Alzheimer Related News Items

News as of 6/6/05

For more info on these abstracts write/call Ed Cabic (edcabic@comcast.net or 410-992-7197)

For more AD information, see Alzheimer Information athttp://www.connext.net/~seniors/infoad.htm

Copies of these reports are posted there

This web page was started in 1998 at the Florence Bain Senior Center in Columbia MD

Top Items

Aborted AD Elan Vaccine on Right Track: Study - An attempt to make a vaccine to treat AD, abandoned after it caused dangerous brain inflammation in some patients, may have done the patients some good, researchers reported on 5/9/05. They found evidence that the vaccine, made by Dublin-based Elan Corp. and Wyeth Pharmaceuticals, helped clear some of the brain- destroying “plaques” that characterize the disease. Some vaccinated patients scored better on memory and a few other tests used to diagnose the fatal, incurable condition. “We now need to see whether we can create an immune response safely and in a way that slows the progression of AD and preserves cognition,” Dr. Sid Gilman of the University of Michigan Medical School, who led one of the studies, said in a statement. Elan’s experimental vaccine, AN-1792, targeted the beta amyloid proteins that form the brain-clogging plaques. It has been shown to generate antibodies against beta amyloid, and Swiss researchers found the patients whose bodies made antibodies in response to the vaccine did not get any worse over the year following vaccination. The vaccine trials were stopped in 2002 after 17 of 300 patients being tested developed a life-threatening inflammation of the brain called meningoencephalitis. But the researchers continued to monitor the patients for a year after their last vaccination and were also able to examine the brains of some patients who died after the trial. Writing in the journal Neurology, the researchers said volunteers whose immune systems mounted a response against beta amyloid did significantly better on a series of memory tests than patients given a placebo injection. Magnetic resonance imaging scans also showed that the brains of patients who had a strong immune response shrank -- possibly because the brain-clogging material was removed. And they had reduced levels of tau, another AD-associated protein, in their spinal fluid.

“Three participants died of causes unrelated to the vaccination, two of whom had developed encephalitis and one other did not develop encephalitis,” Gilman said. “All had large patches of their brains where beta amyloid had apparently been cleared out -- the tangles of tau protein were still visible.” Now the researchers are trying a new approach that uses antibodies against beta amyloid instead of the protein itself. Last month another team reported that a small trial using antibodies seemed safe and may have delayed or even halted progression of the fatal disease. Reuters Health 5/10/05 Neurology 2005;64:1563-1572

Drugs

RAZADYNE ER, New Once-Daily Treatment Option, Now Available for Patients With Mild to Moderate AD - RAZADYNE(TM) ER (galantamine hydrobromide), a new once-daily treatment for the symptoms of mild to moderate AD, is now available by prescription nationwide. It is a once a day Extended Release form. The product is marketed by Ortho-McNeil Neurologics, Inc. Approved by the U.S. Food and Drug Administration (FDA) in December 2004, RAZADYNE ER contains galantamine hydrobromide -- first approved by the FDA in February 2001 as a twice-daily medication, REMINYL(R). In April 2005, the product name was changed to RAZADYNE. Approximately two million patients have been treated with REMINYL to date. In clinical trials, RAZADYNE ER provided comparable efficacy, safety, and tolerability to twice-daily galantamine with the convenience of once-daily dosing. “In a six-month clinical study, patients who started treatment with RAZADYNE ER -- and stayed on it throughout the trial -- had significantly better overall cognition (thinking and memory) and daily activities compared to patients taking placebo,” said Stephen Aronson, M.D., clinical assistant professor, University of Michigan Medical School. The RAZADYNE ER capsules contain a rate-controlling membrane that allows the medication to be released gradually over a 24-hour period. This new formulation contains an immediate and extended release dose that allows for the convenience of once-daily dosing. PRNewswire 5/23/05

J&J: FDA Nixes Risperdal for AD - Johnson & Johnson said 5/26/05 that federal regulators did not approve its schizophrenia drug Risperdal as a treatment for psychosis from AD. The company received a “not approvable” letter from the Food and Drug Administration regarding a supplemental application for Risperdal, which has been cleared to treat bipolar disorder. Johnson & Johnson said it is evaluating the agency’s letter and will determine the appropriate next step. AP 5/26/05

Study: Drug aided victims of AD - A cholesterol-lowering drug aided thinking ability and eased psychiatric impairment among AD patients in a trial at Sun Health Research Institute.

