Alzheimer Related News Items

News as of 12/04/05

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Top Items

Abbott Finds New Amyloid in AD - Among the hallmarks of AD, which include neurofibrillary tangles and amyloid plaques, Abbott Laboratories Inc., Abbott Park, Ill., researchers now say they found a new species of amyloid beta-peptide that selectively binds to nerve cells in the brain and is an important causal factor for the disease. “For years researchers have focused on finding ways to stop the formation of the plaque, believing that the plaques themselves were toxic,” says James Sullivan, PhD, vice president, neuroscience discovery, Abbott. “Over the last five years, however, more and more research suggests that we did not have the whole story.” Preclinical research, Sullivan says, now shows that cognitive function, such as memory retention, started being impaired long before amyloid plaques formed. Clinical research also shows that amyloid plaques are present in the brains of aged people without AD. Thus, the focus has turned to finding other forms of amyloid protein that may represent a toxic or pathologic species. One such form, Sullivan says, is a soluble amyloid, in contrast to the insoluble form found in plaques. Abbott identified a new soluble globular beta-amyloid species, which they call globulomer, present in the brains of AD patients. “These globulomers are structurally distinct from the [fibrous] form of amyloid that dominates in plaque,” says Sullivan. Using highly selective antibodies for the globulomers, he says, they were able to prove the presence of this new form of amyloid in the brains of AD patients, which were not present in age-matched controls. An immunofluorescent imaging technique was used to find the specific sites in the brain where the globulomers bind and found them binding to neurons in the hippocampus, a key region of the brain involved in learning and memory and one of the first areas affected by AD. Research in mice, Sullivan says, suggests that globulomers inhibit the ability to form and retain memory. They are now conducting research to find the proteins on these neurons, with which the globulomers are interacting. “The identification of this unique amyloid species provides the opportunity to generate selective antibodies directed against globulomers,” says Sullivan. “Such antibodies have the potential to address the underlying disease pathology, not just the symptoms, and to be safe because of their selective interaction with this toxic species of amyloid.” By Elizabeth Tolchin Drug Discovery & Development 11/16/05

Insulin Study Backs Theory AD May Be Type of Diabetes - AD researchers at Rhode Island Hospital and Brown Medical School said they found more evidence that the condition may be a new type of diabetes called Type 3 Diabetes, or insulin deficiency, specific to the brain. The researchers discovered a “significant” drop in levels of insulin and insulin receptors in the brains of patients who had early stage AD and died, according to a study released 11/39/05. The scientists reported earlier this year that they’d found lower levels in patients with advanced AD. Without insulin, the brain is unable to make acetylcholine, a chemical that carries signals among neurons and helps in the thinking process, according to researcher Suzanne de la Monte, a neuropathologist at Rhode Island Hospital. “If you don’t have the insulin, or the brain cells don’t respond to it,” the cells will die, de la Monte said in a Nov. 28 telephone interview. “The race is to keep them supported at the time they’re deteriorating.” The research suggests that one way to slow the onset of AD might be a treatment that improves the brain cells’ use of insulin, de la Monte said. Before the findings can be applied, scientists must first determine a way to identify insulin deficiency or insulin resistance in the brains of living patients, she said. For this study the researchers drew on a brain bank for a postmortem study of the brains of about 50 AD patients. Conventional diabetes is diagnosed by measuring blood glucose levels, blood insulin levels and how the body manages high levels of sugar, said de la Monte, who is also a pathology professor at Brown Medical School in Providence, Rhode Island. Different organs can react in varying ways to insulin. Most patients with AD don’t have diabetes, and there is no evidence that diabetes patients have a higher risk for AD, de la Monte said. Bloomberg 11/30/05 Journal of Alzheimer’s Disease Vol. 9, No. 1 (in progress)

Drugs

New Drug Target for AD Identified - Scientists at the Gladstone Institute of Neurological Disease have identified a potential new way to stop brain cell death related to AD. Working with cell cultures, the scientists investigated how amyloid beta proteins -- which build up in the brain tissue of people with AD -- kill neurons. The cell cultures were established from brain tissue of laboratory rats. Study findings showed amyloid beta could be prevented from causing neuronal cell death with a compound called resveratrol, which is also found as a natural ingredient in red wine. “Our study suggests that resveratrol and related compounds may protect against neuronal loss associated with AD” said senior author Li Gan, a staff research investigator at San Francisco institute and an assistant professor of neurology at UCSF. “This could certainly open up new avenues for drug development.” UPI 12/1/05 Journal of Biological Chemistry 280(48), 40364-40374 12/2/05

