Identifying Fleetingly Ordered Protein Structures May Enable Scientists To Better Understand The Molecular Biology And Biophysics Of The Brain

A team of scientists from The Scripps Research Institute and the University of California, San Diego (UCSD) have developed a novel technique to observe previously unknown details of how folded structures are formed from an intrinsically disordered protein. The insights could help scientists to better understand the mechanism of plaque formation in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases.



The results of the study, which has broad implications for the field, were recently published in an advanced, online issue of the journal Nature Methods.



The new technique allows previously unheard-of rapid detection - in less than 0.001 seconds - of transiently folded single-molecule structures from a class of often-amorphous molecules known as "intrinsically disordered proteins." The method also permits new types of observations of short-lived protein complexes.



"This exciting new technique allowed us to visualize multiple short-lived folded states," said Scripps Research Associate Professor Ashok Deniz, Ph.D., who led the study with UCSD Professor Alex Groisman, Ph.D., and Yann Gambin, Ph.D., of Scripps Research. "Further, better understanding of complexity during folding may offer more ways to regulate this interesting class of proteins."



The specific protein examined in the study was A-synuclein, which is highly concentrated in neural tissue. The protein has been implicated in Parkinson's and Alzheimer's diseases, as it is found in high concentrations in aggregates from the brains of patients with these conditions.



Mixing It Up



Unlike typical proteins in the cell, intrinsically disordered proteins such as A-synuclein do not adopt a stable globular form in isolation. Rather, intrinsically disordered proteins are like a messy, unfolded string of yarn, whereas typical globular proteins more closely resemble yarn neatly knit into complicated and functional shapes like that of a glove.



Studying intrinsically disordered proteins has been a challenge. Known techniques to determine protein structures are often designed for ordered proteins, and detection of transient shapes in structurally heterogenous proteins such as A-synuclein has been difficult. To remedy this situation, the Deniz and Groisman labs set out to devise advanced technologies to shed light on this novel class of proteins.



The new experimental technique described in the Nature Methods paper successfully combines and improves upon two established experimental methods: single-molecule F?¶rster Resonance Energy Transfer (smFRET) and microfludic mixing.



smFRET detection allows for the observation of very small distances (in the range of one billionth of a meter), and can reveal changes in the molecular structure in real time. The method works by transfer of energy between single fluorescent dye molecules used as tags on a protein. One dye (donor) absorbs light and can emit red-shifted fluorescent light, whereas the other dye (acceptor) can receive the energy from the donor and emit even more red-shifted light. The relative amount of light emitted by the two dyes depends on the distance between them, and hence can be used as a molecular ruler to measure distances in proteins. Microfluidic mixing in high-speed laminar flows has been used previously to rapidly initiate protein-folding reactions, but most observations have been made on a bulk rather than single-molecule level.
















Detecting Protein Folding in a Chip



The key innovation of the research was to combine rapid mixing in a high-speed flow with single-molecule detection in a slow flow by abruptly decelerating the flow between mixing and detection regions.



The protein started in an aqueous solution and was mixed with a substance known as sodium dodecyl sulfate (SDS), which is normally used to unfold proteins but also facilitates the folding of A-synuclein due to its special interactions with amphipathic environments. This combination of rapid mixing and detection enabled the discovery of short-lived protein states previously invisible to researchers.



The microfluidic mixing itself was performed inside a small chip housing several hollow channels (or tunnels). The main channel is like a freeway upon which the protein travels. This channel connects at junction points to other inlets (on-ramps to the freeway) or outlets (off-ramps from the freeway).



The two inlets were used to funnel buffer and SDS into the central stream, effectively focusing the central protein stream into a narrow, fast-moving lane, and allowing a rapid switch into a solution containing SDS. Further along the channel at another junction, two outlets forced most of the "traffic" to exit. As a result, the speed of the remaining central part of the stream, or central lane, abruptly decreased.



Protein molecules in this slower, focused stream of protein were then detected by smFRET. The rapid slowing was a critical new element in the method, providing just enough time for scientists to examine individual slower-moving proteins as they passed by the detector. A movie of the proteins' changing shapes could be recorded over time.



At the inlet (on-ramp), A-synuclein was introduced to negatively charged SDS, and A-synuclein began to fold. Combined with the rapid mixing, the fluorescence from the dye tags - which had been placed far apart on A-synuclein - revealed previously unknown details of transiently folded structures of A-synuclein, observed in the sub-millisecond timeframe.



Dynamic Conditions



Prior to this work, the equilibrium state of A-synuclein in the SDS-containing solution was known to be an extended helix (like the coil of a phone cord) called the F state. This ordered structure exists in the presence of the negatively charged biological membrane or SDS.



"So the question was: 'Do we go directly from the disordered protein to that F state?'" said Deniz. "And the answer from our experiments was, 'No.' We visit an intermediate structure, which has a similar FRET efficiency to what was previously observed to be a helix-kink-helix (I state), like a coil with a kink that bends the coil into a U-shape instead of a straight coil. Surprisingly, even this initial transition is complex, and provides us views of how the protein shape changes soon after binding to its partner molecules. What this means is that, as conditions in the cell are dynamic, these new states might give us many more points of regulation of A-synuclein."



Next in the lab's research, Deniz plans to examine questions including: "Do different A-synuclein structures aggregate differently, and how do they couple to function?" "What triggers the aggregation?" "What exactly are the roles of aggregates?" and "What kinds of structures will be detected for A-synuclein interacting with other protein, lipid, and small-molecule partners?"



In addition, Deniz believes the developed microfluidic method will improve scientists' understanding of complexity in many other biological and health-related molecules.



Notes:



In addition to Deniz, Groisman, and Gambin (now at the University of Queensland, Australia), authors of the paper, "Visualizing a one-way protein encounter complex by ultrafast single-molecule mixing," included Virginia VanDelinder of UCSD (now at the European Molecular Biology Laboratory), Allan Chris M. Ferreon of Scripps Research, and Edward A. Lemke of Scripps Research (now at the European Molecular Biology Laboratory).



This work was supported by grants from the National Institutes of Health and the National Science Foundation, and a postdoctoral fellowship from the National Institutes of Health; funding by the German Research Foundation is also acknowledged.



Source:

Mika Ono


Scripps Research Institute

Calorie Restriction May Prevent Alzheimer's Through Promotion Of Longevity Program In The Brain

A recent study directed by Mount Sinai School of Medicine suggests that experimental dietary regimens might calm or even reverse symptoms of Alzheimer's Disease (AD). The study, which appears in the July 2006 issue of the Journal of Biological Chemistry, is the first to show that restricting caloric intake, specifically carbohydrates, may prevent AD by triggering activity in the brain associated with longevity.



"Both clinical and epidemiological evidence suggests that modification of lifestyle factors such as nutrition may prove crucial to Alzheimer's Disease management," says Giulio Maria Pasinetti, M.D., Ph.D., Professor of Psychiatry and Neuroscience, Director of the Neuroinflammation Research Center at Mount Sinai School of Medicine and lead author of the study. "This research, however, is the first to show a connection between nutrition and Alzheimer's Disease neuropathy by defining mechanistic pathways in the brain and scrutinizing biochemical functions. We hope these findings further unlock the mystery of Alzheimer's and bring hope to the millions of Americans suffering from this disease."



Alzheimer's Disease is a rapidly growing public health concern with potentially devastating effects. An estimated 4.5 million Americans have Alzheimer's Disease and the number of Americans with Alzheimer's has more than doubled since 1980. Presently, there are no known cures or effective preventive strategies. While genetic factors are relevant in early-onset cases, they appear to play less of a role in late-onset-sporadic AD cases, the most common form of AD.



Longevity Program in the Brain
People with AD exhibit elevated levels of beta-amyloid peptides that cause plaque buildup in the brain (the main characteristic of AD). Beta-amyloid peptides activate SIRT1, a member of a broad family of proteins known as sirtuins which influence a variety of functions including metabolism and aging.



Dr. Pasinetti and colleagues used an experimental mouse model to demonstrate that beta-amyloid peptides in the brain can be reduced by subjecting the mice to dietary caloric restriction, primarily based on low carbohydrate food. Conversely, a high caloric intake based on saturated fat was shown to increase levels of beta-amyloid peptides.



This study is the first to suggest that caloric restriction through promotion of SIRT1 (a molecule associated with brain longevity) may initiate a cascade of events like the activation of alpha-secretase which can prevent AD amyloid neuropathology. Since alpha-secretase is known also to inhibit the generation of beta-amyloid peptides in the AD affected brain, the study demonstrates a mechanism by which dietary caloric restriction might benefit AD. Most remarkably, the study finds that a high caloric intake based on saturated fat promotes AD type beta-amyloidosis, while caloric restriction based on reduced carbohydrate intake is able to prevent it.



Implications
Among lifestyle factors influencing AD, recent studies strongly support the evidence that caloric intake may play a role in the relative risk for AD clinical dementia. Most importantly, as mechanistic pathways are defined and their biochemical functions scrutinized, the evidence supporting a direct link between nutrition and AD neuropathology continues to grow.







Mount Sinai School of Medicine
Located in Manhattan, Mount Sinai School of Medicine is internationally recognized for ground-breaking clinical and basic-science research, and innovative approaches to medical education. Through the Mount Sinai Graduate School of Biological Sciences, Mount Sinai trains biomedical researchers with an emphasis on the rapid translation of discoveries of basic research into new techniques for fighting disease. One indication of Mount Sinai's leadership in scientific investigation is its receipt during fiscal year 2005 of $174.1 million in research support from the NIH. Mount Sinai School of Medicine also is known for unique educational programs such as the Humanities in Medicine program, which creates opportunities for liberal arts students to pursue medical school, and instructional innovations like The Morchand Center, the nation's largest program teaching students and physicians with "standardized patients" to become not only highly skilled, but compassionate caregivers. Long dedicated to improving its community, the School extends its boundaries to work with East Harlem and surrounding communities to provide access to health care and educational programs to at risk populations.



Contact: Mount Sinai Press Office



The Mount Sinai Hospital / Mount Sinai School of Medicine

New Study Demonstrates Accuracy, Validity Of MCI Screen In Early Detection Of Alzheimer's Disease

A new study published in the
June issue of Journal of Alzheimer's Disease demonstrates the accuracy and
validity of a new mathematics-based memory assessment developed by Medical
Care Corporation to detect early signs of memory impairment due to
Alzheimer's disease and other related disorders. The assessment, called the
MCI Screen, outperformed two of the most widely used pen-and-paper tests
and its accuracy helps justify the importance of regular memory assessments
of people over 65 by primary care physicians, according to the study's
authors.


