Alzheimer Related News Items

News as of 11/01/99
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Top Items
An Alzheimer's Advance - Discovery of an Elusive Enzyme Raises New Hopes - The plaques in Alzheimer's brains consist mostly of an abnormal peptide, or protein fragment, called beta amyloid This peptide is part of a longer protein called APP (amyloid precursor protein), which abounds in normal brain cells (chart).                                                                                                                                   Rearchers deduced more than a decade ago that a pair of protease enzymes--think of them as molecular scissors--were clipping the APP molecule at two locations, which were dubbed the "beta" and "gamma" sites. Those enzymes proved elusive, but one of them has now been identified by scientists at the California biotech company Amgen and Harvard Medical School. They unmasked a plaque-causing enzyme called BACE (or beta-site APP-cleaving enzyme). The discovery won't yield new treatments right away, but for the first time, it gives drugmakers a clear target to shoot at. The Amgen team positively identified BACE, the enzyme that cleaves APP at the beta site. Its counterpart, GACE, has yet to be identified, but both enzymes seem critical to the formation of plaques. When the researchers deprived cultured cells of BACE, the cells produced less beta amyloid. The research began two years ago when the researchers began looking for the enzyme - by trying to find the gene that produces it. They began with thousands of candidate genes and slowly narrowed the field, testing genes in batches to discover which one produced enzymes that clipped the precursor protein. Eventually they found a gene that contained the blueprint for an enzyme that snipped the precursor at precisely the right spot. Next, they used the gene to produce the enzyme and demonstrated that it met their expectations, cutting the precursor protein correctly. The implications are obvious. If a clinical treatment could block the action of BACE, it might well stall the production of plaques --and the progression of AD. No one has yet developed such a treatment, but drugmakers are already racing to find one, and the odds seem good. Drugs that inhibit protease enzymes have revolutionized AIDS care in recent years. The new finding suggests that they could help vanquish dementia as well. By Geoffrey Cowley Newsweek 11/1/99 and Steve Sternberg USA Today 10/25/99 Vassar et al Science 22 Oct. 1999;286:735-41

Enzyme Implicated in AD Is Identified by SmithKline Beecham Scientists; Finding Provides New Target for Drug Discovery - Scientists at SmithKline Beecham have identified an enzyme that may contribute to the development of AD. AD is associated with a protein fragment called beta amyloid peptide, which, when produced in multiple copies that tangle together, forms structures in the brain known as amyloid plaques. Since the fragment is excised from a longer protein, amyloid precursor protein, the existence of enzymes that perform this excision has long been assumed. Two distinct enzymes scissor the precursor protein at specific points along its length, each enzyme being essential to producing the plaque-forming peptide. Nevertheless, the actual chemical identities of these enzymes have remained unknown, notwithstanding that preliminary names have been assigned to them, gamma-secretase and beta-secretase. The SB scientists have identified an enzyme possessing the essential activities expected of beta-secretase. The researchers call the enzyme Asp 2; it is a member of a class of enzymes known as aspartic proteases. "The significance of this discovery is that it offers a new target for drug discovery,'' said SB's Dr. Frank Walsh. The goal is to determine whether a compound that inhibits the enzyme will contribute to therapy for AD. PR 10/28/99 online issue of Molecular and Cellular Neuroscience. Complete article is available at
http://darwin.apnet.com/www/journal/cn/mcne.1999.0811/ At the end is: Note added in proof. While our work was under review, Vassar and colleagues (Science 286: 735-741) published a report of beta-secretase activity associated with a transmembrane aspartyl proteinase that they designate BACE. Our data indicate that Asp 2 and BACE are the same enzyme.