Study - Statins May Delay Effects of AD - Cholesterol-lowering drugs may help to delay the progression of AD, the leading cause of dementia in the elderly, French scientists said on 11/17/05. In a three-year study involving 342 AD patients, they found that the illness did not develop as quickly in sufferers with high cholesterol levels who were given statins as in patients not taking the drugs. Professor Florence Pasquier, of the University Hospital in Lille, France, said the drugs “may slow cognitive decline in AD and have a neuroprotective effect.” Nearly 130 patients in the study had high cholesterol levels. About half were given statins while the remainder did not receive any treatment. The findings support the results of other human and animal studies which have suggested that high cholesterol levels may play a role in the progression of AD. Most of the patients in the study were women. Their average age was 73. The progression of the disease was rated at 1.5 points a year for the women taking the drugs, compared to 2.4 for those who were not treated with statins and 2.6 for patients with normal cholesterol levels. Millions of people around the world are prescribed these statin drugs that lower cholesterol by inhibiting an enzyme that controls how much is produced in the body. In an editorial in the journal, Dr Frank-Erik de Leeuw, of University Medical Centre in Nijmegen in the Netherlands, said more work needs to be done before any conclusions about the usefulness of statins for AD can be drawn. “There is conflicting evidence for a causal relation between cholesterol, its treatment, and the incidence of AD,” he added. Reuters 11/17/05 Journal of Neurology Neurosurgery and Psychiatry 2005; 76: 1624-1629

Korea to Support Development of Drug for AD - The Korean Ministry of Health and Welfare said 11/23/05 it will support a private biotech companies’ development of a new AD drug. The drug is AAD-2004, short for anti-Alzheimer’s drug-2004, which is known to help slow the progress of the disease. The ministry will support the biotech company Neurotech Pharmaceutical Inc. in proving the new drug’s efficacy and testing first in animals and then in human volunteers. The parties are now set to conduct clinical trials and to commercialize it by 2013. The Korean Herald 11/24/05

Caregivers

Australian Researchers Find Proof That Stress Makes You Sick - Australian researchers said they had scientifically proven a long-suspected link between emotional stress and illnesses ranging from the common cold to cancer. The group from Sydney’s Garvan Institute found that a hormone released into the body during times of stress, neuropeptide Y (NPY), undermined the body’s immune system and literally made you sick. “Until now there has mostly been circumstantial evidence of a link between the brain and the immune system, but now we have that connection,” said the institute’s Fabienne Mackay. “During periods of stress, nerves release a lot of NPY and it gets into the bloodstream, where it inhibits the cells in the immune system that look out for and destroy pathogens in the body,” she said. “That stress makes you sick is no longer a myth, it is a reality and we need to take it seriously.” The group hopes their work would lead to new kinds of therapeutic intervention. Herbert Herzog, another of the scientists, said neuropeptide Y had been known to affect blood pressure and heart rates, but discovering its impact on the immune system opened up new doors for tackling some illnesses. Breitbart.com 12/05/05 Journal of Experimental Medicine

Spouse Caregivers of AD Patients Show Higher Risk of Gingivitis - Caregiver spouses of patients with AD develop gum disease at twice the rate of their non-caregiver counterparts. 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 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.” By Bruce Sylvester, Contributing Writer Health Behavior News Service 11/22/05 Psychosomatic Medicine 67(6): 930-938 (2005)