The 254-patient study, titled "Detecting Cognitive Impairment in
Primary Care: Performance Assessment of Three Screening Instruments," was
conducted by Douglas Trenkle, D.O., a primary care physician at Maine Coast
Memorial Hospital in Ellsworth, Maine, as a part of the Hancock County
Aging Project. It compared the MCI Screen to the two most widely used
pen-and-paper assessments: the Mini-Mental Status Exam (MMSE) and the Clock
Drawing Test (CDT) in patients over 65 without previous diagnosis of memory
disorders. Those found to be impaired with any of the three assessments
received a standard diagnostic workup including blood tests and brain
imaging.



The MCI Screen, a simple, computer-based memory assessment, was 96
percent accurate in detecting impaired patients, while the MMSE was 72
percent accurate and the CDT 57 percent. The MCI Screen detected memory
disorders from a variety of conditions ranging from Alzheimer's disease (43
percent) to cerebrovascular disease (36 percent) to depression (3 percent).
Of the 254 patients assessed, 20 percent were found to have underlying
medical conditions. However, two-thirds had no subjective complaints of
impairment and would not have received medical attention if they had not
been screened for memory loss.



"This study shows that there is a test that can accurately and
efficiently detect memory disorders at early stages when treatment is most
effective," Dr. Trenkle said. "Too often we have relied on the two
widely-used memory screens, MMSE and CDT, which the study shows are not
valid for early detection. The accuracy of the MCI Screen demonstrates that
primary care physicians, who are the first point of contact in our heath
care system, can play significant roles in assessing and treating several
age-related diseases in a population that is rapidly aging."



William R. Shankle, M.D., of the Department of Cognitive Sciences at UC
Irvine, and Stanley P. Azen, Ph.D., of the Department of Preventative
Medicine, Keck School of Medicine at the University of Southern California,
also co-authored the study.



Many conditions can cause memory impairment. These include Alzheimer's
disease, stroke, heart disease, diabetes, and other disorders. Early
detection and appropriate intervention of any of these disorders improves
treatment outcome significantly and delays or prevents debilitating
conditions. In a typical primary care practice, patients with memory
impairment are either not getting enough attention or are being assessed by
less sensitive tools. This inevitably leads to late stage diagnoses where
treatment is not as effective. With the rapidly aging population and high
prevalence of such disorders in the baby boomer generation, early and
accurate detection of memory impairing disorders benefits the patients, the
caregivers and our health care system.



About Medical Care Corporation



Medical Care Corporation develops highly comprehensive dementia care
products for healthcare professionals. Their technology enables accurate
identification and effective management of memory loss from its earliest
stages onward. The Company's MCI Screen is 97.3% accurate in distinguishing
a pre-dementia stage called mild cognitive impairment (MCI) from normal
aging. The Company is also a leader in communicating the value of
prevention and early detection to patients and caregivers through its
website and educational materials. Additional information about the Company
is available at two websites: For Health Care Providers:
mccare; For Patients and Caregivers: preventad.


Medical Care Corporation

mccare

Spouse Caregivers of Alzheimer's Patients Show Higher Risk of Gingivitis

Caregiver spouses of patients with Alzheimer's disease develop gum disease at twice the rate of their non-caregiver counterparts, researchers report in the latest issue of Psychosomatic Medicine.


Because there was little difference in oral hygiene between the two groups in the study, the researchers say the difference may be related to stress.


Gingivitis is a mild form of gum disease that causes swelling and bleeding. It can progress to more serious disease leading to bone destruction and tooth loss.


Lead investigator Peter Vitaliano, Ph.D., of the University of Washington School of Medicine in Seattle, said of the results: "On a practical level, they speak to relationships between chronic stress and oral health in the general population and suggest that these are independent of oral care. They show that caregivers are at risk for oral health problems and not just physical health problems."


The investigators enrolled 240 subjects, 123 caregivers of spouses with Alzheimer's disease and 117 demographically similar non-caregiver spouses. The percentage of caregivers (17 percent) reporting gum disease was twice that of the non-caregivers (8.5 percent), although there was no significant difference in oral healthcare behaviors between the groups.


In addition to evaluating participants' gum disease, self-reports and medical records, investigators measured blood insulin levels, obesity and intra-abdominal fat. All these are components of metabolic syndrome, the group of symptoms that put people at higher risk for type 2 diabetes. The caregiver spouses scored higher on these measures.


"The implication of this study is considerable," says Neil Schneiderman, Ph.D., director of the University of Miami Behavioral Medicine Research Center. "The study shows that the relationship between caregiver stress and oral health can be explained by psychosocial factors such as depression and hassles, constitutional factors such as obesity and physiological factors such as insulin metabolism."


"The links among psychosocial factors, obesity, insulin metabolism and inflammation are particularly intriguing," Schneiderman added, "because inflammation can have important consequences in terms of the progression of atherosclerosis and coronary heart disease."


The authors note that the link between chronic stress and gingivitis was first observed in World War I when oral infections among soldiers fighting in the trenches was so high that their teeth became loose and the tips between their teeth eroded away. Since then, studies have continued to show a correlation between various forms of stress and oral disease.


According to the authors, this is the first study to specifically examine oral health in caregivers.


Psychosomatic Medicine is the official bimonthly peer-reviewed journal of the American Psychosomatic Society - psychosomaticmedicine.


Vitaliano P, et al. Caregiving and gingival symptom reports: psychological mediators. Psychosomatic Medicine 67(6), 2005.



Health Behavior News Service

Center for the Advancement of Health

2000 Florida Ave. NW, Ste 210

Washington, DC 20009

United States

hbns

Identification Of Key Action Of A Gene Linked To Both Alzheimer's Disease And Type 2 Diabetes

A research team led by Mount Sinai School of Medicine has identified the mechanism behind a single gene linked to the causes of both Alzheimer's disease and Type 2 diabetes. The data show that a gene for a protein called SorCS1, which can cause Type 2 diabetes, impacts the accumulation of amyloid-beta (Abeta) in the brain. Abeta plays a key role in the development of Alzheimer's disease. The study is published in the Journal of Neuroscience.



Sam Gandy, MD, PhD, the Mount Sinai Professor in Alzheimer's Disease Research, Professor of Neurology and Psychiatry, and Associate Director of the Alzheimer's Disease Research Center at Mount Sinai School of Medicine, led the study, together with first author Rachel Lane, PhD, a postdoctoral researcher in Gandy's Lab. Lane and Gandy analyzed both the brains of mice genetically engineered to be deficient in SorCS1 as well as cells engineered to express high levels of SorCS1. They found an increased level of Abeta in SorCS1-deficient mice, and low levels of Abeta in the cells overexpressing SorCS1.



"We knew that Type 2 diabetes could increase the risk for Alzheimer's disease, but we were not sure how that risk was caused or whether that diabetes risk would impact Abeta levels in the brain," said Dr. Gandy. "These results elucidate a common mechanism between diabetes and Alzheimer's and will bring us a step closer to identifying effective treatments for both diseases."



The researchers were also interested to find that the SorCS1-deficient mice had decreased levels of the protein Vps35, which was linked to Alzheimer's by Scott Small, MD, Associate Professor of Neurology, Columbia University College of Physicians and Surgeons, who co-authored the new study with Gandy. They propose that depleted SorCS1 may cause Vps35 levels to also decrease, leading to further accumulation of Abeta in mice. Further studies are required to better understand the impact of SorCS1 on Vps35 levels.



SorCS1 deficiency has been linked to Type 2 diabetes by geneticist Alan Attie, PhD, Professor of Biochemistry, University of Wisconsin, who also co-authored the new study. Rudolph E. Tanzi, PhD, Joseph P. and Rose F. Kennedy Professor of Neurology and Director of Genetics and Aging Research Unit at Harvard Medical School also contributed genetic data to the new study. Now that Dr. Gandy and his team have connected the same protein to increased Abeta levels, they can evaluate this protein and the family of proteins of which it is a member as drug targets for the treatment of both diseases.



"Alzheimer's and Type 2 diabetes are reaching epidemic levels, afflicting millions of Americans," said Dr. Gandy. "Their risk factors overlap and include high cholesterol, obesity, vascular disease, and inflammation. Now that we have a better understanding of where the connection between these two diseases originates on a molecular level, the next step is to develop drugs that will help reduce their devastating impact. Such drugs will require much more research, but having this new target helps put us on the right track."



The study was supported by the Cure Alzheimer's Fund, the National Institute on Aging, and the National Institute of Diabetes and Digestive and Kidney Diseases.



Source:

Mount Sinai Press Office

The Mount Sinai Hospital / Mount Sinai School of Medicine

ExonHit Therapeutics Awarded Two Discovery Grants By The US Federal Government

ExonHit Therapeutics (Paris:ALEHT)(Alternext: ALEHT) announced that the Company was awarded two grants to support two of its Research & Development projects under the Qualifying Therapeutic Discovery Project Program: AclarusDx™ in Alzheimer's disease and the EHT 107 program in oncology.


"We are excited to benefit from these grants as they are a recognition of the potential medical benefit of AclarusDx™ and the EHT 107 program," said Matthew Pando, PhD, Executive Vice President, Therapeutics of ExonHit Therapeutics. "These awards also further highlight the ability of our Genome-Wide SpliceArray™ discovery platform to generate both innovative diagnostic and therapeutic products. These grants will contribute to support the ongoing development of two programs targeting areas of high medical need."


These two grants totaling USD 0.3 million were awarded to ExonHit by the U.S. Secretary of Health and Human Services to support its Alzheimer's disease and oncology research and development projects. Among the determining criteria used by the Secretary in allocating funds were those projects that show potential to result in new therapies to treat areas of unmet medical need.


About the Qualifying Therapeutic Discovery Project Program


The Qualifying Therapeutic Discovery Project Program (QTDP) was created by the U.S. Congress as part of the recent health legislation reform (Patient Protection and Affordable Care Act of 2010) and is designed to foster biotechnology growth and innovation. The program also seeks to create and sustain biotechnology jobs in the US. QTDP grants are awarded to companies with fewer than 250 employees for projects related to the treatment or prevention of diseases through the conduct of preclinical or clinical studies.