Turning Current Theory About AD Inside Out - In a finding that could reconcile two distinct and sometimes warring camps in the AD field, researchers have discovered a link between amyloid plaques and neurofibrillary tangles. Scientists at the R.W. Johnson Pharmaceutical Research Institute presented on 10/24/99 at the annual conference of the Society for Neuro- science several surprising clues that could lead to the development of new drugs to treat the disease. The results show that the amyloid-beta protein, the primary component of amyloid plaques, binds to a receptor on neurons, and that binding leads indirectly to the phosphorylation of the tau protein, which triggers the formation of neurofibrillary tangles. AD researchers have yet to agree on the cellular events that cause brain-cell death and lead to dementia. One group maintains that amyloid plaques, composed primarily of the amyloid-beta protein, accumulate outside of brain neurons, growing larger and larger until they rupture the cells and kill them. Another group says that neurofibrillary tangles kill the cell. In a first presentation by Dr. Wang he showed that the amyloid-beta protein binds specifically to a neuronal surface receptor called the alpha-7 nicotinic acetylcholine receptor (a7nAchR). To prove that the binding is specific, Wang demonstrated that a molecule that blocks a7nAchR, alpha-bungarotoxin prevents the amyloid peptide from associating with the receptor. In a second talk Dr. Lee provided evidence that the interaction of amyloid with a7nAchR leads to tau phosphorylation. "This is the first connection of amyloid-beta to tau phosphorylation by a known receptor," said Lee. In a third talk Dr. D'Andrea presented evidence that an excessive amount of amyloid-beta-42 accumulates inside brain cells, eventually killing the cell and forming a plaque. "We're saying it's more an inside-out phenomenon, not outside-in," he said. He showed images from the microscope that revealed Aß-42 deposits inside the cell rather than outside, and that the deposits appeared in a portion of the brain called the pyramidal layer that contains the bulky bodies of neurons rather than their thin extensions. Taken together, the results suggest a new approach to treating AD. D'Andrea explained where new drugs might act: "You would like to reduce the accumulation of Aß-42, and blocking a7nAchR is one possibility." By Dan Ferber BioMednews 10/25/99 - - the results are to be published in the Journal of Biological Chemistry.

Brain May Grow New Cells Daily - In a new challenge to the longstanding belief that adults never generate new brain cells, biologists Elizabeth Gould and Charles G. Gross at Princeton University have found that thousands of freshly born neurons arrive each day in the cerebral cortex, the outer rind of the brain where higher intellectual functions and personality are centered. If the new brain cells, or neurons, are involved in memory and learning - perhaps with each day's batch of new cells recording that day's experiences -- scientists will have to make major revisions in the longtime view that the adult brain's neurons are static in number and that memory is stored only in the way they interconnect. In addition, if the brain's cells are in constant turnover, as the new finding suggests, physicians may discover ways to use the brain's natural regeneration system for replacing cells that are lost in diseases of aging. By Nicholas Wade New York Times 10/15/99 Science Oct. 15, 1999:286:548-552

Drugs
Novartis Official Sees U.S. Exelon Launch Q1 2000 - Novartis AG expects to launch Exelon for treatment of mild to moderate AD in the United States in the first quarter of 2000, a senior company official said 10/21/99. The company received an approvable letter from U.S. regulators for Exelon and they expect a final clearance for the drug by the end of the year. The drug had so far been launched in over 60 countries worldwide. The Novartis drug is expected to reach peak sales of $550 million worldwide in 2003, with about 60 percent of those sales in the United States Reuters 10/21/99

Flood of New Medications for AD Expected - Although there are currently only two medicat-ions approved by the US FDA for the treatment of AD, there are over 60 investigational medications currently under study. The September/October 1999 issue of the American Journal of AD presents the first comprehensive review of all present and future medications for AD patients as well as the results of research underway, costs/benefits, known side effects, and their personal impressions of the various therapies based on the authors' extensive work in the field of AD. The authors discuss the pharmaceuticals, dietary supplements, and hormonal treatments being investigated in the United States and overseas. These medications include: Rivastigimine (Exelon) - available by prescription, January 2000; Metrifonate (ProMem) - available by prescription, Spring 2000; Galantamine; Epastigmine (heptylphysostigmine, MF 201); dietary supplements -- Gingko biloba, Saint John's Wort, and Vitamin E; Estrogen therapy; anti- inflammatory agents; muscarinic agonists; and monoamine oxidase inhibitors (MAO-B). PR 10/25/99

Statin Drugs May Lead To Lower AD Rate - Nymox Pharmaceutical Corp. announced 10/25 that a method for treating AD to which it has certain rights has shown promise in early studies conducted by Dr. Ben Wolozin, M.D., Ph.D., of the Loyola University Medical Center. Dr. Wolozin presented the results of a study tracking the rates of AD among some 50,000 patients at three major U.S. medical centers at the annual meeting of the Society for Neuroscience on 10/24. They found that the rate of AD for patients taking two kinds of a type of an anti-cholesterol known as statin-lovastatin (Mevacor) and pravastatin (Pravachol) -- was reduced by 60 percent to 73 percent compared to a total patient population or compared to patients taking other medications typically used to treat cardiovascular disease or hypertension. Dr. Wolozin said "Our studies suggests that these two drugs may protect against AD." Dr. Michael Munzar, M.D., medical director of Nymox, said that "while these findings need to be further verified, they might offer a potentially new and exciting approach to the treatment of this dread disease, which is now the fourth-leading cause of death among the elderly in the U.S. This appears to be the first time that a statin drug has been demonstrated in a large study to be associated with reduced AD incidence. The reduction in the rate of AD among the patients taking these two drugs is greater than other proposed therapeutics for the disease investigated to date. An additional positive feature is that these drugs are FDA approved, in common medical use, and well-tolerated by patients," Dr. Munzar added. PR 10/25/99

