington, DC 20510
202-224-5922 (tel)
202-224-0776 (fax)
http://hutchison.senate.gov
PLEASE DO NOT REPLY to this message as this mailbox is only for the delivery of outbound messages, and is not monitored for replies. Due to the volume of mail Senator Hutchison receives, she requests that all email messages be sent through the contact form found on her website at http://hutchison.senate.gov/contact.cfm .
If you would like more information about issues pending before the Senate, please visit the Senator's website at http://hutchison.senate.gov . You will find articles, floor statements, and press releases, along with her weekly column and monthly television show on current events. You can also sign up to receive Senator Hutchison's weekly e-newsletter.
Thank you.
end
========================
BSE101/1 0136
IN CONFIDENCE
CMO
From: Dr J S Metters DCMO
4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
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.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Friday, September 3, 2010
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE
http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html
http://betaamyloidcjd.blogspot.com/
2010 PRION UPDATE
Thursday, August 12, 2010
Seven main threats for the future linked to prions
http://prionpathy.blogspot.com/2010/08/seven-main-threats-for-future-linked-to.html
http://prionpathy.blogspot.com/
TSS
Friday, October 22, 2010
Peripherally Applied Aß-Containing Inoculates Induce Cerebral ß-Amyloidosis
http://betaamyloidcjd.blogspot.com/2010/10/peripherally-applied-containing.html
Thursday, October 28, 2010
Friday, October 22, 2010
Peripherally Applied Aß-Containing Inoculates Induce Cerebral ß-Amyloidosis
Peripherally Applied Aß-Containing Inoculates Induce Cerebral ß-Amyloidosis
Yvonne S. Eisele,1,2 Ulrike Obermüller,1,2 Götz Heilbronner,1,2,3 Frank Baumann,1,2 Stephan A. Kaeser,1,2
Hartwig Wolburg,4 Lary C. Walker,5 Matthias Staufenbiel,6 Mathias Heikenwalder,7 Mathias Jucker1,2*
1Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen,
Germany. 2DZNE - German Center for Neurodegenerative Diseases, Tübingen, Germany. 3Graduate School for Cellular and
Molecular Neuroscience, University of Tübingen, Tübingen, Germany. 4Department of Pathology, University of Tübingen,
Tübingen, Germany. 5Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, GA,
USA. 6Novartis Institutes for Biomedical Research, Neuroscience Discovery, Basel, Switzerland. 7Department of Pathology,
Institute for Neuropathology, University Hospital, Zürich, Switzerland.
*To whom correspondence should be addressed. E-mail: mathias.jucker@uni-tuebingen.de
The intracerebral injection of â-amyloid–containing brain extracts can induce cerebral â-amyloidosis and associated pathologies in susceptible hosts. Here, we found that intraperitoneal inoculation with â-amyloid–rich extracts induced â-amyloidosis in the brains of â-amyloid precursor protein transgenic mice after prolonged incubation times.
Intracerebral (i.c.) inoculation with minute amounts of brain extract containing misfolded ß-amyloid (Aß) from patients with Alzheimer’s Disease or from amyloid-bearing ß-amyloid precursor protein (APP) transgenic (tg) mice induces cerebral ß-amyloidosis and related pathologies in APP tg mice in a time- and concentration-dependent manner (1). However, oral, intravenous, intraocular, or intranasal inoculations have failed to induce cerebral ß-amyloidosis in APP tg hosts (2). These findings suggest that Aß-containing brain material in direct contact with the brain can induce cerebral ß-amyloidosis, but that, unlike prions, either the inducing agent is not readily conveyed from peripheral sites to the brain, or a higher concentration or longer incubation period is required for peripherally delivered Aß seeds.
Intraperitoneal (i.p.) administration of prion-rich material is more efficient at transmitting prion disease than is oral administration (3, 4). To test whether i.p. inoculation of Aß- rich material might similarly trigger Aß misfolding and deposition in the brain, we administered two i.p. injections (100 µl each, 1 week apart) of Aß-laden (10-20 ng/µl) brain extract from aged APP23 tg mice (Tg extract) to a cohort of young (2-month-old) female APP23 tg mice (5). After a 7-month incubation period, cerebral ß-amyloidosis was robustly induced in all i.p. inoculated mice compared to untreated littermate controls (Fig. 1). To confirm this finding, we inoculated a second cohort of 2-month-old female APP23 mice with a different batch of Tg brain extract in another laboratory (cohort 2: Tübingen, vs. cohort 1: Basel). After 6–7 months, mice injected i.p. with the Tg extract exhibited robust cerebral ß-amyloidosis, whereas i.p. inoculation with phosphate-buffered saline (PBS) or brain extract from agematched, non-tg wildtype mice (Wt extract) was ineffective (Fig. 1).
Induced ß-amyloidosis was strongest in the anterior and entorhinal cortices with additional deposition in the hippocampus, resembling the regional development of endogenous ß-amyloidosis in aged APP23 mice (6). However, whereas normal aged APP23 mice manifest mostly parenchymal deposits, the induced ß-amyloid in i.p. seeded mice was predominantly associated with blood vessels (cerebral ß-amyloid angiopathy [Aß-CAA]), often with massive spreading into the neighboring brain parenchyma (Fig. 1). The presence of Aß was confirmed by immunoblotting, and amyloid fibrils were evident ultrastructurally; in addition, the induced ß-amyloidosis was linked to gliosis, hyperphosphorylated tau, and other associated pathologies (Fig. 2), reminiscent of the cerebral ß-amyloid deposition in aged APP23 mice (6, 7).
To compare the efficiency and time course of i.p. versus i.c. inoculation, 2-month-old female APP23 mice were inoculated either i.p. (2 x 100 µl) or i.c. (2.5 µl into the hippocampus) with Tg extract, and then analyzed 4 months later. No cerebral ß-amyloid induction was found in any of the 4 i.p. inoculated mice, while all 6 i.c. inoculated mice revealed ß-amyloid induction identical to that previously reported (1, 2). From this observation, together with previous time course and 1:20 dilution experiments for i.c. inoculations (1), we estimate that i.p. inoculations with 103-fold more Aß take 2–5 months longer to induce cerebral ß-amyloidosis than do i.c. inoculations.
The replication of peripherally applied prions and their translocation into the central nervous system depend on hematopoietic and stromal immune cells, in combination with sympathetic innervation of abdominal lymphoid organs (8). Both activation of the immune system and chronic inflammation promote prion replication (9, 10). To assess the immune response to Aß-rich brain extracts, additional APP23 mice were given single i.p. injections of 200 µl Tg or Wt extract and sacrificed 1 hour, 1 week, or 1 month postinjection (5). An acute immune activation to the injected brain material was indicated by transient increases in plasma chemokines and cytokines (IL6, IL10, TNF-a, MCP-1, MIP-1ß) in both Tg and Wt extract-inoculated mice after 1 hour, with IL-6 still mildly elevated in Tg extract-injected mice 1 week post-inoculation (fig. S1). However, no signs of chronic inflammation in various peripheral organs (e.g. liver,pancreas, kidney, lung) or serum anti-Aß antibody titers were found in any mice investigated at 1 or 7 months postseeding (5). Moreover, no ß-amyloid deposition was found in any of the peripheral tissues at any time point studied.
Thus, like prion disease, cerebral ß-amyloidosis can be seeded in the brain by homologous protein aggregates delivered into the peritoneal cavity, although the i.p. route required more time and was less efficient than was direct injection into the brain (1, 2). The amyloid-inducing factor in the Tg extract is probably a species of misfolded Aß that is generated in its most effective form or composition in vivo (1). Because the expression of tg (human) APP is restricted to the nervous system in APP23 mice (7), in this model it is likely that the seed carried to the brain was the injected material itself, rather than Aß aggregates that were first amplified in peripheral tissues.
There is now persuasive evidence that the aggregation of Aß is a key pathogenic feature of AD and Aß-CAA (11–14), although the majority of these cases are initiated by unknown causes. The possibility that mechanisms exist allowing for the transport of Aß aggregates (and possibly other seeds) from the periphery to the brain justifies further studies to better understand the cellular and molecular origin of these diseases and to clarify the basis of infectious vs. non-infectious proteopathies (15, 16).
References and Notes
References and Notes
1. M. Meyer-Lühmann et al., Science 131, 1781 (2006).
2. Y. S. Eisele et al., Proc Natl Acad Sci USA 106, 12926
(2009).
3. S.B. Prusiner, Prion Biology and Diseases (Cold Spring
Harbor Laboratory Press), 2nd Ed pp. 1050 (2004).
4. R.H. Kimberlin, C.A. Walker, J Comp Path 88, 39 (1978).
5. For methods, see Supporting Online Material.
6. C. Sturchler-Pierrat et al., Proc Natl Acad Sci USA 94,
13287 (1997).
7. M.E. Calhoun et al., Proc Natl Acad Sci USA 96, 14088
(1999).
8. A. Aguzzi, C. Sigurdson, M. Heikenwälder, Ann Rev
Pathol Mech Dis 3, 11 (2008).
9. M. Heikenwalder et al., Science 307, 1107 (2005).
10. J. Bremer et al., PloS One 4, e7160 (2009).
11. J. Hardy, D. J. Selkoe, Science 297, 353 (2002).
12. M. Sorandt, M. A. Mintun, D. Head, J. C. Morris, Arch
Neurol 66, 1476 (2009).
13. J. C. Morris et al., Arch Neurol 66, 1469 (2009).
14. S. X. Zhang-Nunes et al., Brain Pathology 16, 30 (2006).
15. L. C. Walker, H. LeVine, M. P. Mattson, M. Jucker,
Trends Neurosci 29, 438 (2006).
16. A. Aguzzi, L. Rajendran, Neuron 64, 783 (2009).
17. We thank M.-J. Runser, L. Jacobson (Basel), F. Langer, J.
Coomaraswamy, S. Grathwohl, N. Varvel, T. Hamaguchi,
C. Schäfer, A. Bosch, G. Frommer-Kästle, U. Scheurlen
(Tübingen) for experimental help and A. Aguzzi (Zürich)
for insightful comments. Supported by the Competence
Network on Degenerative Dementias (BMBF-01GI0705),
the BMBF in the frame of ERA-Net NEURON
(MIPROTRAN), the CIN (DFG), and NIH RR-00165.
Supporting Online Material
www.sciencemag.org/cgi/content/full/science.1194516/DC1
Materials and Methods
Fig. S1
References
1 July 2010; accepted 24 September 2010
Published online 21 October 2010; 10.1126/science.1194516
Fig. 1. Induced Aß deposition. (A and B) Aß-immunostained frontal cortex of Tg extract- (A) and Wt extract- (B) i.p. inoculated APP23 mice. (C and D) Most induced ß-amyloid was vascular (Aß-CAA), with Aß-immunoreactivity extending into the brain parenchyma (arrows). Amyloid-laden vessels were congophilic (red in D; birefringent under crosspolarized light, insert) and often were surrounded by diffuse, Congo red-negative Aß deposits (arrowheads). (E and F) Analysis of the entire neocortex for Aß-CAA frequency (indicated are all three [I-III] CAA severity grades [5]), and for total Aß load in Tg extract-inoculated mice compared to control (Ctr) mice. Cohort 1 consisted of 6 Tg extractinoculated mice vs. 7 untreated control mice. Aß-CAA: t(11) = 6.78 (all severity grades combined), ***P < 0.0001; Aß load: t(11) = 8.79, ***P < 0.0001. Cohort 2 consisted of 5 Tg extract-inoculated mice vs. 5 Wt extract-inoculated mice and 4 PBS-injected mice. These latter 2 (control) groups did not differ significantly, and were combined for analysis. Aß-CAA: t(12) = 7.79, ***P < 0.0001; Aß load t(12) = 2.71, *P < 0.05. The occasional parenchymal Aß-deposits in control mice are normal for 9-month-old APP23 mice. Indicated are means ±SEM. Scale bars: 200 µm (A,B); 50 µm (C,D).
Fig. 2. Induced Aß deposition was linked to multiple associated pathologies. (A) Ultrastructural analysis showed amyloid deposition within the vascular basal lamina (BL), with typical amyloid fibrils (arrowheads) extending into the brain parenchyma. Insets are low- and high-magnification views of the examined vessel (L = lumen) and the typical non-branching amyloid fibrils. (B to E) Vascular amyloid(stained by Congo Red in B and C) and parenchymal plaques were surrounded by hypertrophic, Iba1-positive microglia (B), GFAP-positive astrocytes (C), hyperphosphorylated taupositive neurites (D; asterisk indicates amyloid core), but a paucity of proximate neurons (cresyl-violet stain, E). (F and G) Vessels with CAA types II and III showed smooth muscle cell loss at the site of amyloid deposition (arrowheads; confocal image, maximum projection of 5 µm z-stack: red, Aß; green, smooth muscle actin). A normal vessel (G) has a complete ring of smooth muscle cells. (H) Immunoblotting of micropunches of Aß-immunoreactive material revealed the expected Aß band. Synthetic Aß40/42 is shown as control. Markers = 3 and 6 kD. Scale bars: 1 µm (A; insets 5 and 0.5 µm); 50 µm (B-E); 10 µm (F, G).
end...see ;
Peripherally Applied Aß-Containing Inoculates Induce Cerebral ß-Amyloidosis
http://www.sciencemag.org/cgi/content/abstract/science.1194516
BSE101/1 0136
IN CONFIDENCE
CMO
From: Dr J S Metters DCMO
4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
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.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Friday, September 3, 2010
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE
http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html
http://betaamyloidcjd.blogspot.com/
2010 PRION UPDATE
Thursday, August 12, 2010
Seven main threats for the future linked to prions
http://prionpathy.blogspot.com/2010/08/seven-main-threats-for-future-linked-to.html
http://prionpathy.blogspot.com/
TSS
Yvonne S. Eisele,1,2 Ulrike Obermüller,1,2 Götz Heilbronner,1,2,3 Frank Baumann,1,2 Stephan A. Kaeser,1,2
Hartwig Wolburg,4 Lary C. Walker,5 Matthias Staufenbiel,6 Mathias Heikenwalder,7 Mathias Jucker1,2*
1Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen,
Germany. 2DZNE - German Center for Neurodegenerative Diseases, Tübingen, Germany. 3Graduate School for Cellular and
Molecular Neuroscience, University of Tübingen, Tübingen, Germany. 4Department of Pathology, University of Tübingen,
Tübingen, Germany. 5Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, GA,
USA. 6Novartis Institutes for Biomedical Research, Neuroscience Discovery, Basel, Switzerland. 7Department of Pathology,
Institute for Neuropathology, University Hospital, Zürich, Switzerland.
*To whom correspondence should be addressed. E-mail: mathias.jucker@uni-tuebingen.de
The intracerebral injection of â-amyloid–containing brain extracts can induce cerebral â-amyloidosis and associated pathologies in susceptible hosts. Here, we found that intraperitoneal inoculation with â-amyloid–rich extracts induced â-amyloidosis in the brains of â-amyloid precursor protein transgenic mice after prolonged incubation times.
Intracerebral (i.c.) inoculation with minute amounts of brain extract containing misfolded ß-amyloid (Aß) from patients with Alzheimer’s Disease or from amyloid-bearing ß-amyloid precursor protein (APP) transgenic (tg) mice induces cerebral ß-amyloidosis and related pathologies in APP tg mice in a time- and concentration-dependent manner (1). However, oral, intravenous, intraocular, or intranasal inoculations have failed to induce cerebral ß-amyloidosis in APP tg hosts (2). These findings suggest that Aß-containing brain material in direct contact with the brain can induce cerebral ß-amyloidosis, but that, unlike prions, either the inducing agent is not readily conveyed from peripheral sites to the brain, or a higher concentration or longer incubation period is required for peripherally delivered Aß seeds.
Intraperitoneal (i.p.) administration of prion-rich material is more efficient at transmitting prion disease than is oral administration (3, 4). To test whether i.p. inoculation of Aß- rich material might similarly trigger Aß misfolding and deposition in the brain, we administered two i.p. injections (100 µl each, 1 week apart) of Aß-laden (10-20 ng/µl) brain extract from aged APP23 tg mice (Tg extract) to a cohort of young (2-month-old) female APP23 tg mice (5). After a 7-month incubation period, cerebral ß-amyloidosis was robustly induced in all i.p. inoculated mice compared to untreated littermate controls (Fig. 1). To confirm this finding, we inoculated a second cohort of 2-month-old female APP23 mice with a different batch of Tg brain extract in another laboratory (cohort 2: Tübingen, vs. cohort 1: Basel). After 6–7 months, mice injected i.p. with the Tg extract exhibited robust cerebral ß-amyloidosis, whereas i.p. inoculation with phosphate-buffered saline (PBS) or brain extract from agematched, non-tg wildtype mice (Wt extract) was ineffective (Fig. 1).
Induced ß-amyloidosis was strongest in the anterior and entorhinal cortices with additional deposition in the hippocampus, resembling the regional development of endogenous ß-amyloidosis in aged APP23 mice (6). However, whereas normal aged APP23 mice manifest mostly parenchymal deposits, the induced ß-amyloid in i.p. seeded mice was predominantly associated with blood vessels (cerebral ß-amyloid angiopathy [Aß-CAA]), often with massive spreading into the neighboring brain parenchyma (Fig. 1). The presence of Aß was confirmed by immunoblotting, and amyloid fibrils were evident ultrastructurally; in addition, the induced ß-amyloidosis was linked to gliosis, hyperphosphorylated tau, and other associated pathologies (Fig. 2), reminiscent of the cerebral ß-amyloid deposition in aged APP23 mice (6, 7).
To compare the efficiency and time course of i.p. versus i.c. inoculation, 2-month-old female APP23 mice were inoculated either i.p. (2 x 100 µl) or i.c. (2.5 µl into the hippocampus) with Tg extract, and then analyzed 4 months later. No cerebral ß-amyloid induction was found in any of the 4 i.p. inoculated mice, while all 6 i.c. inoculated mice revealed ß-amyloid induction identical to that previously reported (1, 2). From this observation, together with previous time course and 1:20 dilution experiments for i.c. inoculations (1), we estimate that i.p. inoculations with 103-fold more Aß take 2–5 months longer to induce cerebral ß-amyloidosis than do i.c. inoculations.
The replication of peripherally applied prions and their translocation into the central nervous system depend on hematopoietic and stromal immune cells, in combination with sympathetic innervation of abdominal lymphoid organs (8). Both activation of the immune system and chronic inflammation promote prion replication (9, 10). To assess the immune response to Aß-rich brain extracts, additional APP23 mice were given single i.p. injections of 200 µl Tg or Wt extract and sacrificed 1 hour, 1 week, or 1 month postinjection (5). An acute immune activation to the injected brain material was indicated by transient increases in plasma chemokines and cytokines (IL6, IL10, TNF-a, MCP-1, MIP-1ß) in both Tg and Wt extract-inoculated mice after 1 hour, with IL-6 still mildly elevated in Tg extract-injected mice 1 week post-inoculation (fig. S1). However, no signs of chronic inflammation in various peripheral organs (e.g. liver,pancreas, kidney, lung) or serum anti-Aß antibody titers were found in any mice investigated at 1 or 7 months postseeding (5). Moreover, no ß-amyloid deposition was found in any of the peripheral tissues at any time point studied.
Thus, like prion disease, cerebral ß-amyloidosis can be seeded in the brain by homologous protein aggregates delivered into the peritoneal cavity, although the i.p. route required more time and was less efficient than was direct injection into the brain (1, 2). The amyloid-inducing factor in the Tg extract is probably a species of misfolded Aß that is generated in its most effective form or composition in vivo (1). Because the expression of tg (human) APP is restricted to the nervous system in APP23 mice (7), in this model it is likely that the seed carried to the brain was the injected material itself, rather than Aß aggregates that were first amplified in peripheral tissues.
There is now persuasive evidence that the aggregation of Aß is a key pathogenic feature of AD and Aß-CAA (11–14), although the majority of these cases are initiated by unknown causes. The possibility that mechanisms exist allowing for the transport of Aß aggregates (and possibly other seeds) from the periphery to the brain justifies further studies to better understand the cellular and molecular origin of these diseases and to clarify the basis of infectious vs. non-infectious proteopathies (15, 16).
References and Notes
References and Notes
1. M. Meyer-Lühmann et al., Science 131, 1781 (2006).
2. Y. S. Eisele et al., Proc Natl Acad Sci USA 106, 12926
(2009).
3. S.B. Prusiner, Prion Biology and Diseases (Cold Spring
Harbor Laboratory Press), 2nd Ed pp. 1050 (2004).
4. R.H. Kimberlin, C.A. Walker, J Comp Path 88, 39 (1978).
5. For methods, see Supporting Online Material.
6. C. Sturchler-Pierrat et al., Proc Natl Acad Sci USA 94,
13287 (1997).
7. M.E. Calhoun et al., Proc Natl Acad Sci USA 96, 14088
(1999).
8. A. Aguzzi, C. Sigurdson, M. Heikenwälder, Ann Rev
Pathol Mech Dis 3, 11 (2008).
9. M. Heikenwalder et al., Science 307, 1107 (2005).
10. J. Bremer et al., PloS One 4, e7160 (2009).
11. J. Hardy, D. J. Selkoe, Science 297, 353 (2002).
12. M. Sorandt, M. A. Mintun, D. Head, J. C. Morris, Arch
Neurol 66, 1476 (2009).
13. J. C. Morris et al., Arch Neurol 66, 1469 (2009).
14. S. X. Zhang-Nunes et al., Brain Pathology 16, 30 (2006).
15. L. C. Walker, H. LeVine, M. P. Mattson, M. Jucker,
Trends Neurosci 29, 438 (2006).
16. A. Aguzzi, L. Rajendran, Neuron 64, 783 (2009).
17. We thank M.-J. Runser, L. Jacobson (Basel), F. Langer, J.
Coomaraswamy, S. Grathwohl, N. Varvel, T. Hamaguchi,
C. Schäfer, A. Bosch, G. Frommer-Kästle, U. Scheurlen
(Tübingen) for experimental help and A. Aguzzi (Zürich)
for insightful comments. Supported by the Competence
Network on Degenerative Dementias (BMBF-01GI0705),
the BMBF in the frame of ERA-Net NEURON
(MIPROTRAN), the CIN (DFG), and NIH RR-00165.
Supporting Online Material
www.sciencemag.org/cgi/content/full/science.1194516/DC1
Materials and Methods
Fig. S1
References
1 July 2010; accepted 24 September 2010
Published online 21 October 2010; 10.1126/science.1194516
Fig. 1. Induced Aß deposition. (A and B) Aß-immunostained frontal cortex of Tg extract- (A) and Wt extract- (B) i.p. inoculated APP23 mice. (C and D) Most induced ß-amyloid was vascular (Aß-CAA), with Aß-immunoreactivity extending into the brain parenchyma (arrows). Amyloid-laden vessels were congophilic (red in D; birefringent under crosspolarized light, insert) and often were surrounded by diffuse, Congo red-negative Aß deposits (arrowheads). (E and F) Analysis of the entire neocortex for Aß-CAA frequency (indicated are all three [I-III] CAA severity grades [5]), and for total Aß load in Tg extract-inoculated mice compared to control (Ctr) mice. Cohort 1 consisted of 6 Tg extractinoculated mice vs. 7 untreated control mice. Aß-CAA: t(11) = 6.78 (all severity grades combined), ***P < 0.0001; Aß load: t(11) = 8.79, ***P < 0.0001. Cohort 2 consisted of 5 Tg extract-inoculated mice vs. 5 Wt extract-inoculated mice and 4 PBS-injected mice. These latter 2 (control) groups did not differ significantly, and were combined for analysis. Aß-CAA: t(12) = 7.79, ***P < 0.0001; Aß load t(12) = 2.71, *P < 0.05. The occasional parenchymal Aß-deposits in control mice are normal for 9-month-old APP23 mice. Indicated are means ±SEM. Scale bars: 200 µm (A,B); 50 µm (C,D).
Fig. 2. Induced Aß deposition was linked to multiple associated pathologies. (A) Ultrastructural analysis showed amyloid deposition within the vascular basal lamina (BL), with typical amyloid fibrils (arrowheads) extending into the brain parenchyma. Insets are low- and high-magnification views of the examined vessel (L = lumen) and the typical non-branching amyloid fibrils. (B to E) Vascular amyloid(stained by Congo Red in B and C) and parenchymal plaques were surrounded by hypertrophic, Iba1-positive microglia (B), GFAP-positive astrocytes (C), hyperphosphorylated taupositive neurites (D; asterisk indicates amyloid core), but a paucity of proximate neurons (cresyl-violet stain, E). (F and G) Vessels with CAA types II and III showed smooth muscle cell loss at the site of amyloid deposition (arrowheads; confocal image, maximum projection of 5 µm z-stack: red, Aß; green, smooth muscle actin). A normal vessel (G) has a complete ring of smooth muscle cells. (H) Immunoblotting of micropunches of Aß-immunoreactive material revealed the expected Aß band. Synthetic Aß40/42 is shown as control. Markers = 3 and 6 kD. Scale bars: 1 µm (A; insets 5 and 0.5 µm); 50 µm (B-E); 10 µm (F, G).
end...see ;
Peripherally Applied Aß-Containing Inoculates Induce Cerebral ß-Amyloidosis
http://www.sciencemag.org/cgi/content/abstract/science.1194516
BSE101/1 0136
IN CONFIDENCE
CMO
From: Dr J S Metters DCMO
4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
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.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Friday, September 3, 2010
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE
http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html
http://betaamyloidcjd.blogspot.com/
2010 PRION UPDATE
Thursday, August 12, 2010
Seven main threats for the future linked to prions
http://prionpathy.blogspot.com/2010/08/seven-main-threats-for-future-linked-to.html
http://prionpathy.blogspot.com/
TSS
Friday, September 3, 2010
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE
Sunday, August 8, 2010
The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids
http://betaamyloidcjd.blogspot.com/2010/08/transcellular-spread-of-cytosolic.html
Are some commoner types of neurodegenerative disease (including Alzheimer's disease and Parkinson's disease) also transmissible? Some recent scientific research has suggested this possibility
Monday, October 12, 2009
SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens TSE 8 October 2009
http://www.seac.gov.uk/pdf/hol-response091008.pdf
see full text and more science on this topic here ;
http://bse-atypical.blogspot.com/2009/10/seac-science-and-technology-committees.html
13
Simultaneous Onset of Alzheimer's Disease in a Husband and Wife in Their Mid Fifties: What do We Really Know?