The project recipients, jointly selected by the Treasury Department and the Department of Health and Human Services (HHS), were required to demonstrate preclinical or clinical research costs incurred in 2009 or 2010 expended on projects fulfilling specific criteria. More precisely, the grant targets therapeutic discovery projects that show a reasonable potential to:


- Result in new therapies to treat areas of unmet medical need or prevent, detect or treat chronic or acute diseases and conditions,

- Reduce the long-term growth of health care costs in the United States, or

- Significantly advance the goal of curing cancer within 30 years.


Source:

ExonHit Therapeutics

Simultaneous Study Of Multiple Variables Allowed With Microgrid

Scientists at the U.S. Department of Energy's Brookhaven National Laboratory have developed a method for correlating the results of microscopic imaging techniques in a way that could lead to improved understanding, diagnosis, and possibly treatment of a variety of disease conditions, including Alzheimer's disease. The Laboratory has filed a U.S. provisional patent application for the invention.



The invention is essentially a micron-scale metallic marking grid upon which scientists place their samples -- biological tissues or inorganic samples such as minerals -- prior to imaging with different methods. "When the findings are analyzed, the grid can be used to 'map,' or orient, the images to one another, allowing us to study multiple variables in a single sample and better understand how they relate to one another," said biophysicist Lisa Miller, leader of the team that developed the new method.



For example, many diseases such as Alzheimer's are characterized by changes in both organic materials, such as proteins, as well as changes in the composition or concentration of inorganic trace metals (e.g., iron, copper, and zinc). Scientists have techniques -- infrared spectroscopy and x-ray fluorescence -- for studying each of these independently. But without a way to correlate the findings from the two methods, important information about the relationship between the organic and inorganic components can be missed.



"The x-ray and infrared-sensitive grid allows for the study of both pathological symptoms by precisely overlapping the results of these imaging methods," Miller said. "This ability to correlate images will ultimately lead to a more complete picture of many disease states."



The grid is deposited in two thicknesses onto an x-ray transparent material like mylar. It can be made of any metal, but gold is preferred. The "bars" of the grid are only a couple of nanometers thick, whereas the remainder of the metal surface is thicker. The dual thicknesses make the pattern sensitive to both infrared reflectivity and x-ray fluorescence imaging.



In another version of the invention, a single-layered grid is used to correlate light microscopy with x-ray fluorescence imaging.



Once the images are collected, custom software uses the grid patterns to align the images and correlate them with each other.



In addition to helping scientists study disease processes, the method could also be applied in monitoring and/or cleaning up environmental contamination, which is also characterized by the interplay of organic and inorganic factors.







This work was performed at Brookhaven Lab's National Synchrotron Light Source (NSLS), a source of intense infrared, ultraviolet, and x-ray beams used for studying atomic level details of a wide range of materials from biological molecules to semiconductor devices. Click here for more information on this study.



This project was funded by the National Institutes of Health with operational support for the NSLS provided by the Office of Basic Energy Sciences within the U.S. Department of Energy's Office of Science.



One of ten national laboratories overseen and funded primarily by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. Brookhaven is operated and managed for DOE's Office of Science by Brookhaven Science Associates, a limited-liability company founded by the Research Foundation of State University of New York on behalf of Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.



Source: Karen McNulty Walsh


DOE/Brookhaven National Laboratory

Dementia Study Launched Within The Deaf Community

Researchers have launched a unique project to improve early diagnosis and management of dementia among Deaf people who use British Sign Language (BSL).


The research, funded by Alzheimer's Society, will examine how to identify dementia in Deaf people and explore how they might best cope with their condition. The study will also investigate how to provide support services for the Deaf community and develop assessment tools in BSL.


The University of Manchester team, working with colleagues at UCL (University College London), City University London, and the Royal Association for Deaf people, brings together Deaf and hearing researchers from a range of disciplines, including dementia care, social work, old-age psychiatry, psychology, Deaf studies and Sign Language research.


Lead researcher Professor Alys Young, from the Social Research with Deaf People programme at The University of Manchester, said: "Nobody knows whether Deaf people are more or less likely to experience dementia than hearing people. Our assumptions about what might be valued in care and support are based on hearing people's preferences, not rooted in an understanding of Deaf people's cultural experiences. Information about dementia and related services does not exist in Deaf people's preferred or only language BSL.


"There are no validated assessment tools in British Sign Language for diagnosis of dementia among Deaf people and using assessments designed for English speakers with an interpreter can lead to misunderstandings; some terms do not mean the same thing to people from different cultures."


The researchers will study normal ageing amongst Deaf signing people with the help of several hundred Deaf people who come together annually for a holiday organised by the English Deaf Darby and Joan Club. The team will also work with Deaf people with a diagnosis of dementia and their carers to explore their experiences of living with the illness, their priorities for care and how to improve early identification and support services.


Professor Bencie Woll, at UCL's Deafness, Cognition and Language research centre, where the BSL assessments will be developed, said: "Early identification of dementia brings many potential benefits, including access to medications, more time for people with dementia and their families to make decisions about care and support and the potential for a better quality of life.


"For Deaf people, the current lack of information in BSL and poor awareness in the Deaf community about dementia, combined with no diagnostic tools in BSL, means early identification is unlikely to happen. This research project aims to resolve that problem."


Professor Jane Marshall, at City University London, added: "The benefits of this project will be felt by Deaf people with dementia, their families and the health professionals who support people with this devastating diagnosis. The project should also add to our general understanding of dementia by studying its manifestations in a previously neglected language and cultural group."


Dr Susanne Sorensen, Head of Research at Alzheimer's Society, said:


"This exciting piece of research will, for the first time, look into the experiences of Deaf people with dementia. A person with dementia may have difficulty communicating and this can become a more complicated problem for Deaf people.


"The fact that many Deaf people struggle to get a diagnosis of dementia means that they're unable to access treatment that could help relieve some of their symptoms and enable them to remain independent for longer. One million people will develop dementia in the next 10 years. We must act now."


Source: Manchester University

Challenging NICE's Restriction For Alzheimer's Drugs May Be Attempt To Undermine Its Processes, UK

According to an editorial written by a senior health economist in this week's British Medical Journal (BMJ), a legal challenge against *NICE (National Institute for Health and Clinical Excellence) over its decision to limit the use of drugs for Alzheimer's disease could well be an attempt to undermine its processes.


* NICE is the body that decides what treatments are supplied on the National Health Service (NHS) in England and Wales.


NICE faces a judicial review over its refusal to make part of its modeling data for the dementia drug donepezil (Aricept) available to the pharmaceutical industry. NICE insists it is crucial to protect the intellectual property rights of external assessment groups, such as the Southampton University's Health Technology Centre. Alan Maynard, Professor of Health Economics at York University, says that NICE's protection of just this part of the assessment process may be unwise - even though this lack of transparency has never been challenged before.


Maynard says that this conflict may be an attempt by the pharmaceutical industry to improve its profits from a marginally cost effective drug, and could also be part of a more subtle drive to undermine processes of assessing health technology, which are designed to make sure taxpayers receive effective treatment which is good value for money.


Maynard says similar attempts to undermine the process have also taken place in Australia, which has a similar system of assessing the cost-effectiveness of drugs and devices.


Maynard argues that NICE is essential for improving the efficiency of the NHS. He adds that NICE's processes are generally sensible and transparent. He also writes that the constraints under which it works can be improved.


Maynard writes "Surely it would have been better to have compensated Southampton for its loss of property rights in its model of treatment for Alzheimer's disease rather than become entangled in litigation. With the NHS seeking to control expenditure and target the use of drugs to improve the health of the population in a cost effective manner, and industry wanting to maximise its profits, conflict is inevitable. It is essential that the trade off between health and wealth is managed with transparent and good science by all participants - both public and private."


"Transparency in health technology assessments"

Editorial

BMJ Volume 334 pp 594-5

bmj


Edited by:




View drug information on ARICEPT.

Metabolon Extends Biochemical Understanding Of Alzheimers Disease

Metabolon, Inc., leaders in global metabolomics, biomarker discovery and biochemical analysis, announces the publication of "Ablation of the Locus Coeruleus (LC) Increases Oxidative Stress in Tg-2576 Transgenic But Not Wild-type Mice" in the International Journal of Alzheimer Disease. The paper examines the role of the LC on markers of oxidative stress in transgenic mice and was carried out as a collaboration among scientists at Pfizer, Proteostasis Therapeutics, the University of Dundee, Duke University and Metabolon. The paper is co-authored by Orest Hurko, Kurt Boudonck, Cathleen Gonzalez, J. Steve Jacobsen, Peter H. Reinhart, Crowther Daniel, Zoe A. Hughes.


Previous research in this area suggested that differences in inflammatory response observed in humans with Alzheimer disease and mouse models reflect a discrepancy in the state of the LC, the major site of norepinephrine synthesis in the brain. LC degeneration is an early change in human Alzheimer disease, but it is preserved in transgenic mouse models of Alzheimer disease. The authors use a non-targeted metabolomic approach to examine the effects of ablating the LC on oxidative stress and intermediary metabolism. Mice transgenic for beta-amyloid (Tg2576A??) in which the LC had been ablated showed greater concordance with human Alzheimer disease, including increased oxidative stress and altered energy metabolism. The results support the proposal that LC degeneration may contribute to key pathophysiological features of Alzheimer disease, and extend the hypothesis from inflammation to oxidative stress and altered carbohydrate metabolism. Moreover, transgenic mice with an LC ablation may provide a more congruent model for human Alzheimer disease than transgenic mice with intact LC.


Source:

Metabolon, Inc.

Elan And Transition Therapeutics Announce Phase 1 Data Showing ELND005 Achieves Desired Concentrations In Brain Tissue And Cerebrospinal Fluid

Elan Corporation, plc (NYSE: ELN) and Transition Therapeutics Inc. (TSX: TTH, NASDAQ: TTHI) today presented Phase 1 data demonstrating that treatment with ELND005 (scyllo-inositol formerly known as AZD-103), achieves desired concentrations in human brain tissue and cerebrospinal fluid when given orally. Preclinical data also were presented showing that ELND005 administration is associated with preservation of choline acetyltransferase (ChAT), reflecting preservation of nerve cells that are critical to memory function in the brain. ELND005 is an orally-administered drug candidate in Phase 2 trials for the treatment of mild to moderate Alzheimer's disease. These results were presented at the 2009 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2009) in Vienna, Austria.