NeoTherapeutics' Research the Subject of Nine Presentations at the Society for Neuroscience Conference - NeoTherapeutics, Inc. announced 10/28 that nine presentations on its lead drug for the treatment of AD, Neotrofin™ (AIT-082), were presented at the Annual Meeting of the Society for Neuroscience. The presentations all were directed to further the understanding of the effects of Neotrofin™ on nerve regeneration, nerve impulse transmission and protection against nerve injury. Abstracts of these presentations may be seen in the technology section of NeoTherapeutics, Inc.'s Web site at: http://www.neotherapeutics.com . Some of the Neotrofin™ presentations showcased at this important international meeting involve nerve repair after spinal cord injury, protection against nerve damage under stroke-like conditions, enhanced synaptic transmission, memory improvement, and the drug's ability to cross the blood-brain barrier. This variety in the research further highlights the uniqueness of Neotrofin™ from other drugs currently in development for AD. Neotrofin™ is being developed for nerve repair and regeneration, with AD as its first clinical indication. Pre-clinical studies have demonstrated that Neotrofin™ causes the production of multiple natural nerve growth factors and restores function in animal models of memory decline, aging, brain injury, and spinal cord injury. Human clinical studies have demonstrated positive effects of Neotrofin™ on memory and behavioral function in patients with AD. PR 10/26/99

Neurosearch Gets FDA AD Drug Trial Go-ahead - Danish pharmaceuticals firm Neurosearch said 10/25/99 it had won approval from the U.S. Food & Drug Administration (FDA) to begin phase two clinical trials in the U.S. to test the tolerance and safety of compound NS2330 in AD patients. Previous tests indicated that NS2330 had a better anti-dementia effect than existing drugs, giving patients improved short and long-term memory and increased alertness. Reuters 10/25/99

Neurobiological Technologies, Inc. Announces That Memantine Alliance Partner, Merz + Co. GmbH & Co. Concludes Two Phase III Trials in Vascular Dementia with Memantine - Neurobiological Technologies, Inc. announced 10/28 that its alliance partner, Merz + Co. GmbH & Co. (Merz) has concluded two major Phase III trials in vascular dementia with Memantine and that the initial results look promising. A total of 900 patients were enrolled in multiple sites in the UK and France. The trials were designed to investigate improvements in cognition, a major focus of drug therapy for dementia. Merz plans to disclose data from the trials in April 2000. PR 10/28/99

Cyclosporin Brain Protection: Swedish Research Wins USA Patent for Maas BiolAB of Hawaii - Maas BiolAB announced the grant of US Patent 5,972,924 for cyclosporin neuroprotection. Acute brain attacks potentially treatable with cyclosporin include stroke, brain and spinal cord injury, and chronic brain diseases include AD, Parkinson's, Huntington's and ALS.  Cyclosporin protects the brain by interfering with the energy-producing mitochondria. It keeps   mitochondria viable during stroke, and blocks mitochondrial cytochrome c release and apoptotic cell death. It also protects brain by blocking calcineurin enzyme activity and nitric oxide product- ion. Cyclosporin is the first member of neuroprotective drugs called "Neuroimmunophilin ligands." Novartis' cyclosporin production patent expired in 1995, and several companies now manufacture it. PR 10/26/99