Riskier AD Treatments Urged - Families battling AD and similar dementias increasingly are calling for a shot at riskier therapies that might bring bigger benefits than today’s pretty safe but largely disappointing drugs. The first formal study of family risk tolerance was published in Neurology November 2005. University of Michigan researchers wondered: Is it OK for a dementia patient to undergo a spinal tap when he doesn’t understand why? What if the research won’t help him but might lead to future AD treatments? Using 10 research scenarios, they surveyed 229 elderly people at increased risk of developing AD because a close relative had it. Most accepted even the greatest potential for side effects, such as gene therapy or a painful spinal tap, for themselves, and were only slightly less risk-tolerant when deciding for a loved one. Yet until now, “the patient community’s been conspicuous by its absence,” Dr. Russell Katz, the Food and Drug Administration’s neurologic drugs chief, said at the meeting. It’s easy to say you’ll accept more risk in hope of more gain. How to quantify that is the vexing problem of regulators like Katz. Does risk mean pain? Premature death? And what benefit justifies those risks: improved functioning or merely hope? An experiment is just that; nobody knows the full risks until participants have been treated, something difficult for desperate families to grasp, cautioned Dr. Steven DeKosky, the University of Pittsburgh’s neurology chief. Still, Katz said the FDA ultimately allows most AD proposals. Among the most invasive: Scientists at Rush University in Chicago recently injected six patients’ brains with a virus carrying a nerve growth factor that might reverse deterioration. A slightly different gene-therapy approach, in California, produced promising preliminary results although two patients experienced dangerous bleeding in their brains. The Chicago researchers are tracking patient reactions, and a follow-up study could begin in a year. By Lauran Neergaard AP 11/22/05 Neurology November 2005; 65: 1395-1401

Testing

Clues to the Progression of AD Revealed in Brain Imaging Studies - A novel imaging agent heralded for its potential to diagnose AD during life is now giving researchers information never before available about how and where the disease progresses in the brain. Results of this new research involving Pittsburgh Compound-B (PIB) - - which binds to the telltale beta- amyloid deposits in the brain of AD patients - - were presented by University of Pittsburgh (U of P) researchers 11/15/05 at Neuroscience 2005, the 35th Annual Meeting of the Society for Neuroscience. PIB, when coupled with positron emission tomography (PET), gives researchers a picture of beta-amyloid, or amyloid plaque, deposits in the brain. The distinguishing factor between AD and other dementias is the presence of amyloid plaques that are thought to cause the death of brain cells. Studies have demonstrated that PIB can detect the accumulation of amyloid plaques when patients are alive. This could lead to accurate diagnosis of AD at very early stages. According to one U of P study reported at the Society for Neuroscience meeting, the pattern of PIB retention in the brain suggests that amyloid plaques deposit sequentially. Amyloid plaques first appear in the brain’s cingulate cortex/ precuneus and frontal cortex areas, then progresses to the parietal and temporal cortex and caudate. Finally, the disease ravages the occipital cortex and sensory-motor cortex. These findings may explain why memory and judgement are often the brain functions first affected in AD. “We’ve had hints about the time course of brain changes in AD from autopsy studies but the current findings in living patients take these observations further,” said William E. Klunk, M.D., Ph.D., associate professor of psychiatry at the U of P School of Medicine and co-inventor of PIB, who presented the findings. “If we can delineate the natural history of brain changes in AD, we then have a baseline against which to judge the success of therapies designed to prevent these changes.” The researchers hope that PIB will be used in clinical trials of AD therapies within the next year or two. PR 11/15/05