In a poster entitled, "Oral Amyloid Anti-aggregating Agent ELND005 is Measurable in CSF and Brain of Healthy Adult Men," the researchers describe results of a Phase 1 study in which eight healthy adults each received 2,000 mg of ELND005 twice a day for 10 days. Concentrations of ELND005 in cerebrospinal fluid were measured directly, while brain tissue concentrations were measured non-invasively using a novel magnetic resonance spectroscopy technique and were determined to be within the range associated with efficacy in previous animal studies that employed a transgenic animal model of Alzheimer's Disease. ELND005 was well tolerated by these study participants with no severe, serious, or treatment-limiting adverse events observed.


"Achieving a clinically beneficial concentration of drug in brain tissue and cerebrospinal fluid has presented a significant hurdle to other drugs investigated to treat Alzheimer's Disease, so this is an important proof of concept for us," said Elan president Carlos V. Paya, MD, PhD. "We look forward to completing and reporting results from our ongoing Phase 2 study of ELND005 in patients with mild to moderate Alzheimer's disease, which completed enrollment in October 2008."


In a second poster, entitled "Quantification of Cholinergic Degradation and Adult Neurogenesis in TgCRND8 Mice Following Treatment with Scyllo-Inositol (ELND005)," Dr. JoAnne McLaurin and colleagues from the University of Toronto analyzed levels of the enzyme Choline Acetyltransferase (ChAT) in an animal model of Alzheimer's disease. As in humans, these Alzheimer's animal models exhibit damage to nerve cells in a region of the brain called the "basal forebrain" that use the neurotransmitter acetylcholine to transmit nerve impulses critical to memory functions to other nerve cells in a brain region important for memory function called the hippocampus. Animals treated with ELND005 exhibited significantly more ChAT levels compared to untreated animals.


"There is evidence that amyloid plaque formation drives the decline in memory and cognition associated with Alzheimer's disease," said JoAnne McLaurin, PhD, professor at the University of Toronto's Centre for Research in Neurodegenerative Diseases. "Although more research is necessary, the findings presented today suggest that ELND005 may have the ability to prevent the loss of ChAT that results from damage to cholinergic neurons in the brain, thereby potentially protecting against cognitive decline in individuals with Alzheimer's disease."















"We have conducted a robust preclinical and Phase 1 research program of ELND005 that has demonstrated that the drug is able to cross the blood-brain barrier, which should allow it to target the disaggregation of amyloid beta in the brain," said Dr. Tony Cruz, chairman and chief executive officer of Transition.


In 2006, Elan and Transition entered into an exclusive, worldwide collaboration agreement for the joint development and commercialization of ELND005 for the treatment of Alzheimer's disease and other indications.


About ELND005 (AZD-103)


ELND005 is an orally-administered therapeutic agent that has received fast track designation from the U.S. Food and Drug Administration (FDA) for treatment of mild to moderate Alzheimer's disease. Fast track designation can facilitate development and may expedite regulatory review of drugs that the FDA recognizes as potentially addressing an unmet medical need for serious or life-threatening conditions.


ELND005 is currently in a Phase 2 clinical study, which completed enrollment in October 2008. The study is a randomized, double-blind, placebo-controlled, dose-ranging, safety and efficacy study in approximately 340 patients with mild to moderate Alzheimer's disease. The planned treatment period for each patient is approximately 18 months.

About Alzheimer's Disease


Alzheimer's disease, a leading cause of dementia, is a progressive brain disorder that gradually destroys a person's memory and ability to learn, reason, make judgments, communicate and carry out daily activities. Alzheimer's disease may result from the build-up of toxic beta-amyloid peptides in the brain. As Alzheimer's disease progresses, individuals may also experience changes in personality and behavior, such as anxiety, suspiciousness or agitation, as well as delusions or hallucinations. It is currently estimated that more than 5 million Americans have Alzheimer's disease and more than 24 million people worldwide over the age of 60 have some form of dementia (Source: Alzheimer's Association and Alzheimer's Disease International).


About Elan


Elan Corporation, plc is a neuroscience-based biotechnology company committed to making a difference in the lives of patients and their families by dedicating itself to bringing innovations in science to fill significant unmet medical needs that continue to exist around the world. Elan shares trade on the New York, London and Dublin Stock Exchanges. For additional information about the company, please visit elan.


Source

Transition

New Campaign Highlighting The Devastating Impact Of Alzheimer's Disease

The Alzheimer Society is launching a new campaign in an effort to raise awareness about the soul wrenching realities of Alzheimer's disease, and the Society's efforts to fund research towards a cure.


Created by the Leo Burnett agency on a pro-bono basis, the 'Forget Everything you Knew' campaign is meant to correct common misconceptions about Alzheimer's disease and to urge greater investment in research. The campaign points to three key facts about the disease: it isn't only a disease of the elderly, in fact it can start in your 40's; it isn't about forgetfulness but rather a disease of the brain that takes away the ability to process information, making it impossible to perform the simplest day-to-day tasks; and it is fatal, normally within five to 10 years of diagnosis.


"Understanding the disease is the first step towards fighting it. Validating the sentiment of loss, and mourning of life as we have known, is the second step," says Kelly Duffin, CEO of the Alzheimer Society of Canada. "Individuals living with dementia and their families tell us that there is much that continues to make life worth living - despite a diagnosis of dementia. However, they also tell us about the intense grief that they feel - long before death occurs - for life as they knew it, and for a shared future that they hoped and planned for."


While the amount of money spent on dementia research has increased over the past few years, when one considers the rapidly increasing prevalence of the disease and its devastating economic impact, much more will need to be invested if we are to accelerate the pace of progress.


"This campaign will shine light on the need for research to ultimately end this disease, so that people living with it today will have confidence that their children and grandchildren will not have to endure its devastation," says Dr. Jack Diamond, Scientific Director of the Alzheimer Society of Canada.


The Public Service Announcement campaign will appear in three different media types, including TV (in English, French, Italian, Spanish, Chinese, Arabic, Punjabi and Urdu), Print (in English and French) and two Radio spots in English. To view the campaign, go to alzheimer.ca.


"I know a poll from 2006 found that Alzheimer's disease is the second most feared disease among Canadians as they age. Based on my family's experience, we would rank it even higher," says Kathy Stevens, a retired marketing executive who assisted with the campaign as one of the lead donors. "Growing funds for research is critical if we are to end the grief and loss."


The Alzheimer Society is the leading, nationwide health organization for people affected by dementia in Canada. The Society is a principal funder of Alzheimer research and training, provides enhanced care and support to people with the disease, their families and their caregivers, and is a prominent voice within all levels of government. Active in more than 140 communities across Canada, the Society is also a key player in Alzheimer's Disease International, an organization at the forefront of world wide efforts to fight dementia of which it is a founding member.

Source
Alzheimer Society

Personality Changes May Help Detect Form Of Dementia

A simple personality test could help doctors detect dementia with Lewy bodies, a form of dementia often confused with Alzheimer's disease, sooner, according to a study published in the May 29, 2007, issue of Neurology®, the scientific journal of the American Academy of Neurology.


Dementia with Lewy bodies is the second most common neurodegenerative cause of dementia. It shares characteristics with both Alzheimer's and Parkinson's disease. Getting the correct diagnosis is especially important because some medications used to treat the mental health symptoms of Alzheimer's disease can be potentially dangerous for people with dementia with Lewy bodies.


The study found that even before diagnosis, people with dementia with Lewy bodies displayed passive personality changes, such as diminished emotional response, disinterest in hobbies, repetitive behaviors, and growing apathy, or lack of interest, more often than those with Alzheimer's.


The study involved 290 people who were part of a larger study and were tested every year for an average of about five years; by the end of the study 128 of the participants had confirmed cases of dementia with Lewy bodies, 128 had Alzheimer's and 34 had no form of dementia. Researchers followed the participants through death, including autopsy results. During annual interviews, participants or their family members were asked about changes in personality, interests and drives.


People with dementia with Lewy bodies were two times more likely to have passive personality traits at the time of the first evaluation than people with Alzheimer's disease. By the time of death, up to 75 percent of those with dementia with Lewy bodies had passive personality changes compared to 45 percent of those with Alzheimer's disease.


"Currently we mainly look for memory problems and other cognitive problems to detect dementia, but personality changes can often occur several years before the cognitive problems," said study author James E. Galvin, MD, MPH, of Washington University School of Medicine in St. Louis, MO, and member of the American Academy of Neurology. "Identifying the earliest features of dementia may enable doctors to begin therapy as soon as possible. This will become increasingly important as newer, potentially disease-modifying medications are developed. It also gives the patient and family members more time to plan for the progressive decline."


Galvin said more detailed personality tests are not often used in most office settings because of time and lack of training. "Our results show incorporating a brief, simple inventory of personality traits may help improve the detection of dementia with Lewy bodies," said Galvin.


The study was supported by grants from the National Institute on Aging, the American Federation for Aging Research, the Alan A. and Edith L. Wolff Charitable Trust and the Paul Beeson Physician Faculty Scholar Award in Aging Research.


The American Academy of Neurology, an association of more than 20,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer's disease, epilepsy, Parkinson's disease, and multiple sclerosis.


For more information about the American Academy of Neurology, visit aan.


American Academy of Neurology (AAN)

1080 Montreal Ave.

St. Paul, MN 55116

United States

neurology

Lovastatin Shown To Slow Progression Of Alzheimer's Disease

High cholesterol levels are considered to be a risk factor for cardiovascular disease including stroke. Therefore, many cholesterol lowering drugs have been developed by pharmaceutical companies in recent years. One class of these drugs, statins, has been found to reduce the incidence of stroke and progression of Alzheimer's disease when prophylactically administered.



In a recent paper published in the Journal of Alzheimer's Disease, Amalia Dolga and co-workers from the University of Groningen show that the statin lovastatin, in addition to lowering cholesterol, can also prevent nerve cells from dying in conditions that occur in Alzheimer's disease. Amalia Dolga discovered a previously unknown cascade of cellular signals in nerve cells that are responsible for this neuroprotective mechanism. This is an important finding because in many diseases such as Alzheimer's or Parkinson's, death of nerve cells is generally thought to be a major cause of the dramatic symptoms that we find in these diseases.



Amalia Dolga found that statins stimulate nerve cells to produce a specific receptor molecule for a protein which plays a central role in the body's immune response: Tumor Necrosis Factor-alpha (TNF-??). Previous studies conducted by Dr. Ulrich Eisel's group in the Department of Molecular Neurobiology (headed by Prof. Paul Luiten) have demonstrated that this specific TNF-?? signaling pathway has a strong beneficial effect on nerve cells and can protect nerve cells against death. This finding now demonstrates that a widely given drug like a statin can activate this protective pathway.