Genes & Genetic Issues
Brain Cell Study Could Help Scientists Understand AD - Yale University researchers say they have found a way to restart the growth of brain cells. Brain cells normally stop growing when people reach adolescence, but the team found that the cells can be stimulated to grow again as people get older. In the study scientists were able to trigger a kind of "on-off switch" in the brains of mice. As the human brain develops through the teen years, new cells or neurons grow by forming extensions and making millions of tiny connections. Once the growth stops, the connections in the brain's cerebral cortex, or thinking center, begin to stabilize. When the cells become stable, the brain establishes long-term memories. But in AD patients, the connections start to disintegrate and memories are lost. Dr. Pasko Rakic and his colleagues say something called the "Notch signaling pathway" gradually inhibits the extension of new cells in the brain and keeps them stable in maturity. By essentially turning the Notch off, researchers were able to get cells to start growing again in a petri dish. However, if the Notch is turned off in AD patients, the cells apparently become so destabilized that the connections between neurons break down, rather than grow, said Rakic. The key is understanding why this happens and how to stop it, since the loss of the connections means a loss of memory. Despite his team's discovery, Rakic said it was more important to preserve and stabilize existing connections than to create new ones. In AD patients, he said, "You have to counteract the activity and make the Notch inactive somehow to prevent the degradation and degeneration and breaking up of connections." In AD, a mutation of the gene presenilin is responsible for the early-onset of the disease. These new results provide a clue to how mutations in presenilin, which is known to affect Notch signaling, may contribute to alteration of neurites found in the disease. AP 10/22/99 and PR 10/21/99 Science Oct 22, 1999;286:741-746

St. Jude Researchers Discover Receptors That Bind to Reelin; This Process is Needed
for Correct Development of the Brain - Scientists at St. Jude Children's Research Hospital have discovered that two lipoprotein receptors bind to the protein made by the Reelin gene. Reelin is a molecule that serves as a "guidepost" for the movement of brain cells during development. Lipoprotein receptors are responsible for removing cholesterol from the blood and they are important for heart disease. However, two of the lipoprotein receptors, the very low-density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2), are present in the brain. The new results place these receptors in a signaling pathway controlled by Reelin.The researchers were surprised to find that Reelin binds directly to the receptor molecules VLDLR and ApoER2. They believe this binding must take place for correct development of the brain. They also discovered that lipoproteins, such as apolipoprotein E which bind to lipoprotein receptors, inhibit the interaction of Reelin with VLDLR. This report presents researchers with another link in the signaling pathway controlled by Reelin and it gives scientists a better under-standing of the molecular bases of brain development. Because some of the components of the pathway have been associated with AD, the findings suggest new opportunities to investigate the role of the Reelin pathway in neurodegenerative disorders. The researchers think the next step is to figure out whether there is a real connection between the Reelin pathway and AD or neurodegeneration because there are many indications that a connection might exist. PR 10/21/99 Neuron 10/21/99

Patients Must Be Gene-Savvy - The National Institutes of Health is sponsoring a daylong class on Nov. 12 to teach anyone who's interested the nuts-and-bolts of genetics. Some participants even will be taken inside NIH laboratories to watch DNA sequencing. Class participants should leave the NIH's Bethesda, Md., campus with answers. Geneticists want consumers to understand basic genetic principles enough to ask their own doctors the best questions about their health - and to critically assess media reports of the latest discoveries. To register for NIH's free gene class, check http://www.nhgri.nih.gov/conf/ on the Internet. If public demand for the class is high, as expected, the science agency will consider additional genetics tutorials next year. Consumers who want to learn on their own can find easy-to-understand genetics primers at: http://www.nhgri.nih.gov/Policy_and_public_affairs/Communications/Publications or http://www.accessexcellence.org/ae/AE/AEPC/NIH . By Lauran Neergaard AP Medical Writer 10/29/99

Scientists Near DNA Breakthrough - An international team of researchers, which is part of a
worldwide collaboration known as the Human Genome Project, says it is on the verge of unraveling for the first time the genetic pattern of a human chromosome and they aim to reveal the structure of the estimated 100,000 genes in human DNA. The group investigating chromo-
some 22 - the second smallest of the 24 kinds of chromosomes that carry human DNA - is putting the finishing touches on its work and plans to submit it for publication in the journal Nature later this year. Genes can promote or cause disease when they don't work properly. Some of the illnesses linked to genes gone bad include cancer, arthritis, diabetes, high blood pressure, AD and multiple sclerosis. Chromosome 22 contains genes involved in the immune response, schizophrenia, heart defects, mental retardation, leukemia and several other cancers. Once all of the chromosomes are sequenced scientists hope eventually to use the knowledge to help them find the causes, cures and prevention of the thousands of genetically influenced diseases afflicting mankind. By Emma Ross AP Writer 10/21/99