AD Onset Tied to Lapses in Attention, Study Suggests - People in early stages of AD have greater difficulty shifting attention back and forth between competing sources of information, a finding that offers new support for theories that contend breakdowns in attention play an important role in the onset of the disease. “Our results provide evidence that breakdowns in attention produce a clear change in the early stages of AD-related dementia,” said study co-author David A. Balota, a professor of psychology in Arts & Sciences at Washington University in St. Louis. The study suggests that subtle breakdowns in attention may offer a reliable clue that a patient is grappling with early symptoms of AD-related dementia. The findings are important because they offer clinicians and researchers another tool by which to better predict and understand dementia of the AD type early in its history. Psychologists focus on early detection in part because current medications are useful only when given very early in the course of the disease. Although memory problems also show up in early stages of the disease, this study suggests that underlying declines in attention may be contributing to these memory mishaps and to other cognitive difficulties often associated with the disease. “Because attention is prerequisite for memory, one might suspect that attention is one of the contributing culprits, at least early on in the disease,” suggests study lead author Janet M. Duchek, an associate professor of psychology. Developed in the 1950s, the dichotic listening test plays off the fact that humans are hardwired to process sensory information in a cross-lateral fashion - words heard in the left ear tend to be processed in the right hemisphere of the brain, and vice-versa. Since the left hemisphere of the brain is typically dominant for language processing, words presented in the right ear often have an advantage over words presented simultaneously in the left ear — the right ear-left hemisphere processing channel is said to be “pre-potent” in that it has a default processing advantage over the left ear-right hemisphere channel. Using the dichotic listening task, Duchek and Balota presented participants with distinct streams of audio information via headphones. One stream of information - - computer-generated speech naming three digits (such as 4, 3, 1) - - went to the left ear; a different stream (such as 9, 2, 5) went to the right ear. By asking participants to recall numbers in the order they were presented to either ear, the researchers were able to measure an individual’s ability to switch back and forth between right-left processing channels, and more importantly, to monitor how well attention skills allowed them to overcome the “pre-potent” tendency to favor information presented to the default right ear-left hemisphere language channel. As predicted, people with early dementia tended to rely more often on the default channel, reporting digits presented to the right ear far better than they reported digits presented to the left ear. The right-ear advantage increased with dementia severity. People farther along in the disease relied even more on the dominant left-side channel. Poor attentional control can leave people falling back on familiar, pre-programmed information pathways. The study confirms that very early in the disease, people have problems with selective attention. This problem, although not as obvious as memory loss, may also explain why early-stage patients start to struggle with everyday tasks that call for processing a lot of information, such as driving. Findings from this study, the research team suggests, converge with accumulating evidence that individuals with early stage AD have breakdowns controlling prepotent pathways across a variety of experimental paradigms, which place minimal demands on memory systems. “Our hope,” Duchek said, “is that this work increases recognition that AD is not simply a disease of memory.” PR 112/05 Neuropsychology 19(5) Sept 2005, 685-695 Full text of the article is available from the APA Public Affairs office: http://www.apa.org/journals/releases/neu195687.pdf

AD Drug Advances By Measuring Early-Stage β-Amyloid Aggregation using Dual Polarisation Interferometry - A key feature of AD is the accumulation of fibrillar deposits on the surface of neuronal cells in the brain. The formation of these plaques is implicated in the pathogenesis of AD. The plaques are thought to result from aggregation processes involving β-amyloid peptides. The molecular events occurring during the formation of β-amyloid fibrils, and how these might be linked to the degeneration of nerve cells, are areas of intensive investigation in the search for AD therapies. Many researchers now consider the early oligomeric forms of β-amyloid to be the most neurotoxic; hence their detection is of critical importance. However, the lack of sensitivity provided by many analytical techniques has made the study of these early-stage events particularly challenging to date. Farfield Sensors reports the use of Dual Polarisation Interferometry (DPI) to produce pioneering real time, quantitative data on the structural processes behind in vitro early-stage β-amyloid aggregation. This study demonstrates DPI as an enabling technique to study interfacial aggregation processes from the previously difficult to measure early stages. Simple fibrillar aggregates of β-amyloid can be formed on a sensor chip surface, and details of the mechanistic and structural events through which growth occurs can be obtained in real time using simple experimental protocols. DPI also displays unsurpassed instrument stability to allow these processes to be measured over a time period of several days. Importantly, the ability to measure early-stage β-amyloid aggregation on a technique such as DPI opens the potential for more detailed work. The mechanistic and structural aspects of inhibitor action and the effects of different surface conditions on aggregation can now be studied and will provide useful information in the search for drugs to combat AD. Aznano.com 11/22/05

Prevention

Chemical in Green Tea May Fight AD - An ingredient in green tea that researchers think might fight cancer may also protect the brain from the memory-destroying AD, a study released 9/20/05 said. Scientists injected mice genetically programmed to develop an AD-like disease with an antioxidant from green tea called epigallocatechin-3-gallate (EGCG) and said it decreased production of beta-amyloid, a protein that forms the plaques that clog the brains of AD victims. Several months of injections reduced plaque formation by as much as 54 percent, according to researchers from the University of South Florida. Drinking ordinary green tea may not lead to the same plaque reduction seen in the study because other ingredients in the beverage appear to block EGCG’s benefits, said Dr. Jun Tan, the study’s senior author and director of the neuroimmunology laboratory at the University of South Florida’s psychiatry department. Supplement pills containing EGCG might help, he said. Scientists are also trying to develop a tea with a high concentration of EGCG that could offer health benefits. Humans would probably need 1,500 to 1,600 milligrams per day of EGCG to get the amount that helped mice in the AD study, Tan said. Researchers have tested the safety of those doses in people and found no major side effects, he said. The next step for researchers is to test an oral form of EGCG in mice and see if it protects the animals’ memory, he said. “If those studies show clear cognitive benefits, we believe (human) trials of EGCG to treat AD would be warranted,” Tan said. Reuters 9/20/05 Journal of Neuroscience, Sept 21, 2005, 25(38):8807-8814