Jonathan Heath1, Lindsay Goicochea2, Mark Smith3, Rudy Castellani4. 1Department of Pathology, University of Maryland; 2University; 3Case Western Reserve University; 4University of Maryland, Baltimore, Maryland
Whereas the genetic factors influencing the development and expression of Alzheimer's disease are well characterized, environmental factors are currently thought to play a marginal role. Such factors as prior closed head injury, post-menopausal estrogen deficiency, aluminum exposure, smoking, diabetes, atherosclerotic cardiovascular disease, and diet, among others, confer only a modest increased risk if any, and are only tangentially considered in the major pathogenic cascades that are presently hypothesized. We present the simultaneous onset of Alzheimer's disease in a husband and wife, with both subjects experiencing cognitive dysfunction within the same month. Both subjects were in their mid-fifties at the time of presentation, both subjects showed progressively neurological decline with prominent memory loss, both subjects experienced myoclonus late in their disease course prompting referral to the National Prion Disease Pathology Surveillance Center, and both subjects expired 12 years after onset, within two months of each other. Review of the family pedigree revealed no family history of dementia or other neurologic illnesses in multiple first degree relatives. The only historical finding of note was that both subjects had moved out of their home briefly while it was being remodeled, and both became symptomatic shortly after moving back in. At autopsy, the subjects had classic advanced Alzheimer's disease, with Braak stage VI pathology that was otherwise identiical in quantity and distribution of amyloid-beta, cerebral amyloid angiopathy, and neurofibrillary degeneration. While no specific toxin or other environmental cause was discerned, these two cases raise the issue of epigenetic factors in Alzheimer's disease that may be more robust than current literature indicates.
http://journals.lww.com/jneuropath/Fulltext/2010/05000/American_Association_of_Neuropathologists,_Inc__.9.aspx
NEUROLOGY 1998;50:684-688 © 1998 American Academy of Neurology
Creutzfeldt-Jakob disease in a husband and wife
P. Brown, MD, L. Cervenáková, MD, L. McShane, PhD, L. G. Goldfarb, MD, K. Bishop, BS, F. Bastian, MD, J. Kirkpatrick, MD, P. Piccardo, MD, B. Ghetti, MD and D. C. Gajdusek, MD From the Laboratory of CNS Studies (Drs. Brown, Cervenáková, Goldfarb, and Gajdusek), NINDS, and Biometric Research Branch (Dr. McShane), NCI, National Institutes of Health, Bethesda, MD; the Department of Obstetrics (K. Bishop), Gynecology and Reproductive Sciences, University of Texas Houston Health Science Center, Houston, TX; the Department of Pathology (Dr. Bastian), University of South Alabama Medical Center, Mobile, AL; the Department of Pathology (Dr. Kirkpatrick), The Methodist Hospital, Houston, TX; and the Department of Pathology (Drs. Piccardo and Ghetti), Indiana University School of Medicine, Indianapolis, IN.
Address correspondence and reprint requests to Dr. Paul Brown, Building 36, Room 5B21, National Institutes of Health, Bethesda, MD 20892.
A 53-year-old man died of sporadic Creutzfeldt-Jakob disease (CJD) after a 1.5-year clinical course. Four and a half years later, his then 55-year-old widow died from CJD after a 1-month illness. Both patients had typical clinical and neuropathologic features of the disease, and pathognomonic proteinase-resistant amyloid protein ("prion" protein, or PrP) was present in both brains. Neither patient had a family history of neurologic disease, and molecular genetic analysis of their PrP genes was normal. No medical, surgical, or dietary antecedent of CJD was identified; therefore, we are left with the unanswerable alternatives of human-to-human transmission or the chance occurrence of sporadic CJD in a husband and wife.
--------------------------------------------------------------------------------
Received May 5, 1997. Accepted in final form September 10, 1997.
http://www.neurology.org/cgi/content/abstract/50/3/684
Research Lead: Dr. David Westaway, University of Alberta
Project: "Extending the spectrum of Prionopathies to Amyotrophic Lateral Sclerosis and Autism"
This project proposes to link the chemistry of the prion protein to the new territory of other nervous system diseases, such as ALS (Lou Gehrig's disease) and the socialization disorder autism-diseases which are at least one thousand times more common than prion diseases. It is believed that a different type or prion protein may operate in other types of brain diseases, which could lead to new ways of thinking about incurable disorders. The project will create changes in the amounts of the various forms of the new membrane protein, and then perform an array of analyses on the behavior and nervous system transmission of laboratory mice. Nervous transmission by electrical impulse can be measured in isolated brain cells, a system that is also convenient to study the effect of stress by adding small amounts of toxins to the fluids bathing the cultures. By these means, the project aims to extend the boundaries of what is considered "prion disease."
Funding: $520,500
http://www.prioninstitute.ca/index.php?page=webpages&menucat=42&id=26&action=displaypage&side=1
Unfolding the Prion Mystery Building and Growing Research Expertise in Alberta Year 4 2008-2009 Annual Report
Dr. David Westaway, University of Alberta Extending the spectrum of prionopathies to amyotrophic lateral sclerosis (ALS) and autism Dr. Westaway’s study aims to extend the boundaries of what is considered prion disease. His project takes the chemistry of the prion protein into the territory of nervous system diseases such as ALS (Lou Gehrig’s disease) and socialization disorder diseases such as autism. These brain diseases are at least 1,000 times more common than diseases currently accepted as prion related. Dr. Westaway hypothesizes that a different type of protein misfolding may operate in brain diseases such as Lou Gehrig’s and autism. This type of protein misfolding may occur in response to stresses in the brain. Unlike misfolded prions, other misfolded proteins may be noninfectious and not viable outside of the affected animal. Dr. Westaway’s research team will investigate these hypotheses by inducing changes in the brain cells of laboratory mice, measuring the resulting electrical impulses in the animals’ nervous systems and analyzing the effect on behaviour. Because nervous transmission by electrical impulse can be measured in isolated brain cells, adding small amounts of toxins to the fluids bathing the cell cultures will make it possible to study the effect of stress. The results could lead to new ways of thinking about nervous system disorders.
http://www.prioninstitute.ca/forms/WEBSITE%20AR.pdf
Sunday, May 18, 2008
MAD COW DISEASE BSE CJD CHILDREN VACCINES
TWA LITTLE STATEMENT 331
http://collections.europarchive.org/tna/20080102163939/http://www.bseinquiry.gov.uk/files/ws/s331.pdf
http://collections.europarchive.org/tna/20080103032631/http://www.bseinquiry.gov.uk/files/yb/1988/11/04003001.pdf
8. The Secretary of State has a number of licences. We understand that the inactivated polio vaccine is no longer being used. There is a stock of smallpox vaccine. We have not been able to determine the source material. (Made in sheep very unlikely to contain bovine ingredients).
CONFIDENTIAL
http://collections.europarchive.org/tna/20080102164642/http://www.bseinquiry.gov.uk/files/yb/1989/02/14010001.pdf
see full text ;
http://bseinquiry.blogspot.com/2008/05/mad-cow-disease-bse-cjd-children.html
Terry S. Singeltary Sr. [flounder@wt.net]
Monday, January 08,200l 3:03 PM
freas@CBS5055530.CBER.FDA.GOV CJD/BSE (aka madcow) Human/Animal TSE’s --U.S.-- Submission To Scientific Advisors and Consultants Staff January 2001 Meeting (short version)
Greetings again Dr. Freas and Committee Members,
http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf
BELOW, PAGE 1 ACTUALLY STARTS ON PAGE 13, then when you get to the bottom, part 3 starts at the top.........TSS
From: Terry S. Singeltary Sr.
To: FREAS@CBER.FDA.GOV
Cc: william.freas@fda.hhs.gov ; rosanna.harvey@fda.hhs.gov
Sent: Friday, December 01, 2006 2:59 PM
Subject: Re: TSE advisory committee for the meeting December 15, 2006 [TSS SUBMISSION
snip...
ONE FINAL COMMENT PLEASE, (i know this is long Dr. Freas but please bear with me)
THE USA is in a most unique situation, one of unknown circumstances with human and animal TSE. THE USA has the most documented TSE in different species to date, with substrains growing in those species (BSE/BASE in cattle and CWD in deer and elk, there is evidence here with different strains), and we know that sheep scrapie has over 20 strains of the typical scrapie with atypical scrapie documented and also BSE is very likely to have passed to sheep. all of which have been rendered and fed back to animals for human and animal consumption, a frightening scenario. WE do not know the outcome, and to play with human life around the globe with the very likely TSE tainted blood from the USA, in my opinion is like playing Russian roulette, of long duration, with potential long and enduring consequences, of which once done, cannot be undone.
These are the facts as i have come to know through daily and extensive research of TSE over 9 years, since 12/14/97. I do not pretend to have all the answers, but i do know to continue to believe in the ukbsenvcjd only theory of transmission to humans of only this one strain from only this one TSE from only this one part of the globe, will only lead to further failures, and needless exposure to humans from all strains of TSE, and possibly many more needless deaths from TSE via a multitude of proven routes and sources via many studies with primates and rodents and other species. ...
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
snip... 48 pages...
http://www.regulations.gov/fdmspublic/ContentViewer?objectId=09000064801f3413&disposition=attachment&contentType=msw8
Subject: Louping-ill vaccine documents from November 23rd, 1946
Date: Sat, 9 Sep 2000 17:44:57 -0700
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
http://www.whale.to/v/singeltary.html
Tuesday, August 03, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html
Monday, August 9, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more PRIONBALONEY ?
http://prionunitusaupdate2008.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html
Wednesday, August 18, 2010
Incidence of CJD Deaths Reported by CJD-SS in Canada as of July 31, 2010
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/incidence-of-cjd-deaths-reported-by-cjd.html
Monday, August 9, 2010
National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)
(please watch and listen to the video and the scientist speaking about atypical BSE and sporadic CJD and listen to Professor Aguzzi)
http://prionunitusaupdate2008.blogspot.com/2010/08/national-prion-disease-pathology.html
TSS
Sunday, August 8, 2010
The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids
http://betaamyloidcjd.blogspot.com/2010/08/transcellular-spread-of-cytosolic.html
Are some commoner types of neurodegenerative disease (including Alzheimer's disease and Parkinson's disease) also transmissible? Some recent scientific research has suggested this possibility
Monday, October 12, 2009
SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens TSE 8 October 2009
http://www.seac.gov.uk/pdf/hol-response091008.pdf
see full text and more science on this topic here ;
http://bse-atypical.blogspot.com/2009/10/seac-science-and-technology-committees.html
13
Simultaneous Onset of Alzheimer's Disease in a Husband and Wife in Their Mid Fifties: What do We Really Know?
Jonathan Heath1, Lindsay Goicochea2, Mark Smith3, Rudy Castellani4. 1Department of Pathology, University of Maryland; 2University; 3Case Western Reserve University; 4University of Maryland, Baltimore, Maryland
Whereas the genetic factors influencing the development and expression of Alzheimer's disease are well characterized, environmental factors are currently thought to play a marginal role. Such factors as prior closed head injury, post-menopausal estrogen deficiency, aluminum exposure, smoking, diabetes, atherosclerotic cardiovascular disease, and diet, among others, confer only a modest increased risk if any, and are only tangentially considered in the major pathogenic cascades that are presently hypothesized. We present the simultaneous onset of Alzheimer's disease in a husband and wife, with both subjects experiencing cognitive dysfunction within the same month. Both subjects were in their mid-fifties at the time of presentation, both subjects showed progressively neurological decline with prominent memory loss, both subjects experienced myoclonus late in their disease course prompting referral to the National Prion Disease Pathology Surveillance Center, and both subjects expired 12 years after onset, within two months of each other. Review of the family pedigree revealed no family history of dementia or other neurologic illnesses in multiple first degree relatives. The only historical finding of note was that both subjects had moved out of their home briefly while it was being remodeled, and both became symptomatic shortly after moving back in. At autopsy, the subjects had classic advanced Alzheimer's disease, with Braak stage VI pathology that was otherwise identiical in quantity and distribution of amyloid-beta, cerebral amyloid angiopathy, and neurofibrillary degeneration. While no specific toxin or other environmental cause was discerned, these two cases raise the issue of epigenetic factors in Alzheimer's disease that may be more robust than current literature indicates.
http://journals.lww.com/jneuropath/Fulltext/2010/05000/American_Association_of_Neuropathologists,_Inc__.9.aspx
NEUROLOGY 1998;50:684-688 © 1998 American Academy of Neurology
Creutzfeldt-Jakob disease in a husband and wife
P. Brown, MD, L. Cervenáková, MD, L. McShane, PhD, L. G. Goldfarb, MD, K. Bishop, BS, F. Bastian, MD, J. Kirkpatrick, MD, P. Piccardo, MD, B. Ghetti, MD and D. C. Gajdusek, MD From the Laboratory of CNS Studies (Drs. Brown, Cervenáková, Goldfarb, and Gajdusek), NINDS, and Biometric Research Branch (Dr. McShane), NCI, National Institutes of Health, Bethesda, MD; the Department of Obstetrics (K. Bishop), Gynecology and Reproductive Sciences, University of Texas Houston Health Science Center, Houston, TX; the Department of Pathology (Dr. Bastian), University of South Alabama Medical Center, Mobile, AL; the Department of Pathology (Dr. Kirkpatrick), The Methodist Hospital, Houston, TX; and the Department of Pathology (Drs. Piccardo and Ghetti), Indiana University School of Medicine, Indianapolis, IN.
Address correspondence and reprint requests to Dr. Paul Brown, Building 36, Room 5B21, National Institutes of Health, Bethesda, MD 20892.
A 53-year-old man died of sporadic Creutzfeldt-Jakob disease (CJD) after a 1.5-year clinical course. Four and a half years later, his then 55-year-old widow died from CJD after a 1-month illness. Both patients had typical clinical and neuropathologic features of the disease, and pathognomonic proteinase-resistant amyloid protein ("prion" protein, or PrP) was present in both brains. Neither patient had a family history of neurologic disease, and molecular genetic analysis of their PrP genes was normal. No medical, surgical, or dietary antecedent of CJD was identified; therefore, we are left with the unanswerable alternatives of human-to-human transmission or the chance occurrence of sporadic CJD in a husband and wife.
--------------------------------------------------------------------------------
Received May 5, 1997. Accepted in final form September 10, 1997.
http://www.neurology.org/cgi/content/abstract/50/3/684
Research Lead: Dr. David Westaway, University of Alberta
Project: "Extending the spectrum of Prionopathies to Amyotrophic Lateral Sclerosis and Autism"
This project proposes to link the chemistry of the prion protein to the new territory of other nervous system diseases, such as ALS (Lou Gehrig's disease) and the socialization disorder autism-diseases which are at least one thousand times more common than prion diseases. It is believed that a different type or prion protein may operate in other types of brain diseases, which could lead to new ways of thinking about incurable disorders. The project will create changes in the amounts of the various forms of the new membrane protein, and then perform an array of analyses on the behavior and nervous system transmission of laboratory mice. Nervous transmission by electrical impulse can be measured in isolated brain cells, a system that is also convenient to study the effect of stress by adding small amounts of toxins to the fluids bathing the cultures. By these means, the project aims to extend the boundaries of what is considered "prion disease."
Funding: $520,500
http://www.prioninstitute.ca/index.php?page=webpages&menucat=42&id=26&action=displaypage&side=1
Unfolding the Prion Mystery Building and Growing Research Expertise in Alberta Year 4 2008-2009 Annual Report
Dr. David Westaway, University of Alberta Extending the spectrum of prionopathies to amyotrophic lateral sclerosis (ALS) and autism Dr. Westaway’s study aims to extend the boundaries of what is considered prion disease. His project takes the chemistry of the prion protein into the territory of nervous system diseases such as ALS (Lou Gehrig’s disease) and socialization disorder diseases such as autism. These brain diseases are at least 1,000 times more common than diseases currently accepted as prion related. Dr. Westaway hypothesizes that a different type of protein misfolding may operate in brain diseases such as Lou Gehrig’s and autism. This type of protein misfolding may occur in response to stresses in the brain. Unlike misfolded prions, other misfolded proteins may be noninfectious and not viable outside of the affected animal. Dr. Westaway’s research team will investigate these hypotheses by inducing changes in the brain cells of laboratory mice, measuring the resulting electrical impulses in the animals’ nervous systems and analyzing the effect on behaviour. Because nervous transmission by electrical impulse can be measured in isolated brain cells, adding small amounts of toxins to the fluids bathing the cell cultures will make it possible to study the effect of stress. The results could lead to new ways of thinking about nervous system disorders.
http://www.prioninstitute.ca/forms/WEBSITE%20AR.pdf
Sunday, May 18, 2008
MAD COW DISEASE BSE CJD CHILDREN VACCINES
TWA LITTLE STATEMENT 331
http://collections.europarchive.org/tna/20080102163939/http://www.bseinquiry.gov.uk/files/ws/s331.pdf
http://collections.europarchive.org/tna/20080103032631/http://www.bseinquiry.gov.uk/files/yb/1988/11/04003001.pdf
8. The Secretary of State has a number of licences. We understand that the inactivated polio vaccine is no longer being used. There is a stock of smallpox vaccine. We have not been able to determine the source material. (Made in sheep very unlikely to contain bovine ingredients).
CONFIDENTIAL
http://collections.europarchive.org/tna/20080102164642/http://www.bseinquiry.gov.uk/files/yb/1989/02/14010001.pdf
see full text ;
http://bseinquiry.blogspot.com/2008/05/mad-cow-disease-bse-cjd-children.html
Terry S. Singeltary Sr. [flounder@wt.net]
Monday, January 08,200l 3:03 PM
freas@CBS5055530.CBER.FDA.GOV CJD/BSE (aka madcow) Human/Animal TSE’s --U.S.-- Submission To Scientific Advisors and Consultants Staff January 2001 Meeting (short version)
Greetings again Dr. Freas and Committee Members,
http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf
BELOW, PAGE 1 ACTUALLY STARTS ON PAGE 13, then when you get to the bottom, part 3 starts at the top.........TSS
From: Terry S. Singeltary Sr.
To: FREAS@CBER.FDA.GOV
Cc: william.freas@fda.hhs.gov ; rosanna.harvey@fda.hhs.gov
Sent: Friday, December 01, 2006 2:59 PM
Subject: Re: TSE advisory committee for the meeting December 15, 2006 [TSS SUBMISSION
snip...
ONE FINAL COMMENT PLEASE, (i know this is long Dr. Freas but please bear with me)
THE USA is in a most unique situation, one of unknown circumstances with human and animal TSE. THE USA has the most documented TSE in different species to date, with substrains growing in those species (BSE/BASE in cattle and CWD in deer and elk, there is evidence here with different strains), and we know that sheep scrapie has over 20 strains of the typical scrapie with atypical scrapie documented and also BSE is very likely to have passed to sheep. all of which have been rendered and fed back to animals for human and animal consumption, a frightening scenario. WE do not know the outcome, and to play with human life around the globe with the very likely TSE tainted blood from the USA, in my opinion is like playing Russian roulette, of long duration, with potential long and enduring consequences, of which once done, cannot be undone.
These are the facts as i have come to know through daily and extensive research of TSE over 9 years, since 12/14/97. I do not pretend to have all the answers, but i do know to continue to believe in the ukbsenvcjd only theory of transmission to humans of only this one strain from only this one TSE from only this one part of the globe, will only lead to further failures, and needless exposure to humans from all strains of TSE, and possibly many more needless deaths from TSE via a multitude of proven routes and sources via many studies with primates and rodents and other species. ...
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
snip... 48 pages...
http://www.regulations.gov/fdmspublic/ContentViewer?objectId=09000064801f3413&disposition=attachment&contentType=msw8
Subject: Louping-ill vaccine documents from November 23rd, 1946
Date: Sat, 9 Sep 2000 17:44:57 -0700
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
http://www.whale.to/v/singeltary.html
Tuesday, August 03, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html
Monday, August 9, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more PRIONBALONEY ?
http://prionunitusaupdate2008.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html
Wednesday, August 18, 2010
Incidence of CJD Deaths Reported by CJD-SS in Canada as of July 31, 2010
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/incidence-of-cjd-deaths-reported-by-cjd.html
Monday, August 9, 2010
National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)
(please watch and listen to the video and the scientist speaking about atypical BSE and sporadic CJD and listen to Professor Aguzzi)
http://prionunitusaupdate2008.blogspot.com/2010/08/national-prion-disease-pathology.html
TSS
Sunday, August 8, 2010
The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids
Neuron
Perspective
The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids
Adriano Aguzzi1,* and Lawrence Rajendran2,* 1Institute of Neuropathology, University Hospital of Zu¨ rich, Schmelzbergstrasse 12, CH-8091 Zu¨ rich, Switzerland 2Systems and Cell Biology of Neurodegeneration, Psychiatry Research, University of Zurich, CH-8008 Zu¨ rich, Switzerland *Correspondence: adriano.aguzzi@usz.ch (A.A.), rajendran@bli.uzh.ch (L.R.) DOI 10.1016/j.neuron.2009.12.016
Recent reports indicate that a growing number of intracellular proteins are not only prone to pathological aggregation but can also be released and ‘‘infect’’ neighboring cells. Therefore, many complex diseases may obey a simple model of propagation where the penetration of seeds into hosts determines spatial spread and disease progression. We term these proteins prionoids, as they appear to infect their neighbors just like prions—but how can bulky protein aggregates be released from cells and how do they access other cells? The widespread existence of such prionoids raises unexpected issues that question our understanding of basic cell biology.
Imagine that you are a neuroscientist vacationing on Mars. One day you encounter a colony of Martians that, as it happens, look similar to water bottles. The Martians are highly distressed and seek your advice, as their community is plagued by an enigmatic transmissible disease. Intrigued, you agree to help. It turns out that the bodies of your exobiotic friends consist of bottles filled with a supersaturated salt solution. At some point crystals have started forming in one individual, and then crystallization has somehow been transferred to other community members. Lacking molecular insight, you would initially conclude that the Martians are affected by an infectious agent. Through ingenuity and technology, you may then discover that the infectious agent is exceedingly simple and homogeneous, that it lacks informational nucleic acids, and that it is generated both by ordered aggregation of an intrinsic precursor and by appositional growth of extrinsically added seeds. Your discovery will earn you the Intergalactic Nobel Prize, yet two crucial questions remain unanswered: how do the crystals transfer between individuals, and what can be done to prevent this from happening?
Middle-aged readers may feel reminded of the plot for Andromeda Strain, a stunningly prescient novel published in 1969 by the late Michael Crichton. But the sci-fi scenario described above is also the blueprint of Prusiner’s hypothesis of prion propagation. Over time, we have learned that prions consist of PrPSc, higher-order aggregates of a physiological protein termed PrPC. Accordingly, prions propagate through elongation and breakage of PrPSc aggregates (Aguzzi and Polymenidou, 2004)—not unlike the crystals vexing our extraterrestrial friends.
There is mounting evidence (Clavaguera et al., 2009; Frost et al., 2009; Ren et al., 2009; Desplats et al., 2009; Luk et al., 2009) suggesting that the events sketched above, far from being confined to science-fiction and prion diseases (whose incidence in humans is just z1/106/year), may underlie highly prevalent human diseases of the brain and many other organs. The unifying characteristics of all these diseases is the aggregation of proteins into highly ordered stacks, henceforth termed ‘‘amyloids’’ irrespective of their size. Since PrPSc undoubtedly fulfills the latter definition of amyloid, one is led to wonder whether the prion principle may be much more pervasive than previously appreciated and whether many more diseases of unknown cause may eventually turn out to rely on prion-like propagation (Table 1, upper panel). Even more intriguingly, a number of proteins appear to exert normal functions when arranged in highly ordered stacks that are similar to amyloids and to prionoids (Table 1, lower panel).
Prions and Prionoids
There is one crucial difference between bona fide prion diseases and all other amyloids and prion-like phenomena hitherto described in uni- and pluricellular organisms (Table 1). Prions are infectious agents, transmissible between individuals, and tractable with microbiological techniques—including, e.g., titer determinations. Even if certain amyloids of yeast and mammals appear to infect neighboring molecules and sometimes neighboring cells, they do not propagate within communities, and none of them were found to cause macroepidemics such as Kuru and bovine spongiform encephalopathy. We have therefore termed these self-aggregating proteins ‘‘prionoids’’ (Aguzzi, 2009), since the lack of microbiological transmissibility precludes their classification as true prions.
Some prionoids may soon qualify for an upgrade to prion status. At least in select settings, amyloid A (AA) amyloidosis may exist as a truly infectious disease based on a self-propagating protein. AA amyloid consists of orderly aggregated fragments of SAA protein, whose deposition can damage many organs of the body. Somewhat bizarrely, AA aggregation is also present in the liver of force-fed geese, hence contributing to the pathophysiology of foie gras (Solomon et al., 2007). AA seeds can induce amyloidosis upon transfer of white blood cells (Sponarova et al., 2008). Furthermore, AA seeds are excreted with the feces, and AA amyloidosis is endemic in populations of cheetah (Zhang et al., 2008). It is therefore tantalizing to suspect that amyloid may entertain the complete life cycle of an infectious agent, including transmission by the orofecal and hematogenous route—similarly to enteroviruses and, perhaps, scrapie prions. While there may be many other good reasons to avoid foie gras, including, e.g., animal welfare concerns, gourmets may not need to panic: under experimental conditions, AA amyloidosis is only transmitted to AgNO3-pretreated mice that display elevated levels of the SAA precursor protein.
Alzheimer’s disease (AD) has long been suspected to be a transmissible disease, but these suspicions have never materialized in epidemiological studies. On the other hand, Mathias Jucker and Lary Walker observed that injection of the Ab peptide from human AD brains induced robust and convincing aggregation of Ab in transgenic mice overexpressing the Ab precursor protein, APP (Kane et al., 2000; Meyer-Luehmann et al., 2006). Jucker’s finding raises an epistemologically significant question: if aggregation depends on the introduction of seeds and on the availability of the monomeric precursor, and if amyloid represents the primordial state of all proteins (Chiti and Dobson, 2006), wouldn’t all proteins—under appropriate conditions— give rise to prionoids in the presence of sufficient precursor?
The issues sketched above go well beyond AD and prions. There are many other diseases—not necessarily involving the nervous system—whose pathogenesis involves ordered aggregation of proteins, but for which there is no evidence of transmission between individuals. The best-studied of these are the systemic amyloidoses, which come about through the nucleation of some aggregation-prone proteins such as transthyretin and immunoglobulin light chains. Yet ordered protein aggregation is by no means confined to the ‘‘classical’’ amyloidoses and extends to a number of conditions, some of which have been rather unexpected.
Type II diabetes is yet another disease whose pathogenesis may involve ordered protein aggregation. Evidence to support this idea was discovered over a century ago (Opie, 1901) but was largely forgotten until recently. It is now evident that aggregation of islet amyloid polypeptide (IAPP) is an exceedingly frequent feature of type II diabetes. IAPP amyloids damage the insulin-producing b cells within pancreatic islets and may crucially contribute to the pathogenesis of diabetes (Hull et al., 2004). It is unknown, however, whether IAPP deposition simply accrues linearly with IAPP production or whether it spreads prion-like from one pancreatic islet to the next.
A body of recent work supports the idea that many aggregation proteinopathies are, in one way or another, transmissible. A recent report showed that a-synuclein is released from neurons and is then taken up by the neighboring cells, thereby aiding in a progressive spread of the protein (Desplats et al., 2009; Lee et al., 2005). When exogenously added to cultured cells, fluorescently labeled, recombinant a-synuclein was internalized from the extracellular milieu into the cytosol. Furthermore, injection of GFP-labeled mouse cortical neuronal stem cells into the hippocampus of a-synuclein-transgenic mice led to the efficient uptake of the host a-synuclein into the grafted cells after just 4 weeks. These findings are reminiscent of the observation that healthy fetal tissue, grafted into the brains of Parkinson’s disease patients, acquired intracellular Lewy bodies. The latter phenomenon is somewhat anecdotal and has been disputed (Mendez et al., 2008), yet it would be entirely compatible with the hypothesis that a-synuclein aggregates are prionoids (Li et al., 2008). A similar study conclusively demonstrated that exogenous a-synuclein fibrils induced the formation of Lewy body-like intracellular inclusions in vitro (Luk et al., 2009). This study also showed that the conversion of the host cell a-synuclein was accompanied by dramatic changes, including hyperphosphorylation and ubiquitination of a-synuclein aggregates—thus recapitulating some key features of the human pathology.