Amalia M. Dolga, Ingrid M. Nijholt, Anghelus Ostroveanu, Quirine ten Bosch, Paul G. M. Luiten and Ulrich L. M. Eisel. (2008) Lovastatin Induces Neuroprotection Through Tumor Necrosis Factor Receptor 2 Signaling Pathways. Journal of Alzheimer's Disease 13 (2):111-122.



Source: Astrid Engelen


IOS Press

Alzheimer's Society Response To The Publication Of Revised NICE Guidance On Alzheimer's Treatments, UK

Thousands of people with Alzheimer's will continue to be denied access to the only drug treatments for the disease following the publication of revised guidance by the National Institute for Health and Clinical Excellence (NICE). The original guidance recommended that only people in the moderate stages of Alzheimer's disease should have access to drugs in the NHS, denying them to people in the early stages.


Amendments were made following a Court of Appeal decision to allow consultees access to the health economic model that NICE used in the development of the guidance and a subsequent review of this model by relevant stakeholders, including Alzheimer's Society.


Despite the concerns raised by the consultees on the flaws in the economic model, the newly published and amended Final Appraisal Determination (FAD) has not altered its original recommendations and people in the early stages of dementia will still be deprived access to effective treatments.
Neil Hunt, Chief Executive, Alzheimer's Society, says,


'Alzheimer's Society has long campaigned for the thousands of people in the early stages of dementia to be given access to the effective treatments that they are currently denied because of cost. It is completely unacceptable to deny people with dementia the only treatments that could improve quality of life for them and their carers.


We are extremely disappointed to see that the NICE guidance is essentially unchanged, despite what we feel are fundamental flaws in the economic model they have used to inform their recommendations.


The glimmer of hope is that NICE has finally committed to for a full review to address these concerns, as soon as possible. This will be little consolation for the thousands of people who will develop Alzheimer's disease this year but provides hope for the future that this incomprehensible decision will be changed. We look forward to working with NICE to ensure the problems with the current economic model are overcome and people with dementia are given a fair deal.'


Notes


- Since May 2006 three Alzheimer's drugs have been denied to people in the early stages of the disease on the NHS.


- One 1 May 2008 the Court of Appeal found in favour of Eisai / Pfizer ruling NICE should have allowed public access to the health economic model that it used to make the decision.


- On 17 June 2008 NICE sought permission from the House of Lords to appeal the Court of Appeal decision.


- The health economic model has since been shared with relevant stakeholders, including Alzheimer's Society, and comments have been fed back to NICE resulting in the publication of an ammended FAD (Final Appraisal Determination) on Thursday 11 June 2009.


- One in three people over 65 will die with dementia.


- Alzheimer's Society research shows that 700,000 people in the UK have a form of dementia, more than half have Alzheimer's disease. In less than 20 years nearly a million people will be living with dementia. This will soar to 1.7 million people by 2051.


- Alzheimer's Society champions the rights of people living with dementia and the millions of people who care for them.


- Alzheimer's Society works in England, Wales and Northern Ireland


- Alzheimer's Society needs to raise money to help people live well with dementia today and for research to find a cure for tomorrow. You can donate now by calling 0845 306 0898 or visiting alzheimers.uk

Source
Alzheimer's Society

Alzheimer's disease, cholesterol treatment, including statins may slow progression

Cholesterol lowering drugs, including statins, may slow the progression of Alzheimer's disease, concludes a study in the Journal of Neurology Neurosurgery and Psychiatry.


The research team assessed the degree of brain function loss caused by Alzheimer's disease in 342 patients attending a memory clinic. They then monitored the progress of the disease for almost three years. The average age of the patients was 73. Most were women.


In all, 129 patients had abnormal cholesterol levels, almost half of whom were being treated exclusively with statins. Of the remainder, 105 had abnormal untreated cholesterol , and 108 had normal cholesterol levels. Drug treatment included fibrates or statins, or a mixture of both.


During the three years, all the patients deteriorated, but the disease progressed significantly more slowly in the patients given cholesterol lowering drugs. Progression of the disease was rated at 1.5 points a year in those given the drugs, 2.4 in those whose cholesterol was not treated, and 2.6 in those with normal cholesterol levels.


The risk factor profile for Alzheimer's disease, including high blood pressure and diabetes, scarcely differed between the two groups with abnormal cholesterol levels.


The authors conclude that cholesterol lowering drugs may effectively slow progression of Alzheimer's disease, but suggest that a large trial will be needed to confirm their findings.


An accompanying editorial argues that it is still too early to definitively conclude that cholesterol lowering treatment is a valid option for patients with Alzheimer's disease.


The editorial also points out that the research was not able to isolate the potential advantages of the drugs other than their ability to lower cholesterol.


Lipid lowering agents are associated with a slower cognitive decline in Alzheimer's disease, J Neurol Neurosurg Psychiatry 2005; 76: 1624-9


Teresa

thaganbma.uk

BMJ Specialty Journals

bmj

Alzheimer's Society Comment On A News Strategy For Carers That Plans To Double The Amount Of Respite Care For Carers In England

The carers strategy is a good start in tackling the large set of problems faced by carers. Greater investment in respite is very good news. It could give thousands of carers the invaluable opportunity to recharge their batteries and access crucial support. However, it's important that this new money is used for short breaks and not only given to people when they reach crisis point. It's also not just about putting someone in a care home for a week, we need to get creative and provide support that fits people's individual needs.


The number of people with dementia will soar to over 1 million by 2025 and we still have a long way to go if we are to equip our care system to meet this need. This strategy fails to address the huge financial burden of caring that is forcing thousands into poverty. Carers of people with dementia are amongst the hardest hit by the current charging system. We need a new national settlement on who pays for care that removes the disproportionate burden carried by carers of people with long term conditions.


Neil Hunt

Chief Executive

Alzheimer's Society


About the Alzheimer's Society


Alzheimer's Society is the leading care and research charity for people with all forms dementia and their carers. It provides information and education, support for carers, and quality day and home care. It funds medical and scientific research and campaigns for improved health and social services and greater public understanding of dementia.


The Alzheimer's Society provides a national help line on 0845 3000 336 and website alzheimers.uk. Please include this information in any publication that uses these comments.

Alzheimer's Society

Cortex Area Thinner In Youth With Alzheimer's-Related Gene

A part of the brain first affected by Alzheimer's disease is thinner in youth with a risk gene for the disorder, a brain imaging study by researchers at the National Institute of Mental Health (NIMH), one of the National Institutes of Health (NIH), has found. A thinner entorhinal cortex, a structure in the lower middle part of the brain's outer mantle, may render these youth more susceptible to degenerative changes and mental decline later in life, propose Drs. Philip Shaw, Judith Rapoport, Jay Giedd, and NIMH and McGill University colleagues. They report on how variation in the gene for apoliproprotein (ApoE), which plays a critical role in repair of brain cells, affects development of this learning and memory hub in the June, 2007 Lancet Neurology.



"People with the Alzheimer's-related variant of the ApoE gene might not be able to sustain much aging-related tissue loss in the entorhinal cortex before they cross a critical threshold," explained Shaw. "But the early thinning appears to be a harmless genetic variation rather than a disease-related change, as it did not affect youths' intellectual ability. Only long-term brain imaging studies of healthy aging adults will confirm whether this anatomical signature detectible in childhood predisposes for Alzheimer's."



It was already known that adults destined to develop Alzheimer's disease tend to have a smaller and less active entorhinal cortex. This structure is the first to shrink in volume and to develop the neurofibrillary tangles characteristic of the disorder.



Previous studies had also implicated in Alzheimer's one of three versions of a gene that produces ApoE. The ApoE4 variant occurs in 10-25 percent of the general population, but in 40 percent of late-onset Alzheimer's patients. The strongest genetic risk factor for the disease discovered to date, ApoE4 has been linked to altered brain activity in adults and impaired neuronal development.



Shaw and colleagues suspected that youth with ApoE4 would have a thinner entorhinal cortex. To confirm this, they compared the MRI (magnetic resonance imaging) scans of 239 healthy children and teens with their ApoE gene types. Many were re-scanned as they grew up to see if there was any ongoing thinning process traceable to ApoE4.



Each individual inherits two copies of the ApoE gene, one from each parent. Youth with at least one copy of the relatively rare ApoE2 variant - which may confer a protective effect against developing Alzheimer's - showed the thickest entorhinal cortex. This was the first evidence that the ApoE2 version, which is carried by 5-10 percent of the population, affects brain structure, say the researchers. Youth with two copies of ApoE3, the most common version (65-85% prevalence), had intermediate cortex thickness. Those with one or two copies of ApoE4 had the thinnest entorhinal cortex.



ApoE4 gene type also predicted thinning of two other brain regions (medial temporal and posterior orbitofrontal areas) affected early in Alzheimer's disease, which, like the entorhinal cortex, are involved in learning and memory. The pattern of changes resembled that seen in early Alzheimer's, but to a far lesser degree. For example, the entorhinal cortex thinning seen in Alzheimer's disease is about 10-fold greater than in the youth with ApoE4.



Although they did not test for possible learning and memory deficits, the researchers found no difference in IQ attributable to ApoE gene type. Nor did the E4 variant accelerate loss of cortex tissue. The differences were fixed, and didn't progress. In fact, the researchers noted evidence that ApoE4 may even promote survival in infancy and protect the brain's thinking capacity against damage from infectious illness.



"In the future we hope to determine whether this thinner cortex is associated with differences in brain activity during tasks of learning and memory in children," said Shaw.






Also participating in the research were: Kristin Taylor, A. Blyth Rose, Deanna Greenstein, Liv Clasen, NIMH; Jason Lerch, Jens Pruessner, Alan Evans, Montreal Neurological Institute, McGill University.



The National Institute of Mental Health (NIMH) mission is to reduce the burden of mental and behavioral disorders through research on mind, brain, and behavior. The National Institutes of Health (NIH) - The Nation's Medical Research Agency - includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases.



Contact: Jules Asher


NIH/National Institute of Mental Health

Supporting Research On Age-Related Diseases And Clinical Care

The American Federation for Aging Research (AFAR), The National Institute on Aging (NIA), The Atlantic Philanthropies, The John A. Hartford Foundation, The Starr Foundation and other program partners are pleased to announce the 2009 recipients of the Paul B. Beeson Career Development Awards in Aging Research Program. This new cohort brings the total to 157 scholars who have been selected for this highly competitive and prestigious award, which seeks to create a cadre of clinically trained faculty who are committed to academic careers in aging research, teaching and practice.