A number of human and animal studies have suggested a link between AD and cholesterol. Also, some population studies have shown that using statins, which are cholesterol-lowering drugs, to head off coronary artery disease may also cut the risk of getting AD later in life. In the year-long placebo-controlled Sun Health study, led by D. Larry Sparks, Ph.D., patients with mild to moderate AD were given atorvastatin, (Lipitor) a cholesterol-lowering drug. The study began with 67 patients getting either the drug or a placebo. A number dropped out along the way, but 46 completed the one-year study: 25 who got the drug and 21 who got the placebo. The study’s authors concluded that a daily dose of 80 milligrams of atorvastatin calcium significantly cut circulating cholesterol “and may have a positive effect on the progressive deterioration of cognitive function and behavior anticipated in mild to moderate AD.” However, they stressed that the trial was a small one, and larger trials with many more patients must be completed to see whether the positive effect proves out. Charles Kelly The Arizona Republic 5/16/05 Archives of Neurology May 2005 62:753-757

FLURIZAN™ and AD - FLURIZAN™ (MPC-7869) is an investigational drug made by Myriad Genetics, Inc. being studied in patients with AD. It is a selective amyloid lowering agent (SALA) that reduces levels of the toxic peptide amyloid beta 42 (Aβ42) in cultured human cells and in animal models. Aβ42 is the primary initiator of neurotoxicity and amyloid plaque development in the brains of AD patients. FLURIZAN™ is currently undergoing a Phase 3 clinical trial in patients with AD. See http://www.myriad.com/alzheimers.flurizan.php

Danish Co. Working on AD Drug - A Danish biotechnology company says it has discovered a potential treatment for AD. Existing drugs can only delay the onset of symptoms during the early phases of the disease. The Danish newspaper Jyllands Posten reports that the synthetic protein FGL developed by Enkom appears to repair nerve damage in animal studies. Enkom has also tested the drug for potential side effects on 24 healthy human subjects. Peter Johannsen, a doctor at the Memory Clinic at the Danish State Hospital, told the newspaper that FGL shows great promise. “The substance attacks at a point in the disease’s process where no other has before, stimulating nerve cells, which for some reason are sick, to possibly cure them,” he said. “We still don’t know if it works in the real life, but it works in the test tubes.” The drug must now be tested in Phase 2 and 3 human trials to determine whether it works against AD and is more effective than existing drugs. UPI 5/19/05

Genes & Genetic Issues

APOE4 Gene Linked to AD Anxiety - U.S. researchers at the Oregon Health and Science University said they have discovered a genetic link to the high anxiety levels experienced by up to 70 percent of AD. A gene called apoE4, which increases the risk of developing AD, also is associated with heightened levels of anxiety the researchers report.“This research recognizes the need to gain a better understanding of factors contributing to anxiety in dementing illnesses,” said Jacob Raber, an associate professor of behavioral neuroscience and neurology at OHSU. The researchers first looked at mice that possessed only the apoE4 gene. The rodents showed higher anxiety levels and were more likely to seek sheltered dark areas than open areas, which can indicate anxiety. The mice also had evidence of brain damage in the amygdala region, which is involved in regulating anxiety. The researchers said the results also held true in human AD patients, where those carrying only the apoE4 gene registered higher levels of anxiety. UPI 5/24/05 Neurobiology of Aging Vol. 26, Issue 5 May 2005 637-643

Revolutionary Nanotechnology Illuminates Brain Cells at Work - Until now it has been impossible to accurately measure the levels of important chemicals in living brain cells in real time and at the level of a single cell. Scientists at the Carnegie Institution’s Department of Plant Biology and Stanford University are the first to overcome this obstacle by successfully applying genetic nanotechnology using molecular sensors to view changes in brain chemical levels. The sensors alter their 3-dimensional form upon binding with the chemical, which is then visible via a process known as fluorescence resonance energy transfer, or FRET. In a new study, the nanosensors were introduced into nerve cells to measure the release of the neurotransmitter glutamate -- the major brain chemical that increases nerve-cell activity in mammalian brains.