Md. Gene Researcher Draws Fire On Filings - Celera Genomics Corp., which is J. Craig Venter's Rockville company, says it has unraveled about a third of the human body's genetic instructions in one month and expects to publish a full gene map next year, five years before the original deadline set by the federal government. Mapping the genetic code promises to open up new possibilities for understanding and treating such ailments as cancer, AIDS and AD. The
potential profit and glory have set off intensive jockeying among researchers. In sworn testimony before Congress last year, Venter said he expected to obtain no more than 100 to 300 genetic patents, and then only after careful study of their potential usefulness as treatments. He said he would put most of his data in the public domain for free, making it difficult for any researcher to stake out big patent claims on the human genetic code. "Our actions will make the human genome unpatentable," Venter said then. However, recent news that his company has filed 6,500 patent applications has his critics upset. Those patent applications filed to date, however, are "provisional" applications that establish the date of a discovery, Venter said. Such applications, permitted by U.S. law since 1995, can be filed cheaply and give a company one year to file a full patent application, which is more detailed and more expensive. The company's commercial interests are protected during that year. Celera expects to keep filing provisional patent applications, possibly totaling 20,000 or 30,000 by the time all genes are mapped. But Venter said a great many of those applications will be abandoned as it becomes clear the gene sequences specified in them are not medically useful. When he's through, Venter said, he expects Celera to have roughly the number of patents he told Congress he would have--a few hundred, not several thousand. Venter said that he remained committed to handing out the complete human genetic sequence without charge by sometime next year. He said the gene map would be put on a high-capacity computer disk, known as a DVD, and given to any researcher who wants it. By Justin Gillis Washington Post Staff Writer 10/26/99 page E01

Caregivers
Report: Feeding Tubes Harm Demented - In a study in the Journal of the American Medical Association that could have broad implications for millions of Americans, researchers reported 10/13/99 that feeding tubes for mentally incapacitated patients may instead cause problems they are meant to prevent, including lung infections and early death. The study may prove important for the more than 4 million Americans who have AD and those who care for them. The illness, the leading cause of dementia, is expected to become more widespread as the U.S. population ages. Unlike feeding tubes, careful hand-feeding lets demented patients live as long as other nursing home patients, the authors concluded. That runs contrary to some nursing home practices and Medicare reimbursement guidelines for demented patients, AD advocates say. The authors found no evidence to support the reasons usually given for using the tubes: preventing early death from malnutrition, averting lung infections caused by inhaling food, and relieving suffering. On the contrary, tube-fed patients typically died within a year, got higher rates of lung infections and became so agitated that they required restraint or sedation, studies showed. Researchers, however, found little data that directly compared tube-feeding to hand-
feeding. Experts on dementia who were not involved in the review praised it as an important contribution toward overturning misconceptions. A nursing home industry spokesman said doctors, not administrators, decide who gets a feeding tube. Also, it is often requested by a patient's family, said Tom Burke, a spokesman for the American Health Care Association, which represents 11,000 nursing homes nationwide. By Brenda C. Coleman AP Medical Writer Journal of the American Medical Association 10/13/99.

Duke Study: Exercise May Be Just as Effective as Medication for Treating Major Depression - A brisk 30-minute walk or jog around the track three times a week may be just as effective in relieving the symptoms of major depression as the standard treatment of anti- depressant medications, according to the results of a Duke University Medical Center study. The researchers concluded that exercise may be just as effective as medication and may be a better alternative for certain patients. While they don't know why exercise confers such a benefit, this study shows that exercise should be considered as a credible form of treatment for these patients. Almost one-third of depressed patients in general do not respond to medications, and for others, the medications can cause unwanted side effects. Exercise should be considered a viable option. On of the researchers suggested that exercise may be beneficial because patients are actually taking an active role in trying to get better. "Simply taking a pill is very passive," he said."Patients who exercised may have felt a greater sense of mastery over their condition and gained a greater sense of accomplishment. They felt more self-confident and had better self-esteem because they were able to do it themselves, and attributed their improvement to their ability to exercise." PR 10/24/99 The Archives of Internal Medicine 10/25/99