Since the program's inception in 1995, Beeson Scholars have received more than $86 million in research grant support and have made their mark with innovative research-from the effects of depression in elderly health outcomes, to the connection between a certain type of cataract and Alzheimer's disease, to the development of new animal models to study the genetic basis of aging, to improving end-of-life care for under-served aging populations.



The Beeson program has become a model of cooperation between foundations and government entities. To that end, the National Institute of Mental Health (NIMH) announced that it would join as a program partner beginning in 2010. The John A. Hartford Foundation has renewed its support through 2012.



"It is crucial to encourage and support researchers who are proficient in clinical aspects of aging," said NIA Director Richard J. Hodes, MD. "The Beeson Awards provide protected research time and mentoring in a strong research environment, helping these young scientists establish their careers. Since the program began, we have seen increasing numbers of Beeson Scholars compete successfully for grant funding both from the NIA and other NIH Institutes and Centers."



The Beeson Award is granted to scholars who are laying clinically relevant groundwork in many areas related to aging, including the biology of aging and age-related diseases, as well as health outcomes, health services and clinical management issues, with the goal of enhancing the health and quality of life of older adults. Scholars receive $600,000 to $800,000 for a three-to five-year period, allowing them flexible and protected time for innovative research.



This year's scholars will study a broad array of topics such as the benefits and burdens of mammography screening for very old women, the challenges of access to kidney transplantation for elderly patients and determining the role of oxidative damage in the onset and progression of muscle loss and wasting, a common age-related condition.



"Research on aging encompasses many areas of investigation and care: from the very basic biology of aging processes to the clinical and social care needs," said Corinne Rieder, EdD, executive director of The John A. Hartford Foundation. "The Beeson program clearly addresses these needs by creating an outstanding network of the top scientists in the country who are helping to tackle the many research and clinical challenges of geriatric medicine - challenges that will only become more urgent in the future. We are pleased to renew our support for the Beeson program and welcome our new partner, the National Institute of Mental Health."
















"NIMH strives to nurture talented physician scientists and to enhance the impact of their research on the enormous public health burden that mental illnesses have across the lifespan," said NIMH Director Thomas R. Insel, MD. "We hope to underwrite such support targeted at our increasingly aging population through the Beeson Scholars program."



"One of the goals of the Beeson program is to cultivate future leaders in aging research and mentor other scientists who follow, ultimately creating a network of the best talent in the field of aging," said Stephanie Lederman, executive director of AFAR. "Our Beeson Scholars have proven that we have succeeded. Critical to the success of the Beeson program, however, are the partners, who enable the program to grow and thrive. We thank the NIMH for joining us and The John A. Hartford Foundation for renewing their long-standing commitment to the program."



2009 Beeson Scholars

Cynthia M. Boyd, MD, MPH, Assistant Professor, Johns Hopkins University School of Medicine: Treatment Burden in Older Adults with Diabetes and Multimorbidity

Dena B. Dubal, MD, PhD, Assistant Adjunct Professor, University of California, San Francisco: Collagen VI: Novel Mechanisms and Functions in Alzheimer's Disease

Christiane Reitz, MD, PhD, Postdoctoral Research Scientist, Columbia University College of Physicians and Surgeons: Mapping Causative Factors in the Sortilin-related Pathway in Alzheimer's Disease

Mara Schonberg, MD, Instructor of Medicine, Harvard Medical School/Beth Israel Deaconess Medical Center: Benefits and Burdens of Screening Oldest-old Women: The Case of Mammography

Dorry Segev, MD, Assistant Professor, Johns Hopkins University School of Medicine: Access to Kidney Transplantation in Elderly Patients

Edmond Teng, MD, PhD, Clinical Instructor, University of California, Los Angeles: Assessment of Biomarkers and Behavior in a Transgenic Rat Model of Alzheimer's Disease

Heidi L. Wald, MD, MSPH, Assistant Professor of Medicine, University of Colorado Denver: Reducing Urinary Tract Infections in the Hospitalized Older Patient

Jonathan Wanagat, MD, PhD, Acting Instructor, University of Washington: Mitochondrial Genetics in Skeletal Muscle Aging



In 2007, supported by The Atlantic Philanthropies, the Beeson program expanded to the Republic of Ireland and Northern Ireland with the goal of helping to train physicians in geriatrics, build Ireland's capacity to provide high-quality care for older adults and advance knowledge of geriatric care. Five physician-scientists have been named Beeson Ireland Scholars thus far, including two this year, who received $450,000 each:



Chie Wei (Mimi) Fan, MD, RCPI, Clinical Director of Technology Research for Independent Living, St. James's Hospital: Age-related Autonomic Dysfunction and its Impact on Cognition, Gait and Falls
Ronan R. Mullan, PhD, Specialist Registrar in Rheumatology and Internal Medicine, University College Dublin: Acute Phase Serum Amyloid-A (A-SAA) in Ageing, Arthritis and Obesity - Potential Common Mechanism for Cardiovascular Disease



The Paul B. Beeson Career Development Awards in Aging Research Program is sponsored by the NIA, The Atlantic Philanthropies, The John A. Hartford Foundation, The National Institute of Mental Health, The Starr Foundation and an anonymous donor, and is administered by the NIA and AFAR. The program is named in honor of the late Paul B. Beeson, MD, who was professor emeritus of medicine at the University of Washington, and whose vision was to increase the number of physicians with a combined clinical, academic, and scientific expertise to care for a growing older population.



Source:
Stacey Harris


American Federation for Aging Research

Alzheimer's is a consequence of inflammation

A group of scientists at The Scripps Research Institute has proposed a new theory about the cause of Alzheimer's disease, the progressive neurodegenerative disorder that currently afflicts some 4.5 million Americans.


According to the hypothesis, the disease arises as a consequence of inflammation, which creates abnormal metabolites out of normal brain molecules.


These abnormal metabolites then modify "amyloid beta" proteins in the brain and cause them to misfold. Misfolded amyloid beta proteins are thought to be a major player in Alzheimer's disease, because they can accumulate into the fibrils and plaques that autopsies reveal in the brains of patients with the disease. These fibrils and plaques and their precursors are implicated in neuronal loss.


The inflammation process that creates these metabolites can be triggered by numerous stimuli, including infections that precede the onset of Alzheimer's disease by a significant amount of time-perhaps years.


"If a certain inflammatory metabolite or family of metabolites confers risk later in life, then we need to know this, and we need to attack the problem," says Scripps Research Professor Jeffery W. Kelly, who is the Lita Annenberg Hazen Professor of Chemistry in The Skaggs Institute for Chemical Biology and vice president of academic affairs at Scripps Research.


Kelly and his Scripps Research colleagues present their new theory in an article that will be published in an upcoming issue of the journal Proceedings of the National Academy of Sciences.


A Progressive, Incurable Disease


Alzheimer's is a progressive neurodegenerative disease marked by memory loss, loss of language ability, loss of the ability to mentally manipulate visual information, poor judgment, confusion, restlessness, and mood swings. According to the Alzheimer's Disease Education and Referral Center, a service of the National Institute on Aging, Alzheimer's disease is now believed to inflict some 4.5 million people and is the most common form of dementia among older people in the United States. Currently, there is no cure for Alzheimer's and no way to slow the progression of the disease.


German doctor Alois Alzheimer discovered the disease in 1906, when he examined a post-mortem patient who had died with an unusual mental illness. Alzheimer found unusual clumps of protein or plaques in her brain. These plaques-made up of aggregated proteins called amyloid beta-are a clear sign of the disease, and the aggregation of amyloid beta protein is an accepted primary pathological marker for Alzheimer's.


But scientists have not been sure whether these fibrils are causing the disease or are simply a marker of it. By analogy, a tidal wave may cause massive destruction to a coastal area, but the tidal wave itself may have been caused by a distant earthquake undetected in that coastal area.















Kelly and his colleagues have studied the basic biology of Alzheimer's and related diseases for many years, looking for new treatment approaches. Now, they think they may have taken a significant step along this path by identifying the distant earthquake that causes Alzheimer's.


Basic Science Brings it All Together


Amyloid diseases are caused by the misfolding of proteins into structures that lead them to cluster together, forming microscopic fibril or plaques, which deposit in internal organs and interfere with normal function, sometimes lethally. In the case of Alzheimer's, these fibrils kill nerve cells in areas of the brain that are crucial for memory.


These diseases include Alzheimer's, Parkinson's, and a peripheral nervous system disease called familial amyloid polyneuropathy (FAP)-a collection of more than 80 rare amyloid diseases caused by the misfolding of the protein transthyretin (TTR), which the liver secretes into the bloodstream to carry thyroid hormone and vitamin A.


In the FAP diseases, mutations in the TTR protein are known to play a direct role in causing the disease. Basically, these mutations change the amino acid sequence of TTR, and these changes alter protein folding in such a way as to predispose the proteins to misfold and accumulate into microscopic fibrils, which can then grow into the protein plaques characteristic of FAP and other amyloid diseases.


However, in Alzheimer's disease, the cause of misfolding is not so obvious. A number of mutations are associated with rare forms of familial Alzheimer's, but not with most common cases (about 95 percent of the cases). This suggests there must be a more common cause of Alzheimer's disease, and Kelly has combined efforts with several of his colleagues at Scripps Research to find it.


A few years ago, Kelly started to think about traumatic head injuries, which are a major risk factor for later developing Alzheimer's disease. The body responds to such injuries with inflammatory reactions that cause the release of components of lipid membranes, such as cholesterol.


Kelly began to discuss this with his colleagues in The Skaggs Institute for Chemical Biology, Scripps Research President Richard A. Lerner, M.D., and Scripps Research Associate Professor Paul Wentworth, Jr., Ph.D. Lerner and Wentworth had recently discovered how inflammation can lead to the production of reactive oxygen species such as ozone, which can trigger pathological changes in other molecules in the body, like cholesterol.


In a paper last year, Lerner, Wentworth, and several colleagues described how ozone reacts with normal metabolites to produce toxic compounds during inflammatory processes taking place in the body. The scientists describe two such compounds, which they call the "atheronals." The scientists suggest these newly identified products are critical to the pathogenesis of the disease atherosclerosis because these atheronals were found in atherosclerotic plaques that were surgically removed from patients with atherosclerosis. (Atherosclerosis is a common vascular disease that increases the risk of heart attacks and strokes and is characterized by a hardening of the arteries over time due to deposits of fibrous tissue, calcium, fat, cholesterol, proteins, cells, and other materials on the inner "endothelial" walls of an artery).