It is involved in everything from learning and memory to mood and perception. Too much glutamate is believed to contribute to conditions such as AD and Parkinson’s disease. “The fluorescent imaging technique allows us to see living cells do their jobs live and in color,” explained Sakiko Okumoto, lead author of the study at Carnegie. “Understanding when and how glutamate is produced, secreted, reabsorbed, and metabolized in individual brain cells, in real time, will help researchers better understand disease processes and construct new drugs.” “This is a tremendously exciting technology,” remarked Wolf Frommer, leader of the FRET team at Carnegie. “I’m anxious to see what we can learn about the vast complexities of the brain over the coming years, such as the role of glial cells in the process of glutamate removal from the synaptic cleft. It’s fascinating to see a tool that we are using in plant biology open new areas in neuroscience.” PR 5/30/05 published online before print June 6, 2005 Proceedings of the National Academy of Sciences 10.1073/pnas.0503274102

Caregivers

AD Patients’ Ability to Make Decisions about Treatment, Study - People with very mild AD are still competent to make decisions about their treatment, while those with moderate AD may no longer be able to competently make those decisions, according to a study published in the 5/10/05 issue of Neurology. The study also found that people who were aware of their AD diagnosis, symptoms, and prognosis were more likely to be able to make competent decisions, regardless of the severity of their disease. “These results are yet another reason why people should consult a doctor if they notice any warning signs of AD in themselves or a loved one,” said study author Jason Karlawish, MD, of the University of Pennsylvania in Philadelphia. “An early diagnosis can help assure that patients can participate in decisions about their care.” The study found that scores on the Mini-Mental State Examination (MMSE), a widely used rating scale for cognitive abilities, can help predict patients’ decision-making abilities. Those with scores of 11 to 19 on the scale, which indicates moderate dementia, were not likely to be competent decision-makers. Those with scores of 24 and higher, which indicates very mild dementia, were likely to be competent decision-makers. Those with scores of 20 to 23, with mild to early moderate AD, are in a gray zone, Karlawish said. “If there are questions about the competence of a person in this range, it would make sense to do a detailed assessment of that person’s decision-making abilities,” he said. “Of course, the MMSE score is just one piece of information. People below this range are less likely to retain adequate decision-making abilities, but some may.” Another finding of the study was that people who were aware of their diagnosis, symptoms, and prognosis were more likely to be able to make competent decisions. This insight into their condition was not related to the severity of the disease. Medical New Today 5/15/05 Neurology 2005;65:1514-1519

Testing

Applied NeuroSolutions Biomarker May Predict AD Progression - A biomarker pioneered by Applied NeuroSolutions and exclusively utilized in its AD diagnostic assay, shows great promise in predicting brain atrophy in patients with AD, according to a group of researchers in the US, Canada, and Europe led by Dr. Harald Hampel and published in May 2005 in the Archives of Neurology. According to Dr. John DeBernardis, President and CEO of Applied NeuroSolutions and a co-author of the study, “Finding a biomarker that effectively predicts who will get AD has been considered the Holy Grail of AD research for many years. We now believe that variations in the levels of p-tau 231 (tau protein phosphorylated on amino acid 231) may be used to effectively predict structural progression of AD.” The data in the study agree with the notion that variations in p-tau 231 levels reflect differences in the degree of neuronal damage across AD patients, thus, p-tau 231 levels may be used to predict progression of brain atrophy in AD patients. In the study of 22 AD patients, all underwent Magnetic Resonance Imaging (MRI) to image the brain and had CSF samples taken. Levels of p-tau 231 predicted the rate of subsequent hippocampal atrophy as measured by MRI. In contrast, levels of total tau, another biomarker also used in the study, did not. In the end, higher p-tau 231 levels were found to correspond with higher rates of neuronal degeneration of the hippocampus. In numerous other studies, the p-tau 231 assay developed by Applied NeuroSolutions has been shown to discriminate AD patients from patients with other neurodegenerative disorders. Currently there is no FDA-approved diagnostic test for AD. Applied NeuroSolutions, Inc. is developing products to diagnose and treat AD based on a novel hypothesis of AD cause and pathology. In partnership with Dr. Peter Davies and a scientific team at Albert Einstein College of Medicine, Applied NeuroSolutions has developed a cerebrospinal fluid (CSF) test to detect AD at a very early stage with 85%-95% accuracy in more than 3,000 patient samples. PR 5/25/05 Archives of Neurology 2005;62:770-773