In experiments conceptually analogous to those discussed above, polyglutamine-containing protein aggregates similar to those present in Huntington’s disease and in spinocerebellar ataxias exhibited prion-like propagation (Ren et al., 2009). There, aggregation of huntingtin progressed from the extracellular space to the cytosol and eventually to the nucleus. What is more, similar phenomena occurred upon exposure of cells to Sup35 aggregates, which consist of a yeast protein for which there are no known mammalian paralogs. This suggests that the prionoid properties are intrinsic to amyloids and are not tied to the origin or function of their monomeric precursor protein.
In another work, Tolnay and colleagues report a similar phenomenon in a mouse model of ‘‘tauopathy,’’ a neurodegenerative disease due to intraneuronal aggregation of the microtubule- associated tau protein (Clavaguera et al., 2009). Aggregation- prone mutant tau, when extracted from the brain of transgenic mice, induced tauopathy in mice overexpressing wild-type tau. Assuming that tau pathology wasn’t elicited by some indirect pathway (tau-overexpressing mice develop tangles when exposed to Ab aggregates [Go¨ tz et al., 2001]), these transgenic mice appear to behave like the Martian bottles, since tauopathy was not induced in mice expressing normal levels of tau. In yet another study, the microtubule binding part of the full-length tau was found to attack and penetrate cells when added exogenously, and this again induced host tau misfolding (Frost et al., 2009). This study also showed that aggregated intracellular Tau spontaneously transferred between two cocultured cell populations (Frost et al., 2009). In the case of both tau and polyglutamines, the protein aggregates appear to gain access to the cytosol and to cause further aggregation of their host counterparts—presumably by nucleation.
The unifying characteristics of all these diseases is the aggregation of proteins into highly ordered stacks, termed amyloids irrespective of their size; the growth of these structures also exhibits generic features (Knowles et al., 2009) shared with a wide class of self-assembly phenomena characterized by elongation and fragmentation, such as the formation of analogous aggregates in micro-organisms and in vitro. Two conclusions can be drawn from the recent studies: (1) an unexpected number of amyloidogenic proteins can be released from affected cells in the form of extracellular amyloid seeds, and (2) even more surprisingly, these seeds can then re-enter other cells and nucleate the aggregation of their intracellular counterparts—in the cytosol or even in the nucleus. The biological and practical implications are far-reaching. On the one hand, cell therapies of aggregation diseases may be more difficult than anticipated, as the transplanted cells may undergo infection. A possible remedy could consist in the removal of the genes encoding the precursor of the offending proteins from the cells utilized for therapy—e.g., using the zinc-finger nuclease strategy (Hockemeyer et al., 2009). On the other hand, a novel paradigm of amyloid pathogenesis is emerging from these data, whereby each prionoid behaves as a self-assembling and self-replicating nanomachine.
Conversely, these findings raise a number of enigmas for which we are lacking any satisfactory answer. Whereas PrPC and the Ab are luminally exposed, a-synuclein and tau are cytoplasmic— and huntingtin is even nuclear. Aggregates of both Ab and PrPSc, as well as their monomeric precursors, are found in the extracellular space; it is hence intuitive that the nucleation process can propagate spatially across large distances. Instead, the propagation of cytoplasmic prionoids challenges our basic cell-biological understanding, since it posits that protein aggregates are released into the extracellular space and can subsequently reenter—and wreak havoc—in the cytosol of other cells. The release of cytosolic amyloids is supported by the amelioration of Lewy body pathology in a-synuclein transgenic mice immunized with human a-synuclein (Masliah et al., 2005). Similarly, anti-tau oligomer immunotherapy reduced brain pathology (Asuni et al., 2007), and immunization with mutant SOD1 led to clearance of SOD1 and delayed the onset of the disease in mice (Urushitani et al., 2007). All of these results indicate that cytosolic amyloids are somehow accessible to extracellular antibodies. This raises the question of how these proteins are released into the extracellular space (‘‘cytosol to lumen’’) and how they subsequently re-enter cellular cytosol (‘‘lumen to cytosol’’). Both events require trespassing lipid bilayer barriers—by no means a trivial feat for proteins, let alone highmolecular- weight aggregates.
snip...
Conclusion
The wave of these recent reports on the prion-like behavior of disparate pathogenic proteins raises many more questions than it answers. Here we have highlighted a number of open issues related to mechanisms of cell-to-cell spread of prionoids. The resolution of such issues may constitute the first step toward the development of rational strategies aimed at blocking transcellular propagation. There is justified hope that the latter may decelerate the progression of pathology and, consequently, help toward fighting the devastating outcome of aggregation proteinopathies.
http://www.cell.com/neuron/abstract/S0896-6273(09)01006-X
Sunday, July 18, 2010
Alzheimer's Assocition International Conference on Alzheimer's Disease (updated diagnostic criteria) 2010 July 10 - 15 Honolulu, Hawaii
http://betaamyloidcjd.blogspot.com/2010/07/alzheimers-assocition-international.html
Saturday, April 24, 2010
New connection between Alzheimer’s and prionic illnesses discovered
http://betaamyloidcjd.blogspot.com/2010/04/new-connection-between-alzheimers-and.html
Sunday, June 7, 2009
ALZHEIMER'S DISEASE IS TRANSMISSIBLE
http://betaamyloidcjd.blogspot.com/2009/06/alzheimers-disease-is-transmissible.html
Wednesday, April 14, 2010
Food Combination and Alzheimer Disease Risk A Protective Diet
http://betaamyloidcjd.blogspot.com/2010/04/food-combination-and-alzheimer-disease.html
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
Perspective
The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids
Adriano Aguzzi1,* and Lawrence Rajendran2,* 1Institute of Neuropathology, University Hospital of Zu¨ rich, Schmelzbergstrasse 12, CH-8091 Zu¨ rich, Switzerland 2Systems and Cell Biology of Neurodegeneration, Psychiatry Research, University of Zurich, CH-8008 Zu¨ rich, Switzerland *Correspondence: adriano.aguzzi@usz.ch (A.A.), rajendran@bli.uzh.ch (L.R.) DOI 10.1016/j.neuron.2009.12.016
Recent reports indicate that a growing number of intracellular proteins are not only prone to pathological aggregation but can also be released and ‘‘infect’’ neighboring cells. Therefore, many complex diseases may obey a simple model of propagation where the penetration of seeds into hosts determines spatial spread and disease progression. We term these proteins prionoids, as they appear to infect their neighbors just like prions—but how can bulky protein aggregates be released from cells and how do they access other cells? The widespread existence of such prionoids raises unexpected issues that question our understanding of basic cell biology.
Imagine that you are a neuroscientist vacationing on Mars. One day you encounter a colony of Martians that, as it happens, look similar to water bottles. The Martians are highly distressed and seek your advice, as their community is plagued by an enigmatic transmissible disease. Intrigued, you agree to help. It turns out that the bodies of your exobiotic friends consist of bottles filled with a supersaturated salt solution. At some point crystals have started forming in one individual, and then crystallization has somehow been transferred to other community members. Lacking molecular insight, you would initially conclude that the Martians are affected by an infectious agent. Through ingenuity and technology, you may then discover that the infectious agent is exceedingly simple and homogeneous, that it lacks informational nucleic acids, and that it is generated both by ordered aggregation of an intrinsic precursor and by appositional growth of extrinsically added seeds. Your discovery will earn you the Intergalactic Nobel Prize, yet two crucial questions remain unanswered: how do the crystals transfer between individuals, and what can be done to prevent this from happening?
Middle-aged readers may feel reminded of the plot for Andromeda Strain, a stunningly prescient novel published in 1969 by the late Michael Crichton. But the sci-fi scenario described above is also the blueprint of Prusiner’s hypothesis of prion propagation. Over time, we have learned that prions consist of PrPSc, higher-order aggregates of a physiological protein termed PrPC. Accordingly, prions propagate through elongation and breakage of PrPSc aggregates (Aguzzi and Polymenidou, 2004)—not unlike the crystals vexing our extraterrestrial friends.
There is mounting evidence (Clavaguera et al., 2009; Frost et al., 2009; Ren et al., 2009; Desplats et al., 2009; Luk et al., 2009) suggesting that the events sketched above, far from being confined to science-fiction and prion diseases (whose incidence in humans is just z1/106/year), may underlie highly prevalent human diseases of the brain and many other organs. The unifying characteristics of all these diseases is the aggregation of proteins into highly ordered stacks, henceforth termed ‘‘amyloids’’ irrespective of their size. Since PrPSc undoubtedly fulfills the latter definition of amyloid, one is led to wonder whether the prion principle may be much more pervasive than previously appreciated and whether many more diseases of unknown cause may eventually turn out to rely on prion-like propagation (Table 1, upper panel). Even more intriguingly, a number of proteins appear to exert normal functions when arranged in highly ordered stacks that are similar to amyloids and to prionoids (Table 1, lower panel).
Prions and Prionoids
There is one crucial difference between bona fide prion diseases and all other amyloids and prion-like phenomena hitherto described in uni- and pluricellular organisms (Table 1). Prions are infectious agents, transmissible between individuals, and tractable with microbiological techniques—including, e.g., titer determinations. Even if certain amyloids of yeast and mammals appear to infect neighboring molecules and sometimes neighboring cells, they do not propagate within communities, and none of them were found to cause macroepidemics such as Kuru and bovine spongiform encephalopathy. We have therefore termed these self-aggregating proteins ‘‘prionoids’’ (Aguzzi, 2009), since the lack of microbiological transmissibility precludes their classification as true prions.
Some prionoids may soon qualify for an upgrade to prion status. At least in select settings, amyloid A (AA) amyloidosis may exist as a truly infectious disease based on a self-propagating protein. AA amyloid consists of orderly aggregated fragments of SAA protein, whose deposition can damage many organs of the body. Somewhat bizarrely, AA aggregation is also present in the liver of force-fed geese, hence contributing to the pathophysiology of foie gras (Solomon et al., 2007). AA seeds can induce amyloidosis upon transfer of white blood cells (Sponarova et al., 2008). Furthermore, AA seeds are excreted with the feces, and AA amyloidosis is endemic in populations of cheetah (Zhang et al., 2008). It is therefore tantalizing to suspect that amyloid may entertain the complete life cycle of an infectious agent, including transmission by the orofecal and hematogenous route—similarly to enteroviruses and, perhaps, scrapie prions. While there may be many other good reasons to avoid foie gras, including, e.g., animal welfare concerns, gourmets may not need to panic: under experimental conditions, AA amyloidosis is only transmitted to AgNO3-pretreated mice that display elevated levels of the SAA precursor protein.
Alzheimer’s disease (AD) has long been suspected to be a transmissible disease, but these suspicions have never materialized in epidemiological studies. On the other hand, Mathias Jucker and Lary Walker observed that injection of the Ab peptide from human AD brains induced robust and convincing aggregation of Ab in transgenic mice overexpressing the Ab precursor protein, APP (Kane et al., 2000; Meyer-Luehmann et al., 2006). Jucker’s finding raises an epistemologically significant question: if aggregation depends on the introduction of seeds and on the availability of the monomeric precursor, and if amyloid represents the primordial state of all proteins (Chiti and Dobson, 2006), wouldn’t all proteins—under appropriate conditions— give rise to prionoids in the presence of sufficient precursor?
The issues sketched above go well beyond AD and prions. There are many other diseases—not necessarily involving the nervous system—whose pathogenesis involves ordered aggregation of proteins, but for which there is no evidence of transmission between individuals. The best-studied of these are the systemic amyloidoses, which come about through the nucleation of some aggregation-prone proteins such as transthyretin and immunoglobulin light chains. Yet ordered protein aggregation is by no means confined to the ‘‘classical’’ amyloidoses and extends to a number of conditions, some of which have been rather unexpected.
Type II diabetes is yet another disease whose pathogenesis may involve ordered protein aggregation. Evidence to support this idea was discovered over a century ago (Opie, 1901) but was largely forgotten until recently. It is now evident that aggregation of islet amyloid polypeptide (IAPP) is an exceedingly frequent feature of type II diabetes. IAPP amyloids damage the insulin-producing b cells within pancreatic islets and may crucially contribute to the pathogenesis of diabetes (Hull et al., 2004). It is unknown, however, whether IAPP deposition simply accrues linearly with IAPP production or whether it spreads prion-like from one pancreatic islet to the next.
A body of recent work supports the idea that many aggregation proteinopathies are, in one way or another, transmissible. A recent report showed that a-synuclein is released from neurons and is then taken up by the neighboring cells, thereby aiding in a progressive spread of the protein (Desplats et al., 2009; Lee et al., 2005). When exogenously added to cultured cells, fluorescently labeled, recombinant a-synuclein was internalized from the extracellular milieu into the cytosol. Furthermore, injection of GFP-labeled mouse cortical neuronal stem cells into the hippocampus of a-synuclein-transgenic mice led to the efficient uptake of the host a-synuclein into the grafted cells after just 4 weeks. These findings are reminiscent of the observation that healthy fetal tissue, grafted into the brains of Parkinson’s disease patients, acquired intracellular Lewy bodies. The latter phenomenon is somewhat anecdotal and has been disputed (Mendez et al., 2008), yet it would be entirely compatible with the hypothesis that a-synuclein aggregates are prionoids (Li et al., 2008). A similar study conclusively demonstrated that exogenous a-synuclein fibrils induced the formation of Lewy body-like intracellular inclusions in vitro (Luk et al., 2009). This study also showed that the conversion of the host cell a-synuclein was accompanied by dramatic changes, including hyperphosphorylation and ubiquitination of a-synuclein aggregates—thus recapitulating some key features of the human pathology.
In experiments conceptually analogous to those discussed above, polyglutamine-containing protein aggregates similar to those present in Huntington’s disease and in spinocerebellar ataxias exhibited prion-like propagation (Ren et al., 2009). There, aggregation of huntingtin progressed from the extracellular space to the cytosol and eventually to the nucleus. What is more, similar phenomena occurred upon exposure of cells to Sup35 aggregates, which consist of a yeast protein for which there are no known mammalian paralogs. This suggests that the prionoid properties are intrinsic to amyloids and are not tied to the origin or function of their monomeric precursor protein.
In another work, Tolnay and colleagues report a similar phenomenon in a mouse model of ‘‘tauopathy,’’ a neurodegenerative disease due to intraneuronal aggregation of the microtubule- associated tau protein (Clavaguera et al., 2009). Aggregation- prone mutant tau, when extracted from the brain of transgenic mice, induced tauopathy in mice overexpressing wild-type tau. Assuming that tau pathology wasn’t elicited by some indirect pathway (tau-overexpressing mice develop tangles when exposed to Ab aggregates [Go¨ tz et al., 2001]), these transgenic mice appear to behave like the Martian bottles, since tauopathy was not induced in mice expressing normal levels of tau. In yet another study, the microtubule binding part of the full-length tau was found to attack and penetrate cells when added exogenously, and this again induced host tau misfolding (Frost et al., 2009). This study also showed that aggregated intracellular Tau spontaneously transferred between two cocultured cell populations (Frost et al., 2009). In the case of both tau and polyglutamines, the protein aggregates appear to gain access to the cytosol and to cause further aggregation of their host counterparts—presumably by nucleation.
The unifying characteristics of all these diseases is the aggregation of proteins into highly ordered stacks, termed amyloids irrespective of their size; the growth of these structures also exhibits generic features (Knowles et al., 2009) shared with a wide class of self-assembly phenomena characterized by elongation and fragmentation, such as the formation of analogous aggregates in micro-organisms and in vitro. Two conclusions can be drawn from the recent studies: (1) an unexpected number of amyloidogenic proteins can be released from affected cells in the form of extracellular amyloid seeds, and (2) even more surprisingly, these seeds can then re-enter other cells and nucleate the aggregation of their intracellular counterparts—in the cytosol or even in the nucleus. The biological and practical implications are far-reaching. On the one hand, cell therapies of aggregation diseases may be more difficult than anticipated, as the transplanted cells may undergo infection. A possible remedy could consist in the removal of the genes encoding the precursor of the offending proteins from the cells utilized for therapy—e.g., using the zinc-finger nuclease strategy (Hockemeyer et al., 2009). On the other hand, a novel paradigm of amyloid pathogenesis is emerging from these data, whereby each prionoid behaves as a self-assembling and self-replicating nanomachine.
Conversely, these findings raise a number of enigmas for which we are lacking any satisfactory answer. Whereas PrPC and the Ab are luminally exposed, a-synuclein and tau are cytoplasmic— and huntingtin is even nuclear. Aggregates of both Ab and PrPSc, as well as their monomeric precursors, are found in the extracellular space; it is hence intuitive that the nucleation process can propagate spatially across large distances. Instead, the propagation of cytoplasmic prionoids challenges our basic cell-biological understanding, since it posits that protein aggregates are released into the extracellular space and can subsequently reenter—and wreak havoc—in the cytosol of other cells. The release of cytosolic amyloids is supported by the amelioration of Lewy body pathology in a-synuclein transgenic mice immunized with human a-synuclein (Masliah et al., 2005). Similarly, anti-tau oligomer immunotherapy reduced brain pathology (Asuni et al., 2007), and immunization with mutant SOD1 led to clearance of SOD1 and delayed the onset of the disease in mice (Urushitani et al., 2007). All of these results indicate that cytosolic amyloids are somehow accessible to extracellular antibodies. This raises the question of how these proteins are released into the extracellular space (‘‘cytosol to lumen’’) and how they subsequently re-enter cellular cytosol (‘‘lumen to cytosol’’). Both events require trespassing lipid bilayer barriers—by no means a trivial feat for proteins, let alone highmolecular- weight aggregates.
snip...
Conclusion
The wave of these recent reports on the prion-like behavior of disparate pathogenic proteins raises many more questions than it answers. Here we have highlighted a number of open issues related to mechanisms of cell-to-cell spread of prionoids. The resolution of such issues may constitute the first step toward the development of rational strategies aimed at blocking transcellular propagation. There is justified hope that the latter may decelerate the progression of pathology and, consequently, help toward fighting the devastating outcome of aggregation proteinopathies.
http://www.cell.com/neuron/abstract/S0896-6273(09)01006-X
Sunday, July 18, 2010
Alzheimer's Assocition International Conference on Alzheimer's Disease (updated diagnostic criteria) 2010 July 10 - 15 Honolulu, Hawaii
http://betaamyloidcjd.blogspot.com/2010/07/alzheimers-assocition-international.html
Saturday, April 24, 2010
New connection between Alzheimer’s and prionic illnesses discovered
http://betaamyloidcjd.blogspot.com/2010/04/new-connection-between-alzheimers-and.html
Sunday, June 7, 2009
ALZHEIMER'S DISEASE IS TRANSMISSIBLE
http://betaamyloidcjd.blogspot.com/2009/06/alzheimers-disease-is-transmissible.html
Wednesday, April 14, 2010
Food Combination and Alzheimer Disease Risk A Protective Diet
http://betaamyloidcjd.blogspot.com/2010/04/food-combination-and-alzheimer-disease.html
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
Tuesday, July 27, 2010
Commons Hansard for The United Kingdom Parliament Written Answers for 26 July 2010 Alzheimer's and CJD
Commons Hansard for The United Kingdom Parliament Written Answers for 26 July 2010 Alzheimer's and CJD
CJD
Mr Weir: To ask the Secretary of State for Health what testing of the relatives of individuals affected by variant Creutzfeldt-Jakob disease his Department undertakes. [10942]
Anne Milton: The Department does not undertake any such testing.
There is no blood or other test currently available for routine variant Creutzfeldt-Jakob disease testing of asymptomatic individuals.
26 July 2010 : Column 823W
Mr Weir: To ask the Secretary of State for Health what recent estimate his Department has made of the time taken for variant Creutzfeldt-Jakob disease to incubate. [10945]
Anne Milton: The incubation period for variant Creutzfeldt-Jakob disease (vCJD) is unknown and may vary due to factors such as route of transmission and genotype of patient. For the majority of cases where consumption of meat or meat products is presumed to be the route of infection the minimum incubation period is likely to be five years, with a mean period of around 10-12 years and the maximum, as in other human transmissible spongiform encephalopathies, may extend over decades. Of the three clinical cases of vCJD presumed to be associated with blood transfusion the incubation periods are estimated to be between six and nine years.
Mr Weir: To ask the Secretary of State for Health (1) how many cases of variant Creutzfeldt-Jakob disease affecting the MV gene type have been reported in (a) Scotland, (b) Wales, (c) England and (d) Northern Ireland since 1996; [11005]
(2) how many cases of (a) definite, (b) probable and (c) possible variant Creutzfeldt-Jakob disease of the MV gene type have been recorded since 1996; [11006]
(3) how many deaths from variant Creutzfeldt-Jakob disease among people with (a) MM variations, (b) MV variations and (c) VV variations there have been since 1996. [11008]
Anne Milton: There have been no definite or probable cases of variant Creutzfeldt-Jakob disease (vCJD) in patients with a MV genotype. A single possible case of vCJD in a patient with a MV genotype was reported in 2008 in Scotland. This case is recorded in the 17th Annual Report of the National Creutzfeldt-Jakob disease Surveillance Unit published in November 2009 and publicly available at:
www.cjd.ed.ac.uk/report17.htm
The 17th Annual Report records that of the four patients with a final classification of possible vCJD, three were of the MM genotype and only one of MV genotype.
The MV case has also been described in a publication: "Variant CJD in an individual heterozygous for PRNP codon 129 Kaski D, Mead S, Hyare H, Cooper S, Jampana R, Overell J, Knight R, Collinge J, Rudge Lancet 2009. 374:212.
The National Creutzfeldt-Jakob disease Surveillance Unit has provided the following information about deaths from vCJD:
United Kingdom definite and probable vCJD deaths 1995 to 2010
Number deaths Genotype known Genotype unknown MM MV VV
1995 3 0 3 0
1996 10 0 10 0
1997 10 0 10 0
1998 18 0 18 0
1999 15 0 15 0
2000 28 25 3 25 0
2001 20 18 2 18 0
2002 17 15 2 15 0
2003 18 8 10 8 0
2004 9 8 1 8 0
26 July 2010 : Column 824W 2005 5 0 5 0
2006 5 0 5 0
2007 5 0 5 0
2008 1 0 1 0
2009 3 0 3 0
2010 2 0 2 0
Total 169 151 18 151 0
Mr Weir: To ask the Secretary of State for Health what definition of (a) probable and (b) possible his Department uses in the identification of variant Creutzfeldt-Jakob disease cases. [11007]
Anne Milton: The Department uses the internationally recognised World Health Organisation diagnostic criteria for case classification, research protocols and official statistics. These are publicly available at:
www.who.int/entity/zoonoses/diseases/Creutzfeldt.pdf
http://www.publications.parliament.uk/pa/cm201011/cmhansrd/cm100726/text/100726w0008.htm#10072719000041
Alzheimer's Disease: Cumbria John Stevenson: To ask the Secretary of State for Health (1) how much funding has been allocated to caring for people with Alzheimer's disease in (a) Cumbria and (b) Carlisle constituency for the next 12 months. [10759]
(2) how many people in (a) Cumbria and (b) Carlisle constituency have been diagnosed with Alzheimer's disease. [10760]
Mr Burstow: The Department currently allocates funding directly to primary care trusts (PCTs). PCT allocations are not broken down by policy area. PCTs make decisions on investment in health care for their communities, taking into account both local and national priorities.
In 2010-11, Cumbria Teaching PCT received a revenue allocation of £826.9 million. Data on the number of people diagnosed with Alzheimer's disease is not collected centrally. However, the Quality and Outcomes Framework includes a disease register for patients who have been diagnosed with any form of dementia (including Alzheimer's disease). The latest available figures are for 2008-09.
There were .3,114 patients on the dementia register in Cumbria PCT in 2008-09. The figures are organised by practice and aggregated into PCT and strategic health authority. It is therefore not possible to give figures for Carlisle constituency.
Notes:
1. QOF: QOF is the national Quality and Outcomes Framework, introduced as part of the new General Medical Services (GMS) contract on 1 April 2004. Participation by practices in the QOF is voluntary, though participation rates are very high, with most Personal Medical Services (PMS) practices also taking part.
2. The published QOF information was derived from the Quality Management Analysis System (QMAS), a national system developed by NHS Connecting for Health.
3. QMAS uses data from general practices to calculate individual practices' QOF achievement. QMAS is a national IT system developed by NHS Connecting for Health to support the QOF. The Quality Management Analysis System captures the number of patients on the various disease registers for each practice.
http://www.publications.parliament.uk/pa/cm201011/cmhansrd/cm100726/text/100726w0008.htm#10072719000040
Greetings,
For anyone that cares, from 1993 to 2005, a steady increase of sporadic CJD from 27 in 1993, to 104 in 2005, tapering off to 94 in 2006, and 88 in 2007, which seems to correlate to other BSE countries, which to me shows a relationship with human Sporadic CJD rising and falling along the same lines as the BSE cases. Course, nobody cares about that factor because of the UKBSEnvCJD only theory. nobody cares that in fact what Collinge, Asante et al showed, that BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein, but who cares about sound science anymore $
2002
BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein
Emmanuel A. Asante, Jacqueline M. Linehan, Melanie Desbruslais, Susan Joiner, Ian Gowland, Andrew L. Wood, Julie Welch, Andrew F. Hill, Sarah E. Lloyd, Jonathan D.F. Wadsworth, and John Collinge1 MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College, Queen Square, London WC1N 3BG, UK 1Corresponding author e-mail: j.collinge@prion.ucl.ac.ukReceived August 1, 2002; Revised September 24, 2002; Accepted October 17, 2002. This article has been cited by other articles in PMC. Other Sections?
Abstract
Variant Creutzfeldt-Jakob disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrPSc type 2. These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a disease arising from BSE exposure.
Keywords: BSE/Creutzfeldt-Jakob disease/prion/transgenic
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC136957/?tool=pubmed
2004
Originally published in Science Express on 11 November 2004 Science 3 December 2004: Vol. 306. no. 5702, pp. 1793 - 1796 DOI: 10.1126/science.1103932
Reports Human Prion Protein with Valine 129 Prevents Expression of Variant CJD Phenotype Jonathan D. F. Wadsworth, Emmanuel A. Asante, Melanie Desbruslais, Jacqueline M. Linehan, Susan Joiner, Ian Gowland, Julie Welch, Lisa Stone, Sarah E. Lloyd, Andrew F. Hill,* Sebastian Brandner, John Collinge
Variant Creutzfeldt-Jakob disease (vCJD) is a unique and highly distinctive clinicopathological and molecular phenotype of human prion disease associated with infection with bovine spongiform encephalopathy (BSE)-like prions. Here, we found that generation of this phenotype in transgenic mice required expression of human prion protein (PrP) with methionine 129. Expression of human PrP with valine 129 resulted in a distinct phenotype and, remarkably, persistence of a barrier to transmission of BSE-derived prions on subpassage. Polymorphic residue 129 of human PrP dictated propagation of distinct prion strains after BSE prion infection. Thus, primary and secondary human infection with BSE-derived prions may result in sporadic CJD-like or novel phenotypes in addition to vCJD, depending on the genotype of the prion source and the recipient.
Medical Research Council (MRC) Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
* Present address: Department of Biochemistry and Molecular Biology and Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia.
To whom correspondence should be addressed. E-mail: j.collinge@prion.ucl.ac.uk
http://www.sciencemag.org/cgi/content/abstract/306/5702/1793
2008
Prominent and Persistent Extraneural Infection in Human PrP Transgenic Mice Infected with Variant CJD
The evolution of the variant Creutzfeldt-Jakob disease (vCJD) epidemic is hazardous to predict due to uncertainty in ascertaining the prevalence of infection and because the disease might remain asymptomatic or produce an alternate, sporadic-like phenotype.