Beat AD with Exercise - Exercise helps to flush a toxic molecule from the brain and causes a beneficial one to move in and protect nerve cells, research on mice shows. The discovery might help to explain why staying fit and keeping mentally active seem to fend off AD in humans. “Our experiments support the idea that exercise is a good approach to all types of problems in the brain and that a sedentary lifestyle is a risk factor,” says Ignacio Torres-Aleman, who led the study at the Cajal Institute in Madrid. Torres-Aleman and his colleagues were intrigued by previous studies showing that exercise slows mental decline in mice engineered to mimic AD. They set out to discover the reason. They found that exercise doubled the levels of a protein that helps to flush molecules thought to underlie AD out of the mice’s brains and into their blood. The protein, called megalin, ejects a potentially destructive protein called amyloid-beta. In AD patients, amyloid-beta accumulates in clumps throughout the brain. Megalin also binds to a beneficial molecule in the blood, called insulin-like growth factor, and transports it to the brain. This growth factor is perhaps best known for bulking up muscles after exercise, but it also helps to keep nerve cells healthy. To reveal the tricks of megalin, the researchers manipulated levels of the protein in the brain of mice with AD-like disease. Artificially boosting megalin partly improved mental performance, as measured in a maze test. Levels of megalin decline with age in normal mice. The researchers suggest that this hints at a molecular link between ageing and neurodegenerative disease. By Charlotte Schubert Nature.com 12/2/05 Journal of Neuroscience 24,0884-10893 (2005)

New Hope in the Fight Against AD: Clinical Study Finds Ginkgo Extract EGb 761(R) Improves Quality of Life of Typical Patients - A major new study provides good news in the fight against, as Ginkgo biloba extract Egb 761™ (manufactured by the Dr. Willmar Schwabe Company) has been shown to improve cognitive functions, neuropsychiatric symptoms and the ability to perform daily living activities among typical patients. Results of the double- blind, placebo-controlled trial were presented at the 21^st International Conference of AD International (ADI) in Istanbul, Turkey, September 2005. “This study shows EGb 761 is effective in typical AD cases,” says Professor A. Napreyenko, principal investigator of the study. “In patients exhibiting the full range of cognitive and non-cognitive features of dementia, EGb 761(R) improves cognitive functioning as well as neuropsychiatric symptoms and activities of daily living.” EGb 761 is a patented (U.S. Patent No. 5,399,348) Ginkgo biloba extract with a unique profile of constituents developed and manufactured by the Dr. Willmar Schwabe Company, Karlsruhe, Germany. It is sold in the U.S. under the Ginkgold(R) brand name. PRNewswire 11/17/05

Can An Apple A Day Keep AD Away? - One of the largest studies of its kind in the nation is finding a link between fruit and vegetable consumption and memory loss in the elderly. Investigators from the Cache County Study on Memory, Health and Aging based at Utah State University are researching this, as well as asking questions such as will cholesterol-reducing drugs protect people from cognitive decline and are they at a higher risk of developing AD if they have diabetes? “We found that the group with the highest intake of fruits and vegetables scored better on the memory test than the group with the lowest intake,” said Heidi Wengreen, a lead investigator on a study of the relation between fruit and vegetable consumption and cognitive function in the elderly. “It appears that higher intake of fruits and vegetables may protect against memory loss in older adults.” Other Cache County Study findings revealed that (1) men with diabetes may be at increased risk of developing AD but not women diabetics, (2) the combined use of non-steroidal anti-inflammatory drugs and antioxidant supplements can prevent cognitive decline, and (3) the use of statin drugs does not influence cognitive performance. This information was presented at the Alzheimer’s Association International Conference on Prevention of Dementia in Washington, D.C. Newswise 11/29/05