This discovery made Kelly sit up straight when he first heard it because inflammation is increasingly seen as playing a role in neurodegenerative diseases. Also, there are a fair number of risk factors in common between the two diseases, including hypercholesterolemia and inflammation.


In their new study, Kelly and his colleagues suggest that inflammation in the brain could create a perfect storm in which cholesterol and lipids react with ozone and other inflammatory chemicals to produce abnormal reactive metabolites, which, in turn, modify the folding of normal amyloid beta protein. These modified amyloid beta proteins can catalyze misfolding in other unmodified amyloid beta proteins, starting an avalanche of misfolding that results-perhaps years or decades later-in Alzheimer's disease.


A New Way of Thinking About Disease in General


To examine the hypothesis that these metabolites may be the root cause of Alzheimer's, Kelly and his colleagues examined the post-mortem brains of Alzheimer's patients and compared these to age-matched controls.


They found evidence of atheronals in the brains of both the Alzheimer's patients and the control subjects. The levels of atheronals in the brains of the Alzheimer's patients were not significantly elevated, but this is not necessarily surprising. According to the new theory, the propagation of misfolding and the buildup of fibrils inside the brain does not depend upon continuous exposure to metabolite-modified proteins, but to exposure during a precipitating event that may occur a decade or more earlier. The creation of these metabolite-linked misfolding proteins is only the initiator of the fibril plaques.


Kelly and colleagues also performed experiments in the test tube and found that atheronals and lipid oxidation products have the ability to dramatically accelerate the misfolding of amyloid beta and to reduce the concentration of the protein needed for misfolding to take place to concentrations found in the brain.


This is an entirely new way of thinking about not only Alzheimer's disease, but disease in general. Historically, science has regarded disease as based on the up or down regulation of gene expression or protein function. But this theory suggests a new sort of pathology-the creation of a reactive metabolite by inflammatory stress, leading to the modification of a protein, the aggregation of that protein over time, and the degeneration of function in the brain or whichever internal organ hosts the aggregation.


The inflammatory metabolite theory of Alzheimer's will be difficult to prove, admits Kelly, because the presence of these abnormal metabolites are hard to detect years after they initiated the aggregation. There is, so far, no smoking gun.


"Is [this theory] right? Time will tell," says Kelly. "That's how science works."


The article, "Metabolite-initiated protein misfolding may trigger Alzheimer's disease" was authored by Qinghai Zhang, Evan T. Powers, Jorge Nieva, Mary E. Huff, Maria A. Dendle, Jan Bieschke, Charles G. Glabe, Albert Eschenmoser, Paul Wentworth, Jr., Richard A. Lerner, and Jeffery W. Kelly and appears in the online edition of the journal Proceedings of the National Academy of Sciences the week of March 15-19, 2004. The article will appear in print later this year. See:
dx.doi/10.1073/pnas.0400924101


This work was supported by The Skaggs Institute for Chemical Biology and the Lita Annenberg Hazen Foundation.



Send comments to: jasonbscripps

Political Debate On Social Care Fails To Reassure The Public, UK

Almost two thirds (59%) of people are worried about the standard of care they could receive in old age while nearly a third (30%) feel none of the three main political parties are addressing the issue successfully.


The new Alzheimer's Society commissioned YouGov poll suggests the pre-election debate on social care has so far failed to convince voters that the current situation is likely to be improved. Not only does the survey of more than 2,000 people show a concern for the standard of care, it also demonstrates mixed opinions on how the care should be funded.


Social care, including help with dressing, washing and eating, is currently means tested and can cost people - including people with dementia - tens of thousands of pounds. However only one in 10 people say putting money aside to pay for a care is currently a priority.


A number of alternative funding methods have been outlined by political parties including insurance models and inheritance tax. Only eight per cent of people say they would rather risk selling their home to pay for care than take out insurance to protect themselves. However, less than a quarter (23%) would rather the government introduce a ??20,000 inheritance tax to fund the social care system than risk having to sell their home to pay for their own care.


Alzheimer's Society is now calling on all political parties to come together to tackle this issue head on and to address the concerns of their voters.


Ruth Sutherland, Acting Chief Executive of Alzheimer's Society, said:


'These results demonstrate that care for older people is a real worry for people ahead of the general election. In the context of the current broken system which burdens older people with huge bills for often substandard care this comes as little surprise.


'People with dementia are often the hardest hit and can pay up to ??40,000 a year, sometimes being forced to sell their homes, to pay for their care. Politicians now have a golden opportunity to change this picture and people with dementia could be some of the biggest winners. With the election looming we need to move away from soundbites and start hearing detailed plans for how the parties will create a care service that guarantees high quality care at a fair price.'


Notes


All figures, unless otherwise stated, are from YouGov Plc. Total sample size was 2282 adults. Fieldwork was undertaken between 5th - 8th March 2010. The survey was carried out online. The figures have been weighted and are representative of all GB adults (aged 18+).

Source
Alzheimer's Society

Study Points To Cocktail Therapy For Alzheimer's - Beverage Supplement Improves Memory, Learning In Gerbils

A dietary cocktail that includes a type of omega-3 fatty acid can improve memory and learning in gerbils, according to the latest study from MIT researchers that points to a possible beverage-based treatment for Alzheimer's and other brain diseases.


The combination of supplements, which contains three compounds normally found in the bloodstream, is now being tested in Alzheimer's patients. The cocktail has previously been shown to promote growth of new brain connections in rodents.


"It may be possible to use this treatment to partially restore brain function in people with diseases that decrease the number of brain neurons, including, for example, Alzheimer's disease, Parkinson's, strokes and brain injuries. Of course, such speculations have to be tested in double-blind, placebo-controlled clinical trials," said Richard Wurtman, Cecil H. Green Distinguished Professor of Neuropharmacology and senior author of a paper on the new work.


Such trials are now underway in Europe. A paper describing preliminary results has been submitted to the Alzheimer's Association International Conference on Alzheimer's Disease, to be held in Chicago July 26-31.


The new findings in gerbils appeared in the July 7 online edition of the Journal of FASEB (Federation of American Societies of Experimental Biology).


The researchers found that normal gerbils treated with the mixture-a combination of DHA (a type of omega-3 fatty acid), uridine and choline-performed significantly better on learning and memory tests than untreated gerbils.


Wurtman developed the treatment as a new approach to tackling Alzheimer's-restoring the synapses, or connections between brain cells, that leads to cognitive decline in Alzheimer's patients.


Synapses, where information is passed between neurons, play a critical role in learning and memory. Wurtman's laboratory has previously shown that the cocktail treatment improves those functions in rats with cognitive impairments.


The three dietary supplements under investigation are precursors to the fatty molecules that make up cell membranes, including the membranes of brain cells, which form synapses.


In the FASEB study, Wurtman and his colleagues found that gerbils that received all three supplements had up to 70 percent more phosphatides (a type of molecule that forms cell membranes) than control mice, suggesting that new synapses are forming.


"The improvements in cognition observed in normal gerbils in this study and in rats with impaired cognition, in a previous study, correlate perfectly with the evidence of increased brain synapses, as shown biochemically and anatomically," said Wurtman. "This suggests that treating the animals with the experimental mixture affects behavior by increasing the number of synapses in important brain regions.


Some of the gerbils in the studies received all three compounds and some received only two. The improvements in apparent synapse growth and cognitive ability were greatest in the rats given all three.


Omega-3 fatty acids are not produced in the body but are found in a variety of sources, including fish, eggs, flaxseed and meat from grass-fed animals. Choline can be synthesized in the body and obtained through the diet; it is found in meats, nuts and eggs. Uridine cannot be obtained from food sources, but is a component of human breast milk and can be produced in the body.


Lead author of the FASEB paper is Sarah Holguin, a recent MIT PhD recipient. Other authors are MIT undergraduates Joseph Martinez and Camille Chow.


The research was funded by the National Institutes of Health and the CBSMCT.



mit

Victory For People With Alzheimer's, UK

People at all stages of Alzheimer's will now be able to access drugs on the NHS that can slow the progression of the disease.


The development comes following final guidance published by The National Institute for Health and Clinical Excellence (NICE). Alzheimer's Society services are holding celebrations around the country all week to mark the occasion.


The decision is a reversal of NICE's previous position - in place since 2007 - limiting access to only those in the moderate stages of the disease.


Andrew Chidgey, Head of Policy and Public Affairs at Alzheimer's Society, says,


'This is a victory for people with Alzheimer's and their carers, many of whom have been campaigning for this day for years. These drugs don't work for everyone, but for some people they can radically improve their quality of life. We now need more people to be diagnosed early and for them to receive the treatment, support and advice that they desperately need.'


There are currently 465,000 people living with Alzheimer's in the UK and a further 62,000 people are developing Alzheimer's each year. The drugs - Aricept, Exelon and Reminyl - will now be available on prescription for people in the early and moderate stages of Alzheimer's disease. These treatments have up to now been restricted to people in the moderate stages. A fourth drug, called Ebixa, will also be made available to people in the moderate to late stages.


Heather Roberts, 56, from Derby has Alzheimer's disease and has been heavily involved in the campaign since 2007. She says,


'It's absolutely fantastic that NICE has changed its guidelines on Alzheimer's drugs, but it's not before time. NICE should be ashamed of itself for restricting access to these essential drugs in the first place. Within six months of taking Aricept my memory had improved to how it had been two years previously. That is a measure of the difference it has made to me. I am still very independent - I've got my driving licence, regularly play tennis and enjoy going on holiday. Thank heavens NICE has finally seen sense.'


Notes


- The final decision by NICE comes following the publication in October 2010 of draft guidance and is part of a review cycle of Alzheimer's drug treatments.


- For more information on the background of Alzheimer's Society's campaigning work around NICE guidance on Alzheimer's drugs, visit here.

- If people are worried about their memory they should visit their GP. For information on drug treatments, an Alzheimer's Society factsheet is available.


Source:

Alzheimer's Society


View drug information on ARICEPT; Exelon; Reminyl.

Hispanics Have More Risk Factors For Developing Alzheimer's Disease Than Other Groups, Research Suggests

The New York Times on Tuesday examined research that found "many Hispanics may have more risk factors for developing dementia than other groups" and that a "significant number appear to be getting Alzheimer's earlier" than most U.S. residents, who commonly develop the disease in their 70s or 80s. According to the Alzheimer's Association, about 200,000 Hispanics in the U.S. have the condition but the number could increase to 1.3 million by 2050. "This is the tip of the iceberg of a huge public health challenge," Yanira Cruz, president of the National Hispanic Council on Aging, said, adding, "We really need to do more research in this population to really understand why it is that we're developing these conditions much earlier."