Transgenic mice were produced that overexpress human prion protein with methionine at codon 129, the only allele found so far in vCJD-affected patients. These mice were infected with prions derived from variant and sporadic CJD (sCJD) cases by intracerebral or intraperitoneal route, and transmission efficiency and strain phenotype were analyzed in brain and spleen. We showed that i) the main features of vCJD infection in humans, including a prominent involvement of the lymphoid tissues compared to that in sCJD infection were faithfully reproduced in such mice; ii) transmission of vCJD agent by intracerebral route could lead to the propagation of either vCJD or sCJD-like prion in the brain, whereas vCJD prion was invariably propagated in the spleen, iii) after peripheral exposure, inefficient neuroinvasion was observed, resulting in an asymptomatic infection with life-long persistence of vCJD prion in the spleen at stable and elevated levels.
Our findings emphasize the possibility that human-to-human transmission of vCJD might produce alternative neuropathogical phenotypes and that lymphoid tissue examination of CJD cases classified as sporadic might reveal an infection by vCJD-type prions. They also provide evidence for the strong propensity of this agent to establish long-lasting, subclinical vCJD infection of lymphoreticular tissues, thus amplifying the risk for iatrogenic transmission.
snip...
Discussion Top In this study we used tg650 mice, a newly developed transgenic line expressing human PrPC, to investigate some aspects of the pathogenesis of vCJD infection. As main findings, we demonstrate that prion strain divergence can occur upon transmission of human, primary vCJD to such mice, and that peripheral challenge leads to an asymptomatic, life-long infection of the lymphoid compartment. A feature of tg650 mice is that following primary intracerebral vCJD challenge they developed a neurological disease with typically 100% attack rate, unlike for previously established PrP129Met, including overexpressing lines [16], [19]. The mean survival time - typically around 500 days in homozygous mice - did not change notably on subpassaging, implying that vCJD agent might clinically infect the tg650 mice with little or no transmission barrier. This discrepant result may reflect the use of different constructs and genetic backgrounds (Text S1), and the transgene expression levels, although the latter does not seem to greatly differ as far as the tg650+/- and tg45 mice [16] are concerned.
A surprising result of these studies is the alternate pattern of disease that was induced by one of the inoculated vCJD cases, a WHO reference case here designated vCJD no. 4. Indeed, while vCJD strain features were faithfully propagated in the majority of tg650 mice, almost half of the vCJD 4-inoculated mice were found to propagate a prion replicating faster than vCJD agent, and exhibiting sCJD-like PrPres and neuropathological features. Although strain divergence upon transmission of BSE/vCJD agent to mice was reported to occur in earlier studies [16], [24], it was unprecedented within a context of homotypic transmission, i.e. full matching between the donor and receiver PrP sequences. To address the issue of a possible contamination, we performed independent transmission experiments, involving separate inoculum batches of the incriminated case, which all produced consistent results. Therefore, we consider the data inconsistent with contamination of the VCJD no. 4 material by a sCJD infectious source within our laboratory. An alternate possibility, i.e. a cross-contamination of the source material, was judged highly improbable owing to the procedures applied during the collect of the specimen and the preparation of the homogenates ([25] and P. Minor, personal communication). On the other hand, our observation intriguingly parallels the phenotypic disjunction observed upon transmission of BSE agent to human PrP129Met mice (tg35 line [16]). Together, these findings lend support to the hypothesis that a minor strain component might be created upon cattle-to-human transmission of BSE agent and could emerge upon subsequent human-to-human transmission. It is also worth mentioning that, while the probability to detect such a variant through mouse bioassay would be expected to depend on the amount - and possibly the regions - of brain tissue taken to establish the source material, the vCJD-4 homogenate was prepared using a larger amount of tissue from the same brain than for the other homogenates analyzed in this study (i.e. 100 mg instead of 1 mg of frontal cortex [25]).
The above finding has obvious implications in terms of public health as it raises the concern that some humans iatrogenically infected by vCJD agent may develop a clinical disease that would not be recognized as of vCJD origin [17], [26]. Strikingly however, all vCJD-4-inoculated mice, notwithstanding the strain phenotype divergence propagated bona fide vCJD agent in their spleen, based on the PrPres pattern and the disease phenotype produced by secondary transmission to tg650 mice. This result is of direct relevance to the diagnosis of variant and sporadic CJD. Indeed, looking for peripheral lymphoreticular deposition of abnormal PrP on cases diagnosed as sporadic CJD might reveal a vCJD infection resulting from human-to-human, or cattle-to-human transmission. In this respect, it would be of interest to examine whether BSE-inoculated tg35 mice showing discordant PrPres signatures [16], or vCJD-challenged PrP129Val transgenic mice producing 'type 5' prion in their brain [17] do accumulate PrPvCJD in their spleens. In any case, our findings provide clear evidence that, as a consequence of strain-related tropism disparities, the same mouse can propagate different prions in different tissues following a single infection event.
Another salient finding emerging from this study was the remarkable ability of vCJD agent to establish asymptomatic infection despite sustained, life-long propagation in extraneural tissues. When challenged peripherally, tg650 mice remained asymptomatic over the whole observation period, and did not accumulate PrPres at detectable levels in their brain before 750 days pi, near the life end-stage. In the spleen of these mice however, PrPres accumulation reached its maximum at an early stage of infection, and remained at stable and substantial levels until death. Plateauing of prion infection in the spleen is consistent with earlier observations, and has been suggested to reflect an exhaustion of target cells (for review [22]) Importantly, the spleen tissue was highly infectious as it killed 100% of intracerebrally challenged mice within the minimal mean incubation time (~500 days). Altogether these data support the view that the sustained multiplication of the vCJD prion in lymphoid tissues was not accompanied by an efficient neuroinvasion in tg650 mice. Such an extremely delayed neuroinvasion appears to be rare in TSE rodent models, and to our knowledge was only reported for the mouse-adapted strain 87V on IM mice infected intraperitoneally with diluted inoculum [27]. Clearly, while early accumulation of prions in lymphoid tissues may be essential for efficient neuroinvasion [22], efficient lymphoinvasion does not inevitably lead to rapid neuroinvasion. This finding strengthens the notion that humans infected by vCJD from a human source - including individuals of the MM genotype - might remain clinically asymptomatic for a very prolonged period of time while harboring relatively high levels of prion infectivity in their lymphoid tissues from an early stage of infection on, thereby amplifying the risk of iatrogenic transmission. It also supports the view that the large-scale survey of lymphoreticular tissues [28] may lead to a reliable assessment of the actual prevalence of vCJD infection in the UK population.
Finally, the human PrP transgenic model described in this study may help to further our understanding of peripheral vCJD pathogenesis, for instance in trying to identify factors that might enhance neuroinvasion efficiency, or modulate the shedding of prion infectivity from the lymphoreticular to the blood compartment. Moreover, preliminary results indicate that the search for abnormal PrP in the spleen of such mice culled at time intervals post infection [29], [30] could allow the detection of low levels of vCJD infectivity within a reasonably short time scale.
Citation: Béringue V, Le Dur A, Tixador P, Reine F, Lepourry L, et al. (2008) Prominent and Persistent Extraneural Infection in Human PrP Transgenic Mice Infected with Variant CJD. PLoS ONE 3(1): e1419. doi:10.1371/journal.pone.0001419
Academic Editor: Adam Ratner, Columbia University, United States of America
Received: September 20, 2007; Accepted: December 17, 2007; Published: January 9, 2008
Copyright: © 2008 Beringue et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by INRA, Institut de Veille Sanitaire (InVS) and the Ministry of Research, France. The sponsors of this study had no role in study conduct, collection analysis, interpretation of the data, writing of the report or approval of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* To whom correspondence should be addressed. E-mail: hubert.laude@jouy.inra.fr (HL); vincent.beringue@jouy.inra.fr (VB)
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001419
Thursday, July 08, 2010
GLOBAL CLUSTERS OF CREUTZFELDT JAKOB DISEASE - A REVIEW 2010
http://creutzfeldt-jakob-disease.blogspot.com/2010/07/global-clusters-of-creutzfeldt-jakob.html
Thursday, July 08, 2010
Nosocomial transmission of sporadic Creutzfeldt-Jakob disease: results from a risk-based assessment of surgical interventions Public release date: 8-Jul-2010
http://creutzfeldt-jakob-disease.blogspot.com/2010/07/nosocomial-transmission-of-sporadic.html
Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America
14th ICID International Scientific Exchange Brochure -
Final Abstract Number: ISE.114
Session: International Scientific Exchange
Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America
update October 2009
T. Singeltary
Bacliff, TX, USA
Background:
An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.
Methods:
12 years independent research of available data
Results:
I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.
Conclusion:
I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.
page 114 ;
http://ww2.isid.org/Downloads/14th_ICID_ISE_Abstracts.pdf
International Society for Infectious Diseases Web: http://www.isid.org/
please see full text ;
http://transmissiblespongiformencephalopathy.blogspot.com/
To date the OIE/WAHO assumes that the human and animal health standards set out in the BSE chapter for classical BSE (C-Type) applies to all forms of BSE which include the H-type and L-type atypical forms. This assumption is scientifically not completely justified and accumulating evidence suggests that this may in fact not be the case. Molecular characterization and the spatial distribution pattern of histopathologic lesions and immunohistochemistry (IHC) signals are used to identify and characterize atypical BSE. Both the L-type and H-type atypical cases display significant differences in the conformation and spatial accumulation of the disease associated prion protein (PrPSc) in brains of afflicted cattle. Transmission studies in bovine transgenic and wild type mouse models support that the atypical BSE types might be unique strains because they have different incubation times and lesion profiles when compared to C-type BSE. When L-type BSE was inoculated into ovine transgenic mice and Syrian hamster the resulting molecular fingerprint had changed, either in the first or a subsequent passage, from L-type into C-type BSE. In addition, non-human primates are specifically susceptible for atypical BSE as demonstrated by an approximately 50% shortened incubation time for L-type BSE as compared to C-type. Considering the current scientific information available, it cannot be assumed that these different BSE types pose the same human health risks as C-type BSE or that these risks are mitigated by the same protective measures.
http://www.prionetcanada.ca/detail.aspx?menu=5&dt=293380&app=93&cat1=387&tp=20&lk=no&cat2
please see full text ;
Wednesday, March 31, 2010
Atypical BSE in Cattle
http://bse-atypical.blogspot.com/2010/03/atypical-bse-in-cattle-position-post.html
2009 UPDATE ON ALABAMA AND TEXAS MAD COWS 2005 and 2006
http://bse-atypical.blogspot.com/2006/08/bse-atypical-texas-and-alabama-update.html
Monday, October 19, 2009
Atypical BSE, BSE, and other human and animal TSE in North America Update October 2009
http://bse-atypical.blogspot.com/2009/10/atypical-bse-bse-and-other-human-and.html
CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER
>>> Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. <<<
Irma Linda Andablo CJD Victim, she died at 38 years old on February 6, 2010 in Mesquite Texas. She left 6 Kids and a Husband.The Purpose of this web is to give information in Spanish to the Hispanic community, and to all the community who want's information about this terrible disease.-
Physician Discharge Summary, Parkland Hospital, Dallas Texas
Admit Date: 12/29/2009 Discharge Date: 1/20/2010
Attending Provider: Greenberg, Benjamin Morris;
General Neurology Team: General Neurology Team Linda was a Hispanic female with no past medical history presents with 14 months of incresing/progressive altered mental status, generalized weakness, inability to walk, loss of appetite, inability to speak, tremor and bowel/blader incontinence. She was, in her usual state of health up until February, 2009, when her husbans notes that she began forgetting things like names and short term memories. He also noticed mild/vague personality changes such as increased aggression. In March, she was involved in a hit and run MVA,although she was not injured. The police tracked her down and ticketed her. At that time, her son deployed to Iraq with the Army and her husband assumed her mentation changes were due to stress over these two events. Also in March, she began to have weakness in her legs, making it difficult to walk. Over the next few months, her mentation and personality changes worsened, getting to a point where she could no longer recognized her children. She was eating less and less. She was losing more weight. In the last 2-3 months, she reached the point where she could not walk without an assist, then 1 month ago, she stopped talking, only making grunting/aggressive sounds when anyone came near her. She also became both bowel and bladder incontinent, having to wear diapers. Her '"tremor'" and body jerks worsened and her hands assumed a sort of permanent grip position, leading her family to put tennis balls in her hands to protect her fingers. The husband says that they have lived in Nebraska for the past 21 years. They had seen a doctor there during the summer time who prescribed her Seroquel and Lexapro, Thinking these were sx of a mood disorder. However, the medications did not help and she continued to deteriorate clinically. Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. The husband says that he does not know any fellow workers with a similar illness. He also says that she did not have any preceeding illness or travel.
http://www.recordandoalinda.com/index.php?option=com_content&view=article&id=19:cjd-english-info&catid=9:cjd-ingles&Itemid=8
>>> Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. <<<
please see full text ;
Monday, March 29, 2010
Irma Linda Andablo CJD Victim, she died at 38 years old on February 6, 2010 in Mesquite Texas
http://creutzfeldt-jakob-disease.blogspot.com/2010/03/irma-linda-andablo-cjd-victim-she-died.html
CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER
http://cjdtexas.blogspot.com/2010/03/cjd-texas-38-year-old-female-worked.html
USA sporadic CJD cases rising ;
There is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection. He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins.
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf
CJD USA RISING, with UNKNOWN PHENOTYPE ;
5 Includes 41 cases in which the diagnosis is pending, and 17 inconclusive cases; 6 Includes 46 cases with type determination pending in which the diagnosis of vCJD has been excluded.
http://www.cjdsurveillance.com/pdf/case-table.pdf
Friday, February 05, 2010
New Variant Creutzfelt Jakob Disease case reports United States 2010 A Review
http://vcjd.blogspot.com/2010/02/new-variant-creutzfelt-jakob-disease.html
Saturday, January 2, 2010
Human Prion Diseases in the United States January 1, 2010 ***FINAL***
http://prionunitusaupdate2008.blogspot.com/2010/01/human-prion-diseases-in-united-states.html
Archive Number 20100405.1091 Published Date 05-APR-2010 Subject PRO/AH/EDR> Prion disease update 1010 (04)
snip...
[Terry S. Singeltary Sr. has added the following comment:
"According to the World Health Organisation, the future public health threat of vCJD in the UK and Europe and potentially the rest of the world is of concern and currently unquantifiable. However, the possibility of a significant and geographically diverse vCJD epidemic occurring over the next few decades cannot be dismissed.
The key word here is diverse. What does diverse mean? If USA scrapie transmitted to USA bovine does not produce pathology as the UK c-BSE, then why would CJD from there look like UK vCJD?"
http://www.promedmail.org/pls/apex/f?p=2400:1001:568933508083034::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1000,82101
Saturday, July 17, 2010
Variant Creutzfeldt-Jakob disease Ironside JW., Haemophilia. 2010 Jul;16 Suppl 5:175-80
REVIEW ARTICLE
http://vcjdtransfusion.blogspot.com/2010/07/variant-creutzfeldtjakob-disease.html
Sunday, July 18, 2010
Alzheimer's Assocition International Conference on Alzheimer's Disease (updated diagnostic criteria) 2010 July 10 - 15 Honolulu, Hawaii
snip...
BSE101/1 0136
IN CONFIDENCE
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 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.
92/11.4/1.1
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
92/11.4/1.2
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
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 B amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegeneradve 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.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Wednesday, April 14, 2010
Food Combination and Alzheimer Disease Risk A Protective Diet
http://betaamyloidcjd.blogspot.com/2010/04/food-combination-and-alzheimer-disease.html
Wednesday, March 31, 2010
Neurobiology of Disease Molecular Cross Talk between Misfolded Proteins in Animal Models of Alzheimer's and Prion Diseases
http://betaamyloidcjd.blogspot.com/2010/03/neurobiology-of-disease-molecular-cross.html
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
snip...
see full text ;
http://betaamyloidcjd.blogspot.com/2010/07/alzheimers-assocition-international.html
http://betaamyloidcjd.blogspot.com/
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
CJD
Mr Weir: To ask the Secretary of State for Health what testing of the relatives of individuals affected by variant Creutzfeldt-Jakob disease his Department undertakes. [10942]
Anne Milton: The Department does not undertake any such testing.
There is no blood or other test currently available for routine variant Creutzfeldt-Jakob disease testing of asymptomatic individuals.
26 July 2010 : Column 823W
Mr Weir: To ask the Secretary of State for Health what recent estimate his Department has made of the time taken for variant Creutzfeldt-Jakob disease to incubate. [10945]
Anne Milton: The incubation period for variant Creutzfeldt-Jakob disease (vCJD) is unknown and may vary due to factors such as route of transmission and genotype of patient. For the majority of cases where consumption of meat or meat products is presumed to be the route of infection the minimum incubation period is likely to be five years, with a mean period of around 10-12 years and the maximum, as in other human transmissible spongiform encephalopathies, may extend over decades. Of the three clinical cases of vCJD presumed to be associated with blood transfusion the incubation periods are estimated to be between six and nine years.
Mr Weir: To ask the Secretary of State for Health (1) how many cases of variant Creutzfeldt-Jakob disease affecting the MV gene type have been reported in (a) Scotland, (b) Wales, (c) England and (d) Northern Ireland since 1996; [11005]
(2) how many cases of (a) definite, (b) probable and (c) possible variant Creutzfeldt-Jakob disease of the MV gene type have been recorded since 1996; [11006]
(3) how many deaths from variant Creutzfeldt-Jakob disease among people with (a) MM variations, (b) MV variations and (c) VV variations there have been since 1996. [11008]
Anne Milton: There have been no definite or probable cases of variant Creutzfeldt-Jakob disease (vCJD) in patients with a MV genotype. A single possible case of vCJD in a patient with a MV genotype was reported in 2008 in Scotland. This case is recorded in the 17th Annual Report of the National Creutzfeldt-Jakob disease Surveillance Unit published in November 2009 and publicly available at:
www.cjd.ed.ac.uk/report17.htm
The 17th Annual Report records that of the four patients with a final classification of possible vCJD, three were of the MM genotype and only one of MV genotype.
The MV case has also been described in a publication: "Variant CJD in an individual heterozygous for PRNP codon 129 Kaski D, Mead S, Hyare H, Cooper S, Jampana R, Overell J, Knight R, Collinge J, Rudge Lancet 2009. 374:212.
The National Creutzfeldt-Jakob disease Surveillance Unit has provided the following information about deaths from vCJD:
United Kingdom definite and probable vCJD deaths 1995 to 2010
Number deaths Genotype known Genotype unknown MM MV VV
1995 3 0 3 0
1996 10 0 10 0
1997 10 0 10 0
1998 18 0 18 0
1999 15 0 15 0
2000 28 25 3 25 0
2001 20 18 2 18 0
2002 17 15 2 15 0
2003 18 8 10 8 0
2004 9 8 1 8 0
26 July 2010 : Column 824W 2005 5 0 5 0
2006 5 0 5 0
2007 5 0 5 0
2008 1 0 1 0
2009 3 0 3 0
2010 2 0 2 0
Total 169 151 18 151 0
Mr Weir: To ask the Secretary of State for Health what definition of (a) probable and (b) possible his Department uses in the identification of variant Creutzfeldt-Jakob disease cases. [11007]
Anne Milton: The Department uses the internationally recognised World Health Organisation diagnostic criteria for case classification, research protocols and official statistics. These are publicly available at:
www.who.int/entity/zoonoses/diseases/Creutzfeldt.pdf
http://www.publications.parliament.uk/pa/cm201011/cmhansrd/cm100726/text/100726w0008.htm#10072719000041
Alzheimer's Disease: Cumbria John Stevenson: To ask the Secretary of State for Health (1) how much funding has been allocated to caring for people with Alzheimer's disease in (a) Cumbria and (b) Carlisle constituency for the next 12 months. [10759]
(2) how many people in (a) Cumbria and (b) Carlisle constituency have been diagnosed with Alzheimer's disease. [10760]
Mr Burstow: The Department currently allocates funding directly to primary care trusts (PCTs). PCT allocations are not broken down by policy area. PCTs make decisions on investment in health care for their communities, taking into account both local and national priorities.
In 2010-11, Cumbria Teaching PCT received a revenue allocation of £826.9 million. Data on the number of people diagnosed with Alzheimer's disease is not collected centrally. However, the Quality and Outcomes Framework includes a disease register for patients who have been diagnosed with any form of dementia (including Alzheimer's disease). The latest available figures are for 2008-09.
There were .3,114 patients on the dementia register in Cumbria PCT in 2008-09. The figures are organised by practice and aggregated into PCT and strategic health authority. It is therefore not possible to give figures for Carlisle constituency.
Notes:
1. QOF: QOF is the national Quality and Outcomes Framework, introduced as part of the new General Medical Services (GMS) contract on 1 April 2004. Participation by practices in the QOF is voluntary, though participation rates are very high, with most Personal Medical Services (PMS) practices also taking part.
2. The published QOF information was derived from the Quality Management Analysis System (QMAS), a national system developed by NHS Connecting for Health.
3. QMAS uses data from general practices to calculate individual practices' QOF achievement. QMAS is a national IT system developed by NHS Connecting for Health to support the QOF. The Quality Management Analysis System captures the number of patients on the various disease registers for each practice.
http://www.publications.parliament.uk/pa/cm201011/cmhansrd/cm100726/text/100726w0008.htm#10072719000040
Greetings,
For anyone that cares, from 1993 to 2005, a steady increase of sporadic CJD from 27 in 1993, to 104 in 2005, tapering off to 94 in 2006, and 88 in 2007, which seems to correlate to other BSE countries, which to me shows a relationship with human Sporadic CJD rising and falling along the same lines as the BSE cases. Course, nobody cares about that factor because of the UKBSEnvCJD only theory. nobody cares that in fact what Collinge, Asante et al showed, that BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein, but who cares about sound science anymore $
2002
BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein
Emmanuel A. Asante, Jacqueline M. Linehan, Melanie Desbruslais, Susan Joiner, Ian Gowland, Andrew L. Wood, Julie Welch, Andrew F. Hill, Sarah E. Lloyd, Jonathan D.F. Wadsworth, and John Collinge1 MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College, Queen Square, London WC1N 3BG, UK 1Corresponding author e-mail: j.collinge@prion.ucl.ac.ukReceived August 1, 2002; Revised September 24, 2002; Accepted October 17, 2002. This article has been cited by other articles in PMC. Other Sections?
Abstract
Variant Creutzfeldt-Jakob disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrPSc type 2. These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a disease arising from BSE exposure.
Keywords: BSE/Creutzfeldt-Jakob disease/prion/transgenic
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC136957/?tool=pubmed
2004
Originally published in Science Express on 11 November 2004 Science 3 December 2004: Vol. 306. no. 5702, pp. 1793 - 1796 DOI: 10.1126/science.1103932
Reports Human Prion Protein with Valine 129 Prevents Expression of Variant CJD Phenotype Jonathan D. F. Wadsworth, Emmanuel A. Asante, Melanie Desbruslais, Jacqueline M. Linehan, Susan Joiner, Ian Gowland, Julie Welch, Lisa Stone, Sarah E. Lloyd, Andrew F. Hill,* Sebastian Brandner, John Collinge
Variant Creutzfeldt-Jakob disease (vCJD) is a unique and highly distinctive clinicopathological and molecular phenotype of human prion disease associated with infection with bovine spongiform encephalopathy (BSE)-like prions. Here, we found that generation of this phenotype in transgenic mice required expression of human prion protein (PrP) with methionine 129. Expression of human PrP with valine 129 resulted in a distinct phenotype and, remarkably, persistence of a barrier to transmission of BSE-derived prions on subpassage. Polymorphic residue 129 of human PrP dictated propagation of distinct prion strains after BSE prion infection. Thus, primary and secondary human infection with BSE-derived prions may result in sporadic CJD-like or novel phenotypes in addition to vCJD, depending on the genotype of the prion source and the recipient.
Medical Research Council (MRC) Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
* Present address: Department of Biochemistry and Molecular Biology and Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia.
To whom correspondence should be addressed. E-mail: j.collinge@prion.ucl.ac.uk
http://www.sciencemag.org/cgi/content/abstract/306/5702/1793
2008
Prominent and Persistent Extraneural Infection in Human PrP Transgenic Mice Infected with Variant CJD
The evolution of the variant Creutzfeldt-Jakob disease (vCJD) epidemic is hazardous to predict due to uncertainty in ascertaining the prevalence of infection and because the disease might remain asymptomatic or produce an alternate, sporadic-like phenotype.
Transgenic mice were produced that overexpress human prion protein with methionine at codon 129, the only allele found so far in vCJD-affected patients. These mice were infected with prions derived from variant and sporadic CJD (sCJD) cases by intracerebral or intraperitoneal route, and transmission efficiency and strain phenotype were analyzed in brain and spleen. We showed that i) the main features of vCJD infection in humans, including a prominent involvement of the lymphoid tissues compared to that in sCJD infection were faithfully reproduced in such mice; ii) transmission of vCJD agent by intracerebral route could lead to the propagation of either vCJD or sCJD-like prion in the brain, whereas vCJD prion was invariably propagated in the spleen, iii) after peripheral exposure, inefficient neuroinvasion was observed, resulting in an asymptomatic infection with life-long persistence of vCJD prion in the spleen at stable and elevated levels.
Our findings emphasize the possibility that human-to-human transmission of vCJD might produce alternative neuropathogical phenotypes and that lymphoid tissue examination of CJD cases classified as sporadic might reveal an infection by vCJD-type prions. They also provide evidence for the strong propensity of this agent to establish long-lasting, subclinical vCJD infection of lymphoreticular tissues, thus amplifying the risk for iatrogenic transmission.
snip...
Discussion Top In this study we used tg650 mice, a newly developed transgenic line expressing human PrPC, to investigate some aspects of the pathogenesis of vCJD infection. As main findings, we demonstrate that prion strain divergence can occur upon transmission of human, primary vCJD to such mice, and that peripheral challenge leads to an asymptomatic, life-long infection of the lymphoid compartment. A feature of tg650 mice is that following primary intracerebral vCJD challenge they developed a neurological disease with typically 100% attack rate, unlike for previously established PrP129Met, including overexpressing lines [16], [19]. The mean survival time - typically around 500 days in homozygous mice - did not change notably on subpassaging, implying that vCJD agent might clinically infect the tg650 mice with little or no transmission barrier. This discrepant result may reflect the use of different constructs and genetic backgrounds (Text S1), and the transgene expression levels, although the latter does not seem to greatly differ as far as the tg650+/- and tg45 mice [16] are concerned.
A surprising result of these studies is the alternate pattern of disease that was induced by one of the inoculated vCJD cases, a WHO reference case here designated vCJD no. 4. Indeed, while vCJD strain features were faithfully propagated in the majority of tg650 mice, almost half of the vCJD 4-inoculated mice were found to propagate a prion replicating faster than vCJD agent, and exhibiting sCJD-like PrPres and neuropathological features. Although strain divergence upon transmission of BSE/vCJD agent to mice was reported to occur in earlier studies [16], [24], it was unprecedented within a context of homotypic transmission, i.e. full matching between the donor and receiver PrP sequences. To address the issue of a possible contamination, we performed independent transmission experiments, involving separate inoculum batches of the incriminated case, which all produced consistent results. Therefore, we consider the data inconsistent with contamination of the VCJD no. 4 material by a sCJD infectious source within our laboratory. An alternate possibility, i.e. a cross-contamination of the source material, was judged highly improbable owing to the procedures applied during the collect of the specimen and the preparation of the homogenates ([25] and P. Minor, personal communication). On the other hand, our observation intriguingly parallels the phenotypic disjunction observed upon transmission of BSE agent to human PrP129Met mice (tg35 line [16]). Together, these findings lend support to the hypothesis that a minor strain component might be created upon cattle-to-human transmission of BSE agent and could emerge upon subsequent human-to-human transmission. It is also worth mentioning that, while the probability to detect such a variant through mouse bioassay would be expected to depend on the amount - and possibly the regions - of brain tissue taken to establish the source material, the vCJD-4 homogenate was prepared using a larger amount of tissue from the same brain than for the other homogenates analyzed in this study (i.e. 100 mg instead of 1 mg of frontal cortex [25]).