Long-Term Care for Frail Elderly People -- The On Lok Model - Long-term care ranks high on the list of our health care system's failings. Many elderly people spend their life savings to pay for assistance in the home or for nursing home care. Family members (usually women) make personal and financial sacrifices to care for a disabled spouse or parent. One institution offers a time-tested solution to some of these vexing problems. On Lok Senior Health Services in San Francisco provides comprehensive health and supportive services to frail elderly people; its costs are lower than those of care for similar people confined to nursing homes. Under a publicly fund- ed program, On Lok look-alikes have sprouted up in other cities. On Lok's focus on the day health center keeps frail elderly people out of nursing homes, allows their family members to work during the day, and enables the elderly to receive health care, supervised exercise, and recreation services and to escape the isolation of the home. People using On Lok's services are called partici-pants rather than enrollees, patients, or "covered lives." Medical Director Catherine Eng explains how On Lok can succeed financially: "We manage risk by common-sense preventive care. It's not just prevention of a single illness -- with stool occult-blood tests or mammograms. It is constant observation by the multiple eyes of the team, looking for reduced health and functioning." Early intervention allows On Lok to boast low rates of hospitalization and nursing home use, resulting in savings that finance On Lok's intensive primary care and supportive services. Whereas 43 % of U.S. health care expenditures go to hospital services and nursing home care, On Lok spends a mere 17 % on these items, making 83 % of the capitation dollar available for home- and community-based care. By Thomas Bodenheimer The New England Journal of Medicine Oct. 21, 1999;341:1324-1328

Nursing Homes Face Cutbacks, Closures - After years of reaping generous profits and anticipating more of the same, much of the nursing home industry is now heavily in debt, under-staffed and losing money. Expansion plans and special rehabilitation programs that looked so lucrative a few years ago are now a financial drain. Industry leaders blame their problems on a reduction in Medicare payments required by the Balanced Budget Act of 1997. Others say they brought the troubles on themselves through bad business decisions. Either way, lenders and stockholders are anxious. But their anxiety pales next to that of the families of the 1.5 million Americans who live in the nation's 17,000 nursing homes. "If it's your mother, you're more than a little concerned about this," says Don Muse, a health care consultant in Washington. Cases of nursing homes abruptly closing, leaving aged, disoriented residents uprooted, their health threat-ened, are not new. But fears are growing that such stories may become more common as the industry's financial troubles deepen. Few experts expect widespread nursing home closures. But money-strapped companies could scrimp on staffing, food or linen changes. These are things that could have a dramatic and direct impact on the quality of life say advocates for nursing home residents. Staffing has always been a problem. Even in the best of circumstances, experts say, it is difficult to find qualified employees willing to work a challenging and often low-paying job. Certified nurse assistants, the backbone of the nursing home industry, earn a median hourly wage of $7.44, often without benefits. With bankruptcies possible and a strong economy luring workers to better paying and less emotionally taxing work, vacancies are up. By Julie Appleby, USA Today 9/30/99

Highlights From Gore-Bradley Debate - In the Highlights from the 10/27 debate between Democratic presidential candidates Al Gore and Bill Bradley on 10/27 Bradley said : "One of the things that I've offered as a part of the health care plan was to allow Medicare to pay not only for health, but also for plans that would cover health and provide the social services to people who were in their homes. Now, it wouldn't be quite the special services that an AD patient needs, but it would give relief to someone who is caring for an AD patient in the home." AP 10/27/99

Testing
AMA Guide Helps Doctors Diagnose, Treat Dementia -The American Medical Association introduced a guide 10/25 to help physicians diagnose and treat dementia, an incurable disorder that worsens progressively over years. The guide advises primary case physicians on how to tell the difference between, mental confusion caused by drugs or normal aging. It includes tests for gauging dementia -- asking patients to draw a clock face, identify a pencil and provide the current day, month and year. The guide also recommends ways to prevent and respond to elder abuse. The guide, called "Diagnosis, Management and Treatment of Dementia: A Practical Guide for Primary Care Physicians," says caregivers of dementia sufferers are often the "hidden patients." Caregivers are usually family members, mostly women, and "are physically, emotionally and financially vulnerable." Doctors are advised to refer caregivers to support groups and "respite programs," such as adult day care so they can take time off. The guide covers treatment and care for the rest of a patient's life. "The physician should help the patient function as independently as possible, which minimizes the stress and burden of the caregiver," says Dr. Coble an AMA Board of Trustees member. Ways to prevent and respond to elder abuse are also outlined in the guide. $5 from AMA 800-621-8335 ext 5563 CNN and AP 10/25/99