Praying, Writing, Gardening Reduce Risk of AD - Gardening, reading, writing and praying are among the brain-exercising activities that can stave off the development of AD, while TV watching increases the risk, according to new research reported by scientists at the Technion- Israel Institute of Technology with colleagues at Case Western Reserve University in Cleveland. The findings were presented recently at an international neurology conference in Istanbul. “The connection between leisure activities and damage to cognitive ability has been examined in a number of studies,” neurologist Dr. Rivka Inzelberg of the Technion’s Rappaport Faculty of Medicine and Hillel Yaffe Hospital in Hadera said. “It is known that active intellectual activity can delay development of AD. We looked at more passive activities such as watching TV and leisure time interests that were pursued between the age of 20 and 60.” The researchers, who conducted door-to-door interviews with 600 Israeli Arabs in the Wadi Ara area, found that incurable dementia was delayed or prevented in people who spent a lot of time in intellectual pursuits such as reading, writing and even prayer. However, TV watching, which is “not intellectually demanding,” had the opposite effect and could even encourage the development of AD. Although genetic influences are important in the development of this type of dementia, smoking, being exposed to others’ tobacco smoke, a high consumption of fats and inadequate physical exercise also contribute to the development of the disease. Prof. Robert Friedland of Case Western and Prof. Lindsay Farrer of Boston University collaborated in the gene mapping. They mapped the chromosomes that increase the tendency for dementia and conducted genome analyses of individuals in specific family groupings who had a high prevalence of AD. Their findings strengthened the evidence of a genetic factor in AD, said Inzelberg, who added that inbreeding (consanguinity or marriage of close relatives) intensified the risk. She said she believed the findings were relevant in any population, and that with a US National Institutes of Health grant, her team plans on expanding their study. By Judy Siegel-itzkovich, The Jerusalem Post 11/13/05

Other Items

Vasogen’s VP025 Shown to Impact Inflammation-Signaling Pathways - Dr. Marina Lynch’s team from the Trinity College Institute of Neuroscience, Dublin, Ireland, presented results on 11/16/05 at the Society for Neuroscience’s 35th Annual Meeting in Washington, DC from a model showing the ability of VP025 to reverse age-related inflammation in the brain. The process of ageing is associated with increased inflammation in the brain resulting from activation of microglial cells, (inflammatory immune cells of the brain), as evidenced by increases in inflammatory cytokines, including IL-1beta, and a reduction in memory and learning function (measured as long-term potentiation). CD200, a protein that controls inflammation and maintains microglial cells in an unactivated state, decreases with ageing. Treatment with VP025 in this model reversed age-related decreases in CD200 levels in the brain, reduced levels of microglial cell activation, and restored memory and learning function. Many neurological conditions are associated with an inflammatory response in the nervous system, including AD, Parkinson’s disease, and ALS (also known as Lou Gehrig’s disease). These conditions are characterized by increased levels of inflammatory mediators, including cytokines, leading to the death of nerve cells and the eventual loss of functional activity. Dr. Anthony Bolton, Vasogen’s Chief Scientific Officer, said “The growing body of evidence demonstrating the ability of VP025 to reduce inflammation within the central nervous system, suggests therapeutic potential in a range of neurological disorders and continues to support our plans to initiate phase II development.” PRNewswire 11/16/05

