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