Other Items
McLean Researchers Find Way to Regulate Protein Involved in AD - Researchers at McLean Hospital in Mass. have provided the first evidence in laboratory rats that increasing the activity of cholinergic nerve cells, which produce a neurotransmitter that enables brain cells to com- municate, decreases levels of amyloid precursor protein (APP) in the brain. This study suggests that it is possible to regulate the build-up of APP in the brain by using drugs that restore normal cholinergic functioning. If the finding is confirmed in people, they believe they may be able to prevent the build up of amyloid deposits that typically takes place in the brains of individuals with AD. Although previous studies have shown that certain drugs could increase the breakdown of APP in cell cultures, this is the first paper to show that such effects also occur in the intact brain. These findings provide a new perspective on the relationship between dementia, amyloid deposits and nerve cell dysfunction in the progression of AD. The researchers compared APP levels and behavior in three groups of rats: young, aged and those whose brains had been altered to mimic the changes of AD. In all three groups, when a drug was administered to increase cholinergic activity, levels of APP decreased in the brain while a possibly neuroprotective secreted form of APP increased in the spinal fluid. "This suggests that when functioning properly, the brain expels APP into the cerebrospinal fluid and avoids a build up of amyloid protein," explains Dr. Ole Isacson the senior author of the paper. The researchers also compared APP levels and cognitive behavior, as measured by how quickly the rats were able to navigate a water maze. The rats whose brains had been altered, and who had high APP levels, performed less well on the test. PR 10/20/99 Proceedings of the National Academy of Sciences Oct. 12 1999: 96, issue 21, pages 12108-12113.

Good News, Gramps - Brain power is not inevitably lost as we get older, according to
researchers at the Rotman Research Institute in Toronto who found that older brains can
compensate for cognitive decline by routing tasks away from weak areas of the brain toward other, stronger brain circuits. In their study, 10 adults in their 20s and nine adults between 60 and 80 took the same visual, short-term memory tests while their brain activity was measured by positron emission tomography (PET). While the subjects were being tested, PET measured blood flow in regions of their brains and marked which brain areas were used during the memory task.  The PET showed that the pathways used to perform the tasks were different between the young and old. The younger subjects used mainly the occipital, temporal, and inferior prefrontal cortices during the test. The older individuals showed weaker neural communication in those areas. To compensate, the elderly brains recruited the hippocampus and dorsal prefrontal cortices. The hippocampus is often used for more complicated tasks, such as memorizing the lines of a Shakespeare play, or navigating around a convention center. But since the elderly brains recruited the hippocampus for simple tasks during the test, that leaves the hippocampus unavailable for more complicated cognitive functions. The researchers conclude that if the hippocampus is being recruited for simpler functions, then for harder tasks the resources are not available because the hippocampus is already engaged. This could be a cause of the age-related changes we see in memory. Researchers say the study paints a brighter picture of the golden years and is really very good news because the standard teaching has been that as you get older it's a lose/lose world. The newer studies are showing that's probably not true. By Kristen Philipkoski Wired News 10/26/99

Common Thread Found Among Types of AD Brain Damage - There are three types of AD-related brain damage known as plaques, tangles and granulovacuolar degeneration (GVD) bodies. Researchers at the Ohio State University who had previously found elevated levels of three proteins in two types of AD-affected cells have now found elevated levels of these proteins in all three types of brain damage seen in the disease. The proteins are in a class known as casein kinase-1 (CK1) enzymes. Whether they cause or result from brain cell damage is unknown. Finding the high levels of the proteins in GVD bodies was a "huge surprise," according to the researchers and it ties together the three types of lesions. When the researchers compared the AD-damaged brain tissue to normal tissue samples, they found that the concentration of one of the CK1 proteins was 30 times higher in the diseased tissue; another was nine times higher and the third was more than twice as high. Now they have to ask "how does this 30-fold increase happen?" They want to get at the earliest stages. If the CK1 proteins are found to actually damage brain cells, drugs may be developed to prevent this action. If the protein elevation is just the body's response to brain damage, then it may serve as a chemical marker for AD and aid in research and diagnosis of the disease. By Amy Norton Reuters Health 10/11/99 American Journal of Pathology 1999;155:1163-1172