Coffee Boosts Short Term Memory - A cup of coffee is good for the memory, at least the short term memory, according to research reported 11/30/05. In a study of 15 healthy men ages 26 to 47, functional magnetic resonance imaging (fMRI) detected significant activity in the brain’s memory centers 20 minutes after the men consumed 100 mg of caffeine, according an Austrian study reported at the Radiological Society of North America meeting in Chicago. The activity was significantly greater than men who were imaged after consuming a matched placebo (P<0.05), said Florian Koppelstatter, M.D., of the University Hospital Innsbruck. He said the fMRI scan detected activity in the anterior cingulate cortex of the brain, which is responsible for some short-term memory functions. Dr. Koppelstatter said that fMRI routinely detected activity as participants completed memory tasks during the scan, but caffeine significantly boosted brain function beyond that expected level. In addition to greater activity in the anterior cingulate cortex, men taking caffeine had increased activity in frontal cortex, and the inferior parital cortex. Moreover, since the men were all right handed, the increased activity was greater in the left hemisphere. Twenty-minutes after consuming the drinks -- a time that Dr.Koppelstatter said was calculated as the caffeine’s peak potency time in the brain -- the men underwent fMRI scans. He noted that caffeine’s effect diminishes after 45 minutes. Dr.Koppelstatter said the scans clearly demonstrated that caffeine has a definite impact on short-term memory processes. “This effect takes part in the distinct part of the working memory network that controls attention and concentration.” Michael Brant-Zawadzki, M.D., chairman of the RSNA communications committee and moderator at press conference where Dr. Koppelstatter discussed his research, said the findings will probably not surprise anyone because “we all know that coffee makes us more alert, but now we know how that works.” He said that finding also suggests a possible research target for the development of drugs to improve memory function. “It may be possible to develop drugs like caffeine that can stimulate these same brain regions,” he said. By Peggy Peck MedPage Today Staff Writer 11/30/05

Anti-Amyloid Treatment Section

3-D Structure of AD Filament Shows How It Zips Up Peptides - Researchers have solved the three dimensional structure of the long thread-like fibers that fill the brains of AD patients. The structure reveals the proteins that make up the fibrils lock onto each other much like a zipper on a jacket. This advance helps illuminate the molecular roots of AD and possibly other degenerative diseases of the brain. “Now that we understand at an atomic level how these fibrils form, it might help researchers develop a biomarker test to diagnose AD at an early stage, as well as drugs to treat it,” says the study’s lead investigator, Salk Institute for Biological Studies scientist Roland Riek, Ph.D., who collaborated with researchers at the University of Lausanne and Roche pharmaceuticals, both in Switzerland. As a result of the study, Riek and his colleagues may now understand how a potential AD medication now in clinical trials in Europe reacts to the fibril. The drug binds to the end of the fibril chain of beta amyloid proteins, halting their lethal accumulation, an early step in the formation of the amyloid plaque deposits that are a hallmark of AD. The research team discovered that beta amyloid proteins (peptides) that make up these fibrils attach to each other on one end with an ever-growing property. “From this structure we can nicely see what happens physically, where the fibril forms a template on which to bind other amyloid peptides in an inter-collated way,” Riek says. “The way these peptides lock on to each other is like a zipper on a jacket.” Due to the ever-growing property the zipper binds more and more loose peptides together to produce dense “plaque” filaments that may be toxic to the functioning of brain nerve cells. In AD, amyloid plaque form when enzymes cleave the amyloid precursor protein (APP), thereby releasing the toxic beta amyloid fragments. Healthy brains can clear away excess beta amyloid peptides, but for reasons that are not understood, these proteins, made up of between 39-42 amino acids, change shape in some people, leading to a sticky aggregation. Riek already demonstrated how the flexible peptide can be altered, and in this study, he showed how a clump of them can attract and bind other molecules. “There are at least four stages needed to get to the point where a structure is created that can form filaments, and what we show here is that end stage. Scientists are debating whether these long filaments produce the nerve damage that results in dementia, or whether the shorter, more mobile threads, which are also composed of beta amyloid. Riek and his team are now working on solving the 3D structure of these smaller aggregates, in their quest to sculpture the molecular roots of AD. Newswire 11/14/05 Proceedings of the National Academy of Sciences Nov. 29, 2005, 102(48):17342-17347

Korean Scientists Give Hope to AD Patients - A team of Korean scientists may have found a way to control AD. The team, led by In-hee Mook of Seoul National University Medical School, said 11/28/05 it found the protein that inhibits the harmful protein beta-amyloid, a cause of senile dementia. The controlling protein is called ERK1/2. It is known that the enzymes beta- secretase and gamma-secretase are involved in the creation of beta-amyloid. Beta-secretase’s role in causing AD has been well known, and pharmaceutical giants worldwide have been trying to develop drugs to control the enzyme, to little avail. Prof. Mook and her team discovered that ERK1/2 controls the function of gamma-secretase, and as a result, prevents creation of beta-amyloid. The discovery could open up a new way to treat senile dementia, the team said. In animal experiments, artificial control of the function of ERK1/2 sharply increased the amount of beta-amyloid produced. A treatment for AD would conversely have to boost the function of ERK1/2. Chosun.com 11/28/05 Journal of the Federation of American Societies for Experimental Biology published online doi:10.1096/fj.05-4055fje