The above finding has obvious implications in terms of public health as it raises the concern that some humans iatrogenically infected by vCJD agent may develop a clinical disease that would not be recognized as of vCJD origin [17], [26]. Strikingly however, all vCJD-4-inoculated mice, notwithstanding the strain phenotype divergence propagated bona fide vCJD agent in their spleen, based on the PrPres pattern and the disease phenotype produced by secondary transmission to tg650 mice. This result is of direct relevance to the diagnosis of variant and sporadic CJD. Indeed, looking for peripheral lymphoreticular deposition of abnormal PrP on cases diagnosed as sporadic CJD might reveal a vCJD infection resulting from human-to-human, or cattle-to-human transmission. In this respect, it would be of interest to examine whether BSE-inoculated tg35 mice showing discordant PrPres signatures [16], or vCJD-challenged PrP129Val transgenic mice producing 'type 5' prion in their brain [17] do accumulate PrPvCJD in their spleens. In any case, our findings provide clear evidence that, as a consequence of strain-related tropism disparities, the same mouse can propagate different prions in different tissues following a single infection event.
Another salient finding emerging from this study was the remarkable ability of vCJD agent to establish asymptomatic infection despite sustained, life-long propagation in extraneural tissues. When challenged peripherally, tg650 mice remained asymptomatic over the whole observation period, and did not accumulate PrPres at detectable levels in their brain before 750 days pi, near the life end-stage. In the spleen of these mice however, PrPres accumulation reached its maximum at an early stage of infection, and remained at stable and substantial levels until death. Plateauing of prion infection in the spleen is consistent with earlier observations, and has been suggested to reflect an exhaustion of target cells (for review [22]) Importantly, the spleen tissue was highly infectious as it killed 100% of intracerebrally challenged mice within the minimal mean incubation time (~500 days). Altogether these data support the view that the sustained multiplication of the vCJD prion in lymphoid tissues was not accompanied by an efficient neuroinvasion in tg650 mice. Such an extremely delayed neuroinvasion appears to be rare in TSE rodent models, and to our knowledge was only reported for the mouse-adapted strain 87V on IM mice infected intraperitoneally with diluted inoculum [27]. Clearly, while early accumulation of prions in lymphoid tissues may be essential for efficient neuroinvasion [22], efficient lymphoinvasion does not inevitably lead to rapid neuroinvasion. This finding strengthens the notion that humans infected by vCJD from a human source - including individuals of the MM genotype - might remain clinically asymptomatic for a very prolonged period of time while harboring relatively high levels of prion infectivity in their lymphoid tissues from an early stage of infection on, thereby amplifying the risk of iatrogenic transmission. It also supports the view that the large-scale survey of lymphoreticular tissues [28] may lead to a reliable assessment of the actual prevalence of vCJD infection in the UK population.
Finally, the human PrP transgenic model described in this study may help to further our understanding of peripheral vCJD pathogenesis, for instance in trying to identify factors that might enhance neuroinvasion efficiency, or modulate the shedding of prion infectivity from the lymphoreticular to the blood compartment. Moreover, preliminary results indicate that the search for abnormal PrP in the spleen of such mice culled at time intervals post infection [29], [30] could allow the detection of low levels of vCJD infectivity within a reasonably short time scale.
Citation: Béringue V, Le Dur A, Tixador P, Reine F, Lepourry L, et al. (2008) Prominent and Persistent Extraneural Infection in Human PrP Transgenic Mice Infected with Variant CJD. PLoS ONE 3(1): e1419. doi:10.1371/journal.pone.0001419
Academic Editor: Adam Ratner, Columbia University, United States of America
Received: September 20, 2007; Accepted: December 17, 2007; Published: January 9, 2008
Copyright: © 2008 Beringue et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by INRA, Institut de Veille Sanitaire (InVS) and the Ministry of Research, France. The sponsors of this study had no role in study conduct, collection analysis, interpretation of the data, writing of the report or approval of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* To whom correspondence should be addressed. E-mail: hubert.laude@jouy.inra.fr (HL); vincent.beringue@jouy.inra.fr (VB)
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001419
Thursday, July 08, 2010
GLOBAL CLUSTERS OF CREUTZFELDT JAKOB DISEASE - A REVIEW 2010
http://creutzfeldt-jakob-disease.blogspot.com/2010/07/global-clusters-of-creutzfeldt-jakob.html
Thursday, July 08, 2010
Nosocomial transmission of sporadic Creutzfeldt-Jakob disease: results from a risk-based assessment of surgical interventions Public release date: 8-Jul-2010
http://creutzfeldt-jakob-disease.blogspot.com/2010/07/nosocomial-transmission-of-sporadic.html
Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America
14th ICID International Scientific Exchange Brochure -
Final Abstract Number: ISE.114
Session: International Scientific Exchange
Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America
update October 2009
T. Singeltary
Bacliff, TX, USA
Background:
An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.
Methods:
12 years independent research of available data
Results:
I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.
Conclusion:
I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.
page 114 ;
http://ww2.isid.org/Downloads/14th_ICID_ISE_Abstracts.pdf
International Society for Infectious Diseases Web: http://www.isid.org/
please see full text ;
http://transmissiblespongiformencephalopathy.blogspot.com/
To date the OIE/WAHO assumes that the human and animal health standards set out in the BSE chapter for classical BSE (C-Type) applies to all forms of BSE which include the H-type and L-type atypical forms. This assumption is scientifically not completely justified and accumulating evidence suggests that this may in fact not be the case. Molecular characterization and the spatial distribution pattern of histopathologic lesions and immunohistochemistry (IHC) signals are used to identify and characterize atypical BSE. Both the L-type and H-type atypical cases display significant differences in the conformation and spatial accumulation of the disease associated prion protein (PrPSc) in brains of afflicted cattle. Transmission studies in bovine transgenic and wild type mouse models support that the atypical BSE types might be unique strains because they have different incubation times and lesion profiles when compared to C-type BSE. When L-type BSE was inoculated into ovine transgenic mice and Syrian hamster the resulting molecular fingerprint had changed, either in the first or a subsequent passage, from L-type into C-type BSE. In addition, non-human primates are specifically susceptible for atypical BSE as demonstrated by an approximately 50% shortened incubation time for L-type BSE as compared to C-type. Considering the current scientific information available, it cannot be assumed that these different BSE types pose the same human health risks as C-type BSE or that these risks are mitigated by the same protective measures.
http://www.prionetcanada.ca/detail.aspx?menu=5&dt=293380&app=93&cat1=387&tp=20&lk=no&cat2
please see full text ;
Wednesday, March 31, 2010
Atypical BSE in Cattle
http://bse-atypical.blogspot.com/2010/03/atypical-bse-in-cattle-position-post.html
2009 UPDATE ON ALABAMA AND TEXAS MAD COWS 2005 and 2006
http://bse-atypical.blogspot.com/2006/08/bse-atypical-texas-and-alabama-update.html
Monday, October 19, 2009
Atypical BSE, BSE, and other human and animal TSE in North America Update October 2009
http://bse-atypical.blogspot.com/2009/10/atypical-bse-bse-and-other-human-and.html
CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER
>>> Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. <<<
Irma Linda Andablo CJD Victim, she died at 38 years old on February 6, 2010 in Mesquite Texas. She left 6 Kids and a Husband.The Purpose of this web is to give information in Spanish to the Hispanic community, and to all the community who want's information about this terrible disease.-
Physician Discharge Summary, Parkland Hospital, Dallas Texas
Admit Date: 12/29/2009 Discharge Date: 1/20/2010
Attending Provider: Greenberg, Benjamin Morris;
General Neurology Team: General Neurology Team Linda was a Hispanic female with no past medical history presents with 14 months of incresing/progressive altered mental status, generalized weakness, inability to walk, loss of appetite, inability to speak, tremor and bowel/blader incontinence. She was, in her usual state of health up until February, 2009, when her husbans notes that she began forgetting things like names and short term memories. He also noticed mild/vague personality changes such as increased aggression. In March, she was involved in a hit and run MVA,although she was not injured. The police tracked her down and ticketed her. At that time, her son deployed to Iraq with the Army and her husband assumed her mentation changes were due to stress over these two events. Also in March, she began to have weakness in her legs, making it difficult to walk. Over the next few months, her mentation and personality changes worsened, getting to a point where she could no longer recognized her children. She was eating less and less. She was losing more weight. In the last 2-3 months, she reached the point where she could not walk without an assist, then 1 month ago, she stopped talking, only making grunting/aggressive sounds when anyone came near her. She also became both bowel and bladder incontinent, having to wear diapers. Her '"tremor'" and body jerks worsened and her hands assumed a sort of permanent grip position, leading her family to put tennis balls in her hands to protect her fingers. The husband says that they have lived in Nebraska for the past 21 years. They had seen a doctor there during the summer time who prescribed her Seroquel and Lexapro, Thinking these were sx of a mood disorder. However, the medications did not help and she continued to deteriorate clinically. Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. The husband says that he does not know any fellow workers with a similar illness. He also says that she did not have any preceeding illness or travel.
http://www.recordandoalinda.com/index.php?option=com_content&view=article&id=19:cjd-english-info&catid=9:cjd-ingles&Itemid=8
>>> Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. <<<
please see full text ;
Monday, March 29, 2010
Irma Linda Andablo CJD Victim, she died at 38 years old on February 6, 2010 in Mesquite Texas
http://creutzfeldt-jakob-disease.blogspot.com/2010/03/irma-linda-andablo-cjd-victim-she-died.html
CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER
http://cjdtexas.blogspot.com/2010/03/cjd-texas-38-year-old-female-worked.html
USA sporadic CJD cases rising ;
There is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection. He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins.
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf
CJD USA RISING, with UNKNOWN PHENOTYPE ;
5 Includes 41 cases in which the diagnosis is pending, and 17 inconclusive cases; 6 Includes 46 cases with type determination pending in which the diagnosis of vCJD has been excluded.
http://www.cjdsurveillance.com/pdf/case-table.pdf
Friday, February 05, 2010
New Variant Creutzfelt Jakob Disease case reports United States 2010 A Review
http://vcjd.blogspot.com/2010/02/new-variant-creutzfelt-jakob-disease.html
Saturday, January 2, 2010
Human Prion Diseases in the United States January 1, 2010 ***FINAL***
http://prionunitusaupdate2008.blogspot.com/2010/01/human-prion-diseases-in-united-states.html
Archive Number 20100405.1091 Published Date 05-APR-2010 Subject PRO/AH/EDR> Prion disease update 1010 (04)
snip...
[Terry S. Singeltary Sr. has added the following comment:
"According to the World Health Organisation, the future public health threat of vCJD in the UK and Europe and potentially the rest of the world is of concern and currently unquantifiable. However, the possibility of a significant and geographically diverse vCJD epidemic occurring over the next few decades cannot be dismissed.
The key word here is diverse. What does diverse mean? If USA scrapie transmitted to USA bovine does not produce pathology as the UK c-BSE, then why would CJD from there look like UK vCJD?"
http://www.promedmail.org/pls/apex/f?p=2400:1001:568933508083034::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1000,82101
Saturday, July 17, 2010
Variant Creutzfeldt-Jakob disease Ironside JW., Haemophilia. 2010 Jul;16 Suppl 5:175-80
REVIEW ARTICLE
http://vcjdtransfusion.blogspot.com/2010/07/variant-creutzfeldtjakob-disease.html
Sunday, July 18, 2010
Alzheimer's Assocition International Conference on Alzheimer's Disease (updated diagnostic criteria) 2010 July 10 - 15 Honolulu, Hawaii
snip...
BSE101/1 0136
IN CONFIDENCE
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 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.
92/11.4/1.1
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
92/11.4/1.2
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
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 B amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegeneradve 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.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Wednesday, April 14, 2010
Food Combination and Alzheimer Disease Risk A Protective Diet
http://betaamyloidcjd.blogspot.com/2010/04/food-combination-and-alzheimer-disease.html
Wednesday, March 31, 2010
Neurobiology of Disease Molecular Cross Talk between Misfolded Proteins in Animal Models of Alzheimer's and Prion Diseases
http://betaamyloidcjd.blogspot.com/2010/03/neurobiology-of-disease-molecular-cross.html
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
snip...
see full text ;
http://betaamyloidcjd.blogspot.com/2010/07/alzheimers-assocition-international.html
http://betaamyloidcjd.blogspot.com/
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
Sunday, July 18, 2010
Alzheimer's Assocition International Conference on Alzheimer's Disease (updated diagnostic criteria) 2010 July 10 - 15 Honolulu, Hawaii
Alzheimer's Assocition International Conference on Alzheimer's Disease (updated diagnostic criteria) 2010 July 10 - 15 Honolulu, Hawaii
I think it's a step forward. small step, but at least it is not a step backward. Most of these type scans have been around for some time, although technology has improved over the years. We have floundered much too long with Alzheimer's and other neurological disease. Just to hear them say they are now going to try and start to _identify_ these cases, as oppose to in the past i.e. only search for nvCJD i.e. UKBSEnvCJD only theory. Maybe, just maybe, a light bulb went off in some of the minds of the ones that matter (prion Gods), and now say something like 'maybe we should start to identify all these potential TSE, including Alzheimer's type dementia, Parkinson's and other neurodegenerative diseases, and regardless of any poential sources. We know now science is leaning towards it's potential to be transmissible, we know there is a common denominator('s?), we just don't have the complete formula to figure it out with yet$ so let's not wait around like we did with the nvCJD and sporadic CJD's debate on the potential for blood and blood products being transmissible, let's not wait around like we did that, until we exposed everyone around the globe, let's not wait around like that, let's ACT NOW, instead of later, regardless.' Let's _indentify_, ACT when something is indentified, act as if it is likely to be Iatrogenic FIRST, then let's prove it's is not, NOT the other way around, like saying it is not transmissible first, acting on that, then taking over 2 decades and finding out it is transmissible. By then it is too late. Let's not sit around and talk about if for over two decades. I know that there has been a blood ban restriction due to CJD, but the USA has failed terribly in it's regulation there from, as with everything esle related to Transmissible Spongiform Encephalopathy regulations. ... just my take.
EMBARGOED FOR RELEASE UNTIL WEDNESDAY, JULY 14, 2010 7:30 am HST / 1:30 pm ET „P
John R. McCarten, et al. Changes In Outpatient Costs Following Screening And Diagnosis Of Cognitive Impairment. (Funded by: Strategic Initiative, Veterans Integrated Service Network 23)
All materials to be presented at the Alzheimer's Association 2010 International Conference on Alzheimer's Disease are embargoed for publication and broadcast until the date and time of presentation at the conference, unless the Alzheimer's Association provides advance written notice of change of date and/or time.
Control #: 10-HT-3470-ALZ O4-04 - Hot Topics 3 (Presentation #O4-04-04; Speaking Time: 7/14/2010 1:45-2:00 PM)
Changes In Outpatient Costs Following Screening And Diagnosis Of Cognitive Impairment
John R. McCarten, M.D.1, Pauline Anderson, MSN2, Michael A. Kuskowski, Ph.D.1, Yvonne Jonk, Ph.D.3, Maurice W. Dysken, M.D.1. 1VA Medical Center, Minneapolis, MN, USA, 2Veterans Integrated Service Network 23, Minneapolis, MN, USA, 3University of Minnesota, Minneapolis, MN, USA. Contact: J Riley McCarten, mccar034@umn.edu Disclosure Block: J.R. McCarten, MN/ND Chapter of the Alzheimer's Association's BOD.
Background: Dementia is a common, costly, and often unrecognized problem in older adults. Early identification and intervention holds the promise of improving care through chronic disease management strategies. We integrated a program of screening, evaluation, and management for cognitive impairment into primary care. Here we report the impact of that program on total and line item outpatient costs.
Methods: The Dementia Demonstration Project (DDP) employed specially trained Advanced Practice Registered Nurses functioning as Dementia Care Coordinators (DCCs) to lead interdisciplinary teams in the identification, evaluation, diagnosis and management of cognitive impairment (CI). Typical primary care clinics were identified at seven VA Medical Centers and the DDP was implemented in those clinics. The DCCs screened eligible veterans (age 70 and older, medically stable, able to comply with the screen, and without a prior diagnosis of CI) using the Mini-Cog at the time of a routine primary care clinic appointment. All patients newly diagnosed with CI, both in DDP and non-DDP PC clinics, who had data available for at least one year before and one year after diagnosis were analyzed. Risk adjusted differences in log transformed outpatient health care utilization and costs were analyzed using the mixed effects Poisson regression and difference-in-differences models.
Results: Of the 8278 veterans screened, 26% failed the screen. A total of 34% of those who failed completed a further evaluation and 95% of this group was found to have CI, including 76% with dementia. Data for one year before and after CI diagnosis were available on 347 DDP patients and 1261 non-DDP patients. Median DDP outpatient care costs declined over 54% (- 2 $5,519) compared with 25% decline (-$1,759) in patients diagnosed in non-DDP clinics. Median number of line-item outpatient costs declined by 53% (-54) in the DDP patients compared to 32% (-21) in non-DDP patients.
Conclusions: Diagnosing cognitive impairment was associated with a decrease in total and line item health care costs in the year following diagnosis compared to the year prior to diagnosis. The decreases were more dramatic in patients who were identified through cognitive screening and subsequently had case management available by a dementia care team.
http://www.alz.org/icad/documents/abstracts/2010_early_detection.pdf
National Institute on Aging and Alzheimer's Association Lead Effort to Update Diagnostic Criteria for Alzheimer's Disease
- News briefing/Q&A: AAICAD 2010, Tuesday, July 13, 2010, 11:45 am-12:45 pm Hawai'i Convention Center, Room 321A, 1801 Kalakaua Avenue, Honolulu -
Honolulu, Hawaii, July 13, 2010 – Scientists at the Alzheimer's Association International Conference on Alzheimer's Disease 2010 (AAICAD 2010) today presented the first draft reports from three workgroups convened by the National Institute on Aging (NIA) and the Alzheimer's Association to update the diagnostic criteria for Alzheimer's disease for the first time in 25 years.
The current criteria for the diagnosis of Alzheimer's were established by a National Institute of Neurological Disorders and Stroke (NINDS)/Alzheimer's Disease and Related Disorders Association (ADRDA) workgroup in 1984. These criteria were almost universally adopted and have been useful; they have survived intact without modification for more than 25 years. However, experts note, the field has evolved to a great extent since then.
"Important scientific discoveries have been made in Alzheimer's, and there have been significant changes in our knowledge and conception of the disease," said Creighton H. Phelps, Ph.D., Director of the Alzheimer's Disease Centers Program, Division of Neuroscience, National Institute on Aging at the National Institutes of Health. "The NIA and the Alzheimer's Association, after consultation with the Alzheimer's scientific and medical community, concluded that the diagnostic criteria may need to be revised to incorporate scientific advances. We decided to convene workgroups to examine the literature and make recommendations."
At AAICAD 2010, leaders of the three workgroups – which covered Alzheimer's disease dementia, mild cognitive impairment (MCI) due to Alzheimer's disease, and preclinical Alzheimer's disease – presented preliminary reports at a special session for initial comment by the Alzheimer's community.
"The proposals would change the 1984 criteria by better reflecting the various stages of the disease and the inclusion of Alzheimer's disease biomarkers," said William Thies, PhD, Chief Medical and Scientific Officer at the Alzheimer's Association. "While the role of biomarkers differs in each of the three stages, much remains to be understood concerning their reliability and validity in diagnosis. This makes it critical that we thoroughly test any new recommendations."
Further input will be solicited by the NIA and the Association through a website launched immediately after the AAICAD presentations at www.alz.org/research/diagnostic_criteria. After that input is incorporated, next steps are publication in a peer-reviewed journal followed by systematic validation through incorporation of the criteria into clinical trials.
"The proposed criteria for Alzheimer's disease dementia must be flexible enough to eventually be used – once they are validated – by both general health care providers without access to neuropsychological testing, advanced imaging, and CSF measures, as well as specialized investigators involved in research or clinical trial studies with access to these measures," said Guy McKhann, MD, of John Hopkins University School of Medicine, who chaired this workgroup.
The Importance of Moving to Earlier Diagnosis
Alzheimer's is thought to begin years, perhaps even decades, before symptoms are noticeable. But there is no single, generally accepted way to identify the disease in its earliest stages – before symptoms are evident.
According to Phelps, earlier detection of people at highest risk for Alzheimer's and those who have the earliest forms of the disease will facilitate finding the right individuals to participate in risk reduction and prevention research studies.
"The NIA and the Alzheimer's Association hope this process of updating and revising the Alzheimer's diagnostic criteria with modern technologies and the latest advances will provide standards that move the field further in the direction of early detection and treatment," Thies said.
Significant Advances in Alzheimer Research Since 1984
Among the most important advances in the Alzheimer's field since the publication of the 1984 NINDS/ADRDA diagnostic criteria are:
•Alzheimer's-driven changes in the brain, as well as the accompanying cognitive deficits, develop slowly over many years with dementia representing the end stage of years of pathology accumulation. At the same time, we know that some people have the brain changes associated with Alzheimer's and yet don't show symptoms of dementia.
•Predictive genes in early onset Alzheimer's indicate that the initial events ultimately leading to both clinical symptoms and pathological brain changes begin with disordered beta amyloid metabolism. •The e4 allele of the APOE gene is well accepted as a major genetic risk factor for late onset Alzheimer's disease, which is defined as onset at 65 or older.
•Biomarkers for Alzheimer's have been developed and are being validated. These fall into several categories:
Biomarkers of beta amyloid pathology, including amyloid PET imaging and levels of beta amyloid in cerebrospinal fluid (CSF).
Biomarkers of neuronal injury, including levels of CSF tau and phospho-tau.
Biomarkers of neuronal dysfunction, including decreased uptake of FDG on PET scans.
Biomarkers of neurodegeneration, including brain atrophy on structural MRI scans. In addition, it has been only in the past decade that a better understanding of the distinctions and overlaps of Alzheimer's with non-Alzheimer's dementias has begun to emerge. Knowledge of the non-Alzheimer's dementias was rudimentary in 1984, and the current diagnostic criteria are vague in defining distinctions between Alzheimer's and the major alternatives. The common co-existence of Alzheimer's and cerebrovascular disease is now appreciated. Much more is known about dementia resulting from Lewy Body disease, and also about Pick's disease and other frontotemporal dementias.
Three Work Group Reports Present New Ideas for Research Criteria and Better Define Early Stages of Alzheimer's Disease
The NIA/Alzheimer's Association working groups were organized around the three stages of Alzheimer's disease that are commonly thought to exist today – pre-clinical Alzheimer's, mild cognitive impairment (MCI) due to Alzheimer's, and Alzheimer's dementia.
•Pre-clinical – The group is laying out a research agenda to identify methods of assessment that may help predict risk for developing the disease. Biomarkers and other clinical assessment tools to identify early cognitive decline are being investigated to establish the presence of Alzheimer's brain changes in people with no overt symptoms and to identify those who may eventually develop the disease.
•Mild cognitive impairment – The group is refining the MCI criteria, which will help to indicate cognitive change before dementia and better differentiate MCI from Alzheimer's. Research is underway to better understand the cognitive changes taking place, how they may relate to biomarkers, and which of these methods best indicate the likelihood of imminent progression to Alzheimer's dementia.
•Alzheimer's dementia – The group is revising the existing criteria for diagnosing Alzheimer's to include possible biomarkers and other assessments that may aid in diagnosis. About AAICAD The Alzheimer's Association International Conference on Alzheimer's Disease (AAICAD) is the world's largest conference of it's kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.
About the Alzheimer's Association The Alzheimer's Association is the leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's.
www.alz.org/icad/
Workgroup members (2 pages)
http://www.alz.org/icad/documents/abstracts/2010_diag.pdf
Contact: Alzheimer's Association Media line: 312.335.4078 E-mail: media@alz.org AAICAD 2010 press room, July 10-15: 1-808-792-6523
http://www.alz.org/icad/2010_release_diagnostic_071310_130pm.asp
Early Detection, Diagnosis & Care Management for People with Dementia May Reduce Healthcare Costs
Honolulu, Hawaii; July 14, 2010 – Early detection, diagnosis and care management for people newly diagnosed with cognitive impairment and dementia reduces outpatient costs by almost 30 percent, according to new research reported today at the Alzheimer's Association International Conference on Alzheimer's Disease 2010 (AAICAD 2010) in Honolulu.
Dementia is loss of memory and other mental abilities severe enough to interfere with daily life. According to the Alzheimer's Association, dementia is a common, costly, and often unrecognized problem in older adults. In order to provide better medical care and outcomes for people with Alzheimer's and other dementias, the conditions must first be detected and diagnosed, and needed care management must be provided.
"Research suggests that when the family of someone who is officially diagnosed with Alzheimer's becomes educated about the disease, and they work together with medical professionals on a care plan, it can reduce the patient's difficult behavioral and psychiatric symptoms," said Maria Carrillo, PhD, Senior Director of Medical and Scientific Relations at the Alzheimer's Association. "It can also lower the family caregiver's anxiety, depression and stress."
Generally, care management in Alzheimer's provides assistance for people with the disease and their families in finding resources, making decisions, and managing stress. For example, a care manager can help families with decisions about in-home health services, or long-term care whether at home or in a nursing facility.
"We see in this study's findings that early diagnosis and case management in dementia may also significantly lower healthcare costs. This could have a reverberating positive impact throughout the entire healthcare system," Carrillo said.
Demonstration Project Shows Early Diagnosis and Care Management Can Lower Costs
The Dementia Demonstration Project (DDP) was an interdisciplinary effort led by the Geriatric Research, Education and Clinic Center at the Minneapolis Veterans (VA) Medical Center. Seven VA Medical Centers took part in the project, which was created to increase detection and diagnosis of dementia in primary care and provide information, support, and care coordination for veterans with newly diagnosed dementia. An Advanced Practice Registered Nurse trained in dementia – the Dementia Care Coordinator – led a dementia care team that became part of a primary care clinic in each of the seven VA Medical Centers participating in the project.
The DDP added a brief, three-item memory test to regularly scheduled primary care visits for veterans age 70 and older without a diagnosis of Alzheimer's or another dementia. Among the 8,278 veterans who received the memory test, 26 percent failed. Thirty-four percent of those who failed the test returned for a comprehensive evaluation; 95 percent of that group were diagnosed with cognitive impairment, including 76 percent with dementia.
In the DDP clinics, following evaluation, the dementia care team met with the patient and family to review the results, discuss the diagnosis, and outline treatment recommendations. Interventions were targeted to the severity of dementia and the specific needs of the patient and their caregivers. Informational material, assistance in identifying needed services, and direct support and training from team members was provided, as needed.
Healthcare costs data for one year before and after diagnosis were available for 347 DDP patients and 1,260 patients from non-DDP clinics in the same VA Medical Centers.