Prevention

Fish Oil Holds Promise In AD Fight - Researchers with the Department of Veterans Affairs (VA) and the University of California at Los Angeles (UCLA) found that a diet high in docosahexenoic acid, or DHA--an omega-3 fatty acid found in relatively high concentrations in cold-water fish--dramatically slowed the progression of AD in mice. Specifically, DHA cut the harmful brain plaques that mark the disease. Senior author Greg M. Cole, Ph.D., a neuroscientist at the Greater Los Angeles VA Healthcare System and UCLA, said that unlike many studies with mice, this one points to the benefits of a therapy that is easily available and already touted for other medical conditions. DHA--either from food sources such as fish and soy, or in fish-oil supplements--is recommended by many cardiologists for heart health, based on scores of previous studies. “The good news from this study is that we can buy the therapy at a supermarket or drug store,” said Cole. “DHA has a tremendous safety profile--essentially no side effects--and clinical trial evidence supports giving DHA supplements to people at risk for cardiovascular disease.” The new study involved older mice genetically altered to develop AD. The researchers fed one group of the mice DHA-fortified chow. The control mice ate a normal or DHA-depleted diet. After three to five months--the equivalent of several years in human biology--the high-DHA group had 70-percent less buildup of amyloid protein in the brain. This sticky protein makes up the plaques, or patches, that are a hallmark of AD. A similar study by Cole’s group published in Neuron last fall showed that DHA protected against damage to the “synaptic” areas where brain cells communicate and enabled mice to perform better on memory tests. The studies, say the scientists, suggest that even people who are genetically predisposed to the disease may be able to delay it by boosting their DHA intake. Food sources of omega-3 fatty acids include fish such as salmon, halibut, mackerel and sardines, as well as almonds, walnuts, soy, and DHA-enriched eggs. Concerns about mercury contamination in fish have helped popularize purified DHA supplements based on fish oil or algae.

            Last year, Cole’s team identified another nutrient that appears to combat AD plaques in mice: curcumin, the yellow pigment in turmeric, one of the spices that make up curry powder. Researchers became interested in curcumin’s potential to prevent or treat AD after noting the low prevalence of dementia among the elderly in India, where curry is a staple. PR 5/29/05 The Journal of Neuroscience, March 23, 2005, 25(12):3032-3040

Other Items

Latinos Have Earlier AD Onset - Onset of AD symptoms is apparent some 7 years sooner in US mainland Latinos than in their white non-Latino compatriots, a new study shows. Although Latino people are a geographically and genetically diverse group, some reports suggest that they may differ from whites in respect to several characteristics of AD. To investigate further, researchers evaluated 119 Latino and 55 white non-Latino patients with a diagnosis of AD. They found that AD symptoms began at about 67 years of age in the Latinos compared with 73 years of age in the whites -- close to a 7-year difference. The basis for the difference “remains obscure,” Dr. Christopher M. Clark of the University of Pennsylvania, Philadelphia, and colleagues admit. Regardless, Clark told Reuters Health, Latino families and health professionals who care for Latinos need to “recognize that symptoms of memory loss and confused thinking in someone in their sixties may represent AD.” The findings, he added, “also demonstrate the need for Latinos to participate in clinical studies in order to help healthcare researchers better understand how dementia affects members of their ethnic group.” Reuthers Health 5/18/05 Archives of Neurology 2005;62:774-778