Early Anti-amyloid Treatments in AD Are Most Effective - One approach to the treatment of AD is to limit the production of amyloid-β (Aβ) from its precursor by inhibiting one or both of the enzymes that cleave the amyloid precursor protein (APP) to produce the Aβ. However, it is not yet clear whether this approach will prevent the brain lesions and cognitive symptoms from getting worse, and if it will then promote the removal of preexisting plaques and reverse cognitive decline. Joanna Jankowsky at the Johns Hopkins School of Medicine and colleagues have developed mice that produce Aβ at levels sufficient to induce severe amyloid burden by six months of age. The animals carry an additional transgene that acts as a switch to control when Aβ is produced. Commonly known as the tet-off system, the switch is turned off when the mice are fed tetracycline or its analog, doxycycline. Once given the drug, Aβ production in the brains of these mice diminishes by more than 95% of pretreatment levels within two weeks. This system, thus, mimics the effect of shutting down Aβ production with enzyme inhibitors that are being developed for use in human patients. In the study, the researchers used doxycycline to switch off production of Aβ, and examined what happened to the amyloid pathology. Not surprisingly, the increase in number and size of amyloid lesions that normally occurs as the mice get older was completely prevented by suppressing Aβ production. However, the researchers also found no substantial clearance of preexisitng plaques, even after six months of treatment (one-quarter of the normal mouse lifespan). What do these findings mean for human AD research? First, the study provides evidence that the lesions found in AD may be more difficult for the brain to repair than protein aggregates found in other diseases such as Huntington or prion disease. Second, the findings suggest that the removal of plaques, once formed, may require more than simply halting the production of the Aβ peptide. However, as with all animal models, there are differences in comparison to the human disease, leading to both over- and underestimation of the relative importance of an effect in humans. The researchers do not yet know whether the plaques formed in mice may be more resistant to clearance than those seen in human disease. Conversely, the human brain, unlike the murine one, may have a more efficient way of clearing amyloid plaques. What this study makes clear is that treatments directed at reducing Aβ peptide production in AD will likely be most effective when started as early as possible. By PLoS Medicine 11/15/05 vol. 2, No. 2, e418 DOI:10.1371/journal.pmed.0020355

UIC Chemists Characterize AD Plaque Precursor - Using a nuclear magnetic resonance technique, University of Illinois at Chicago (UIC) chemists have obtained the first molecular-level images of precursors of bundled fibrils that form the brain plaques seen in AD. Untangling the molecular structure of these pre-fibril forms, which may be the key neurotoxins in AD, may help identify targets for new drugs to combat many neurodegenerative diseases. Microscopic bundled fibrils made of proteins called amyloid-beta are presumed to be the toxic culprits in the senile plaques found in the brain with AD. But there is increasing evidence that even smaller assemblies of amyloid-beta found prior to formation of pre-fibrils are the real nerve-killers. Scientists have been frustrated that electron microscope images of these nanometer-scale spherical assemblies have failed to reveal any distinct molecular structure. Yoshitaka Ishii, assistant professor of chemistry at UIC, and graduate student Sandra Chimon have now determined this structure using a methodology developed with high-resolution solid-state nuclear magnetic resonance, or SSNMR. “This is the first case showing that these intermediate species, the smaller assemblies, have a well-defined structure,” said Ishii, who conducted a two-year search to map the structure of the pre-fibril assemblies, then spent another year confirming his findings. “We’re interested in how the molecules assemble in this shape, and eventually into fibrils,” Ishii said. “We wanted to find out what kind of structure each amino acid takes in a certain site of a protein at the atomic level. It gives us an idea of how these molecules interact with each other to make this structure. You want to design molecules that will interact and prevent this,” said Ishii. “That’s been difficult. Now we have a new clue to learn how.” PR 11/2/05 Journal of the American Chemical Society, 127(39) 13472-13473 2005

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