•Veterans diagnosed in the DDP clinics saw their average outpatient healthcare costs decline by about 29 percent (-$1,991) in the year after diagnosis of cognitive impairment compared with the year before diagnosis. •Veterans diagnosed in the non-DDP clinics also saw declines in average outpatient healthcare costs, but not as much (-$406). "In our study, the cost decreases were more dramatic in patients who were identified through cognitive evaluation and who subsequently had case management available by a dementia care team," said J. Riley McCarten, MD, the project's lead physician. He added that the cost of the DDP intervention to the VA was captured in the patient care costs reported.
"The most important goals of the program were making sure that all family members understood the disease and were on the same page, that patients remained physically active and socially engaged, and that caregivers had the support they needed," McCarten said.
About AAICAD The Alzheimer's Association International Conference on Alzheimer's Disease (AAICAD) is the world's largest conference of it's kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.
About the Alzheimer's Association The Alzheimer's Association is the leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit www.alz.org or call 800-272-3900.
Abstracts (2 pages)
http://www.alz.org/icad/documents/abstracts/2010_early_detection.pdf
Contact: Alzheimer's Association Media line: 312.335.4078 E-mail: media@alz.org AAICAD 2010 press room, July 10-15: 1-808-792-6523
http://www.alz.org/icad/2010_release_early_071410_1230pm.asp
"Hot Topics" from the Alzheimer's Association International Conference on Alzheimer's Disease 2010
- New Alzheimer's Risk Gene May Affect Memory Scores and Brain Atrophy in Middle Age -
- Clinical Trial of Intranasal Insulin Shows Benefits in Alzheimer's and MCI –
- Known Alzheimer's Risk Gene May Change Shape of Brain Deposits -
Honolulu, Hawaii; July 14, 2010 – Last minute scientific submissions to the Alzheimer's Association International Conference on Alzheimer's Disease 2010 (AAICAD 2010) in Honolulu, HI, known as "hot topics," suggest that (1) a newly-discovered risk gene for Alzheimer's may have early impact on memory skills and brain volume, (2) intranasal insulin may be beneficial in Alzheimer's, and (3) beta amyloid deposits in the brains of people with Alzheimer's disease may take different shapes based on a known Alzheimer's risk gene.
Two studies reported at AAICAD 2010 give us more information about the TOMM40 gene – a newly identified risk gene for Alzheimer's. They found that healthy, middle aged people who have the high risk version of TOMM40 (a) did worse on memory tests and (b) had reduced brain volume in two regions affected early in Alzheimer's. A short-term trial of intranasal insulin in Alzheimer's and MCI showed statistically significant benefits on certain tests of memory and functioning, but no changes on some others. In those who showed benefits on memory tests, there were also positive changes in Alzheimer's biomarkers in spinal fluid. Researchers using a new imaging tool suggest that there are different shapes of beta amyloid deposits in the Alzheimer brain based on which version a person has of a well-established Alzheimer's risk gene, known as APOE. This may be especially important because in some recent drug trials the therapy provided benefits in people who had certain types of APOE but were less effective or not effective in others. "These are some of the fantastic findings from this year's AAICAD, full of potential to move the field forward," said William Thies, PhD, Alzheimer's Association Chief Medical and Scientific Officer. "But there is too little happening in the field, and no plan in place from the federal government to stem the massive wave of Alzheimer's coming with the aging of the Baby Boomers."
"Alzheimer's is clearly the #1 public health challenge of the 21st century and research is the only way to solve this problem," Thies added. "There are more than 5 million Americans with the disease and about 11 million caregivers supporting them. Reliable estimates say that by 2050 those numbers could triple. Government must make an investment in Alzheimer research that proves they understand what's at stake – for individuals, families, the healthcare system, and the nation as a whole."
New Risk Gene for Alzheimer's is Associated with Poorer Memory Function and Grey Matter Loss in Middle Aged Persons Without Dementia
The TOMM40 gene has very recently been shown to influence age of onset in Alzheimer's disease. Two studies reported at AAICAD 2010 give us more information about this newly identified risk gene for Alzheimer's; they found that middle aged people without dementia who have the high risk version of the TOMM40 gene did worse on tests of memory and learning and had reduced brain volume in two regions that are often affected early in the course of Alzheimer's.
"These are exciting, initial results, but the exact role that TOMM40 plays in Alzheimer's remains to be determined," said William Thies, PhD, Chief Medical and Scientific Officer at the Alzheimer's Association. "The story of TOMM40 is evolving and may give us new insights into Alzheimer's disease."
"We desperately need to know more about the causes of Alzheimer's, and the factors that affect our risk of getting or not getting the disease. This kind of research will provide more targets for therapies and prevention strategies," Thies said.
In one study, Mark Sager, MD, of the University of Wisconsin Medical School, and colleagues studied a total of 726 people in middle-age with a family history of Alzheimer's from the Wisconsin Registry for Alzheimer's Prevention who were genotyped for TOMM40 and APOE, the latter of which is a well-established risk gene for Alzheimer's. Of these, 129 had the low risk version of TOMM40 and 229 had the high risk version. The average age of the study population was 54.
The researchers found that the group with the high risk version of the TOMM40 gene performed significantly worse on the tests of learning and memory (Rey Auditory Verbal Learning Test) than the group with the low risk version. These results remained significant regardless of APOE gene type.
"The deficits shown by the high risk group are similar to the kinds of changes in memory and learning that are seen in very early Alzheimer's," Sager said. "In this study population, TOMM40 genotyping is allowing us to find evidence of very early Alzheimer's disease at least 20 years before people begin to show the outward symptoms. This is a step forward in Alzheimer's prevention research."
In a second study, Sterling Johnson, PhD, also of the University of Wisconsin School of Medicine and Public Health, and colleagues found that among healthy, middle aged adults (mean age 57) who have the APOE e3/e3 gene type, those with the high risk version of the TOMM40 gene had significantly less gray matter volume in two brain regions affected early in Alzheimer's disease than those with the low risk version of the gene.
According to the researchers, the study suggests that there is a connection between TOMM40 and brain cell loss in people who are relatively young and currently not symptomatic.
"This is the first study to associate TOMM40 to brain imaging in people at risk for Alzheimer's disease," Johnson said. "The brain differences between TOMM40 groups were very similar but less severe that what is observed in full-blown Alzheimer's. It may be that the TOMM40 gene will be a useful measure of Alzheimer's risk in middle-age, but additional research with longitudinal follow-up is needed."
Allen Roses, MD, and colleagues at Duke University first discovered that the TOMM40 gene helped explain differences in age of onset among people with sporadic Alzheimer's disease.
Clinical Trial of Intranasal Insulin Shows Some Benefits in Alzheimer's and MCI
Previous research has strongly suggested that Alzheimer's and diabetes/insulin resistance are closely related. For example, Alzheimer's is associated with reduced brain insulin signaling and low levels of insulin in cerebrospinal fluid (CSF).
"These deficiencies may reduce or eliminate insulin's beneficial roles in the brain," said Suzanne Craft, PhD, of VA Puget Sound Health Care System/University of Washington in Seattle. "We believe that restoring normal insulin function in the brain may provide therapeutic benefits to adults with Alzheimer's. Intranasal administration enables insulin to access brain regions that are compromised in Alzheimer's."
Craft and colleagues had previously shown enhanced cognition and daily functioning in adults with MCI and early Alzheimer's using intranasal insulin treatment for 21 days. This new study expanded the time frame to four months, during which 109 participants with MCI or Alzheimer's received either placebo, or 20 or 40 IU daily intranasal insulin treatment.
The researchers found that in the 20 IU dose group (10 IU twice daily) results on a test of delayed story recall significantly improved compared with those who received placebo, as did functional status measured by the Dementia Severity Rating Scale. Improvements in delayed memory recall persisted for two months after the insulin treatment ended. However, memory and learning on the ADAS-Cog and ability to do activities of daily living measured by the ADCS-ADL scores were unchanged.
For 15 of the insulin-treated participants who agreed to have a spinal tap, improved memory and functional status were associated with an improved Alzheimer's biomarker profile as reflected by a lowered CSF tau/Aß42 ratio.
"These results provide encouraging support for further study of intranasal insulin as a therapy for Alzheimer's," Craft said. "We are currently planning a large, multi-center clinical trial."
New Imaging Compounds for Alzheimer's Protein Deposits in the Brain Show that Different Forms of the APOE Risk Gene Create Different Shapes of Beta Amyloid
A new class of biomarkers has been discovered that can stick to protein structures in the body and emit colors reflecting the different shapes or forms of the proteins. They are called luminescent conjugated oligothiophenes (LCOs) or luminescent conjugated polymers (LCPs). Among other uses, they are currently being employed in test tubes, animal models and autopsied Alzheimer's brains to study the structure of proteins deposits caused by the disease. The new markers bind to the two well-established hallmarks of Alzheimer's – beta amyloid plaques and tau tangles – and glow different colors depending on which forms of the deposits they "stick" to (e.g., plaques often "glow" orange, while tangles "glow" yellowish green).
In this study reported at AAICAD 2010, Sam Gandy, MD, PhD, of Mount Sinai School of Medicine, New York, and colleagues used LCOs/LCPs to investigate the possibility that the shape of brain protein deposits in people with Alzheimer's who have the APOE e4/e4 gene type (highest risk) is different from those having APOE e3/e3 (neutral risk).
Frozen brain sections from people who died with Alzheimer's were stained using two LCPs/LCOs: pentamer formyl thiophene acetic acid (pFTAA) and polythiophene acetic acid (PTAA). Using PTAA, the researchers observed that Alzheimer patients with APOE e4/e4 had core and cerebrovascular amyloid of different shapes, while in people with APOE e3/e3 the two amyloid structures had the same shape. Using pFTAA revealed that tau tangle densities in e4/e4 Alzheimer patients that were apparently greater than those with e3/e3.
"The findings support our hypothesis that APOE genotype changes amyloid structure," Gandy said. "This is important because the different shapes might respond differently to treatments that attempt to clear amyloid deposits from the brain."
In some recent drug trials, the experimental therapy provided benefits in people who had a certain type of the APOE gene (known as e3) but were less or not effective in another type (e4).
LCOs/LCPs were pioneered by Peter Nilsson of the Department of Chemistry, Linköping University, Sweden. The study also involved collaborating teams from Charité – Universitätsmedizin Berlin, Germany (led by Frank Heppner), Washington University, St Louis (led by David Holtzman), and other labs at Mount Sinai (led by Patrick Hof and Dara Dickstein).
About AAICAD The Alzheimer's Association International Conference on Alzheimer's Disease (AAICAD) is the world's largest conference of it's kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.
About the Alzheimer's Association The Alzheimer's Association is the leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit www.alz.org or call 800-272-3900.
Abstracts (6 pages)
14, 2010, 6:30-7:30 am, Hawai’i Convention Center, 1801 Kalakaua Avenue, Honolulu, Room 321A.
Mark A. Sager, et al. TOMM40 Variable Length Polymorphism Is Associated With Memory Function In Asymptomatic Middle-aged Persons. (Funded by: National Institute on Aging, Helen Bader Foundation, Extendicare Foundation)
Sterling C. Johnson, et al. TOMM40 Is Associated With Gray Matter Volume In Middle-aged Persons With Apoe e3/e3 Genotype. (Funded by: National Institute on Aging, Department of Veterans Affairs)
Suzanne Craft, et al. Intranasal Insulin- And Biomarker-associated Improvement In Memory And Functional Status In Mild Cognitive Impairment And Alzheimer's Disease: Results Of A Randomized, Double-blind, Placebo-controlled Pilot Trial. (Funded by: Department of Veterans Affairs, National Institute on Aging)
Hannah Brautigam, Sam Gandy, et al. New Conformation-Sensing Imaging Compounds Distinguish Protein Deposits In APOE e3/e3 Alzheimer’s Patients From That In APOE e4/e4 Alzheimer’s Patients. (Funded by: National Institutes of Health, Cure Alzheimer’s Fund, European Union FP7 HEALTH (Project LUPAS), German Research Foundation, Knut and Alice Wallenberg Foundation, Swedish Foundation for Strategic Research)
All materials to be presented at the Alzheimer's Association 2010 International Conference on Alzheimer's Disease are embargoed for publication and broadcast until the date and time of presentation at the conference, unless the Alzheimer's Association provides advance written notice of change of date and/or time.
Control #: 10-HT-3354-ALZ
TOMM40 Variable Length Polymorphism Is Associated With Memory Function In Asymptomatic Middle-aged Persons Mark A. Sager, M.D.1, Asenath La Rue, Ph.D.1, Sterling C. Johnson, Ph.D.1, Ann M. Saunders, Ph.D.2, Allen D. Roses, M.D.2, Rebecca Koscik, Ph.D.1, Erin Jonaitis, Ph.D.1, Michael W. Lutz, Ph.D.2, Sanjay Asthana, M.D.1, Robert C. Green, Ph.D., M.Ph.3, Bruce P. Hermann, Ph.D.1.
1UW Medical School-Madison, Madison, WI, USA, 2Duke University, Durham, NC, USA, 3Boston University, Boston, MA, USA. Contact Email: masager@wisc.edu
Disclosure Block: M.A. Sager, None.
Background: A TOMM40 polymorphism, a variable length intronic poly T repeat (rs10524523), has been shown to influence age of Alzheimer’s disease (AD) onset. In this study, we tested the hypothesis that subjects homozygous for TOMM40 short poly T sequences <21 (SPT) would show better performance on measures of learning and memory than those who were homozygous for longer poly T sequences =21 (LPT) in middle-aged subjects with a family history of AD.
Methods: The study population includes 726 middle-aged asymptomatic persons enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) who had been genotyped for APOE and 2 TOMM40. A total of 129 were homozygous for SPT sequences <21 (low risk) and 229 were homozygous for LPT sequences =21 (high risk). Study groups were defined by TOMM40 genotyping based on the length of the poly T sequences regardless of APOE genotype. Serial position profiles and total learning on the Rey Auditory Verbal Learning Test (AVLT) were compared between groups controlling for age, gender and education.
Results: The mean age of the study population was 54 and 69% were female. There were no significant age, gender or education differences between SPT and LPT groups. The two TOMM40 groups differed significantly in total words learned on the AVLT (p = .012) with the LPT TOMM40 group remembering fewer words. There were significant differences in the serial position curve with significantly poorer recall from the primacy region on the AVLT (p = .001). Nineteen percent of the SPT group had an APOE e4 compared with 55% of the LPT group. When APOE genotype (e4 carrier vs. non-carrier) was added to the model, TOMM40 remained significant on both measures.
Conclusions: Longer TOMM40 poly T sequence length was associated with differences in memory and learning that are seen in early AD. These changes were seen in middle-aged asymptomatic persons, suggesting that TOMM40 genotyping may prove useful in stratifying persons at different levels of AD risk in studies of pre-symptomatic AD. The role that TOMM40 plays in AD pathogenesis and its relationship to APOE genotype as a genetic risk factor for AD remain to be determined.
All materials to be presented at the Alzheimer's Association 2010 International Conference on Alzheimer's Disease are embargoed for publication and broadcast until the date and time of presentation at the conference, unless the Alzheimer's Association provides advance written notice of change of date and/or time.
Control #: 10-HT-3432-ALZ O4-03 - Hot Topics 2 (Presentation #O4-03-04; Speaking Time: 7/14/2010 1:45-2:00 PM)
TOMM40 Is Associated With Gray Matter Volume In Middle-aged Persons With APOE e3/e3 Genotype
Sterling C. Johnson, Ph.D.1,2, Asenath La Rue, Ph.D.1, Bruce P. Hermann, Ph.D.1, Guofan Xu, Ph.D.1, Rebecca L. Koscik, Ph.D.1, Erin M. Jonaitas, Ph.D.1, Barbara B. Bendlin, Ph.D.1,2, Allen D. Roses, MD3, Ann M. Saunders, Ph.D.3, Michael W. Lutz, Ph.D.3, Sanjay Asthana, MD1,2, Robert C. Green, MD4, Mark A. Sager, MD1. 1University of Wisconsin, Madison, WI, USA, 2Wm. S. Middleton Veterans Hospital, Madison, WI, USA, 3Duke University, Durham, NC, USA, 4Boston University, Boston, MA, USA. Contact Email: scj@medicine.wisc.edu Disclosure Block: S.C. Johnson, None
Background: Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late onset Alzheimer’s disease (LOAD), with APOE e4 having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of the TOMM40 gene has very recently been shown to influence age of onset in LOAD, where very long poly-T length was associated with earlier disease onset, and short poly-T length associated with later onset. In this study, we tested the hypothesis that brain changes antedating symptomatic LOAD may be associated with this TOMM40 polymorphism.
Methods: Among healthy APOE e3 homozygous adults (mean age 57), we compared those homozygous for very long (VL/VL; n=33) TOMM40 poly-T lengths (who are presumably at 3 higher risk) to those homozygous for short (S/S; n=37) poly-T lengths on structural brain imaging. Voxel-based morphometry was used to assess gray matter volume using the software SPM8. Gray matter probability maps were entered into a voxel-wise ANCOVA where Age and Intracranial volume were covariates
Results: Results were that the VL/VL TOMM40 group had significantly less gray matter volume in the ventral posterior cingulate and precuneus, a region of the brain affected early in LOAD.
Conclusions: To our knowledge, this is the first study to associate TOMM40 523 genotypes to brain imaging in people at risk for AD. These findings suggest that the group with very long TOMM40 poly-T lengths may be experiencing incipient LOAD-related cognitive and brain changes. The participants in this study are being followed over time to determine genetic and other factors that predict cognitive decline and dementia 4 5
All materials to be presented at the Alzheimer's Association 2010 International Conference on Alzheimer's Disease are embargoed for publication and broadcast until the date and time of presentation at the conference, unless the Alzheimer's Association provides advance written notice of change of date and/or time.
Control #: 10-HT-3439-ALZ O4-04 - Hot Topics 3 (Presentation #O4-04-01; Speaking Time: 7/14/2010 1:00-1:15 PM)
Intranasal Insulin- And Biomarker-associated Improvement In Memory And Functional Status In Mild Cognitive Impairment And Alzheimer's Disease: Results Of A Randomized, Double-blind, Placebo-controlled Pilot Trial
Suzanne Craft, PhD1, Laura D. Baker, PhD1, Thomas J. Montine, MD, PhD2, Jing Zhang, MD, PhD2, G. Stennis Watson, PhD1, Stephen Plymate, MD1, Elaine Tsai, MD1, Maureen Callaghan, MD1, James Leverenz, MD1, Brooke Gerton, MD1, Emily Trittschuh, PhD1. 1University of Washington/VA Puget Sound, Seattle, WA, USA, 2University of Washington, Seattle, WA, USA. Contact Email: scraft@u.washington.edu Disclosure Block: S. Craft, None.
Background: Alzheimer’s disease (AD) is associated with reduced brain insulin signaling and low CSF insulin levels. These deficiencies may abrogate insulin’s role in synaptic maintenance, Aß regulation, and other mechanisms related to AD pathogenesis. Restoring normal insulin function in brain may thus provide therapeutic benefit to adults with AD. Intranasally administered insulin follows extracellular pathways to the brain, bypassing the periphery and blood brain barrier, and accessing the CNS within 15 minutes. Previously, we showed that cognition and daily function are enhanced following intranasal insulin treatment for 21 days in adults with amnestic mild cognitive impairment (MCI) and early AD.
Methods: Participants with MCI or AD (n=109) received either placebo, or 20 or 40 IU daily intranasal insulin treatment for four months. ADAS-Cog/MCI and delayed story recall scores were primary outcome measures and were administered at baseline, at 2 and 4 months during treatment, and 2 months after treatment cessation. Secondary measures of functional status included the Dementia Severity Rating Scale (DSRS) and Alzheimer Disease Cooperative Study Activity of Daily Living Scale (ADCS-ADL). A subset of participants (n=23) received lumbar punctures at baseline and after 4 months of treatment. For the intent-to-treat analysis, outcome measures for each dose group were compared to the placebo group with repeated measures analysis of variance.
Results: Delayed story recall improved in the 20 IU dose group compared with placebo (p=0.0201), as did functional status reflected by DSRS (p=0.0054). Improved delayed memory persisted 2 months after insulin treatment ended (p=0.0209). ADAS-Cog and ADCS-ADL scores were unchanged. The 40 IU dose group had improved daily function relative to placebo on the DSRS (p=0.0095), but no differences in cognition. For CSF biomarker analysis, the two insulin dose groups were combined to increase power. For insulin-treated participants (n=15), improved delayed memory and functional status were associated with an improved AD biomarker profile as reflected by a lowered CSF tau/Aß42 ratio (Spearman rhos=-.52 and .53, ps<0.05). n="8;">.90).
Conclusions: These results provide strong support for further investigation of intranasal insulin as a therapeutic approach for patients with MCI and AD.
All materials to be presented at the Alzheimer's Association 2010 International Conference on Alzheimer's Disease are embargoed for publication and broadcast until the date and time of presentation at the conference, unless the Alzheimer's Association provides advance written notice of change of date and/or time.
Control #: 10-HT-3369-ALZ
O4-04 - Hot Topics 3 (Presentation #O4-04-06; Speaking Time: 7/14/2010 2:15-2:30 PM)
6
New Conformation-Sensing Imaging Compounds Distinguish Protein Deposits In APOE e3/e3 Alzheimer’s Patients From That In APOE e4/e4 Alzheimer’s Patients
Hannah Brautigam, BS Psychology1, Thérese Klingstedt, MS Biomedicine2, Stefan Prokop, MD3, David M. Holtzman, MD4, Frank L. Heppner, MD3, Vahram Haroutunian, PhD1, Dara L. Dickstein, PhD1, Patrick R. Hof, MD1, Peter R. Nilsson, PhD2, Sam Gandy, MD, PhD1,5. 1Mount Sinai School of Medicine, New York, NY, USA, 2Linköping University, Linköping, Sweden, 3Charité-Universitäsmedizin Berlin, Berlin, Germany, 4Washington University School of Medicine, St. Louis, MO, USA, 5James J. Peters VA Medical Center, Bronx, NY, USA. Contact Email: hannah.brautigam@mssm.edu; samgandy@gmail.com
Disclosure Block: H. Brautigam, None.
Background: A novel class of biomarkers, luminescent conjugated oligothiophenes (LCOs) or luminescent conjugated polymers (LCPs), has been designed to intercalate into proteinaceous structures and emit spectra reflecting discrete conformation states. LCOs/LCPs have enabled the discrimination of prion strain isotypes and are currently being employed in vitro and in vivo to study the structure of aggregated proteins in Alzheimer’s disease (AD); LCOs/LCPs bind to amyloid beta (Aß) deposits and neurofibrillary tangles (NFTs) in histological brain sections of AD patients, emitting spectra related to the conformation(s) of these deposits. In addition to Aß, apolipoprotein E (APOE) is a component of human brain amyloid, and the APOE e4 allele is the major genetic risk factor for sporadic AD. We employed LCOs/LCPs to investigate the possibility that the conformation of brain protein deposits in AD patients having e4/e4 alleles differed from deposits in AD patients having e3/e3 alleles.
Methods: Frozen brain sections were analyzed from pairs of AD patients matched for age, gender, CDR score, and duration of disease; only APOE genotype, e4/e4 or e3/e3, differed between pairs. Adjacent sections from each pair were stained using two LCPs/LCOs: pentamer formyl thiophene acetic acid (pFTAA) and polythiophene acetic acid (PTAA). Fluorescence spectra from tissue sections were recorded with an LSM 510 META confocal laser scanning microscope, and spectral processing was achieved with an LSM Image browser.
Results: Using PTAA, we observed that AD patients with e4/e4 exhibited a different conformational spectrum for core and cerebrovascular amyloid whereas their respective matched e3/e3 pair exhibited indistinguishable conformational spectra between the two amyloid structures. pFTAA, sensitive for different conformations for Aß and NFTs, revealed NFT densities in e4/e4 AD patients that were apparently greater than those in e3/e3 AD patients.
Conclusions: The observation that PTAA core amyloid and cerebrovascular amyloid spectra distinguish the amyloid deposits of APOE e4/e4 from APOE e3/e3 AD patients supports the hypothesis that APOE genotype modulates amyloid structure. pFTAA holds promise as an especially sensitive reagent for visualizing NFTs. LCOs/LCPs show great potential as research tools for the study of proteinopathies, including the pathogenesis of sporadic AD and possibly the influence of APOE genotype.
# # #
http://www.alz.org/icad/documents/abstracts/2010_hot_topics.pdf
Contact: Alzheimer's Association Media line: 312.335.4078 E-mail: media@alz.org AAICAD 2010 press room, July 10-15: 1-808-792-6523
http://www.alz.org/icad/2010_release_hot_071410_1230pm.asp
ICAD Press ReleasesMore News> 07/14/10 "Hot Topics" from the Alzheimer's Association International Conference on Alzheimer's Disease 2010 07/14/10 Early Detection, Diagnosis & Care Management for People with Dementia May Reduce Healthcare Costs 07/14/10 New Research Advances from the Alzheimer's Association International Conference on Alzheimer's Disease 2010 07/13/10 National Institute on Aging and Alzheimer's Association Lead Effort to Update Diagnostic Criteria for Alzheimer's Disease 07/13/10 Alzheimer's Disease may Increase Risk of Anemia and Seizures 07/13/10 Four New Research Studies Describe Experimental Immunotherapies for Alzheimer's 07/12/10 Alzheimer's Association Launches TrialMatch™ – First-of-its-Kind Clinical Trials Matching Service in Alzheimer's National News 07/15/10 Fighting Alzheimer's disease -ABC World News Tonight 07/15/10 Insulin via nasal spray shows benefit in people with Alzheimer's -USA Today 07/15/10 Early diagnosis of Alzheimer's yields savings -The Wall Street Journal
http://www.alz.org/icad/
BSE101/1 0136
IN CONFIDENCE
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 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.
92/11.4/1.1
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
92/11.4/1.2
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
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 B amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegeneradve 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.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Wednesday, April 14, 2010
Food Combination and Alzheimer Disease Risk A Protective Diet
http://betaamyloidcjd.blogspot.com/2010/04/food-combination-and-alzheimer-disease.html
Wednesday, March 31, 2010
Neurobiology of Disease Molecular Cross Talk between Misfolded Proteins in Animal Models of Alzheimer's and Prion Diseases
http://betaamyloidcjd.blogspot.com/2010/03/neurobiology-of-disease-molecular-cross.html
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
P03.139
Cellular Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer's Amyloid Precursor Protein
Hooper, NM1; Parkin, ET1; Watt, NT1; Baybutt, H2; Manson, J2; Hussain, I3; Turner, AJ1 1University of Leeds, Institute of Molecular and Cellular Biology, UK; 2Roslin Institute, Neuropathogenesis Unit, UK; 3GlaxoSmithKline, Neurodegeneration Research, UK
Background: The normal cellular function of the prion protein (PrP), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD) in humans, remains enigmatic. Several studies have reported combinations of Alzheimer's Disease (AD) and CJD neuropathology and the Val/Met129 polymorphism in the PrP gene has been identified as a risk factor for early-onset AD, leading to speculation that there may be some pathogenic connection between these two neurodegenerative conditions. The amyloid ß (Aß) peptides that cause AD are derived from the amyloid precursor protein (APP) through sequential proteolytic cleavage by the ß-secretase (BACE1) and the g-secretase complex.
Aim: As both APP and PrP are cleaved by zinc metalloproteases of the ADAM family, we investigated whether PrP alters the proteolytic processing of APP.