Finding an AD Switch- Unsuspected Protein Regulates the Production of Plaque-Forming Peptides - Researchers at the Department of Energy’s Lawrence Berkeley National Laboratory have discovered an unsuspected subunit of the protein complex gamma-secretase, which plays a central role in AD. The researchers have shown that the newly discovered component, the protein CD147, regulates the production of the toxic peptides that cause amyloid plaques, the brain lesions that are the defining feature of AD. The discovery and role of CD147 as a subunit of gamma-secretase by Bing Jap of Berkeley Lab’s Life Sciences Division and his colleagues Shuxia Zhou, Hua Zhou, and Peter Walian. The most persuasive hypothesis of how AD invades the brain is the so-called “amyloid beta protein cascade,” in which a protein called APP is clipped into shorter pieces by enzymes known as secretases. (APP stands for “amyloid precursor protein;” it is found in many tissues besides brain, but its functions are largely unknown.) If the portion of APP clipped by the beta form of secretase is further clipped by a third form, gamma secretase, the resulting fragments are amyloid beta peptides, A-beta 40 and A-beta 42. A-beta 42 in particular is toxic and causes the formation of amyloid plaques. Unlike the majority of membrane proteins, gamma-secretase performs its proteolytic function neither inside nor outside the cell; instead, the crucial cut is made within the cell’s thin membrane. In fact all the proteins and protein complexes involved - APP and the alpha, beta, and gamma secretases - are cell-membrane proteins, which penetrate the walls of the brain’s neural cells. AD research would greatly benefit if their structures, particularly that of gamma-secretase, could be established at high resolution by x-ray crystallography. The researchers found that in addition to the four known subunits of gamma-secretase, there is also a fifth one which is the membrane protein CD147. CD147 is expressed in many tissues and has many biological functions. It also has a role in neural function: when the CD147 gene is deleted in mice, the result is defective nervous system development, loss of working memory, spatial learning deficits, and disorientation - behaviors remarkably suggestive of AD. To investigate CD147’s part in the activity of gamma-secretase, the researchers used targeted RNA to silence CD147 in cell cultures. The four previously known components of the gamma-secretase complex, as well as the APP protein on which they operate, were unaffected by this silencing. But when CD147 was silenced, the production of amyloid beta peptides increased markedly. The researchers established that the native form of gamma-secretase, incorporating CD147, appears in other cell lines. CD147 itself is found in many contexts besides gamma- secretase, but only as a part of gamma-secretase does it regulate the production of A-beta peptides and thus amyloid plaques. Medical News Today 5/15/05 Proceedings of the National Academy of Sciences May 24, 2005 vol. 102, no. 21:7499-7504

Potential for Reducing the Progression of AD Revealed - University of Florida researchers have discovered a way to reduce plaque deposits on the brain that could slow the progression of AD. “This is the first time this approach has been used to treat AD,” said Jeffrey Hughes, Ph.D., of the University of Florida College of Pharmacy. “After only one injection, the plaque on the brain has stopped forming.” For years scientists have recognized a connection between plaque deposits on the brain and the progression of AD. Plaque deposits are formed when amyloid precursor protein (APP), found widely throughout the body, releases itself into fragments, called beta-amyloids, which in turn form plaque. The University of Florida team has sought to reduce plaque by using a naturally occurring human-binding protein, gelsolin, to absorb the beta- amyloids. Preliminary data from the National Institute of Aging-sponsored research reveals that gelsolin has succeeded in reducing amyloid deposition by as much as two-thirds to three- quarters. “We are excited by the preliminary results,” Dr. Hughes said. “We look forward to further testing our approach to see if gelsolin continues to act as a sponge, absorbing and reducing plaque and ultimately affecting the progression of AD.” PRNewswire 5/25/05

D:\AD18\aadn0605.htm