Neurons Produced During Adulthood React to Stimuli - Brain cells that are produced in adult mammals respond to sexual stimuli, according to a team of biologists at the University of Mass.
Until recently, it was believed that production of neurons in mammals ceased soon after birth. However, research within the past decade has shown that adult mammals do, in fact, continue to produce these cells. But the function of neurons produced after birth - and whether they manage to hook properly into the brain's complex circuitry at all - was unclear. The team's research suggests that these cells are activated during sexual behavior, providing the first direct evidence that brain cells produced in adulthood may function in a naturally occurring behavior, Prof. Eric Bittman said. Scientists had previously determined that adults produce new brain cells in two regions of the forebrain. Many of these neurons migrate to another portion of the brain called the
olfactory bulb, which allows animals to sense and identify odors. Many neurons in this region respond to the stimulation of sexual activity. "If there's to be clinical relevance for patients suffering from stroke, or brain injuries, it's not enough just to have new cells produced," said Bittman. "You need to know if the cells are actually working." Although the research was conducted on hamsters, scientists hope that this insight into how neurons are produced, and how they behave, may be a step toward new treatments for disorders such as AD, Parkinson's disease, and stroke, which are related to the premature death or dysfunctioning of neurons. PR 10/25/99

Prions May Cause AD, Says Nobel Winner - Dr. Stanley Prusiner, who won a Nobel Prize in 1997 for his discovery that prions cause certain neurodegenerative diseases such as Creutzfeldt- Jakob disease, now suggests that prions may play a role in other neurological diseases, including AD, Parkinson's disease, and amyotrophic lateral sclerosis (Lou Gehrig's disease). He explained that prion infection causes proteins in the brain to change from a normal spiral conformation to an abnormal conformation called a beta-sheet. He suggested that prion-induced protein changes can be seen in the lesions characteristic of AD. "In AD this misfolding of proteins leads to plaques and tangles in the brain," Prusiner told the annual meeting of the American Neurological Association. "These are 'misprocessed' proteins." Prusiner noted that "something is pushing this process, although we don't know what it is. It's not a chronic infection like AIDS, and it may be 10 different things." The search is on, he said, for drugs that prevent prion-induced abnormal protein folding. Reuters Health 10/20/99

We Must Fund The Scientific Revolution - The highest investment priority in Washington should be to double the federal budget for scientific research according to Newt Gingrich. No other federal expenditure would create more jobs and wealth or do more to strengthen our world leadership, protect the environment and promote better health and education for all Americans. For the security of our future, we must make this investment now. New instruments (largely a product of National Science Foundation grants) make possible new measurements of the human brain while it is working (largely funded by NIH grants). This synergistic investment in better knowledge through better technology will prove that mental health parity is essential to any health policy and will offer opportunities to cure schizophrenia, bipolar disease, AD and other current challenges. By Newt Gingrich Washington Post 10/18/99 page A19

Molecular Biologist Wins Nobel Prize in Medicine - Dr. Günter Blobel, a cellular and molecular biologist at Rockefeller University in Manhattan, won the 1999 Nobel Prize in Medicine 10/11/99 for discovering that proteins carry signals that act as ZIP codes, helping them find their correct locations within the cell. There are a billion protein molecules in an average human cell. Cells are constantly dividing or being repaired to replace those damaged or lost to everyday wear and tear. The mystery that Dr. Blobel (pronounced BLO-bul) helped solve was learning how the cells regulate internal traffic so the protein molecules "go to the right address."   Dr. Blobel said that with more research he expected that scientists would unravel the mysteries of how brain cells are damaged by AD, cells are destroyed by the AIDS virus and other infections, and normal cells become malignant. By Lawrence K. Altman New York Times 10/12/99

Maureen Reagan Says Father's World Getting Smaller - The world around former President Ronald Reagan, who suffers from AD, "gets smaller every day," his daughter Maureen said 10/21/99. Maureen Reagan was asked by Diane Sawyer, who conducted the interview, to comment on a quote to Morris, author of "Dutch: A Memoir of Ronald Reagan,"saying, "I saw this splendid person beginning to become mad." "It makes me very angry," said Maureen Reagan, who was joined by two other people to discuss their personal experiences in dealing with family members suffering from AD. "And the reason it does is that AD is a physical illness," she said. "It's the same as if your liver or your lungs or your heart were affected, but it happens to be the brain." In another article Patti Reagan wrote for the German news magazine Focus 10/18/99 about the disease and its effect on her father, she said: "There came the day I knew he couldn't remember me. He was in his office. He sat at his desk. I stood up, said I must go, kissed him on the cheek, said goodbye and 'I love you'. Usually he always said: 'I love you too'. This time he said 'Thanks'. I know that should have been very sad for me. But I was not sad, just glad that I had his thanks." Reuters 10/21/99 and The Daily Record 10/18/99

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