Overall, the number of U.S. residents with Alzheimer's is expected to increase from five million in 2008 to 16 million in 2050. According to experts, Hispanics are not more genetically predisposed to Alzheimer's but factors related to low income or cultural dislocation -- such as higher rates of diabetes, obesity, cardiovascular disease, stroke and high blood pressure -- may put them at a higher risk for dementia. Cruz said the immigration experience, along with the changes in diet and social network that it entails, could play a role in increased the risk of Alzheimer's. She said, "As you acculturate, you lose those protective factors linked to nutrition, physical activity [and a] social support system that come with you when you first arrive here."

According to the Times, less education also could make this group more vulnerable to risk factors and to dementia because, scientists say, education may increase the plasticity of the brain and its ability to compensate for symptoms. Some research also cites stress related to financial troubles or cultural adjustment as risk factors for dementia. In addition, Hispanics, who are less likely to see doctors because of financial and language barriers, often mistake the symptoms of dementia as a result of aging, according to the Times. "There's some taboos," Liany Arroyo, director of the Institute for Hispanic Health at the National Council of La Raza, said, adding that surveys his group completed indicated that some Hispanics "do not necessarily understand" what Alzheimer's is.

Alzheimer's and Hispanic groups have responded to such findings by setting up health fairs and support groups, the Times reports. Some Alzheimer's centers have opened offices in Hispanic neighborhoods, according to the Times (Belluck, New York Times, 10/21).


Reprinted with kind permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation.

© 2008 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

Recovery Funds Advance Alzheimer's Disease Research

American Recovery and Reinvestment Funds are being used to promote the national research efforts to better understand, diagnose and treat Alzheimer's disease. The National Institute on Aging (NIA), part of the National Institutes of Health, has targeted promising areas of research in granting the awards, such as new and ongoing studies to identify additional risk factor genes associated with Alzheimer's, improve diagnostic tools, find biomarkers, develop therapies, conduct clinical trials and explore preventive measures.


"We are delighted to announce the award of Recovery Act funds to many dedicated, hardworking scientists committed to advancing scientific discovery into Alzheimer's disease and cognitive impairment," said NIA Director Richard J. Hodes, M.D. "Over the next two years, the recipients will use this unprecedented boost in research funds to help reach our ultimate goal of understanding age-related cognitive decline and reducing the individual and societal burden of this devastating disease."


More than 100 Alzheimer's or Alzheimer's-related research grants were awarded under the Recovery Act. The full list of NIH grants can be found at grants.nih/recovery/. The grants featured here highlight how these funds will expand research. Some of the funding will advance the work of existing NIA initiatives that benefit from large-scale collaborative, interdisciplinary research:


The Neuroimaging Initiative - Identifying brain changes before symptoms appear


The Alzheimer's Disease Neuroimaging Initiative (ADNI) will receive $24 million in stimulus funds - half from the NIA and half contributed by the NIH Office of the Director - to further groundbreaking research to establish neuroimaging and biomarker measures. These funds will enable researchers - and ultimately practicing physicians - to track changes in the living brain as older people transition from normal cognitive aging to amnestic mild cognitive impairment (MCI), in which individuals have a memory deficit but generally retain other cognitive abilities, and from MCI to Alzheimer's disease. ADNI, a research partnership supported primarily by the NIA with private sector support through the Foundation for NIH, seeks to find neuroimaging and other biological markers that can be used to detect Alzheimer's disease progression and measure the effectiveness of potential therapies.


The original ADNI involved the study of 800 people who ranged from normal to those with late-stage MCI or overt Alzheimer's disease. This new grant expands the scope of ongoing research under ADNI by allowing for the enrollment of participants at an earlier stage of MCI, when symptoms are milder. Furthermore, the funding for this new grant will allow ADNI investigators to extend the length of the original study to better assess changes in individuals over time. All of the participants will have neuroimaging scans and blood and cerebrospinal fluid analyses to look for changes in the brain.















The overall impact of the added funding will be increased knowledge of the sequence and timing of events leading to MCI and Alzheimer's disease and development of better clinical and imaging/fluid biomarker methods for early detection and for monitoring the progression of these conditions. This will facilitate clinical trials of treatments to slow disease progression and will ultimately contribute to the prevention of Alzheimer's disease. Just this year, ADNI made a significant step forward in developing a test to help diagnose the beginning stages of Alzheimer's disease sooner and more accurately by measuring levels of two biomarkers - tau and beta-amyloid proteins - in cerebrospinal fluid.


"Researchers and clinicians need imaging and biomarker tools to detect and understand the very earliest signs of pathology that cause changes in the brain some 10 to 20 years before any clinical symptoms of cognitive impairment or Alzheimer's may appear,"said ADNI Principal Investigator Michael Weiner, M.D., of the San Francisco Department of Veterans Affairs Medical Center and the University of California, San Francisco. "This grant will help us in our goal of establishing a panel of biomarkers that predict those at risk of developing the disease and also reveal which therapies may be effective in treating the disease or preventing its progression."


The grant was awarded to the Northern California Institute for Research and Education, a nonprofit research foundation affiliated with the San Francisco VA Medical Center. ADNI is the largest public-private partnership on brain research under way at the NIH. In addition to the NIA, the federal ADNI partners are the National Institute of Biomedical Imaging and Bioengineering, also part of NIH, and the U.S. Food and Drug Administration, another agency of the U.S. Department of Health and Human Services.


The AD Genetics Consortium and more " Identifying genes affecting risk for late-onset Alzheimer's


A grant of more than $5.4 million will add 3,800 Alzheimer's patients and an equal number of people free of the disease to a previously funded study by the Alzheimer' Disease Genetics Consortium (ADGC). Gerard Schellenberg, Ph.D., University of Pennsylvania School of Medicine, Philadelphia, leads the consortium, which aims to identify the additional risk factor genes for late-onset Alzheimer's disease. All of these study participants are currently enrolled in the NIA-funded national network of 29 Alzheimer's Disease Centers. When added to the samples from other sources, this will make available one of the largest collections of samples to perform genome-wide association studies (GWAS) in an effort to identify the susceptibility and protective genes influencing the onset and progression of late-onset disease. The large number of DNA samples brought together in this study may enable the researchers to detect genes whose individual effects in the disorder may be small but may still play a role.


The ADGC will use research infrastructures previously established by NIA to store and make available to qualified researchers DNA samples, datasets containing a wealth of information about participants, and genetic analysis data. The combined resources will allow scientists also to search for genes associated with a number of traits associated with Alzheimer's, as well as for genes related to cognitive decline.


"This funding will bring us closer to identifying the elusive genetic variations that contribute to overall risk and development of late-onset Alzheimer's disease," said Marcelle Morrison-Bogorad, Ph.D., director of the NIA Division of Neuroscience. "With this large sample size and the rapid DNA sample and data sharing, there are tremendous opportunities for defining new disease pathways that could lead to the development of new therapies."


Additionally, $4.7 million in Recovery Act funds will be used for another important study - a GWAS project examining cognitive decline in older African-Americans. Denis Evans, M.D., of Rush University Medical Center in Chicago, will collect and analyze the DNA of 4,140 elderly African-Americans enrolled in NIA-funded aging studies already taking place in Chicago and Indianapolis. Data from this analysis will also be shared with the ADGC to help identify risk factor genes for cognitive decline and late-onset Alzheimer's. The study will assess the associations of over 900,000 genetic markers with other co-morbidities, including stroke and high blood pressure.


Another $820,000 in Recovery Act funds will advance Alzheimer's genetics research by developing methods for identifying combinations of genes that might influence age-related risk of AD. The role of different forms of translocase of outer mitochondrial membrane (TOMM40), a gene that makes a protein thought to play a role in disease onset, will be studied by Allen Roses, M.D., of the Duke University School of Medicine in Durham, N.C.; Roses discovered the link between the apolipoprotein E (APOE)-epsilon 4 gene and increased risk for late-onset Alzheimer's disease. This new study will investigate whether particular variants of TOMM40 that tend to co-occur with the APOE3 gene also interact with that gene, and if this interaction plays a role in the age of disease onset.


Additional Recovery Act research opportunities


Other studies made possible by the Recovery Act range from clinical trials to epigenomic studies to translational research:


Drug, exercise clinical trials - A clinical trial exploring whether low doses of an anti-epileptic seizure drug, levetiracetam, can improve memory and affect brain function in people with MCI will be conducted with $1.2 million in support. Michela Gallagher, Ph.D., of Johns Hopkins University, Baltimore, will use functional MRI to visualize activity in the hippocampus - a brain area that becomes overactive in MCI patients - while the clinical trial participants receiving either the drug or a placebo engage in memory tasks. In another trial, researchers will examine how exercise training, cognitive training, or a combination of both, might impact immune and inflammatory biomarkers and cognitive health in older adults with MCI. The randomized trial, under a $1 million grant to David Lowenstein, Ph.D., of the University of Miami, will examine a broad array of outcomes and will include Hispanic and non-Hispanic volunteers.


Epigenetics/translational research - A $1 million grant will support a study exploring whether changes in histone acetylation (an epigenetic, or non-genetic factor that causes genes to behave differently) are one way in which a variety of life experiences may influence the risk of developing age-related cognitive decline and dementia. David Bennett, M.D., of Rush University Medical Center, Chicago, will use brain tissues from the NIA-funded Memory and Aging Project and the Religious Orders Study to examine this question. Another epigenomics grant of $819,000 will be used in translational research to test whether overexpressing histone deacetylase (HDAC1) with small molecule probes in the brain may demonstrate therapeutic potential for Alzheimer's and stroke patients. Li-Huei Tsai, Ph.D., of Massachusetts Institute of Technology, Boston, will lead the study, which seeks to find out whether abnormal regulation of the protein may play a role in neurological disorders.


The NIA leads the federal effort supporting and conducting research on aging and the medical, social and behavioral issues of older people. For more information on research and aging, go to nia.nih.The NIA provides information on age-related cognitive change and neurodegenerative disease specifically at its Alzheimer's Disease Education and Referral (ADEAR) Center site at nia.nih/Alzheimers. To sign up for e-mail alerts about new findings or publications, please visit either website.


Source

National Institutes of Health (NIH)