Results: Here we show that expression of PrP in SH-SY5Y cells dramatically downregulated the cleavage of APP by BACE1 and reduced the secretion of Aß peptides into the conditioned medium by >92%. Conversely, siRNA reduction of endogenous PrP in N2a cells led to an increase in secreted Aß. Furthermore, levels of Aß were significantly increased in the brains of PrP null mice as compared with wild type mice. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases, did not inhibit the BACE1 cleavage of APP. To investigate whether the Val/Met129 polymorphism in human PrPC would alter the production of Aß, brains from mice with the human PrP gene with MM or VV 129 genotypes were analysed. In the MM mice there was a significant increase in Aß in the brains as compared with the VV mice. In the brains of two strains (79A and 87V) of scrapie-infected mice there was a significant increase in Aß peptides as compared to uninfected mice.
Conclusions: Together these data reveal a novel function for PrP in regulating the processing of APP through inhibition of BACE1. The increase in APP processing in cells expressing disease-associated forms of PrP and in scrapie-infected brains raises the possibility that the increase in Aß may contribute to the neurodegeneration observed in prion diseases. Funded by the Medical Research Council of Great Britain.
P03.140
Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer's Amyloid Precursor Protein through Interaction with Glycosaminoglycans
Griffiths, HH; Parkin, ET; Watt, NT; Turner, AJ; Hooper, NM University of Leeds, Institute of Molecular and Cellular Biology, UK
Background: Proteolytic processing of the amyloid precursor protein (APP) by ßsecretase, BACE1, is the initial step in the production of the amyloid ß (Aß) peptide which is involved in the pathogenesis of Alzheimer's disease. We have shown that the cellular prion protein (PrP) inhibits the cleavage of APP by BACE1 in cell and animal models.
Aim: To investigate the mechanism by which PrP inhibits the action of BACE1.
Results: Neither PrPdeltaGPI, which is not membrane attached, nor PrP-CTM, which is anchored by a transmembrane domain and is excluded from cholesterol-rich lipid rafts, reduced cleavage of APP, suggesting that to inhibit the BACE1 cleavage of APP PrP has to be localised to lipid rafts. Coimmunoprecipitation experiments demonstrated that PrP physically interacts with BACE1. However, PrP did not alter the activity of BACE1 towards a fluorogenic peptide substrate nor perturb the dimerisation of BACE1. Using constructs of PrP lacking either the octapeptide repeats or the 4 residues KKRP at the N-terminus of the mature protein (PrPdeltaN), we demonstrate that the KKRP sequence but not the octapeptide repeats, is essential for regulating the BACE1 cleavage of APP. As the KKRP sequence is known to participate in glycosaminoglycan (GAG) binding, we confirmed that PrPdeltaN did not bind to immobilised heparin. Addition of heparin to SH-SY5Y cells increased the amount of APP cleaved by BACE1 in a concentration-dependent manner and reduced the amount of BACE1 coimmunoprecipitated with PrP, suggesting that GAGs are required for PrP to interact with BACE1 and inhibit APP processing. Of a range of GAGs, including dextran sulphate, hyaluronic acid and chondroitin sulphate, investigated there was complete correlation between those that could restore BACE1 cleavage of APP in PrP expressing cells and those that bound PrP.
Conclusion: These data suggest a possible mechanism by which PrP regulates the ßcleavage of APP is through the N-terminus of PrP interacting via GAGs with one or more of the heparin binding sites on BACE1 within a subset of cholesterol-rich lipid rafts, thereby restricting access of BACE1 to APP. Funded by the Medical Research Council of Great Britain.
P04.37
Comparison of the Neuropsychological Profile of Patients with Sporadic Creutzfeldt-Jakob Disease and Patients with Alzheimer's
Krzovska, M1; Cepek, L1; Ratzka, P2; Döhlinger, S3; Uttner, I1; Wolf, Stefanie4; Irle, Eva4; Mollenhauer, Brit5; Kretzschmar, Hans A.6; Riepe, Matthias7; v. Arnim, Christine1; Otto, Markus1 1University of Ulm, Germany; 2Department of Neurology, Germany; 3University of Goettingen, Germany; 4University of Goettingen, Germany; 5Elena Klinik, Germany; 6LMU, Germany; 7University of Berlin, Germany
Background:To evaluate the neuropsychological profile of sCJD we administered the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) in order to determine if and how the sCJD-Subgroups (Met/Met, Met/Val, Val/Val) have different results in the item analysis of the ADAS-cog. Furthermore, we studied how the scores differ from that of patients with Alzheimer's disease (AD).
Methods:33 sCJD patients (11 with definite CJD and 22 with probable CJD) underwent neuropsychological testing with the ADAS-cog and Mini Mental State Exam (MMSE). Of these 31 were genotyped at the Codon 129 (11 Val/Val, 18 Met/Val and 2 Met/Met). The patients were matched in regards to sex and total ADAS-cog score with AD patients. The scores of the 11 ADAS-cog items were compared between the sCJD and the AD groups as well as between the sCJD-subgroups Met/Val and Val/Val and the AD group.
Results:The ADAS-cog total score of the sCJD and AD groups was 22.6+/- 6.5, respectively. Regarding the single Item scores of the sCJD patient group and the AD patient group, there were statistically significant differences in the Items Constructional praxis, Word-finding difficulty in spontaneous speech and Spoken language ability. When comparing the sCJD subtypes with each other no statistically significant difference was found in the items.
Conclusion: In the speech and constructional praxis there is indication of greater impairment in sCJD patients in general when compared with AD patients. A disturbance of the speech appears to be an important characteristic of the Met/Val and Val/Val subtypes of sCJD, and should therefore be the focus of special attention in future neuropsychological studies.
http://www.neuroprion.com/pdf_docs/conferences/prion2007/abstract_book.pdf
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2007/abstract_book.pdf
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease
http://betaamyloidcjd.blogspot.com/2008/04/re-association-between-deposition-of.html
Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures
http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html
Monday, January 4, 2010
Rising Tide: The Impact of Dementia in Canada Huge wave of dementia cases coming, warns report
http://betaamyloidcjd.blogspot.com/2010/01/rising-tide-impact-of-dementia-in.html
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Are some commoner types of neurodegenerative disease (including Alzheimer's disease and Parkinson's disease) also transmissible? Some recent scientific research has suggested this possibility
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Could cases of protease sensitive prionopathy (PSP) be missed by conventional tests which, in all other TSEs, rely on the resistance of the prion protein in the nervous system that accompanies disease to digestion by protease enzymes?
Can we develop reliable methods for removing and detecting protein on re-usable surgical instruments?
SNIP...
FULL TEXT ;
Monday, October 12, 2009
SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens TSE 8 October 2009
http://bse-atypical.blogspot.com/2009/10/seac-science-and-technology-committees.html
Sunday, June 7, 2009
ALZHEIMER'S DISEASE IS TRANSMISSIBLE
http://betaamyloidcjd.blogspot.com/2009/06/alzheimers-disease-is-transmissible.html
http://betaamyloidcjd.blogspot.com/
TSS
I think it's a step forward. small step, but at least it is not a step backward. Most of these type scans have been around for some time, although technology has improved over the years. We have floundered much too long with Alzheimer's and other neurological disease. Just to hear them say they are now going to try and start to _identify_ these cases, as oppose to in the past i.e. only search for nvCJD i.e. UKBSEnvCJD only theory. Maybe, just maybe, a light bulb went off in some of the minds of the ones that matter (prion Gods), and now say something like 'maybe we should start to identify all these potential TSE, including Alzheimer's type dementia, Parkinson's and other neurodegenerative diseases, and regardless of any poential sources. We know now science is leaning towards it's potential to be transmissible, we know there is a common denominator('s?), we just don't have the complete formula to figure it out with yet$ so let's not wait around like we did with the nvCJD and sporadic CJD's debate on the potential for blood and blood products being transmissible, let's not wait around like we did that, until we exposed everyone around the globe, let's not wait around like that, let's ACT NOW, instead of later, regardless.' Let's _indentify_, ACT when something is indentified, act as if it is likely to be Iatrogenic FIRST, then let's prove it's is not, NOT the other way around, like saying it is not transmissible first, acting on that, then taking over 2 decades and finding out it is transmissible. By then it is too late. Let's not sit around and talk about if for over two decades. I know that there has been a blood ban restriction due to CJD, but the USA has failed terribly in it's regulation there from, as with everything esle related to Transmissible Spongiform Encephalopathy regulations. ... just my take.
EMBARGOED FOR RELEASE UNTIL WEDNESDAY, JULY 14, 2010 7:30 am HST / 1:30 pm ET „P
John R. McCarten, et al. Changes In Outpatient Costs Following Screening And Diagnosis Of Cognitive Impairment. (Funded by: Strategic Initiative, Veterans Integrated Service Network 23)
All materials to be presented at the Alzheimer's Association 2010 International Conference on Alzheimer's Disease are embargoed for publication and broadcast until the date and time of presentation at the conference, unless the Alzheimer's Association provides advance written notice of change of date and/or time.
Control #: 10-HT-3470-ALZ O4-04 - Hot Topics 3 (Presentation #O4-04-04; Speaking Time: 7/14/2010 1:45-2:00 PM)
Changes In Outpatient Costs Following Screening And Diagnosis Of Cognitive Impairment
John R. McCarten, M.D.1, Pauline Anderson, MSN2, Michael A. Kuskowski, Ph.D.1, Yvonne Jonk, Ph.D.3, Maurice W. Dysken, M.D.1. 1VA Medical Center, Minneapolis, MN, USA, 2Veterans Integrated Service Network 23, Minneapolis, MN, USA, 3University of Minnesota, Minneapolis, MN, USA. Contact: J Riley McCarten, mccar034@umn.edu Disclosure Block: J.R. McCarten, MN/ND Chapter of the Alzheimer's Association's BOD.
Background: Dementia is a common, costly, and often unrecognized problem in older adults. Early identification and intervention holds the promise of improving care through chronic disease management strategies. We integrated a program of screening, evaluation, and management for cognitive impairment into primary care. Here we report the impact of that program on total and line item outpatient costs.
Methods: The Dementia Demonstration Project (DDP) employed specially trained Advanced Practice Registered Nurses functioning as Dementia Care Coordinators (DCCs) to lead interdisciplinary teams in the identification, evaluation, diagnosis and management of cognitive impairment (CI). Typical primary care clinics were identified at seven VA Medical Centers and the DDP was implemented in those clinics. The DCCs screened eligible veterans (age 70 and older, medically stable, able to comply with the screen, and without a prior diagnosis of CI) using the Mini-Cog at the time of a routine primary care clinic appointment. All patients newly diagnosed with CI, both in DDP and non-DDP PC clinics, who had data available for at least one year before and one year after diagnosis were analyzed. Risk adjusted differences in log transformed outpatient health care utilization and costs were analyzed using the mixed effects Poisson regression and difference-in-differences models.
Results: Of the 8278 veterans screened, 26% failed the screen. A total of 34% of those who failed completed a further evaluation and 95% of this group was found to have CI, including 76% with dementia. Data for one year before and after CI diagnosis were available on 347 DDP patients and 1261 non-DDP patients. Median DDP outpatient care costs declined over 54% (- 2 $5,519) compared with 25% decline (-$1,759) in patients diagnosed in non-DDP clinics. Median number of line-item outpatient costs declined by 53% (-54) in the DDP patients compared to 32% (-21) in non-DDP patients.
Conclusions: Diagnosing cognitive impairment was associated with a decrease in total and line item health care costs in the year following diagnosis compared to the year prior to diagnosis. The decreases were more dramatic in patients who were identified through cognitive screening and subsequently had case management available by a dementia care team.
http://www.alz.org/icad/documents/abstracts/2010_early_detection.pdf
National Institute on Aging and Alzheimer's Association Lead Effort to Update Diagnostic Criteria for Alzheimer's Disease
- News briefing/Q&A: AAICAD 2010, Tuesday, July 13, 2010, 11:45 am-12:45 pm Hawai'i Convention Center, Room 321A, 1801 Kalakaua Avenue, Honolulu -
Honolulu, Hawaii, July 13, 2010 – Scientists at the Alzheimer's Association International Conference on Alzheimer's Disease 2010 (AAICAD 2010) today presented the first draft reports from three workgroups convened by the National Institute on Aging (NIA) and the Alzheimer's Association to update the diagnostic criteria for Alzheimer's disease for the first time in 25 years.
The current criteria for the diagnosis of Alzheimer's were established by a National Institute of Neurological Disorders and Stroke (NINDS)/Alzheimer's Disease and Related Disorders Association (ADRDA) workgroup in 1984. These criteria were almost universally adopted and have been useful; they have survived intact without modification for more than 25 years. However, experts note, the field has evolved to a great extent since then.
"Important scientific discoveries have been made in Alzheimer's, and there have been significant changes in our knowledge and conception of the disease," said Creighton H. Phelps, Ph.D., Director of the Alzheimer's Disease Centers Program, Division of Neuroscience, National Institute on Aging at the National Institutes of Health. "The NIA and the Alzheimer's Association, after consultation with the Alzheimer's scientific and medical community, concluded that the diagnostic criteria may need to be revised to incorporate scientific advances. We decided to convene workgroups to examine the literature and make recommendations."
At AAICAD 2010, leaders of the three workgroups – which covered Alzheimer's disease dementia, mild cognitive impairment (MCI) due to Alzheimer's disease, and preclinical Alzheimer's disease – presented preliminary reports at a special session for initial comment by the Alzheimer's community.
"The proposals would change the 1984 criteria by better reflecting the various stages of the disease and the inclusion of Alzheimer's disease biomarkers," said William Thies, PhD, Chief Medical and Scientific Officer at the Alzheimer's Association. "While the role of biomarkers differs in each of the three stages, much remains to be understood concerning their reliability and validity in diagnosis. This makes it critical that we thoroughly test any new recommendations."
Further input will be solicited by the NIA and the Association through a website launched immediately after the AAICAD presentations at www.alz.org/research/diagnostic_criteria. After that input is incorporated, next steps are publication in a peer-reviewed journal followed by systematic validation through incorporation of the criteria into clinical trials.
"The proposed criteria for Alzheimer's disease dementia must be flexible enough to eventually be used – once they are validated – by both general health care providers without access to neuropsychological testing, advanced imaging, and CSF measures, as well as specialized investigators involved in research or clinical trial studies with access to these measures," said Guy McKhann, MD, of John Hopkins University School of Medicine, who chaired this workgroup.
The Importance of Moving to Earlier Diagnosis
Alzheimer's is thought to begin years, perhaps even decades, before symptoms are noticeable. But there is no single, generally accepted way to identify the disease in its earliest stages – before symptoms are evident.
According to Phelps, earlier detection of people at highest risk for Alzheimer's and those who have the earliest forms of the disease will facilitate finding the right individuals to participate in risk reduction and prevention research studies.
"The NIA and the Alzheimer's Association hope this process of updating and revising the Alzheimer's diagnostic criteria with modern technologies and the latest advances will provide standards that move the field further in the direction of early detection and treatment," Thies said.
Significant Advances in Alzheimer Research Since 1984
Among the most important advances in the Alzheimer's field since the publication of the 1984 NINDS/ADRDA diagnostic criteria are:
•Alzheimer's-driven changes in the brain, as well as the accompanying cognitive deficits, develop slowly over many years with dementia representing the end stage of years of pathology accumulation. At the same time, we know that some people have the brain changes associated with Alzheimer's and yet don't show symptoms of dementia.
•Predictive genes in early onset Alzheimer's indicate that the initial events ultimately leading to both clinical symptoms and pathological brain changes begin with disordered beta amyloid metabolism. •The e4 allele of the APOE gene is well accepted as a major genetic risk factor for late onset Alzheimer's disease, which is defined as onset at 65 or older.
•Biomarkers for Alzheimer's have been developed and are being validated. These fall into several categories:
Biomarkers of beta amyloid pathology, including amyloid PET imaging and levels of beta amyloid in cerebrospinal fluid (CSF).
Biomarkers of neuronal injury, including levels of CSF tau and phospho-tau.
Biomarkers of neuronal dysfunction, including decreased uptake of FDG on PET scans.
Biomarkers of neurodegeneration, including brain atrophy on structural MRI scans. In addition, it has been only in the past decade that a better understanding of the distinctions and overlaps of Alzheimer's with non-Alzheimer's dementias has begun to emerge. Knowledge of the non-Alzheimer's dementias was rudimentary in 1984, and the current diagnostic criteria are vague in defining distinctions between Alzheimer's and the major alternatives. The common co-existence of Alzheimer's and cerebrovascular disease is now appreciated. Much more is known about dementia resulting from Lewy Body disease, and also about Pick's disease and other frontotemporal dementias.
Three Work Group Reports Present New Ideas for Research Criteria and Better Define Early Stages of Alzheimer's Disease
The NIA/Alzheimer's Association working groups were organized around the three stages of Alzheimer's disease that are commonly thought to exist today – pre-clinical Alzheimer's, mild cognitive impairment (MCI) due to Alzheimer's, and Alzheimer's dementia.
•Pre-clinical – The group is laying out a research agenda to identify methods of assessment that may help predict risk for developing the disease. Biomarkers and other clinical assessment tools to identify early cognitive decline are being investigated to establish the presence of Alzheimer's brain changes in people with no overt symptoms and to identify those who may eventually develop the disease.
•Mild cognitive impairment – The group is refining the MCI criteria, which will help to indicate cognitive change before dementia and better differentiate MCI from Alzheimer's. Research is underway to better understand the cognitive changes taking place, how they may relate to biomarkers, and which of these methods best indicate the likelihood of imminent progression to Alzheimer's dementia.
•Alzheimer's dementia – The group is revising the existing criteria for diagnosing Alzheimer's to include possible biomarkers and other assessments that may aid in diagnosis. About AAICAD The Alzheimer's Association International Conference on Alzheimer's Disease (AAICAD) is the world's largest conference of it's kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.
About the Alzheimer's Association The Alzheimer's Association is the leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's.
www.alz.org/icad/
Workgroup members (2 pages)
http://www.alz.org/icad/documents/abstracts/2010_diag.pdf
Contact: Alzheimer's Association Media line: 312.335.4078 E-mail: media@alz.org AAICAD 2010 press room, July 10-15: 1-808-792-6523
http://www.alz.org/icad/2010_release_diagnostic_071310_130pm.asp
Early Detection, Diagnosis & Care Management for People with Dementia May Reduce Healthcare Costs
Honolulu, Hawaii; July 14, 2010 – Early detection, diagnosis and care management for people newly diagnosed with cognitive impairment and dementia reduces outpatient costs by almost 30 percent, according to new research reported today at the Alzheimer's Association International Conference on Alzheimer's Disease 2010 (AAICAD 2010) in Honolulu.
Dementia is loss of memory and other mental abilities severe enough to interfere with daily life. According to the Alzheimer's Association, dementia is a common, costly, and often unrecognized problem in older adults. In order to provide better medical care and outcomes for people with Alzheimer's and other dementias, the conditions must first be detected and diagnosed, and needed care management must be provided.
"Research suggests that when the family of someone who is officially diagnosed with Alzheimer's becomes educated about the disease, and they work together with medical professionals on a care plan, it can reduce the patient's difficult behavioral and psychiatric symptoms," said Maria Carrillo, PhD, Senior Director of Medical and Scientific Relations at the Alzheimer's Association. "It can also lower the family caregiver's anxiety, depression and stress."
Generally, care management in Alzheimer's provides assistance for people with the disease and their families in finding resources, making decisions, and managing stress. For example, a care manager can help families with decisions about in-home health services, or long-term care whether at home or in a nursing facility.
"We see in this study's findings that early diagnosis and case management in dementia may also significantly lower healthcare costs. This could have a reverberating positive impact throughout the entire healthcare system," Carrillo said.
Demonstration Project Shows Early Diagnosis and Care Management Can Lower Costs
The Dementia Demonstration Project (DDP) was an interdisciplinary effort led by the Geriatric Research, Education and Clinic Center at the Minneapolis Veterans (VA) Medical Center. Seven VA Medical Centers took part in the project, which was created to increase detection and diagnosis of dementia in primary care and provide information, support, and care coordination for veterans with newly diagnosed dementia. An Advanced Practice Registered Nurse trained in dementia – the Dementia Care Coordinator – led a dementia care team that became part of a primary care clinic in each of the seven VA Medical Centers participating in the project.
The DDP added a brief, three-item memory test to regularly scheduled primary care visits for veterans age 70 and older without a diagnosis of Alzheimer's or another dementia. Among the 8,278 veterans who received the memory test, 26 percent failed. Thirty-four percent of those who failed the test returned for a comprehensive evaluation; 95 percent of that group were diagnosed with cognitive impairment, including 76 percent with dementia.
In the DDP clinics, following evaluation, the dementia care team met with the patient and family to review the results, discuss the diagnosis, and outline treatment recommendations. Interventions were targeted to the severity of dementia and the specific needs of the patient and their caregivers. Informational material, assistance in identifying needed services, and direct support and training from team members was provided, as needed.
Healthcare costs data for one year before and after diagnosis were available for 347 DDP patients and 1,260 patients from non-DDP clinics in the same VA Medical Centers.
•Veterans diagnosed in the DDP clinics saw their average outpatient healthcare costs decline by about 29 percent (-$1,991) in the year after diagnosis of cognitive impairment compared with the year before diagnosis. •Veterans diagnosed in the non-DDP clinics also saw declines in average outpatient healthcare costs, but not as much (-$406). "In our study, the cost decreases were more dramatic in patients who were identified through cognitive evaluation and who subsequently had case management available by a dementia care team," said J. Riley McCarten, MD, the project's lead physician. He added that the cost of the DDP intervention to the VA was captured in the patient care costs reported.
"The most important goals of the program were making sure that all family members understood the disease and were on the same page, that patients remained physically active and socially engaged, and that caregivers had the support they needed," McCarten said.
About AAICAD The Alzheimer's Association International Conference on Alzheimer's Disease (AAICAD) is the world's largest conference of it's kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.
About the Alzheimer's Association The Alzheimer's Association is the leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit www.alz.org or call 800-272-3900.
Abstracts (2 pages)
http://www.alz.org/icad/documents/abstracts/2010_early_detection.pdf
Contact: Alzheimer's Association Media line: 312.335.4078 E-mail: media@alz.org AAICAD 2010 press room, July 10-15: 1-808-792-6523
http://www.alz.org/icad/2010_release_early_071410_1230pm.asp
"Hot Topics" from the Alzheimer's Association International Conference on Alzheimer's Disease 2010
- New Alzheimer's Risk Gene May Affect Memory Scores and Brain Atrophy in Middle Age -
- Clinical Trial of Intranasal Insulin Shows Benefits in Alzheimer's and MCI –
- Known Alzheimer's Risk Gene May Change Shape of Brain Deposits -
Honolulu, Hawaii; July 14, 2010 – Last minute scientific submissions to the Alzheimer's Association International Conference on Alzheimer's Disease 2010 (AAICAD 2010) in Honolulu, HI, known as "hot topics," suggest that (1) a newly-discovered risk gene for Alzheimer's may have early impact on memory skills and brain volume, (2) intranasal insulin may be beneficial in Alzheimer's, and (3) beta amyloid deposits in the brains of people with Alzheimer's disease may take different shapes based on a known Alzheimer's risk gene.
Two studies reported at AAICAD 2010 give us more information about the TOMM40 gene – a newly identified risk gene for Alzheimer's. They found that healthy, middle aged people who have the high risk version of TOMM40 (a) did worse on memory tests and (b) had reduced brain volume in two regions affected early in Alzheimer's. A short-term trial of intranasal insulin in Alzheimer's and MCI showed statistically significant benefits on certain tests of memory and functioning, but no changes on some others. In those who showed benefits on memory tests, there were also positive changes in Alzheimer's biomarkers in spinal fluid. Researchers using a new imaging tool suggest that there are different shapes of beta amyloid deposits in the Alzheimer brain based on which version a person has of a well-established Alzheimer's risk gene, known as APOE. This may be especially important because in some recent drug trials the therapy provided benefits in people who had certain types of APOE but were less effective or not effective in others. "These are some of the fantastic findings from this year's AAICAD, full of potential to move the field forward," said William Thies, PhD, Alzheimer's Association Chief Medical and Scientific Officer. "But there is too little happening in the field, and no plan in place from the federal government to stem the massive wave of Alzheimer's coming with the aging of the Baby Boomers."
"Alzheimer's is clearly the #1 public health challenge of the 21st century and research is the only way to solve this problem," Thies added. "There are more than 5 million Americans with the disease and about 11 million caregivers supporting them. Reliable estimates say that by 2050 those numbers could triple. Government must make an investment in Alzheimer research that proves they understand what's at stake – for individuals, families, the healthcare system, and the nation as a whole."
New Risk Gene for Alzheimer's is Associated with Poorer Memory Function and Grey Matter Loss in Middle Aged Persons Without Dementia
The TOMM40 gene has very recently been shown to influence age of onset in Alzheimer's disease. Two studies reported at AAICAD 2010 give us more information about this newly identified risk gene for Alzheimer's; they found that middle aged people without dementia who have the high risk version of the TOMM40 gene did worse on tests of memory and learning and had reduced brain volume in two regions that are often affected early in the course of Alzheimer's.
"These are exciting, initial results, but the exact role that TOMM40 plays in Alzheimer's remains to be determined," said William Thies, PhD, Chief Medical and Scientific Officer at the Alzheimer's Association. "The story of TOMM40 is evolving and may give us new insights into Alzheimer's disease."
"We desperately need to know more about the causes of Alzheimer's, and the factors that affect our risk of getting or not getting the disease. This kind of research will provide more targets for therapies and prevention strategies," Thies said.
In one study, Mark Sager, MD, of the University of Wisconsin Medical School, and colleagues studied a total of 726 people in middle-age with a family history of Alzheimer's from the Wisconsin Registry for Alzheimer's Prevention who were genotyped for TOMM40 and APOE, the latter of which is a well-established risk gene for Alzheimer's. Of these, 129 had the low risk version of TOMM40 and 229 had the high risk version. The average age of the study population was 54.
The researchers found that the group with the high risk version of the TOMM40 gene performed significantly worse on the tests of learning and memory (Rey Auditory Verbal Learning Test) than the group with the low risk version. These results remained significant regardless of APOE gene type.
"The deficits shown by the high risk group are similar to the kinds of changes in memory and learning that are seen in very early Alzheimer's," Sager said. "In this study population, TOMM40 genotyping is allowing us to find evidence of very early Alzheimer's disease at least 20 years before people begin to show the outward symptoms. This is a step forward in Alzheimer's prevention research."
In a second study, Sterling Johnson, PhD, also of the University of Wisconsin School of Medicine and Public Health, and colleagues found that among healthy, middle aged adults (mean age 57) who have the APOE e3/e3 gene type, those with the high risk version of the TOMM40 gene had significantly less gray matter volume in two brain regions affected early in Alzheimer's disease than those with the low risk version of the gene.
According to the researchers, the study suggests that there is a connection between TOMM40 and brain cell loss in people who are relatively young and currently not symptomatic.
"This is the first study to associate TOMM40 to brain imaging in people at risk for Alzheimer's disease," Johnson said. "The brain differences between TOMM40 groups were very similar but less severe that what is observed in full-blown Alzheimer's. It may be that the TOMM40 gene will be a useful measure of Alzheimer's risk in middle-age, but additional research with longitudinal follow-up is needed."
Allen Roses, MD, and colleagues at Duke University first discovered that the TOMM40 gene helped explain differences in age of onset among people with sporadic Alzheimer's disease.
Clinical Trial of Intranasal Insulin Shows Some Benefits in Alzheimer's and MCI
Previous research has strongly suggested that Alzheimer's and diabetes/insulin resistance are closely related. For example, Alzheimer's is associated with reduced brain insulin signaling and low levels of insulin in cerebrospinal fluid (CSF).
"These deficiencies may reduce or eliminate insulin's beneficial roles in the brain," said Suzanne Craft, PhD, of VA Puget Sound Health Care System/University of Washington in Seattle. "We believe that restoring normal insulin function in the brain may provide therapeutic benefits to adults with Alzheimer's. Intranasal administration enables insulin to access brain regions that are compromised in Alzheimer's."
Craft and colleagues had previously shown enhanced cognition and daily functioning in adults with MCI and early Alzheimer's using intranasal insulin treatment for 21 days. This new study expanded the time frame to four months, during which 109 participants with MCI or Alzheimer's received either placebo, or 20 or 40 IU daily intranasal insulin treatment.
The researchers found that in the 20 IU dose group (10 IU twice daily) results on a test of delayed story recall significantly improved compared with those who received placebo, as did functional status measured by the Dementia Severity Rating Scale. Improvements in delayed memory recall persisted for two months after the insulin treatment ended. However, memory and learning on the ADAS-Cog and ability to do activities of daily living measured by the ADCS-ADL scores were unchanged.
For 15 of the insulin-treated participants who agreed to have a spinal tap, improved memory and functional status were associated with an improved Alzheimer's biomarker profile as reflected by a lowered CSF tau/Aß42 ratio.
"These results provide encouraging support for further study of intranasal insulin as a therapy for Alzheimer's," Craft said. "We are currently planning a large, multi-center clinical trial."
New Imaging Compounds for Alzheimer's Protein Deposits in the Brain Show that Different Forms of the APOE Risk Gene Create Different Shapes of Beta Amyloid
A new class of biomarkers has been discovered that can stick to protein structures in the body and emit colors reflecting the different shapes or forms of the proteins. They are called luminescent conjugated oligothiophenes (LCOs) or luminescent conjugated polymers (LCPs). Among other uses, they are currently being employed in test tubes, animal models and autopsied Alzheimer's brains to study the structure of proteins deposits caused by the disease. The new markers bind to the two well-established hallmarks of Alzheimer's – beta amyloid plaques and tau tangles – and glow different colors depending on which forms of the deposits they "stick" to (e.g., plaques often "glow" orange, while tangles "glow" yellowish green).
In this study reported at AAICAD 2010, Sam Gandy, MD, PhD, of Mount Sinai School of Medicine, New York, and colleagues used LCOs/LCPs to investigate the possibility that the shape of brain protein deposits in people with Alzheimer's who have the APOE e4/e4 gene type (highest risk) is different from those having APOE e3/e3 (neutral risk).
Frozen brain sections from people who died with Alzheimer's were stained using two LCPs/LCOs: pentamer formyl thiophene acetic acid (pFTAA) and polythiophene acetic acid (PTAA). Using PTAA, the researchers observed that Alzheimer patients with APOE e4/e4 had core and cerebrovascular amyloid of different shapes, while in people with APOE e3/e3 the two amyloid structures had the same shape. Using pFTAA revealed that tau tangle densities in e4/e4 Alzheimer patients that were apparently greater than those with e3/e3.
"The findings support our hypothesis that APOE genotype changes amyloid structure," Gandy said. "This is important because the different shapes might respond differently to treatments that attempt to clear amyloid deposits from the brain."
In some recent drug trials, the experimental therapy provided benefits in people who had a certain type of the APOE gene (known as e3) but were less or not effective in another type (e4).
LCOs/LCPs were pioneered by Peter Nilsson of the Department of Chemistry, Linköping University, Sweden. The study also involved collaborating teams from Charité – Universitätsmedizin Berlin, Germany (led by Frank Heppner), Washington University, St Louis (led by David Holtzman), and other labs at Mount Sinai (led by Patrick Hof and Dara Dickstein).
About AAICAD The Alzheimer's Association International Conference on Alzheimer's Disease (AAICAD) is the world's largest conference of it's kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.
About the Alzheimer's Association The Alzheimer's Association is the leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit www.alz.org or call 800-272-3900.
Abstracts (6 pages)
14, 2010, 6:30-7:30 am, Hawai’i Convention Center, 1801 Kalakaua Avenue, Honolulu, Room 321A.
Mark A. Sager, et al. TOMM40 Variable Length Polymorphism Is Associated With Memory Function In Asymptomatic Middle-aged Persons. (Funded by: National Institute on Aging, Helen Bader Foundation, Extendicare Foundation)
Sterling C. Johnson, et al. TOMM40 Is Associated With Gray Matter Volume In Middle-aged Persons With Apoe e3/e3 Genotype. (Funded by: National Institute on Aging, Department of Veterans Affairs)
Suzanne Craft, et al. Intranasal Insulin- And Biomarker-associated Improvement In Memory And Functional Status In Mild Cognitive Impairment And Alzheimer's Disease: Results Of A Randomized, Double-blind, Placebo-controlled Pilot Trial. (Funded by: Department of Veterans Affairs, National Institute on Aging)
Hannah Brautigam, Sam Gandy, et al. New Conformation-Sensing Imaging Compounds Distinguish Protein Deposits In APOE e3/e3 Alzheimer’s Patients From That In APOE e4/e4 Alzheimer’s Patients. (Funded by: National Institutes of Health, Cure Alzheimer’s Fund, European Union FP7 HEALTH (Project LUPAS), German Research Foundation, Knut and Alice Wallenberg Foundation, Swedish Foundation for Strategic Research)
All materials to be presented at the Alzheimer's Association 2010 International Conference on Alzheimer's Disease are embargoed for publication and broadcast until the date and time of presentation at the conference, unless the Alzheimer's Association provides advance written notice of change of date and/or time.
Control #: 10-HT-3354-ALZ
TOMM40 Variable Length Polymorphism Is Associated With Memory Function In Asymptomatic Middle-aged Persons Mark A. Sager, M.D.1, Asenath La Rue, Ph.D.1, Sterling C. Johnson, Ph.D.1, Ann M. Saunders, Ph.D.2, Allen D. Roses, M.D.2, Rebecca Koscik, Ph.D.1, Erin Jonaitis, Ph.D.1, Michael W. Lutz, Ph.D.2, Sanjay Asthana, M.D.1, Robert C. Green, Ph.D., M.Ph.3, Bruce P. Hermann, Ph.D.1.
1UW Medical School-Madison, Madison, WI, USA, 2Duke University, Durham, NC, USA, 3Boston University, Boston, MA, USA. Contact Email: masager@wisc.edu
Disclosure Block: M.A. Sager, None.
Background: A TOMM40 polymorphism, a variable length intronic poly T repeat (rs10524523), has been shown to influence age of Alzheimer’s disease (AD) onset. In this study, we tested the hypothesis that subjects homozygous for TOMM40 short poly T sequences <21 (SPT) would show better performance on measures of learning and memory than those who were homozygous for longer poly T sequences =21 (LPT) in middle-aged subjects with a family history of AD.
Methods: The study population includes 726 middle-aged asymptomatic persons enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) who had been genotyped for APOE and 2 TOMM40. A total of 129 were homozygous for SPT sequences <21 (low risk) and 229 were homozygous for LPT sequences =21 (high risk). Study groups were defined by TOMM40 genotyping based on the length of the poly T sequences regardless of APOE genotype. Serial position profiles and total learning on the Rey Auditory Verbal Learning Test (AVLT) were compared between groups controlling for age, gender and education.
Results: The mean age of the study population was 54 and 69% were female. There were no significant age, gender or education differences between SPT and LPT groups. The two TOMM40 groups differed significantly in total words learned on the AVLT (p = .012) with the LPT TOMM40 group remembering fewer words. There were significant differences in the serial position curve with significantly poorer recall from the primacy region on the AVLT (p = .001). Nineteen percent of the SPT group had an APOE e4 compared with 55% of the LPT group. When APOE genotype (e4 carrier vs. non-carrier) was added to the model, TOMM40 remained significant on both measures.
Conclusions: Longer TOMM40 poly T sequence length was associated with differences in memory and learning that are seen in early AD. These changes were seen in middle-aged asymptomatic persons, suggesting that TOMM40 genotyping may prove useful in stratifying persons at different levels of AD risk in studies of pre-symptomatic AD. The role that TOMM40 plays in AD pathogenesis and its relationship to APOE genotype as a genetic risk factor for AD remain to be determined.
All materials to be presented at the Alzheimer's Association 2010 International Conference on Alzheimer's Disease are embargoed for publication and broadcast until the date and time of presentation at the conference, unless the Alzheimer's Association provides advance written notice of change of date and/or time.
Control #: 10-HT-3432-ALZ O4-03 - Hot Topics 2 (Presentation #O4-03-04; Speaking Time: 7/14/2010 1:45-2:00 PM)
TOMM40 Is Associated With Gray Matter Volume In Middle-aged Persons With APOE e3/e3 Genotype
Sterling C. Johnson, Ph.D.1,2, Asenath La Rue, Ph.D.1, Bruce P. Hermann, Ph.D.1, Guofan Xu, Ph.D.1, Rebecca L. Koscik, Ph.D.1, Erin M. Jonaitas, Ph.D.1, Barbara B. Bendlin, Ph.D.1,2, Allen D. Roses, MD3, Ann M. Saunders, Ph.D.3, Michael W. Lutz, Ph.D.3, Sanjay Asthana, MD1,2, Robert C. Green, MD4, Mark A. Sager, MD1. 1University of Wisconsin, Madison, WI, USA, 2Wm. S. Middleton Veterans Hospital, Madison, WI, USA, 3Duke University, Durham, NC, USA, 4Boston University, Boston, MA, USA. Contact Email: scj@medicine.wisc.edu Disclosure Block: S.C. Johnson, None
Background: Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late onset Alzheimer’s disease (LOAD), with APOE e4 having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of the TOMM40 gene has very recently been shown to influence age of onset in LOAD, where very long poly-T length was associated with earlier disease onset, and short poly-T length associated with later onset. In this study, we tested the hypothesis that brain changes antedating symptomatic LOAD may be associated with this TOMM40 polymorphism.
Methods: Among healthy APOE e3 homozygous adults (mean age 57), we compared those homozygous for very long (VL/VL; n=33) TOMM40 poly-T lengths (who are presumably at 3 higher risk) to those homozygous for short (S/S; n=37) poly-T lengths on structural brain imaging. Voxel-based morphometry was used to assess gray matter volume using the software SPM8. Gray matter probability maps were entered into a voxel-wise ANCOVA where Age and Intracranial volume were covariates
Results: Results were that the VL/VL TOMM40 group had significantly less gray matter volume in the ventral posterior cingulate and precuneus, a region of the brain affected early in LOAD.
Conclusions: To our knowledge, this is the first study to associate TOMM40 523 genotypes to brain imaging in people at risk for AD. These findings suggest that the group with very long TOMM40 poly-T lengths may be experiencing incipient LOAD-related cognitive and brain changes. The participants in this study are being followed over time to determine genetic and other factors that predict cognitive decline and dementia 4 5
All materials to be presented at the Alzheimer's Association 2010 International Conference on Alzheimer's Disease are embargoed for publication and broadcast until the date and time of presentation at the conference, unless the Alzheimer's Association provides advance written notice of change of date and/or time.
Control #: 10-HT-3439-ALZ O4-04 - Hot Topics 3 (Presentation #O4-04-01; Speaking Time: 7/14/2010 1:00-1:15 PM)
Intranasal Insulin- And Biomarker-associated Improvement In Memory And Functional Status In Mild Cognitive Impairment And Alzheimer's Disease: Results Of A Randomized, Double-blind, Placebo-controlled Pilot Trial
Suzanne Craft, PhD1, Laura D. Baker, PhD1, Thomas J. Montine, MD, PhD2, Jing Zhang, MD, PhD2, G. Stennis Watson, PhD1, Stephen Plymate, MD1, Elaine Tsai, MD1, Maureen Callaghan, MD1, James Leverenz, MD1, Brooke Gerton, MD1, Emily Trittschuh, PhD1. 1University of Washington/VA Puget Sound, Seattle, WA, USA, 2University of Washington, Seattle, WA, USA. Contact Email: scraft@u.washington.edu Disclosure Block: S. Craft, None.
Background: Alzheimer’s disease (AD) is associated with reduced brain insulin signaling and low CSF insulin levels. These deficiencies may abrogate insulin’s role in synaptic maintenance, Aß regulation, and other mechanisms related to AD pathogenesis. Restoring normal insulin function in brain may thus provide therapeutic benefit to adults with AD. Intranasally administered insulin follows extracellular pathways to the brain, bypassing the periphery and blood brain barrier, and accessing the CNS within 15 minutes. Previously, we showed that cognition and daily function are enhanced following intranasal insulin treatment for 21 days in adults with amnestic mild cognitive impairment (MCI) and early AD.
Methods: Participants with MCI or AD (n=109) received either placebo, or 20 or 40 IU daily intranasal insulin treatment for four months. ADAS-Cog/MCI and delayed story recall scores were primary outcome measures and were administered at baseline, at 2 and 4 months during treatment, and 2 months after treatment cessation. Secondary measures of functional status included the Dementia Severity Rating Scale (DSRS) and Alzheimer Disease Cooperative Study Activity of Daily Living Scale (ADCS-ADL). A subset of participants (n=23) received lumbar punctures at baseline and after 4 months of treatment. For the intent-to-treat analysis, outcome measures for each dose group were compared to the placebo group with repeated measures analysis of variance.
Results: Delayed story recall improved in the 20 IU dose group compared with placebo (p=0.0201), as did functional status reflected by DSRS (p=0.0054). Improved delayed memory persisted 2 months after insulin treatment ended (p=0.0209). ADAS-Cog and ADCS-ADL scores were unchanged. The 40 IU dose group had improved daily function relative to placebo on the DSRS (p=0.0095), but no differences in cognition. For CSF biomarker analysis, the two insulin dose groups were combined to increase power. For insulin-treated participants (n=15), improved delayed memory and functional status were associated with an improved AD biomarker profile as reflected by a lowered CSF tau/Aß42 ratio (Spearman rhos=-.52 and .53, ps<0.05). n="8;">.90).
Conclusions: These results provide strong support for further investigation of intranasal insulin as a therapeutic approach for patients with MCI and AD.
All materials to be presented at the Alzheimer's Association 2010 International Conference on Alzheimer's Disease are embargoed for publication and broadcast until the date and time of presentation at the conference, unless the Alzheimer's Association provides advance written notice of change of date and/or time.
Control #: 10-HT-3369-ALZ
O4-04 - Hot Topics 3 (Presentation #O4-04-06; Speaking Time: 7/14/2010 2:15-2:30 PM)
6
New Conformation-Sensing Imaging Compounds Distinguish Protein Deposits In APOE e3/e3 Alzheimer’s Patients From That In APOE e4/e4 Alzheimer’s Patients
Hannah Brautigam, BS Psychology1, Thérese Klingstedt, MS Biomedicine2, Stefan Prokop, MD3, David M. Holtzman, MD4, Frank L. Heppner, MD3, Vahram Haroutunian, PhD1, Dara L. Dickstein, PhD1, Patrick R. Hof, MD1, Peter R. Nilsson, PhD2, Sam Gandy, MD, PhD1,5. 1Mount Sinai School of Medicine, New York, NY, USA, 2Linköping University, Linköping, Sweden, 3Charité-Universitäsmedizin Berlin, Berlin, Germany, 4Washington University School of Medicine, St. Louis, MO, USA, 5James J. Peters VA Medical Center, Bronx, NY, USA. Contact Email: hannah.brautigam@mssm.edu; samgandy@gmail.com
Disclosure Block: H. Brautigam, None.
Background: A novel class of biomarkers, luminescent conjugated oligothiophenes (LCOs) or luminescent conjugated polymers (LCPs), has been designed to intercalate into proteinaceous structures and emit spectra reflecting discrete conformation states. LCOs/LCPs have enabled the discrimination of prion strain isotypes and are currently being employed in vitro and in vivo to study the structure of aggregated proteins in Alzheimer’s disease (AD); LCOs/LCPs bind to amyloid beta (Aß) deposits and neurofibrillary tangles (NFTs) in histological brain sections of AD patients, emitting spectra related to the conformation(s) of these deposits. In addition to Aß, apolipoprotein E (APOE) is a component of human brain amyloid, and the APOE e4 allele is the major genetic risk factor for sporadic AD. We employed LCOs/LCPs to investigate the possibility that the conformation of brain protein deposits in AD patients having e4/e4 alleles differed from deposits in AD patients having e3/e3 alleles.
Methods: Frozen brain sections were analyzed from pairs of AD patients matched for age, gender, CDR score, and duration of disease; only APOE genotype, e4/e4 or e3/e3, differed between pairs. Adjacent sections from each pair were stained using two LCPs/LCOs: pentamer formyl thiophene acetic acid (pFTAA) and polythiophene acetic acid (PTAA). Fluorescence spectra from tissue sections were recorded with an LSM 510 META confocal laser scanning microscope, and spectral processing was achieved with an LSM Image browser.
Results: Using PTAA, we observed that AD patients with e4/e4 exhibited a different conformational spectrum for core and cerebrovascular amyloid whereas their respective matched e3/e3 pair exhibited indistinguishable conformational spectra between the two amyloid structures. pFTAA, sensitive for different conformations for Aß and NFTs, revealed NFT densities in e4/e4 AD patients that were apparently greater than those in e3/e3 AD patients.
Conclusions: The observation that PTAA core amyloid and cerebrovascular amyloid spectra distinguish the amyloid deposits of APOE e4/e4 from APOE e3/e3 AD patients supports the hypothesis that APOE genotype modulates amyloid structure. pFTAA holds promise as an especially sensitive reagent for visualizing NFTs. LCOs/LCPs show great potential as research tools for the study of proteinopathies, including the pathogenesis of sporadic AD and possibly the influence of APOE genotype.
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http://www.alz.org/icad/documents/abstracts/2010_hot_topics.pdf
Contact: Alzheimer's Association Media line: 312.335.4078 E-mail: media@alz.org AAICAD 2010 press room, July 10-15: 1-808-792-6523
http://www.alz.org/icad/2010_release_hot_071410_1230pm.asp
ICAD Press ReleasesMore News> 07/14/10 "Hot Topics" from the Alzheimer's Association International Conference on Alzheimer's Disease 2010 07/14/10 Early Detection, Diagnosis & Care Management for People with Dementia May Reduce Healthcare Costs 07/14/10 New Research Advances from the Alzheimer's Association International Conference on Alzheimer's Disease 2010 07/13/10 National Institute on Aging and Alzheimer's Association Lead Effort to Update Diagnostic Criteria for Alzheimer's Disease 07/13/10 Alzheimer's Disease may Increase Risk of Anemia and Seizures 07/13/10 Four New Research Studies Describe Experimental Immunotherapies for Alzheimer's 07/12/10 Alzheimer's Association Launches TrialMatch™ – First-of-its-Kind Clinical Trials Matching Service in Alzheimer's National News 07/15/10 Fighting Alzheimer's disease -ABC World News Tonight 07/15/10 Insulin via nasal spray shows benefit in people with Alzheimer's -USA Today 07/15/10 Early diagnosis of Alzheimer's yields savings -The Wall Street Journal
http://www.alz.org/icad/
BSE101/1 0136
IN CONFIDENCE
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 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.
92/11.4/1.1
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
92/11.4/1.2
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
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 B amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegeneradve 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.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Wednesday, April 14, 2010
Food Combination and Alzheimer Disease Risk A Protective Diet
http://betaamyloidcjd.blogspot.com/2010/04/food-combination-and-alzheimer-disease.html
Wednesday, March 31, 2010
Neurobiology of Disease Molecular Cross Talk between Misfolded Proteins in Animal Models of Alzheimer's and Prion Diseases
http://betaamyloidcjd.blogspot.com/2010/03/neurobiology-of-disease-molecular-cross.html
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
P03.139
Cellular Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer's Amyloid Precursor Protein
Hooper, NM1; Parkin, ET1; Watt, NT1; Baybutt, H2; Manson, J2; Hussain, I3; Turner, AJ1 1University of Leeds, Institute of Molecular and Cellular Biology, UK; 2Roslin Institute, Neuropathogenesis Unit, UK; 3GlaxoSmithKline, Neurodegeneration Research, UK
Background: The normal cellular function of the prion protein (PrP), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD) in humans, remains enigmatic. Several studies have reported combinations of Alzheimer's Disease (AD) and CJD neuropathology and the Val/Met129 polymorphism in the PrP gene has been identified as a risk factor for early-onset AD, leading to speculation that there may be some pathogenic connection between these two neurodegenerative conditions. The amyloid ß (Aß) peptides that cause AD are derived from the amyloid precursor protein (APP) through sequential proteolytic cleavage by the ß-secretase (BACE1) and the g-secretase complex.
Aim: As both APP and PrP are cleaved by zinc metalloproteases of the ADAM family, we investigated whether PrP alters the proteolytic processing of APP.
Results: Here we show that expression of PrP in SH-SY5Y cells dramatically downregulated the cleavage of APP by BACE1 and reduced the secretion of Aß peptides into the conditioned medium by >92%. Conversely, siRNA reduction of endogenous PrP in N2a cells led to an increase in secreted Aß. Furthermore, levels of Aß were significantly increased in the brains of PrP null mice as compared with wild type mice. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases, did not inhibit the BACE1 cleavage of APP. To investigate whether the Val/Met129 polymorphism in human PrPC would alter the production of Aß, brains from mice with the human PrP gene with MM or VV 129 genotypes were analysed. In the MM mice there was a significant increase in Aß in the brains as compared with the VV mice. In the brains of two strains (79A and 87V) of scrapie-infected mice there was a significant increase in Aß peptides as compared to uninfected mice.
Conclusions: Together these data reveal a novel function for PrP in regulating the processing of APP through inhibition of BACE1. The increase in APP processing in cells expressing disease-associated forms of PrP and in scrapie-infected brains raises the possibility that the increase in Aß may contribute to the neurodegeneration observed in prion diseases. Funded by the Medical Research Council of Great Britain.
P03.140
Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer's Amyloid Precursor Protein through Interaction with Glycosaminoglycans
Griffiths, HH; Parkin, ET; Watt, NT; Turner, AJ; Hooper, NM University of Leeds, Institute of Molecular and Cellular Biology, UK
Background: Proteolytic processing of the amyloid precursor protein (APP) by ßsecretase, BACE1, is the initial step in the production of the amyloid ß (Aß) peptide which is involved in the pathogenesis of Alzheimer's disease. We have shown that the cellular prion protein (PrP) inhibits the cleavage of APP by BACE1 in cell and animal models.
Aim: To investigate the mechanism by which PrP inhibits the action of BACE1.
Results: Neither PrPdeltaGPI, which is not membrane attached, nor PrP-CTM, which is anchored by a transmembrane domain and is excluded from cholesterol-rich lipid rafts, reduced cleavage of APP, suggesting that to inhibit the BACE1 cleavage of APP PrP has to be localised to lipid rafts. Coimmunoprecipitation experiments demonstrated that PrP physically interacts with BACE1. However, PrP did not alter the activity of BACE1 towards a fluorogenic peptide substrate nor perturb the dimerisation of BACE1. Using constructs of PrP lacking either the octapeptide repeats or the 4 residues KKRP at the N-terminus of the mature protein (PrPdeltaN), we demonstrate that the KKRP sequence but not the octapeptide repeats, is essential for regulating the BACE1 cleavage of APP. As the KKRP sequence is known to participate in glycosaminoglycan (GAG) binding, we confirmed that PrPdeltaN did not bind to immobilised heparin. Addition of heparin to SH-SY5Y cells increased the amount of APP cleaved by BACE1 in a concentration-dependent manner and reduced the amount of BACE1 coimmunoprecipitated with PrP, suggesting that GAGs are required for PrP to interact with BACE1 and inhibit APP processing. Of a range of GAGs, including dextran sulphate, hyaluronic acid and chondroitin sulphate, investigated there was complete correlation between those that could restore BACE1 cleavage of APP in PrP expressing cells and those that bound PrP.
Conclusion: These data suggest a possible mechanism by which PrP regulates the ßcleavage of APP is through the N-terminus of PrP interacting via GAGs with one or more of the heparin binding sites on BACE1 within a subset of cholesterol-rich lipid rafts, thereby restricting access of BACE1 to APP. Funded by the Medical Research Council of Great Britain.
P04.37
Comparison of the Neuropsychological Profile of Patients with Sporadic Creutzfeldt-Jakob Disease and Patients with Alzheimer's
Krzovska, M1; Cepek, L1; Ratzka, P2; Döhlinger, S3; Uttner, I1; Wolf, Stefanie4; Irle, Eva4; Mollenhauer, Brit5; Kretzschmar, Hans A.6; Riepe, Matthias7; v. Arnim, Christine1; Otto, Markus1 1University of Ulm, Germany; 2Department of Neurology, Germany; 3University of Goettingen, Germany; 4University of Goettingen, Germany; 5Elena Klinik, Germany; 6LMU, Germany; 7University of Berlin, Germany
Background:To evaluate the neuropsychological profile of sCJD we administered the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) in order to determine if and how the sCJD-Subgroups (Met/Met, Met/Val, Val/Val) have different results in the item analysis of the ADAS-cog. Furthermore, we studied how the scores differ from that of patients with Alzheimer's disease (AD).
Methods:33 sCJD patients (11 with definite CJD and 22 with probable CJD) underwent neuropsychological testing with the ADAS-cog and Mini Mental State Exam (MMSE). Of these 31 were genotyped at the Codon 129 (11 Val/Val, 18 Met/Val and 2 Met/Met). The patients were matched in regards to sex and total ADAS-cog score with AD patients. The scores of the 11 ADAS-cog items were compared between the sCJD and the AD groups as well as between the sCJD-subgroups Met/Val and Val/Val and the AD group.
Results:The ADAS-cog total score of the sCJD and AD groups was 22.6+/- 6.5, respectively. Regarding the single Item scores of the sCJD patient group and the AD patient group, there were statistically significant differences in the Items Constructional praxis, Word-finding difficulty in spontaneous speech and Spoken language ability. When comparing the sCJD subtypes with each other no statistically significant difference was found in the items.
Conclusion: In the speech and constructional praxis there is indication of greater impairment in sCJD patients in general when compared with AD patients. A disturbance of the speech appears to be an important characteristic of the Met/Val and Val/Val subtypes of sCJD, and should therefore be the focus of special attention in future neuropsychological studies.
http://www.neuroprion.com/pdf_docs/conferences/prion2007/abstract_book.pdf
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2007/abstract_book.pdf
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease
http://betaamyloidcjd.blogspot.com/2008/04/re-association-between-deposition-of.html
Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures
http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html
Monday, January 4, 2010
Rising Tide: The Impact of Dementia in Canada Huge wave of dementia cases coming, warns report
http://betaamyloidcjd.blogspot.com/2010/01/rising-tide-impact-of-dementia-in.html
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Are some commoner types of neurodegenerative disease (including Alzheimer's disease and Parkinson's disease) also transmissible? Some recent scientific research has suggested this possibility
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Could cases of protease sensitive prionopathy (PSP) be missed by conventional tests which, in all other TSEs, rely on the resistance of the prion protein in the nervous system that accompanies disease to digestion by protease enzymes?
Can we develop reliable methods for removing and detecting protein on re-usable surgical instruments?
SNIP...
FULL TEXT ;
Monday, October 12, 2009
SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens TSE 8 October 2009
http://bse-atypical.blogspot.com/2009/10/seac-science-and-technology-committees.html
Sunday, June 7, 2009
ALZHEIMER'S DISEASE IS TRANSMISSIBLE
http://betaamyloidcjd.blogspot.com/2009/06/alzheimers-disease-is-transmissible.html
http://betaamyloidcjd.blogspot.com/
TSS
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